- Fever / Pyrexia
- Anti-infection defense mechanism that appears with body temperature exceeding the normal range due to an increase in the body's temperature set point in the hypothalamus.
- The increase in set point triggers increased muscle contractions and causes a feeling of cold or chills. This results in greater heat production and efforts to conserve heat. When the set point temperature returns to normal, a person feels hot, becomes flushed, and may begin to sweat.
- May rarely trigger a febrile seizure. This is more common in young children.
- Fevers do not typically go higher than 41 to 42 °C (106 to 108 °F).
- A fever can be caused by many medical conditions ranging from non-serious to life-threatening. This includes viral, bacterial, and parasitic infections—such as influenza, the common cold, meningitis, urinary tract infections, appendicitis, Lassa fever, COVID-19, and malaria.
- Non-infectious causes include vasculitis, deep vein thrombosis, connective tissue disease, side effects of medication or vaccination, and cancer.
- Treatment of associated pain and inflammation, may be useful and help a person rest.
- Medications (e.g. ibuprofen or paracetamol) may help with this as well as lower temperature.
- Children younger than three months require medical attention, as might people with serious medical problems such as a compromised immune system or people with other symptoms.
- One of the most common medical signs.
- It is part of about 30% of healthcare visits by children and occurs in up to 75% of adults who are seriously sick.
- A fever is usually accompanied by sickness behavior, which consists of lethargy, depression, loss of appetite, sleepiness, hyperalgesia, dehydration,and the inability to concentrate.
- Sleeping with a fever can often cause intense or confusing nightmares, commonly called "fever dreams".
- Mild to severe delirium (which can also cause hallucinations) may also present itself during high fevers.
- Clinically, it is important to distinguish between fever and hyperthermia as hyperthermia may quickly lead to death and does not respond to antipyretic medications. The distinction may however be difficult to make in an emergency setting, and is often established by identifying possible causes.
Behavior
- Various patterns of measured patient temperatures have been observed, some of which may be indicative of a particular medical diagnosis:
- Continuous fever, where temperature remains above normal and does not fluctuate more than 1 °C in 24 hours (e.g. in bacterial pneumonia, typhoid fever, infective endocarditis, tuberculosis, or typhus).
- Intermittent fever is present only for a certain period, later cycling back to normal (e.g., in malaria, leishmaniasis, pyemia, sepsis, or African trypanosomiasis).
- Remittent fever, where the temperature remains above normal throughout the day and fluctuates more than 1 °C in 24 hours (e.g., in infective endocarditis or brucellosis).
- Pel–Ebstein fever is a cyclic fever that is rarely seen in patients with Hodgkin's lymphoma.
- Undulant fever, seen in brucellosis.
- Typhoid fever is a continuous fever showing a characteristic step-ladder pattern, a step-wise increase in temperature with a high plateau.
- Among the types of intermittent fever are ones specific to cases of malaria caused by different pathogens. These are:
- Quotidian fever, with a 24-hour periodicity, typical of malaria caused by Plasmodium knowlesi (P. knowlesi);
- Tertian fever, with a 48-hour periodicity, typical of later course malaria caused by P. falciparum, P. vivax, or P. ovale;
- Quartan fever, with a 72-hour periodicity, typical of later course malaria caused by P. malariae.
Causes
- Fever is a common symptom of many medical conditions:
- Infectious disease such as:
- COVID-19
- Dengue
- Ebola
- Gastroenteritis
- HIV
- Influenza
- Lyme disease
- Rocky Mountain spotted fever
- Secondary syphilis
- Malaria
- Mononucleosis
- As well as infections of the skin:
- Immunological diseases such as:
- Relapsing polychondritis
- Autoimmune hepatitis
- Granulomatosis with polyangiitis
- Horton disease
- Inflammatory bowel diseases
- Kawasaki disease
- Lupus erythematosus
- Sarcoidosis
- Still's disease
- Rheumatoid arthritis
- Lymphoproliferative disorders
- Psoriasis
- Tissue destruction
- As a result of cerebral bleeding
- Crush syndrome
- Hemolysis
- Infarction
- Rhabdomyolysis
- Surgery
- Etc.
- Cancers, particulary blood cancers such as:
- Metabolic disorders such as:
- Inherited metabolic disorder such as:
- Adult and pediatric manifestations for the same disease may differ; for instance, in COVID-19, one metastudy describes 92.8% of adults versus 43.9% of children presenting with fever.
- In addition, fever can result from a reaction to an incompatible blood product.
- Assist the healing process in ways, including:
- Increased mobility of leukocytes;
- Increased proliferation of T cells.
- Enhanced leukocyte phagocytosis;
- Decreased endotoxin effects;
- Temperature is regulated in the hypothalamus. The trigger of a fever, called a pyrogen, results in the release of prostaglandin E2 (PGE2). PGE2 in turn acts on the hypothalamus, which creates a systemic response in the body, causing heat-generating effects to match a new higher temperature set point. There are four receptors in which PGE2 can bind (EP1-4), with a previous study showing the EP3 subtype is what mediates the fever response. When the set point is raised, the body increases its temperature through both active generation of heat and retention of heat. Peripheral vasoconstriction both reduces heat loss through the skin and causes the person to feel cold. Norepinephrine increases thermogenesis in brown adipose tissue, and muscle contraction through shivering raises the metabolic rate.
- If these measures are insufficient to make the blood temperature in the brain match the new set point in the hypothalamus, the brain orchestrates heat effector mechanisms via the autonomic nervous system or primary motor center for shivering. These may be:
- Increased heat production by increased muscle tone, shivering (muscle movements to produce heat) and release of hormones like epinephrine; and
- Prevention of heat loss, e.g., through vasoconstriction.
- L-Tyrosine
- Can also be synthesized in the body from phenylalanine
- found in many high-protein food products such as
- meat
- fish
- cheese
- cottage cheese
- milk
- yogurt
- peanuts
- almonds
- pumpkin seeds
- sesame seeds
- soy protein
- lima beans
- egg whites
- about 250 mg per egg
- In dopaminergic cells in the brain, tyrosine is converted to L-DOPA by the enzyme tyrosine hydroxylase (TH). TH is the rate-limiting enzyme involved in the synthesis of the neurotransmitter dopamine. Dopamine can then be converted into other catecholamines, such as norepinephrine (noradrenaline) and epinephrine (adrenaline).
- L-Tryptophan
- Functions as a biochemical precursor for the following compounds:
- Serotonin (a neurotransmitter), synthesized by tryptophan hydroxylase.
- Melatonin (a neurohormone) is in turn synthesized from serotonin, via N-acetyltransferase and 5-hydroxyindole-O-methyltransferase enzymes.
- Kynurenine, to which tryptophan is mainly (more than 95%) metabolized. Two enzymes, namely indoleamine 2,3-dioxygenase (IDO) in the immune system and the brain, and tryptophan 2,3-dioxygenase (TDO) in the liver, are responsible for the synthesis of kynurenine from tryptophan. The kynurenine pathway of tryptophan catabolism is altered in several diseases, including psychiatric disorders such as schizophrenia, major depressive disorder, and bipolar disorder.
- Niacin, also known as vitamin B3, is synthesized from tryptophan via kynurenine and quinolinic acids.
- Auxins (a class of phytohormones) are synthesized from tryptophan.
- Potential side effects of tryptophan supplementation include nausea, diarrhea, drowsiness, lightheadedness, headache, dry mouth, blurred vision, sedation, euphoria, and nystagmus (involuntary eye movements).
- Tryptophan taken as a dietary supplement (such as in tablet form) has the potential to cause serotonin syndrome when combined with antidepressants of the MAOI or SSRI class or other strongly serotonergic drugs.
- Turmeric
- Phytochemical components of turmeric include diarylheptanoids, a class including numerous curcuminoids, such as curcumin, demethoxycurcumin, and bisdemethoxycurcumin.
- Curcumin constitutes up to 3.14% of assayed commercial samples of turmeric powder (the average was 1.51%); curry powder contains much less (an average of 0.29%). Some 34 essential oils are present in turmeric, among which turmerone, germacrone, atlantone, and zingiberene are major constituents.
- Curcuma, or turmeric, induces CYP1A2, potentially decreasing levels of antidepressants and antipsychotics, and increases sulfasalazine levels.
- Coffee
- PLACEHOLDER
- Cow Milk
- Cow milk contains components like antibodies and lactoferrin, which may bolster the immune system, especially in young children. It also has anti-inflammatory and antimicrobial properties, potentially aiding in fighting infections. However, its hormonal content, like IGF-1, may influence growth, though this is still being researched.
- Beyond nutrition, cow milk has bioactive compounds like transforming growth factor β (TGF-β), used in treating conditions like Crohn’s disease, showing its potential beyond just food.
- Cow milk is primarily composed of water (about 87%), with the remainder consisting of proteins, fats, lactose, vitamins, and minerals. The average composition, as outlined in "Milk composition and microbiology - Milk composition", includes 4.9% lactose, 3.4% fat, 3.3% protein, and 0.7% minerals.
- Cow milk, particularly colostrum, contains high levels of antibodies and immune factors, which can modulate the immune system. Lactoferrin, a key protein found in cow milk at concentrations of 2–3 g/L.
- Cow milk contains casein, which can be broken down into casomorphins, peptides with opioid-like activity. These compounds have been detected in blood after milk consumption, potentially influencing gastrointestinal function or appetite, though their physiological significance in humans is not fully established.
- Lactose, the primary carbohydrate in cow milk, provides energy but can cause digestive issues in individuals with lactose intolerance, leading to symptoms like diarrhea and bloating ("Milk: Health benefits and nutrition"). Additionally, milk contains oligosaccharides that act as prebiotics, supporting gut health by promoting beneficial bacteria, as discussed in "Frontiers | Composition, Structure, and Digestive Dynamics of Milk From Different Species—A Review". These gastrointestinal effects are significant pharmacological actions, particularly for those with sensitivities.
- A milk cytokine, has been shown to promote remission in pediatric Crohn’s disease when supplemented in enteric nutrition formulas.
- Milk glycans, including oligosaccharides, show promise as antimicrobial and anti-inflammatory agents in preclinical studies.
Component Percentage (%) Water 87.7 Lactose 4.9 Fat 3.4 Protein 3.3 Minerals (Ash) 0.7 - Vitamin D
- Supplementation with vitamin D is a reliable method for preventing or treating rickets.
- Vitamin D supplements do not alter the outcomes for myocardial infarction, stroke or cerebrovascular disease, cancer, bone fractures or knee osteoarthritis.
- Vitamin D supplementation at low doses may slightly decrease the overall risk of acute respiratory tract infections.
- Vitamin D deficiency has been linked to the severity of inflammatory bowel disease (IBD).
- Supplementation leads to improvements in scores for clinical inflammatory bowel disease activity and biochemical markers, and less frequent relapse of symptoms in IBD.
- Vitamin D deficiency and insufficiency have been associated with adverse outcomes in COVID-19.
- Vitamin D supplementation substantially reduced the rate of moderate or severe exacerbations of chronic obstructive pulmonary disease (COPD).
- A meta-analysis reported that vitamin D supplementation significantly reduced the risk of type 2 diabetes for non-obese people with prediabetes.
- Another meta-analysis reported that vitamin D supplementation significantly improved glycemic control [homeostatic model assessment-insulin resistance (HOMA-IR)], hemoglobin A1C (HbA1C), and fasting blood glucose (FBG) in individuals with type 2 diabetes.
- In prospective studies, high versus low levels of vitamin D were respectively associated with a significant decrease in risk of type 2 diabetes, combined type 2 diabetes and prediabetes, and prediabetes.
- A systematic review included one clinical trial that showed vitamin D supplementation together with insulin maintained levels of fasting C-peptide after 12 months better than insulin alone.
- A meta-analysis of observational studies showed that children with ADHD have lower vitamin D levels and that there was a small association between low vitamin D levels at the time of birth and later development of ADHD.
- Several small, randomized controlled trials of vitamin D supplementation indicated improved ADHD symptoms such as impulsivity and hyperactivity.
- Clinical trials of vitamin D supplementation for depressive symptoms have generally been of low quality and show no overall effect, although subgroup analysis showed supplementation for participants with clinically significant depressive symptoms or depressive disorder had a moderate effect.
- A systematic review of clinical studies found an association between low vitamin D levels with cognitive impairment and a higher risk of developing Alzheimer's disease.
- People diagnosed with schizophrenia tend to have lower serum vitamin D concentrations compared to those without the condition.
- Erectile dysfunction can be a consequence of vitamin D deficiency.
- In women, vitamin D receptors are expressed in the superficial layers of the urogenital organs.
- Pregnant women often do not take the recommended amount of vitamin D.
- Low levels of vitamin D in pregnancy are associated with gestational diabetes, pre-eclampsia, and small for gestational age infants.
- Obesity increases the risk of having low serum vitamin D.
- Supplementation does not lead to weight loss, but weight loss increases serum vitamin D. The theory is that fatty tissue sequesters vitamin D.
- Bariatric surgery as a treatment for obesity can lead to vitamin deficiencies. Long-term follow-up reported deficiencies for vitamins D, E, A, K and B12, with D the most common at 36%.
- There is evidence that the pathogenesis of uterine fibroids is associated with low serum vitamin D and that supplementation reduces the size of fibroids.
- The US Adequate Intake recommendations from 1997 were 200 IU/day for infants, children, adults to age 50, and women during pregnancy or lactation, 400 IU/day for ages 51–70, and 600 IU/day for 71 and older.
- Conversion: 1 μg (microgram) = 40 IU (international unit).
- SAMe
- Also known as: S-adenosyl-L-methionine and AdoMet
- Pharmacological Actions
- Depression: SAMe is implicated in enhancing neurotransmitter activity, particularly dopamine and serotonin turnover, which may improve mood regulation. Research indicates it increases levels of homovanillic acid and 5-hydroxyindoleacetic acid in cerebrospinal fluid, lowers serum prolactin, and impacts the noradrenergic system by modifying adrenergic receptor activity. It enhances methylation of catecholamines, inhibits norepinephrine reuptake, and may boost gene expression of brain-derived neurotrophic factor (BDNF), potentially supporting neurogenesis. Clinical effects often take weeks to manifest, with studies suggesting improvements noticeable after 4-12 weeks at doses of 200-1600 mg/day, though individual response times vary.
- Osteoarthritis: SAMe appears to support joint health by stimulating the production of collagen and proteoglycans, key components of cartilage. It also exhibits painkilling and anti-inflammatory properties, potentially reducing joint pain and stiffness. Mechanisms may include reducing inflammatory mediators, increasing glutathione levels, and signaling cartilage synthesis or survival, though exact pathways are not fully elucidated. Studies suggest benefits may be seen after several weeks, with doses of 600-1200 mg/day used for up to 84 days, showing gradual improvements in functional limitations and pain.
- Liver Disease: SAMe plays a critical role in liver health, acting as a precursor for glutathione, which enhances antioxidant defenses against reactive oxygen species (ROS). It attenuates pro-inflammatory TNFα-mediated liver injury, induces anti-inflammatory IL-10 production, and protects hepatocytes from apoptosis by reducing mitochondrial cytochrome-c release and caspase-3 activation. It also influences membrane fluidity and bile salt export, aiding in conditions like intra-hepatic cholestasis. Clinical trials, such as a multi-center study with 220 patients at 1600 mg/day, showed symptom improvement within weeks, with effects on cholestasis indices noted early in treatment.
- Pharmacokinetic Properties
- Half-life: The half-life for intravenous administration is approximately 80-100 minutes, based on studies with doses like 100 mg, 500 mg, and 0.5 mg/kg body weight. For oral administration, the apparent half-life may be longer due to absorption dynamics, with some studies reporting values around 7.77-16.01 hours for novel formulations, suggesting variability based on formulation and absorption rate. This discrepancy highlights the need for further research into oral pharmacokinetics.
- Bioavailability: Oral bioavailability is notably low, estimated at 1-3% for standard formulations, attributed to poor intestinal absorption and high first-pass metabolism in the liver. Novel formulations, such as enteric-coated tablets (e.g., MSI-195), can increase bioavailability to around 9%, as seen in pharmacokinetic studies comparing AUC ratios. Intramuscular bioavailability is higher, at 80-90%, offering a more efficient route for systemic exposure. The presence of food can reduce absorption, with studies showing a 55% reduction in AUC when taken with food compared to fasted states.
- Dosage and Safety Considerations
- Dosage Ranges:
- Safe Range: Clinical studies commonly use doses up to 1600 mg/day, with evidence suggesting safety for periods up to two years in conditions like alcohol-related liver disease. Doses are typically divided, taken with or without food, though absorption may be better on an empty stomach.
- Minimum Effective Dose: This varies by condition. For depression, studies start at 200 mg/day, escalating to 1600 mg/day for non-responders. For osteoarthritis, effective doses range from 600-1200 mg/day, and for liver disease, 800-1200 mg/day is common, based on trial data.
- Maximum Safe Dose: While 1600 mg/day is well-tolerated, higher doses lack extensive safety data. Given mild side effects at higher doses, caution is advised beyond this, especially without medical supervision.
- Toxicity and LD50:
- Animal studies provide insight into acute toxicity, with an oral LD50 in rats greater than 4650 mg/kg, indicating low acute toxicity. Human data on LD50 is unavailable due to ethical constraints, but studies at 1600 mg/day show no significant toxic methylated metabolites or homocysteine elevation, suggesting a wide safety margin.
- Chronic toxicity is less studied, but long-term use at therapeutic doses shows mild side effects like gastrointestinal upset, headache, and insomnia, particularly at higher doses.
- Onset of Danger: Determining when SAMe becomes dangerous is complex. High doses may exacerbate side effects, and in vulnerable populations, such as those with bipolar disorder, even therapeutic doses (e.g., 200-1600 mg/day) can trigger mania, as noted in case reports. The risk increases with pre-existing conditions, and individual sensitivity varies, necessitating medical oversight for high-dose regimens.
- Comparative Table of Pharmacokinetic and Dosage Parameters
Parameter Details Half-life (IV) 80-100 minutes Half-life (Oral, Approx) 7.77-16.01 hours (varies by formulation) Bioavailability (Oral) 1-3% (standard), up to 9% (novel formulations) Bioavailability (IM) 80-90% Safe Dosage Range Up to 1600 mg/day, divided doses Minimum Effective Dose 200-600 mg/day, depending on condition LD50 (Rat, Oral) >4650 mg/kg - Multivitamins and Multiminerals
- PLACEHOLDER
- Vortioxetine
- PLACEHOLDER
- Bromantane
- Increase the expression of neurotrophins including brain-derived neurotrophic factor and nerve growth factor in certain rat brain areas.
- Anticholinergic effects.
- Antimuscarinic actions.
- Antinicotinic actions.
- Upregulation of the expression of Tyrosine Hydroxylase (TH) in rat, from 2 to 2.5 fold increase in TH expression.
- Upregulation of the expression of Aromatic L-amino Acid Decarboxylase (AAAD) (also known as DOPA decarboxylase).
- Piracetam
- Piracetam may facilitate the deformability of erythrocytes in capillary which is useful for cardiovascular disease.
- Potential for vertigo, dyslexia, Raynaud's phenomenon and sickle cell anemia.
- Symptoms including anxiety, insomnia, irritability, headache, agitation, tremor, and hyperkinesia are occasionally reported. Other reported side effects include somnolence, weight gain, clinical depression, weakness, increased libido, and hypersexuality.
- PAM of the AMPA receptor
- GABA brain metabolism and GABA receptors are not affected
- Increases the action of the neurotransmitter acetylcholine via muscarinic cholinergic (ACh) receptors
- Inhibits N-type calcium channels
- Spirulina
- PLACEHOLDER
- Jarrow Formula Probiotiques et Prébiotiques
- PLACEHOLDER
- Methylene Blue
- Methylene blue is used to treat methemoglobinemia by chemically reducing the ferric iron in hemoglobin to ferrous iron.
- Methylene blue, when injected intravenously as an antidote, is itself first reduced to leucomethylene blue, which then reduces the heme group from methemoglobin to hemoglobin.
- At high doses, however, methylene blue actually induces methemoglobinemia, reversing this pathway.
- Since its reduction potential is similar to that of oxygen and can be reduced by components of the electron transport chain, large doses of methylene blue are sometimes used as an antidote to potassium cyanide poisoning, a method first successfully tested in 1933 by Matilda Moldenhauer Brooks in San Francisco, although first demonstrated by Bo Sahlin of Lund University, in 1926.
- Severe methemoglobinemia may be treated with methylene blue.
- Another use of methylene blue is to treat ifosfamide neurotoxicity.
- Methylene blue increases blood pressure in people with vasoplegic syndrome (redistributive shock), but does not improve delivery of oxygen to tissues or decrease mortality.
- Methylene blue has been used in calcium channel blocker toxicity as a possible rescue therapy for distributive shock unresponsive to first line agents.
- Methylene blue is a dye behaving as a redox indicator that is commonly used in the food industry to test the freshness of milk and dairy products.
- ALCAR
- Chemotherapy-induced peripheral neuropathy (CIPN): A review of two studies concluded that ALC may be a treatment option for paclitaxel- and cisplatin-induced CIPN, while a clinical trial showed it did not prevent CIPN and appeared to worsen the conditions in taxane therapy.
- ALCAR improves blood ammonia levels.
- Mitochondrial decay and oxidative damage to RNA/DNA increases with age in the rat hippocampus, a region of the brain associated with memory. Memory performance declines with age. These increases in decay and damage, and memory loss itself, can be partially reversed in old rats by feeding acetyl-L-carnitine.
- Inositol
- Pharmacological Actions
- Cellular Signaling: Inositol is a critical component of the phosphoinositide cycle, serving as a second messenger in intracellular signal transduction pathways. It facilitates communication within cells, influencing processes like hormone response and growth factor signaling (source).
- Insulin Sensitization: It enhances insulin sensitivity, which is particularly beneficial for conditions like polycystic ovary syndrome (PCOS) and metabolic syndrome. Studies suggest it improves insulin action, potentially reducing blood glucose levels and aiding in conditions associated with insulin resistance (source).
- Neurotransmitter Modulation: Inositol influences neurotransmitter synthesis, notably serotonin, which impacts mood and mental health. It has been explored for treating depression, anxiety, and obsessive-compulsive disorder (OCD), with evidence suggesting it modulates neurotransmitter activity in the brain (source).
- Osmoregulation: In the brain, Inositol acts as an osmolyte, helping maintain cell volume and fluid balance, which is crucial for neurological function. Its concentration is notably high in brain tissue, supporting osmoregulation (source).
- Structural Role: As phosphatidylinositol, it is a structural component of cell membranes, contributing to membrane integrity and function (source).
- The onset of clinical effects for these actions varies, with research indicating that therapeutic benefits, particularly for mental health and metabolic conditions, are typically observed within 2-4 weeks (source). This timeline aligns with the need for sustained supplementation to achieve significant physiological changes, especially for chronic conditions.
- Pharmacokinetics
- Half-Life: Studies in preterm infants report a half-life of approximately 5-8 hours, with specific values ranging from 5.22 hours to 7.90 hours (source).
- Bioavailability: Inositol is absorbed from the small intestine, with oral ingestion leading to peak plasma concentrations around 4 hours post-dose, indicating good oral bioavailability (source).
- Dosage and Safety
- Therapeutic Doses: For mental health conditions like depression and anxiety, doses typically range from 12-18 g/day, often taken in divided doses (source).
- Safe Range and Side Effects: Inositol is generally considered safe up to 18 g/day, with side effects like nausea, diarrhea, and gas reported at doses above 12 g/day (source).
- Minimum Effective Dose: This varies by condition, with research suggesting 1-2 g/day as effective for some metabolic benefits, while higher doses are needed for mental health, starting at 12 g/day (source).
- Maximum Safe Dose: Not explicitly defined, but studies using doses up to 18 g/day for extended periods (e.g., 3 months) report no significant adverse effects, indicating a high safety margin (source).
- LD50 and Toxicity: In rats, the LD50 is reported as 10 g/kg body weight orally, indicating very low toxicity (source). For a 70 kg human, this translates to 700 g, far exceeding typical therapeutic doses, suggesting minimal risk of toxicity at recommended levels.
- Dangerous Doses: Given the high LD50 and lack of reported serious toxicity, dangerous levels likely exceed 18 g/day, but specific thresholds are not established. Side effects at higher doses are mild, suggesting a wide therapeutic window, though caution is advised above 18 g/day due to potential mineral absorption issues at very high doses (source).
Condition Therapeutic Dose (g/day) Minimum Effective Dose (g/day) Notes Mental Health (e.g., Depression, Anxiety) 12-18 12 Effects seen in 2-4 weeks PCOS and Metabolic Syndrome 2-4 1-2 Often combined with folic acid Gestational Diabetes 4 (2 g twice daily with folic acid) 2 Prevents onset, used during pregnancy - Choline
- PLACEHOLDER
- Agmatine
- Nitric oxide (NO) synthesis modulation. Both differential inhibition and activation of NO synthase (NOS) isoforms is reported.
- Polyamine metabolism. Precursor for polyamine synthesis, competitive inhibitor of polyamine transport, inducer of spermidine/spermine acetyltransferase (SSAT), and inducer of antizyme.
- Protein ADP-ribosylation. Inhibition of protein arginine ADP-ribosylation.
- Matrix metalloproteases (MMPs). Indirect down-regulation of the enzymes MMP 2 and 9.
- Advanced glycation end product (AGE) formation. Direct blockade of AGEs formation.
- NADPH oxidase. Activation of the enzyme leading to H2O2 production.
- Oral agmatine is absorbed from the gastrointestinal tract and readily distributed throughout the body.
- Rapid elimination from non-brain organs of ingested (un-metabolized) agmatine by the kidneys has indicated a blood half life of about 2 hours.
- It is synthesized in the brain.
- Binds to α2-adrenergic receptor
- Binds to imidazoline receptor binding sites
- Blocks NMDA receptors
- Blocks other cation ligand-gated channels
- Systemic agmatine can potentiate opioid analgesia
- Systemic agmatine can prevent tolerance to chronic morphine in laboratory rodents
- Cumulative evidence amply shows that agmatine inhibits opioid dependence and relapse in several animal species
- Flmodafinil
- Wakefulness-promoting agent
- Developed for treatment of a variety of different medical conditions. These include chronic fatigue syndrome, idiopathic hypersomnia, narcolepsy, attention deficit hyperactivity disorder (ADHD), and Alzheimer's disease.
- The drug has been found to act as a selective atypical dopamine reuptake inhibitor.
- Produces wakefulness-promoting effects in animals.
- Unlike modafinil, flmodafinil does not induce cytochrome P450 enzymes.
- Selective dopamine reuptake inhibitor (DRI).
- Affinity (Ki) for the DAT is 4,090 nM.
- At the serotonin transporter (SERT), its affinity (Ki) was 48,700 nM (12-fold lower than for the DAT).
- Negligible affinity for the sigma σ1 receptor (Ki > 100,000 nM).
- The drug has been found to block the dopamine transporter (DAT) by 83%, to a greater extent than methylphenidate without unfavorable concomitant adrenergic effects.
- Atypical DRI similarly to modafinil.
- Similarly to modafinil, (S)-(+)-flmodafinil and (R)-(–)-flmodafinil increase dopamine levels in the nucleus accumbens in animals. They have been found to increase dopamine levels by up to 150 to 200% of baseline at the highest assessed dose.
- In contrast to modafinil, flmodafinil is not an inducer of the cytochrome P450 CYP3A4 or CYP3A5 enzymes.
- Nicotine
- PLACEHOLDER
- Sulbutiamine
- Used to treat symptoms of weakness or fatigue.
- Prescribed when there is thiamine deficiency, mainly in patients with asthenia, overwork, apathy, depressive states, memory disorders, and iatrogenic disorders of wakefulness.
- Potent cholinergic ?
- Endurance athletes may use it to try to enhance their performance.
- Side effects can include diarrhea, bladder infections, bronchitis, back pain, abdominal pain, insomnia, constipation, gastroenteritis, headache, vertigo, and sore throat.
- Fluoxetine
- SSRI
- Fluoxetine can affect the electrical currents that heart muscle cells use to coordinate their contraction, specifically the potassium currents Ito and IKs that repolarise the cardiac action potential. Under certain circumstances, this can lead to prolongation of the QT interval, a measurement made on an electrocardiogram reflecting how long it takes for the heart to electrically recharge after each heartbeat. When fluoxetine is taken alongside other drugs that prolong the QT interval, or by those with a susceptibility to long QT syndrome, there is a small risk of potentially lethal abnormal heart rhythms such as torsades de pointes. A study completed in 2011 found that fluoxetine does not alter the QT interval and has no clinically meaningful effects on the cardiac action potential.
- Fluoxetine is a potent inhibitor of CYP2D6 enzymes.
- Patients who are taking NSAIDs, antiplatelet drugs, anticoagulants, omega-3 fatty acids, vitamin E, and garlic supplements must be careful when taking fluoxetine or other SSRIs, as they can sometimes increase the blood-thinning effects of these medications.
- Fluoxetine inhibit many isozymes of the cytochrome P450 system that are involved in drug metabolism.
- Potent inhibitor of CYP2D6 (which is also the chief enzyme responsible for their metabolism) and CYP2C19, and mild to moderate inhibitors of CYP2B6 and CYP2C9.
- They also inhibit the activity of P-glycoprotein, a type of membrane transport protein that plays an important role in drug transport and metabolism and hence P-glycoprotein substrates, such as loperamide, may have their central effects potentiated.
- Binding affinities (Ki in nM)
Molecular Target Fluoxetine SERT 1 NET 660 DAT 4180 5-HT1A 32400 5-HT2A 147 5-HT2C 112 α1 3800 M1 702-1030 M2 2700 M3 1000 M4 2900 M5 2700 H1 3'250 - Increases the concentration of circulating allopregnanolone, a potent GABAA receptor positive allosteric modulator, at concentrations that are inactive on serotonin reuptake.
- Has been found to act as an agonist of the σ1-receptor, with a potency greater than that of citalopram but less than that of fluvoxamine.
- Channel blocker of anoctamin 1, a calcium-activated chloride channel.
- A number of other ion channels, including nicotinic acetylcholine receptors and 5-HT3 receptors, are also known to be inhibited at similar concentrations.
- Fluoxetine has been shown to inhibit acid sphingomyelinase, a key regulator of ceramide levels which derives ceramide from sphingomyelin.
- The bioavailability of fluoxetine is relatively high (72%).
- Peak plasma concentrations are reached in 6–8 hours.
- TAK-653
- Also named Osavampator and NBI-1065845.
- Selective positive allosteric modulator (PAM) of the AMPA receptor.
- Potentiate the effects of agonists at the main site of the AMPA receptor by slowing the rate of desensitization and internalization of the receptor.
- Terminal half-life is 33.1–47.8 hours.
- Possesses minimal direct AMPA agonist properties.
- Provides a 419-fold safety margin against convulsions relative to therapeutic doses in rats.
- Tropisetron
- 5-HT3 receptor antagonist
- α7-nicotinic receptor partial agonist.
- Also used as a biological stain.
- Also used as a trypanocide.
- NAD+
- Nicotinamide adenine dinucleotide (NAD+) is a coenzyme essential for energy production and cellular health, often linked to anti-aging benefits. However, when it comes to taking pure NAD+ orally, the evidence leans toward it being ineffective due to challenges with absorption in the digestive system.
- Pure NAD+ seems likely to be broken down in the stomach, reducing its ability to reach cells in an active form. This is why supplements often use precursors like NR and NMN, which the body can convert into NAD+ more efficiently.
- If you're considering NAD+ for health benefits, oral supplements are typically in the form of precursors, not pure NAD+.
- Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme found in all living cells, playing a central role in metabolism, particularly in redox reactions that generate energy. It exists in two forms: NAD+ (oxidized) and NADH (reduced), and is essential for processes like mitochondrial function, DNA repair, and sirtuin activation, which are linked to healthy aging. Given its importance, there has been growing interest in NAD+ supplementation, especially as levels decline with age, potentially contributing to age-related diseases.
- To provide context, precursors like NR and NMN have been more extensively studied for oral use. Chronic supplementation with NR was well-tolerated and increased NAD+ levels in healthy middle-aged and older adults, with potential benefits for blood pressure and arterial stiffness Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults.
Study Focus Form Administered Findings Human/Animal Source URL NAD+ precursors in aging NR, NMN Increased NAD+ levels, potential cardiovascular benefits Human Dietary Supplementation With NAD+-Boosting Compounds in Humans Oral nicotinamide effects Nicotinamide 500 mg increased blood NAD+ after 12 hours in small cohort Human A single oral supplementation of nicotinamide Bioavailability of NADH NADH Increased brain levels in rats, limited human data Animal Bioavailability of reduced nicotinamide-adenine-dinucleotide Clinical trials on NAD+ NAD+, precursors Mixed results, more focus on precursors, 8 studies on oral NAD+ Human Clinical Evidence for Targeting NAD Therapeutically - Huperzine A
- Inhibits the breakdown of the neurotransmitter acetylcholine (ACh) by the enzyme acetylcholinesterase.
- Antagonist of the NMDA-receptor.
- Reversible acetylcholinesterase inhibitor
- Mild cholinergic side effects such as nausea, vomiting, and diarrhea.
- Toxicology studies show huperzine A to be non-toxic even when administered at 50-100 times the human therapeutic dose.
- The extract is active for 6 hours at a dose of 2 μg/kg with no remarkable side effects.
- Huperzine A might be useful in the treatment of organophosphate nerve agent poisoning by preventing damage to the central nervous system caused by such agents.
- Safinamide Mesylate
- Pharmacological Actions and Potencies
- Reversible Inhibition of Monoamine Oxidase B (MAO-B): Safinamide acts as a selective and reversible inhibitor of MAO-B, an enzyme responsible for dopamine degradation. This action increases dopamine levels in the brain, enhancing dopaminergic activity. The IC50 for MAO-B inhibition is consistently reported as 98 nM, with a selectivity ratio over MAO-A of approximately 5918-fold, indicated by an MAO-A IC50 of 580 μM. This high selectivity reduces the risk of hypertensive crises associated with non-selective MAO inhibitors.
- Blockade of Voltage-Dependent Sodium Channels: Safinamide also blocks voltage-dependent sodium channels, with a noted IC50 of 8 μM at depolarized potentials and 262 μM at resting potentials. This use- and frequency-dependent blockade suggests a preference for active neuronal states, potentially contributing to its effects on neuronal excitability and neurotransmitter release.
- Blockade of N-Type Calcium Channels: The drug is known to block N-type calcium channels, a subtype critical for neurotransmitter release. However, specific IC50 values for this action were not found in the reviewed literature, indicating a gap in detailed potency data. This mechanism likely contributes to its neuroprotective effects by modulating calcium-dependent processes.
- Inhibition of Glutamate Release: Safinamide inhibits glutamate release, with an IC50 of 8 μM, which may be a downstream effect of its sodium and calcium channel blockade. This action is particularly relevant in Parkinson's disease, where excessive glutamatergic activity can exacerbate motor symptoms and contribute to neuronal damage.
- Pharmacokinetic Properties
- Half-Life: The terminal half-life ranges from 20 to 26 hours, allowing for sustained effects and steady-state concentrations achieved within 5-6 days of consistent dosing. This duration supports its use in maintaining therapeutic levels over extended periods.
- Bioavailability: Oral bioavailability is reported at 95%, with no significant first-pass metabolism. Food slightly delays the time to maximum concentration (Tmax, 2-3 hours) but does not affect the area under the curve (AUC) or maximum concentration (Cmax), ensuring reliable absorption.
- Distribution and Metabolism: The volume of distribution at steady state (Vss) is approximately 165 L, with an unbound fraction of 11-12%. Metabolism primarily occurs via non-microsomal cytosolic amidases and minor CYP3A4 activity, producing inactive metabolites like NW-1689 (161% parent exposure), NW-1689 AG (18%), and NW-1153 (11%). Excretion is predominantly renal (76%), with 5% excreted unchanged.
- Special Populations: No significant effects on pharmacokinetics were noted for age, race, sex, or renal impairment. However, hepatic impairment increases exposure, with mild impairment raising AUC by 30% and moderate by 80%, necessitating dosage adjustments (maximum 50 mg/day in moderate hepatic impairment, contraindicated in severe).
- Dosage and Safety Considerations
- Recommended Dosage Range: The standard dosage is 50-100 mg once daily, initiated at 50 mg and potentially increased after two weeks based on individual response and tolerability. Dosages above 100 mg daily have not shown additional benefits and may increase the risk of hypertensive reactions, particularly in the context of MAO-B inhibition.
- Minimum Effective Dose: Clinical studies, such as the SETTLE and MOTION trials, indicate that 50 mg/day is effective, improving ON-time without troublesome dyskinesias and motor function, making it the minimum effective dose.
- Maximum Safe Dose: The maximum recommended dose is 100 mg/day, as higher doses are not advised due to potential increased adverse effects without therapeutic gain. This is supported by pharmacodynamic data showing no additional benefit and increased risk at higher doses.
- LD50 and Toxicity Thresholds: Specific LD50 values for Safinamide were not found in public literature, and there is no human experience with overdose reported. Preclinical toxicology data from the EMA assessment report indicate adverse effects at high doses in animals (e.g., convulsions at ≥70 mg/kg/day in monkeys, hepatotoxicity at NOAEL 45 mg/kg/day in rats), but these do not translate directly to human LD50. Overdose symptoms, as noted in clinical observations, include hypertension, hallucinations, and dyskinesia, with no specific antidote available, requiring supportive care and dietary tyramine restriction for several weeks post-overdose.
- When It Starts to Become Too Dangerous: Doses exceeding 100 mg/day are considered potentially dangerous, as they increase the risk of adverse effects without additional benefit, based on clinical trial data and regulatory guidance. However, exact thresholds for severe toxicity are not well-defined due to limited overdose data.
- Summary of Pharmacological and Pharmacokinetic Parameters
Parameter Value MAO-B Inhibition IC50 98 nM MAO-A Inhibition IC50 580 μM Sodium Channel Blockade IC50 8 μM (depolarized), 262 μM (resting) Calcium Channel Blockade IC50 Not available Glutamate Release Inhibition IC50 8 μM Half-Life 20-26 hours Oral Bioavailability 95% Recommended Dosage Range 50-100 mg/day Minimum Effective Dose 50 mg/day Maximum Safe Dose 100 mg/day LD50 Not available - L-DOPA
- Another names: l-3,4-dihydroxyphenylalanine and levodopa.
- Precursor of dopamine, noradrenaline and adrenaline.
- Has a counterpart with opposite chirality that is d-DOPA.
- Produced from the amino acid l-tyrosine by the enzyme tyrosine hydroxylase.
- Can be directly metabolized by catechol-O-methyl transferase to 3-O-methyldopa, and then further to vanillactic acid.
- Neboglamine
- Another names: CR-2249, XY-2401 and Nebostinel.
- Positive allosteric modulator of the glycine site of the NMDA receptor, which is linked to improved cognition and memory.
- Also shows potential as an antipsychotic, particularly for schizophrenia and cocaine dependence, by increasing neuronal activity in key brain areas like the prefrontal cortex.
- Safe dose range of 10 to 600 mg per day.
- Preferred range of 30 to 300 mg per day.
- Research suggests it enhances cognition and memory, as demonstrated in animal models, where it shows cognition- and memory-enhancing effects.
- Studies showing it increases neuronal activation in areas relevant to schizophrenia, potentially addressing negative and cognitive symptoms.
- Binds very weakly to the NMDA receptor recognition site (IC50 0.7 mM) and shows no significant binding affinity to AMPA and kainic receptors, suggesting a selective action at the glycine site (source).
- Antipsychotic-like effects are further evidenced by its ability to inhibit phencyclidine (PCP)-induced hyperlocomotion and rearing behavior in rat models, supporting its clinical evaluation for schizophrenia treatment.
- Licorice Root
- Contain: Glycyrrhizin (7% to 10%), Glabridin, Liquiritin, Isoliquiritigenin, Licochalcone A, Glabridin, 18β-Glycyrrhetinic acid, Licoricidin, Licochalcone C; Isoliquiritin, Liquiritigenin, Hispaglabridin A and Hispaglabridin B.
- Table of Estimated Percentages
Compound Estimated Percentage Range Notes Glycyrrhizin 2% to 25% Major component, varies by species Glabridin 0.1% to 0.5% Higher in G. glabra Liquiritin 1% to 5% Significant in medicinal use Isoliquiritigenin 0.1% to 1% Minor, with pharmacological activity Licochalcone A 1% to 5% Abundant in G. inflata 18β-Glycyrrhetinic acid Negligible (<0.01%) Metabolite, not significant in raw roots Licoricidin 0.02% to 0.72% Species-dependent, higher in G. uralensis Licochalcone C Very small Likely negligible, limited data Isoliquiritin 0.1% to 2% Minor flavonoid, anti-angiogenic Liquiritigenin 0.1% to 1% Related to liquiritin, minor component Hispaglabridin A Very small (<0.1%) Limited quantitative data Hispaglabridin B Very small (<0.1%) Limited quantitative data - Selenium
- In humans, selenium is a trace element nutrient that functions as cofactor for reduction of antioxidant enzymes, such as glutathione peroxidases and certain forms of thioredoxin reductase found in animals and some plants (this enzyme occurs in all living organisms, but not all forms of it in plants require selenium).
- The glutathione peroxidase family of enzymes (GSH-Px) catalyze reactions that remove reactive oxygen species such as hydrogen peroxide and organic hydroperoxides.
- The thyroid gland and every cell that uses thyroid hormone also use selenium,[117] which is a cofactor for the three of the four known types of thyroid hormone deiodinases, which activate and then deactivate various thyroid hormones and their metabolites; the iodothyronine deiodinases are the subfamily of deiodinase enzymes that use selenium as the otherwise rare amino acid selenocysteine.
- Increased dietary selenium reduces the effects of mercury toxicity.
Summary Table of Pharmacological Actions
Action Mechanism Examples/Notes Antioxidant Activity Via glutathione peroxidase, thioredoxin reductase, reduces ROS Protects against cardiovascular disease, supports cell survival Thyroid Regulation Deiodinase enzymes convert T4 to T3, protects thyroid gland Reduces thyroid autoantibodies in autoimmune thyroiditis, doses 80-200 mcg/day Reproductive Health Supports sperm maturation, phospholipid hydroperoxide glutathione peroxidase Improves sperm motility, doses 100-300 mcg/day, results inconsistent Immune Support Enhances host defense, reduces oxidative stress in infections Increased requirements during viral infections, e.g., HIV, hepatitis Chemopreventive Potential DNA repair, apoptosis, immune modulation, pro-oxidant at high doses Increased requirements during viral infections, e.g., HIV, hepatitis Chemopreventive Potential DNA repair, apoptosis, immune modulation, pro-oxidant at high doses Mixed trial results, e.g., SELECT trial showed no prostate cancer risk reduction Bimodal Action (Dose-Dependent) Antioxidant at low doses, pro-oxidant at high doses, induces cell death Toxicity at >400 μg/day, potential cancer therapy at supra-nutritional levels Compound-Specific (e.g., Ebselen) Catalyzes hydrogen peroxide destruction, anti-oxidative stress Experimental, not widely used clinically Compound-Specific (Selenium Sulfide) Anti-fungal, kills Malassezia, treats dandruff, Tinea versicolor Used in shampoos, dermatological applications - Vinpocetine
- PLACEHOLDER
- Idebenone
- PLACEHOLDER
- DMAE
- Animal tests show possible benefit for improving spatial memory and working memory.
- Cordyceps Militaris
- PLACEHOLDER
- Hemp
- Hemp, from the Cannabis sativa plant, is known for its low THC content and high levels of other compounds like CBD, which contribute to its pharmacological actions.
- These effects are primarily therapeutic and are being studied for conditions like epilepsy, anxiety, and inflammation.
- Hemp's key actions include reducing inflammation, helping control seizures, and easing anxiety, thanks to CBD and other cannabinoids. It also shows promise in protecting brain cells, fighting oxidative stress, and relieving pain, though more research is needed to confirm these benefits.
- Beyond CBD, hemp contains over 545 compounds, including terpenes and flavonoids.
- Hemp, derived from the Cannabis sativa plant, is distinguished by its low tetrahydrocannabinol (THC) content, typically below 0.3%.
- Its pharmacological actions are primarily attributed to a rich profile of bioactive compounds, including cannabinoids (such as cannabidiol [CBD], cannabigerol [CBG], and cannabidiolic acid [CBDA]), terpenes, flavonoids, and other secondary metabolites.
- Compound
- Pharmacological Action
- Mechanism/System
- Cannabidiol (CBD)
- Antiepileptic, anxiolytic, antipsychotic, anti-inflammatory, reduces trauma-induced anxiety
- Endocannabinoid system, serotonin system (5-HT1A), TRP channels, GABA-A receptors
- Cannabidiolic Acid
- Anticonvulsant, anti-inflammatory, inhibits COX-2, inhibits cancer cell migration
- Cyclooxygenase-2 inhibition, TRP channels
- Cannabigerol
- Anti-inflammatory, beneficial for inflammatory bowel disease
- TRPA1 agonist, cannabinoid receptors
- Terpenes (e.g., Beta-caryophyllene)
- Anti-inflammatory, dietary cannabinoid
- CB2 receptor activation
- Flavonoids (e.g., Cannflavin A)
- Antioxidant, neuroprotective, inhibits prostaglandin production
- Non-specific interactions, antioxidant activity
Anti-inflammatory Action
- CBD, CBDA, CBG, and terpenes like beta-caryophyllene contribute to anti-inflammatory effects by inhibiting COX-2 and activating CB2 receptors, which are part of the immune response regulation.
Antiepileptic Action
- CBD is particularly noted for its antiepileptic properties, with FDA approval for treating certain epilepsy types, such as Dravet syndrome. This effect is mediated through interactions with GABA-A receptors and TRP channels.
Anxiolytic Action
- CBD's interaction with the serotonin 5-HT1A receptor is believed to reduce anxiety, offering potential for mental health applications.
Neuroprotective Action
- Both CBD and flavonoids exhibit neuroprotective effects, potentially beneficial in neurodegenerative diseases like Huntington's. This is linked to their antioxidant properties and interactions with the endocannabinoid system.
Antioxidant Action
- Flavonoids and other compounds in hemp, such as cannflavin A, provide antioxidant effects by neutralizing free radicals.
Analgesic Action
- CBD and other cannabinoids may relieve pain by interacting with the endocannabinoid system and pain pathways, offering potential for pain management.
Anticancer Potential
- CBDA has shown preliminary evidence of inhibiting cancer cell migration, suggesting a role in cancer research.
Modulation of the Endocannabinoid System
- Many hemp compounds interact with CB1 and CB2 receptors, influencing mood, pain perception, appetite, and immune function.
Nutritional and Additional Pharmacological Considerations
- Hemp seeds, rich in omega-3 and omega-6 fatty acids, contribute to cardiovascular health and anti-inflammatory effects, though these are more nutritional than directly pharmacological in the context of bioactive compounds.
- Essential oils from hemp also exhibit antibacterial and insecticidal properties, which may have therapeutic applications in infection control, though these are less directly relevant to human pharmacology.
- Rhodiola rosea
- Acts as a monoamine oxidase (MAO) inhibitor, particularly MAO-A.
- Interacts with the HPA axis, reducing cortisol levels under stressful conditions.
- Exhibits antioxidant properties through compounds like salidroside, p-tyrosol, and rosavins, which neutralize free radicals, reduce reactive oxygen species (ROS), and up-regulate enzymes like glutathione peroxidase (GPx) and thioredoxin (Trx).
- Cytotoxic on tumor cells, induces apoptosis, and inhibits angiogenesis, with salidroside showing growth inhibition at 1–32 µg/ml and effects on breast cancer at 5–80 µm.
- Inhibits influenza (H1N1, H9N2, EC50 30.2 µM, 18.5 µM) and coxsackievirus B3, protecting myocardial cells, with compounds like kaempferol and salidroside playing roles, as per the same source.
- Reduces blood glucose, increases GLUT4, and enhances antioxidant levels, with Rhodiola-water extract up-regulating GPx, catalase, and SOD, detailed in the aforementioned study.
- Protects against homocysteine-induced endothelial dysfunction and neuroinflammation, with salidroside inhibiting NO production and modulating microglia.
- Reduces inflammation and extends lifespan by 10–20% in C. elegans at 10–25 µg/ml, depending on diet, with salidroside and rosavins inducing DAF-16 translocation.
Table of Pharmacological Actions and Mechanisms
- Action
- Mechanism
- Clinical Evidence
- Key Compounds
- MAO Inhibition
- Inhibits MAO-A, increases serotonin, dopamine, norepinephrine
- Significant in depression, 170 mg/day SHR-5, 6 weeks
- Salidroside, Rosavins
- HPA Axis Modulation
- Reduces cortisol, enhances stress resilience
- Anti-fatigue, burnout reduction
- Salidroside
- Antioxidant Activity
- Neutralizes ROS, up-regulates GPx, Trx
- Protects against oxidative stress
- Anticancer Activity
- Induces apoptosis, inhibits angiogenesis
- Cytotoxic at 1–32 µg/ml
- Polyphenols, Salidroside
- Antiviral Activity
- Inhibits influenza, protects myocardial cells
- EC50 30.2 µM for H1N1
- Kaempferol, Salidroside
- Black Pepper
Nutrition
- One tablespoon (6 grams) of ground black pepper contains moderate amounts of vitamin K (13% of the daily value or DV), iron (10% DV), and manganese (18% DV), with trace amounts of other essential nutrients, protein, and dietary fibre.
Antioxidant and Anti-inflammatory Effects
- Studies indicate black pepper has strong antioxidant properties, helping to neutralize harmful free radicals that can damage cells.
- This can potentially reduce the risk of chronic diseases. It also shows anti-inflammatory effects, which might help with conditions like arthritis, by inhibiting pro-inflammatory pathways.
Digestive and Antimicrobial Support
- Black pepper is traditionally used to aid digestion, stimulating gastric acid and possibly easing issues like indigestion or constipation. It also has antimicrobial properties, effective against bacteria and fungi, which could be useful for treating infections.
- Category
- Action
- Details and Mechanisms
- Antioxidant
- Free-radical scavenging
- Protects against oxidative stress by neutralizing free radicals, potentially preventing chronic diseases.
- Anti-inflammatory
- Reduces inflammation
- Inhibits pro-inflammatory cytokines (e.g., NF-κB, TNF-α) and pathways, useful for conditions like arthritis.
- Antimicrobial
- Antibacterial, antifungal
- Active against strains like Staphylococcus aureus, Escherichia coli, and Aspergillus niger, aiding infection control.
- Gastro-protective
- Aids digestion, enhances nutrient absorption
- Stimulates gastric acid secretion, increases protease and lipase activities, and enhances bioavailability via piperine.
- Analgesic
- Pain relief
- May block pain receptors or modulate pain pathways, supported by traditional uses for toothache and muscle pain.
- Respiratory Benefits
- Treats cough, cold, dyspnea
- Traditionally used for respiratory issues, likely due to antimicrobial and anti-inflammatory effects.
- Potential Anticancer
- Anti-tumor effects
- Induces apoptosis in cancer cells, inhibits tumor growth (e.g., prostate, lung), but requires further human trials.
- Bioavailability Enhancement
- Increases absorption of other compounds
- Piperine inhibits P-glycoprotein and cytochrome P450 enzymes, enhancing the absorption of drugs and nutrients.
- Shiitake
- Immune System Enhancement: Lentinan, a β-glucan, is known to stimulate the immune system, potentially aiding in slowing tumor growth and enhancing resistance to infections. Studies indicate it increases immune cell proliferation and activation, such as γδ-T cells and natural killer T (NK-T) cells, and boosts secretory immunoglobulin A (sIgA) in saliva, as seen in a 2015 study involving daily consumption (source).
- Antiviral and Antibacterial Effects: Lentinan has shown antiviral effects against poliovirus type 1 and bovine herpes virus type 1, and antibacterial effects by increasing T-helper (Th1) cell immunity and activating macrophage-mediated responses, according to research from Memorial Sloan Kettering Cancer Center.
- Antifungal Properties: Shiitake extracts have demonstrated antifungal activity, inhibiting the growth of certain fungal pathogens.
- Cancer-Related Effects: Lentinan does not directly kill cancer cells but enhances immune responses that may slow tumor growth. It has been studied for its potential to inhibit leukemic cell proliferation, suppress HIV-1 reverse transcriptase activity, and induce apoptosis in human hepatocellular carcinoma (HepG2) cells via caspase-3 and -8 pathways. A clinical trial showed oral lentinan formulations extending survival in patients with stomach, colorectal, pancreatic, and liver cancers, though a Shiitake extract alone was ineffective for prostate cancer treatment.
- Immune Modulation: Shiitake alters immune function by increasing levels of cytokines like IL-1alpha, IL-4, IL-10, and TNF-α, while decreasing MIP-1alpha/CCL3 levels, suggesting a less inflammatory state, as noted in immune studies.
- Antihypercholemic Effects: Eritadenine, a compound in Shiitake, regulates lipid metabolism by inhibiting S-adenosyl homocysteine hydrolase and upregulating CYP7A1 mRNA, potentially lowering blood cholesterol. Studies in rats fed Shiitake showed reduced plasma cholesterol levels, attributed to both eritadenine and dietary fiber.
- Anti-Obesity Potential: High doses of Shiitake in rat studies prevented obesity by increasing plasma triacylglycerol accumulation in the liver, suggesting a role in fat metabolism regulation.
- Other Effects: Shiitake inhibits lung cancer cells via the Latcripin-13 domain, suppresses cytochrome P450 1A enzymes, and increases serum IL-2 levels and TNF-α production, indicating broad pharmacological activity.
- Safe Dose Range
- Food Consumption: Shiitake mushrooms are generally considered safe when cooked and consumed in typical dietary amounts. Studies and dietary guidelines suggest a range of 50-200 grams per day for healthy adults, based on nutritional intake. For instance, a cup of cooked Shiitake (approximately 145 grams) provides significant nutrients like copper and selenium, and sources like Verywellfit suggest up to 2 cups (290 grams) for balanced diets, though this may be high for daily consumption. FreshCap Mushrooms notes three to eight mushrooms per day, which, at an average weight of 15-20 grams each, translates to 45-160 grams, aligning with this range (source).
- Medicinal Use: For medicinal purposes, such as extracts or dried forms, the safe dosage is less defined. A specific extract, AHCC (Active Hexose Correlated Compound), derived from Shiitake, is considered possibly safe at 4.5-6 grams daily for up to 6 months or 3 grams daily for up to 9 years, according to WebMD. Studies on dried Shiitake used doses of 5-10 grams daily, equivalent to about 50-100 grams fresh, showing immune benefits. However, using Shiitake in larger medicinal amounts or raw can be unsafe, potentially causing stomach discomfort, blood abnormalities, and skin reactions like shiitake dermatitis.
- Considerations: The literature emphasizes consulting healthcare professionals for medicinal use, especially for those with autoimmune diseases, as Shiitake may increase immune activity, potentially worsening conditions like multiple sclerosis or lupus. Pregnant or breastfeeding individuals should avoid medicinal amounts due to insufficient safety data.
- Given the variability, a safe dose range for food is likely 50-200 grams daily of cooked Shiitake, while medicinal doses should be guided by product labels or professional advice, typically 5-10 grams of dried extract daily based on studies.
- Safe Dose Range
- General Bioavailability: Research indicates that Shiitake’s active compounds, especially polysaccharides, have low oral bioavailability. Lentinan, a key β-glucan, is noted for poor systemic absorption due to its high molecular weight (400-800 kDa) and is often administered intraperitoneally in studies for better efficacy, as mentioned in Drugs.com, due to rapid metabolism and low oral bioavailability. This suggests that oral ingestion may not result in significant blood levels, with effects likely mediated through gut interactions.
- Gut Microbiome Interaction: Edible mushroom polysaccharides (EMPs) are resistant to human digestive enzymes and serve as energy sources for gut microbiota, promoting beneficial bacteria growth, as per a PMC review. This implies that their bioactivity is more local, affecting gut immunity and microbiome composition rather than systemic circulation.
- Effect of Food (Empty vs. Full Stomach): There is no specific data on whether taking Shiitake on an empty stomach versus with food significantly alters bioavailability. Given that polysaccharides are not readily absorbed and act primarily in the gut, it seems likely that the presence of food would not substantially change absorption, as their effects are mediated through fermentation and immune modulation rather than systemic uptake.
- Commercial Claims: Some commercial products, like Hifas da Terra, claim enhanced bioavailability through extraction methods, but these are not backed by peer-reviewed studies for general Shiitake consumption. For instance, a French Mush X post mentions 92% bioavailability for their extracts, but this is a marketing claim without scientific validation.
- The safe dose range was inferred from both culinary consumption patterns (50-200 grams daily) and medicinal studies (5-10 grams dried).
Aspect Details Pharmacology Actions Immune enhancement, antiviral, antibacterial, anticancer, cholesterol-lowering, anti-obesity effects. Safe Dose Range 50-200 grams daily as food; 5-10 grams dried for medicinal use, consult professional. Oral Bioavailability Low for active compounds like lentinan; no clear difference with food intake. - Paracetamol
- Inhibition of COX (cyclooxygenase).
- Actions of its metabolite N-arachidonoylphenolamine (AM404).
- St. John's Wort (Mildac)
- MAOI (target mainly (at least) MAOAs) through some contained beta-carboline harmala alkaloids.
- Phloroglucinols (2–5%)
- Adhyperforin (0.2–1.9%)
- Hyperforin (2–4.5%)
- Naphthodianthrones (0.03-3%)
- Hypericin (0.003–0.3%)
- Pseudohypericin (0.2–0.23%)
- Flavonoids (2–12%)
- Amentoflavone (0.01–0.05%)
- Apigenin (0.1–0.5%)
- Catechin (2–4%)
- Epigallocatechin
- Hyperoside (0.5–2%)
- Kaempferol
- Luteolin
- Quercetin (2–4%)
- Rutin (0.3–1.6%)
- Phenolic acids (~0.1%)
- Caffeic acid (0.1%)
- Chlorogenic acid (<0.1%)
- It induces the cytochrome P450 system, particularly the CYP3A4 enzyme, and P-glycoprotein, which are critical for metabolizing and transporting various drugs. This induction can lead to increased metabolism of co-administered medications, potentially reducing their efficacy. For instance, a 2009 PMC article by Izzo highlights that St. John's wort induces CYP3A4, CYP2E1, and CYP2C19, with no effect on CYP1A2, CYP2D6, or CYP2C9, and notes that the primary site is intestinal CYP3A4, with effects returning to baseline after about a week (Herb–Drug Interactions with St John’s Wort (Hypericum perforatum): an Update on Clinical Observations).
- This induction is particularly relevant for drugs like digoxin, where a 33.3% decrease in trough concentration and 25% reduction in area under the curve (AUC) have been observed after 10 days of St. John's wort use. Such interactions are crucial for patients, as they can lead to reduced effectiveness of medications like cyclosporine, ethinylestradiol, and others, especially with low hyperforin extracts showing weaker effects.
Enzyme/Transporter Effect Examples of Affected Drugs Notes CYP3A4 Induced, increases metabolism Midazolam, cyclosporine Primary site is intestinal, half-life 46.2 h P-glycoprotein Induced, affects transport Digoxin, fexofenadine Effect seen after ≥10 days, no effect 1–3 days Hyperforin Role Potent inducer, determines interaction magnitude Alprazolam, tolbutamide Low hyperforin (<0.5%) shows weak effect - Specific interactions include:
- Cyclosporine, used in organ transplants, may have decreased effectiveness, risking rejection.
- Indinavir, an HIV protease inhibitor, may have reduced antiviral activity.
- Oral contraceptives may fail, increasing the risk of unintended pregnancy.
- Coumadin (warfarin) and digoxin levels may drop, affecting anticoagulation and heart function.
- Benzodiazepines, used for anxiety, may have diminished sedative effects.
- Passiflora
- MAOI (target mainly (at least) MAOAs) through some contained beta-carboline harmala alkaloids.
- Contain:
- Flavonoids: apigenin, luteolin, vitexin, isovitexin, orientin and isoorientin.
- Alkaloids: harman, harmin, and harmaline.
- GABA.
- More detailed names:
- A detailed breakdown from one study shows varying flavonoid content by extraction method, as seen in the following table:
Extract Total Flavonoid Content (% w/w of freeze-dried extract) Relative Content of Individual Flavonoids (% of total flavonoid) PAS 1 3.0% - Isoorientin-2″-O-β-glucopyranoside: 1.8%
- Vicenin-2: 3.6%
- Isoschaftoside: 14.5%
- Schaftoside: 19.1%
- Isoorientin: 13.2%
- Isovitexin-2″-O-β-glucopyranoside: 20.1%
- Isovitexin: 18.9%
PAS 4 30.6% - Isoorientin-2″-O-β-glucopyranoside: 0.5%
- Vicenin-2: 2.8%
- Isoschaftoside: 13.3%
- Schaftoside: 18.3%
- Isoorientin: 7.6%
- Isovitexin-2″-O-β-glucopyranoside: 24.2%
- Isovitexin: 14.5%
PAS 5 2.8% - Isoorientin-2″-O-β-glucopyranoside: 1.6%
- Vicenin-2: 3.9%
- Isoschaftoside: 15.4%
- Schaftoside: 19.7%
- Isoorientin: 16.1%
- Isovitexin-2″-O-β-glucopyranoside: 15.9%
- Isovitexin: 20.0%
PAS 7 46.4% - Isoorientin-2″-O-β-glucopyranoside: 0.9%
- Vicenin-2: 5.3%
- Isoschaftoside: 20.7%
- Schaftoside: 13.9%
- Isoorientin: 10.3%
- Isovitexin-2″-O-β-glucopyranoside: 17.4%
- Isovitexin: 19.3%
PAS 8 20.3% - Isoorientin-2″-O-β-glucopyranoside: 1.1%
- Vicenin-2: 7.1%
- Isoschaftoside: 23.4%
- Schaftoside: 14.9%
- Isoorientin: 8.0%
- Isovitexin-2″-O-β-glucopyranoside: 17.6%
- Isovitexin: 12.2%
- Studies like Passiflora incarnata L. (Passionflower) extracts elicit GABA currents in hippocampal neurons in vitro, and show anxiogenic and anticonvulsant effects in vivo show GABA content varying by extraction method, with levels up to 3.8% w/w in some extracts, as seen in the table below:
- Extract
- GABA Content (% w/w of the extract)
- PAS 1
- 3.8%
- PAS 4
- 2.0%
- PAS 5
- 2.1%
- PAS 7
- 2.2%
- PAS 8
- 2.9%
Flavonoids
- Flavonoids such as vitexine, isovitexine, chrysin, apigenin, luteolin, quercetin, and kaempferol are found in Passiflora. These compounds are known for their sedative, anxiolytic (anxiety-reducing), anti-inflammatory, antioxidant, antiallergic, antitumor, antiviral, and neuroprotective properties. They may help calm the nervous system and protect against oxidative stress.
Alkaloids
- Alkaloids, including harman, harmine, harmidine, and harmol, are significant for their MAO-A inhibiting action, which can increase neurotransmitter levels like serotonin, potentially acting as antidepressants and mood elevators. They also show anti-inflammatory effects and may suppress tumor growth.
Glycosides
- Cyanogenic glycosides are present and are potentially toxic, though their specific beneficial actions are less documented.
Phenolic compounds
- Including stilbenes like scirpusin B and piceatannol, these have antioxidant effects, can inhibit α-glucosidase, and may improve insulin sensitivity, supporting metabolic health.
Triterpenoid saponins
- Such as cyclopacifloside XII and XIII, these are linked to sedative and antidepressant effects.
Other compounds
- 2S albumins have antifungal properties, and benzoflavone may prevent cannabinoid dependence and treat nicotine addiction, offering unexpected benefits for addiction management.
- Passiflora may enhance the effects of sedatives, including anticonvulsants, barbiturates, and benzodiazepines, which could lead to increased drowsiness or other sedative effects.
- CBD
- Low affinity for, and acts as a negative allosteric modulator of the CB1 cannabinoid receptor.
- May be an antagonist of GPR55.
- May interact with various neurotransmitters, such as serotonin, dopamine, and GABA.
- In humans, oral bioavailability is
- Approximately 6% in fasting state
- Approximately 36.5-57.3% in fed-state
- Aripiprazol
- Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All data are for human cloned proteins, except 5-HT3 (rat), D4 (human/rat), H3 (guinea pig), and NMDA/PCP (rat). Percentages is for Intrinsic Activity.
- 5-HT1E
- 3000 - >10000 Ki (nM)
- ?
- 5-HT2A
- 6.7 - 39 Ki (nM)
- 12.7%
- Very Weak Partial Agonist or Antagonist
- 5-HT2B
- 0.25 - 0.47 Ki (nM)
- Inverse Agonist
- 5-HT2C
- 11 - 197 Ki (nM)
- 82%
- Partial Agonist
- 5-HT3
- 520 - 740 Ki (nM)
- ?
- 5-HT5A
- 960 - 1520 Ki (nM)
- 87%
- Near-Full Agonist
- 5-HT6
- 475 - 665 Ki (nM)
- Antagonist
- 5-HT7
- 6.6 - 14 Ki (nM)
- 58%
- Partial Agonist
- α1A
- 26 Ki (nM)
- Antagonist
- α1B
- 35 Ki (nM)
- Antagonist
- α2A
- 74.3 Ki (nM)
- Antagonist
- α2B
- 102 Ki (nM)
- ?
- α2C
- 38 Ki (nM)
- Antagonist
- β1
- 141 Ki (nM)
- Antagonist
- β2
- 163 Ki (nM)
- Antagonist
- D1
- 1290 - 2630 Ki (nM)
- Partial Agonist
- D2S
- 2.2 - 4.4 Ki (nM)
- ~60%
- Partial Agonist
- D2L
- 0.65 - 0.83 Ki (nM)
- ~50%
- Partial Agonist
- D3
- 4.3 - 15.1 Ki (nM)
- ~30%
- Partial Agonist
- D4
- 417 - 603 Ki (nM)
- ~30%
- Partial Agonist
- D5
- 1240 - 3940 Ki (nM)
- Antagonist
- H1
- 22.5 - 27.7 Ki (nM)
- Neutral Antagonist
- H2
- >10000 Ki (nM)
- ?
- H3
- 60 - 388 Ki (nM)
- ?
- H4
- >10000 Ki (nM)
- ?
- M1
- 6780 Ki (nM)
- ?
- M2
- 3510 Ki (nM)
- ?
- M3
- 4680 Ki (nM)
- ?
- M4
- 1520 Ki (nM)
- ?
- M5
- 2330 Ki (nM)
- ?
- GABAA-rho (GABAC)
- ?
- Orthostatic Negative Allosteric Modulator
- NMDA (PCP1)
- 1824 Ki (nM)
- Uncompetitive Channel Blocker, Antagonist
- NMDA (PCP2)
- 1824 Ki (nM)
- Uncompetitive Agonist
SERT 900 - 1260 Ki (nM) Reuptake Inhibitor NET 1340 - 2840 Ki (nM) Reuptake Inhibitor DAT 2560 - 3880 Ki (nM) Reuptake Inhibitor 5-HT1A 1.7 - 6.4 Ki (nM) ~68% Partial Agonist 5-HT1B 570 - 1090 Ki (nM) ? 5-HT1D 57 - 79 Ki (nM) ? PLACEHOLDER PLACEHOLDER PLACEHOLDER PLACEHOLDER PLACEHOLDER PLACEHOLDER
TODO END
- Venlafaxine
- Usually categorized as a SNRI.
- Has also been referred to as a SNDRI.
- SERT
- 82 Ki [nM]
- 27 IC50 [nM]
- NET
- 2480 Ki [nM]
- 535 IC50 [nM]
- DAT
- 7647 Ki [nM]
- ? IC50 [nM]
- 5-HT2A
- 2230 Ki [nM]
- Human
- 5-HT2C
- 2004 Ki [nM]
- Human
- 5-HT6
- 2792 Ki [nM]
- Human
- α1A
- >1000
- Human
- GABA
- PLACEHOLDER
- 5-MeO-DALT HCI
- Serotonin Receptor Agonism (5-HT Receptors):
- Mechanism: 5-MeO-DALT acts as a partial agonist at the 5-HT2A receptor, which is primarily responsible for its psychedelic effects. It also binds to other serotonin receptors, including 5-HT1A, 5-HT1D, 5-HT1E, 5-HT2B, 5-HT2C, and 5-HT6, with Ki values (binding affinities) lower than 10 μM. The 5-HT2A receptor is critical for hallucinogenic effects, while 5-HT1A binding may modulate emotional and sensory effects.
- Effects: Produces altered perceptions, euphoria, visual hallucinations (primarily closed-eye visuals), increased sensory awareness, and emotional amplification. The head-twitch response (HTR) in rodents, a behavioral proxy for psychedelic effects, is positively correlated with 5-HT2A receptor affinity and negatively correlated with 5-HT1A affinity.
- Timeline:
- Onset: <15 minutes (oral administration).
- Peak: ~30 minutes post-administration.
- Duration: 2–4 hours (oral route, based on Shulgin’s reports).
- Notes: The psychedelic effects are described as primarily physical (e.g., tingling sensations, body high) with fewer visual distortions compared to other psychedelics like LSD or psilocybin.
- Monoamine Reuptake Inhibition:
- Mechanism: 5-MeO-DALT inhibits the reuptake of dopamine (DAT) and serotonin (SERT), increasing extracellular levels of these neurotransmitters. This contributes to its euphoric and energizing effects.
- Effects: Enhanced mood, increased energy, and heightened arousal. User reports describe a “sensual” and “energized” body state.
- Physiological Effects:
- Mechanism: Likely mediated by a combination of serotonin receptor activation and monoamine reuptake inhibition, with possible contributions from adrenergic and histamine receptor binding.
- Effects:
- Body High: Described as a sharp, all-encompassing tingling sensation that rises during the onset and peaks at ~30 minutes.
- Cardiovascular Effects: Potential for tachycardia and increased blood pressure, as reported with other synthetic tryptamines.
- Other Effects: Agitation, hyperthermia, and loss of limb control (making walking difficult) have been reported, particularly at higher doses.
- Adverse Effects: Acute delirium and rhabdomyolysis have been reported in rare cases, indicating potential for severe toxicity at high doses or in combination with other substances.
- Timeline: Onset within 15 minutes, peaking at 30 minutes, and resolving within 2–4 hours for most effects. Severe adverse effects (e.g., delirium) may persist longer in overdose scenarios.
- Pharmacokinetics
- Half-Life:
- Data Availability: There is no direct data on the half-life of 5-MeO-DALT in humans. Based on its short duration of action (2–4 hours), the elimination half-life is likely on the order of 1–2 hours, similar to other short-acting tryptamines like 5-MeO-DMT (half-life ~1 hour) (source).
- Metabolism: 5-MeO-DALT is metabolized by hepatic cytochrome P450 enzymes (CYP1A2, CYP2C19, CYP2D6, CYP3A4) through 6-hydroxylation, O-demethylation, or N-dealkylation, with metabolites conjugated to glucuronide or sulfate. (source 1 and 2)
- Estimation: Assuming similar pharmacokinetics to 5-MeO-DMT, the half-life is likely short, with rapid clearance contributing to the brief duration of effects.
- Bioavailability:
- Oral Bioavailability: Not explicitly quantified in the literature, but oral administration is effective, suggesting moderate bioavailability. Anecdotal reports indicate that oral doses of 12–25 mg produce effects, while higher oral doses (30–35 mg) of 5-MeO-DMT have low potency due to first-pass metabolism by MAO-A, suggesting 5-MeO-DALT may have better oral bioavailability due to less MAO-A susceptibility. A rough estimate based on related tryptamines (e.g., mitragynine ~21%) suggests oral bioavailability of 20–40%. (source 1 and 2)
- Other Routes:
- Insufflation (Snorting): Likely higher bioavailability (50–70% estimated, based on 5-MeO-DMT’s intranasal bioavailability), with faster onset (~5–10 minutes). (source)
- Intravenous: Near 100% bioavailability, but no specific data exists for 5-MeO-DALT.
- Rectal: Potentially higher than oral (40–60% estimated), with faster onset than oral but slower than insufflation.
- Vaporization/Inhalation: High bioavailability (70–90% estimated), with very rapid onset (within minutes). (source)
- Dosage Information
- Safe Dosage Range:
- Minimum Effective Dose: 12 mg (oral), based on Shulgin’s reports and anecdotal data. Lower doses (e.g., 4–10 mg) may produce mild effects but are often subthreshold. (source)
- Typical Recreational Dose: 12–25 mg (oral), producing moderate psychedelic effects with manageable intensity. (source)
- Upper Safe Limit: Up to 25 mg (oral) is generally considered within the safe range for most users, though individual sensitivity varies. Doses up to 50 mg have been reported anecdotally but are associated with increased risk of adverse effects (e.g., agitation, loss of motor control). (source)
- Maximum Dose Without High Risks:
- Threshold for Increased Risk: Doses above 25 mg (oral) increase the risk of adverse effects such as agitation, tachycardia, hyperthermia, and loss of limb control. Doses approaching 50 mg are considered high-risk due to potential for delirium and rhabdomyolysis. (source 1 and source 2)
- Context: A reported death involved a user under the influence of 5-MeO-DALT who was hit by a vehicle, suggesting impaired judgment and motor control at higher doses. (source 1 and source 2)
- LD50 (Lethal Dose 50%):
- Data Availability: No specific LD50 values are available for 5-MeO-DALT in humans or animals. For comparison, 5-MeO-DMT has an LD50 in mice ranging from 48–278 mg/kg depending on the route of administration. Assuming similar toxicity, the human LD50 for 5-MeO-DALT (for a 70 kg individual) could be estimated at 3,360–19,460 mg (3.36–19.46 g), but this is highly speculative and not directly applicable. (source)
- Dangerous Dose Estimation: Doses above 50 mg (oral) are likely dangerous due to increased risk of severe agitation, hyperthermia, delirium, and rhabdomyolysis. A fatal outcome is more likely from behavioral risks (e.g., accidents due to impaired judgment) than direct pharmacological toxicity, as seen in the reported death case. (source 1 and source 2)
- When It Becomes Too Dangerous:
- Threshold: Doses ≥50 mg (oral) or equivalent via other routes (e.g., 20–30 mg insufflated) are considered dangerous due to heightened risk of severe physiological and psychological effects. Combining 5-MeO-DALT with MAO-A inhibitors (e.g., harmaline) significantly increases the risk of serotonin toxicity, even at lower doses, due to potentiation of serotonergic effects. (source 1 and source 2)
- Signs of Danger: Agitation, hyperthermia, tachycardia, delirium, and loss of motor control indicate overdose. Immediate medical attention is required if these occur. (source)
- Additional Notes
- Limited Data: The pharmacological profile of 5-MeO-DALT is poorly characterized due to limited human studies and sparse toxicology data. Most information comes from anecdotal reports and rodent studies, which may not fully translate to humans. (source 1 and source 2)
- Harm Reduction: Due to the lack of comprehensive safety data, users should start with low doses (e.g., 10–12 mg oral), avoid combinations with other psychoactive substances (especially MAOIs), and ensure a safe environment. Standard drug tests (e.g., urine EIA) do not detect 5-MeO-DALT, complicating clinical management of toxicity. (source)
- Summary Table
Parameter Value Minimum Effective Dose 12 mg (oral) Safe Dosage Range 12–25 mg (oral) Maximum Safe Dose ~25 mg (oral) Dangerous Dose ≥50 mg (oral) or equivalent (e.g., 20–30 mg insufflated) LD50 Unknown; estimated 3.36–19.46 g (speculative, based on 5-MeO-DMT) Half-Life ~1–2 hours (estimated) Oral Bioavailability ~20–40% (estimated) Insufflation Bioavailability ~50–70% (estimated) Onset (Oral) <15 minutes Peak (Oral) ~30 minutes Duration (Oral) 2–4 hours - AMT HCI
- Pharmacological Actions
- AMT exhibits a range of pharmacological effects, primarily through its interaction with monoamine systems. It acts as a releasing agent for serotonin, norepinephrine, and dopamine, with specific EC50 values indicating potency: serotonin release ranges from 22 to 68 nM, dopamine from 79 to 112 nM, and norepinephrine from 79 to 180 nM. Additionally, AMT is a non-selective serotonin receptor agonist, with notable activity at the 5-HT2A receptor, showing an EC50 of 23 nM and an Emax of 103%, suggesting strong agonist properties. It also functions as a reversible inhibitor of monoamine oxidase A (MAO-A), with an IC50 of 380 nM, and its potency in rats is comparable to harmaline at 7 μM/kg (1.5 mg/kg harmaline, 1.2 mg/kg AMT). These actions contribute to its stimulant, entactogenic, and psychedelic effects, mediated by increased neurotransmitter availability and receptor activation.
- Metabolites identified in male Wistar rats include 2-Oxo-αMT, 6-hydroxy-αMT, 7-hydroxy-αMT, and 1′-hydroxy-αMT, indicating metabolic pathways involving hydroxylation and conjugation, consistent with tryptamine metabolism.
- Pharmacokinetics
- The pharmacokinetics of AMT are not fully elucidated in the literature. The onset of action is typically 3-4 hours, with effects lasting 12-24 hours, suggesting a prolonged duration that may indicate a long half-life. However, specific half-life data is not available, though the alpha substitution is noted to make AMT a poor substrate for MAO-A, potentially prolonging its presence in the system. Bioavailability, particularly for the oral route, is not quantitatively documented, but its effectiveness when taken orally implies sufficient absorption, supported by predicted high human intestinal absorption (probability 1.0) and blood-brain barrier penetration (probability 0.9856) from ADMET models.
- Metabolic studies in human hepatocytes show slow metabolism, with a 25% decrease in signal intensity after 3 hours, which may explain the prolonged psychedelic effects. Postmortem concentrations in overdose cases range from 2.0 µg/mL to 4.7 µg/mL in blood, with higher levels in urine and bile, but these do not directly translate to pharmacokinetic parameters like half-life or bioavailability.
- Pharmacokinetics
- Dosage recommendations vary based on intended effects and user reports. For antidepressant purposes, under the brand name Indopan, doses of 5-10 mg were prescribed. Recreational use for psychedelic effects typically starts at 20-30 mg, with strong effects at 40-60 mg and heavy effects at 60-80 mg. Erowid reports include individuals taking doses as high as 400 mg, though with severe effects, and recommends starting at threshold or light levels (5-25 mg) to avoid dangerously strong reactions, especially for new users or with new batches. The minimum effective dose for psychedelic effects is around 20 mg, while doses above 60 mg are associated with increased risks, including hospitalization, based on unverifiable reports.
- Safety and Toxicity
- Safety concerns are significant, particularly at higher doses. Doses exceeding 60 mg have been linked to hospitalization, and there were 22 deaths associated with AMT in England and Wales from 2012 to 2015, though exact doses are not specified. Case reports, such as a fatality in Miami in 2003, involved a 22-year-old college student with postmortem blood concentrations of 2.0 mg/L, but ingested dose is unclear. Another case reported a plasma concentration of 440 µg/L with severe serotoninergic syndrome, indicating potential toxicity at high exposures.
- Animal toxicity data from the European Chemicals Agency (ECHA) lists an oral LD50 of less than 5 mg/kg, dermal LD50 less than 50 mg/kg, and inhalation LD50 less than 0.5 mg/L/4h, classifying it as Acute Tox. 2, indicating high acute toxicity. However, this animal data seems inconsistent with human use, where doses up to 80 mg (approximately 1.14 mg/kg for a 70 kg person) are reported without immediate fatality, though with significant adverse effects. This discrepancy highlights the need for caution, as individual sensitivity varies widely, and AMT's MAO-A inhibition may increase risks of interactions with tyramine-rich foods or other drugs, potentially leading to hypertensive crises or serotonin syndrome.
- The maximum safe dose without high risks is difficult to determine, but based on reports, it seems likely that doses above 60-80 mg are increasingly dangerous, with potential for severe adverse effects like anxiety, tachycardia, vomiting, and in extreme cases, fatality. The evidence leans toward starting with low doses and having a trusted companion present, given the variability in response.
- Time Influence and Risk Assessment
- The influence of AMT's pharmacological actions over time is reflected in its long duration (12-24 hours), which may be due to slow metabolism and prolonged neurotransmitter effects. The onset, taking 3-4 hours, can lead to redosing errors, increasing overdose risk, as effects may take time to fully develop. Risks increase significantly at higher doses, with reports of severe reactions at 40 mg and above, and fatalities associated with use, particularly in polydrug contexts.
- Conclusion
- AMT's pharmacological profile includes monoamine release, serotonin receptor agonism, and MAO-A inhibition, with effects lasting 12-24 hours and significant safety concerns at doses above 60 mg. While exact half-life and bioavailability data are lacking, its oral effectiveness is clear. Dosage should start low, with careful monitoring for adverse effects, given the potential for severe toxicity and fatalities at higher exposures. Further research is needed to clarify pharmacokinetics and establish precise LD50 values in humans, given the controversy around animal data and human use patterns.
- NM-2-AI HCl
- Other name: N-methyl-2-aminoindane.
- A stimulant substance of the aminoindane class.
- Selective norepinephrine reuptake inhibitor and releasing agent, with a IC50 of 2.4 μM for norepinephrine reuptake inhibition.
- TAAR1 receptor agonist, with an EC50 of 3.3 μM.
- Alpha-2A adrenergic receptor agonist, with a Ki of 0.49 μM.
- Binding affinity to 5-HT1A receptor, with a Ki of 3.6 μM.
- Binding affinity to 5-HT2A receptor, with a Ki of 5.4 μM.
- Notably, it does not significantly release serotonin or dopamine even at high concentrations (up to 100 μM), suggesting a selective profile focused on norepinephrine systems. This selectivity is derived from in vitro studies, as detailed in Wikipedia: NM-2-AI.
- User reports from platforms like Bluelight.org suggest that effects are felt within an hour of oral ingestion, with one report noting effects at 50 mg after one hour, described as mood uplift and clear-headedness. The duration isn't specified, but related compounds and user experiences imply effects may last several hours, aligning with its stimulant nature.
- The half-life, based on animal studies, is estimated at 1-2 hours. This estimation comes from a metabolism study in mice, where blood concentrations decreased from 2.7 µg/mL at 30 minutes to 0.23 µg/mL at 300 minutes, suggesting a half-life around 1.3 hours via rough calculation, consistent with a reported 1-2 hour half-life for its metabolite, 2-AI, in rat brain from a study on MDAI pharmacokinetics (source).
- Dosage recommendations are primarily derived from user reports and online sources like PsychonautWiki, with the following ranges for oral administration:
- Threshold: Listed as 5 mg, though user reports suggest 50 mg is often the effective starting dose, indicating potential variability.
- Light: 50-100 mg, where users report positive effects like mood uplift and enhanced reaction times.
- Common: 100-150 mg, noted as a typical range, but with some reports of negative effects like mood depression and irritability.
- Strong: 150-200 mg, potentially increasing intensity but also risks.
- Heavy: Over 200 mg, considered high risk with limited data on safety.
- User reports from Bluelight.org provide additional context:
- At 50 mg, effects included uplifted mood, clear head, and improved gaming performance, suggesting this as a minimum effective dose for many.
- At 100-150 mg, some users reported it as a "mood killer," with depressive effects and potential anger, indicating the start of adverse effects.
- Related compound 2-AI reports mention nausea and vomiting at higher doses, which may apply to NM-2-AI at similar levels.
- The safe range and maximum dose without high risks are also unclear due to limited toxicity data. User reports suggest that doses above 100-150 mg may start to become too dangerous, with potential for adverse effects like mood changes and physical symptoms. The minimum effective dose appears to be around 50 mg based on user experiences, aligning with light dose ranges.
- 3-MMA (Metaphedrine)
- Other name: 3-Methoxy-4-methylamphetamine.
- 3-MMA is an amphetamine derivative, structurally related to methamphetamine but with a methyl group at the 3-position on the phenyl ring and an N-methyl group.
- As an amphetamine derivative, it is expected to act as a monoamine releasing agent, increasing the release of dopamine, norepinephrine, and possibly serotonin by interacting with their respective transporters (SERT, NET, DAT).
- Monoamine Release: Research on related compounds, such as 3-Methoxyamphetamine (3-MA), shows EC50 values of 58.0 nM for norepinephrine and 103 nM for dopamine in rat brain synaptosomes (source). While 3-MMA is structurally different, it likely shares similar properties, but no specific data exist.
- MAO Inhibition: User discussions on platforms like Bluelight suggest 3-MMA may act as a monoamine oxidase inhibitor (MAOI), potentially stronger than amphetamine (affinity 11 µM) but weaker than para-substituted amphetamines like pMTA or pMA (nanomolar range). For comparison, 3-MeOA (a related compound) has an affinity of 23 µM, indicating 3-MMA might be safer than 4-MeOA (pMA, sub-micromolar affinity) (source). However, these are speculations without scientific validation.
- Receptor Binding: No studies on 3-MMA's receptor binding (e.g., to 5-HT1A, 5-HT2A, or adrenergic receptors) were found. Related compounds like 3-Methylmethcathinone (3-MMC) show binding to serotonin and adrenergic receptors, but 3-MMA's profile remains unknown (source).
- There is no detailed pharmacokinetic data for 3-MMA, such as oral bioavailability, half-life, or Tmax. For comparison, related compounds like 3-MMC have an oral bioavailability of 7% and a half-life of 50 minutes (source), but these cannot be directly applied to 3-MMA due to structural differences.
- Onset and Duration: Oral administration reportedly has an onset around 90 minutes, with peak effects at 2.5 hours and a soft comedown after 4.5 hours. Higher doses (e.g., 50% filled 00 capsule) show quicker serotonin effects, with a total duration of 4.5 hours (source).
- Administration Routes: Insufflation (snorting) causes a burning sensation, with effects noted without a harsh comedown, but exact durations are unclear.
- Given the lack of studies, 3-MMA's safety profile is uncertain. User reports highlight potential risks:
- Vasoconstriction and Tachycardia: Noted at higher doses, with vein pain reported, suggesting cardiovascular effects similar to other stimulants.
- Neurotoxicity: There is concern about neurotoxicity, especially at high doses, due to MDMA-like serotonin flood stages, but no scientific evidence confirms this.
- Comparison to Related Compounds: Studies on 4-Methylmethamphetamine (4-MMA) suggest minimal dopaminergic neurotoxicity in mice compared to methamphetamine , but human data for 3-MMA are lacking.
- User reports provide approximate dosing, though without precise measurements:
- Insufflation: ~2 cm line (~0.8 inches), burning sensation, no harsh comedown.
- Oral: 00 capsule 25% filled, peak at 2.5 hours, soft comedown after 4.5 hours; higher dose (50% filled) shows quicker serotonin effects.
- Effects include clean stimulation, mild tachycardia, blurry vision (similar to high MDMA doses), weaker empathogenic effects, mood lift, and dry mouth, with increased water intake needed. The risk of redosing is noted due to delayed onset, which could exacerbate side effects.
- 3-MMA is a positional isomer of schedule I controlled substances in the US (e.g., EtAMP, dimethyl-AMP), making it "born illegal" with unambiguous legal risks (source). Its status as a designer drug underscores the need for caution, given the lack of regulation and research.
- To provide context, tables below summarize data for related compounds, though not directly applicable to 3-MMA:
Compound EC50 Norepinephrine (nM) EC50 Dopamine (nM) Notes 3-Methoxyamphetamine 58.0 103 Combined SNDRA, no serotonin EC50 reported 4-Methylmethamphetamine 22.2 44.1 Well-balanced SNDRA, minimal neurotoxicity Compound MAO Inhibition Affinity (µM) Notes Amphetamine 3-MeOA pMA (4-MeOA) 11 23 Sub-micromolar Baseline comparison (source) Less potent than amphetamine Stronger MAOI, higher risk - 4-HO-MET
- 5-HT1A
- 0.228 Ki (μM)
- 5-HT2A
- 0.057 Ki (μM)
- 5-HT2C
- 0.141 Ki (μM)
- D1
- >25 Ki (μM)
- D2
- 4 Ki (μM)
- D3
- 6.7 Ki (μM)
- α1A
- 9.7 Ki (μM)
- α2A
- 2.4 Ki (μM)
- TAAR1
- 3.1 Ki (μM)
- H1
- 0.82 Ki (μM)
- SERT
- 0.2 Ki (μM)
- DAT
- >26 Ki (μM)
- NET
- 13 Ki (μM)
- Tianeptine
- MOR full agonist.
- DOR full agonist.
- Inhibition of glutamate receptor activity (i.e., AMPA receptors and NMDA receptors).
- Release of BDNF.
- DCK (DeschloroKetamine)
- thought to act as an NMDA receptor antagonist
- 5-MeO-MiPT
- Non-Selective Serotonin Receptor Agonist.
- SNRI
- MAOI might be involved.
- Norflurazepam
- It is long-acting, prone to accumulation, and binds unselectively to the various benzodiazepine receptor subtypes.
- No metabolites were detected for norflurazepam in hepatocytes.
- Moclobemide (Moclamine)
- RIMA
- Ibuprofene
- Inhibition of the COX (cyclooxygenase) enzymes.
- Noopept
- Prodrug of cGP (cycloprolylglycine).
- cGP (cycloprolylglycine)
- Metabolite of hormone insulin-like growth factor-1 (IGF-1).
- IGF-1 (Insulin-like growth factor 1, somatomedin C)
- Excessive IGF-1 activity promotes tumorigenesis.
- Tranylcypromine
- Irreversible or "semi-irreversible" MAOI.
- PRL-8-53
- Cholinergic
- Potentiates dopamine.
- Partially inhibiting serotonin.
- PRL-8-53 reverses the catatonic and ptotic effects of reserpine.
- Oral LD50 in mice of 860 mg/kg
- Doses above 8 mg/kg have brief hypotensive effects in canines.
- High doses depress motor activity in the rat and mouse, with the ED50 for a 50% reduction in motor activity of mice at 160 mg/kg.
- PRL-8-53 displays spasmolytic effects.
- Sulforaphane
- Activates the nuclear factor erythroid 2-related factor 2 (Nrf2).
- Inhibiting NF-κB signaling pathways.
- Inhibiting MAPK signaling pathways.
- Melatonin
- Anti-inflammatory effect.
- High-affinity with MT1 and MT2 receptors.
- Preclinical investigations suggest that melatonin may augment cytokine production and promote the expansion of T cells, thereby potentially mitigating acquired immunodeficiencies.
- Inosine
- Knowledge of inosine metabolism has led to advances in immunotherapy.
- It is used in the treatment of a variety of autoimmune diseases including granulomatosis with polyangiitis because the uptake of purine by actively dividing B cells can exceed 8 times that of normal body cells, and, therefore, this set of white cells (which cannot operate purine salvage pathways) is selectively targeted by the purine deficiency resulting from inosine monophosphate dehydrogenase (IMD) inhibition.
- Inosine is also an intermediate in a chain of purine nucleotide reactions required for muscle movements.
- After ingestion, inosine is metabolized into uric acid.
- In addition, the side effect of the treatment was the development of kidney stones in four of 16 patients.
- Inosine is a natural ligand for the benzodiazepine binding site on the GABA A receptor.
- Caffeine
- Stimulant
- Adenosinergic
- Eugeroic
- Nootropic
- Anxiogenic
- Analeptic
- Competitive Nonselective PDE inhibitor
- Diuretic
- Raises Intracellular Cyclic AMP
- Activates Protein Kinase A
- Inhibits TNF-alpha Synthesis
- Inhibits Leukotriene Synthesis
- Reduces Inflammation
- Reduces Innate Immunity
- Metabolized in the liver via a single demethylation, resulting in three primary metabolites
- Paraxanthine (84%)
- Theobromine (12%)
- Theophylline (4%)
- Paraxanthine
- Psychoactive CNS stimulant
- Antagonism of Adenosine Receptors
- Paraxanthine adenosine receptor binding affinity
- 21 μM for A1
- 32 μM for A2A
- 4.5 μM for A2B
- >100 for μM for A3
- Selective Inhibitor of cGMP-preferring Phosphodiesterase (PDE9) activity
- Inhibits TNF-alpha Synthesis
- Inhibits Leukotriene Synthesis
- Reduces Inflammation
- Reduces Innate Immunity
- Theobromine
- PLACEHOLDER
- Theophylline
- PLACEHOLDER
- Lactoferrine
- Stimulation of phagocytosis.
- Targets H+-ATPase and interferes with proton translocation in the cell membrane, resulting in a lethal effect in vitro.
- Prevents the attachment of H. pylori in the stomach.
- In sufficient strength acts on a wide range of human and animal viruses based on DNA and RNA genomes, including
- herpes simplex virus 1 and 2
- cytomegalovirus
- HIV
- hepatitis C virus
- hantaviruses
- rotaviruses
- poliovirus type 1
- human respiratory syncytial virus
- murine leukemia viruses
- Mayaro virus
- Activity against COVID-19 has been speculated but not proven.
- Suppresses virus replication after the virus penetrated into the cell.
- This indirect antiviral effect is achieved by affecting natural killer cells, granulocytes and macrophages cells.
- Collagen
- PLACEHOLDER
- Green Tea
- PLACEHOLDER
- Guarana
- Chemical component, Parts per million
- Caffeine, 9 100 – 76 000
- Protein, < 98 600
- Resin, < 70,000
- Starch, 50 000 – 60 000
- Tannin, 50 000 – 120 000
- Theobromine, 200 – 400
- Theophylline, 0 – 2 500
- Dihexa
- Binds with high affinity to hepatocyte growth factor (HGF) and potentiates its activity at its receptor, c-Met.
- Homotaurine
- Homotaurine, also known as Tramiprosate, is a sulfonic acid compound found naturally in seaweed and has been extensively studied for its potential therapeutic effects, particularly in Alzheimer's disease (AD). This survey note provides a detailed examination of its pharmacological actions, pharmacokinetics, dosage regimens, and safety profile, drawing from a wide range of scientific literature and clinical trial data available as of May 29, 2025.
- Pharmacological Actions
- Tramiprosate exhibits a multifaceted pharmacological profile, primarily targeting mechanisms implicated in AD pathology. The key actions include:
- Inhibition of Amyloid-β (Aβ) Aggregation: Tramiprosate binds to soluble Aβ, particularly at residues Lys16, Lys28, and Asp23, stabilizing monomers and reducing the formation of toxic oligomers and fibrillar plaques. This action is crucial as Aβ aggregation is a hallmark of AD, contributing to neuronal damage. Preclinical studies in transgenic mice have shown reduced plaque burden and decreased CSF Aβ levels, supporting its potential as a disease-modifying agent. (source)
- GABAergic Activity: Structurally similar to γ-amino butyric acid (GABA), Tramiprosate acts as a functional agonist at GABA-A receptors, which may contribute to its neuroprotective effects. This activity is thought to modulate neuronal excitability and provide protection against Aβ-induced neurotoxicity (source). It also reduces caspase 3/7 and 9 activities in organotypic hippocampal slice cultures, suggesting a GABA-dependent neuroprotective mechanism. (source)
- Anti-inflammatory Effects: Clinical studies, particularly in mild cognitive impairment (MCI) patients, have demonstrated reduced levels of inflammatory markers such as IL-18, indicating an anti-inflammatory role (source). This action may mitigate the inflammatory component of AD pathology.
- Neuroprotection: Beyond GABA-dependent pathways, Tramiprosate inhibits Aβ42-induced ERK1/2 activation through a GABA-independent mechanism, further enhancing its neuroprotective profile (source). This dual mechanism suggests broad protective effects against neuronal damage.
- Promotion of Tau Polymerization: Interestingly, Tramiprosate promotes the polymerization of tau into non-toxic aggregates without affecting tau-microtubule binding, potentially reducing the formation of neurofibrillary tangles, another AD hallmark. (source)
- The time course of these actions is not fully detailed in the literature, but clinical studies indicate that effects on biomarkers like CSF Aβ levels are observable after three months of treatment, suggesting a gradual onset. (source)
- Pharmacokinetics
- Pharmacokinetic data for Tramiprosate are primarily derived from studies involving its prodrug, ALZ-801, due to its improved pharmacokinetic profile. Key parameters include:
- Half-life: Studies with ALZ-801 suggest a half-life for Tramiprosate of approximately 15-18 hours. For instance, a 2025 study reported a terminal phase elimination half-life of about 14.8 hours, while a 2018 study indicated around 18 hours (Clinical Pharmacokinetics: Clinical Pharmacokinetics of Oral ALZ-801, PubMed: Clinical Pharmacokinetics and Safety of ALZ-801).
- Bioavailability: Specific oral bioavailability for Tramiprosate is not directly available, but for ALZ-801, an estimated oral bioavailability of approximately 52% was reported in a 2018 study, suggesting efficient absorption and conversion to active moieties (source). Given ALZ-801's design to improve upon Tramiprosate's pharmacokinetics, the bioavailability of Tramiprosate itself may be lower, but exact figures are lacking.
- Metabolism and Excretion: Tramiprosate is metabolized to 3-sulfopropanoic acid (3-SPA), an endogenous metabolite with anti-Aβ activity, and is primarily eliminated via renal excretion, with plasma exposures inversely correlated with estimated glomerular filtration rate (eGFR) (source).
- Dosage Regimens
- Range of Doses Tested: Doses in clinical studies ranged from 50 mg to 150 mg twice daily (BID). For example, a phase II study randomized patients to 50 mg, 100 mg, or 150 mg BID for three months, with an open-label extension at 150 mg BID for 17 months (source). Phase III trials, such as the Alphase Study, used 100 mg and 150 mg BID for 78 weeks (source).
- Minimum Effective Dose: The minimum effective dose appears to be around 100 mg BID, as this dose showed a dose-dependent reduction in CSF Aβ42 levels in phase II studies, suggesting therapeutic activity (source). Lower doses like 50 mg BID showed less pronounced effects.
- Maximum Safe Dose: The maximum tested dose in humans is 150 mg BID, which was generally well-tolerated, with adverse events primarily gastrointestinal, such as nausea and vomiting, leading to discontinuation in about 3.6% of patients (source). No amyloid-related imaging abnormalities (ARIAs) were observed, indicating a favorable safety profile at this dose.
- LD50 and Toxicity Thresholds: Specific LD50 values for Homotaurine are not publicly available in the literature reviewed. Preclinical toxicology data are sparse, with studies focusing more on efficacy and safety in animal models rather than acute toxicity. Given its use in clinical trials at doses up to 150 mg BID without serious adverse events, it is considered safe at therapeutic levels, but higher doses have not been tested in humans, making the toxicity threshold unclear (source).
- Safety Profile
- Common Adverse Effects: The most frequent adverse events are gastrointestinal, including nausea, vomiting, and weight loss, which are dose-dependent but not significantly different from placebo at 100 mg BID (source). Syncope was also reported in some cases.
- Mortality and Serious Events: In the Alphase Study, mortality rates were 4.0% for placebo, 2.8% for 100 mg BID, and 2.3% for 150 mg BID, with no significant difference, suggesting no increased risk at therapeutic doses (source).
- Subgroup Safety: APOE4 carriers, particularly homozygotes, showed a similar safety profile, with no increased incidence of vasogenic edema compared to non-carriers (source).
- Given the lack of LD50 data and the focus on chronic safety in elderly patients, the point at which Tramiprosate becomes dangerously toxic is not established, but clinical data suggest it remains safe within the tested range of 50-150 mg BID.
- Summary Table of Key Parameters
Parameter Details Half-life Approximately 15-18 hours (from ALZ-801 studies) Oral Bioavailability Estimated ~52% (from ALZ-801, exact for Tramiprosate not specified) Minimum Effective Dose Likely 100 mg BID, based on CSF Aβ42 reduction Maximum Safe Dose 150 mg BID, well-tolerated with gastrointestinal side effects LD50 Not publicly available, safety established at therapeutic doses Common Side Effects Nausea, vomiting, weight loss, dose-dependent - Phenibut
- full agonist of the GABAB receptor
- between 30- and 68-fold lower affinity for the GABAB receptor than baclofen
- (R)-Phenibut has more than 100-fold higher affinity for the GABAB receptor than does (S)-phenibut
- binds to and blocks α2δ subunit-containing VDCCs, similarly to gabapentin and pregabalin, and hence is a gabapentinoid
- reported to be well-absorbed
- It distributes widely throughout the body and across the blood–brain barrier.
- Phenibut can be used recreationally due to its ability to produce euphoria, anxiolysis, and increased sociability
- Recreational users usually take the drug orally
- Lemon Balm Water
- Inhibitory effect on acetylcholinesterase
- Raises levels of GABA by inhibiting the enzyme GABA transaminase
- Tilorone
- Interferon inducer
- Alanine
- Blood Sugar Regulation
- Essential amino acids for protein synthesis and energy
- Supports the immune system, though the exact mechanisms are not fully clear.
- Agonist at the NMDA-glycine site.
- Is a glucogenic amino acid, meaning it can be converted into glucose in the liver through gluconeogenesis.
- L-alanine is released from muscle tissues during protein breakdown and transported to the liver, where it undergoes transamination via alanine transaminase (ALT), producing pyruvate. Pyruvate is then converted into glucose, contributing to blood glucose homeostasis and preventing hypoglycemia, especially in glucose-dependent tissues like the brain and red blood cells.
- Care must be taken, as it can be harmful if blood sugar is already normal or high, necessitating careful monitoring.
- It serves as an energy source for muscles and the central nervous system.
- It is often used in combination with other amino acids, such as in alanine-glutamine dipeptides, to enhance solubility and stability in nutritional solutions.
- An unexpected and less commonly discussed aspect is the pharmacological action of D-alanine, the enantiomer of L-alanine. D-alanine is a selective and potent agonist at the NMDA-glycine site, a receptor involved in excitatory neurotransmission. Research has shown it improves cognition and negative symptoms in schizophrenia, particularly when used alongside antipsychotics, with a small randomized controlled trial (n=22) demonstrating benefits without significant side effects (Alanine).
- Alanine also has structural roles in proteins, with 31 residues in the I2S structure, and mutations at alanine sites can lead to disease phenotypes. For example, mutations like p.Ala68Glu, p.Ala85Ser, and p.Ala205Thr are associated with severe or attenuated phenotypes, depending on their location (mid-helix or buried positions) (Studie).
Action Mechanism Clinical Relevance Gluconeogenesis Support Converted to glucose via ALT in liver, part of glucose-alanine cycle Manages hypoglycemia, supports fasting/exercise states Nutritional Support Provides amino acids for protein synthesis, energy source Used in total parenteral nutrition, critical illness care Immune System Support Contributes to immune function, often in dipeptides like alanine-glutamine Potential in reducing infections, improving patient outcomes NMDA Agonist (D-alanine) Agonist at NMDA-glycine site, improves cognition in schizophrenia Investigational for neurological disorders, not for depression Structural Role and Disease Mutations affect protein stability, linked to disease phenotypes Informative for genetic and therapeutic research - Lysine
- Antiviral activity, anxiety reduction, calcium absorption, cardiovascular health, glucose metabolism, muscle growth, and wound healing.
- Used to prevent and treat cold sores caused by the herpes simplex virus. It works by competing with arginine, an amino acid the virus needs to replicate, potentially reducing outbreak frequency and severity.
- It may affect serotonin and GABA receptors, reducing cortisol levels and improving stress-induced anxiety, particularly in populations with low dietary lysine intake.
- Lysine enhances calcium absorption in the gut and reduces its loss in urine, which could help maintain bone health and prevent osteoporosis.
- Some research indicates Lysine may lower blood pressure and prevent arterial calcification, especially in conditions like uremia. However, the evidence is not yet robust, and more studies are needed to confirm these cardiovascular benefits.
- Lysine can attenuate the glucose response to ingested glucose without altering insulin levels, suggesting a role in managing blood sugar, which may benefit individuals with diabetes.
- Lysine supports muscle growth by aiding protein synthesis, essential for athletes and those recovering from injuries. It activates satellite cells and enhances muscle protein production, potentially improving muscle strength and mass.
- By contributing to collagen formation, Lysine promotes wound healing, supporting skin and tissue repair.
- Not synthesized by the human body.
- Research, including a 2020 review on Healthline, suggests that lysine supplementation, at doses over 3 g per day, may reduce the duration and severity of cold sores by blocking arginine, an amino acid essential for HSV replication.
- A study cited on WebMD found that oral lysine up to 3 g daily for up to a year is possibly safe and effective for prevention, though not all studies agree on its efficacy for treatment.
Action Details Supporting Evidence Antiviral Activity Reduces HSV replication by competing with arginine, effective for cold sores. WebMD, 2020 review on Healthline Anxiolytic Effects Reduces anxiety and stress, lowers cortisol, affects serotonin/GABA pathways. 2007 study on PubMed, Syrian community study on PMC Calcium Absorption Enhancement Increases gut absorption, reduces urinary loss, benefits bone health. 1992 study on PubMed, 2018 study on Healthline Cardiovascular Benefits May lower blood pressure, prevent arterial calcification, needs more research. 2017 study on BMC Nutrition, rat study on PMC Glucose Metabolism Modulation Attenuates glucose response, may improve fasting glucose in diabetes. 2009 study on ScienceDirect, 2016 study on PubMed Muscle Mass Support Enhances protein synthesis, activates satellite cells, improves muscle function. 2012 study on PubMed, piglet study on PMC Wound Healing Promotion Aids collagen formation, enhances repair, beneficial for diabetic ulcers. 2023 study on PMC, noted on Healthline - Isoleucine
- Studies indicate Isoleucine can strengthen the immune system, particularly by helping produce β-defensins, which are peptides that fight off infections and support both innate and adaptive immunity.
- Isoleucine is crucial for making muscle proteins, which helps with muscle growth and recovery after exercise. It also seems to help with how our muscles use glucose, potentially aiding energy levels and reducing muscle soreness post-workout.
- There's evidence suggesting Isoleucine helps muscles take in glucose and break it down for energy, which might help manage blood sugar levels.
- Enhances immune function by inducing the expression of host defense peptides, specifically β-defensins.
- Reduces post-exercise muscle soreness and markers of muscle damage when taken as part of BCAAs, though it is less effective than Leucine.
Muscle Growth & Recovery Essential for muscle protein synthesis, reduces post-exercise muscle soreness and damage when part of BCAAs, but less effective than leucine. Optimal synthesis requires all nine essential amino acids. Glucose Metabolism Enhances glucose uptake by muscle cells, increases glucose breakdown into energy, reduces hepatic gluconeogenesis in rodents. Rat dosages of 0.3–0.45 mg/kg effective for reducing blood glucose, extrapolated to human dose of 48–72 mg/kg (3.3–4.9 g for 150 lb person). Inconsistent human trial results. Other Functions Acts as a signaling molecule, regulates protein, glucose, lipid metabolism, glucose transport, and immune function. Potential Negative Associations Increased blood levels associated with insulin resistance, type 2 diabetes, cardiovascular disease, and obesity in observational studies. Cause-effect unclear. Side Effects Gastrointestinal upset (nausea, diarrhea) when taken as part of BCAAs. Side effects of isoleucine alone undetermined. Recommended Intake RDA: 19 mg/kg bodyweight daily. No strong evidence for supplementing isoleucine alone above RDA. - Aspartic acid
- Aspartic acid, particularly the L-form, is thought to act as a neurotransmitter, exciting neurons in the brain.
- While less common, D-aspartic acid is used as a dietary supplement and may influence hormone levels, such as increasing testosterone. This is more of a supplement claim and not a standard pharmacological use, with mixed research results.
- Is non-essential, as the body can synthesize it from oxaloacetate and glutamate, particularly in the liver and muscles (Aspartic Acid in Health and Disease).
- Research suggests that aspartic acid, particularly L-aspartic acid, acts as a potent neuronal excitant, activating the same receptors as glutamic acid.
- The excitatory nature of aspartic acid can contribute to excitotoxicity under pathological conditions, where excessive activation of excitatory amino acid (EAA) receptors may lead to brain injury. This is managed by Na+-dependent transport mechanisms to clear EAAs, highlighting the importance of its transport in limiting potential neurotoxicity (Aspartic Acid - an overview | ScienceDirect Topics).
- It is particularly important in maintaining intracellular NAD(H) redox balance via the malate-aspartate shuttle and facilitating amino acid metabolism (Aspartic Acid in Health and Disease).
- D-aspartic acid, distinct from L-aspartic acid, has been studied for its potential pharmacology actions in hormone regulation, particularly testosterone. It is naturally found in the pituitary gland, hypothalamus, and testes, and is often used as a dietary supplement to increase testosterone and growth hormone levels, potentially improving sexual potency and athletic performance (D-Aspartic Acid benefits, dosage, and side effects).
- Research, such as studies on resistance-trained men, shows mixed results, with some indicating increased testosterone in sedentary individuals but less effect in trained athletes, suggesting dosage and baseline hormone levels may influence outcomes (Three and six grams supplementation of d-aspartic acid in resistance trained men | Journal of the International Society of Sports Nutrition).
Action Description Context Evidence Level Neurotransmitter Role Acts as a neuronal excitant, potentially excitatory in CNS, similar to glutamic acid Neurological signaling, cerebellum Sparse, mixed studies Nutritional Support Provides amino acids for protein synthesis, gluconeogenesis, and metabolic processes Total parenteral nutrition Well-established Hormone Regulation (D-form) May increase testosterone and growth hormone levels, used as supplement Reproductive health, athletics Mixed, debated efficacy Liver Function Support (Indirect) Part of LOLA, reduces ammonia levels in hepatic encephalopathy Liver disease treatment Combined with ornithine - Proline
- Research suggests Proline supports connective tissue health, especially skin and joints, through collagen synthesis.
- It seems likely that Proline aids wound healing and muscle preservation, often used in supplements.
- The evidence leans toward Proline having neurological effects via NMDA receptors, potentially linked to conditions like hyperprolinemia.
- Proline is used in total parenteral nutrition for nutritional support, with metabolic roles in pathways like arginine metabolism.
- Proline is a key building block of collagen.
- Interestingly, Proline can affect brain cells by interacting with NMDA receptors, which are involved in nerve signaling. While this might contribute to neurological issues in conditions like hyperprolinemia (high Proline levels), its direct therapeutic use in this area is less clear and requires more research.
- Proline plays a role in metabolic pathways, such as arginine and proline metabolism, which are important for overall body function.
- This is supported by studies indicating topical application may be more effective for wound treatment than oral supplementation (L-Proline: Benefits, Side Effects & Dosage | BulkSupplements).
- The quality of Proline supplements is also a consideration, with a study assessing seven dietary supplements finding content variability (73–121% in capsules, 103–156% in tablets) and detecting five contaminants, emphasizing the need for quality control (Dietary Supplements with Proline—A Comprehensive Assessment of Their Quality | PMC).
- Proline’s most prominent pharmacological action is its role in collagen synthesis, where it constitutes a significant portion of the glycine-proline-hydroxyproline triplets forming the triple-helical structure of collagens. Clinically, this translates to its use in addressing conditions requiring tissue repair, such as arthritis or post-surgical recovery (L-Proline | Health Benefits and Uses of L-Proline | Xtendlife).
- Proline is involved in several metabolic pathways, notably arginine and proline metabolism, which are crucial for energy production and amino acid interconversion. It is a substrate for Proline dehydrogenase 1, mitochondrial (PRODH), which converts Proline to delta-1-pyrroline-5-carboxylate, a step in its catabolism. This enzyme’s activity is linked to cell proliferation and tumor development, suggesting Proline’s role in metabolic stress responses, particularly in cancer cells (Proline Dehydrogenase - an overview | ScienceDirect Topics).
- At the molecular level, Proline binds to peptidyl-prolyl cis-trans isomerases (e.g., PPIB, PPIA), enzymes that catalyze the cis-trans isomerization of proline imidic peptide bonds, influencing protein folding and conformation. This action is significant for structural proteins like collagen. Additionally, Proline inhibits monocarboxylate transporter 10 (SLC16A10), which transports thyroid hormones and aromatic acids, potentially affecting hormonal and metabolic regulation (Proline: Uses, Interactions, Mechanism of Action | DrugBank Online).
- A study on CA1 hippocampal pyramidal cells demonstrated that L-Proline induces depolarization, primarily via postsynaptic NMDA receptor activation, leading to multiple orthodromic population spikes and potential depolarization block. This action suggests neuroexcitatory and neurotoxic potential, with implications for conditions like hyperprolinemia, where elevated Proline levels may contribute to seizures and mental retardation (NMDA receptor-mediated depolarizing action of proline on CA1 pyramidal cells | ScienceDirect).
- Additionally, defects in neural Proline transport, mediated by transporters like SLC6A7 (PROT1) and SLC6A19 (B0AT1), are associated with ataxia and psychosis. Genetic or pharmacological inhibition of SLC6A7 has been shown to reduce locomotor activity and improve learning and memory in mice, highlighting Proline’s role in cognitive and motor functions (Frontiers | The Multifaceted Roles of Proline in Cell Behavior).
- Proline’s role in pathology is notable, particularly in parasitic infections. For instance, in Trypanosoma cruzi (the causative agent of Chagas disease), Proline is essential for survival under oxidative and thermal stress, and inhibiting its uptake is explored as a novel drug target, with studies developing transporter inhibitors to reduce parasite proliferation (Frontiers | Targeting L-Proline Uptake as New Strategy for Anti-chagas Drug Development).
- In cancer, increased Proline metabolism is observed in metastatic cell lines, correlating with invasiveness and resistance to oxidative stress, suggesting its role in tumor progression (Proline Dehydrogenase - an overview | ScienceDirect Topics).
Molecular Target/Interaction Description Peptidyl-prolyl cis-trans isomerase B Binds, affects protein folding, crucial for collagen structure. Peptidyl-prolyl cis-trans isomerase A Binds, influences protein conformation, supports structural integrity. Proline dehydrogenase 1, mitochondrial. Substrate, converts Proline to delta-1-pyrroline-5-carboxylate, metabolic role. Monocarboxylate transporter 10 Inhibited, affects thyroid hormone and aromatic acid transport. - Phenylalanine
- L-Phenylalanine is converted into tyrosine.
- L-Phenylalanine, especially when combined with UV light, is used to treat vitiligo, a condition causing white patches on the skin. It seems to work by boosting melanin production, helping repigment the skin, with studies showing benefits in over 90% of early cases.
- D-Phenylalanine may interact with the niacin receptor 2.
- DL-Phenylalanine is noted for potential pain relief, possibly by preventing the breakdown of enkephalins, the body's natural painkillers, and may also have antidepressant properties.
- It is converted to tyrosine by the enzyme phenylalanine hydroxylase.
- DL-Phenylalanine is a mixture of L- and D-forms.
- High levels of phenylalanine can be neurotoxic, particularly in phenylketonuria (PKU), a genetic disorder where individuals cannot metabolize phenylalanine properly. Chronic high serum levels can lead to seizures, organ damage, intellectual disability, and behavioral issues like ADHD (Phenylalanine | C9H11NO2 | CID 6140 - PubChem).
- For PKU, early dietary restriction and medication are recommended to manage levels, with D-Phenylalanine potentially arresting fibril formation by L-Phenylalanine, suggesting a therapeutic role (Phenylalanine | C9H11NO2 | CID 6140 - PubChem).
- For instance, a study on energy intake showed that high doses (10 g) increased nausea ratings in overweight/obese women, with no significant effect on energy intake compared to controls (Phenylalanine | C9H11NO2 | CID 6140 - PubChem).
Form Pharmacological Action Details L-Phenylalanine Precursor to neurotransmitters Converts to tyrosine, then dopamine, norepinephrine, epinephrine; affects mood, cognition. L-Phenylalanine Treatment for vitiligo Combined with UV light, stimulates melanin production; effective in early cases. D-Phenylalanine Activity at niacin receptor 2 Interacts with niacin receptor 2; specific effects unclear. DL-Phenylalanine Analgesic effects Inhibits enkephalin degradation, potentially relieving chronic pain. DL-Phenylalanine Potential antidepressant effects May enhance neurotransmitter levels; evidence mixed. - Serine
Pharmacological Actions of L-Serine
- L-serine exhibits a range of pharmacological actions, primarily centered on the nervous system and immune function:
- Neuroprotective Effects: L-serine is crucial for protecting neurons from damage. It mitigates neurotoxicity through the activation of glycine receptors and upregulation of PPAR-γ, a nuclear receptor involved in inflammation and metabolism. This action helps reduce neuronal damage in conditions like stroke and neurodegenerative diseases (L-serine: Neurological Implications and Therapeutic Potential).
- Anti-inflammatory Effects: It reduces neuroinflammation by downregulating the proliferation of microglia and astrocytes, which are immune cells in the brain, and decreasing the production of proinflammatory cytokines. This anti-inflammatory property is vital for managing conditions like multiple sclerosis and brain injuries (L-serine: Neurological Implications and Therapeutic Potential).
- Neurotransmitter Synthesis: L-serine serves as a precursor to glycine and D-serine, which are essential for excitatory glutamatergic neurotransmission. This process is critical for long-term potentiation and synaptic plasticity, underpinning learning and memory. Its role in neurotransmitter synthesis makes it a potential target for cognitive enhancement (L-serine: Neurological Implications and Therapeutic Potential).
- Immune Modulation: Through mTOR signaling, L-serine supports the proliferation and function of immune cells, such as natural killer cells (enhancing IFN-γ production) and neutrophils (supporting IL-17/IL-22 production). This immunomodulatory effect could be beneficial in conditions requiring immune support, such as chronic fatigue syndrome (L-serine: Neurological Implications and Therapeutic Potential).
- Circadian Rhythm Regulation: L-serine influences the circadian clock, particularly through its effects on the suprachiasmatic nuclei, the brain's master clock. This action may regulate sleep-wake cycles, offering potential benefits for insomnia and related disorders (Serine - an overview | ScienceDirect Topics).
- Metabolic Roles: Beyond neurological effects, L-serine is involved in one-carbon metabolism, providing intermediates for nucleotide synthesis and methylation reactions. It is also a building block for phosphatidylserine and sphingolipids, critical components of cell membranes. These roles suggest potential impacts on metabolic disorders like diabetes and steatohepatitis, though more research is needed (Dietary serine supplementation: Friend or foe? - ScienceDirect).
Pharmacological Actions of D-Serine
- D-serine, derived from L-serine via serine racemase, has distinct pharmacological actions, primarily in the nervous system:
- NMDA Receptor Co-agonist: D-serine acts as a co-agonist at the glycine site of NMDA receptors, which are crucial for excitatory neurotransmission. This action is vital for synaptic plasticity, learning, and memory, making D-serine a target for cognitive and psychiatric research (Serine - an overview | ScienceDirect Topics).
- Therapeutic Potential in Schizophrenia: D-serine is being studied for its role in improving symptoms of schizophrenia when used alongside standard antipsychotic therapy. It enhances NMDA receptor function, potentially alleviating negative symptoms, though it is less effective when used alone (SERINE: Overview, Uses, Side Effects, Precautions, Interactions, Dosing and Reviews).
- Biomarker for Alzheimer’s Disease: Recent studies suggest D-serine levels in cerebrospinal fluid may serve as a biomarker for early Alzheimer’s disease diagnosis, highlighting its role in neurodegenerative processes (Serine - Wikipedia).
Therapeutic Uses and Clinical Applications
- Both forms of serine are under investigation for various therapeutic uses, with L-serine showing broader application:
- L-Serine Therapeutic Uses:
- Hereditary Sensory Neuropathy Type 1 (HSAN1): Supplementation at 400 mg/kg/day for 52 weeks reduced neurotoxic 1-deoxysphingolipids, improving neurological outcomes (L-serine: Neurological Implications and Therapeutic Potential).
- Amyotrophic Lateral Sclerosis (ALS): A phase I trial demonstrated safety, with no contribution to disease progression rate, and a phase II trial is planned (L-serine: Neurological Implications and Therapeutic Potential).
- Severe Encephalopathy (GRIN2B-related): Improved motor, cognitive performance, and communication after 11 and 17 months at doses like 500 mg/kg/day in pediatric cases (L-serine: Neurological Implications and Therapeutic Potential).
- Alzheimer’s Disease (AD): Rescued cognitive deficits in AD mouse models, outperforming D-cycloserine in passive avoidance tests, suggesting potential for human trials (L-serine: Neurological Implications and Therapeutic Potential).
- Investigational Uses: Ongoing research for Parkinson’s Disease, schizophrenia, epilepsy, and multiple sclerosis, driven by its neuroprotective and anti-inflammatory properties (L-serine: Neurological Implications and Therapeutic Potential).
Safety Profile and Dosage Considerations
- The safety of serine supplementation varies by form and dose:
- L-Serine Safety: Commonly consumed in foods, with a typical dietary intake of 3.5-8 grams daily. It is possibly safe at higher doses, up to 25 grams daily for up to 1 year, with side effects like upset stomach and bloating. Very high doses (25 grams or more daily) may lead to increased stomach issues and seizures, making it possibly unsafe (SERINE: Overview, Uses, Side Effects, Precautions, Interactions, Dosing and Reviews).
- D-Serine Safety: Doses of 2-4 grams daily for up to 4 weeks have been used safely, but higher doses (8 grams or more daily) may increase the risk of side effects, similar to L-serine (SERINE: Overview, Uses, Side Effects, Precautions, Interactions, Dosing and Reviews).
- The main targets are the transporters for serotonin (SERT), noradrenaline (NET), and dopamine (DAT). These are not traditional receptors but proteins that manage neurotransmitter levels. St. John's wort likely inhibits these transporters, preventing them from removing the neurotransmitters from the brain's communication spaces, thus increasing their availability.
- The binding strength, measured as IC50 values, is based on hyperforin, a key active compound in St. John's wort. Research suggests:
- Serotonin transporter: IC50 around 2.5 nM
- Noradrenaline transporter: IC50 around 10 nM
- Dopamine transporter: IC50 around 100 nM
- These values indicate how much of the compound is needed to block half of the transporter's activity, with lower numbers showing stronger binding.
- While the primary focus is on neurotransmitter transporters, St. John's wort's pharmacology extends beyond these targets. For instance, it is a potent activator of the pregnane-X-receptor (PXR), leading to the induction of cytochrome P450 enzymes (notably CYP3A4) and P-glycoprotein, which are crucial for drug metabolism and can result in significant herb-drug interactions (Clinical relevance of St. John's wort drug interactions revisited - Nicolussi - 2020 - British Journal of Pharmacology - Wiley Online Library).
- Additionally, other components like hypericin have been studied for antiviral and antibacterial properties, and there is some evidence suggesting interactions with GABA(A) receptors, though these are less central to its antidepressant effects (In vitro binding studies with two Hypericum perforatum extracts - Hyperforin, hypericin and biapigenin - On 5-HT6, 5-HT7, GABAA/benzodiazepine, ... | ResearchGate). Hyperforin has also been shown to activate transient receptor potential canonical C6 (TRPC6) channels, which may have roles in other physiological processes, but their relevance to depression is not well-established (Hyperforin activates gene transcription involving transient receptor potential C6 channels - ScienceDirect).
Aspect L-Serine D-Serine Primary Mechanism Precursor to glycine and D-serine, activates glycine receptors, upregulates PPAR-γ Co-agonist at NMDA receptor glycine site, enhances glutamatergic transmission Neuroprotective Role Mitigates neurotoxicity, reduces brain lesion volume post-injury Supports synaptic plasticity, potentially protects against cognitive decline Anti-inflammatory Role Downregulates microglia/astrocyte proliferation, reduces proinflammatory cytokines Less direct, but may modulate inflammation via NMDA receptor activity Immune Effects Supports mTOR signaling, enhances NK cell and neutrophil function Minimal direct evidence, primarily neurological focus Therapeutic Focus HSAN1, ALS, encephalopathy, AD, PD, schizophrenia, epilepsy, MS Schizophrenia, potential AD biomarker - Valine
- Our bodies cannot produce it.
Action Details Source Muscle Growth and Repair Stimulates protein synthesis, reduces muscle breakdown, aids recovery DrugBank: Valine, Annual Reviews Energy and Endurance Enhancement Enhances energy, increases endurance when combined with leucine, isoleucine DrugBank: Valine, Examine.com Blood Sugar Regulation Lowers elevated blood sugar levels, combined effect with other BCAAs DrugBank: Valine, PubMed Growth Hormone Production Increases growth hormone production with supplementation DrugBank: Valine Insulin Sensitivity Catabolite 3-hydroxyisobutyrate promotes insulin resistance, affects glucose metabolism Wikipedia: Valine, PubMed Stem Cell Self-Renewal Essential for hematopoietic stem cell self-renewal, impacts transplantation Wikipedia: Valine, PMC Nutritional Support Component of total parenteral nutrition, essential for growth and nitrogen balance DrugBank: Valine, Wikipedia: Valine - NMN
- Research suggests NMN boosts NAD+ levels, potentially aiding heart, brain, and metabolic health.
- The half-life of NMN seems likely to be short, on the order of minutes, due to rapid conversion to NAD+.
- Nicotinamide mononucleotide (NMN) is a precursor to NAD+, a coenzyme essential for energy production and cellular repair.
- Animal studies showing plasma levels peaking within minutes and then declining quickly.
- NMN is a naturally occurring molecule found in small amounts in foods like avocados and broccoli, but its levels in the body decline with age, contributing to reduced NAD+ availability.
- NAD+ is a critical coenzyme involved in over 500 cellular reactions, including energy production, DNA repair, and sirtuin activation, which are linked to longevity and metabolic health. NMN supplementation aims to replenish NAD+ levels, potentially mitigating aging-related disorders such as oxidative stress, DNA damage, neurodegeneration, and inflammation.
- Preclinical studies, primarily in murine models, have demonstrated a wide range of pharmacological actions for NMN, mediated through its role in NAD+ biosynthesis. These actions are detailed in the following table, derived from a comprehensive review of the literature:
Condition Pharmacological Action Dose and Administration Mechanism/Effect References Ischemia-Reperfusion Injury Ameliorates myocardial injury, reduces infarct size by 44% (before ischemia) and 29% (during reperfusion) 500 mg/kg, intraperitoneal, 30 min before or every 6 hours for 24 hours Activates SIRT1, mimics ischemic preconditioning, increases glycolysis or induces acidosis for cardioprotection Nicotinamide Mononucleotide: Exploration of Diverse Therapeutic Applications of a Potential Molecule Improves neurologic outcome and hippocampal CA1 neuronal death in cerebral ischemia 62.5 mg/kg, in transient forebrain ischemic mice Reduces PAR formation and NAD+ catabolism Nicotinamide mononucleotide protects septic hearts in mice via preventing cyclophilin F modification and lysosomal dysfunction Alzheimer's Disease Increases mitochondrial maximal OCR, reduces Aβ oligomers induced LTP by 140%, decreases cell death by 65% 500 mg/kg, intraperitoneal, for mitochondrial OCR assay; 100 mg/kg, subcutaneous, for 28 days Crosses blood-brain barrier, activates SIRT1, stimulates PGC-1α for mitochondrial biogenesis, inhibits amyloidogenic APP Nicotinamide Mononucleotide: A Promising Molecule for Therapy of Diverse Diseases by Targeting NAD+ Metabolism Intracerebral Hemorrhage (ICH) Increases intracerebral NAD+ concentration, improves conditions like edema, neuronal death, ROS content 300 mg/kg, intraperitoneal, 30 min after ICH episode Activates Nrf2/HO-1 signaling pathway, reduces neurological inflammation Nicotinamide mononucleotide protects septic hearts in mice via preventing cyclophilin F modification and lysosomal dysfunction Diabetes Improves insulin intolerance, ameliorates glucose intolerance 500 mg/kg/day, intraperitoneal, for 7-10 days (high-fat diet); 11 consecutive doses (age-induced) Activates SIRT1, deacetylates p65-NFκB, restores insulin secretion by suppressing IL-1β The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial Obesity and Related Complications Reduces body weight by 4% (100 mg/kg) and 9% (300 mg/kg) over 12 months, improves NAD+ content 100-300 mg/kg, over 12 months; 500 mg/kg daily for 17 days (HFD-induced) Stimulates mitochondrial ATP production, improves glucose intolerance, reduces hepatic citrate synthase activity Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice Ageing Increases hepatic NAD+ and PARP1 activity, reduces fundus spots, increases tear production, reverses bone density depletion 500 mg/kg/day, intraperitoneal, for 1 week (DNA repair); 100-300 mg/kg/day, for 12 months (optical and bone) Reverses age-related NAD+ decline, upregulates compromised genes (76.3% skeletal muscle, 73.1% white adipose, 41.7% liver) The Science Behind NMN–A Stable, Reliable NAD+Activator and Anti-Aging Molecule - The pharmacokinetics of NMN are characterized by rapid absorption and conversion to NAD+, with a short half-life due to its quick metabolic turnover. In animal studies, particularly in mice, NMN is absorbed from the gut into blood circulation within 2-3 minutes and transported into tissues within 10-30 minutes after oral administration (Absolute quantification of nicotinamide mononucleotide in biological samples by double isotope-mediated liquid chromatography-tandem mass spectrometry).
- When given by oral gavage, plasma NMN levels show a steep increase within 2.5 minutes, peak at 5-10 minutes, and then decline to baseline, suggesting a half-life on the order of minutes (The Science Behind NMN–A Stable, Reliable NAD+Activator and Anti-Aging Molecule).
- This rapid decline is attributed to immediate utilization for NAD+ biosynthesis, leading to marked increases in tissue NAD+ levels (2-3-fold in liver over 60 minutes) (NAD+ intermediates: The biology and therapeutic potential of NMN and NR).
- In humans, specific half-life data is scarce, but clinical trials suggest similar rapid metabolism. For instance, a study administering 250 mg/day NMN found no significant increase in blood NMN concentration, while higher doses (1000-2000 mg/day) showed dose-dependent increases, indicating that at lower doses, NMN is quickly converted and not detectable in plasma (Nicotinamide mononucleotide (NMN) intake increases plasma NMN and insulin levels in healthy subjects).
- This supports the notion of a short half-life, likely less than an hour, due to rapid conversion to NAD+ and its metabolites, such as N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-5-carboxamide, which were measured in some trials (Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men).
- The short half-life has implications for dosing regimens, with recommendations for split doses throughout the day to maintain NAD+ levels, as seen in product guidelines suggesting morning and afternoon intake due to NMN's rapid clearance (Nicotinamide Mononucleotide (NMN) Supplement | Double Wood Supplement).
- However, the exact half-life remains poorly characterized in humans, with ongoing research needed to establish precise pharmacokinetic parameters, especially given the variability in absorption and metabolism across individuals (Pharmacokinetics: The Missing Metric to Determine Dosage).
- Clinical trials, such as a 60-day study with doses up to 900 mg/day, have shown NMN to be safe with no significant adverse effects, increasing blood NAD+ levels dose-dependently, with optimal efficacy at 600 mg/day (The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial).
- However, the FDA has classified NMN as an investigational drug since late 2022, limiting its availability as a supplement in the U.S., which underscores the need for further safety and efficacy studies (Nicotinamide mononucleotide - Wikipedia).
- Besides oral ingestion, NMN can be taken sublingually (under the tongue) or via nasal spray, both bypassing the digestive system for potentially higher bioavailability. Sublingual supplements and nasal sprays are available and marketed for enhanced absorption.
- A daily dose of 250 mg NMN for 12 weeks significantly increased NAD+ levels in healthy subjects, suggesting high bioavailability.
- Given the lack of specific data, it seems likely that taking NMN on an empty stomach is preferable for optimal absorption, but this is based on general principles rather than conclusive evidence. The evidence leans toward empty stomach for potentially better results, but further research is needed to quantify the difference.
- Sublingual NMN involves placing the supplement under the tongue, where it dissolves and is absorbed directly into the bloodstream through the mucous membranes, bypassing the digestive system.
- A source from NOVOS (Can you take NMN orally? Or only sublingually?) confirms that NMN can be taken orally or sublingually, with recent research showing good absorption by mouth, but sublingual administration is often preferred for bypassing the GI tract.
Aspect Details Exact Numbers Study Design Randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent 80 participants, 60-day duration Dosing Placebo, 300 mg, 600 mg, 900 mg NMN daily, oral, once daily before breakfast 300 mg, 600 mg, 900 mg Primary Objective Blood NAD concentration increase Significant increase at day 30 and 60 for all NMN groups (p ≤ 0.001), highest at 600 mg and 900 mg Safety and Tolerability No safety issues, well tolerated up to 900 mg daily, based on adverse events, lab, clinical measures Safety and Tolerability No safety issues, well tolerated up to 900 mg daily, based on adverse events, lab, clinical measures Physical Performance Six-minute walking test, distance increase higher in 300 mg, 600 mg, 900 mg vs. placebo at day 30 and 60 (p < 0.01), longest at 600 mg and 900 mg Blood Biological Age Increased in placebo at day 60, unchanged in all NMN groups, significant difference vs. placebo (p > 0.05) HOMA-IR No significant differences for NMN groups vs. placebo at day 60 Subjective General Health SF-36 scores better in 300 mg, 600 mg, 900 mg vs. placebo at day 30 and 60 (p > 0.05), except 300 mg at day 30 Conclusion NMN increases blood NAD, safe up to 900 mg, efficacy highest at 600 mg daily oral intake - Increased Blood NAD+ Levels:
- A randomized, multicenter, double-blind, placebo-controlled trial involving 80 healthy middle-aged adults (aged 40–65 years) demonstrated that NMN supplementation at doses of 300 mg, 600 mg, or 900 mg daily for 60 days significantly increased blood NAD+ concentrations compared to placebo and baseline. Specifically, the 900 mg group saw an increase from 10.5 ± 6.8 nM to 48.5 ± 19.8 nM at day 60, indicating a substantial boost in NAD+ levels [1]. This enhancement is crucial for cellular function and is a primary mechanism for NMN's effects.
- Improved Physical Performance:
- In the same trial, physical performance was assessed using the six-minute walking test. Participants receiving 900 mg NMN daily showed a significant increase in walking distance from 323 ± 113 meters at baseline to 480 ± 128 meters at day 60. This represents an approximate 48.6% increase ((480 - 323) / 323 * 100%), highlighting NMN's potential to enhance physical capabilities, particularly in middle-aged adults [1].
- Stabilized Biological Age:
- The trial also measured blood biological age using the Aging.Ai 3.0 calculator. While the placebo group's biological age increased significantly by day 60 (from 39.8 ± 7.2 years to 45.4 ± 8.2 years), NMN-treated groups showed no significant change. For instance, the 300 mg group went from 42.2 ± 6.0 to 43.7 ± 6.7 years (p = 0.46), suggesting NMN may help maintain biological age, a key anti-aging indicator [1].
- Enhanced Insulin Sensitivity:
- A 10-week, randomized, placebo-controlled, double-blind trial in 25 postmenopausal women with prediabetes and overweight or obesity (BMI 25.3 to 39.1 kg/m²) found that 250 mg/day of NMN increased muscle insulin sensitivity by 25 ± 7%. This was measured via insulin-stimulated glucose disposal using the hyperinsulinemic-euglycemic clamp, with no change in the placebo group. This improvement is clinically relevant, comparable to effects seen after 10% weight loss or certain diabetes treatments [2].
- Weight Reduction and Metabolic Health:
- A study involving middle-aged and older overweight or obese adults (aged 45+ years) taking 2,000 mg/day of NMN (MIB-626 formulation) for 28 days showed a significant body weight reduction of 1.9 kg (95% CI: -3.3 to -0.5, p=0.008). Additionally, total cholesterol decreased by 26.89 mg/dL (95% CI: -44.34 to -9.44, p=0.004), LDL cholesterol by 18.73 mg/dL (95% CI: -31.85 to -5.60, p=0.007), and diastolic blood pressure by 7.01 mmHg (95% CI: -13.44 to -0.59, p=0.034), indicating broad metabolic benefits [3].
- Improved General Health Assessment:
- The SF-36 survey, measuring subjective general health, showed significant improvements in NMN-treated groups compared to placebo at day 60 in the first trial. For example, the 900 mg group improved from 122 ± 17 at baseline to 140 ± 11 at day 60, suggesting better overall health perception [1].
- Table of Quantifiable Benefits from Human Trials
Benefit Quantifiable Data Study Context Increased Blood NAD+ Levels From 10.5 ± 6.8 nM to 48.5 ± 19.8 nM (900 mg/day, 60 days) Healthy middle-aged adults [1] Improved Physical Performance Walking distance: 323 ± 113 m to 480 ± 128 m (900 mg/day) Healthy middle-aged adults [1] Enhanced Insulin Sensitivity 25 ± 7% increase (250 mg/day, 10 weeks) Postmenopausal women with prediabetes [2] Weight Reduction 1.9 kg reduction (2,000 mg/day, 28 days) Overweight/obese adults [3] Lower Total Cholesterol 26.89 mg/dL reduction (2,000 mg/day, 28 days) Overweight/obese adults [3] Lower LDL Cholesterol 18.73 mg/dL reduction (2,000 mg/day, 28 days) Overweight/obese adults [3] Lower Diastolic Blood Pressure 7.01 mmHg reduction (2,000 mg/day, 28 days) Overweight/obese adults [3] - [1]
- [2]
- [3]
- Biochemical Link Between NAD+ and Testosterone
- NAD+ plays a vital role in steroidogenesis, the process of hormone synthesis, by supporting enzymes like 3β-Hydroxysteroid Dehydrogenase, which is essential for converting precursors into testosterone. A review article, "Regulation of 3β-hydroxysteroid dehydrogenase/Δ⁵-Δ⁴ isomerase: a review" , highlights that this enzyme requires NAD+ as a cofactor, suggesting that declining NAD+ levels could theoretically impair testosterone production. However, in young individuals with presumably sufficient NAD+, the impact might be negligible.
- Animal Studies: Insights from Boars and Mice
- Animal studies provide the most direct evidence on NMN's effect on testosterone. A study on Landrace boars, "Supplementing Boar Diet with Nicotinamide Mononucleotide Improves Sperm Quality Probably through the Activation of the SIRT3 Signaling Pathway" (source), found that NMN supplementation (at doses of 8, 16, or 32 mg/kg/day for 9 weeks) significantly increased serum testosterone levels (p < 0.05). This suggests that in adult male pigs, NMN enhances testosterone, contradicting the idea of lowering it. The study design involved 32 boars, with serum samples analyzed for testosterone, showing increased levels in supplemented groups compared to controls, as detailed in Figure 2D of the article.
- Contrastingly, a mouse study, "Low NAD+ Levels Are Associated With a Decline of Spermatogenesis in Transgenic ANDY and Aging Mice" (source), investigated NAD+ deficiency and found no significant impact on testicular testosterone levels. This study used transgenic ANDY mice, where NAD+ levels were experimentally lowered, and measured testosterone via radioimmuno-assays and LC-MS/MS, with results indicating no suppression in testosterone synthesis despite NAD+ deficiency (see Figure 4A and 4B). This suggests that within a certain range, testosterone production may not be sensitive to NAD+ levels, at least in mice.
- Human Studies: Limited Evidence
- Human clinical trials on NMN have primarily focused on safety, NAD+ levels, and outcomes like muscle function, without directly measuring testosterone. For instance, "Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men" (source) involved 65 men over 65, administering 250 mg/day NMN for 12 weeks, and reported improvements in gait speed and grip strength, with no adverse effects. However, testosterone was not measured, limiting direct applicability.
- Another trial, "The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults" (source), included 80 middle-aged adults (40-65 years) with doses of 300, 600, or 900 mg/day for 60 days, focusing on NAD+ levels and physical performance, again without testosterone data. These studies suggest NMN is safe and well-tolerated, but do not address testosterone effects, especially in younger populations.
- Understanding Downregulation
- NAD+ biosynthesis involves multiple pathways, with the salvage pathway being predominant in mammals, mediated by nicotinamide phosphoribosyltransferase (NAMPT), which converts nicotinamide (a byproduct of NAD+ consumption) to NMN, subsequently converted to NAD+ by nicotinamide mononucleotide adenylyltransferases (NMNATs). Research highlights a feedback loop involving NAD+, SIRT1 (a NAD+-dependent deacetylase), and NAMPT, regulated by circadian rhythms. Specifically, the circadian clock machinery (CLOCK–BMAL1) upregulates NAMPT, increasing NAD+ levels, which in turn activates SIRT1. High SIRT1 activity can suppress CLOCK:BMAL1, reducing NAMPT expression, thus forming a negative feedback loop to maintain NAD+ homeostasis.
- This loop suggests that elevated NAD+ levels from NMN supplementation could lead to reduced NAMPT expression, potentially downregulating endogenous NAD+ production via the salvage pathway. However, NMN supplementation bypasses NAMPT by directly providing NMN, which is converted to NAD+ by NMNATs, potentially mitigating the impact of reduced NAMPT activity.
- Evidence from Clinical and Preclinical Studies
- Current research, primarily from short-term human trials and longer-term animal studies, provides insights into the effects of NMN supplementation. A 12-week randomized, double-blind, placebo-controlled trial in healthy middle-aged adults showed that NMN (250 mg/day) significantly increased NAD+ and metabolite concentrations without adverse effects, suggesting no immediate downregulation issues (source).
- In animals, long-term studies (e.g., 1-year administration in mice at 100–300 mg/kg/day) showed NMN was safe, improved insulin sensitivity, and caused no significant side effects, with no evidence of downregulation affecting efficacy (source).
- Potential Risks and Theoretical Concerns
- Despite these findings, theoretical risks exist. High NAD+ levels from NMN could enhance SIRT1 activity, potentially suppressing NAMPT expression via the feedback loop, reducing endogenous NAD+ production. However, since NMN supplementation directly provides the precursor, this might not significantly impact overall NAD+ levels during supplementation. Long-term effects remain uncertain, with concerns about potential adaptation, such as reduced activity of other NAD+ biosynthetic enzymes or increased degradation by enzymes like CD38, though no human studies have confirmed this.
- Another concern is the accumulation of nicotinamide, a byproduct of NAD+ consumption, which at high concentrations (1–5 mM) can inhibit NAD+-dependent enzymes like sirtuins and PARPs, potentially affecting feedback regulation (source). However, clinical trials have not observed significant adverse effects, suggesting these risks are minimal at current doses.
- Safety Profile and Long-Term Considerations
- NMN has been tested in doses up to 1,250 mg/day in humans without significant adverse effects, with studies up to 24 weeks showing safety (source). The lack of long-term human studies means potential downregulation risks over extended periods are not fully understood, though animal data suggest no major issues.
- Comparative Analysis: NMN vs. Other NAD+ Precursors
- Compared to nicotinamide riboside (NR), another NAD+ precursor, NMN shows similar benefits but with different metabolic fates. NR also increases NAD+ levels, with some studies noting increased LDL cholesterol and fatty liver risks at high doses, but no specific downregulation concerns (source). Both precursors seem to bypass significant downregulation, with efficacy maintained in trials.
- Reported Negative Impacts and Side Effects
- Clinical trials and anecdotal reports provide insights into potential negative impacts, though specific incidence rates are often lacking. Below is a detailed breakdown based on available data:
- Gastrointestinal Disorders: The most commonly reported side effects include nausea, diarrhea, bloating, and abdominal pain. A systematic review noted these as predominant in long-term supplementation, consistent with gastrointestinal sensitivity to new supplements (source). These effects are typically mild and may occur initially as the body adjusts, especially at higher doses.
- Headaches and Dizziness: Some users, particularly from X posts and Reddit discussions, report mild headaches and dizziness, often diminishing with continued use . These are not consistently quantified in trials but are noted as transient.
- Fatigue: Fatigue is another reported side effect, potentially linked to metabolic adjustments. An X post mentioned feeling unusually tired initially, which subsided over time.
- Skin Reactions: Itching or rash is rare, possibly due to sensitivity, and may resolve over time. The Longevity Technology article highlights potential skin irritations, advising consultation with a dermatologist if persistent (source).
- Neurological Symptoms: Anecdotal reports, particularly on Reddit, mention rare neurological symptoms like blurry vision, tiredness, and depression after long-term use, attributed to quality issues or methylation pathways (source). These are not supported by clinical data and may vary by individual.
- Potential Organ Function Impacts: High doses may affect liver enzymes and kidney health, as noted in the Longevity Technology article, though clinical trials like one with doses up to 900 mg daily found no significant abnormalities (source).
- Medication Interactions: Potential interactions with blood thinners and diabetes medications are noted, possibly due to NMN's influence on blood flow and metabolism, requiring dosage adjustments (source).
- Insomnia: Some Reddit users report mild insomnia due to increased energy, often mitigated by morning dosing (source).
- Allergic Reactions: Rare reports of allergic reactions exist, though not detailed in clinical studies, suggesting individual sensitivity.
- Clinical Trial Data and Safety Profile
- Several clinical trials provide quantitative insights into adverse events (AEs):
- A 60-day trial with 80 participants (20 per group: placebo, 300 mg, 600 mg, 900 mg NMN daily) reported 9 total AEs, with 6 in the placebo group (5 participants, 25%) and 3 in the 300 mg NMN group (2 participants, 10%), including hyperacidity, skin problems, and mouth ulcers. No AEs were reported in the 600 mg and 900 mg groups, and none were attributed to NMN, indicating good tolerability (source).
- Another study with single doses of 100, 250, and 500 mg NMN in 10 healthy men found no significant clinical symptoms, with laboratory changes (e.g., serum bilirubin, creatinine) within normal ranges, suggesting safety (source).
- A 12-week trial with 250 mg/day NMN showed no adverse effects, reinforcing short-term safety (source).
- A systematic review involving 513 participants across 12 studies noted mild side effects, primarily gastrointestinal, but did not provide specific incidence rates, highlighting the need for more long-term data (source).
- Pharmacological Actions and Theoretical Risks
- NMN is rapidly absorbed and converted to NAD+, enhancing energy metabolism, DNA repair, and sirtuin activity. Pharmacologically, it may influence insulin sensitivity and reduce oxidative stress, but high doses could theoretically lead to:
- Methylation Concerns: Excess NMN may increase niacinamide elimination via methylation, potentially depleting methyl groups, though no clinical evidence confirms negative impacts (source).
- Organ Function: High doses might strain liver and kidney function, as suggested by anecdotal reports, but clinical trials up to 1250 mg/day show no significant changes in liver enzymes (source).
- Sirtuin Over-Activation: Theoretical risk of over-activating sirtuins, potentially exacerbating SASP, but evidence is lacking (source).
- Anecdotal Reports and User Experiences
- Anecdotal evidence from platforms like Reddit and X provides additional insights, though not quantified:
- Users report digestive discomfort, headaches, and fatigue, often resolving with time (source).
- Rare reports of neurological symptoms, like blurry vision and depression, are attributed to quality issues or methylation, but clinical correlation is weak (source).
- Some users note insomnia, mitigated by morning dosing, suggesting energy-related effects (source).
- Dosage and Safety Considerations
- Doses in studies range from 250 mg to 2000 mg daily, with up to 1250 mg/day tolerated without significant side effects. The Longevity Technology article advises starting with recommended doses and adjusting gradually, especially for those with sensitive conditions (source).
- Research Gaps and Future Directions
- While short-term studies show safety, long-term effects remain under-investigated, with calls for more extensive trials across diverse demographics. The ScienceDirect article emphasizes the need for proper clinical investigations to address effectiveness and safety concerns (source).
- NMN supplementation appears safe based on current clinical data, with mild side effects primarily gastrointestinal and transient. Anecdotal reports suggest additional rare effects, but without quantified incidence, caution is advised, especially at high doses. Consulting healthcare providers before starting NMN is recommended, given the evolving research landscape.
- Storage Recommendations: Fridge vs. Shelf
- Research suggests that the best way to store NMN is in a cool, dry place away from sunlight to minimize degradation. The choice between fridge and shelf depends on the storage duration:
- Short-Term Storage (Up to 3 Months): A cool, dry shelf is generally sufficient. Sources like RT Medical USA and Neurogan Health recommend storing NMN in a cupboard, avoiding humid areas like bathrooms, to prevent moisture-related degradation. Modern stabilized NMN formulations, such as those from NOVOS, are noted to be stable even at room temperature due to advanced crystalline arrangements, reducing the urgency for refrigeration in the short term.
- Long-Term Storage (Beyond 3 Months): Refrigeration is recommended to maintain full potency. NAD Lab EU and Neurogan Health suggest that storing NMN in the refrigerator can extend its stability, with Neurogan Health specifically noting up to 18 months of stability under these conditions. David Sinclair, a prominent researcher, has historically emphasized keeping NMN cold to prevent degradation, though this may refer to older, non-stabilized forms. Current evidence leans toward refrigeration being beneficial for long-term storage, especially for maintaining potency over extended periods.
- Environmental Factors to Avoid: Heat, light, and moisture are critical factors that can accelerate degradation. For instance, RT Medical USA advises against storing NMN in high-temperature areas or humid environments, as these can lead to the breakdown into nicotinamide, reducing effectiveness.
- Special Case: Mixed with Water: If NMN is mixed with water, its potency is limited to about a week, as noted by RT Medical USA and Neurogan Health. This is relevant for liquid formulations but not for dry supplements, which are the focus of this analysis.
- Shelf Life of NMN
- The shelf life of NMN varies based on storage conditions and formulation, with the following details emerging from the analysis:
- Room Temperature Storage: NMN typically maintains full potency for at least 3 months when stored correctly at room temperature, as per RT Medical USA. Neurogan Health extends this to a range of 3–12 months, advising use within 3 months for best results. NOVOS claims their stabilized NMN maintains over 99% purity even after months, suggesting good stability, though exact timelines vary by product.
- Refrigerated Storage: When stored in the refrigerator, NMN can remain stable for up to 18 months, according to Neurogan Health. This aligns with NAD Lab EU's recommendation to refrigerate for storage beyond 3 months to maintain potency, especially for stabilized forms.
- Degradation Risks: Degradation into nicotinamide is a concern, particularly for non-stabilized NMN. Sources like NOVOS and NAD Lab EU note that this process is slow in stabilized forms but can be accelerated by improper storage (e.g., exposure to humidity). RT Medical USA mentions that potency might decrease minimally after 3 months at room temperature, highlighting the importance of storage conditions.
- Manufacturer-Specific Considerations
- Different NMN products may have varying stability profiles due to formulation differences. For example:
- NOVOS emphasizes their next-generation NMN, which is more stable due to a crystalline arrangement, suggesting it can be stored at room temperature with minimal degradation.
- RT Medical USA and Neurogan Health provide general guidelines, noting that stabilized NMN does not require refrigeration unless stored for extended periods, but always recommend following manufacturer instructions for specific products.
- Scientific and Expert Insights
- Scientific papers, such as those from PMC, indicate NMN's stability in water for 7–10 days at room temperature, with 93%–99% remaining intact. While this pertains to liquid forms, it underscores NMN's sensitivity to environmental conditions. Expert opinions, like those from David Sinclair, historically stressed cold storage, but modern production techniques have improved stability, reducing the necessity for strict refrigeration for short-term storage.
- Leucine
- Leucine, an essential branched-chain amino acid (BCAA).
Action Mechanism Clinical Relevance Muscle Protein Synthesis Activates mTOR pathway Muscle growth, recovery, sarcopenia Insulin Secretion Enhancement Acts as insulin secretagogue with carbs Blood sugar regulation, diabetes management Anti-Inflammatory Effects Reduces inflammation, lowers CRP Exercise recovery, chronic inflammation Growth Hormone Stimulation Modulates GH-IGF-1 system Growth, metabolism, animal studies strong Wound Healing and Tissue Repair Promotes protein synthesis Injury recovery, tissue regeneration Prevention of Muscle Breakdown Maintains nitrogen balance, anti-catabolic Stress, trauma, cachexia prevention Blood Sugar Regulation Enhances glucose uptake via insulin Metabolic health, glucose control
- Threonine
- Research suggests that Threonine supplementation enhances hepatic lipid metabolism, reducing the risk of fat accumulation in the liver, which can lead to conditions like hepatic steatosis.
- Threonine deficiency can induce hepatic triglyceride accumulation, while supplementation exerts a protective effect by regulating lipogenesis signaling pathways and thermogenic gene expression. For example, a study on obese mice showed that Threonine supplementation restored decreased UCP1 expression, highlighting its potential in managing lipid metabolic disorders.
- Supplementing a Threonine-deficient diet in rats reduced liver fat accumulation, supporting the notion that adequate Threonine levels are crucial for preventing fatty liver (Prevention of Fatty Liver due to Threonine Deficiency by Moderate Caloric Restriction | Nature).
- Threonine's role in protein synthesis is fundamental, given its status as an essential amino acid. It is a building block for proteins, notably collagen, elastin, and enamel protein, which are critical for the structural integrity of connective tissues. This is evident from sources like Dr. Axe, which detail Threonine's involvement in forming the foundation of bones, muscles, and skin (Threonine Benefits, Uses, Foods, Supplements and Side Effects - Dr. Axe). The PMC review further elaborates that Threonine is required for synthesizing Threonine-rich proteins like mucins, with 71% of total Threonine usage in piglets dedicated to mucosal protein synthesis, underscoring its importance in tissue repair and maintenance.
- Threonine's impact on intestinal health is another significant pharmacological action, with high intestinal extraction rates (40–60% of dietary intake) used for mucosal protein synthesis and oxidation. The PMC article provides detailed insights, noting that Threonine maintains mucosa integrity, enhances villus height, and affects digestive enzyme synthesis, with specific demands like 11% of total protein for amylase synthesis in broilers. It also plays a role in gut microbiota, reducing pathogenic bacteria like Salmonella and E. coli while increasing beneficial microbes like Lactobacillus, as seen in studies with dietary Threonine levels 26% above NRC recommendations.
- Moreover, Threonine supports immune function within the gut, comprising 7–11% of IgA and modulating cytokine expression via pathways like MAPK and TOR. For instance, it up-regulates IL-6 in piglets and affects mRNA expression of immune-related genes, suggesting a role in enhancing gastrointestinal immune responses (Physiological Functions of Threonine in Animals: Beyond Nutrition Metabolism).
- Threonine serves as a precursor to other amino acids, notably glycine and serine, which have their own physiological roles. This is highlighted in DrugBank, where it is noted that Threonine is changed in the body to glycine, potentially reducing muscle contractions, though evidence for clinical benefits is limited (DrugBank Online: Threonine). The Wikipedia entry also mentions its use in synthesizing glycine for L-carnitine production in the brain and liver, particularly in rats, indicating a broader metabolic role (Threonine - Wikipedia).
- While there is interest in Threonine's potential for neurological conditions like ALS and multiple sclerosis, current evidence does not strongly support its effectiveness. WebMD notes that taking Threonine by mouth does not slow ALS progression or reduce symptoms, and there is insufficient reliable information for other uses, suggesting a need for further research (WebMD: Threonine).
- An unexpected detail is Threonine's role in cell proliferation and epigenetic regulation, particularly in embryonic stem cells (ESCs). The PMC review details that Threonine is necessary for the undifferentiated state and proliferation of mouse ESCs, with TDH mRNA levels 1000 times higher in ESCs than in differentiated cells. It also participates in histone methylation via Thr catabolism, maintaining the pluripotent state by affecting H3K4 di- and trimethylation, which could have implications for regenerative medicine and tissue repair.
Action Category Description Supporting Evidence Liver Health Aids fat metabolism, prevents hepatic fat accumulation PMC review, Nature study, DrugBank Protein Synthesis Essential for collagen, elastin, and mucin synthesis Dr. Axe, PMC review, DrugBank Intestinal Health Supports mucin production, enhances gut barrier, reduces pathogens PMC review, Nutrivore, ScienceDirect articles Immune Modulation Enhances gut immune responses, modulates cytokine expression PMC review, studies on broilers and piglets Precursor Role Precursor to glycine and serine, supports metabolic pathways DrugBank, Wikipedia Cell Proliferation Necessary for ESC proliferation, affects epigenetic regulation PMC review, unexpected in clinical pharmacology context Neurological Potential Limited evidence for ALS, MS; speculative for mental health WebMD, DrugBank, no strong clinical support
- Cystine
- Cystine’s main pharmacological action is as a precursor for Cysteine, which helps produce glutathione, a key antioxidant. This can protect cells from damage, potentially aiding skin conditions where oxidative stress is a factor.
- Cystine, the oxidized dimer of the amino acid Cysteine, is a sulfur-containing compound with significant biochemical and potential pharmacological roles, particularly in dermatology and cellular health.
- Cystine is formed by the oxidation of two Cysteine molecules, linked by a disulfide bond. This process is reversible, as Cystine can be converted back to Cysteine through reduction, typically by the addition of hydrogen. This interconversion is crucial, as Cysteine is a precursor for glutathione, a tripeptide (glutamate, cysteine, glycine) known for its antioxidant properties. Glutathione helps neutralize free radicals, protecting cells from oxidative damage, which is particularly relevant in skin health and conditions like acne, where oxidative stress is implicated.
- Cystine serves as a major precursor for glutathione synthesis
- Cystine interacts with the cystine-glutamate antiporter (system xc-), a sodium-independent transporter that exchanges extracellular cystine for intracellular glutamate. This system is critical for maintaining cellular redox balance, as it provides cystine for glutathione synthesis and regulates glutamate levels.
- Cystine is a component of keratin, a structural protein found in high quantities in hair (constituting about 5% of human hair) and nails.
- Its deficiency has been shown to slow skin and hair growth, suggesting a role in maintaining tissue integrity.
- In skin lightening, a randomized controlled trial found that oral supplementation of L-Cystine with reduced L-Glutathione significantly lightened dark spots, suggesting a synergistic effect.
Action Mechanism Relevance to Dermatology Precursor for Glutathione Synthesis Converted to Cysteine, supports antioxidant production May help manage oxidative stress in skin conditions like acne Cystine-Glutamate Transporter Interaction Exchanges cystine for glutamate, maintains redox balance Potential influence on skin cell function, limited direct evidence Support for Skin, Hair, Nail Health Component of keratin, structural role Used in supplements for hair loss, nail strength, indirect skin benefits
- Amandatine
- It seems likely that Amantadine acts as a PDE1 inhibitor, which may increase cyclic AMP levels and contribute to its neuroprotective effects.
- Studies indicate Amantadine increases AADC expression, enhancing dopamine synthesis from L-DOPA, which is crucial for its antiparkinsonian effects.
- Amantadine is known to block dopamine reuptake, increasing extracellular dopamine levels, which helps in managing Parkinson’s symptoms.
- The evidence leans toward Amantadine indirectly interacting with D2 receptors by raising dopamine levels, though it doesn’t directly bind to them, affecting receptor activity.
- Research suggests Amantadine stimulates noradrenergic responses, potentially enhancing noradrenaline release, which may contribute to its effects on mood and fatigue.
- It appears Amantadine has immunomodulatory effects, reducing T lymphocytes and altering cytokine levels, which could be relevant in conditions like multiple sclerosis.
- Beyond the listed terms, Amantadine also shows effects like NMDA receptor antagonism, acting as a sigma-1 receptor agonist, and modulating nicotinic acetylcholine receptors, among others, expanding its therapeutic potential.
- Amantadine is identified as a phosphodiesterase inhibitor, particularly affecting PDE1, with an IC50 of approximately 5 μM, potentially increasing cyclic AMP levels. This action may contribute to its neuroprotective and anti-inflammatory properties, as noted in studies like Kakkar et al. (1997) and Sancesario et al. (2014). This effect is significant in neurological conditions, where PDE1 inhibition can modulate cAMP signaling, potentially reducing levodopa-induced dyskinesias.
- Research, including a 1998 study by Hsu et al., demonstrates that Amantadine increases AADC mRNA in PC12 cells at concentrations of 10 and 100 μM, enhancing the enzyme’s activity by up to 27% in human striatum imaging studies. This increase is crucial for dopamine synthesis from L-DOPA, supporting its role in Parkinson’s disease therapy, as seen in studies like those by UCL Discovery.
- Amantadine’s ability to block dopamine reuptake is well-documented, with studies showing it increases extracellular dopamine levels in the striatum, an effect attenuated by coadministration of nomifensine, a known dopamine reuptake inhibitor. This action, detailed in research by Mizoguchi et al. (1994), enhances dopaminergic neurotransmission, aiding in symptom management for Parkinson’s and depression-like conditions.
- While Amantadine does not directly bind to D2 receptors, it indirectly interacts with them by increasing dopamine levels, which can enhance D2 receptor activity. This is supported by studies like Moresco et al. (2002), which observed increased [11C-]raclopride binding, indicating higher D2 receptor availability, likely due to elevated dopamine. This indirect effect is part of its dopaminergic actions, as noted in Wikipedia and ScienceDirect overviews.
- Amantadine’s noradrenergic effects include stimulating norepinephrine release, as evidenced by studies like Farnebo et al. (1971), which suggest it enhances noradrenergic transmission. This action is part of its broader neurotransmitter modulation, potentially contributing to its antidepressant and fatigue-reducing effects in conditions like multiple sclerosis, as seen in reviews by PMC.
- Amantadine exhibits immunomodulatory effects, reducing T lymphocytes and altering cytokine levels (e.g., IL-2, TNF, IFN-γ), as shown in studies on multiple sclerosis patients by Clark et al. (1989) and Wandinger et al. (1999). This action is particularly relevant in neuroinflammatory conditions, with evidence from ScienceDirect indicating its anti-inflammatory function.
- NMDA Receptor Antagonism: Amantadine acts as a weak, non-competitive NMDA receptor antagonist, stabilizing channel closure and reducing glutamatergic excitotoxicity, as detailed in Blanpied et al. (2005).
- Sigma-1 Receptor Agonist: It binds to and activates sigma-1 receptors, potentially contributing to neuroprotection, as noted in DrugBank and Wikipedia overviews.
- Nicotinic Acetylcholine Receptor Negative Allosteric Modulator: Amantadine modulates nicotinic acetylcholine receptors, affecting cholinergic signaling, which may play a role in its side effect profile and therapeutic actions.
- Induction of GDNF Expression: Studies like Caumont et al. (2006) report that Amantadine induces glial-derived neurotrophic factor (GDNF) expression in astroglia, supporting neuronal survival and potentially aiding in neurodegenerative disease management.
- Antiviral Action: Its inhibition of the M2 proton channel of influenza A virus prevents viral replication, though resistance has limited its use, as noted in MedlinePlus.
- Possible Weak 5-HT3 Receptor Antagonist: Some research suggests weak antagonistic effects at 5-HT3 receptors, potentially contributing to its effects on nausea and mood, though this is less studied.
- Blockade of Certain Ion Channels: Amantadine blocks ion channels like those encoded by SARS-CoV-2 (e.g., Protein E, ORF10), and studies on viral potassium channels suggest it affects channel function, as seen in PMC articles.
Action Description Relevance PDE1 Inhibition Inhibits PDE1, increasing cAMP levels, potentially neuroprotective. Neurological conditions, anti-inflammatory. AADC Expression Increase Enhances AADC activity, boosting dopamine synthesis from L-DOPA. Parkinson’s disease therapy. Dopamine Reuptake Inhibition Blocks dopamine reuptake, increasing extracellular dopamine. Antiparkinsonian, antidepressant effects. D2 Receptor Interactions (Indirect) Increases dopamine, indirectly affecting D2 receptor activity. Dopaminergic modulation. Noradrenergic Actions Stimulates norepinephrine release, enhancing noradrenergic transmission. Mood, fatigue management. Immunomodulation Reduces T lymphocytes, alters cytokines, anti-inflammatory. Neuroinflammatory conditions. NMDA Receptor Antagonism Weak non-competitive antagonist, reduces glutamatergic excitotoxicity. Neuroprotection, antiparkinsonian. Sigma-1 Receptor Agonist Activates sigma-1 receptors, potentially neuroprotective. Neuroprotection. Nicotinic ACh Receptor Modulator Negative allosteric modulator, affects cholinergic signaling. Side effect profile, therapeutic actions. GDNF Induction Induces GDNF expression in astroglia, supports neuronal survival. Neurodegenerative disease support. Antiviral Action Blocks M2 proton channel, inhibits influenza A replication (resistance noted). Historical antiviral use. Weak 5-HT3 Receptor Antagonist Possible weak antagonism, may affect nausea and mood. Less studied, potential side effects. Ion Channel Blockade Blocks certain viral and potassium channels, affects channel function. Antiviral, potential neurological effects.
- Glycine
Neurotransmitter and Brain Function
- Glycine is known to function as an inhibitory neurotransmitter, particularly in the spinal cord, where it helps calm nerve activity. This action might help reduce muscle spasms. Additionally, glycine interacts with NMDA receptors in the brain, which are involved in learning and memory, and this interaction is being studied for potential benefits in treating schizophrenia, especially for symptoms like social withdrawal.
Therapeutic Uses
- In medical settings, glycine is used as part of total parenteral nutrition, providing essential nutrients for patients who can’t eat normally. It’s also used as an irrigation solution during certain surgeries, like prostate procedures, due to its non-hemolytic properties. Emerging research suggests glycine may have antioxidant and anti-inflammatory effects, which could be helpful in conditions involving inflammation, though more studies are needed.
Unexpected Detail: Stroke Recovery Controversy
- An unexpected finding is the mixed evidence on glycine’s role in stroke recovery. Some studies suggest it can protect brain cells after an ischemic stroke, potentially improving outcomes, while others indicate high glycine intake might increase stroke mortality risk in certain groups, highlighting a need for careful consideration.
Survey Note: Comprehensive Analysis of Glycine’s Pharmacology Actions
- Glycine, a simple non-essential amino acid, plays a multifaceted role in pharmacology, extending beyond its basic function as a protein building block.
Neurotransmitter Actions
- Glycine is recognized as an inhibitory neurotransmitter, primarily in the brainstem and spinal cord. It binds to strychnine-sensitive glycine receptors, which are part of the ligand-gated ion channel superfamily and include a chloride channel. This binding increases chloride conductance, leading to neuronal hyperpolarization and inhibition of activity, which may contribute to its potential antispastic effects. For instance, interference with glycine release, as seen in Clostridium tetani infections, can cause spastic paralysis due to uninhibited muscle contraction, underscoring its role in motor control.
- Additionally, glycine interacts with the N-methyl-D-aspartate (NMDA) receptor complex at a strychnine-insensitive site, acting as a co-agonist. This modulation enhances NMDA receptor-mediated neurotransmission, which is crucial for excitatory signaling in the brain. This property has been explored in psychiatric contexts, particularly for schizophrenia, where supplemental glycine, when taken with some antipsychotic drugs, has shown potential in reducing negative symptoms like social withdrawal in patients unresponsive to conventional treatments. However, the evidence is mixed, with some studies showing no benefit with newer medications like clozapine.
Therapeutic Uses and Clinical Applications
- In clinical pharmacology, glycine is utilized in several practical applications. It is a common component of total parenteral nutrition, providing essential amino acids for patients unable to consume food orally, supporting metabolic needs.
- Another significant use is as a 1.5% irrigation solution during transurethral resection of the prostate (TURP), valued for its non-hemolytic properties, though excessive absorption can lead to complications like TUR syndrome, characterized by neurologic symptoms.
- Emerging research suggests glycine has antioxidant and anti-inflammatory properties, potentially beneficial in conditions like cardiovascular diseases, diabetes, and various inflammatory disorders. For example, studies indicate glycine can decrease pro-inflammatory cytokines and improve insulin response, possibly through modulation of nuclear factor kappa B (NF-κB) expression.
- These effects are thought to involve glycine’s interaction with neutrophils, reducing oxidant production and protecting against ischemia-reperfusion injury, as seen in animal models.
Sleep and Neurological Functions
- Glycine has also been studied for its impact on sleep quality and neurological functions. Research suggests that longer-term administration can improve sleep in healthy populations, potentially by altering body temperature and circadian rhythms, though studies often have small sample sizes and high risk of bias.
- Its role in enhancing neurological functions, such as memory and mood, is linked to its involvement in serotonin production and nerve signal transmission, though evidence is still developing.
Stroke Recovery: A Controversial Area
- An area of particular interest and controversy is glycine’s role in stroke recovery, specifically in ischemic stroke. Some studies suggest neuroprotective effects, with glycine treatment reducing infarct volume, improving neurologic function scores, and decreasing neuronal and microglial death. For instance, a 2000 trial in Cerebrovasc Dis found that doses of 1.0-2.0 g/day improved outcomes on scales like the Orgogozo Stroke Scale and Barthel Index, potentially through reducing glutamate levels and increasing GABA concentrations in cerebrospinal fluid.
- Another study from 2019 highlighted glycine’s ability to inhibit M1 microglial polarization via the NF-κB p65/Hif-1α pathway, suggesting anti-inflammatory benefits in stroke.
- However, contrasting evidence exists, particularly from dietary intake studies. A 2015 study in the Journal of Nutrition found that high glycine intake was associated with increased risk of mortality from ischemic stroke in men without hypertension, with hazard ratios suggesting a potential risk.
Precursor Role and Metabolic Contributions
- Beyond its direct actions, glycine serves as a precursor for several key metabolites, including glutathione, creatine, heme, purines, and porphyrins. Its role in glutathione synthesis is particularly notable, as glutathione is a powerful antioxidant that protects cells against oxidative stress, potentially reducing inflammation and supporting aging-related health.
- Creatine, another derivative, is vital for muscle energy, and glycine’s contribution here is explored in athletic supplements.
Safety and Considerations
- While glycine is generally considered safe, its safety profile, especially at high doses, requires further study. Some reports note mild sedation as a side effect, and caution is advised for use in young children, pregnant or breastfeeding women, and those with liver or kidney disease.
- The quality of glycine supplements varies, and users are encouraged to choose independently tested products and consult healthcare providers.
Target Actions Glutamate receptor ionotropic, NMDA 2A (GRIN2A, Q12879) Antagonist 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial (GCAT, O75600) Substrate 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1, P13196) Substrate 5-aminolevulinate synthase, erythroid-specific, mitochondrial (ALAS2, P22557) Substrate Glycine--tRNA ligase (GARS1, P41250) Substrate Bile acid-CoA:amino acid N-acyltransferase (BAAT, Q14032) Substrate N-arachidonyl glycine receptor (GPR18, Q14330) Substrate Glutathione synthetase (GSS, P48637) Substrate Glutamate receptor ionotropic, NMDA 2C (GRIN2C, Q14957) Agonist Serine hydroxymethyltransferase (Q53ET4) Product of Glycine N-acyltransferase (GLYAT, Q6IB77) Substrate Serine hydroxymethyltransferase, mitochondrial (SHMT2, P34897) Product of Glycine N-acyltransferase-like protein 2 (GLYATL2, Q8WU03) Substrate Glycine N-acyltransferase-like protein 1 (GLYATL1, Q969I3) Substrate Alanine--glyoxylate aminotransferase 2, mitochondrial (AGXT2, Q9BYV1) Product of Peroxisomal sarcosine oxidase (PIPOX, Q9P0Z9) Product of Glutamate receptor ionotropic, NMDA 3B (GRIN3B, O60391) Substrate Glycine receptor subunit alpha-1 (GLRA1, P23415) Ligand Alanine--glyoxylate aminotransferase (AGXT, P21549) Substrate Glycine receptor subunit beta (GLRB, P48167) Ligand Serine hydroxymethyltransferase, cytosolic (SHMT1, P34896) Product of Glycine receptor subunit alpha-3 (GLRA3, O75311) Ligand Glycine receptor subunit alpha-2 (GLRA2, P23416) Ligand Glycine N-methyltransferase (GNMT, Q14749) Substrate Glycine amidinotransferase, mitochondrial (GATM, P50440) Substrate
- Histidine
- Precursor to Histamine: Histidine turns into histamine, a chemical that helps with immune responses (like allergies), stomach acid production, and brain functions like wakefulness.
- Metal Ion Chelation: Histidine can bind to metals like iron and copper, which is important for enzyme activity and protecting against metal-related damage.
- Antioxidant Activity: It fights off harmful free radicals, protecting cells from damage, especially through a derivative called carnosine.
- Part of Active Peptides: Histidine is found in peptides like carnosine, which help with muscle pH balance and have antioxidant effects.
- Research suggests Histidine might help with conditions like metabolic syndrome, heart diseases, and inflammation, but these areas are still being studied, so we don’t have definitive answers yet.
- An unexpected detail is that it’s used in solutions for organ preservation, which is not something most people associate with amino acids.
- Histidine (HIS) is one of the nine essential amino acids that humans must obtain from their diet, found in protein-rich foods such as meat, fish, eggs, and beans. Its unique imidazole side chain, with pKa values around physiological pH, gives it distinctive chemical properties, making it a versatile player in biological systems.
- Pharmacological Actions
- Precursor to Histamine
- Histidine is decarboxylated by the enzyme histidine decarboxylase to form histamine, a critical mediator in multiple systems.
- Immune Response: Histamine is involved in allergic reactions, released from basophils and mast cells, causing symptoms like itching, swelling, and increased vascular permeability. It is treatable with antihistamines for conditions such as urticaria, asthma, and allergic rhinitis, and in severe cases like anaphylaxis, epinephrine is used.
- Gastric Acid Secretion: Histamine binds to H2 receptors on parietal cells, triggering hydrochloric acid release via proton pump activation, essential for digestion.
- Neurotransmission: In the brain, histamine modulates appetite, wakefulness, and emotions, with dysregulation linked to conditions like Tourette Syndrome, where mutations in the histidine decarboxylase gene and H3 receptor activity are implicated.
- No reported allergic reactions or peptic ulcers have been associated with increased Histidine intake, suggesting safety in typical supplementation.
- Precursor to Histamine
- The imidazole ring of Histidine, with pKa values of 6.2 and 6.5 for free L-HIS, 7.0 in carnosine, and 7.1 in anserine, acts as an effective pH buffer near physiological conditions.
- This property is clinically utilized in organ preservation solutions, such as the histidine-tryptophan-ketoglutarate (HTK) solution, containing 198 mM Histidine, and in myocardial protection during cardiac surgery, highlighting its role in maintaining cellular pH during stress.
- Metal Ion Chelation
- Histidine forms complexes with metal ions such as Fe²⁺, Cu²⁺, Co²⁺, Ni²⁺, Cd²⁺, and Zn²⁺, binding iron in haemoglobin and myoglobin, and is present in metalloenzymes like carbonic anhydrase and cytochromes.
- This chelation is crucial for enzyme function and protects against metal-induced neurotoxicity, with carnosine (CAR) specifically noted for protecting against copper- and zinc-induced damage.
- Antioxidant Activity
- Histidine mediates antioxidant effects through metal chelation, scavenging reactive oxygen species (ROS) and reactive nitrogen species (RNS), and sequestering advanced glycation end products (AGE) and lipoxidation end products (ALE).
- Carnosine is particularly effective, more so than free Histidine, in combating oxidative stress, with studies showing protective roles in conditions like chronic kidney disease and diabetes.
- Component of Biologically Active Peptides
- Histidine is integral to histidine-rich proteins (e.g., haemoproteins, histatins, histidine-rich calcium-binding protein, filaggrin) and dipeptides like carnosine and homocarnosine.
- These peptides have specific functions: carnosine maintains pH buffering in muscle tissue, combating intramuscular acidosis, and exhibits antibacterial activity, while histatins contribute to immunity.
- Therapeutic Potential and Clinical Studies
- Metabolic Syndrome and Inflammation: A 2013 study improved insulin resistance in obese women with metabolic syndrome by suppressing inflammation. Another 2014 study alleviated inflammation in adipose tissue of high-fat diet-induced obese rats via NF-κB- and PPARγ-involved pathways.
- Cardiovascular Protection: Histidine prevented brain infarction in postischemic rats (2005 study) and, in combination with vitamin C, protected against isoproterenol-induced acute myocardial infarction in rats (2016). It also mitigated doxorubicin-induced cardiomyopathy in rats when combined with N-acetylcysteine (2014).
- Diabetes and Oxidative Stress: A 2005 study delayed diabetic deterioration in mice and protected human low-density lipoprotein against oxidation and glycation, while a 2018 study highlighted its protective role against oxidative stress in anemia of chronic kidney disease.
- Inflammatory Bowel Disease: A 2009 study ameliorated murine colitis by inhibiting proinflammatory cytokine production from macrophages.
Safety and Dosing
- Histidine supplements are considered possibly safe when taken short-term, up to 4 grams daily for up to 12 weeks, and are well-tolerated. Precautions include avoiding use in folic acid deficiency due to potential formiminoglutamic acid (FIGLU) buildup, and insufficient reliable information exists for safety in larger amounts during pregnancy or breastfeeding, recommending sticking to dietary amounts.
Pharmacological Action Details pH Buffering Used in organ preservation (e.g., 198 mM in HTK solution), myocardial protection in surgery. Metal Ion Chelation Binds Fe²⁺, Cu²⁺, protects against neurotoxicity, essential for metalloenzymes. Antioxidant Activity Scavenges ROS/RNS, carnosine more effective, protects in diabetes, kidney disease. Histamine Precursor Affects immune cells, gastric acid, brain functions, no adverse reactions reported. Role in Peptides Carnosine buffers muscle pH, histatins provide immunity, antibacterial activity.
- Glutamic acid
- Neurotransmitter Role:
- Glutamic acid is the primary excitatory neurotransmitter in the central nervous system (CNS). It binds to various glutamate receptors, including ionotropic receptors (e.g., NMDA, AMPA, and kainate receptors) and metabotropic glutamate receptors (mGluRs).
- Activation of these receptors facilitates neuronal communication by increasing the influx of cations (like calcium and sodium) into neurons, leading to depolarization and signal transmission.
- This excitatory action is essential for learning, memory, and synaptic plasticity. However, excessive glutamate release can lead to excitotoxicity, a process implicated in neurodegenerative diseases like Alzheimer's, Parkinson's, and stroke-related brain damage.
- Excitotoxicity and Neuroprotection:
- In pharmacological contexts, glutamic acid's overactivation of receptors (especially NMDA receptors) can cause excessive calcium influx, triggering neuronal injury or death. This is a key mechanism in conditions like epilepsy, traumatic brain injury, and ischemia.
- Drugs targeting glutamate receptors (e.g., NMDA receptor antagonists like memantine) are used to mitigate excitotoxicity in such conditions.
- Metabolic Functions:
- Glutamic acid is a precursor to gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter, via the enzyme glutamic acid decarboxylase (GAD). This conversion is pharmacologically significant in treatments for anxiety, seizures, and other disorders where GABA modulation is beneficial (e.g., with drugs like benzodiazepines indirectly enhancing GABA activity).
- It also participates in the synthesis of glutathione, a major antioxidant, which protects cells from oxidative stress—a property exploited in therapies for liver disease and neurodegenerative conditions.
- Role in Protein Synthesis:
- As an amino acid, glutamic acid is incorporated into proteins, influencing cellular structure and function. Pharmacologically, this is relevant in nutritional supplements or therapies aimed at muscle repair or metabolic support.
- Gastrointestinal and Taste Effects:
- Glutamic acid, often in the form of monosodium glutamate (MSG), stimulates umami taste receptors. While not a direct pharmacological action, this property is used in studies of appetite regulation and sensory pharmacology.
- In the gut, glutamate signaling via receptors may influence digestion and nutrient absorption, an emerging area of pharmacological research.
- Acid-Base Balance:
- Glutamic acid contributes to ammonia detoxification in the liver by forming glutamine, a process critical in managing metabolic acidosis or hyperammonemia (e.g., in hepatic encephalopathy). Pharmacological agents enhancing this pathway are sometimes explored in such conditions.
- Agonists/Antagonists: Drugs targeting glutamate receptors (e.g., ketamine, an NMDA antagonist) are used in anesthesia, depression treatment, and chronic pain management.
- Neurological Disorders: Modulation of glutamatergic activity is a focus in epilepsy (e.g., lamotrigine reduces glutamate release), multiple sclerosis, and schizophrenia research.
- Nutritional Pharmacology: Glutamic acid supplementation is studied for its potential in muscle recovery and immune function, though evidence is mixed.
- Oxiracetam
- Oxiracetam is generally considered safe at doses up to 2,400 mg, with few side effects reported.
- It enhances the release and uptake of acetylcholine.
- While its primary effects are on acetylcholine and glutamate, there is some indication it may influence dopamine and serotonin to a lesser extent.
- Oxiracetam exhibits neuroprotective effects, protecting neurons from oxidative stress and excitotoxicity.
- Studies in rats with chronic cerebral hypoperfusion show it decreases neuronal degeneration and white matter lesions, particularly at doses of 100-200 mg/kg, with significant reductions in the hippocampus and cortex.
- Inhibits astrocyte activation.
- Increases cerebral blood flow.
- In animal studies, doses of 100 mg/kg and 200 mg/kg significantly increased cerebral blood flow, with statistical significance (P < 0.01 and P < 0.05, respectively).
- Increases ATP synthesis.
- In the acute phase post-cerebral hypoperfusion, it decreases abnormal accumulation of glucose and citric acid while increasing levels of ATP, ADP, AMP, and GMP in the cortex.
- enhances antioxidant levels, such as glutathione and ascorbic acid, with significant increases observed (P < 0.01 for glutathione, P < 0.001 for ascorbic acid with (S)-oxiracetam).
- When administered systemically to rats at 200 mg/kg orally or 100 mg/kg intra-arterially, it is found unmetabolized, with the highest amounts in the septum, followed by the hippocampus, and smaller amounts in the cerebral cortex and striatum. Its distribution pattern is similar when administered directly into the lateral ventricles, indicating its tropism is independent of the administration route.
- Estimated brain amounts range from 1.9 to 19 nmols/rat, delivered via cannula in conscious, freely moving rats, highlighting its effective brain penetration.
- Oxiracetam demonstrates specific therapeutic effects, such as dose-dependently antagonizing scopolamine-induced amnesia in rats, which is indicative of its ability to counteract cholinergic deficits.
- The (S)-enantiomer is identified as the active ingredient, showing higher absorption rates and slower elimination compared to the racemic mixture, and it induces long-term synaptic potentiation in rat hippocampal slices, further supporting its cognitive-enhancing potential.
- Oxiracetam is generally considered safe, with studies reporting no significant side effects at single and repeated oral dosages up to 2,400 mg.
Summary Table of Key Pharmacological Actions
Action Details Cognitive Enhancement Improves memory, learning, and cognitive performance, especially in dementia. Neurotransmitter Modulation Enhances acetylcholine release, modulates glutamate via AMPA receptors. Neuroprotection Protects against oxidative stress, reduces neuronal damage and inflammation. Cerebral Blood Flow Increases blood flow, supporting neuronal function. Energy Metabolism Increases ATP, regulates glutamine-glutamate cycle, enhances antioxidants. Brain Penetration Crosses blood-brain barrier, targets septum, hippocampus, cortex. Specific Effects Antagonizes scopolamine-induced amnesia, (S)-enantiomer is active. Safety Safe up to 2,400 mg, few side effects, not FDA-approved in the US.
- 1P-LSD
- Also known as 1-propanoyl-lysergic acid diethylamide (1-propionyl-LSD).
- Psychoactive substance related to LSD.
- Thought to work by turning into LSD in the body, leading to similar effects.
- 1P-LSD is quickly changed into LSD after you take it, whether by mouth or injection. Studies show it’s almost fully converted, with LSD detectable in blood and urine soon after.
- 1P-LSD’s effects are mainly due to LSD.
- Mainly affects serotonin receptors, especially the 5-HT2A type, which is key for the mind-altering effects like hallucinations and altered perception.
- Interacts with other serotonin and dopamine receptors, but these are less understood for 1P-LSD specifically.
- Can boost brain plasticity, potentially helping with memory and neural growth, similar to LSD.
- It seems likely that 1P-LSD is not addictive, with no signs of compulsive use or withdrawal.
- Tolerance builds quickly, meaning repeated use within a short time reduces its effects, resetting after a few days without use.
- Theoretical risk of heart issues due to effects on 5-HT2B receptors.
- Effects last around 7–12 hours, similar to LSD.
- Blood half-life of about 6.4 hours for 1P-LSD.
- Almost fully absorbed when taken by mouth, and LSD can be detected in urine for up to 80 hours.
- A study published in Drug Testing and Analysis in 2020 found that after oral or intravenous administration of 100 μg 1P-LSD hemitartrate (equivalent to 71.2 μg LSD base), 1P-LSD was detectable in serum for up to 4.16 hours, after which it was completely converted to LSD. This conversion was confirmed by detecting LSD in all serum samples, with the last sampling after approximately 24 hours, and in urine for up to 80 hours. The bioavailability of LSD after oral ingestion of 1P-LSD was close to 100%, indicating efficient conversion.
- LSD (and thus 1P-LSD) binds with high affinity to most serotonin receptors except 5-HT3 and 5-HT4, affecting 5-HT1A, 5-HT2B, 5-HT2C, 5-HT5A, and 5-HT6 at recreational doses. Specific affinity values include:
- 5-HT1A: 0.64 – 7.3 nM
- 5-HT2A: 0.47 – 21 nM
- 5-HT2B: 0.98 – 30 nM
- 5-HT2C: 1.1 – 48 nM
- It also shows significant affinity for dopamine receptors, with Ki values such as D1: 155–340 nM and D2: 61–126 nM, though these are lower than for serotonin receptors.
- The conversion of 1P-LSD to LSD leads to increased glutamate release in the cerebral cortex, specifically in layer V, enhancing excitation.
- 1P-LSD, like LSD, exhibits significant tachyphylaxis, with tolerance developing almost immediately after ingestion, as noted in PsychonautWiki. Tolerance is reduced to half after 5–7 days and returns to baseline after 14 days without further consumption. There is cross-tolerance with other psychedelics, such as mescaline and psilocybin.
- While 1P-LSD itself shows 38% the potency of LSD in mice, as per PsychonautWiki, its effects are primarily due to conversion to LSD.
- The elimination half-life for 1P-LSD is approximately 6.4 hours, while for LSD, it is about 5.7 hours, as per the PubMed entry.
- 1P-LSD is metabolized in the liver by CYP450 enzymes, with the major metabolite being LSD.
- Given its prodrug nature, 1P-LSD’s pharmacological actions mirror those of LSD, with differences primarily in pharmacokinetics, such as rate of absorption and duration.
Table: Summary of Pharmacological Actions
Aspect Details for 1P-LSD (via LSD Conversion) Primary Mechanism Serotonin 5-HT2A receptor agonist, psychedelic effects mediated by this. Receptor Affinity High affinity for 5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C; moderate for dopamine. Neurotransmitter Effects Increases glutamate release, enhances D2–5-HT2A signaling. Psychoplastogenic Effects Promotes neural plasticity, binds to TrkB receptor. Tolerance Rapid tolerance, resets after 3–4 days; cross-tolerance with psychedelics. Addiction Liability Non-addictive, no withdrawal, low abuse potential. Potency Effects at low doses (via LSD), 200x psilocybin, 5,000x mescaline potency. Duration 7–12 hours, onset 0.4–1.0 hours. Metabolism Converted to LSD, liver metabolism by CYP450, 13% urine elimination in 24h. Potential Risks Theoretical cardiac risk due to 5-HT2B agonism, needs more research. Condition Bioavailability Onset of Effects Duration Notes Empty Stomach Likely close to 100% Faster, more intense Potentially shorter Based on user reports and inferred from light meal study. Light Meal (Study) Close to 100% (92-100%) Not specified, likely slow Not specified Grumann et al. (2020), experiments started 2 hours after light breakfast. Full Stomach Possibly high, data limited Slower, less intense Potentially longer Inferred from LSD studies and user reports, no direct data for 1P-LSD.
- O-DSMT
- Also known as desmetramadol and O-desmethyltramadol.
- Key component of the pain medication tramadol.
- Known for its strong pain-relieving effects.
- Works primarily by mimicking natural painkillers in the body.
- Influences other systems to help manage pain, especially in complex cases.
- Mainly activates μ-opioid receptors.
- Much stronger than tramadol, with studies showing it’s 2–4 times more potent.
- Block the reuptake of norepinephrine, particularly with the (-)-enantiomer.
- Research indicates it may cause fewer breathing issues compared to other strong painkillers.
- For people with kidney problems, O-DSMT can build up, increasing risks like seizures or breathing difficulties, so doctors often lower the dose.
- It's the primary active metabolite of tramadol.
- O-DSMT is formed through the demethylation of tramadol by the liver enzyme CYP2D6, a process analogous to the metabolism of codeine to morphine.
- As of May 7, 2025, O-DSMT is not approved for medicinal use in any country but is significant in research and has been noted as a designer drug due to its unscheduled status in some jurisdictions (source).
- The (+)-enantiomer is identified as a G-protein biased full agonist, which means it preferentially activates the G-protein signaling pathway over the β-arrestin pathway. This bias is significant as it may reduce adverse effects like respiratory depression, a major concern with opioids.
- Up to 200 times greater affinity for μ-opioid receptor than tramadol.
- Also shows far lower affinity for δ- and κ-opioid receptors.
- Both enantiomers are inactive as serotonin reuptake inhibitors, distinguishing it from tramadol, which has dual serotonin and norepinephrine reuptake inhibition properties (source).
Enantiomer Serotonin Reuptake Norepinephrine Reuptake (+)-O-DSMT Inactive Inactive (-)-O-DSMT Inactive Active (retains inhibition) - Antagonism at the 5-HT2C receptor at pharmacologically relevant concentrations. This antagonism can lead to increased release of dopamine and norepinephrine, potentially influencing mood, anxiety, feeding behavior, and reproductive behavior (source).
- Genetic variations in CYP2D6 can significantly impact its efficacy and safety.
- CYP2D6 poor metabolizers may experience reduced analgesia, while ultra-rapid metabolizers may face increased risks of side effects like respiratory depression and death due to higher O-DSMT levels (source).
- Galantamine
- Galantamine has a dual approach:
- It stops an enzyme called acetylcholinesterase from breaking down acetylcholine, letting more of this memory-boosting chemical stay active in the brain.
- It also enhances the activity of nicotinic acetylcholine receptors, which are like switches that help acetylcholine work better, potentially improving communication between brain cells.
- Galantamine may protect brain cells from damage by acting as an antioxidant and reducing inflammation.
- Tertiary alkaloid drug.
- Reversible, competitive inhibitor of acetylcholinesterase (AChE). This enzyme typically hydrolyzes acetylcholine (ACh), a neurotransmitter critical for memory, thinking, and reasoning, into choline and acetate. By inhibiting AChE, Galantamine increases the concentration of ACh in the synaptic cleft, thereby enhancing cholinergic neurotransmission. This action is particularly relevant in AD, where cholinergic deficits are a hallmark.
- Research indicates Galantamine is 50-fold more selective for AChE over butyrylcholinesterase (BuChE), with an IC50 for AChE of 0.35 μM and for BuChE of 18.6 μM.
- It has a bioavailability of 80–100%, a protein binding of 18%, and an elimination half-life of 7 hours, with peak AChE inhibition occurring approximately 1 hour after an 8 mg oral dose in healthy volunteers (source).
- Acts as a positive allosteric modulator of nicotinic acetylcholine receptors (nAChRs), particularly the α7 and α4β2 subtypes. This means it binds to allosteric sites on these receptors, triggering a conformational change that enhances their response to ACh. At concentrations of 0.1–1 μM, it potentiates agonist responses, while at higher concentrations (>10 μM), it may inhibit activity ().
- Exhibits significant neuroprotective properties. It acts as an antioxidant, scavenging reactive oxygen species (ROS) and protecting neurons from oxidative damage (source).
- Prevents the activation of microglia and astrocytes, key players in neuroinflammation, and counters the expression of inflammatory markers such as NF-κB, p65, TNF-α, IL-1β, and IL-6 in the hippocampus (source).
- Increases the levels of glutamate, serotonin, norepinephrine, dopamine, and GABA.
- Stimulates vascular endothelial growth factor (VEGF) through nicotine receptors, increasing phosphorylation of Akt and CREB, and reducing the expression of FoXO1, MuRF-1, and atrogin-1. This enhances the release of acetylcholine, ATP, and brain-derived neurotrophic factor (BDNF), potentially supporting muscle function.
- It stimulates proliferation in the hippocampus subgranular zone via M1 muscarinic receptors and supports cell survival through α7 nAChRs, involving insulin-like growth factor 2.
- Clinical studies have shown Galantamine reduces cocaine use frequency at 8 mg/day and improves sustained attention and response inhibition in cigarette smokers, as well as decreasing alcohol consumption in detoxified individuals.
- The dual mechanism of AChE inhibition and nAChR modulation is central to Galantamine's efficacy in AD. Clinical trials have demonstrated improvements in cognitive function, with doses ranging from 8–32 mg/day showing benefits over 3–6 months, sustained at 24 mg/day for 12 months.
- Galantamine is well-absorbed, with linear pharmacokinetics and rapid, complete absorption. About 75% is metabolized in the liver via CYP2D6 and CYP3A4, with key pathways including O-demethylation, N-demethylation, epimerization, and glucuronidation. Within 24 hours, approximately 20% is excreted unchanged in urine.
Summary Table: Key Pharmacological Actions
-
Action Description AChE Inhibition Reversible, competitive, selective; increases ACh levels, IC50 for AChE: 0.35 μM. nAChR Modulation Positive allosteric modulator of α7, α4β2 subtypes; enhances receptor sensitivity at 0.1–1 μM. Neuroprotection Antioxidant, inhibits Aβ aggregation, promotes neurogenesis via M1, α7 receptors. Anti-Inflammatory Activity Prevents microglia/astrocyte activation, reduces NF-κB, TNF-α, IL-1β, IL-6. Neurotransmitter Modulation Increases glutamate, serotonin, norepinephrine, dopamine, GABA release. Neuromuscular Effects Stimulates VEGF, enhances ACh, ATP, BDNF release, affects Akt, CREB pathways. Neural Proliferation Stimulates hippocampal progenitor cells via M1, α7 receptors, involves IGF-2. SUDs Treatment Reduces cocaine use, improves attention in smokers, decreases alcohol consumption.
- Eutropoflavin
- Also known as: 4'-Dimethylamino-7,8-dihydroxyflavone
- Acts as a selective TrkB receptor agonist and function:
- PI3K/Akt Pathway: Promotes cell survival by inhibiting apoptosis.
- MAPK/ERK Pathway: Enhances synaptic strength and memory consolidation, supporting cognitive functions.
- PLCγ Pathway: Involved in long-term potentiation, which is essential for learning and memory.
- Studies suggest it may protect brain cells, promote new cell growth, and have effects similar to antidepressants in animals.
- Might improve memory and mental clarity.
- Could influence systems like dopamine and serotonin, which are involved in mood and thinking.
- Orally bioavailable and readily reaches the brain.
- Exhibits robust neuroprotective properties, particularly in protecting dopaminergic neurons from toxicity, such as rotenone-induced damage.
- Reduces oxidative stress and promotes neuron survival, potentially offering greater efficacy than tropoflavin due to stronger TrkB binding.
- Enhances hippocampal neurogenesis and synaptic plasticity, which are crucial for brain repair and cognitive function. These effects are supported by preclinical studies showing improved neuronal growth and connectivity in animal models.
- Eutropoflavin has demonstrated antidepressant-like effects in rodents, notably reducing immobility time in the forced swim test and tail suspension test, indicators of antidepressant potential. These effects are dependent on the TrkB pathway, suggesting a role in modulating mood through BDNF signaling.
- Indirectly influences several neurotransmitter systems through its BDNF/TrkB activation:
System Effect Dopaminergic Enhances dopamine signaling and neuroprotection, particularly in the prefrontal cortex and striatum. Glutamatergic Enhances NMDA and AMPA receptor function through increased synaptic plasticity, supporting cognitive processes. Serotonergic Tied to antidepressant responses, potentially enhancing serotonin-based treatments. - Impacts sleep regulation, with studies indicating a reduction in non-REM sleep and decreased orexin A levels, which may influence wakefulness and sleep architecture (source).
- Tmax of approximately 10 minutes and a plasma half-life of about 2 hours, with effects peaking at 4 hours and partially decaying at 8-16 hours (source). It is fat-soluble, and absorption is enhanced when taken with a meal containing fat. In rodents, Eutropoflavin has a Tmax of approximately 10 minutes and a plasma half-life of about 2 hours, with effects peaking at 4 hours and partially decaying at 8-16 hours (source). It is fat-soluble, and absorption is enhanced when taken with a meal containing fat.
- Generally well-tolerated, with rare anecdotal reports of headaches, fatigue, or overstimulation, especially at higher doses (source).
- There are no known tolerance issues, though cycling (e.g., 5 days on/2 days off) is recommended as a precaution.
- GB-115
- Also known as: Ranquilon, L-Tryptophanamide, N-(1-oxo-6-phenylhexyl)glycyl-, N-6-Phenylhexanoyl-glycyl-L-tryptophan, N-(1-Oxo-6-phenylhexyl)glycyl-L-tryptophanamide, N-phenylhexanoyl-glycyl-L-tryptophan amide
- Retroanalogue of cholecystokinin-4 (CCK-4).
- Research indicates GB-115 has significant anxiolytic properties, making it a candidate for treating generalized anxiety disorder (GAD). A clinical study involving 31 patients with GAD, diagnosed per ICD-10 (F41.1), determined an effective dose of 6 mg per day. The treatment, administered over 21 days, was associated with a fast onset of anxiolytic effects, beneficial impacts on sleep disturbances, and improvements in autonomic symptoms. Additionally, it favorably altered attention parameters, suggesting cognitive benefits alongside anxiety reduction.
- In preclinical models, GB-115 demonstrated anxiolytic effects in behavioral tests. For instance, in outbred mice, doses ranging from 0.1 to 0.5 mg/kg were effective in the open field test, while in inbred BALB/c mice, doses of 0.1 and 5.0 mg/kg showed efficacy. In the elevated plus-maze test, a standard measure of anxiety, GB-115 increased the time spent in open arms in outbred rats at 0.5-0.7 mg/kg and in BALB/c mice at 0.1 mg/kg, indicating reduced anxiety-like behavior (source).
- Further, a study on pharmaceutical compositions of GB-115 found that a controlled-release formulation (composition 4) increased residence time in the elevated plus-maze open arms at doses of 0.3 mg/kg and 0.9 mg/kg (p < 0.01) compared to placebo, highlighting its potential for optimized delivery (source).
- GB-115’s impact on cognitive functions is notable, particularly in GAD patients. A study with 25 patients (mean age 35.76 ± 8.55 years) treated with 6 mg/day for 21 days reported significant improvements in cognitive metrics (source). The results, summarized in the table below, show enhancements in reaction time, attention parameters, and performance in the Shulte-Platonov tables test:
Measure Background Day 3 Day 7 Day 14 Day 21 % Improvement (Day 21 vs Background) Reaction Time (msec) 449.19±64.91 - 418.17±61.49* 422.25±70.69* 406.5±52.79* 9.5% Attention Parameters (msec) 316.41±42.35 305.95±45.31* - - 300.14±47.74* 5.14% Shulte-Platonov Tables (sec) 68.84±16.78 - 59.40±13.71* 57.88±12.82* 53.40±13.19* 22.4% - (*p≤0.01 for reaction time and Shulte-Platonov on Days 7, 14, 21; p≤0.05 for attention parameters on Days 3, 21 compared to background). These improvements suggest GB-115 not only mitigates anxiety but also enhances cognitive processing, potentially benefiting patients with GAD-related cognitive deficits.
- GB-115 exhibits immunocorrecting properties, particularly in animal models. In intact mice, doses of 0.1–10 mg/kg stimulated phagocytic activity of peritoneal macrophages and enhanced humoral immune responses. In mice with secondary immunodeficiency induced by cyclophosphamide, GB-115 demonstrated activity in restoring immune function, suggesting potential applications in conditions involving immune dysregulation (source).
- The anti-inflammatory actions of GB-115 are evident in preclinical models. In studies using ConA- and carrageenan-induced inflammation, intraperitoneal injections at doses of 0.1, 1, and 10 mg/kg reduced inflammatory responses. Notably, at 1 mg/kg, GB-115 alleviated symptoms in a model of experimental autoimmune encephalomyelitis, improving spontaneous locomotor activity, promoting recovery of thymus weight, and reducing edema and neutrophil infiltration in brain tissue. It also suppressed the generation of active oxygen forms by neutrophils, as measured by chemiluminescence, indicating a role in mitigating oxidative stress-related inflammation (source).
- GB-115’s interaction with pain pathways is complex, involving opioidergic systems. In mice, it potentiated morphine-induced analgesia in the hot-plate test, an effect that was naloxone-dependent, suggesting involvement with opioid receptors. However, it did not modulate behavior in the tail-flick test, indicating specificity to certain pain modalities, likely supraspinal mechanisms. Further, research suggests GB-115 (4 mg/kg) increases response latency in the hot-plate test in a naloxone-independent manner, while producing a moderate naloxone-reversible effect in the tail-flick test, pointing to spinal-level opioidergic interactions (source1 and source2).
- The primary mechanism of GB-115 involves antagonism of CCK2 receptors, which are critical in anxiety and pain modulation.
- GB-115 is under investigation in clinical trials for anxiety in neurasthenia and adjustment disorders, suggesting broader applications beyond GAD. Its ability to improve cognitive functions, modulate immune responses, and reduce inflammation positions it as a candidate for conditions involving these systems (source).
- Rapastinel
- Also known as: GLYX-13
- Tetrapeptide with the amino acid sequence Thr-Pro-Pro-Thr-NH2.
- Rapastinel failed to demonstrate efficacy in phase III clinical trials for MDD, as announced by Allergan on March 6, 2019.
- Positive allosteric modulator of N-methyl-D-aspartate receptors (NMDARs), which are critical for synaptic plasticity and neurotransmission.
- Unlike ketamine, which blocks NMDARs, Rapastinel enhances NMDAR activity through a novel binding domain independent of the glycine coagonist site.
- Acts as a weak coagonist with glutamate, facilitating NMDAR-mediated signal transduction. This mechanism is believed to underlie its potential antidepressant effects by promoting long-term potentiation (LTP) and enhancing synaptic plasticity, particularly in the hippocampus and medial prefrontal cortex (mPFC).
- Detailed pharmacological studies indicate that Rapastinel does not bind to the NMDAR glycine site, with 0% displacement observed at 30 μM, suggesting a high-affinity site near the amino terminal-ligand binding interface. Critical amino acids, such as R392E in NR2A and R393E in NR2B, are essential for its effects, and their mutation abolishes Rapastinel’s activity.
- In preclinical models, Rapastinel’s brain concentrations associated with antidepressant-like efficacy range from 30 to 100 nM.
- A dose of 10 mg/kg results in approximately 30 nM, while 30 mg/kg achieves about 100 nM.
- Pharmacokinetic data show a T_max of approximately 20 minutes and a half-life of about 20 minutes in the extracellular fluid, indicating rapid distribution and clearance.
- Pharmacodynamics
- NMDAR Subtype Modulation: Rapastinel enhances [3H] MK-801 binding in HEK cells expressing NR2A-D subtypes with the following EC50 values:
- NR2A: 9.8 pM
- NR2B: 9.9 nM
- NR2C: 2.2 pM
- NR2D: 1.7 pM
- In comparison, glycine has EC50 values ranging from 100 to 350 nM for these subtypes, highlighting Rapastinel’s higher potency at certain NMDAR subtypes.
- Calcium Mobilization: At concentrations of 10 to 300 nM, Rapastinel enhances NMDA-induced calcium influx by approximately 30%. At concentrations ≥1 μM, it inhibits calcium influx by about 25%. The EC50 for NMDA is 2.8 μM, and for D-serine, it is 290 nM, indicating its modulatory effects on calcium signaling pathways.
- Electrophysiological Effects: In rat mPFC slices, 100 nM Rapastinel increases NMDAR-mediated excitatory postsynaptic currents (EPSCs) and enhances the magnitude of LTP, with the effect being maximal at 100 nM and reduced at 1 μM. It does not affect paired-pulse facilitation or miniature EPSCs, suggesting a postsynaptic action. This enhancement is linked to increased synaptic plasticity, potentially contributing to its antidepressant effects.
- Comparison to Ketamine: Unlike ketamine, which inhibits NMDARs with an IC50 of approximately 1.0 μM and 98% displacement at the MK-801 site, Rapastinel enhances NMDAR activity. Additionally, Rapastinel does not affect presynaptic glutamate release, a mechanism observed with ketamine, further distinguishing its pharmacological profile.
- Clinical Trials
- Phase II Trial: A randomized, double-blind, placebo-controlled proof-of-concept study involved 116 patients with MDD who had not responded to at least one biogenic amine antidepressant. Patients received a single intravenous (IV) dose of Rapastinel at 1, 5, 10, or 30 mg/kg or placebo. The results, published by Preskorn et al. in 2015, showed that doses of 5 and 10 mg/kg significantly reduced depressive symptoms as measured by the Hamilton Depression Rating Scale (Ham-D17) from day 1 to day 7, with an onset of action within 2 hours as assessed by the Bech-6 subscale (source). No psychotomimetic or significant side effects were reported, and the effect was maintained for an average of 7 days.
- Phase III Trials: Despite the promising phase II results, multiple phase III studies failed to demonstrate efficacy. Three trials involving a total of 1,510 patients with MDD who had a partial response to antidepressant therapy were conducted. In two studies totaling 872 patients, participants received weekly IV injections of 450 mg Rapastinel or placebo in addition to their oral antidepressants. A third study with 638 participants included a third treatment arm of 225 mg Rapastinel weekly. The primary endpoint was the change in scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline at the end of three weeks. In all three trials, Rapastinel did not significantly differ from placebo, as reported in March 2019 (source). This failure raised questions about its clinical utility, despite earlier promise.
- Safety and Tolerability
- In the phase II trial, Rapastinel was well tolerated, with no reports of psychotomimetic effects or other significant side effects, distinguishing it from ketamine, which is known for such side effects. In phase III trials, Rapastinel was also found to be well tolerated, but its lack of efficacy over placebo limited its clinical advancement. Additional studies, such as a randomized trial assessing effects on driving performance, showed that single doses of 900 or 1800 mg did not impair driving compared to placebo, further supporting its safety profile (source).
- Preclinical studies provided insights into Rapastinel’s effects on synaptic plasticity. It increases dendritic spines 24 hours post-treatment in the rat dentate gyrus and layer V of the mPFC, enhances LTP, and reduces long-term depression (LTD) at Schaffer collateral-CA1 synapses in the hippocampus. It also facilitates metaplasticity processes, differing from NMDA receptor antagonists. The BDNF-TrkB-mTOR signaling pathway in the midbrain ventrolateral periaqueductal gray is required for its antidepressant effects, and genetic deletion of GluN2B from excitatory neurons in the mPFC blocks these effects, highlighting cell-type specificity (source).
- HHC
Condition Onset of Effects Bioavailability Likely Mechanism Empty Stomach Faster (e.g., 1.5 hours) Lower (e.g., ~6% for CBD) Quick absorption, limited fat for solubility Full Stomach Delayed (e.g., 5-10 hours) Higher (potentially 4x, e.g., ~24% for CBD) Enhanced by fats, lymphatic uptake, delayed gastric emptying
- Matrine
- Other name: CAS 519-02-8.
- Alkaloid extracted from plants such as Sophora flavescens.
- Research suggests the following actions, with mechanisms often involving key signaling pathways:
- Anti-cancer Effects: Matrine inhibits cancer cell proliferation and induces apoptosis, potentially through pathways like NF-κB, PI3K/AKT, and Wnt/β-catenin. It arrests the cell cycle at G1/G0 phase and inhibits metastasis, as seen in studies on colorectal and lung cancer cells . For example, it reduced tumor volume in mouse models with inhibition rates of 16.29% and 35.35% (source).
- Anti-inflammatory Effects: It reduces pro-inflammatory cytokines such as IL-4, IL-5, IL-13, and TNF-α, making it promising for conditions like asthma and rheumatoid arthritis. Studies on asthmatic mice showed reduced eosinophils and IgE levels, suggesting modulation of Th2 cytokines (source).
- Anti-microbial Effects: Matrine demonstrates activity against bacteria and viruses, potentially due to its ability to disrupt microbial cell processes, though specific time courses are not detailed.
- Neuroprotective Effects: It may protect against neuronal damage in conditions like Alzheimer's and Parkinson's, possibly by regulating apoptosis and reducing oxidative stress, as noted in reviews (source).
- Cardioprotective Effects: Matrine has shown potential in treating myocardial ischemia, likely through anti-inflammatory and anti-apoptotic mechanisms, though exact durations of effect are not specified.
- Half-Life: Research suggests a plasma half-life of approximately 10.0 ± 2.8 hours in humans, based on a study involving oral administration of Antitumor B (ATB) tablets containing matrine, with individual variations up to 17.06 hours (source). In rats, half-lives are shorter, at 92-142 minutes, indicating species differences.
- Bioavailability: Oral bioavailability is low, with rat studies showing 17.1 ± 5.4% at 2 mg/kg, but human data are less clear. The evidence leans toward poor absorption, with efforts to improve it via transdermal routes noted (source). High pre-systemic clearance in humans is suggested, consistent with low exposure levels.
- Clinical Doses: Human studies have used oral doses of 100, 200, and 400 mg matrine in soft gelatin capsules, showing dose-related pharmacokinetics (source).
- Safe Range and Minimum Effective Dose: The safe range is not fully established, but doses up to 400 mg have been used without severe adverse effects in trials. The minimum effective dose varies by condition; for example, in cancer studies, in vitro concentrations of 50-800 mg/L showed effects, with IC50 at 312.53 mg/L for Hep3B cells (source).
- Maximum Safe Dose and Danger Threshold: The maximum safe dose is unclear, with reports of toxicity at high concentrations (>140 mg/L in 72 hours causing hepatocyte effects). Given potential hepatotoxicity and neurotoxicity, doses exceeding clinical trial levels (e.g., >400 mg) may become dangerous, though exact thresholds are not defined.
- LD50: In mice, the intraperitoneal LD50 is 157.13 mg/kg (95% CI 88.08-280.31 mg/kg), and intravenous LD50 is 72.1 mg/kg (95% CL 68.2-76.5 mg/kg), based on acute toxicity tests (source). Oral LD50 data for humans are not available, but animal data suggest high doses are toxic, with oral LD50 in rats reported as >10000 mg/kg for formulated products, likely not pure matrine.
- Human Toxicity: Potential adverse effects include gastrointestinal discomfort (nausea, vomiting), hepatotoxicity (elevated liver enzymes), cardiovascular issues (heart rate changes), neurological effects (dizziness, seizures at high doses), allergic reactions (rashes, swelling), and reproductive toxicity (impacts on fertility, fetal development) (source).
- Below is a table summarizing key pharmacokinetic and toxicity data:
Parameter Value (Human, where available) Value (Animal, for reference) Half-life ~10.0 ± 2.8 hours (plasma) 92-142 minutes (rats, oral/IV) Bioavailability Not specified, low (rat: 17.1%) 17.1 ± 5.4% (rats, oral, 2 mg/kg) Clinical Dosage 100-400 mg (oral) - LD50 (IP, mice) - 157.13 mg/kg LD50 (IV, mice) - 72.1 mg/kg Oral LD50 Not available >10000 mg/kg (rats, formulated) - Another table for pharmacological actions and mechanisms:
Action Mechanism Example Conditions Anti-cancer Inhibits NF-κB, PI3K/AKT, induces apoptosis Colorectal, lung cancer Anti-inflammatory Reduces IL-4, IL-5, TNF-α, modulates Th2 cytokines Asthma, rheumatoid arthritis Neuroprotective Regulates apoptosis, reduces oxidative stress Alzheimer's, Parkinson's Antimicrobial Disrupts microbial cell processes Bacterial, viral infections Cardioprotective Anti-inflammatory, anti-apoptotic effects Myocardial ischemia
- Creatine
- Pharmacological Actions
- Creatine’s primary pharmacological action is to facilitate the recycling of adenosine triphosphate (ATP) by converting adenosine diphosphate (ADP) back to ATP through the donation of phosphate groups from phosphocreatine. This process, catalyzed by creatine kinase, is crucial for rapid energy production during high-intensity, short-duration activities such as sprinting or weightlifting. This mechanism is detailed in sources like Wikipedia: Creatine, which notes its role in ATP recycling, primarily in muscle and brain tissue.
- Beyond energy metabolism, creatine may exhibit additional actions, including acting as a pH buffer during intense exercise, potentially reducing acidosis. Emerging research suggests possible antioxidant properties, anti-inflammatory effects, and neuroprotective benefits, particularly in conditions like neurodegenerative diseases. For instance, DrugBank: Creatine lists creatine as a ligand for various creatine kinases and a product of guanidinoacetate N-methyltransferase, indicating its involvement in cellular energy pathways. However, these secondary actions are less established and require further investigation, as noted in Metabolic Basis of Creatine in Health and Disease, which discusses potential mechanisms beyond energy metabolism.
- Time to Effect and Influence
- The time to observe creatine’s pharmacological effects depends on the dosing strategy and the specific action in question. For its primary role in enhancing muscle performance, the key is saturating muscle creatine stores. A loading phase of 20-25 grams per day, divided into 4-5 doses, for 5-7 days can achieve saturation quickly, with performance benefits often noticeable within a week, as supported by Creatine Loading Phase: Research, Benefits, Safety, and How To. Without loading, a maintenance dose of 3-5 grams daily can take approximately 28 days to achieve similar saturation, as noted in Does one dose of creatine supplementation fit all?.
- For brain-related effects, such as improved cognitive function, higher single doses (e.g., 0.35 g/kg, or about 24.5 g for a 70 kg person) have shown benefits during sleep deprivation, as seen in Single dose creatine improves cognitive performance, but long-term supplementation may be needed for sustained effects. The influence of these actions is dose-dependent, with higher doses accelerating the onset but potentially increasing side effects like gastrointestinal discomfort.
- Half-Life
- The plasma half-life of creatine is approximately 3 hours, as consistently reported in pharmacokinetic studies. This is evident from Creatine - Wikipedia, which states an elimination half-life of just under 3 hours, requiring frequent dosing to maintain elevated plasma levels. This short half-life pertains to plasma clearance and does not reflect the retention time in muscle stores, which can remain elevated for weeks after supplementation ceases, as muscle creatine turnover is slower.
- Bioavailabilities
- Creatine monohydrate, the most common supplement form, is considered to have high oral bioavailability, often cited as nearly 100%. This is based on the understanding that it is either absorbed by tissues or excreted in urine, as noted in Bioavailability, Efficacy, Safety, and Regulatory Status of Creatine. However, exact bioavailability percentages in humans are less frequently reported, with animal studies providing some insight. For instance, a rat study found oral bioavailability of 53% at a low dose (10 mg/kg) and 16% at a high dose (70 mg/kg), suggesting dose-dependent absorption, as detailed in Absolute Oral Bioavailability of Creatine Monohydrate in Rats. Given the lack of direct human data, it’s reasonable to conclude that oral bioavailability is high but may vary with dose and formulation, with creatine monohydrate being the most bioavailable form compared to others like creatine lysinate or ethyl ester.
- Other routes, such as intravenous, are not typically used for supplementation, so bioavailability data for these are limited and not relevant for standard use.
- Dosages and Safety Profile
Dosage Type Details Loading Phase 20-25 grams per day, divided into 4-5 doses (e.g., 5 g every few hours), for 5-7 days, to rapidly saturate muscle stores. Maintenance Dose 3-5 grams per day, sufficient to maintain elevated stores after loading, or as a standalone dose over weeks. Alternative Strategy 0.1-0.14 g/kg/day (e.g., 7-10 g/day for a 70 kg person) without loading, effective for older adults, as seen in Does one dose of creatine supplementation fit all?. Minimum Effective Dose Approximately 3 grams per day, based on studies showing benefits at this level for performance enhancement. Safe Range Generally, up to 20-25 g/day for loading and 3-5 g/day for maintenance are considered safe for healthy individuals, supported by Common questions and misconceptions about creatine supplementation. Maximum Without High Risks Doses up to 30 grams per day have been used in research without serious adverse effects, but higher doses may cause gastrointestinal issues like nausea or diarrhea, as noted in Can You Take Too Much Creatine?. LD50 In animal studies, LD50 is >2000 mg/kg in rats for creatine monohydrate and >8000 mg/kg orally in mice for creatine lysinate, indicating low acute toxicity, from Registration Dossier - ECHA and Creatine lysinate – part I. When It Starts to Become Dangerous There is no specific threshold, but excessive doses beyond recommended levels may lead to side effects like gastrointestinal discomfort, with no clear evidence of serious harm at typical supplementation levels in healthy individuals. - Safety is well-supported, with creatine classified as generally recognized as safe (GRAS) by the FDA in 2020, as seen in FDA Media. Studies over 25 years show no significant adverse effects on kidney function in healthy individuals at recommended doses, addressing early misconceptions from case studies like a 1998 report of renal dysfunction at 15 g/day for 7 days, later debunked by controlled trials.
- Muscular Performance Enhancements (source)
Positive Impact Percentage Pharmacological Action Increases Muscle Creatine and Phosphocreatine (PCr) Levels 20–40% Enhances ATP regeneration by increasing PCr stores, supporting energy for muscle contractions. Enhances High-Intensity Exercise Performance 10–20% Improves ATP availability, enabling longer and more intense workouts, especially in sprints and lifts. Improves Weight Lifting Capacity Up to 32% Increases power output, likely due to enhanced energy availability and muscle fiber recruitment. Increases Muscle Mass, Particularly Upper Body 7.2% May stimulate protein synthesis and cell volumization, promoting hypertrophy, especially with resistance training. Greater Peak Strength During Rehabilitation +25% Supports faster strength recovery post-injury, possibly via improved energy metabolism and reduced fatigue. - Recovery and Injury Prevention (source)
Positive Impact Percentage Pharmacological Action Lower Plasma Creatine Kinase (CK) Levels After Recovery -84% Reduces muscle cell membrane damage, indicating less muscle breakdown during recovery. Attenuates Changes in CK -19% Stabilizes muscle cells, minimizing leakage of CK, a marker of muscle injury. Attenuates Changes in Prostaglandin E2 -61% Reduces inflammation, as prostaglandin E2 is a pro-inflammatory mediator. Attenuates Changes in TNF-alpha -34% Lowers pro-inflammatory cytokine levels, supporting faster recovery and reduced swelling. Reduction in Frequency of Symptomatic Muscle Cramping 60% Improves muscle hydration and electrolyte balance, reducing cramp incidence. Significant Reductions in Cramping, Heat Illnesses, Dehydration, Muscle Tightness, Muscle Strains, and Total Injuries in Athletes Significant, p-values provided Enhances cellular hydration and energy, potentially reducing physical stress and injury risk. - Brain Function and Neuroprotection (source)
Positive Impact Percentage Pharmacological Action Increases Brain Creatine Content 5–15% Enhances brain energy metabolism, potentially improving cognitive function and resilience. Ameliorates Cortical Damage in Traumatic Brain Injury (TBI) 36–50% Protects neurons by maintaining ATP levels and reducing oxidative stress during injury. Reduces Brain Infarct Size Following Ischemic Event 40% Preserves energy stores, minimizing tissue damage during oxygen deprivation. Increases Brain PCr to Pi Ratio and Reduces Edemic Brain Tissue 25% reduction Improves energy status, reducing brain swelling and supporting recovery. Increase in Brain Creatine Content in Healthy Adults During Hypoxia 9.2% Enhances brain resilience under low oxygen, supporting energy needs during stress. - Other Physiological Effects (source)
Positive Impact Percentage Pharmacological Action Increase in Total Body Water (TBW) 7.0% Draws water into cells, enhancing hydration and potentially triggering anabolic signals. Increase in Intracellular Water (ICW) 9.2% Increases cell volumization, supporting cellular health and recovery. Increase in Serum Dihydrotestosterone (DHT) Concentrations 56% after 7 days, 40% above baseline after 21 days May enhance androgenic effects, potentially supporting muscle growth and strength. Increase in GLUT-4 Transporter During Rehabilitation After Atrophy 40% Facilitates glucose uptake, improving energy availability for recovery and rehabilitation. Greater Changes in Muscle Fiber Cross-Sectional Area During Rehabilitation +10% Promotes hypertrophy, likely through increased training capacity and cellular signaling. - Background and Context
- Creatine, a naturally occurring compound found in small amounts in foods like meat and fish, is synthesized in the body from amino acids such as glycine, arginine, and methionine. It plays a crucial role in energy production, particularly in muscles, by increasing phosphocreatine stores, which help regenerate adenosine triphosphate (ATP) during high-intensity exercise. Supplementation, often at doses of 3-5 grams daily after an optional loading phase of 20 grams daily for 5-7 days, is common among athletes and fitness enthusiasts to enhance performance and muscle mass. However, potential negative impacts have been reported, and this section aims to quantify these effects with percentages and explain their pharmacological basis.
- Comprehensive List of Negative Impacts with Incidences
Negative Impact Incidence (Standard Dosing) Incidence (High Single Doses, e.g., 10g) Pharmacological Action Gastrointestinal Distress (Diarrhea) ~5.5% Up to 56% High doses cause osmotic effects in the gut, drawing water and leading to diarrhea. Gastrointestinal Distress (Stomach Upset) ~5.5% (part of GI issues) Not specified, likely similar to diarrhea Osmotic and irritative effects on the stomach lining, potentially exacerbated by high doses. Gastrointestinal Distress (Belching) ~5.5% (part of GI issues) Not specified, likely similar to diarrhea Possible gas production or irritation from high doses, though not well-quantified. Weight Gain due to Water Retention Nearly 100% (1-2 kg typical) Not specified, likely similar Increases intracellular water in muscles by enhancing phosphocreatine storage, causing weight gain. Muscle Cramping/Pain ~0.5% Not specified, likely similar Potential dehydration or electrolyte shifts, though evidence does not support a direct link. Dehydration Very rare, not significantly different from placebo Not specified Anecdotal, possibly linked to perceived water shifts, but studies show no increased risk. Kidney Damage/Renal Dysfunction Very rare, not significantly different from placebo Not specified Concerns arise from increased creatinine levels, but studies show no renal impact at recommended doses. Liver Damage Very rare, not significantly different from placebo Not specified Anecdotal reports exist, but controlled studies find no significant liver function changes. - Detailed Analysis of Each Impact
- Gastrointestinal Distress:
- Incidence: A comprehensive analysis of 685 clinical trials involving 12,839 creatine users found that 5.51% reported gastrointestinal issues, including diarrhea, stomach upset, and belching, compared to 4.05% in placebo groups, with no significant difference (p = 0.820) Safety of creatine supplementation: analysis of the prevalence of reported side effects in clinical trials and adverse event reports. However, a specific study on top-level athletes taking a single 10g dose reported a 56% incidence of diarrhea, significantly higher than the 28.6% in divided doses (2 x 5g) and 35.0% in placebo, indicating dose-dependent effects Gastrointestinal distress after creatine supplementation in athletes: are side effects dose dependent?.
- Pharmacology Action: Creatine, particularly in high doses, can exert an osmotic effect in the gastrointestinal tract, drawing water into the intestines and causing diarrhea. This is more pronounced with single large doses due to rapid absorption and concentration in the gut, potentially irritating the stomach lining and leading to stomach upset or belching.
- Weight Gain due to Water Retention:
- Incidence: Nearly all users (100%) experience weight gain, typically 1-2 kg, especially during the loading phase (20g/day for 5-7 days). A study found an average increase of 1.7 kg over 4 weeks with high doses (30g initially, then 15g) Creatine monohydrate supplementation on body weight and percent body fat. This effect is consistent across studies, with weight gain primarily due to water retention rather than fat gain.
- Pharmacology Action: Creatine increases phosphocreatine stores in muscles, which draws water into the cells via osmotic pressure, leading to intracellular water retention. This is a direct result of creatine’s role in enhancing cellular hydration, which can be perceived as unwanted weight gain, especially for those not seeking muscle mass increase.
- Muscle Cramping/Pain:
- Incidence: Approximately 0.5% of creatine users reported muscle cramping or pain, compared to 0.07% in placebo groups, with a marginally significant p-value of 0.085, suggesting no strong evidence of increased risk Safety of creatine supplementation: analysis of the prevalence of reported side effects in clinical trials and adverse event reports. Anecdotal reports are common, but controlled studies refute a direct link.
- Pharmacology Action: The mechanism is unclear, but potential dehydration or electrolyte imbalances might contribute, though studies show creatine may reduce cramping in certain contexts, such as hemodialysis patients, indicating a protective rather than causative role.
- Other Reported Side Effects:
- Dehydration, Kidney Damage, Liver Damage, etc.: These are often mentioned anecdotally but lack robust scientific support. The International Society of Sports Nutrition position stand notes that assessments of adverse event reports revealed creatine was rarely mentioned and not associated with significant patterns of adverse events, with no support for increased renal or liver dysfunction International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine. A meta-analysis on renal function found no significant alteration in serum creatinine or urea levels, reinforcing safety Effects of Creatine Supplementation on Renal Function: A Systematic Review and Meta-Analysis.
- Incidence: Very rare, with incidences not significantly different from placebo, often less than 1% based on comprehensive analyses.
- Scientific Evidence and Study Findings
- Research on creatine's impact on testosterone levels reveals a mixed picture, with the majority of studies suggesting no significant effect. A review by Examine.com: Can creatine increase your testosterone levels? analyzed multiple trials and concluded that it is unlikely to increase testosterone levels, with the preponderance of evidence supporting no notable change. Similarly, Harvard Health: What is creatine? Potential benefits and risks of this popular supplement explicitly states that creatine does not increase testosterone levels, reinforcing the view that it is not an anabolic steroid.
- However, some studies suggest potential effects. For instance, a study published in PubMed: Three weeks of creatine monohydrate supplementation affects dihydrotestosterone to testosterone ratio in college-aged rugby players found no change in serum testosterone levels after 7 days of loading and 14 days of maintenance, but noted changes in the dihydrotestosterone (DHT) to testosterone ratio, which could have implications for hair health. In contrast, another study from ScienceDirect: Effects of short term creatine supplementation and resistance exercises on resting hormonal and cardiovascular responses reported significant increases in resting testosterone concentrations after 5 and 7 days of creatine loading combined with resistance exercises, compared to a placebo group.
- To reconcile these findings, a review in the Journal of the International Society of Sports Nutrition: Common questions and misconceptions about creatine supplementation provides insight. It notes that while one study (van der Merwe et al., 2009) found a 56% increase in DHT after 7 days and 40% above baseline after 14 days, most other studies (12 total, with doses ranging from 3–25 g/day for 6 days to 12 weeks) showed no significant increase in total or free testosterone, with only two studies reporting small increases and five showing no change in free testosterone. This suggests that any effect on testosterone is not consistent across studies.
- Analysis of Variability and Context
- The variability in findings may be attributed to differences in study design, participant populations, and supplementation protocols. For example, studies combining creatine with resistance training, like the ScienceDirect study, seem more likely to show increases in testosterone, possibly due to the synergistic effect of exercise on hormonal responses. In contrast, studies without specific exercise interventions, like the PubMed rugby player study, tend to show no change. This suggests that the context of use—particularly whether combined with resistance training—may influence outcomes.
- Additionally, the Examine.com review highlighted that all trials involved healthy young men with normal testosterone levels, and no studies have examined the effect on individuals with abnormally low testosterone. This limits the generalizability of findings to other populations, such as older adults or those with hormonal imbalances.
- Tables Summarizing Key Studies
- To organize the evidence, the following tables summarize key studies and their findings:
Study Source Participants Dose/Duration Effect on Testosterone/DHT Notes PubMed: Three weeks of creatine monohydrate supplementation... 20 college-aged rugby players 25 g/day for 7 days, then 5 g/day for 14 days No change in serum T, increased DHT/T ratio Conducted during competitive season, no exercise details specified ScienceDirect: Effects of short term creatine supplementation... 20 active males 3, 5, 7 days loading with resistance exercises Increased resting T after 5, 7 days (P < 0.05) Included resistance exercises, parallel group design JISSN: Common questions and misconceptions about creatine... Review of 12 studies 3–25 g/day, 6 days to 12 weeks Mostly no significant change, 2 showed small increases Comprehensive review, notes DHT increase in one study not replicated Summary of Examine.com Review (2025) Details 3 RCTs showing small increases Increased DHT by 12 ng/dL, Testosterone by 57 ng/dL and 150 ng/dL 10 trials (218 participants) showing no effect No statistically significant effect on testosterone Conclusion Unlikely to increase testosterone in healthy young men with normal levels - These tables illustrate the mixed evidence, with the majority leaning toward no significant effect, but highlighting the potential for small increases in specific contexts.
- Implications and Considerations
- For most users, particularly healthy individuals engaging in regular exercise, the evidence suggests that creatine supplementation is unlikely to significantly alter testosterone levels. This is reassuring for those concerned about potential decreases, as no studies indicate a reduction. However, for those hoping for an increase, the small and inconsistent findings mean it's not a reliable strategy for boosting testosterone.
- It's also worth noting that changes in DHT, as seen in some studies, have been linked to hair loss concerns, but the JISSN review clarifies that these changes remain within normal clinical limits and have not been consistently replicated. This suggests that while there may be minor hormonal shifts, they are unlikely to have significant clinical impacts.
- Pramipexole
- Pharmacological Actions and Timing
- Pramipexole works by mimicking dopamine, primarily targeting D3 receptors, which helps reduce symptoms like tremors in Parkinson's and discomfort in RLS. For RLS, it's typically taken 2-3 hours before bedtime, suggesting effects begin shortly after to last through the night. For Parkinson's, the onset might take longer, often days to weeks, as the body adjusts to the medication.
- Half-Life and Bioavailability
- The half-life is around 8 hours for younger individuals and 12 hours for those over 65, meaning it stays in the system longer in older adults. Oral bioavailability is greater than 90%, showing it's well-absorbed with minimal loss.
-
Dosage Details
- Starting Doses: For RLS, begin at 0.125 mg once daily; for Parkinson's, start at 0.375 mg/day, split into three doses.
- Maximum Doses: RLS can go up to 0.5-0.75 mg/day, while Parkinson's can reach 4.5 mg/day.
- Safe Range: Stay within these limits to minimize risks, as higher doses increase side effects like hallucinations or impulse control issues.
- Survey Note: Comprehensive Analysis of Pramipexole's Pharmacological Profile
- This detailed survey note provides an in-depth examination of Pramipexole's pharmacological actions, timing, pharmacokinetics, and dosage considerations, based on current medical literature and regulatory documents as of June 20, 2025. Pramipexole, a non-ergot dopamine agonist, is primarily indicated for managing Parkinson's disease and Restless Legs Syndrome (RLS), with potential off-label uses in mood disorders.
- Pharmacological Actions
- Pramipexole exerts its primary effects through dopamine receptor agonism, with a high affinity for D3 receptors, and also interacts with D2 and D4 subtypes. This action helps alleviate motor symptoms in Parkinson's, such as tremors, rigidity, and bradykinesia, by stimulating dopamine receptors in the striatum. For RLS, it modulates dopamine pathways to reduce leg discomfort and the urge to move, particularly at night. Research also suggests potential neuroprotective effects, possibly through antioxidant properties and mitochondrial function modulation, though these are not fully established and require further study (source). Common side effects include somnolence, impulse control disorders, and hallucinations, which can impact long-term use.
- Timing of Influence
- The timing of Pramipexole's effects varies by condition. For RLS, it is typically administered 2-3 hours before bedtime, indicating an onset within this timeframe to manage nighttime symptoms, with effects lasting through the night based on its pharmacokinetics (source).
- Pharmacokinetics
- Pramipexole exhibits linear pharmacokinetics over the clinical dosage range, achieving steady-state concentrations within 2 days of dosing. The terminal half-life is approximately 8 hours in young healthy volunteers and extends to 12 hours in elderly individuals, reflecting age-related changes in renal clearance (source). It is widely distributed, with a volume of distribution around 500 L and low plasma protein binding (15%), and is primarily eliminated unchanged in urine (90%), with renal clearance approximately three times higher than the glomerular filtration rate, indicating active tubular secretion.
- Special Populations
- Clearance is reduced by about 30% in women compared to men, largely due to body weight differences, and decreases with age, with a 40% longer half-life and 30% lower clearance in those over 65, likely due to reduced renal function. In Parkinson's patients, clearance is also about 30% lower compared to healthy elderly, possibly reflecting poorer renal function. For renal impairment, clearance drops significantly: 75% lower in severe impairment (creatinine clearance ~20 mL/min) and 60% lower in moderate impairment (~40 mL/min), correlating with creatinine clearance, with negligible removal by dialysis. Hepatic impairment is not expected to significantly affect elimination, given the drug's renal excretion profile (source).
- Dosage Details
- Dosage regimens are tailored to the condition and patient factors. For Parkinson's disease, treatment begins at 0.375 mg/day, divided into three doses, with increases every 5-7 days, up to a maximum of 4.5 mg/day, based on response and tolerability. For RLS, the starting dose is 0.125 mg once daily, 2-3 hours before bedtime, with increments every 4-7 days, typically not exceeding 0.5 mg/day, though some cases may reach 0.75 mg/day. In renal impairment, doses are adjusted: for moderate impairment (creatinine clearance 35-59 mL/min), start at 0.125 mg twice daily, with a maximum of 1.5 mg twice daily; for severe impairment (15-34 mL/min), start at 0.125 mg once daily, with a maximum of 1.5 mg once daily; very severe impairment (<15 mL/min) requires caution, as it is not well-studied (source).
- The minimum effective dose appears to be around 0.75 mg/day for Parkinson's, based on clinical trial data showing efficacy at this level, while for RLS, the starting dose of 0.125 mg/day is often effective. The maximum dose without high risks aligns with the labeled maxima, as exceeding these increases the likelihood of adverse effects like hallucinations, dyskinesias, and impulse control disorders, which are more pronounced at higher doses.
- Safety and Toxicity
- The safe range is within the labeled doses, up to 4.5 mg/day for Parkinson's and 0.75 mg/day for RLS. The LD50 in rats is reported as >800 mg/kg orally, but human LD50 is not established. Overdose cases, such as one involving 11 mg/day for 2 days, have shown symptoms like increased pulse rate (100-120 beats/minute), nausea, vomiting, confusion, and respiratory depression, managed with supportive care, including gastric lavage and intravenous fluids (source). Doses above the recommended maximum are considered too dangerous due to increased risk of serious adverse effects, though the exact threshold varies by individual tolerance and condition.
-
Comparative Analysis
Parameter Young Adults Elderly (>65 years) Notes Half-life ~8 hours ~12 hours Reflects age-related renal clearance reduction. Bioavailability >90% >90% High oral absorption, unaffected by food extent. Peak Time (T_max) ~2 hours (IR), ~6 hours (ER) Same Delayed by food: ~1 hour for IR, ~2 hours for ER. Starting Dose (PD) 0.375 mg/day Same Divided into tdree doses, titrated every 5-7 days. Maximum Dose (PD) 4.5 mg/day Adjusted for renal function Risk of adverse effects increases above tdis. Starting Dose (RLS) 0.125 mg/day Same Taken once daily, 2-3 hours before bedtime. Maximum Dose (RLS) 0.5-0.75 mg/day Same May require dose adjustment based on response.
- Hair loss associated with Pramipexole is often classified as telogen effluvium, a condition where hair prematurely enters the resting (telogen) phase, leading to increased shedding. This type of hair loss is typically reversible, as it does not permanently damage hair follicles, unlike conditions like androgenetic alopecia.
- Research from early 2000s, such as a 2002 study published in Neurology and reported by ScienceDaily: Baldness Induced By Dopamine Treatments May Be Reversible, examined two women with Parkinson's disease who developed alopecia while on Pramipexole or ropinirole (another dopamine agonist). In both cases, hair loss stopped after discontinuing the drugs and switching to alternative treatments, with one case showing new hair growth within a month and no recurrence after a year on ropinirole. The second case saw hair loss cessation within a week after switching to carbidopa/levodopa, with partial regrowth over six months.
- A 2003 review in Parkinsonism & Related Disorders, referenced in Parkinson's News Today: Does Parkinson’s Play a Role in Hair Loss and Thinning?, noted hair loss as a possible side effect of dopamine agonists, including Pramipexole, and emphasized that medication-induced hair loss is often reversible upon discontinuation, aligning with supervised medical adjustments.
- Further, a 2006 case report by Katz et al. in the Journal of the American Academy of Dermatology described telogen effluvium in a 55-year-old woman on Pramipexole, a condition typically reversible, though the specific outcome in this case was not detailed in accessible summaries.
- Patient anecdotes, such as those found on Reddit, provide additional context. For instance, a user on r/depressionregimens reported "massive hair loss" from Pramipexole, which was managed with oral minoxidil, leading to significant regrowth, as seen in Reddit: Anyone else tried pramipexole?. This supports the notion that hair loss can be addressed post-discontinuation, though interventions may be necessary.
- Another blog, Journey with Parkinson's: Brief Report: Hair Loss Linked to Dopamine Agonists, detailed cases where switching from Pramipexole to other medications like ropinirole or carbidopa/levodopa halted hair loss, with partial reversal noted, though not always complete. This variability suggests individual differences in response, potentially influenced by dosage, duration of use, and concurrent treatments.
- The mechanism behind Pramipexole-induced hair loss may involve dopamine receptors in hair follicles, which are implicated in melanin production and hair growth cycles. Studies like Langan et al. (2013) in British Journal of Dermatology suggest dopamine can induce catagen (the regression phase of the hair cycle), potentially explaining the hair loss. Notably, most reported cases involve women, which may reflect gender-specific sensitivities or reporting biases.
- Resveratrol
- Pharmacological Actions
- Resveratrol exhibits a broad spectrum of pharmacological actions, primarily due to its antioxidant, anti-inflammatory, and modulatory effects on cellular pathways. Below is a detailed list of its key actions, with insights into how they influence health:
- Antioxidant Effects: Resveratrol acts as a free radical scavenger, reducing oxidative stress, which is implicated in aging and chronic diseases. It enhances the activity of antioxidant enzymes, protecting cells from oxidative damage.
- Anti-inflammatory Effects: It inhibits pro-inflammatory enzymes like cyclooxygenase (COX-2) and reduces levels of cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), potentially alleviating conditions like arthritis and cardiovascular disease.
- Cardioprotective Effects: Research suggests resveratrol improves endothelial function, reduces blood pressure, and has anti-atherosclerotic properties, possibly by enhancing nitric oxide production and inhibiting platelet aggregation.
- Neuroprotective Effects: It may protect against neurodegenerative diseases like Alzheimer's by reducing oxidative stress and inflammation in the brain, potentially through sirtuin activation.
- Anticancer Effects: Resveratrol induces apoptosis in cancer cells, inhibits cell proliferation, and suppresses angiogenesis, showing promise in preventing and treating various cancers, though human evidence is limited.
- Anti-diabetic Effects: It enhances insulin sensitivity and improves glucose metabolism, potentially benefiting type 2 diabetes management by activating AMP-activated protein kinase (AMPK).
- Anti-obesity Effects: Resveratrol reduces fat accumulation and promotes lipolysis, possibly aiding weight management by inhibiting adipogenesis.
- Antimicrobial Effects: It exhibits antibacterial activity against pathogens like Listeria and Staphylococcus aureus, and antiviral effects against herpes simplex virus, by disrupting cellular energy production.
- The effective doses for these actions vary widely, often ranging from 100 mg to 2 grams daily in human studies, depending on the condition and study design. For instance, a meta-analysis found that doses of 150 mg/day or more effectively lowered systolic blood pressure (source: medicalnewstoday.com), while anticancer effects have been studied at doses up to 5 grams daily, with mixed results.
- Half-Life and Bioavailability
- The pharmacokinetics of resveratrol are characterized by rapid metabolism, affecting its half-life and bioavailability. Studies indicate:
- Half-life: The half-life of free resveratrol is approximately 1-5 hours, with variations depending on the study. For example, a bioavailability study reported a mean half-life of 5.114 hours for free resveratrol after a 500 mg oral dose (source: en.wikipedia.org).
- Bioavailability: Oral bioavailability is notably low, less than 1%, due to extensive first-pass metabolism in the liver and intestines, involving glucuronidation and sulfation. Despite this, absorption is high, estimated at 70-75%, as shown in a study where a 25 mg oral dose achieved at least 70% absorption (source: pubmed.ncbi.nlm.nih.gov). This discrepancy highlights the challenge of delivering effective concentrations systemically.
- Dosages and Safety Profile
- Dosage recommendations for resveratrol are not universally standardized, with variations based on intended use, individual tolerance, and study outcomes. Key details include:
- Supplement Dosages: Commercial supplements typically contain 250-500 mg per serving, reflecting common market availability (source: webmd.com).
- Study Dosages: Clinical trials have explored a wide range, from 100 mg daily for 12 weeks in breast cancer marker studies to 5 grams daily in multiple myeloma patients, with the latter showing minimal efficacy and adverse events (source: drugs.com).
- Safe Range: Literature suggests that up to 1 gram per day is generally safe for healthy adults, with no serious adverse effects reported in trials lasting up to 29 days (source: pmc.ncbi.nlm.nih.gov).
- Minimum Effective Dose: This varies by condition; for example, 150 mg/day has been effective for lowering systolic blood pressure (source: medicalnewstoday.com), while higher doses (1-2 grams/day) have been used for insulin sensitivity improvements.
- Maximum Safe Dose: Doses above 2.5 grams daily are associated with gastrointestinal side effects like nausea, diarrhea, and abdominal pain, as reported in clinical trials (source: webmd.com).
- LD50 and Toxicity: The lethal dose 50 (LD50) is not well-defined for humans, but animal studies provide insight. In rats, doses up to 3000 mg/kg for 28 days showed adverse effects like renal toxicity but no mortality, suggesting LD50 > 3000 mg/kg (source: 2013.igem.org), indicating low acute toxicity. High doses in humans (>5 grams/day) have shown adverse events, such as hypersensitivity and elevated liver enzymes, in some trials.
- Detailed Pharmacokinetic and Safety Considerations
- To organize the pharmacokinetic data, the following table summarizes key parameters from human studies:
Parameter Value Notes Half-life (Free) 1-5 hours Varies by study; likely reflects elimination phase, with initial phase shorter. Half-life (Metabolites) 7-9 hours Longer persistence due to conjugation. Oral Absorption 70-75% High absorption despite low bioavailability. Oral Bioavailability <1% Due to rapid glucuronidation and sulfation in liver and intestines. Cmax (500 mg dose) 71.2 ng/ml (free) Peak concentration for free resveratrol, low due to metabolism. Tmax 1.3 hours (free) Time to peak concentration for free resveratrol. - For dosage safety, another table outlines the dosage ranges and associated effects:
Dosage Range Effect Notes 100-150 mg/day Potentially effective for blood pressure Supported by meta-analysis for systolic pressure reduction. 250-500 mg/day Common supplement dose, generally well-tolerated Typical in commercial products, few adverse effects reported. 1-2 grams/day Used in studies for metabolic effects May improve insulin sensitivity, but data mixed. >2.5 grams/day Increased risk of side effects Gastrointestinal issues like nausea, diarrhea reported. >5 grams/day Potential serious adverse events Seen in some trials, e.g., hypersensitivity, elevated liver enzymes.
- Resveratrol (trans)
- Pharmacological Actions
- Trans-Resveratrol exhibits a plethora of biological activities, primarily due to its antioxidant, anti-inflammatory, antitumor, cardioprotective, and neuroprotective properties. These actions are mediated through various mechanisms, such as scavenging free radicals, inhibiting inflammatory cytokines, inducing apoptosis in cancer cells, improving endothelial function, and protecting against neurodegenerative processes like β-amyloid plaque formation in Alzheimer's disease. For instance, studies have shown it can reduce oxidative stress by acting as an efficient scavenger of hydroperoxyl radicals and protect cells against hydrogen peroxide-induced damage (source).
- The user's request for "values for each of time to know how each pharmacological action influences" is somewhat ambiguous, but it likely refers to the time course of these effects, which is tied to its pharmacokinetics. Specific time-dependent values for each action are not universally standardized, as they depend on the condition and study design. However, the pharmacokinetic profile, such as time to peak concentration and half-life, provides insight into the duration and onset of these effects.
- Pharmacokinetic Parameters
- The pharmacokinetics of trans-Resveratrol are well-documented, with key parameters including:
- Time to Peak Concentration (Tmax): Research indicates that after oral administration, peak plasma concentrations are reached between 0.8 and 1.5 hours, depending on the dose and formulation. For example, a study with doses ranging from 0.5 g to 5 g showed peak times within this range (source).
- Half-Life (t1/2): The half-life varies based on dosing regimen. For single doses, it ranges from 1 to 3 hours, while with repeated dosing, it extends to 2 to 5 hours, reflecting potential accumulation and altered metabolism.
- Bioavailability: Oral bioavailability is notably low, less than 1%, due to extensive first-pass metabolism in the liver and intestines, where it is rapidly conjugated into glucuronides and sulfates. Intravenous administration, however, achieves 100% bioavailability, though this route is less common in clinical settings, but standard bioavailability remains low. (source)
- Other routes, such as intraperitoneal in animal studies, are not typically relevant for human administration, so the focus remains on oral and intravenous routes.
- Dosage and Safety Profile
- Dosage recommendations and safety margins are critical for practical application:
- Typical Supplement Doses: Commonly available supplements range from 100 mg to 1 g per day, reflecting typical usage for health benefits like cardiovascular support and anti-aging effects (source).
- Studied Doses in Clinical Trials: Clinical trials have explored a wide range, from 8 mg/day for certain cardiovascular effects to as high as 5 g/day, with no marked toxicity reported at the higher end (source).
- Safe Range: Studies suggest that doses up to 5 g per day are generally well-tolerated, with side effects like nausea, diarrhea, and abdominal pain reported at higher doses, typically above 1 g/day. These effects are generally mild and reversible. (source)
- Minimum Effective Dose: The minimum effective dose varies by condition. For example, a meta-analysis found cardiovascular benefits at doses as low as 10 mg/day, while diabetes management often requires 300 mg/day. This variability underscores the need for condition-specific dosing. (source)
- Maximum Dose Without High Risks: Based on clinical data, up to 5 g per day appears safe, with no severe adverse effects reported, though gastrointestinal issues may occur at the higher end (source).
- LD50 and Acute Toxicity: The LD50 (lethal dose for 50% of subjects) is not readily available in the literature, which suggests low acute toxicity. Animal studies, such as those in rats and mice, use high doses (e.g., 50 mg/kg/day) without reporting lethality, indicating a wide safety margin. For zebrafish, LD50 values of 51.4-75.3 mg/L are reported for aquatic toxicity, but these are not directly comparable to oral mammalian toxicity. (source)
- Estimation of When It Becomes Too Dangerous: Given the lack of reported LD50 and the tolerance of high doses in humans (up to 5 g/day), it seems likely that significant danger would only arise at doses far exceeding this, potentially in the range of grams per kilogram, but specific thresholds are not established due to limited toxicity data.
- Comparative Analysis
- The user's query implies a comparison between "Resveratrol (trans)" and "Resveratrol," which, given the context, likely refers to trans-Resveratrol versus the general term, potentially including cis-Resveratrol. Trans-Resveratrol is the dominant and biologically active form, with cis-Resveratrol being less stable and less studied. Literature consistently highlights trans-Resveratrol's superior bioavailability and efficacy, with no significant pharmacological actions attributed to cis-Resveratrol in comparison (source). Thus, the comparison is largely moot, as trans-Resveratrol encompasses the actions and parameters discussed.
- Disulfiram
- Pharmacological Actions
- Inhibition of Aldehyde Dehydrogenase (ALDH):
- Mechanism: Disulfiram irreversibly inhibits ALDH, particularly ALDH1A1, by competing with NAD at the cysteine residue. This prevents the conversion of acetaldehyde to acetic acid, leading to its accumulation and causing the disulfiram-alcohol reaction, characterized by symptoms such as diaphoresis, palpitations, facial flushing, nausea, vertigo, hypotension, and tachycardia.
- Time Course: The disulfiram-alcohol reaction typically begins about 10 minutes after alcohol ingestion and can last for 1 hour or more, as noted in clinical observations (source).
- Inhibition of Dopamine Beta-Hydroxylase (DBH):
- Mechanism: Disulfiram inhibits DBH, the enzyme converting dopamine to norepinephrine, potentially increasing dopamine levels and decreasing norepinephrine, which may underlie its experimental use in cocaine dependence by correcting underlying dopamine deficits.
- Time Course: Specific duration data for DBH inhibition is less documented, but given Disulfiram's daily administration, it seems likely that its effects are maintained with regular dosing. Studies on cocaine-related behaviors suggest effects are observed over days with chronic administration, but exact onset and duration remain unclear (source).
- Other Potential Actions:
- Disulfiram also inhibits aldehyde dehydrogenase family 3 member A2 (ALDH3A2) and competitively binds the peripheral benzodiazepine receptor, though these actions are less studied and their clinical significance, including time courses, is not well-established (source).
- Pharmacokinetic Properties
- Half-Life: Disulfiram has a half-life of approximately 7 hours, while its active metabolite, diethyldithiocarbamate (DDTC), has a half-life of about 15 hours. There is significant inter-subject variability, which may stem from differences in metabolism, lipid content, enterohepatic circulation, or protein-binding capacity (source).
- Bioavailability: Oral absorption is reported at 80-90%, indicating high bioavailability via the oral route, which is the standard administration method. This high absorption rate is supported by clinical pharmacokinetics data, though exact bioavailability figures may vary due to metabolic conversion to active metabolites (source).
- Dosage Considerations
- Forms and Administration: Available as 250 mg and 500 mg oral tablets, which can be crushed and mixed with water, coffee, milk, or fruit juice for administration (source).
- Safe Range: The recommended safe daily dose is up to 500 mg, with no additional benefit observed above this level (source).
- Minimum Effective Dose: Typically ranges from 125 mg to 250 mg daily, with some sources indicating effectiveness at 125 mg, particularly for maintenance therapy (source).
- Maximum Dose Without High Risks: 500 mg per day is the maximum recommended dose to avoid significant risks, as higher doses do not enhance efficacy and increase toxicity risk (source).
- Toxic Threshold and LD50: Doses above 500 mg per day can lead to toxicity, with clinical manifestations rare below 3 g in a single dose for adults. Lethal doses are estimated at 10-30 g in a single ingestion for humans, based on case reports and clinical observations (source).
- Resiquimod
- Availability in Oral Form
- Research indicates that Resiquimod is not currently available in oral form for general use. While it has been investigated in clinical trials for oral administration, particularly for chronic hepatitis C virus (HCV) infection, these studies did not lead to approval for oral use. For instance, a phase IIa study published in 2007 explored oral Resiquimod at doses of 0.01 mg/kg and 0.02 mg/kg twice weekly for 4 weeks, but it was associated with adverse effects similar to interferon-alpha, such as fever and lymphopenia (source).
- Regulatory data from the FDA's Orphan Drug Designations page, updated as of recent reports, shows Resiquimod has a designation for treating cutaneous T-cell lymphoma since May 24, 2017, but it is not FDA-approved for this indication, and the form is not specified as oral (source), it seems unlikely that oral Resiquimod is available for public use as of June 29, 2025.
- Clinical Trials and Safety Concerns
- The clinical trials for oral Resiquimod, particularly for HCV, provide insight into its safety profile. The 2007 study mentioned above noted that while a 0.01 mg/kg dose was tolerated, the 0.02 mg/kg dose led to severe adverse events, including systemic cytokine induction symptoms like fever, headache, and shivering, leading to discontinuation in some cases (source). These findings suggest that oral administration is not pursued further due to safety concerns.
- For other conditions, such as genital herpes, phase III trials of topical Resiquimod were suspended due to lack of efficacy, and there is no recent evidence of renewed interest in oral forms (source). The evidence leans toward oral Resiquimod being unsafe for general use, especially given the lack of approval and the adverse effects observed in trials.
- Recommendations for Use
- Given the evidence, it is not recommended to take Resiquimod orally outside of controlled clinical trial settings. The adverse effects observed in trials, combined with the lack of approval, suggest potential risks that outweigh benefits for lay use. For medical advice, consulting a healthcare provider is essential, especially considering individual health conditions and the specific indications for Resiquimod.
- Resiquimod, also known as R-848, is an immune response modifier classified as a potent agonist for Toll-like receptors 7 and 8 (TLR7/TLR8). Its pharmacological profile and clinical applications have been extensively studied, particularly for antiviral and antitumor activities. This note provides a detailed examination of its pharmacological actions, pharmacokinetics, dosages, and safety profiles, based on available literature as of June 27, 2025.
- Pharmacological Actions
- Resiquimod's primary mechanism involves activating TLR7 and TLR8, which are endosomal pattern recognition receptors critical for antiviral immune responses. This activation triggers the MyD88-dependent signaling pathway, leading to the activation of transcription factors such as NF-κB and interferon regulatory factor (IRF). Consequently, it induces the upregulation of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and type I interferons (IFN-α), which are essential for enhancing innate and adaptive immunity.
- Specific pharmacological actions include:
- Cytokine Induction: Resiquimod significantly increases levels of TNF-α, IL-6, IL-12, and IFN-α, as noted in studies on mouse bone marrow-derived macrophages and human peripheral blood mononuclear cells (source).
- Immune Cell Activation: It activates dendritic cells, macrophages, and other immune cells, promoting antigen presentation and T-cell activation, which is beneficial for antiviral and antitumor responses (source).
- Antiviral Activity: Demonstrated efficacy against viruses such as hepatitis C virus (HCV) and herpes simplex virus, with studies showing reduced viral loads in clinical trials (source).
- Antitumor Activity: Used in treating cutaneous T-cell lymphoma and other skin cancers, with potential as an adjuvant in cancer immunotherapy, enhancing tumor-associated macrophage stimulation (source).
- Pharmacokinetics
- Pharmacokinetic data for Resiquimod is limited, particularly for half-life and bioavailability, but available studies provide insights into its absorption and systemic exposure:
- Topical Application: Studies indicate low systemic absorption, with systemic exposure less than 1% of the applied dose in humans, assessed by urinary recovery, and approximately 8.5% in rats, as reported in a randomized, single-blind study (source).
- Oral Administration: In a phase IIa study for chronic HCV infection, oral doses of 0.01 mg/kg and 0.02 mg/kg resulted in mean maximum serum concentrations of 3.82 ± 1.47 ng/mL and 7.55 ± 4.17 ng/mL, respectively, administered twice weekly for 4 weeks (source). However, specific half-life and bioavailability data were not detailed in accessible literature, with moderate oral bioavailability suggested (26.5 ± 7.84%) in some references, though not universally confirmed.
- The lack of precise half-life data indicates a gap in current research, with estimates potentially ranging from 2-3 hours based on related studies, but this requires further validation.
- Dosages
- Dosage regimens vary by administration route and therapeutic intent:
- Topical Use: Commonly applied as a gel, with concentrations such as 0.01% for genital herpes and 0.03-0.06% for actinic keratosis (AK), covering up to 100 cm², with dosing frequencies adjusted based on tolerability (e.g., 3 times weekly, escalating to daily) (source).
- Oral Use: In the HCV study, doses of 0.01 mg/kg were tolerated, while 0.02 mg/kg led to increased adverse events, suggesting a minimum effective dose around 0.01 mg/kg and a maximum safe dose likely below 0.02 mg/kg, though exact ranges are not standardized (source).
- Safe Range, Minimum Effective Dose, and Maximum Safe Dose:
- Safe Range: Topical use appears safe with low systemic absorption, while oral use at 0.01 mg/kg is generally tolerated, with 0.02 mg/kg showing increased risk.
- Minimum Effective Dose: Likely 0.01 mg/kg orally for systemic effects, and 0.01% gel topically for local effects.
- Maximum Safe Dose: Oral administration at 0.02 mg/kg showed adverse effects, suggesting this as an upper limit, but precise maximum without high risks is unclear.
- LD50 and Danger Threshold:
- Specific LD50 values were not found, indicating a lack of comprehensive toxicity studies in public domains. For topical use, low systemic absorption suggests minimal risk of systemic toxicity, while oral use at higher doses (e.g., 0.02 mg/kg) is associated with systemic cytokine induction and adverse effects, potentially starting to become dangerous at doses exceeding this, though exact thresholds are not established.
- Detailed Safety and Toxicity Profile
- Toxicity data is sparse, with literature emphasizing local reactions for topical use (e.g., erythema, induration) and systemic effects for oral use (e.g., fever, lymphopenia). The ResearchGate PDF notes that topical 0.01% gel is unlikely to cause systemic toxicity due to low absorption, while oral capsules cause systemic cytokine induction, suggesting potential toxicity at higher doses (source). No LD50 values were identified, highlighting a research gap in systemic toxicity assessments.
Parameter Value Route Notes Systemic Exposure (Topical) <1% of applied dose Topical Based on urinary recovery in humans Absorption (Topical, Rats) ~8.5% Topical From animal studies Cmax (Oral, 0.01 mg/kg) 3.82 ± 1.47 ng/mL Oral From HCV study Cmax (Oral, 0.02 mg/kg) 7.55 ± 4.17 ng/mL Oral From HCV study Bioavailability (Oral, Est.) Moderate, 26.5 ± 7.84% (not confirmed) Oral Suggested, needs validation Dosage Type Dose Range Safety Notes Topical (Gel) 0.01-0.06% Safe, low systemic absorption, local reactions Oral (HCV Study) 0.01-0.02 mg/kg 0.01 mg/kg tolerated, 0.02 mg/kg adverse effects
- Meclofenoxate
- Pharmacological Actions
- Meclofenoxate's pharmacological actions are centered around its nootropic and neuroprotective properties. Research suggests it acts as a cholinergic agent, improving performance on memory tests, especially in elderly patients, as noted in Wikipedia: Meclofenoxate. It is believed to increase cellular membrane phospholipids, which may support neuronal membrane integrity and function, potentially contributing to cognitive enhancement. Additionally, studies indicate it may reduce lipofuscin accumulation, a cellular waste product associated with aging, suggesting anti-aging benefits (source). However, the exact mechanisms and time course of these effects are not fully detailed in the literature, and further research is needed to quantify how each action influences over time.
- Half-life
- The half-life of Meclofenoxate is estimated at approximately 6 hours, derived from a pharmacokinetic study comparing capsule and tablet formulations in healthy Chinese male volunteers. The study measured the elimination half-time (T1/2) of its active metabolite, chlorophenoxyacetic acid, at 5.8 to 6.0 hours (source). This indicates that the drug's effects may persist for several hours after administration, but specific onset, peak, and duration data for pharmacological actions are not readily available.
- Bioavailability
- Meclofenoxate is administered via oral and parenteral routes, with both shown to be effective. It is a prodrug, rapidly hydrolyzed into DMAE and pCPA, which likely influences its bioavailability. Specific bioavailability percentages, particularly for the oral route, are not widely documented. However, a study on bioequivalence suggests that both capsule and tablet formulations are similarly absorbed, with 90% confidence intervals for Cmax and AUC within the FDA's 80%-125% range, indicating comparable bioavailability (source).
- Dosages
- Dosage recommendations vary based on the condition and administration route. Typical daily dosages range from 500 mg to 1,000 mg, as suggested by Nootropics Expert: Centrophenoxine, with higher doses up to 2,000 mg daily used in clinical trials for age-related cognitive disorders like Alzheimer's disease, as noted by the Alzheimer's Drug Discovery Foundation (source). This suggests a safe range of 500 mg to 2,000 mg daily, with the minimum effective dose likely around 500 mg daily based on typical use, and the maximum safe dose potentially up to 2,000 mg, though safety concerns increase at higher levels.
- Safety and Side Effects
- Meclofenoxate is considered safe with high tolerability, as noted in Wikipedia: Meclofenoxate, with possible side effects including insomnia, dizziness, restlessness, muscle tremor, depression, nausea, muscle tension, and headache, which may indicate overdosage. The Alzheimer's Drug Discovery Foundation highlights that most side effects are mild, such as gastrointestinal issues and mild stimulant effects, but raises concerns about DMAE, with serious adverse events reported in a trial, including cardiac failure leading to death, cardiac arrest, and seizures (source). Preclinical studies also link DMAE to neural tube defects, advising against use in women of child-bearing age, and it is contraindicated in individuals with severely high blood pressure. Drug interactions are unknown, and consultation with a healthcare provider is recommended before use.
- Palmitoylethanolamide
- Pharmacological Actions
- Anti-inflammatory: PEA reduces inflammation by modulating mediators and inhibiting mast cell activation, as seen in animal models of colitis where effects were measured 3 days post-induction (source).
- Analgesic: It provides pain relief, with clinical studies showing reductions in pain intensity within 10 to 14 days to 4 weeks (source).
- Neuroprotective: PEA protects nerve cells, potentially beneficial in neurodegenerative conditions, with mechanisms involving PPAR-α and GPR55 receptors (source).
- Immunomodulatory: It modulates immune responses, aiding in conditions like allergies and autoimmune disorders (source).
- Antimicrobial: Limited evidence suggests antimicrobial properties, though less studied compared to other actions (source).
- These actions are mediated through targets like PPAR-α (EC50 3 μM), GPR55 (EC50 4 nM), and entourage effects on CB1, CB2, and TRPV1, as noted in pharmacological reviews (source).
- Time to Effect
- The time to observe PEA's effects varies by action and condition:
- Pain Relief: Clinical trials indicate significant pain reduction can occur within 10 to 14 days in some studies, with others showing effects after 4 weeks, reflecting the chronic nature of conditions treated (source).
- Anti-inflammatory Effects: In a murine colitis model, anti-inflammatory effects were assessed 3 days after induction, suggesting rapid action in acute inflammation (source).
- Plasma Concentration: Pharmacokinetic studies show plasma levels peak at approximately 2 hours after oral administration in humans, with a study on 300 mg micronized PEA showing a twofold increase at this time, returning to baseline by 4-6 hours (source).
- This variability suggests that while plasma levels rise quickly, clinical effects, especially for chronic conditions, may require days to weeks.
- Half-Life
- The half-life of PEA is relatively short, with data primarily from animal studies:
- In Rats: Plasma elimination half-time is approximately 12 minutes, calculated from a study using a one-compartment model with first-order kinetics (source).
- In Vitro: Rat liver homogenates show a half-life of about 25 minutes at 50 nM concentration (source).
- In Humans: Not explicitly stated, but plasma levels return to baseline within 4-6 hours after peaking at 2 hours, suggesting a half-life likely in the range of 1-2 hours, based on the observed pharmacokinetics (source).
- In Humans: Not explicitly stated, but plasma levels return to baseline within 4-6 hours after peaking at 2 hours, suggesting a half-life likely in the range of 1-2 hours, based on the observed pharmacokinetic.
- Bioavailability
- PEA's bioavailability, particularly via the oral route, is a critical factor due to its lipophilic nature:
- General Oral Bioavailability: Initially low due to poor water solubility, with estimates suggesting limited absorption in standard forms (source).
- Improved Formulations: Micronized and ultra-micronized forms enhance bioavailability. A study on PEAΩ and PEA DynoΩ showed absorption rates of 82-63% at 3 hours, compared to 30-60% for micronized, ultra-micronized PEA, and commercial products, with optimal doses at 300-600 mg (source).
- Human Studies: A study with 300 mg micronized PEA showed a twofold increase in plasma levels at 2 hours, indicating improved bioavailability with advanced formulations (source).
- Dosage
- Dosage recommendations vary by population and condition, based on clinical and experimental data:
- Adults: Typical oral doses range from 300 to 1200 mg per day, used for conditions like chronic pain, diabetic neuropathy, and ALS, with durations from 2 to 12 weeks (source).
- Children: Recommended at 600 mg per day for up to 3 months, primarily for conditions like migraine (source).
- Animal Studies: Doses like 10 mg/kg subcutaneously in mice and 100 mg/kg orally in rats have been used, providing context for experimental efficacy (source).
- Safety, LD50, and Risk Thresholds
- PEA is generally considered safe, with extensive data supporting its tolerability:
- Safe Range: Clinical trials suggest doses up to 1200 mg per day are safe, with no serious adverse effects reported for treatment durations up to 49 days at an incidence of 1/200 or greater (source).
- Minimum Effective Dose: Evidence suggests 300 mg per day can be effective, as seen in studies on pain and inflammation (source).
- Maximum Safe Dose: Given the high LD50 and lack of toxicity at therapeutic doses, up to 1200 mg per day appears safe, with reports of 1.8 g/day showing excellent tolerability (source).
- LD50: In rats, LD50 is >2000 mg/kg body weight, indicating low acute toxicity (source).
- When It Starts to Become Dangerous: Given the high LD50 and safety profile, significant risks are likely only at doses far exceeding typical use, potentially above 2000 mg/kg, but specific human thresholds are not well-defined due to limited high-dose studies.
- Ivermectin
- Pharmacological Actions
- Ivermectin is an anti-parasitic agent primarily indicated for treating infections such as onchocerciasis, strongyloidiasis, and scabies. Its mechanism of action involves binding selectively and with high affinity to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells, particularly in microfilaria. This binding increases permeability to chloride ions, leading to hyperpolarization, paralysis, and death of the parasite. Additionally, Ivermectin acts as an agonist of gamma-aminobutyric acid (GABA), disrupting central nervous system neurosynaptic transmission in parasites, which further contributes to its efficacy.
- Recent studies, such as those published in Ivermectin: A Multifaceted Drug With a Potential Beyond Anti-parasitic Therapy, suggest emerging roles in anti-inflammatory, anti-viral, and even anti-cancer activities, though these are less established and require further research, especially for human applications.
- The time course of these actions is influenced by pharmacokinetics. Peak plasma concentrations (Cmax) are typically reached around 4 hours post-oral administration, with effects on parasites beginning shortly thereafter, as evidenced by studies in The Pharmacokinetics and Interactions of Ivermectin in Humans—A Mini-review. The duration of action aligns with its half-life, ensuring sustained activity against parasites over approximately 18 hours.
- Pharmacokinetics
- Half-Life: The elimination half-life of Ivermectin following oral administration is approximately 18 hours, as detailed in Ivermectin: Uses, Interactions, Mechanism of Action | DrugBank Online. This indicates that it takes about 18 hours for the plasma concentration to reduce by half, influencing dosing intervals for repeated treatments.
- Bioavailability: Oral bioavailability is moderate and can be enhanced with a high-fat meal, improving absorption. Specific percentages are not universally reported, but studies indicate variability. For instance, an oral solution (ethanolic) has been shown to have approximately twice the systemic availability compared to tablets or capsules, as noted in The Pharmacokinetics and Interactions of Ivermectin in Humans—A Mini-review. Factors such as co-administration with beverages like beer can increase plasma levels, while orange juice may decrease bioavailability, highlighting the importance of administration conditions.
- Other routes, such as topical, are used for conditions like rosacea, but bioavailability data for these are less relevant to the oral focus here. The drug does not cross the blood-brain barrier significantly, with a volume of distribution of 3 to 3.5 L/kg, and is 93% protein-bound, primarily metabolized hepatically and excreted in feces (>99%).
- Dosage Considerations
- Dosages vary based on the condition and patient weight, with detailed guidelines provided in clinical resources like Medscape: Stromectol (ivermectin) dosing. Below is a table summarizing key dosage information:
Condition Typical Dose (Adults, Oral) Notes Strongyloidiasis 200 μg/kg (e.g., 15 mg for >80 kg) once Repeat doses not usually necessary; verify eradication with stool exams Onchocerciasis (River Blindness) 150 μg/kg (e.g., 12 mg for 80 kg) once, may repeat in 3-12 months Does not treat adult worms, which may require surgical excision Scabies (Immunocompromised, Off-label) 200 μg/kg once, may repeat in 14 days Higher doses for severe cases under medical supervision - Therapeutic Range: The standard therapeutic dose is 150-200 μg/kg, translating to approximately 10.5-14 mg for a 70 kg individual, administered as a single dose for most indications.
- Minimum Effective Dose: For onchocerciasis, the minimum effective dose is around 150 μg/kg, ensuring sufficient plasma levels to paralyze microfilaria, as supported by INCHEM: Ivermectin.
- Maximum Safe Dose: Typically, single doses up to 200 μg/kg are considered safe, with clinical experience showing 9% adverse effects at 150 μg/kg, mostly Mazzotti-type reactions (e.g., edema, pruritis), and 0.25% severe, as per INCHEM: Ivermectin. Higher or repeated doses, such as in crusted scabies, may reach up to seven doses over a month, but this is under strict medical supervision.
- LD50 and Toxicity: The LD50, or lethal dose for 50% of subjects, is estimated at 2-43 mg/kg in humans, extrapolated from animal studies (e.g., mice LD50 oral 25 mg/kg, dogs 80 mg/kg, rats around 50 mg/kg subcutaneously, as per Comparative evaluation of acute toxicity of ivermectin by two methods after single subcutaneous administration in rats - PubMed and Ivermectin - Wikipedia). This indicates a wide margin of safety at therapeutic doses, with the therapeutic range (0.15-0.2 mg/kg) being significantly lower.
- When It Becomes Dangerous: Case reports suggest toxicity symptoms, such as mydriasis, vomiting, and neurological effects, at doses around 5-10 mg/kg. For example, a 16-month-old boy ingesting 100-130 mg (approximately 6.7-8.7 mg/kg for 15 kg) experienced symptoms but recovered, as noted in INCHEM: Ivermectin. Higher doses, such as those reported in overdose cases (e.g., up to 125 mg in veterinary formulations, potentially 1.8 mg/kg for a 70 kg adult), can lead to severe effects like coma, as per Toxic Effects from Ivermectin Use Associated with Prevention and Treatment of Covid-19 | New England Journal of Medicine. The evidence leans toward doses above 7 mg/kg being considered toxic, especially for off-label uses like COVID-19, where achieving anti-viral effects in vitro required such high doses, as mentioned in Ivermectin - Wikipedia.
- The controversy around Ivermectin, particularly its off-label use for COVID-19, has led to increased reports of toxicity, with the FDA and CDC issuing warnings about overdoses, as seen in Ivermectin toxicity, treatment: Self-medicating COVID-19 danger. This highlights the importance of adhering to approved indications and dosages, with therapeutic levels being well-tolerated in non-infected individuals, while higher doses in infected patients may exacerbate adverse reactions due to parasite die-off.
- In summary, Ivermectin’s pharmacological actions are well-established for parasitic treatment, with clear pharmacokinetic profiles and dosage guidelines. However, caution is advised at doses exceeding therapeutic ranges, with toxicity thresholds identified around 5-10 mg/kg, and severe risks at higher levels, particularly in non-approved uses.
- Positive Impacts by Condition
- Ivermectin has shown effectiveness across several parasitic infections, with specific percentages from clinical studies:
- Onchocerciasis (River Blindness): Reduces skin microfilariae by 98-99% after 1-2 months and decreases female worms with live microfilariae by about 70%.
- Lymphatic Filariasis: Achieves 100% microfilarial clearance at day 12, with levels at 18-20% of pretreatment at 6 months.
- Strongyloidiasis: Offers a 96.8% cure rate with a single dose, increasing to 98% with two doses.
- Scabies: Provides a 62.4% cure rate with one dose, rising to 92.8% with two doses, and up to 100% in some studies with appropriate dosing.
- Head Lice: Shows a 95.2% efficacy rate in difficult-to-treat cases with oral administration.
- Safety and Convenience
- Ivermectin is generally safe, with adverse reactions occurring in 6-13 per 1000 people for onchocerciasis initially, decreasing with subsequent doses. Its single-dose oral administration improves compliance, especially in resource-limited settings.
- Pharmacological Actions
- Ivermectin works by binding to glutamate-gated chloride channels in parasites, causing paralysis and death. It’s selective for parasites, ensuring safety in humans, and also prevents adult female worms from releasing microfilariae in conditions like onchocerciasis.
- Detailed Side Effects with Percentages
- Below, side effects are categorized by system, with percentages from various sources, including the Stromectol prescribing information for strongyloidiasis and onchocerciasis, and a COVID-19 trial (JAMA, 2021, at 400 μg/kg dose). Post-marketing reports are included where percentages are not available.
- Neurological Side Effects
- These are linked to Ivermectin’s potential CNS effects, especially at higher doses:
- Dizziness: 2.8% (strongyloidiasis), 34.0% (COVID-19 trial)
- Somnolence: 0.9% (strongyloidiasis)
- Vertigo: 0.9% (strongyloidiasis)
- Tremor: 0.9% (strongyloidiasis), 6.5% (COVID-19 trial)
- Headache: 0.2% (onchocerciasis), 52.0% (COVID-19 trial)
- Confusion, ataxia, seizures: Reported in overdose or misuse cases, frequencies not quantified.
- Gastrointestinal Side Effects
- Often mild and transient, possibly due to direct irritation:
- Diarrhea: 1.8% (strongyloidiasis), 26.0% (COVID-19 trial)
- Nausea: 1.8% (strongyloidiasis), 23.0% (COVID-19 trial)
- Vomiting: 0.9% (strongyloidiasis), 1.5% (COVID-19 trial)
- Abdominal pain: 0.9% (strongyloidiasis), 18.0% (COVID-19 trial)
- Anorexia: 0.9% (strongyloidiasis)
- Constipation: 0.9% (strongyloidiasis)
- Dermatological Side Effects
- Linked to immune responses, especially in onchocerciasis:
- Pruritus: 2.8% (strongyloidiasis), 27.5% (onchocerciasis)
- Rash: 0.9% (strongyloidiasis), 6.0% (COVID-19 trial)
- Urticaria: 0.9% (strongyloidiasis)
- Skin involvement (edema, papular/pustular rash): 22.7% (onchocerciasis)
- Skin discoloration: 6.5% (COVID-19 trial)
- Toxic epidermal necrolysis, Stevens-Johnson syndrome: Post-marketing reports, frequencies not quantified.
- Musculoskeletal Side Effects
- Often part of the Mazzotti reaction in onchocerciasis:
- Arthralgia/synovitis: 9.3% (onchocerciasis)
- Myalgia: 0.4% (onchocerciasis)
- Lymphatic Side Effects
- Common in onchocerciasis due to immune response:
- Lymph node enlargement and tenderness: Various, e.g., inguinal lymph node enlargement 12.6%, tenderness 13.9% (onchocerciasis)
- Cardiovascular Side Effects
- Linked to systemic effects, possibly dose-related:
- Tachycardia: 3.5% (onchocerciasis)
- Orthostatic hypotension: 1.1% (onchocerciasis)
- Hypotension: Post-marketing reports, frequencies not quantified.
- Ophthalmological Side Effects
- Noted in both standard and high-dose uses, transient in many cases:
- Disturbances of vision: 16.5% (COVID-19 trial)
- Blurry vision: 11.5% (COVID-19 trial)
- Photophobia: 3.5% (COVID-19 trial)
- Reduction in visual acuity: 2.0% (COVID-19 trial)
- Conjunctival hemorrhage: Post-marketing reports, frequencies not quantified.
- General Side Effects
- Non-specific, often mild:
- Asthenia/fatigue: 0.9% (strongyloidiasis)
- Fever: 22.6% (onchocerciasis)
- Edema: Facial 1.2%, peripheral 3.2% (onchocerciasis)
- Swelling: 2.0% (COVID-19 trial)
- Respiratory and Hepatic Side Effects
- Rare but serious, often from post-marketing data:
- Worsening of bronchial asthma: Post-marketing reports
- Hepatitis, elevation of liver enzymes, elevation of bilirubin: Post-marketing reports, frequencies not quantified.
- Other Side Effects
- Severe and rare, linked to neurotoxicity:
- Neurotoxicity: Somnolence/drowsiness, stupor, coma, confusion, disorientation, death (post-marketing reports)
- Impact in Medical Contexts: Bacterial Biofilms
- In medical settings, the focus shifts to bacterial biofilms, which are implicated in chronic infections and are notoriously resistant to antibiotics. Research here has yielded mixed results, with Ivermectin's effectiveness varying based on the bacterial strain, concentration, and whether it is used alone or in combination:
- A study published in PubMed (2021) investigated the antimicrobial and biofilm properties of Ivermectin and its derivative, D4, against Methicillin-resistant Staphylococcus aureus (MRSA). The minimum inhibitory concentration (MIC) for Ivermectin was 20 μg/mL, while D4 had a lower MIC of 5 μg/mL, indicating greater potency. However, the impact on biofilms was starkly different: Ivermectin showed no significant change in biofilm formation at 40 μg/mL after 24 hours, with weak and limited effects noted in previous studies, such as against Acinetobacter baumannii. In contrast, D4 reduced biofilm percentages by 21.2% at 10 μg/mL, 92.9% at 40 μg/mL, and 93.6% at 20 μg/mL, with scanning electron microscopy (SEM) confirming complete inhibition at 20 μg/mL. The antibiofilm effect of D4 was achieved by regulating the expression of biofilm-related genes, including relQ, rsbU, spA, icaD, RSH, and sigB, suggesting a mechanism involving gene expression modulation (source).
- Another study, published in ScienceDirect (2023), explored repurposing Ivermectin and ciprofloxacin in nanofibers for wound healing and infection control against multidrug-resistant (MDR) wound pathogens. The composite nanofiber (CIP-IVM NF), with Ivermectin concentrations ranging from 0.3–0.5 μg/mL and ciprofloxacin from 1.6–2.5 μg/mL, successfully disintegrated biofilms of Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis. This suggests that Ivermectin, when combined with other antimicrobial agents, can enhance biofilm disruption, particularly in wound healing contexts (source).
- Research on the gut microbial ecosystem, published in MDPI (2023), investigated Ivermectin's impact on gut microbiota using a Triple-SHIME® simulator with fecal material from healthy adults. The study found that Ivermectin introduced minor and temporary changes to the gut microbial community in terms of composition and metabolite production, as revealed by 16S rRNA amplicon sequencing, flow cytometry, and GC-MS. While this study did not explicitly focus on biofilms, the gut microbial community includes biofilm-forming bacteria, suggesting a potential indirect effect (source).
- Positive Impacts and Efficacy Rates
- Ivermectin's efficacy varies by condition, with clinical trials providing robust data on cure rates and reductions in parasite load. Below is a detailed list, organized by disease, with percentages derived from peer-reviewed studies:
- Onchocerciasis (River Blindness):
- Impact: Ivermectin significantly reduces microfilarial density, crucial for preventing blindness and skin manifestations.
- Efficacy: Community-based studies, such as one conducted in Liberia, show an 84% reduction in microfilarial density after two years of annual treatment with doses around 150 μg/kg. This is vital for interrupting transmission and reducing morbidity.
- Source: PubMed - Community-based treatment of onchocerciasis with ivermectin
- Strongyloidiasis:
- Impact: Highly effective in eradicating Strongyloides stercoralis, preventing severe complications like hyperinfection syndrome.
- Efficacy: Clinical trials indicate a 96% eradication rate with a single dose (200 μg/kg) and 98% with two doses given two weeks apart, based on follow-up stool exams.
- Source: ScienceDirect - Efficacy of ivermectin for chronic strongyloidiasis
- Scabies:
- Impact: Provides effective treatment, reducing itching and skin lesions caused by Sarcoptes scabiei.
- Efficacy: Studies show a 62.4% cure rate with one dose (200 μg/kg), increasing to 92.8% with two doses at a two-week interval, compared to permethrin's 96.9% with two applications.
- Source: PubMed - The efficacy of permethrin 5% vs. oral ivermectin for the treatment of scabies
- Lymphatic Filariasis:
- Impact: Clears microfilariae, reducing transmission and preventing lymphedema and elephantiasis.
- Efficacy: A controlled trial showed 100% clearance of microfilariae at day 12 with a single dose (ranging from 21.3 to 126.2 μg/kg), though levels returned to 18-19% of pretreatment at six months, indicating some recurrence.
- Source: NEJM - A Controlled Trial of Ivermectin and Diethylcarbamazine in Lymphatic Filariasis
- Head Lice:
- Impact: Effective in treating Pediculus humanus capitis, especially in cases resistant to topical treatments.
- Efficacy: Oral Ivermectin at 400 μg/kg showed a 95.2% efficacy rate on day 15 in difficult-to-treat cases, based on intention-to-treat analysis.
- Source: NEJM - Oral Ivermectin versus Malathion Lotion for Difficult-to-Treat Head Lice
- Enterobiasis (Pinworms):
- Impact: Offers moderate efficacy against Enterobius vermicularis, reducing perianal pruritus and infection rates.
- Efficacy: Literature suggests a cure rate of up to 85% with a single oral dose ranging from 50 to 200 μg/kg, though it is less effective compared to albendazole.
- Source: ScienceDirect - Ivermectin - an overview
- Ascariasis:
- Impact: Effective in treating Ascaris lumbricoides, reducing worm burden and preventing complications like intestinal obstruction.
- Efficacy: Comparable to albendazole, with a high parasitological cure rate, estimated at around 95%, based on Cochrane reviews showing no significant difference from albendazole's 95.7% cure rate.
- Source: Cochrane - Anthelmintic drugs for treating ascariasis
- Pharmacological Actions
- Ivermectin's mechanism of action is highly specific to parasites, ensuring minimal impact on human hosts. It primarily acts by binding to glutamate-gated chloride channels (GluCl) in invertebrates, which are critical for nerve and muscle function. This binding increases chloride ion permeability, leading to hyperpolarization of the cell membrane, paralysis, and subsequent death of the parasite.
- Technical Details: Ivermectin selectively binds to GluCl channels, causing an influx of chloride ions, which hyperpolarizes the parasite's nerve and muscle cells. This disrupts neurotransmission, leading to flaccid paralysis and death. It may also affect GABA-gated chloride channels, enhancing its antiparasitic effect.
- Safety in Mammals: In mammals, GluCl and GABA-gated channels are primarily located in the central nervous system. Ivermectin does not significantly cross the blood-brain barrier, limiting its action to peripheral tissues and ensuring safety. This selective action is due to differences in P-glycoprotein expression between parasites and mammals, with parasites lacking effective efflux mechanisms.
- Immune Modulation: Some studies suggest Ivermectin may enhance the host immune response by suppressing parasite-secreted proteins that evade immune detection, though this is secondary to its direct antiparasitic action.
- Source: Drugs.com - Ivermectin: Uses, Dosage, Side Effects, Warnings, Cureus - Ivermectin: A Multifaceted Drug With a Potential Beyond Anti-parasitic Therapy
- Anticancer Effects
- Ivermectin has emerged as a candidate for anticancer therapy, with mechanisms including inhibition of cell proliferation, induction of apoptosis, and enhancement of chemotherapy efficacy. Its action involves regulating signaling pathways like Akt/mTOR and PAK1, which are critical in cancer cell survival.
- Breast Cancer: A notable study using a 4T1 mouse model for triple-negative breast cancer (TNBC) demonstrated Ivermectin’s synergy with anti-PD1 therapy. Complete tumor regression was observed in 40% of mice (6 out of 15) on combination therapy, compared to 5% (1 out of 20) on Ivermectin alone and 10% (1 out of 10) on anti-PD1 alone [1]. Long-term survival rates varied, with approximately 75% survival in neoadjuvant settings with Ivermectin, anti-PD1, and IL-2, and 40% in adjuvant and metastatic settings [1]. These findings suggest Ivermectin converts “cold” tumors to “hot,” enhancing immune response, but are limited to animal models, with human trials ongoing.
- Glioblastoma: Research indicates Ivermectin inhibits glioblastoma cell proliferation dose-dependently, inducing apoptosis via caspase-dependent pathways and mitochondrial dysfunction. It also blocks angiogenesis by affecting endothelial cells, potentially preventing tumor metastasis [2]. However, its inability to cross the blood-brain barrier limits clinical application, and no specific percentages were provided for human outcomes.
- Other Cancers: Ivermectin shows antitumor effects across various cell lines, including colon, ovarian, and leukemia, by promoting programmed cell death (apoptosis, autophagy, pyroptosis) and reversing multidrug resistance. A study noted its efficacy in combination with chemotherapy, enhancing outcomes, but lacked specific human efficacy percentages [3].
- Antiviral Effects
- Ivermectin’s antiviral properties have been extensively studied, particularly against SARS-CoV-2, with broader implications for RNA and DNA viruses. Its mechanism involves inhibiting viral replication, potentially by interfering with host factors like importin α/β1.
- SARS-CoV-2 (COVID-19): In vitro, Ivermectin achieved a remarkable 5000-fold reduction in viral RNA at 48 hours in Vero-hSLAM cells, suggesting potent antiviral activity [4]. Clinical trials have shown mixed results. A meta-analysis of 15 RCTs involving 2438 participants found Ivermectin reduced the risk of death by 62% (risk ratio 0.38, 95% CI 0.19–0.73), with moderate-certainty evidence [5]. However, another RCT found no significant difference in symptom resolution time (82% vs. 79% resolved by day 21, hazard ratio 1.07, p=0.53), highlighting variability [6]. Controversy surrounds these findings, with some studies retracted and debates over dosage and efficacy, especially given FDA and WHO cautions against its use for COVID-19 outside clinical trials.
- Other Viruses: Ivermectin has shown activity against Zika, dengue, and influenza in vitro, with studies reporting reductions in viral load, but specific percentages for human outcomes are scarce. A systematic review noted its broad-spectrum potential, but most data are preclinical [7].
- Anti-inflammatory Effects
- Ivermectin’s anti-inflammatory effects are well-documented, particularly in dermatological and respiratory contexts, mediated by reducing proinflammatory cytokines like TNF-alpha, IL-1, and IL-6, and suppressing NF-κB pathways.
- Rosacea: Clinical trials for papulopustular rosacea demonstrate high efficacy. Two RCTs (Stein Gold et al., 2014a) showed treatment success (IGA 0 or 1) in 38.4% and 40.1% of patients after 12 weeks with Ivermectin 1% cream, compared to 11.6% and 18.8% with vehicle (p<0.001) [8]. Another study comparing Ivermectin to metronidazole found 84.9% success versus 75.4% after 16 weeks (p<0.001) [9]. Long-term data (40 weeks) showed success rates rising to 71.1% and 76.0% [8]. A review also noted 40-80% lesion clearance in 1371 patients after 3 months, supporting its role in improving quality of life [10].
- Other Inflammatory Conditions: Ivermectin’s anti-inflammatory effects extend to conditions like asthma, where it suppressed mucus hypersecretion and immune cell recruitment in mice, and late-stage COVID-19, with a meta-analysis suggesting a 68% mortality reduction in hospitalized patients [11]. These findings indicate systemic and lung-specific anti-inflammatory actions, but human data beyond rosacea are preliminary.
- Antibacterial Effects
- While less emphasized, Ivermectin shows antibacterial activity, particularly against Staphylococcus aureus. An in vitro study reported minimum inhibitory concentrations (MICs) of 6.25 μg/ml for methicillin-sensitive S. aureus (MSSA) and 12.5 μg/ml for methicillin-resistant S. aureus (MRSA), indicating potential against bacterial infections [12]. However, clinical data on human antibacterial use are limited, and its relevance for intake is unclear without further studies.
- Treatment Protocols
- Oral Ivermectin is mainly used for parasitic infections, with specific protocols based on the condition:
- Strongyloidiasis: Typically a single dose of 200 mcg/kg.
- Onchocerciasis: A single dose of 150 mcg/kg, possibly repeated every 3 to 12 months.
- Scabies: Usually 200 mcg/kg as a single dose, sometimes repeated after 1-2 weeks, with multiple doses for severe cases like crusted scabies.
- Head Lice: Often treated with topical forms, but oral use can be 200 mcg/kg, sometimes needing a second dose.
- Pharmacological Actions Outside Parasitic Purposes
- Beyond its role in treating parasitic infections, Ivermectin has been explored for other pharmacological effects, particularly antiviral, anticancer, and anti-inflammatory properties. These are based on in vitro, animal, and some clinical studies, but their clinical utility remains under investigation.
- Antiviral Properties: Ivermectin's antiviral potential has been extensively studied, particularly during the COVID-19 pandemic. A seminal study by Caly et al. (2020) demonstrated that Ivermectin inhibits SARS-CoV-2 replication in vitro, achieving a ~5000-fold reduction in viral RNA at 48 hours [ScienceDirect: Ivermectin Inhibits SARS-CoV-2 In Vitro, https://www.sciencedirect.com/science/article/pii/S0166354220302011]. A systematic review by Nature (2020) also summarizes its effects against RNA viruses like Zika, dengue, and yellow fever, and DNA viruses like BK polyomavirus, suggesting mechanisms such as blocking nuclear import of viral proteins [Nature: Ivermectin Antiviral Effects, https://www.nature.com/articles/s41429-020-0336-z]. However, clinical trials, such as those reviewed in eClinicalMedicine, show mixed results, with concentration-dependent antiviral activity but no clear clinical benefit for COVID-19, highlighting the need for large trials [eClinicalMedicine: Antiviral Effect of High-Dose Ivermectin, https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370%2821%2900239-X/fulltext]. The controversy around its use for COVID-19, with some studies suggesting reduced mortality and others showing no benefit, underscores the need for cautious interpretation.
- Anticancer Properties: Recent research has explored Ivermectin's potential as an anticancer agent, with preclinical studies showing promising results. A PMC article (2020) notes that Ivermectin inhibits proliferation, metastasis, and angiogenic activity in various cancer cells, potentially through regulating PAK1 kinase and promoting programmed cell death like apoptosis and autophagy [PMC: Ivermectin Anticancer Effects, https://pmc.ncbi.nlm.nih.gov/articles/PMC7505114/]. Another study in Frontiers (2021) found it effective against colorectal cancer cells, inducing cytotoxicity and inhibiting growth [Frontiers: Ivermectin in Colorectal Cancer, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.717529/full]. It also reverses multidrug resistance in cancer cells, as shown in a Journal of Experimental & Clinical Cancer Research study (2019), by targeting the EGFR/ERK/Akt/NF-κB pathway. However, these findings are primarily in vitro and animal models, with no established human cancer treatment protocols, and claims of it being a "cure" for cancer are false, as clarified by AP News (2023) [AP News: Ivermectin and Cancer Claims, https://apnews.com/article/fact-check-ivermectin-nih-cancer-cure-629592291079].
- Anti-inflammatory Effects: Ivermectin's anti-inflammatory properties have been observed in models of skin inflammation and asthma. A PMC article (2024) discusses its ability to mitigate skin inflammation and reduce cytokine production (e.g., TNF-alpha, IL-1β, IL-6) in lipopolysaccharide-induced inflammation models, suggesting potential for managing inflammatory skin conditions and possibly autoimmune diseases [PMC: Ivermectin Multifaceted Therapeutic, https://pmc.ncbi.nlm.nih.gov/articles/PMC11008553/]. Another study in a murine asthma model showed diminished immune cell recruitment and cytokine production in bronchoalveolar lavage fluid, indicating immunomodulatory effects [PMC: Ivermectin Anti-inflammatory Properties, https://pmc.ncbi.nlm.nih.gov/articles/PMC7539925/]. These effects are promising but require further clinical validation.
- Detailed Protocols by Condition
- COVID-19
- COVID-19 has been a significant focus for repurposing ivermectin, given its in vitro antiviral activity against SARS-CoV-2. Several clinical trials have explored oral ivermectin, with the following protocols noted:
- 12 mg Daily for 5 Days: A randomized, double-blind, placebo-controlled trial in Dhaka, Bangladesh, involved 72 hospitalized patients, with one arm receiving 12 mg once daily for 5 days. This protocol showed earlier virological clearance (9.7 days vs. 12.7 days for placebo, p = 0.02), but no significant clinical symptom improvement [Reference: International Journal of Infectious Diseases, DOI: https://www.ijidonline.com/article/S1201-9712(20)32506-6/fulltext].
- 24 mg Daily for 5 Days: A multi-center, double-blind randomized controlled trial in hospitalized patients with mild to moderate COVID-19 used 24 mg daily for 5 days (400 μg/kg for an average 60 kg patient). This resulted in a statistically significant lower viral load but no significant effect on clinical symptoms [Reference: BMC Infectious Diseases, DOI: https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-024-09563-y].
- 400 μg/kg Once Daily for 3 Days: A double-blind, randomized, placebo-controlled trial in Brazil involved outpatients with early COVID-19, using 400 μg/kg once daily for 3 days. This did not prevent hospitalization or extended emergency department observation, indicating limited clinical benefit [Reference: New England Journal of Medicine, DOI: https://www.nejm.org/doi/full/10.1056/NEJMoa2115869].
- Despite these protocols, the efficacy remains debated. The World Health Organization and FDA recommend use only within clinical trials, citing inconclusive evidence and potential risks from self-medication, especially with animal formulations [Reference: WHO, https://www.who.int/news-room/feature-stories/detail/who-advises-that-ivermectin-only-be-used-to-treat-covid-19-within-clinical-trials; FDA, https://www.fda.gov/consumers/consumer-updates/ivermectin-and-covid-19].
- Rosacea
- Rosacea, an inflammatory skin condition, is primarily treated with topical ivermectin (1% cream, FDA-approved). However, oral ivermectin has been used off-label in refractory cases, based on case reports:
- Single Dose of 200–250 μg/kg: One case report described a 44-year-old man with chronic rosacea treated with a single 250 μg/kg dose, showing significant improvement and remission for 6 months [Reference: Actas Dermo-Sifiliográficas, DOI: https://www.actasdermo.org/es-oral-ivermectin-treat-papulopustular-rosacea-articulo-S1578219017301944]. Another report used 200 μg/kg with subsequent topical permethrin, effective for rosacea-like demodicidosis [Reference: PubMed, DOI: https://pubmed.ncbi.nlm.nih.gov/10534645/].
- Dengue
- 400 μg/kg Daily for 3 Days: A combined phase 2/3 randomized double-blinded placebo-controlled trial in adult dengue patients used 400 μg/kg daily for 3 days. This accelerated NS1 antigenemia clearance (71.5 hours vs. 95.8 hours for placebo, p = 0.014), but no clinical efficacy was observed, with similar rates of dengue hemorrhagic fever (24.0% vs. 31.1%, p = 0.260) [Reference: PubMed, DOI: https://pubmed.ncbi.nlm.nih.gov/33462580/].
- Emerging Research and Other Potential Uses
- Beyond these, research suggests potential for ivermectin in other non-parasitic conditions, though specific oral protocols are less established:
- Cancer: Preclinical studies show antiproliferative and proapoptotic effects in cancer cell lines, but no clinical trials provide human dosing protocols. Safety data indicate doses up to 2 mg/kg in healthy volunteers with no serious adverse reactions, but this is not specific to cancer [Reference: PMC, DOI: https://pmc.ncbi.nlm.nih.gov/articles/PMC7505114/].
- Autoimmune Diseases: Research, including a patent (WO2019136211A1), suggests ivermectin may treat autoimmune conditions by reducing Demodex mites, potentially linked to diseases like rheumatoid arthritis. A mouse study on experimental autoimmune encephalomyelitis used 10 mg/kg orally, showing protective effects, but human protocols are lacking [Reference: PMC, DOI: https://pmc.ncbi.nlm.nih.gov/articles/PMC10209955/].
- Agomelatine
- Pharmacological Actions
- Agomelatine's mechanism of action involves dual receptor interactions, which are critical to its therapeutic effects. It acts as a potent agonist at melatonin MT1 and MT2 receptors and as an antagonist at serotonin 5-HT2C receptors, with some affinity for 5-HT2B receptors, though the clinical relevance of the latter is less established.
- Melatonin MT1 Receptor Agonism: Agomelatine binds with high affinity to MT1 receptors, with a Ki value of approximately 0.1 nM. This agonism is believed to regulate circadian rhythms, promoting sleep onset and improving sleep quality, particularly by attenuating alerting signals to the cortex.
- Melatonin MT2 Receptor Agonism: Similarly, it has a Ki of about 0.12 nM for MT2 receptors, contributing to phase-shifting circadian rhythms, which is beneficial for patients with disrupted sleep-wake cycles. This action is thought to advance the timing of sleep and body temperature decline.
- Serotonin 5-HT2C Receptor Antagonism: With a Ki of approximately 631 nM, agomelatine acts as a neutral antagonist at 5-HT2C receptors, leading to increased release of norepinephrine and dopamine in the frontal cortex. This disinhibition is thought to enhance mood and cognitive function, a key aspect of its antidepressant effect.
- Serotonin 5-HT2B Receptor Antagonism: It also interacts with 5-HT2B receptors, with a Ki of about 660 nM, but the functional significance is less clear, with limited evidence on its contribution to therapeutic outcomes.
- These actions influence over time in a biphasic manner. Acute effects, particularly on sleep and circadian rhythms, are observed shortly after administration, often within hours to days, due to its rapid absorption and receptor interactions. For instance, studies have shown improvements in sleep onset and quality from the first week of treatment, likely due to MT1/MT2 agonism. Chronic effects, such as antidepressant efficacy, develop over weeks, with clinical trials indicating significant mood improvements after 6-8 weeks, mediated by the combined melatonergic and serotonergic effects.
- Pharmacokinetic Profile
- Agomelatine's pharmacokinetics are characterized by rapid absorption and metabolism, with significant implications for its clinical use:
- Half-life: The mean plasma half-life is between 1 and 2 hours, indicating rapid elimination, which aligns with its once-daily dosing at bedtime to mimic natural melatonin rhythms.
- Bioavailability: Oral bioavailability is less than 5% at therapeutic doses, attributed to extensive first-pass hepatic metabolism, with substantial interindividual variability. This low bioavailability is higher in women and increased by oral contraceptives, while smoking reduces it.
- Absorption and Distribution: It is rapidly absorbed, with peak plasma concentrations reached within 1 to 2 hours. The volume of distribution is about 35 L, and it is 95% bound to plasma proteins, with no significant changes in binding with age or renal impairment, though free fraction doubles in hepatic impairment.
- Metabolism and Excretion: Metabolized mainly via CYP1A2 (90%), with minor contributions from CYP2C9 and CYP2C19, producing inactive metabolites that are rapidly conjugated and excreted, primarily in urine (80%), with negligible unchanged drug.
- Dosage and Safety Considerations
- Standard Dosage: The recommended starting dose is 25 mg once daily at bedtime, taken orally with or without food. This dose is effective for many patients, as evidenced by clinical trials showing significant antidepressant effects at this level.
- Dose Adjustment: If there is no improvement after two weeks, the dose may be increased to 50 mg once daily, based on individual benefit/risk assessment and strict liver function monitoring. Treatment duration should be at least 6 months to ensure symptom-free status.
- Safe Range and Minimum Effective Dose: The safe range is 25-50 mg daily, with 25 mg identified as the minimum effective dose from studies comparing doses of 1, 5, and 25 mg, where 25 mg showed the best effectiveness.
- Maximum Recommended Dose: 50 mg daily is the maximum recommended dose, with higher doses not advised due to increased risk of liver enzyme elevations.
- Overdose and Toxicity: In overdose cases, doses up to 7.5 g have been reported, primarily causing drowsiness, dizziness, and nausea in sole ingestions, with no severe toxicity. Polydrug overdoses showed more severe effects, but these were likely due to co-ingested substances. Liver transaminase rises, a known risk at therapeutic doses, were not reported in overdose scenarios, suggesting a wide safety margin.
- LD50: Specific LD50 values are not available in public sources, but animal studies and overdose data suggest it is likely high, given the lack of severe toxicity even at high doses in humans.
- When It Becomes Too Dangerous: Doses above 50 mg may increase the risk of adverse effects, particularly liver enzyme elevations, with monitoring recommended. The exact threshold for danger is unclear, but clinical guidelines contraindicate use in hepatic impairment and advise caution above recommended doses.
- Clinical Implications and Research Gaps
- Agomelatine's dual action offers benefits for both sleep and mood, with acute effects on sleep architecture observed in polysomnography studies, showing increased slow-wave sleep and improved efficiency. However, research gaps remain, particularly in precise functional EC50 values for MT1/MT2 agonism and long-term safety at higher doses. The controversy around its efficacy, as noted in some reviews, highlights the need for further studies, especially in diverse populations.
- In conclusion, agomelatine presents a novel therapeutic option with a favorable safety profile within recommended doses, but careful monitoring for liver function is essential. Its pharmacological actions and pharmacokinetic properties underpin its clinical utility, with ongoing research needed to fully elucidate its safety at higher doses and in special populations.
- Citicoline
- Pharmacological Actions
- Citicoline’s pharmacological actions are multifaceted, primarily centered on supporting neuronal health and function:
- Enhancement of Phospholipid Synthesis: Citicoline acts as a precursor for phosphatidylcholine, crucial for maintaining the structural integrity of neuronal membranes. It is involved in the CDP-choline pathway, where it is converted into phosphatidylcholine via the enzyme diacylglycerol cholinephosphotransferase. This action is vital for membrane repair and maintenance, especially in conditions like ischemia where membrane integrity is compromised (source).
- Neuroprotective Effects: Citicoline exhibits neuroprotective properties through several mechanisms, including preservation of cardiolipin and sphingomyelin, restoration of phosphatidylcholine levels, and stimulation of glutathione synthesis, which has antioxidant effects. It also reduces phospholipase A2 activity and decreases arachidonic acid levels, particularly important post-ischemia to mitigate inflammation and cell damage. These effects are suggested to protect against neuronal injury in conditions like stroke and traumatic brain injury (source).
- Increase in Acetylcholine Synthesis: By providing choline, Citicoline supports the synthesis of acetylcholine, a neurotransmitter critical for memory, learning, and muscle control. This is particularly relevant in cognitive enhancement, as acetylcholine levels are often reduced in age-related cognitive decline. The brain preferentially uses choline for acetylcholine synthesis, which can limit availability for phospholipid synthesis, making Citicoline supplementation beneficial (source).
- Potential Modulation of Other Neurotransmitters: There is emerging evidence that Citicoline may increase brain levels of noradrenaline, dopamine, and serotonin, potentially explaining its antidepressant effects in some studies, though this is less robust and requires further research (source).
- Time Course of Actions
- The time course for Citicoline’s pharmacological actions varies depending on the specific effect and condition:
- Phospholipid Synthesis and Neuroprotection: Given Citicoline’s rapid metabolism, with hydrolysis occurring within minutes in the liver, effects on phospholipid synthesis and neuroprotection likely begin within hours. In acute settings like stroke, administration within 24 hours is common, with outcomes such as reduced infarct size observed over days to weeks in animal models (source).
- Acetylcholine Synthesis: The increase in acetylcholine levels is likely to occur shortly after administration, potentially within hours, as Citicoline provides choline that can be rapidly utilized by cholinergic neurons. However, clinical cognitive benefits, such as improved memory, are typically observed after weeks of supplementation, with studies showing improvements after 12 weeks in older adults with memory impairment (source).
- Long-Term Cognitive Effects: For chronic conditions like age-related cognitive decline, benefits are generally seen over extended periods, often requiring consistent daily intake for several weeks to months, as seen in trials like the IDEALE study (source).
- Half-Life and Bioavailability
- Citicoline’s pharmacokinetics are complex due to its rapid metabolism:
- Half-Life: Citicoline itself has a very short plasma half-life, likely on the order of minutes, as it is quickly hydrolyzed in the intestine and liver into choline and cytidine. The elimination half-lives of its metabolites are reported as approximately 56 hours for CO2 via respiration and 71 hours for urinary excretion, reflecting the longer duration of metabolite clearance (source).
- Bioavailability: Oral bioavailability is nearly 100%, with absorption being virtually complete, as noted in pharmacological reviews. This high bioavailability is comparable to intravenous administration, where bioavailability is 100% by definition. The drug is water-soluble, with minimal excretion in feces, supporting its efficient absorption (source).
- Dosage Information
- Dosage recommendations and safety profiles are well-established in clinical and supplemental use:
- Typical Doses: Doses range from 250 mg to 2000 mg per day, depending on the indication. For cognitive enhancement in healthy individuals, doses of 250–1000 mg per day are common, while for medical conditions like stroke, doses up to 2000 mg per day are used (source).
- Safe Range: The safe range is considered up to 2000 mg per day, with clinical trials supporting this level without significant adverse effects. Data from meta-analyses show adverse event frequencies comparable to placebo at these doses (source).
- Minimum Effective Dose: The minimum effective dose varies by condition; for cognitive support, 250 mg per day may suffice, but effectiveness can depend on individual factors and specific studies, with some trials using 500 mg as a starting point (source).
- Maximum Safe Dose: Doses up to 2000 mg per day are commonly used in clinical settings, with no significant safety concerns reported, suggesting this as the practical maximum safe dose (source).
- LD50: The lethal dose for 50% of subjects (LD50) is approximately 8 g/kg orally in rodents, indicating very low toxicity. For a 70 kg human, this translates to 560 g, far exceeding typical therapeutic doses, underscoring its safety profile (source).
- Dangerous Levels: Given the high LD50, Citicoline is unlikely to become dangerous at standard doses. Adverse effects are rare and mild, typically gastrointestinal, such as stomach pain and diarrhea, with no evidence of serious toxicity at therapeutic levels. Risks might emerge at doses in the grams per kilogram range, which are not relevant for human use (source).
- Emoxypine
- Pharmacological Actions and Time to Effect
- Emoxypine exhibits a broad spectrum of pharmacological actions, as identified through multiple studies. These include:
- Anxiolytic: Reduces anxiety, with evidence suggesting effects observable after two weeks in patients with panic disorder, as seen in a study combining it with antidepressants. (source)
- Anti-stress: Helps manage stress responses, with animal studies showing reduced anxiety in extreme conditions like bright light or immobilization. (source)
- Anti-alcohol: Supports treatment for alcohol withdrawal, with typical therapy periods of 5-7 days, though specific onset times are not detailed. (source)
- Anticonvulsant: Prevents seizures, with mechanisms linked to membrane stabilization, but time to effect is not specified in available data.
- Nootropic: Enhances cognitive functions, potentially improving memory and learning, with effects likely taking days to weeks, as anecdotal reports suggest. (source)
- Neuroprotective: Protects nerve cells, with effects seen within 24 hours in stroke models, as demonstrated in a study on thrombolytic therapy efficiency. (source)
- Anti-inflammatory: Reduces inflammation, though specific onset times are not detailed, likely tied to its antioxidant properties.
- Antioxidant: Scavenges free radicals, with potential benefits in neurodegenerative diseases, but some claims are debated and require further validation. (source)
- Cardioprotective: Protects heart tissue, with effects possibly seen in days, linked to improved blood flow and reduced ischemia. (source)
- Antiatherosclerotic: Reduces atherosclerosis, with mechanisms involving cholesterol lowering, but time to effect is not specified.
- Improves cerebral blood circulation: Enhances brain blood flow, likely with effects seen within days, as part of its anti-ischemic action. (source)
- Inhibits thrombocyte aggregation: Reduces blood clotting, with potential immediate effects on blood rheology, though long-term benefits may take weeks.
- Lowers cholesterol levels: Reduces cholesterol, with effects likely seen over weeks, tied to its cardiovascular benefits.
- Iron chelating property: Shown in vitro, suggesting potential for managing conditions like Alzheimer's, but clinical onset times are unclear. (source)
- Antihypoxic: Improves oxygen use, with animal studies showing increased survival in hypoxic conditions, effects possibly immediate. (source)
- Anti-ischemic: Reduces tissue damage from poor blood flow, with effects seen in acute settings like stroke within hours to days.
- Vegetotrophic: Supports cellular functions, with mechanisms not fully detailed, and time to effect unclear.
- Geroprotective: Potentially slows aging, with long-term effects likely requiring months, based on its antioxidant properties.
- The time to effect for each action varies significantly, depending on the condition treated and the model studied. For acute conditions like stroke, effects can be seen within 24 hours, while chronic conditions may require weeks, as seen in anxiety and cognitive enhancement studies.
- Half-Life and Bioavailability
- The elimination half-life of Emoxypine is consistently reported as 2 to 2.6 hours across multiple sources, indicating rapid clearance from the body (source). This short half-life suggests it may require multiple daily doses for sustained effects.
- Dosage Information
- Dosage recommendations vary by administration route:
- Oral: Typically 125-250 mg three times a day, with a maximum daily dose of 750 mg, as seen in product descriptions and clinical guidelines (source). Therapy duration is generally 2-6 weeks, with gradual tapering over 2-3 days.
- Injections: Administered intramuscularly or intravenously, with a maximum daily dose of 1200 mg, depending on the condition and doctor's recommendations (source).
- The minimum effective dose is likely around 375 mg/day for oral use, based on studies showing efficacy at this level, while the safe range extends up to the maximum daily doses mentioned. The maximum dose without high risks is 750 mg/day orally and 1200 mg/day for injections, based on clinical safety data.
- Specific LD50 (lethal dose for 50% of test subjects) data was not found, but Emoxypine is considered safe at therapeutic doses, with studies showing minimal adverse events compared to placebo (source). The point at which it starts to become dangerous is likely above the maximum recommended doses, but exact thresholds are not detailed in available sources.
- Safety and Risk Assessment
- Emoxypine, marketed as Mexidol, has a well-established safety profile, particularly in Russian medical practice. Studies, including randomized controlled trials like "Epica" (2017) and "MEMO" (2021), show no significant adverse events compared to placebo, indicating low risk at therapeutic doses (source).
- Common side effects, when reported, include nausea, dry mouth, and allergic reactions, but these are rare (source). The lack of LD50 data suggests it is not commonly associated with lethal toxicity at standard doses, and its use is generally well-tolerated, especially in neurological and cardiovascular applications.
- Oroxylin A
- Pharmacological Actions
- Oroxylin A exhibits a broad spectrum of pharmacological activities, which have been extensively studied in preclinical models. These include:
- Anti-cancer Effects: Oroxylin A inhibits tumor growth and metastasis by modulating pathways such as PI3K/Akt, MAPK, and NF-κB. It has shown potential against various cancers, including brain, breast, and lung cancer, by inducing apoptosis and inhibiting proliferation. Specific studies, such as those cited in Pharmacological and Toxicological Properties of Oroxylin A, highlight its role in reversing chemotherapy resistance in leukemia through STAT3 inhibition.
- Anti-inflammatory Properties: It reduces inflammation by downregulating pro-inflammatory cytokines like TNF-α and IL-6, and signaling molecules such as MMPs and VEGF. Research, including Oroxylin A: A Promising Flavonoid for Chronic Diseases, indicates its modulation of NF-κB and MAPK pathways, which are pivotal in inflammatory responses.
- Neuroprotective Effects: Oroxylin A enhances memory and cognitive function, potentially through increasing brain-derived neurotrophic factor (BDNF) levels, as noted in studies like The Effects of Oroxylin A on Memory Impairment in Mice. It has been shown to ameliorate memory deficits in models of Alzheimer’s disease, suggesting a role in neurodegenerative disorder treatment.
- Anti-viral Activity: It demonstrates antiviral effects, particularly against influenza A virus, with dose-dependent inhibition rates reported in cell studies, as seen in Oroxylin A Suppresses Influenza A Virus Replication.
- Other Actions: Additional benefits include anti-bacterial, anti-thrombotic, and potential cardiovascular and neurological protective effects, supported by reviews like Overview of Oroxylin A as a Flavonoid Compound.
- Pharmacokinetics
- Pharmacokinetic data for Oroxylin A is primarily derived from animal studies, particularly in rats, with the following insights:
- Half-life: Exact half-life values are not explicitly stated in the literature reviewed. However, studies indicate rapid elimination following intravenous administration (2 mg/kg), suggesting a short half-life, though precise numerical data is lacking. (source)
- Bioavailability: Oral bioavailability is notably low, with relative bioavailability less than 2% for intragastric doses of 40, 120, and 360 mg/kg in rats, as detailed in Pharmacokinetics and Tissue Distribution Study. This low bioavailability may limit its oral therapeutic potential, necessitating alternative delivery methods.
- Distribution: Following oral administration, Oroxylin A and its metabolites (Oroxylin A 7-O-glucuronide and Oroxylin A sodium sulfonate) show rapid and widespread tissue distribution, with high concentrations in the liver, kidney, stomach, and intestine. This distribution pattern is consistent across studies, indicating systemic exposure. (source)
- Excretion: Excretion profiles vary, with Oroxylin A primarily excreted via feces, Oroxylin A 7-O-glucuronide via bile and urine, and Oroxylin A sodium sulfonate showing minimal excretion, as noted in the same study.
- Dosage and Safety
- Dosage information is predominantly from animal models, with limited human data due to the absence of clinical trials:
- Animal Studies: In mice, a single oral dose of 5 mg/kg has been effective in reversing memory impairments, as seen in Memory Impairment Study in Mice. Higher doses, up to 200 mg/kg orally, showed no toxicity in immunodeficient mice, suggesting a relatively wide safety margin in preclinical settings. (source)
- Human Dosage: There is no established safe range, minimum effective dose, or maximum safe dose for humans. The lack of clinical trials means that LD50 (lethal dose 50%) and thresholds for danger are not determined. Reviews like Oroxylin A for Chronic Diseases highlight the need for dose standardization and toxicity assessments in humans, currently unknown.
- Safety and Toxicity: Preclinical studies suggest low toxicity, particularly in cancer research, with no significant adverse effects reported at tested doses in animals. However, the translation to humans remains uncertain, and milder side effects may not be captured in rodent models, as noted in Oroxylin A Benefits and Side Effects.
- Uridine
- Pharmacological Actions
- The pharmacological actions of uridine triacetate are condition-specific, reflecting its role as a uridine replacement and antidote:
- Hereditary Orotic Aciduria:
- This rare metabolic disorder results from mutations in the uridine monophosphate synthase (UMPS) gene, leading to uridine deficiency. Uridine triacetate compensates by supplying uridine, enabling the synthesis of uridine nucleotides essential for DNA and RNA production. This action reduces the overproduction of orotic acid, mitigating symptoms such as anemia and developmental delays. The mechanism involves replacing the deficient uridine, thus restoring normal pyrimidine nucleotide synthesis and reducing urinary orotic acid excretion.
- Fluorouracil or Capecitabine Overdose/Toxicity:
- In cases of overdose or early-onset severe toxicity (within 96 hours post-administration), uridine triacetate acts as a biochemical antagonist. It competes with 5-FU metabolites, such as 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP), for incorporation into the RNA and DNA of non-cancerous cells. This competition mitigates cell damage and death, reducing toxicities like neutropenia, mucositis, diarrhea, and hand-foot syndrome, and allows for higher 5-FU doses with improved efficacy and fewer side effects.
- The time course for these actions is not explicitly detailed for each effect, but pharmacokinetic data suggest onset within 2–3 hours post-dose, aligning with peak plasma uridine concentrations. The duration of effect is influenced by the drug's half-life, discussed below, and its ability to sustain uridine levels sufficient for therapeutic action.
- Pharmacokinetics
- The pharmacokinetic profile of uridine triacetate is critical for understanding its clinical utility:
- Absorption and Bioavailability:
- Uridine triacetate is orally active, delivering 4- to 6-fold more uridine into systemic circulation compared to equimolar doses of uridine itself, as noted in DrugBank: Uridine triacetate. This enhanced bioavailability is due to its prodrug nature, which undergoes rapid deacetylation by nonspecific esterases in the gastrointestinal tract and liver. Peak plasma uridine concentrations are generally achieved within 2–3 hours post-oral administration, with no significant difference in rate and extent of exposure under fed versus fasted conditions, as observed in healthy adults receiving a 6-gram dose.
- Distribution:
- Uridine, once released, is taken up by cells via nucleoside transporters and crosses the blood-brain barrier, ensuring systemic and central nervous system availability. This distribution is crucial for addressing toxicities affecting the cardiac and central nervous systems.
- Metabolism and Excretion:
- It is metabolized by normal pyrimidine catabolic pathways present in most tissues and excreted via the kidneys. This process aligns with its short half-life, ensuring rapid clearance.
- Half-life:
- The half-life is approximately 2–2.5 hours, with an extension to 8.2 ± 6.8 hours at higher doses (120 mg/kg) for hereditary orotic aciduria, as detailed in the Xuriden prescribing information. This variability suggests dose-dependent pharmacokinetics, particularly at higher therapeutic levels.
- Specific pharmacokinetic parameters from clinical studies include:
Parameter Day 0 (Uridine, 150-200 mg/kg) Day 1 (XURIDEN, 60 mg/kg) Day 28 (XURIDEN, 60 mg/kg) Day 160 (XURIDEN, 120 mg/kg) C_max (μM, mean ± SD) 56.0 ± 16.6 91.3 ± 32.2 88.7 ± 43.2 80.9 ± 20.0 T_max (hours, median, range) 2.0 (1.0, 4.0) 2.0 (1.2, 2.1) 1.3 (1.0, 2.5) 3.0 (2.0, 4.0) t_1/2 (hours, mean ± SD) 1.6 ± 0.7 1.6 ± 0.6 2.3 ± 1.6 8.2 ± 6.8 AUC(0-8) (μM·hr, mean ± SD) 238.0 ± 163.2 311.2 ± 153.3 278.7 ± 148.5 465.6 ± 95.3 - These parameters indicate rapid absorption and variable half-life, influencing the timing of therapeutic effects.
- Drug Interactions:
- In vitro studies show it is a weak substrate for P-glycoprotein (P-gp), with potential interactions with orally administered P-gp substrates like digoxin (IC50 344 μM). It does not significantly inhibit or induce major CYP enzymes, suggesting minimal risk of clinically important interactions with other drugs.
- Special Populations:
- Pharmacokinetic analyses indicate no significant effect of sex, age (range 20–83 years), or body surface area on uridine pharmacokinetics, ensuring consistent dosing across diverse patient groups.
- Dosage Regimens
- Dosage varies by indication, with specific guidelines for administration:
- Hereditary Orotic Aciduria (Xuriden):
- Starting Dose: 60 mg/kg once daily, administered orally.
- Increased Dose: May be escalated to 120 mg/kg once daily, not exceeding 8 grams daily, for insufficient efficacy, such as elevated urinary orotic acid, worsening laboratory values (e.g., red blood cell or white blood cell indices), or worsening symptoms.
- Administration: Measure using a scale accurate to at least 0.1 gram or a graduated teaspoon. Mix with 3–4 ounces of soft food (applesauce, pudding, yogurt) or 5 mL milk/infant formula for doses up to 2 grams, and consume immediately, followed by at least 4 ounces of water. Do not chew granules.
- Fluorouracil or Capecitabine Overdose/Toxicity (Vistogard):
- Adults: 10 grams (1 packet) orally every 6 hours for 20 doses, totaling 5 days, without regard to meals.
- Pediatric: 6.2 grams/m² of body surface area every 6 hours for 20 doses, not exceeding 10 grams per dose.
- Administration: Mix each dose with 3–4 ounces of soft food, ingest within 30 minutes, and follow with at least 4 ounces of water. If vomiting occurs within 2 hours, administer another complete dose as soon as possible. Can be administered via nasogastric or gastrostomy tube if necessary, using a food starch-based thickening product.
- Safe Range and Minimum Effective Dose:
- The minimum effective dose is 60 mg/kg daily for hereditary orotic aciduria, with escalation to 120 mg/kg if needed. For overdose, the regimen of 10 grams every 6 hours is standard, with no lower effective dose specified, as it’s an emergency treatment.
- The safe range aligns with prescribed doses, with maximums of 8 grams daily for orotic aciduria and 10 grams per dose for overdose, suggesting these are the upper limits without high risks based on clinical data.
- Maximum Dose Without High Risks:
- For orotic aciduria, 120 mg/kg (max 8 grams daily); for overdose, 10 grams every 6 hours for 20 doses, as these are the approved maximums with minimal adverse effects reported.
- LD50 and Toxicity:
- Specific LD50 values for uridine triacetate are not publicly available, likely due to its high safety profile within therapeutic ranges. Clinical studies and prescribing information indicate no significant toxicity at prescribed doses, with animal studies showing no teratogenicity at half the maximum human dose. Side effects like nausea and vomiting are rare and mild, suggesting a wide therapeutic index.
- Estimation of When It Starts to Become Too Dangerous:
- Given the lack of reported toxicity at prescribed doses and the absence of LD50 data, it’s challenging to estimate. However, exceeding the maximum recommended doses (e.g., >120 mg/kg daily for orotic aciduria or >10 grams per dose for overdose) may increase risks, potentially leading to gastrointestinal distress or other unstudied effects, though no specific threshold is documented.
- Safety and Adverse Effects
- Uridine triacetate is generally well-tolerated, with safety profiles varying by indication:
- Hereditary Orotic Aciduria: No adverse reactions reported in clinical use, as noted in Xuriden Prescribing Information.
- Fluorouracil/Capecitabine Toxicity: Common adverse reactions include vomiting, nausea, and diarrhea, with serious events like Grade 3 nausea and vomiting reported in <2% of patients, as per DailyMed - VISTOGARD.
- No contraindications exist, and hypersensitivity reactions are rare, managed by discontinuation and supportive care. Animal studies (rats) at half the maximum human dose showed no teratogenicity or embryofetal effects, with limited human pregnancy data suggesting caution.
- Tongkat Ali
- Pharmacological Actions and Time to Effect
- Tongkat Ali, scientifically known as Eurycoma longifolia, is a traditional herbal medicine with a wide range of potential pharmacological effects, supported by both in vitro and in vivo studies. Below is a detailed breakdown, including the time it takes for each action to manifest, based on clinical and preclinical evidence:
- Male Fertility Enhancement: This action includes enhancing semen volume, spermatozoa count, and motility, as well as increasing testosterone production and improving erectile function and sexual libido. Studies show sperm motility increased by 44.4% and semen volume by 18.2% after 12 weeks of supplementation, with testosterone increases of 30.2% in rat models (source).
- Antimalarial Effect: Effective against Plasmodium falciparum, with IC50, IC90, and IC99 values for extract at 14.72, 139.65, and 874.15 μg/L respectively, compared to artemisinin at 4.30, 45.48, and 310.97 μg/L. Time to effect is not well-documented in humans, primarily studied in vitro (source).
- Cytotoxic and Anti-Proliferative Effects: Demonstrates cytotoxicity against cancer cell lines like A-549, MCF-7, and HeLa, with IC50 values for NF-κB inhibitors <1 μM and cell viability ranging from 21.01%–66.9% at 100 μM for HeLa cells. These effects are typically measured in vitro, with no specific time to effect in humans (source).
- Antimicrobial Effects: Active against Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa) bacteria, with inhibition zones of 7–25 mm and minimum inhibitory concentrations of 75 mg/mL for S. aureus and 25 mg/mL for P. aeruginosa. Time to effect is not specified, as it’s primarily an in vitro measure (source).
- Anti-Inflammatory Effects: Inhibits NF-κB with IC50 values <1 μM, activates Nrf2 via ROS-dependent p38 MAPK pathway, and shows antioxidant activity at 10–250 µg/mL. Time to effect in humans is not well-documented, but animal studies suggest rapid onset (source).
- Anti-Anxiolytic Effects: Reduces anxiety in mice, similar to diazepam, and improves stress hormone profiles in humans, with significant effects observed after 4 weeks in clinical trials (source).
- Antidiabetic Effects: Decreases blood glucose by 38%–47% at 150 mg/kg in hyperglycemic rats and enhances glucose uptake >200% at 50 μg/mL. Time to effect in humans is not specified, but animal studies suggest weeks of supplementation (source).
- Osteoporosis Preventive Effects: Prevents bone calcium loss, stimulates osteoblast proliferation, and enhances testosterone levels, with no specific time to effect documented in humans, likely requiring chronic use (source).
- Miscellaneous Effects: Includes hormonal (anti-estrogenic), ergogenic (increases muscle strength), insecticidal, muscular, antiulcer, and anti-rheumatism effects. For ergogenic effects, benefits are seen after 5-8 weeks, with Cmax and Tmax for eurycomanone at 0.33 ± 0.03 mcg/mL and 4.40 ± 0.98 h, respectively (source).
- Pharmacokinetics
- The pharmacokinetics of Tongkat Ali, particularly for its active compounds like eurycomanone, are crucial for understanding its efficacy and safety. Below are the detailed parameters:
- Half-life: For eurycomanone, studies report a half-life of 0.35 ± 0.04 h in one study and 1.00 ± 0.26 h in another, suggesting variability possibly due to formulation or species (source). For 13α(21)-epoxy-eurycomanone, the half-life is 0.75 ± 0.25 h, longer due to lower elimination rate.
- Bioavailability: Oral bioavailability for eurycomanone is 10.5%, with C_max at 0.33 ± 0.03 mcg/mL and T_max at 4.40 ± 0.98 h. For 9-methoxycanthin-6-one, absorption is <1% orally, indicating poor bioavailability for some compounds (source).
- Distribution and Excretion: Eurycomanone has a volume of distribution (V_d) of 0.68 ± 0.30 L/kg, well distributed in extravascular fluids, with an elimination rate constant (k_e) of 0.88 ± 0.19 h⁻¹ and clearance (CL) of 0.39 ± 0.08 L/h/kg (source).
- CYP Inhibition: Eurycomanone shows IC50 >250 μg/mL for CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, and CYP3A4, indicating a low likelihood of drug-herb interactions (source).
- Dosage and Safety
- Dosage recommendations and safety profiles are critical for practical use. Below is a detailed table summarizing the dosage ranges, safety data, and toxicity information:
Aspect Details General Dosing Range 100 to 800 mg daily, with specific uses like male infertility at 200 mg twice daily up to 3 months. (source) Safe Range Possibly safe at 200 mg daily for up to 9 months or 400 mg daily for 3 months (source) Minimum Effective Dose Often 100 mg daily for testosterone and muscle effects, varying by condition (source) Maximum Safe Dose Not clearly defined, but exceeding 800 mg daily is not recommended due to potential risks (source) LD50 In mice, LD50 for alcoholic extract is 1500-2000 mg/kg, and for aqueous extract >3000 mg/kg, indicating low acute toxicity (source) Risks at High Doses Potential for DNA damage and genotoxicity, with positive results in chromosome aberration tests at 500-2500 μg/mL and in vivo comet assays at 2000 mg/kg bw, particularly affecting stomach and duodenum (source) Side Effects Possible mercury or lead poisoning from contaminated supplements, presence of sildenafil in some products, and rare cases of liver injury, especially in bodybuilders (source)
- Lithium Orotate
- Pharmacological Actions
- The pharmacological effects of lithium orotate are primarily due to the lithium ion, which dissociates in solution and is believed to exert similar actions as other lithium salts. The following actions are inferred from general lithium research, given the limited specific data for orotate:
- Mood Stabilization: Lithium is well-known for stabilizing mood swings in bipolar disorder, likely through modulation of neurotransmitter systems and second messenger pathways. It may reduce mania and prevent depressive episodes, though lithium orotate's efficacy is less studied (source).
- Neuroprotection: Lithium promotes neurogenesis and increases brain-derived neurotrophic factor (BDNF), protecting against oxidative stress and apoptosis. This is supported by studies on lithium's role in neurodegenerative diseases, potentially applicable to orotate (source).
- Neurotransmitter Modulation: Lithium affects dopamine, serotonin, glutamate, and GABA levels. It modulates excitatory and inhibitory neurotransmission, which may contribute to its mood-stabilizing effects (source).
- Inhibition of Second Messenger Systems: Lithium inhibits inositol monophosphatase and glycogen synthase kinase-3 (GSK-3), impacting cellular signaling pathways like the phosphoinositide cycle, which is crucial for mood regulation (source).
- Circadian Rhythm Regulation: Lithium stabilizes circadian rhythms, which is important for mood disorders, potentially through effects on biological clocks (source).
- Anti-inflammatory Effects: Lithium reduces inflammation, which may play a role in its therapeutic effects, particularly in mood disorders with an inflammatory component (source).
- The time to effect for these actions varies. Acute effects, such as neurotransmitter modulation, may be felt within hours or days, as anecdotal reports suggest (source). However, for therapeutic effects like mood stabilization, which involve neuroprotection and circadian regulation, it may take 1-3 weeks, similar to prescription lithium, though specific data for orotate is scarce.
- Pharmacokinetics: Half-Life and Bioavailability
- The pharmacokinetics of lithium orotate are not as well-documented as those of lithium carbonate. The half-life, or the time it takes for half the dose to be eliminated, is likely similar to lithium carbonate, which ranges from 18-36 hours, with an average of about 24 hours, based on studies showing no significant differences in uptake, distribution, and excretion between lithium orotate and other salts in rats (source).
- Bioavailability, particularly via the oral route, is high for lithium salts, with lithium carbonate having nearly 100% absorption. For lithium orotate, some sources suggest enhanced bioavailability due to its orotate form, which may cross the blood-brain barrier more easily, potentially allowing for lower doses (source). Given the conflicting evidence, it seems likely that oral bioavailability is high, but exact figures are not established.
- Dosage and Safety Profile
- Dosage recommendations for lithium orotate are based on its use as a supplement, with much lower doses compared to prescription lithium:
- Supplemental Doses: Typically, lithium orotate supplements provide 5-20 mg of elemental lithium per day. For example, a 120 mg lithium orotate capsule may contain about 4.6 mg of lithium, calculated from its composition (3.83 mg lithium per 100 mg lithium orotate, as per Lithium orotate - Wikipedia).
- Safe Range: The safe range is generally considered to be up to 20 mg elemental lithium daily, based on supplemental use, with no well-defined RDA, though 1 mg/day is sometimes suggested as a dietary intake (source).
- Minimum Effective Dose: Not well-defined due to its supplemental nature, but low doses like 5 mg are commonly used for mood support.
- Maximum Safe Dose: Not established; exceeding recommended doses may lead to toxicity, similar to prescription lithium, with symptoms like nausea and tremors reported at higher intakes (e.g., 69 mg lithium causing minor symptoms, as per a case report in Lithium orotate: A superior option for lithium therapy? - PMC).
- LD50: Specific LD50 values for humans are not available. Animal studies, such as a toxicological evaluation, found a no observed adverse effect level (NOAEL) of 400 mg/kg bw/day in rats, which translates to high doses, but human extrapolation is uncertain (source).
- Danger Threshold: Toxicity may start when doses lead to serum lithium levels above 1.5 mmol/L, similar to prescription lithium, but exact thresholds for orotate are unclear due to limited data. Higher doses may cause symptoms like nausea, vomiting, diarrhea, tremors, and in severe cases, seizures and coma, as seen with prescription lithium.
- Comparative Context and Controversies
- Lithium orotate is often compared to lithium carbonate, with claims of better bioavailability and lower toxicity at lower doses. However, these claims are controversial, with early studies suggesting higher brain concentrations (Kling et al., 1978), while later research found no significant pharmacokinetic differences (Smith, 1976). The lack of large-scale clinical trials for lithium orotate, especially for therapeutic uses, adds to the uncertainty, making it not recommended as an alternative for bipolar disorder treatment compared to lithium carbonate (source).
- Table: Summary of Key Parameters for Lithium Orotate
Parameter Details Pharmacological Actions Mood stabilization, neuroprotection, neurotransmitter modulation, etc. Time to Effect Hours to days for acute effects; 1-3 weeks for therapeutic effects (estimated) Half-Life Approximately 24 hours (similar to lithium carbonate, based on limited data) Oral Bioavailability High, possibly better than lithium carbonate, but evidence is conflicting Safe Dose Range 5-20 mg elemental lithium daily (supplemental use) Toxicity Threshold May start at doses leading to serum levels >1.5 mmol/L, exact data lacking
- Magnesium L-Threonate
- Pharmacological Actions
- Magnesium L-threonate is primarily investigated for its effects on brain health due to its ability to cross the blood-brain barrier, a feature not as pronounced in other magnesium forms. The following actions are supported by various studies:
- Cognitive Enhancement: Research suggests Magnesium L-threonate can improve memory, learning, and overall cognitive function. A study involving 109 healthy Chinese adults aged 18-65, published in Nutrients in 2022, found that a daily dose of 2 grams of a Magnesium L-threonate-based formula (Magtein®PS) for 30 days significantly improved scores in all categories of "The Clinical Memory Test" compared to a placebo group A Magtein®, Magnesium L-Threonate, -Based Formula Improves Brain Cognitive Functions in Healthy Chinese Adults. Another randomized, double-blind, placebo-controlled trial with 50 adults aged 50-70, as noted in a 2018 Metagenics review, showed a 13.1% improvement in working memory at week 6 with 1.5-2 grams daily, with effects approaching significance by week 12 (source).
- Neuroprotection: Animal studies, such as a 2020 study on zebrafish published in BMC Neuroscience, indicate Magnesium L-threonate may protect against brain cell death and preserve cognitive function under hypoxic conditions (source). While promising, human data is limited.
- Sleep Improvement: Emerging evidence suggests it may enhance sleep quality, particularly deep sleep. A study mentioned in Verywell Health observed improved deep sleep with 1,000 milligrams daily, supporting memory retention and learning, though details on study duration and population were not specified (source).
- Potential Mental Health Benefits: Research indicates possible benefits for anxiety and depression, potentially due to its influence on gamma-aminobutyric acid (GABA) neurotransmitters. A study reported improved stress and anxiety levels with Magnesium L-threonate compared to placebo, but these findings are preliminary and require further human studies (source).
- The time to observe these effects varies, with cognitive improvements typically noted after 30 days to 12 weeks of consistent supplementation, based on the aforementioned studies.
- Pharmacokinetics
- Pharmacokinetic data for Magnesium L-threonate, particularly in humans, is limited, which complicates precise assessments of half-life and bioavailability.
- Half-life: Specific half-life data for Magnesium L-threonate was not found in the reviewed literature. However, a study on calcium L-threonate, published in Acta Pharmacologica Sinica in 2011, reported a mean plasma half-life of approximately 2.5 hours for L-threonate, which may provide an indirect comparison (source). Given the structural similarities, this might suggest a similar range, but confirmation for Magnesium L-threonate is needed.
- Bioavailability: The European Food Safety Authority (EFSA) concluded in a 2024 opinion that magnesium is bioavailable from Magnesium L-threonate, based on a dissociation study, two rat studies, and one human trial (source). The human trial (Liu et al., 2016; Krieger, 2013, unpublished) showed a 41% increase in urinary magnesium and a 4.9% increase in plasma magnesium at week 6 with doses of 1.5-2 grams daily. However, exact bioavailability percentages were not quantified, and sources like Healthline and product descriptions claim high bioavailability, especially for brain uptake, without specific figures (source).
- Dosages
- Dosage recommendations are derived from clinical studies and safety assessments:
- Common Dosages: Studies typically use 1.5-2 grams per day of Magnesium L-threonate. For instance, the Chinese study used 2 grams daily, and product labels like Life Extension's Neuro-Mag provide 2,000 mg (approximately 144 mg elemental magnesium) per serving. The EFSA opinion notes that 3,000 mg daily provides about 250 mg of magnesium, aligning with the upper limit for supplemental magnesium (source).
- Minimum Effective Dose: Based on cognitive benefit studies, the minimum effective dose appears to be around 1.5 grams daily, as seen in the working memory improvement study.
- Maximum Safe Dose: The EFSA panel considers 3,000 mg/day safe for adults, excluding pregnant and lactating women, corresponding to 250 mg of magnesium, which aligns with the tolerable upper intake level (UL) for supplemental magnesium from readily dissociable salts.
- Safety and Toxicity
- Safety assessments are crucial for understanding the risk profile:
- Safe Range: Up to 3 grams daily is deemed safe based on the EFSA opinion, with no significant safety concerns at this level, considering the magnesium and L-threonate content.
- LD50: Specific LD50 data for Magnesium L-threonate is not available in the literature. For magnesium in general, toxicity is rare with oral supplements due to renal excretion, but high doses can lead to hypermagnesemia, especially in renal impairment. Animal studies, such as those cited in the EFSA report, did not provide human LD50 values.
- When It Starts to Become Too Dangerous: Exceeding recommended doses can cause gastrointestinal side effects like diarrhea, nausea, and abdominal cramping, as noted in WebMD (source). Serious effects such as irregular heartbeat, low blood pressure, confusion, and coma are rare and typically associated with very high doses, particularly in individuals with kidney issues. The EFSA opinion suggests that intakes beyond 3 grams daily should be monitored, especially given the lack of extensive long-term human data.
- Comparative Analysis
- To organize the data, the following table summarizes key study findings on human trials:
Study Reference Population Dose (g/day) Duration Key Findings Zhang et al., 2022, Nutrients A Magtein®, Magnesium L-Threonate, -Based Formula... 109 healthy Chinese adults, 18-65 years 2 30 days Significant cognitive test improvements, especially in older participants Metagenics Review, 2018, citing Liu et al., 2016 ([Science Review: Magnesium L-Threonate Metagenics Institute 50 adults, 50-70 years, memory issues 1.5-2 13.1% working memory improvement at week 6, approached significance at week 12 Verywell Health, citing sleep study Not specified 1 Not specified Improved deep sleep, supporting memory retention and learning
- Methocarbamol
- Pharmacological Actions
- Methocarbamol's primary action is as a CNS depressant, suppressing multisynaptic pathways in the spinal cord, which likely contributes to muscle relaxation and pain relief. It does not directly affect muscle contractility, motor nerve fibers, or motor end plates, suggesting its effects are mediated centrally rather than peripherally. This mechanism is theorized to break the "pain-spasm-pain cycle," though rigorous clinical and electrophysiologic studies have not fully confirmed this.
- Timing of Pharmacological Actions
- The onset of action varies by administration route:
- Oral Administration: Research suggests an onset of approximately 30 minutes, with peak plasma concentrations typically reached in 1 to 2 hours, based on pharmacokinetic studies in healthy volunteers.
- Intravenous (IV) Administration: The evidence leans toward an almost immediate onset, with blood concentrations of 19 mcg/mL attained immediately after a 1 g IV dose at 300 mg/minute, as noted in clinical data.
- The duration of action is generally 4 to 6 hours, inferred from dosing recommendations every 6 hours, though specific duration studies are limited. This aligns with its short half-life, discussed below.
- Half-Life
- The plasma elimination half-life of methocarbamol is consistently reported as 1 to 2 hours in healthy adults. Variations exist in specific populations:
- Elderly: Approximately 1.5 hours (± 0.4) compared to 1.1 hours (± 0.27) in younger adults.
- Renally impaired: Around 1.2 hours (± 0.6) versus 1.1 hours (± 0.3) in normal subjects.
- Hepatically impaired: Extended to 3.38 hours (± 1.62) versus 1.11 hours (± 0.27) in normal subjects.
- This short half-life necessitates frequent dosing, typically every 6 hours, to maintain therapeutic levels.
- Bioavailability
- Bioavailability data, particularly for oral administration, show some uncertainty:
- Oral: It is rapidly and almost completely absorbed, with studies suggesting high bioavailability, though exact percentages are not universally specified. Rat studies indicate a range of 77% to 112%, suggesting near-complete absorption, but human data are less precise. Some sources imply "complete" bioavailability, but this lacks robust confirmation.
- IV: By definition, IV administration has 100% bioavailability, as it bypasses gastrointestinal and first-pass metabolism.
- Intramuscular (IM): While not detailed, IM is expected to have high bioavailability, similar to IV, but specific figures are unavailable.
- Food does not significantly affect absorption, allowing administration with or without meals.
- Dosage Details
- Dosage recommendations vary by route and condition, with the following ranges:
- Oral Administration:
- Initial Dose: Typically 1500 mg (three 500 mg tablets or two 750 mg tablets) four times daily, totaling 6 grams per day.
- Maintenance Dose: Reduced to 1000 mg (two 500 mg tablets or one 750 mg tablet) four times daily, approximately 4 grams per day.
- Severe Conditions: Up to 8 grams per day may be utilized initially, particularly in hospitalized patients, with typical doses like 500 mg every 8 hours noted for some cases.
- IV/IM Administration:
- Initial dose: 1 gram every 8 hours, with a maximum of 3 grams per day, not exceeding 3 consecutive days. For tetanus, higher doses (up to 24 grams daily orally) have been used, but IV is limited to 3 grams daily.
- Special Populations:
- Cirrhosis: 500 mg twice daily is well tolerated.
- Renal Impairment: Caution with oral, IV contraindicated due to polyethylene glycol.
- Hepatic Impairment: No specific dose adjustments, but clearance is reduced.
- Pediatric: Efficacy and safety not established for under 16 years.
- Elderly: Included in Beers Criteria, avoid in patients over 65 due to increased injury risk (absolute risk increase ~0.2%).
- Safety Range, Minimum Effective Dose, and Maximum Safe Dose
- Minimum Effective Dose: Likely around 500 mg every 8 hours for hospitalized patients, though initial doses often start at 1500 mg four times daily for efficacy.
- Safe Range: Generally up to 8 grams per day orally for severe cases, with IV limited to 3 grams daily for 3 days.
- Maximum Without High Risks: Exceeding 8 grams daily orally or continuing IV beyond 3 days may increase risks, but specific thresholds are not well-defined. The evidence leans toward caution above recommended maximums due to potential CNS depression and overdose risks.
- LD50 and Toxicity
- LD50: In rats, the oral LD50 is 3576.2 mg/kg, but human data are not available due to ethical constraints. Animal studies provide a reference, but direct human applicability is limited.
- Toxicity and Overdose: Isolated methocarbamol overdose is rare and unlikely life-threatening without multiple drug exposures. Symptoms include nausea, drowsiness, blurred vision, hypotension, seizures, and coma, especially when combined with alcohol or other CNS depressants. Deaths have been reported in post-marketing experience, particularly with polysubstance use. Specific populations at risk include those with cirrhosis, renal impairment, substance use disorders, and the elderly. Treatment is supportive, with no antidote available, focusing on airway maintenance, monitoring, and IV fluids if necessary.
- Estimation of When It Becomes Too Dangerous
- The point at which methocarbamol becomes dangerously toxic is not precisely defined, but research suggests risks increase significantly with doses exceeding recommended maximums (e.g., above 8 grams daily orally) and in the presence of other CNS depressants. Case reports and clinical data indicate severe symptoms like seizures and coma at high doses, particularly in overdose scenarios, but exact thresholds vary by individual factors such as age, liver function, and concurrent medications.
- Imiquimod
- Pharmacological Actions
- Imiquimod is classified as an immune response modifier, specifically acting as a Toll-like receptor 7 (TLR7) agonist. This action stimulates the innate immune system by activating immune cells, leading to the production of cytokines such as interferons, interleukins, and tumor necrosis factors. This immune activation is crucial for its therapeutic effects in treating conditions like external genital and perianal warts (EGW), actinic keratoses (AK), and superficial basal cell carcinoma. While the exact mechanism for AK and EGW is not fully elucidated, it is associated with increased markers of cytokines and immune cells upon topical application, with no direct antiviral activity observed in cell culture for EGW. The immune response is thought to help eliminate abnormal skin cells and viral infections, making it effective for these dermatological conditions.
- The time course of these pharmacological actions is influenced by the drug's pharmacokinetics, particularly its prolonged retention in the skin when applied topically. This sustained presence, with an apparent half-life of 24-29 hours, suggests a gradual release and prolonged immune activation, which is beneficial for local treatment but may contribute to local skin reactions over time.
- Pharmacokinetics and Bioavailability
- The pharmacokinetics of Imiquimod vary significantly between topical and oral routes, reflecting its primary use as a topical agent.
- Topical Application:
- Absorption: Systemic absorption is minimal, with mean peak serum concentrations ranging from 0.1 ng/mL to 3.5 ng/mL depending on the dose and application area (e.g., face, scalp, hands/arms). Urinary recovery data indicate systemic absorption is less than 1%, with recovery rates of 0.08% to 2.41% of the applied dose, suggesting very low bioavailability into the bloodstream.
- Half-life: The apparent half-life is approximately 24-29 hours, significantly longer than subcutaneous dosing (2 hours), due to prolonged retention in the skin. This prolonged half-life supports its efficacy for local immune activation over extended periods.
- Steady-state: Achieved by Day 7 with once-daily dosing, indicating a build-up effect over the initial treatment phase.
- Topical Application:
- Bioavailability: Research from a clinical study indicates an oral bioavailability of 47% relative to subcutaneous administration, with no significant effect from food intake on absorption rate or extent. This suggests it can be administered orally in fasted or non-fasted states, though this is not a standard route.
- Absorption Half-life: Approximately 1 hour, with T_max around 2.6 hours in fasted states and 3.6 hours in non-fasted states, showing a slight delay with food.
- Elimination Half-life: About 2.5 hours, with total body clearance around 970 ml/h×kg, indicating rapid systemic clearance compared to topical use.
- Dose and Study Context: The study involved a 100 mg oral dose, significantly higher than typical topical doses, highlighting its experimental nature for oral use.
- The difference in bioavailability and half-life between routes underscores Imiquimod's design for topical application, where local effects are prioritized over systemic exposure.
- Dosage and Administration
- Imiquimod is available as a 3.75% cream for topical use, with specific dosing regimens based on the condition:
- Actinic Keratosis (AK):
- Apply a thin layer (0.5 grams, equivalent to 18.75 mg Imiquimod) once daily at bedtime to the affected area (face or balding scalp) for two 2-week treatment cycles, separated by a 2-week no-treatment period. Leave on for about 8 hours, then remove with mild soap and water. Dosage interruption may be necessary for local skin reactions, but cycles should not be extended.
- External Genital Warts (EGW):
- Apply a thin layer (0.25 grams, equivalent to 9.375 mg Imiquimod) once daily at bedtime until total clearance or for up to 8 weeks, leave on for about 8 hours, then remove. Dosage interruption may be needed for local skin reactions.
- General Notes: Not for oral, ophthalmic, intra-anal, or intravaginal use. Prescribe no more than 2 boxes (56 packets) or two 7.5 g bottle pumps per treatment course to limit exposure.
- Safety Profile and Toxicity
- The safety range is defined by adherence to prescribed doses, with exceeding these increasing the risk of adverse reactions. The minimum effective dose aligns with the prescribed regimens, as lower doses may not achieve therapeutic efficacy. The maximum dose without high risks is the prescribed amount, as higher doses can lead to severe local skin reactions and potential systemic effects.
- Adverse Reactions: Common side effects include local skin reactions (erythema, scabbing, flaking, edema, erosion, exudate), headache, application site pain, irritation, pruritus, fatigue, influenza-like illness, and nausea, reported in ≥4% of patients. Postmarketing reports include application site tingling, angioedema, cardiovascular events, endocrine disorders, hematological decreases, hepatic issues, infections, musculoskeletal pain, neuropsychiatric events, respiratory issues, urinary retention, skin changes, and vascular events.
- Overdosage: Topical overdosage can increase severe local skin reactions. Oral ingestion of doses >200 mg has been associated with hypotension in clinical trials, indicating a threshold for systemic toxicity. For management, contact the Poison Help line at 1-800-222-1222.
- LD50 (Lethal Dose 50%): From animal toxicity studies, the following LD50 values were observed:
- Oral: 1665 mg/kg in rats, 200 mg/kg in Cynomolgus monkeys.
- Intravenous: 6-8 mg/kg.
- Intraperitoneal: 763 mg/kg in rats, 879 mg/kg in mice.
- Subcutaneous: 20 mg/kg in rats. These values are from preclinical studies and not directly applicable to humans, but they provide insight into potential toxicity thresholds, especially for accidental ingestion.
- When It Becomes Too Dangerous: For topical use, exceeding recommended doses can lead to severe local skin reactions, potentially requiring dosage interruption. For oral ingestion, doses above 200 mg are concerning, with hypotension reported, suggesting a point where systemic effects become significant.
- Oxytocin
- Pharmacological Actions
- Oxytocin's pharmacological actions are multifaceted, reflecting its therapeutic and physiological roles:
- Stimulation of Uterine Contractions: Oxytocin is renowned for inducing and strengthening uterine contractions, essential during labor and for managing postpartum hemorrhage. It activates oxytocin receptors on the myometrium, increasing intracellular calcium and enhancing contraction frequency and strength, regulated by a positive feedback loop during childbirth (source).
- Milk Ejection: It facilitates milk ejection during breastfeeding by stimulating the release of milk from mammary glands, crucial for lactation post-delivery.
- Behavioral and Social Effects: Research suggests oxytocin influences social cognition, pair bonding, maternal behavior, and fear conditioning. It is implicated in enhancing social interactions and has been explored for potential therapeutic uses in conditions like autism and anxiety, with receptors distributed in the brain stem and amygdala (source).
- Metabolic and Cardiovascular Effects: Oxytocin has pleiotropic effects, including impacts on metabolic functions and cardiovascular regulation, though these are less emphasized in clinical settings.
- The time course for these actions varies: uterine contractions and milk ejection effects are rapid, typically within minutes, while behavioral effects may have longer, less defined durations, often studied in hours to days for central effects.
- Half-Life
- The plasma half-life of oxytocin ranges from 1 to 6 minutes, with a noted decrease during late pregnancy and lactation, reflecting its rapid metabolism and clearance. This short half-life necessitates continuous or frequent administration for sustained effects, such as during labor induction (source).
- Bioavailabilities
- Bioavailability varies significantly by administration route, influenced by oxytocin's peptide nature and susceptibility to degradation:
- Parenteral (IV, IM): Administered intravenously or intramuscularly, oxytocin is fully bioavailable (100%), as it enters directly into systemic circulation, reaching steady-state plasma concentrations in approximately 40 minutes (source).
- Intranasal: Intranasal administration is effective for central nervous system effects, with evidence suggesting it crosses the blood-brain barrier, exhibiting psychoactive effects. However, specific bioavailability percentages are not consistently reported, though studies indicate central duration of at least 2.25 hours (source).
- Sublingual: Studies in male volunteers show sublingual bioavailability is very low, ranging from 0.007% to 0.07%, due to limited absorption through oral mucosa (source).
- Oral (Swallowed): Oral administration faces significant challenges due to degradation in the gastrointestinal tract by enzymes like pepsin. Research suggests bioavailability is extremely low, likely less than 1%, with one study noting a 200 IU tablet's effect equivalent to a 0.02 IU/min IV infusion, indicating negligible absorption without protective measures like proton pump inhibitors (source). Studies in mice with omeprazole pretreatment show increased plasma levels, but human data remain limited.
- Dosages
- Dosages are tailored to the clinical indication, with precise administration guided by patient response and monitoring:
- Labor Induction: Initiated at 0.5 to 1 milliunits per minute (mU/min) intravenously, titrated by increasing 1 to 2 mU/min every 30 to 60 minutes until a contraction pattern similar to normal labor is achieved, typically up to 6 mU/min, rarely exceeding 9 to 10 mU/min at term due to lower uterine sensitivity before term (source).
- Postpartum Hemorrhage: Administered as 10 units intramuscularly after placenta delivery, or 10 to 40 units added to 1000 mL of IV solution, infused at a rate to sustain uterine contraction and control atony, not exceeding 40 units total in the solution (source).
- Incomplete or Inevitable Abortion: Typically 10 to 20 mU/min IV, with a total dose not exceeding 30 units in 12 hours to mitigate risks like water intoxication (source).
- Safe Range, Minimum Effective Dose, Maximum Safe Dose, and LD50
- Safe Range: The safe dosage range is highly individualized, requiring continuous monitoring of uterine activity and fetal heart rate to prevent hyperstimulation and fetal distress. Adjustments are made based on clinical response, with guidelines suggesting not exceeding 10 mU/min for labor induction at term and limiting total doses for abortion to avoid water intoxication.
- Minimum Effective Dose: For labor induction, the minimum effective dose is approximately 0.5 mU/min IV, initiating contractions, with titration based on response.
- Maximum Safe Dose: There is no universal maximum, but clinical practice suggests rarely exceeding 9 to 10 mU/min for labor induction at term, and for postpartum hemorrhage, up to 40 units in IV solution. Prolonged high doses increase risks of adverse effects.
- LD50: Lethal dose 50% (LD50) data are derived from animal studies, with rats showing an LD50 of approximately 20.520 mg/kg and mice 514 mg/kg for systemic administration, indicating relatively low toxicity in animals. Human LD50 is not established due to ethical constraints, but clinical overdose risks include uterine hyperstimulation and water intoxication (source).
- When It Starts to Become Too Dangerous
- Oxytocin becomes dangerous when it leads to adverse effects such as uterine hyperstimulation, potentially causing fetal distress, or water intoxication from prolonged high doses due to its antidiuretic effect, leading to hyponatremia. Monitoring is critical, with discontinuation recommended if hyperactivity or fetal distress is observed, and oxygen administration may be necessary (source).
- Pharmacological Actions and Side Effect Mechanisms
- Oxytocin's primary pharmacological action is to bind to G-protein-coupled Oxytocin receptors in the myometrium, increasing intracellular calcium levels and triggering uterine contractions. This mechanism is essential for labor but can lead to hyperstimulation if doses are excessive, reducing placental blood flow and causing fetal distress. The antidiuretic effect, mediated by V2 receptors in the renal collecting ducts, promotes water reabsorption, which can result in water intoxication, especially with prolonged infusion and large fluid volumes, leading to hyponatremia, seizures, and coma in severe cases.
- Cardiovascular effects include vasodilation, which can cause hypotension, particularly with rapid intravenous administration, and may lead to arrhythmias. The risk of uterine rupture is heightened in scarred uteri due to pre-existing weaknesses, exacerbated by Oxytocin's strong contractile effects. For unscarred uteri, rupture is rare but can occur with prolonged or high-dose use, likely due to overstretching of the uterine wall.
- Incidence Data and Limitations
- Incidence rates for common side effects (e.g., tachycardia, nausea) are derived from drug information sources like Drugs.com, indicating a 1-10% range, which aligns with clinical trial data for similar medications. For rarer events like uterine rupture, specific studies provide estimates: in women with a scarred uterus undergoing TOLAC with Oxytocin, incidence is around 1-2% (source). However, exact frequencies for many side effects, such as water intoxication or neonatal jaundice, are not consistently reported, reflecting underreporting in clinical trials and the need for further research.
- Clinical Implications and Monitoring
- Given the potential for serious side effects, clinical guidelines emphasize careful monitoring during Oxytocin administration, including continuous fetal heart rate monitoring and maternal vital signs. The FDA has issued a "black box" warning for Pitocin due to its high-risk profile, highlighting the need for judicious use (source). Water intoxication, for instance, requires monitoring of fluid intake and sodium levels, while uterine rupture risk necessitates avoiding Oxytocin in high-risk cases like multiple prior cesareans.
- Dihydromyricetin
- Pharmacological Actions
- DHM exhibits a broad spectrum of pharmacological effects, primarily observed in preclinical studies. These include:
- Cardioprotection: DHM demonstrates anti-atherosclerotic properties by reducing pyroptosis in human umbilical vein endothelial cells (HUVECs) at concentrations of 0.5–1 μM via the Nrf2 pathway, and enhances cholesterol efflux in THP-1 macrophages at 1–100 μM through LXRα, ABCA1, and ABCG1 upregulation (source). It also protects against myocardial ischemia/reperfusion injury with 7-day pre-treatment, and reduces adriamycin-induced cardiotoxicity at 125–500 mg/kg in mice, suppressing apoptosis and ROS.
- Anti-diabetes: DHM improves insulin sensitivity via AMPK, Akt, and AS160 phosphorylation, with an 8-week treatment reducing blood glucose and plasma insulin in high-fat diet (HFD) rats, and 50 mg/kg/day for 12 weeks enhancing sensitivity in mice, involving the AMPK-PGC-1α-SIRT3 pathway (source).
- Hepatoprotection: DHM protects against liver ischemia/reperfusion injury at 100 mg/kg/d for 7 days, activating autophagy via FOXO3a, Atg5, Atg12, beclin 1, and LC3. It ameliorates alcoholic liver disease at 75–150 mg/kg/d for 6 weeks, activating Nrf2 and inhibiting NF-κB, and improves non-alcoholic fatty liver disease (NAFLD) by enhancing mitochondrial function, with a clinical trial using 150 mg twice daily showing benefits (source).
- Neuroprotection: DHM inhibits catechol-O-methyltransferase (COMT) activity in a dose-dependent manner, protecting dopaminergic neurons in Parkinson's models, and shows antidepressant effects at 10–20 mg/kg for 3–7 days, enhancing BDNF and reducing TNF-α, IL-6 (source).
- Anti-tumor: It induces apoptosis in hepatocellular carcinoma cells via Akt/Bad and G2/M arrest via Chk2, with autophagy mediated by mTOR, ERK1/2, and AMPK, and shows effects against melanoma at 1.25–10 μM, suppressing proliferation and inducing G1/S arrest (source).
- Dermatoprotection: DHM protects against UVA-induced damage and inhibits melanoma proliferation, with mechanisms involving ROS-NF-κB signaling and tyrosinase inhibition.
- These actions are supported by mechanisms involving AMPK, MAPK, Akt, NF-κB, Nrf2, and other pathways, as detailed in supplementary materials .
- Pharmacokinetic Parameters
- DHM's pharmacokinetics have been studied primarily in rats, with the following parameters:
- Half-life: Approximately 2.05 hours for intravenous administration at 2 mg/kg and 3.70 hours for oral administration at 20 mg/kg, based on LC-MS/MS analysis.
- Bioavailability: Oral bioavailability is low, at 4.02% in rats, due to poor absorption via passive diffusion and efflux by transporters like MRP2 and BCRP, with rapid distribution and elimination mostly in feces within 12 hours (source).
- Efforts to improve bioavailability include solid dispersions, nanocapsules, and phospholipid complexes, which have shown promise in enhancing absorption in animal models.
- Dosage and Administration
- Human dosage data is limited but includes:
- A clinical trial for NAFLD used 150 mg twice daily (300 mg/day) for three months, showing improvements in glucose and lipid metabolism without reported adverse effects (source).
- Suggested dosages for other uses, such as hangover prevention, range from 300 mg per drink to 2000–4000 mg for reducing alcohol intoxication, based on commercial recommendations and extrapolations from animal studies (source).
- Animal studies suggest dosages like 1.8–11.8 mg/kg in rats for behavioral effects, translating to approximately 126–824 mg for a 70 kg human, aligning with clinical trial doses.
- Safety and Toxicity
- DHM is generally considered safe, with traditional use in Asia for centuries and minimal adverse effects reported:
- LD50: Greater than 5 g/kg in mice, indicating low acute toxicity (source).
- Acute Toxicity: No significant side effects at 150 mg/kg to 1.5 g/kg in mice, with a human equivalent dose (HED) suggesting safety up to 15.68 g for a 70 kg person, based on a 22 g/kg no-effect level in mice (source).
- Chronic Toxicity: No negative effects on development, hematology, or pathology in long-term rat studies, with enhanced immunologic function observed (source).
- However, some controversy exists, with studies suggesting potential pro-oxidant and mutagenic effects, though these are not well-supported in human contexts (source).
- DIM
- Also known as: 3,3′-Diindolylmethane
- Pharmacological Actions
- DIM exhibits a wide range of pharmacological actions, supported by both preclinical and clinical evidence. These actions include:
- Antioxidant Effects: DIM reduces oxidative stress, particularly in radiation-damaged cells, through pathways like NRF2/ARE/HO-1, as noted in studies on cellular protection mechanisms (source).
- Anti-inflammatory Properties: It decreases levels of pro-inflammatory markers such as NO, PGE2, TNF-α, and IL-6 in LPS-treated cells, suggesting a role in mitigating inflammation (source).
- Antiapoptotic Activity: DIM increases antiapoptotic protein Bcl-2 and decreases pro-apoptotic Bax, potentially protecting cells from programmed cell death, especially in bone marrow cells post-injury (source).
- Immunomodulatory Effects: DIM induces proliferation of splenocytes and augments cytokine production like IFN-γ and IL-12, with effects varying by dose and duration, such as at 100 mg/kg showing significant immune cell modulation (source).
- Anticancer Properties: DIM is noted for inducing apoptosis, cell cycle arrest (e.g., G1 arrest in breast cancer cells), and inhibiting tumor growth, with mechanisms involving AKT, NF-κB, and FOXO3 pathways, supported by both in vitro and in vivo studies (source).
- Estrogen Metabolism Modulation: DIM alters estrogen metabolism, increasing the ratio of 2-hydroxyestrones to 16α-hydroxyestrone, potentially reducing risks of hormone-related cancers, as seen in thyroid proliferative disease studies (source).
- Histone Deacetylase Inhibition: In vitro, DIM acts as an inhibitor against HDAC1, HDAC2, and HDAC3, which may contribute to its anticancer effects (source).
- Mild Cannabinoid Agonist: DIM shows low binding affinity for CB1 and CB2 receptors, suggesting minor cannabinoid-like effects (source).
- Biofilm Reduction: Research indicates DIM can reduce biofilms responsible for dental plaque by up to 90%, potentially aiding oral health (source).
- The influence of these actions over time varies by study, with effects typically observed within hours to weeks depending on dosage and administration route. For instance, anti-inflammatory effects may peak within 24 hours at certain doses, while anticancer effects may require weeks of supplementation to manifest in clinical trials.
- Half-Life
- The half-life of DIM in humans, based on pharmacokinetic studies, is approximately 4.3 hours for the parent compound, with variations depending on formulation. For example, a study reported a mean noncompartmental half-life of 4.29 ± 2.48 hours, with metabolites showing longer half-lives, such as 9.34 ± 3.13 hours for monohydroxylated forms (source).
- Bioavailability
- DIM's bioavailability is naturally low due to poor solubility and limited membrane penetration, particularly in its crystalline form. However, enhanced formulations like BR-DIM significantly improve absorption. In human studies, oral administration of BR-DIM resulted in a Cmax of 111 ± 160 ng/ml and Tmax of 2.67 ± 0.98 hours, indicating improved bioavailability compared to crystalline DIM (source).
- Dosage Considerations
- Dosage recommendations for DIM vary based on safety, efficacy, and intended use, with the following details derived from clinical and preclinical studies:
- Safe Range: Clinical studies suggest DIM is safe up to 150-200 mg per day. For instance, a study on single-dose pharmacokinetics found no adverse effects up to 200 mg, with mild side effects like nausea at 300 mg (source).
- Minimum Effective Dose: The minimum effective dose varies by condition, typically ranging from 100 mg to 300 mg per day. For example, studies on estrogen metabolism used 300 mg/day, while chemoprevention trials targeted doses achieving Cmax with less than 150 mg (source).
- Maximum Dose Without High Risks: Doses up to 200 mg per day are well-tolerated, with 300 mg showing infrequent mild side effects like nausea and headache, suggesting a threshold around this level (source).
- When It Starts to Become Too Dangerous: At 600 mg per day, there may be risks such as lowering sodium levels, as noted by WebMD, but exact thresholds for danger are not well-established, indicating a need for further research (source).
- LD50: The lethal dose 50 (LD50) for DIM was not found in the available literature, suggesting it may not be determined or is not publicly documented, which underscores the need for additional toxicological studies.
- Clinical and Safety Considerations
- Clinical trials have used doses ranging from 50 mg to 300 mg daily, with most studies reporting DIM as safe at lower doses. However, higher doses (e.g., 300 mg) may cause mild adverse effects, and at 600 mg, potential risks like hyponatremia are noted. The lack of LD50 data highlights a gap in toxicological research, and case reports of serious side effects at excessive intakes suggest caution, particularly for vulnerable populations like pregnant women or those on hormonal therapies (source).
- Luteolin
- Pharmacological Actions and Specific Effects
- Luteolin's pharmacological profile is extensive, with effects observed across multiple systems. Below, we detail each action with specific values and mechanisms where available, primarily from preclinical studies, as human clinical data remains limited.
- Anti-inflammatory: Luteolin suppresses key inflammatory mediators such as COX-2, IL-1β, TNF-α, and IL-6. In animal models, oral administration at doses of 10-50 mg/kg and intraperitoneal doses of 25-100 mg/kg have demonstrated significant reductions in these cytokines, particularly in conditions like sepsis, mastitis, and pancreatitis (source). For instance, at 50 mg/kg orally, it reduced IL-6 levels in a sepsis model.
- Antioxidant: Luteolin acts as a scavenger of reactive oxygen species (ROS) and enhances antioxidant enzyme activities, such as superoxide dismutase (SOD) and glutathione (GSH). It activates the Nrf2/Gpx4 pathway, with studies showing increased SOD levels and reduced ROS fluorescence intensity at doses around 10-20 μM in cell models (source).
- Anticancer: Luteolin exhibits proapoptotic and antiproliferative effects, inhibiting carcinogenesis, metastasis, and angiogenesis. Specific values include an IC50 of 5.9 μM for colon cancer cells and a 24% reduction in liver metastasis in animal models. It affects pathways like K-ras/GSK-3β/NF-κB and upregulates p53 and caspase-3, effective in cancers such as colon, pancreatic, hepatocellular, head and neck, ovarian, mammary, and prostate (source).
- Neuroprotective: Luteolin improves memory and reduces neuroinflammation, particularly in Alzheimer's and Parkinson's disease models. It enhances autophagy via TRAF6 and Nrf2 pathways, with doses of 5-10 mg/kg/day in rats showing about 2.8 μM in blood and brain tissues, inhibiting microglia overactivation (source).
- Cardioprotective: It protects against ischemia/reperfusion injury by activating PI3K/Akt and TLR4/NLRP3 pathways, reducing infarct size, and enhancing peroxiredoxin II activity. Doses in animal studies range from 10 to 50 mg/kg, with significant effects on cardiac function (source).
- Antidiabetic: Luteolin reverses glucose intolerance and improves insulin sensitivity via Nrf2 and RIP140/NF-κB pathways, with dietary supplementation at 0.002-0.01% showing benefits in animal models (source).
- Antimicrobial and Antiviral: Luteolin demonstrates antibacterial properties and potential antiviral effects, including against SARS-CoV-2, with proposed mechanisms involving inhibition of viral replication, though specific values are less documented (source).
- Other actions include hepatoprotective effects, musculoskeletal benefits (increasing bone mineral density), and psychiatric effects (antidepressant at 1-3 mg/kg in animals), as detailed in comprehensive reviews (source).
- Pharmacokinetics
- Half-life: Research suggests a half-life of approximately 2-3 hours in humans, based on a crossover study with artichoke leaf extract providing 14.4-35.2 mg luteolin equivalents, reaching peak plasma concentrations of 59.08-156.58 ng/mL within 30-40 minutes (source). Another study in rats reported a half-life of 4.94 ± 1.2 hours, indicating potential species differences.
- Bioavailability: Luteolin exhibits low oral bioavailability, with only 17.5% of unchanged luteolin detected in rats due to extensive first-pass metabolism, primarily forming glucuronide and sulfate conjugates. In humans, free luteolin is minimally detected in plasma, requiring enzymatic hydrolysis for measurement, suggesting systemic bioavailability is limited (source).
- Dosage Considerations
- Dosage varies by study and condition, with human clinical trials providing the most relevant data:
- Human Studies: In an autism spectrum disorder trial, a formulation with 100 mg luteolin per capsule was dosed at 1 capsule per 10 kg body weight per day, translating to 300-500 mg/day for children weighing 30-50 kg, with no significant adverse effects reported over 26 weeks (source>).
- Animal Studies: Effective doses range from 10 to 200 mg/kg, with anti-inflammatory effects at 10-50 mg/kg orally and anticancer effects at similar ranges. The LD50 in rats is above 5000 mg/kg, determined via modified Lorke’s method, with no deaths at doses up to 5000 mg/kg, classifying it as practically non-toxic (source).
- Safe Range and Minimum Effective Dose: The safe range in humans appears to be 100-500 mg/day based on clinical trials, with the minimum effective dose likely condition-specific, potentially starting at 100 mg/day for anti-inflammatory effects. Higher doses may be explored, but data is limited.
- Maximum Dose Without High Risks: Given the LD50 in rats and lack of toxicity at 500 mg/day in children, it seems likely that doses up to 1000 mg/day could be tolerated, but this requires further human studies. Supplements often recommend 500-1000 mg/day, as seen in commercial products (source).
- LD50 and Danger Threshold: The LD50 in rats is >5000 mg/kg, suggesting a high safety margin. For a 70 kg human, this would equate to over 350,000 mg, far exceeding typical doses. The threshold for danger is unclear in humans, but chronic high doses (e.g., 200 mg/kg in rats) showed increased liver enzyme activity, suggesting potential hepatotoxicity at very high levels (source).
- GPR55
- Central Nervous System (CNS) Effects
- GPR55, often classified as a novel cannabinoid receptor, is expressed in various brain regions, including the hippocampus, thalamus, and cortex. Activation of GPR55 is associated with several CNS effects, primarily through its signaling pathways involving Gq and G12/13 proteins, which lead to increased intracellular calcium via phospholipase C activation and inhibition of M-type potassium currents.
- Neuronal Excitation and Neurotransmitter Release: Activation enhances glutamate release in hippocampal slices, suggesting a presynaptic role that increases neuronal excitability Advances in the Physiology of GPR55 in the Central Nervous System. This is mediated by calcium release from intracellular stores, contrasting with the inhibitory effects of CB1/CB2 receptors.
- Neural Development: GPR55 is implicated in neural development, influencing morphology and axon growth in retinal projections and spinal cord, indicating a role in sensory system maturation [ibid].
- Neuroprotection and Inflammation: The effects are dual-edged; in adult rat hippocampus, GPR55 agonists induce microglia-dependent neuroprotection post-excitotoxic lesions, but under certain conditions, activation can promote neuro-inflammation, potentially lowering pain thresholds [ibid].
- Pain Modulation: GPR55 activation shows both pronociceptive and antinociceptive effects. For instance, injections of lysophosphatidylinositol (LPI) into the periaqueductal gray induce pronociceptive effects, while palmitoylethanolamide (PEA) exhibits pain-killing actions, possibly involving GPR55, with ongoing clinical trials for chronic pain [ibid].
- Cognitive and Emotional Effects: Central GPR55 stimulation induces anxiolytic-like effects, blocked by antagonists, which induce anxiety. Alterations in GPR55 expression are linked to autism and anxiety models, suggesting a role in emotional regulation [ibid].
- Motor Coordination and Memory: GPR55 knockout mice show impaired motor coordination, and bilateral infusions of CID16020046 in the dorsolateral striatum impair rat performance in the Rotarod test. GPR55 blockade shifts learning curves in T-maze tasks, indicating a role in procedural memory, though motor effects require further investigation [ibid].
- Cardiovascular System Effects
- GPR55's role in the cardiovascular system is less definitive, with conflicting evidence on its impact on blood pressure and cardiac function.
- Blood Pressure Regulation: Initial hopes linked GPR55 to the hypotensive effects of cannabinoids, but GPR55 knockout mice showed no altered blood pressure regulation after administration of abnormal cannabidiol, suggesting controversy GPR55 - Wikipedia. However, some studies indicate hypotensive effects upon activation GPR55 - an overview | ScienceDirect Topics.
- Cardiac Function: Research on GPR55 knockout mice revealed reduced contractile reserve in response to dobutamine, indicating a role in cardiac contractility GPR55 EXERTS DIFFERENTIAL EFFECTS ON CARDIAC ADRENOCEPTOR SUBTYPES IN MICE | Heart. This suggests GPR55 may modulate adrenoceptor responsiveness.
- Atherosclerosis: Activation in macrophages increases lipid accumulation and proinflammatory responses, potentially exacerbating atherosclerosis, as seen with the agonist O-1602 enhancing CD36- and SRB-I-mediated lipid uptake and blocking cholesterol efflux Activation of GPR55 Receptors Exacerbates oxLDL-Induced Lipid Accumulation and Inflammatory Responses | PLOS ONE.
- Metabolic System Effects
- GPR55's role in metabolism is increasingly recognized, particularly in energy balance and glucose homeostasis, making it a potential target for metabolic disorders.
- Insulin Secretion: Activation by agonists like O-1602 and abnormal cannabidiol (Abn-CBD) increases glucose-induced insulin secretion in pancreatic β-cells, mediated through inositol trisphosphate-mediated calcium release G-protein coupled receptor 55 agonists increase insulin secretion | ScienceDirect. Studies on isolated mouse and human islets confirm this effect, with GPR55 knockout reducing the response GPR55-dependent stimulation of insulin secretion from isolated mouse and human islets of Langerhans | PubMed.
- Glucose Homeostasis and Adiposity: GPR55 activation improves glucose tolerance in preclinical models, and its deficiency is associated with increased adiposity and impaired insulin signaling in peripheral tissues, suggesting a role in regulating body weight and metabolic health GPR55 deficiency is associated with increased adiposity and impaired insulin signaling | PMC. This is supported by reviews focusing on energy balance GPR55: a new promising target for metabolism? | Journal of Molecular Endocrinology.
- Gastrointestinal System Effects
- GPR55's presence in the gastrointestinal tract, particularly on myenteric neurons, suggests a role in gut motility and function.
- Motility: Activation, particularly with agonists like O-1602, reduces gastrointestinal motility, with significant effects on colonic contractions. For instance, O-1602 concentration-dependently reduced evoked contractions in mouse and human colon muscle strips, an effect reversed by the antagonist cannabidiol (CBD) A role for O-1602 and G protein-coupled receptor GPR55 in the control of colonic motility in mice | PMC. Studies in rodents also show GPR55 ligands influencing GI transit, with implications for conditions like septic ileus A novel CB receptor GPR55 and its ligands are involved in regulation of gut movement in rodents | PubMed.
- Immune System Effects
- GPR55's role in the immune system is complex, with evidence for both pro-inflammatory and anti-inflammatory actions, depending on the context.
- Inflammation: Some studies suggest anti-inflammatory effects, such as in experimental models of Dravet syndrome and Parkinson's disease where CBD, acting as a GPR55 antagonist, elicited anti-inflammatory responses GPR55 - an overview | ScienceDirect Topics. Conversely, other research indicates a pro-inflammatory role, with GPR55 activation enhancing cytokine production and inflammatory responses in macrophages, as seen in atherosclerosis models Activation of GPR55 Receptors Exacerbates oxLDL-Induced Lipid Accumulation and Inflammatory Responses | PLOS ONE. In a multiple sclerosis model, GPR55 knockout reduced disease severity, suggesting a pro-inflammatory contribution [ibid]. This duality is further highlighted in reviews discussing GPR55 as a potential therapeutic target in inflammation, with context-dependent effects GPR55 – a putative “type 3” cannabinoid receptor in inflammation | De Gruyter Brill.
- Cancer-Related Effects
- GPR55's role in cancer is another area of interest, with implications for tumor growth and progression.
- Tumor Growth: Activation is associated with increased tumor growth in certain cancers, such as glioma, where GPR55 knockdown delayed tumor growth in animal models GPR55 - an overview | ScienceDirect Topics. This is linked to its signaling pathways promoting proliferation and cytoskeletal modulation, making it a potential target for anti-cancer therapeutics [ibid].
- Valaciclovir
- Pharmacological Actions
- Valaciclovir is a prodrug that is rapidly converted to acyclovir and L-valine via first-pass metabolism in the intestines and liver. Acyclovir, the active moiety, undergoes intracellular phosphorylation to form acyclovir triphosphate, which exhibits several key pharmacological actions:
- Competitive Inhibition of Viral DNA Polymerase: Acyclovir triphosphate competes with deoxyguanosine triphosphate for binding to viral DNA polymerase, inhibiting its activity.
- Incorporation and Termination of Viral DNA Chain: It incorporates into the growing viral DNA chain, leading to chain termination due to the lack of a 3'-hydroxyl group, halting viral replication.
- Inactivation of Viral DNA Polymerase: The drug inactivates the polymerase, further preventing viral DNA synthesis.
- Antiviral Spectrum: These actions are effective against herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus 6 (HHV-6), with higher efficacy against HSV due to efficient phosphorylation by viral thymidine kinase.
- The targets include thymidine kinase (Q9QNF7, HHV-1) and DNA polymerase catalytic subunit (P04293, HHV-1), as noted in pharmacological databases.
- Timing of Pharmacological Actions
- The time to influence, or onset of action, is complex due to the distinction between pharmacokinetic and clinical effects. Pharmacokinetically, valaciclovir is rapidly absorbed, with peak plasma concentrations of acyclovir, the active form, reached in approximately 2-3 hours post-dose, as supported by clinical pharmacokinetics studies [Ref: Synapse.patsnap.com, 2024]. This suggests that the drug begins to exert its antiviral effects at the cellular level within hours, inhibiting viral DNA replication.
- Clinically, the time to noticeable effects varies by condition. For cold sores, clinical trials indicate that when taken within two hours of symptom onset (e.g., tingling, itching), valaciclovir can reduce the duration by about one day compared to placebo, with effects becoming apparent over several days [Ref: Hims.com, 2023]. For herpes zoster, studies show accelerated resolution of zoster-associated pain, with durations reduced from 51 to 38 days compared to acyclovir, indicating a longer-term clinical effect [Ref: ScienceDirect, 1995]. Thus, while the pharmacological action starts within hours, clinical benefits may take days to manifest, depending on the timing of administration and the condition treated.
- Half-Life
- The plasma elimination half-life of acyclovir, following valaciclovir administration, is 2.5 to 3.3 hours in volunteers with normal renal function, as per FDA labeling [Ref: FDA Label, 2008]. This half-life can extend significantly in patients with end-stage renal disease (ESRD), reaching approximately 14 hours, and is reduced to about 4 hours during hemodialysis, with about one-third of acyclovir removed during a 4-hour session.
- Bioavailabilities
- Valaciclovir is administered orally, with the absolute bioavailability of acyclovir after a 1 gram oral dose being 54.5% ± 9.1%, as determined in 12 healthy volunteers [Ref: FDA Label, 2008]. This bioavailability is not significantly altered by food, with studies showing similar levels 30 minutes after a high-fat breakfast. No other routes of administration are commonly used for valaciclovir, as it is designed for oral delivery to improve acyclovir bioavailability compared to direct acyclovir administration.
- Dosages
- Dosages are condition-specific and adjusted for renal function, as detailed in the FDA prescribing information:
- Cold Sores: 2 grams every 12 hours for 1 day, initiated at the earliest symptom (e.g., tingling, burning, itching).
- Initial Genital Herpes: 1 gram twice daily for 10 days.
- Recurrent Genital Herpes: 500 mg twice daily for 3 days.
- Suppressive Therapy for Genital Herpes: 1 gram once daily for immunocompetent patients, or 500 mg once daily for those with ≤9 recurrences per year; for HIV-infected patients, 500 mg twice daily.
- Herpes Zoster: 1 gram three times daily for 7 days, initiated within 48 hours of rash onset.
- Chickenpox (Pediatric, 2 to <18 years): 20 mg/kg three times daily for 5 days, not to exceed 1 gram three times daily, initiated within 24 hours of rash onset.
- For patients with renal impairment, dosages are adjusted based on creatinine clearance (CrCl), as shown in the following table:
Indications Normal Dose (CrCl ≥50 mL/min) CrCl 30-49 mL/min CrCl 10-29 mL/min CrCl <10 mL/min Cold Sores 2 g every 12 hr, 1 day 1 g every 12 hr, 1 day 500 mg every 12 hr, 1 day 500 mg single dose Genital Herpes: Initial 1 g every 12 hr No reduction 1 g every 24 hr 500 mg every 24 hr Genital Herpes: Recurrent 500 mg every 12 hr, 3 days No reduction 500 mg every 24 hr 500 mg every 24 hr Genital Herpes: Suppressive 1 g/500 mg once daily/500 mg twice daily 500 mg every 24 hr/500 mg every 48 hr/500 mg every 24 hr 500 mg every 24 hr/500 mg every 48 hr/500 mg every 24 hr 500 mg every 24 hr/500 mg every 48 hr/500 mg every 24 hr Herpes Zoster 1 g every 8 hr, 7 days 1 g every 12 hr 1 g every 24 hr 500 mg every 24 hr - Hemodialysis patients should receive the dose post-session, with acyclovir half-life during dialysis approximately 4 hours, and no supplemental doses are needed post-peritoneal dialysis.
- Safe Range, Minimum Effective Dose, and Maximum Safe Dose
- The safe range is defined by the prescribed dosages for each indication, with adjustments for renal function ensuring safety. The minimum effective dose is 500 mg once daily for suppressive therapy in patients with fewer recurrences. The maximum prescribed dose is 1 gram three times daily for herpes zoster, totaling 3 grams per day, considered safe for adults with normal renal function. However, exceeding these doses, especially in patients with renal impairment, increases risks.
- LD50 and Toxicity Thresholds
- The oral LD50 for valaciclovir in rats is 903.5 mg/kg, as reported in pharmacological databases [Ref: DrugBank, 2021]. For humans, there is no direct LD50 value, but case reports indicate that overdoses of up to 20 grams have been associated with neurotoxicity, particularly in patients with renal failure or those receiving excessive doses relative to their renal function [Ref: PMC, 2014]. Symptoms include confusion, hallucinations, and acute renal failure, with risks heightened in the elderly or those with underlying kidney disease.
- The point at which valaciclovir starts to become too dangerous is when doses significantly exceed prescribed levels, especially in the context of renal impairment. For example, doses leading to plasma acyclovir levels causing precipitation in renal tubules (solubility 2.5 mg/mL) can induce acute renal failure, and neurotoxicity can manifest at high doses, as seen in overdoses of 20 grams.
- Voriconazole
- Pharmacological Actions
- Voriconazole's primary pharmacological action is the inhibition of fungal cytochrome P450 enzyme 14α-demethylase, a critical enzyme in the biosynthesis of ergosterol, a vital component of fungal cell membranes. This inhibition leads to the accumulation of 14α-methylated sterols and a decrease in ergosterol, altering cell membrane permeability and ultimately inhibiting fungal growth. Research indicates it is active against pathogens such as Aspergillus, Candida, Fusarium, Scedosporium, Exserohilum rostratum, Cryptococcus neoformans, and C. gattii, with variable activity against Fusarium and Scedosporium apiospermum.
- The effectiveness over time is concentration-dependent, with optimal therapeutic plasma concentrations typically maintained between 2 and 5 mcg/mL. Higher concentrations may lead to adverse effects, as discussed later.
- Half-life
- The elimination half-life of Voriconazole is approximately 6 hours for a 200 mg oral dose, based on studies in healthy adults. However, due to its non-linear pharmacokinetics, the half-life is dose-dependent, varying from 6 to 9 hours at steady state following multiple oral doses of 200 mg every 12 hours. This non-linearity is likely due to saturable hepatic metabolism, primarily via cytochrome P450 isoenzymes CYP2C19, CYP2C9, and CYP3A4, which can lead to dose-dependent accumulation.
- Bioavailabilities
- Oral Bioavailability: Approximately 96%, allowing for effective switching between IV and oral administration. Peak plasma concentrations are achieved within 1–2 hours, though food can reduce mean peak plasma concentrations by 34% and the extent of absorption by 24%, suggesting it should be taken on an empty stomach.
- Intravenous (IV) Bioavailability: 100%, as it is directly administered into the bloodstream, ensuring complete bioavailability.
- Dosages
- Dosages vary by condition, patient weight, and administration route. Below is a detailed breakdown for adults with invasive aspergillosis, a common indication:
Route Weight (kg) Loading Dose Maintenance Dose Maximum Dose Notes Oral ≥40 Not specified 200 mg every 12 hours 300 mg every 12 hours Increase if response inadequate, reduce by 50 mg steps if not tolerated. Oral <40 Not specified 100 mg every 12 hours 150 mg every 12 hours Adjust based on response and tolerance. IV All 6 mg/kg every 12 hours for 2 doses 4 mg/kg every 12 hours 4 mg/kg every 12 hours Reduce to 3 mg/kg if not tolerated; monitor for toxicity. - For other conditions such as candidemia or fungal infections caused by Scedosporium and Fusarium, dosages may differ, and specific guidelines should be consulted. Pediatric dosages also vary, typically based on body weight, with maximum oral doses up to 350 mg every 12 hours for certain age groups.
- Safe Range, Minimum Effective Dose, and Maximum Dose
- Safe Range: Research suggests maintaining serum trough concentrations between 2 and 5 mcg/mL is safe and effective. Concentrations above 5 mcg/mL are associated with increased risk of adverse effects, including neurotoxicity, visual disturbances, and liver toxicity.
- Minimum Effective Dose: While not explicitly defined, standard maintenance doses start at 100 mg every 12 hours orally for adults weighing less than 40 kg, indicating a likely minimum effective dose for many patients.
- Maximum Dose: For adults ≥40 kg, the maximum oral dose is 300 mg every 12 hours, and IV maintenance is up to 4 mg/kg every 12 hours, with reductions recommended if toxicity is observed.
- LD50 and Toxicity
- LD50: In animal studies, specifically rats, the oral LD50 is reported to be between 800 and 1600 mg/kg body weight. Human LD50 data is not available, as such values are typically derived from animal models and not directly applicable to humans due to ethical and practical constraints.
- Toxicity and Dangerous Dosage: Serum concentrations exceeding 5 mcg/mL are considered potentially dangerous, with risks including visual disturbances (e.g., photophobia, blurred vision), liver toxicity (elevated transaminases, jaundice), and severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Overdose symptoms may include prolonged QTc interval and other systemic toxicities, requiring immediate medical intervention. Monitoring and dose adjustments are crucial, especially in patients with hepatic impairment, where metabolism may be altered.
- Additional Considerations
- Food Interaction: Food reduces oral absorption, decreasing peak plasma concentrations by 34% and extent by 24%, so it is recommended to take Voriconazole on an empty stomach, at least 1 hour before or after meals.
- Special Populations: Dose adjustments may be necessary for patients with liver dysfunction (e.g., reduce maintenance dose by half for mild to moderate impairment), and caution is advised in renal impairment for IV administration due to potential accumulation of the vehicle (sulfobutyl ether beta-cyclodextrin sodium). Safety and efficacy are not established for children under 2 years.
- Drug Interactions: Voriconazole is metabolized by hepatic cytochrome P450, leading to significant interactions with drugs like rifampin, carbamazepine, and certain protease inhibitors, which may necessitate dose adjustments or contraindications.
- Amoxicillin
- Pharmacological Actions
- Amoxicillin is a beta-lactam antibiotic belonging to the aminopenicillin class, primarily exerting its pharmacological action by inhibiting bacterial cell wall synthesis. It achieves this by competitively binding to penicillin-binding proteins (PBPs), specifically PBP1 and other high molecular weight PBPs, which are crucial for glycosyltransferase and transpeptidase reactions. These reactions cross-link D-alanine and D-aspartic acid in the bacterial cell wall, and their inhibition prevents proper cell wall formation. As a result, bacteria upregulate autolytic enzymes, leading to cell wall disruption and bactericidal activity against susceptible gram-positive and some gram-negative bacteria, such as Streptococcus species, Listeria monocytogenes, and Enterococcus spp.
- While its primary action is antibacterial, amoxicillin does not exhibit significant pharmacological effects on human cells beyond potential side effects, which are not considered intended actions. Its spectrum of activity includes coverage against beta-lactamase-negative isolates, making it effective for infections like ear, nose, throat, lower respiratory, and urinary tract infections, as well as Helicobacter pylori eradication.
- Pharmacokinetic Parameters
- The pharmacokinetic profile of amoxicillin is well-documented, with the following key parameters:
- Half-Life: The elimination half-life is approximately 61.3 minutes, indicating rapid clearance from the body, which necessitates frequent dosing to maintain therapeutic levels.
- Bioavailability: Oral bioavailability is reported to vary across studies, with values ranging from 60% to 93%. Recent sources, such as DrugBank and the electronic medicines compendium (emc), suggest approximately 60-70%, while older studies (e.g., a 1977 PMC article) reported 93% based on AUC comparisons with intravenous administration. This discrepancy may reflect differences in formulations or study conditions, with the consensus leaning toward 60-70% for standard oral administration. The absorption is rapid, with peak plasma concentrations (Tmax) typically reached within 1-2 hours, and is not significantly influenced by food intake, though some sources suggest taking it with food for better absorption.
- Detailed Pharmacokinetic Values:
- For a 250 mg oral dose: Cmax 3.93 ± 1.13 mg/L, Tmax 1.31 ± 0.33 hours, AUC 27.29 ± 4.72 mg*h/L.
- For an 875 mg oral dose: Cmax 11.21 ± 3.42 mg/L, Tmax 1.52 ± 0.40 hours, AUC 55.04 ± 12.68 mg*h/L.
- Volume of distribution: 27.7 L, indicating moderate distribution into body tissues.
- Protein binding: Approximately 17-20%, suggesting minimal binding and high free drug availability.
- Clearance: Mean clearance is 21.3 L/h, with 70-78% excreted unchanged in urine within 6-8 hours, primarily via renal elimination.
- Other Routes: Intramuscular administration shows high bioavailability, with AUC 92% of intravenous, and urinary recovery at 91%, indicating complete and reliable absorption compared to oral routes.
- Dosage Guidelines
- Dosing recommendations vary by age, weight, infection severity, and renal function, with the following details:
- Standard Adult Doses:
- For mild to moderate infections (e.g., ear, nose, throat, genitourinary, skin): 500 mg every 12 hours or 250 mg every 8 hours.
- For severe infections: 875 mg every 12 hours or 500 mg every 8 hours, with durations typically 10-14 days for certain conditions.
- For Helicobacter pylori (triple therapy): 1 g every 12 hours with lansoprazole and clarithromycin for 14 days.
- For prophylaxis (e.g., infective endocarditis): 2 g 30-60 minutes before procedure.
- Pediatric Doses:
- For infants <3 months: Up to 30 mg/kg/day divided every 12 hours.
- For children >3 months and <40 kg, mild to moderate: 25 mg/kg/day divided every 12 hours or 20 mg/kg/day divided every 8 hours; severe: 45 mg/kg/day divided every 12 hours or 40 mg/kg/day divided every 8 hours.
- For community-acquired pneumonia (off-label, ≥3 months): Up to 90 mg/kg/day divided every 12 hours, not exceeding 4,000 mg/day, for 10 days.
- Dosage Forms and Strengths:
- Dosage Forms and Strengths:
Form Strengths Oral Suspension 125mg/5mL, 200mg/5mL, 250mg/5mL, 400mg/5mL Capsule 250mg, 500mg Tablet 500mg, 875mg Tablet, Chewable 125mg, 250mg - Safe Range and Minimum Effective Dose:
- The safe range aligns with standard doses, typically 250-875 mg every 8-12 hours for adults, depending on severity. The minimum effective dose varies by infection, often starting at 250 mg every 8 hours for mild cases.
- Maximum Safe Dose:
- The usual maximum is 875 mg per dose or 2 g/day for suspension, but in high-risk cases (e.g., acute bacterial sinusitis), doses up to 4 g/day (2 g twice daily) may be used, though not routinely recommended without medical oversight.
- LD50 and Toxicity:
- LD50 in rats is >15 g/kg orally and >2000 mg/kg dermally, indicating low acute toxicity. For humans, therapeutic doses are far below these levels, suggesting a wide safety margin.
- Overdose and Danger Threshold:
- Research, including a prospective study of 51 pediatric patients, suggests overdoses <250 mg/kg are not associated with significant clinical symptoms. For a 70 kg adult, this equates to ~17.5 g, far above typical doses. Higher doses may lead to renal issues like interstitial nephritis or crystalluria, potentially causing kidney failure, but these are reversible with cessation and supportive care. Poison control notes that overdoses are rarely dangerous, with symptoms like stomach upset and diarrhea, and serious effects require very high doses.
- Trimethoprim/Sulfamethoxazole
- Pharmacological Actions and Temporal Influences
- TMP-SMX is an antimicrobial combination primarily used to treat and prevent bacterial infections by targeting folate synthesis, a critical pathway for bacterial DNA and protein synthesis. Sulfamethoxazole, a sulfonamide, acts as a competitive inhibitor of dihydropteroate synthase, preventing the conversion of p-aminobenzoic acid (PABA) to dihydropteroate, an early step in folate synthesis. Trimethoprim complements this by inhibiting dihydrofolate reductase, blocking the reduction of dihydrofolate to tetrahydrofolate, the active form needed for purine synthesis. This dual inhibition creates a synergistic effect, often rendering the combination bactericidal, particularly in environments like urine, where concentrations can be high.
- The pharmacodynamic profile suggests a time-dependent killing mechanism, akin to beta-lactams and macrolides, where efficacy is maximized by maintaining drug concentrations above the minimum inhibitory concentration (MIC) for a significant portion of the dosing interval. This is supported by studies indicating that the duration of exposure, rather than peak concentration, correlates with bacterial kill rates. For instance, research on E. coli showed significant CFU reductions at concentrations above MIC for extended periods, with pharmacodynamic thresholds like fAUC/MIC ratios (e.g., 40.7 for stasis, 59.5 for 1-log reduction) highlighting the importance of time above MIC.
- Temporal influences include:
- Onset of Action: Peak blood levels occur 1-4 hours post-oral administration, with steady-state concentrations achieved after approximately 3 days of repeat dosing.
- Duration of Effect: Given the half-lives (6-12 hours for sulfamethoxazole, 8-10 hours for trimethoprim), dosing every 12 hours ensures adequate coverage, aligning with time-dependent killing requirements.
- Half-Life and Bioavailability
- The half-life of sulfamethoxazole ranges from 6 to 12 hours in healthy individuals, extending to 20-50 hours in renal failure due to reduced clearance. Trimethoprim has a half-life of 8-10 hours, which may prolong in renal dysfunction. These values are critical for dosing intervals to maintain therapeutic levels.
- Bioavailability is high for both components via the oral route:
- Sulfamethoxazole: Approximately 85-90%, with rapid absorption and distribution into various fluids like sputum, vaginal fluid, and breast milk.
- Trimethoprim: Close to 100%, as evidenced by studies in AIDS patients showing oral bioavailability of 102.7% ± 19.8%, suggesting near-complete absorption, with values over 100% likely due to measurement variability.
- Other routes, such as intravenous, are used in severe cases, but oral administration is standard due to high bioavailability, ensuring systemic efficacy.
- Dosage Regimens
- Dosage varies by indication, patient factors, and renal function, as detailed below:
Indication Dosage (Adult, ≥40kg) Duration Bacterial Infections (e.g., UTI) 800 mg SMX + 160 mg TMP every 12 hours 10-14 days Pneumocystis jirovecii Pneumonia (Treatment) 75-100 mg/kg SMX + 15-20 mg/kg TMP daily, divided 14-21 days Pneumocystis jirovecii Pneumonia (Prophylaxis) 800 mg SMX + 160 mg TMP daily Continuous Traveler's Diarrhea 800 mg SMX + 160 mg TMP every 12 hours 5 days Chronic Bronchitis (Acute Exacerbation) 800 mg SMX + 160 mg TMP every 12 hours 10-14 days Shigellosis 800 mg SMX + 160 mg TMP every 12 hours 5 days - Safe Range and Adjustments:
- Standard doses are generally safe for adults without comorbidities. For renal impairment, adjust as follows:
- CrCl >30 mL/min: No change.
- CrCl 15-30 mL/min: Reduce dose by 50%.
- CrCl <15 mL/min: Avoid use.
- Not recommended for infants <2 months due to toxicity risks like hyperbilirubinemia.
- Minimum Effective Dose: Depends on infection and bacterial susceptibility; prophylaxis uses lower doses (e.g., 800 mg SMX + 160 mg TMP daily or thrice weekly).
- Maximum Safe Dose: Up to 100 mg/kg SMX + 20 mg/kg TMP per day for severe infections, but increased monitoring is required due to higher adverse effect risks, especially in elderly or immunocompromised patients.
- Toxicity and Safety Thresholds
- Toxicity data from animal studies provide insight into lethal doses:
- Trimethoprim LD50: >5300 mg/kg oral in rats.
- Sulfamethoxazole LD50: 2300 mg/kg in mice, 6200 mg/kg in rats.
- In humans, LD50 is not ethically determined, but therapeutic doses are significantly lower, with toxicity manifesting at standard doses in susceptible individuals. Common adverse effects include nausea, diarrhea, and skin rashes, while severe reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis, and hematological toxicities like thrombocytopenia or leukopenia, particularly at higher doses or in patients with renal impairment.
- When It Becomes Too Dangerous:
- Toxicity becomes significant with signs like severe skin reactions, significant blood count drops, or hyperkalemia, necessitating immediate dose adjustment or discontinuation. Elderly patients, those with kidney issues, or those on interacting medications (e.g., diuretics, digoxin) are at higher risk, requiring careful monitoring.
- Flibanserin
- Pharmacological Actions and Their Influence
- Flibanserin’s pharmacological profile is characterized by its interactions with serotonin and dopamine receptors, which are central to its therapeutic effects in HSDD. It acts as an agonist at 5-HT1A receptors, with a high binding affinity (Ki = 1 nM in human cells, as per IUPHAR/BPS Guide to PHARMACOLOGY: flibanserin), and an antagonist at 5-HT2A receptors (Ki = 49 nM, from the same source). Additionally, it exhibits antagonist or weak partial agonist activity at dopamine D4 receptors (Ki = 4-24 nM, as noted in Flibanserin - Wikipedia), with lower affinities for 5-HT2B (Ki = 89.3 nM) and 5-HT2C (Ki = 88.3 nM) receptors, where it acts as an antagonist Flibanserin - Wikipedia.
- These interactions lead to a reduction in serotonin levels and an increase in dopamine and norepinephrine in the brain, particularly in the prefrontal cortex, which is thought to enhance sexual desire and reduce distress associated with HSDD Multifunctional Pharmacology of Flibanserin: Possible Mechanism of Therapeutic Action in Hypoactive Sexual Desire Disorder | ScienceDirect. The onset of effect was observed from the first measurement point after 4 weeks of treatment, with effects maintained throughout the treatment period, as evaluated in three phase 3 clinical trials Flibanserin - Wikipedia.
- Specific values for the time course of these actions include a Tmax of 0.75 hours (range 0.75-4.0 hours), indicating rapid absorption and peak plasma concentration, with a half-life of approximately 11 hours influencing the duration of action Fda. The EC50 for agonist activity at 5-HT1A receptors is approximately 630.96 nM, suggesting the concentration needed for half-maximal effect in certain functional assays IUPHAR/BPS Guide to PHARMACOLOGY: flibanserin.
- Half-Life and Bioavailabilities
- The half-life of Flibanserin is consistently reported as approximately 11 hours across multiple sources, including the FDA label Fda, indicating the time required for the plasma concentration to reduce by half, which is crucial for determining dosing intervals. Its oral bioavailability is 33%, meaning only about a third of the ingested dose is absorbed systemically, a factor influenced by first-pass metabolism primarily via CYP3A4, with lesser involvement of CYP2C19 Flibanserin: Uses, Interactions, Mechanism of Action | DrugBank Online. Other routes of administration, such as intravenous, are not clinically relevant for Flibanserin, so additional bioavailability data are not available.
- Dosage Details
- The recommended dosage for Flibanserin is 100 mg once daily at bedtime, as per the FDA label Fda, which is also considered the minimum effective dose based on clinical trials where lower doses (e.g., 50 mg twice daily) were less effective Flibanserin - Wikipedia. The maximum safe dose is generally 100 mg, with higher doses not recommended due to increased risk of adverse effects, as evidenced by clinical development where doses above 250 mg were not tolerated by adults Accidental Flibanserin Ingestion in Children Causing Acute Respiratory and Central Nervous System Depression | PMC.
- Case reports of accidental ingestion in children provide insight into the effects of higher doses. For instance, doses ranging from 400 mg to 1500 mg (4 to 15 tablets of 100 mg each) led to severe symptoms such as ataxia, somnolence, respiratory depression, and CNS depression, requiring intubation in some cases, but all recovered within a few days with supportive care Accidental Flibanserin Ingestion in Children Causing Acute Respiratory and Central Nervous System Depression | PMC. This suggests that while high doses are dangerous, they are not necessarily lethal, though the LD50 for humans is not publicly available.
- The safe range is thus 100 mg daily, with the FDA contraindicating use with alcohol, moderate/strong CYP3A4 inhibitors, and in hepatic impairment due to increased risk of hypotension and syncope Fda. The estimation of when it starts to become too dangerous aligns with doses above 100 mg, particularly given the narrow safety margin and reports of severe effects at higher doses.
- Umifenovir
- Pharmacological Actions
- Umifenovir is a dual direct-acting antiviral and host-targeting agent, primarily utilized for the treatment and prophylaxis of influenza and other respiratory viral infections in Russia and China. Its pharmacological actions include:
- Antiviral Activity: Umifenovir inhibits the fusion of the viral lipid membrane with the host cell membrane, preventing viral entry. This is achieved by interacting with viral glycoproteins, such as hemagglutinin (HA), and the plasma membrane, interfering with clathrin-mediated exocytosis. It is effective against a broad spectrum of viruses, including influenza A and B, SARS-CoV-2, hepatitis B and C, and others like Zika virus and Ebola virus, as demonstrated in vitro studies [DrugBank: https://go.drugbank.com/drugs/DB13609, ScienceDirect: https://www.sciencedirect.com/topics/medicine-and-dentistry/umifenovir].
- Immunomodulatory Effects: Beyond its antiviral properties, Umifenovir exhibits modulatory effects on the immune system. It stimulates the humoral immune response, induces interferon production, and enhances the phagocytic function of macrophages. These effects contribute to a strengthened immune defense, particularly noted in patients with lower baseline immunity, where improvements in CD4, CD8 lymphocytes, B lymphocytes, and serum immunoglobulin levels have been observed [NCATS Inxight Drugs: https://drugs.ncats.io/drug/8CXV4OU367].
- The onset of these actions is rapid, with pharmacokinetic data indicating peak plasma concentrations (C_max) achieved within 1.38 hours for a 200 mg dose, suggesting early antiviral and immune-modulating effects [PMC: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623363/].
- Pharmacokinetic Parameters
- The pharmacokinetic profile of Umifenovir is critical for understanding its clinical utility. Key parameters include:
- Half-Life (t₁/₂): The half-life ranges from 15.7 to 21 hours, with a study in healthy male Chinese volunteers reporting 15.7 ± 3.8 hours after a 200 mg oral dose, indicating a relatively slow elimination that supports twice-daily dosing in some regimens [PMC: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623363/, Wikipedia: https://en.wikipedia.org/wiki/Umifenovir].
- Bioavailability: Oral bioavailability is approximately 40%, meaning 40% of the administered dose is absorbed into systemic circulation, unaffected by food intake. This is consistent across multiple sources, ensuring reliable absorption for oral administration [Wikipedia: https://en.wikipedia.org/wiki/Umifenovir].
- Time to Maximum Concentration (T_max): For a 200 mg dose, T_max is 1.38 ± 1.11 hours, with variations noted for lower doses (e.g., 1.2 hours for 50 mg, 1.5 hours for 100 mg), reflecting rapid absorption [PMC: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623363/, Wikipedia: https://en.wikipedia.org/wiki/Umifenovir].
- Maximum Concentration (C_max) and Area Under the Curve (AUC): After a 200 mg oral dose, C_max is 467 ± 174 ng/mL, and AUC_0-∞ is 2,203 ± 691 ng·h/mL, with linear increases observed with higher doses, supporting dose-dependent pharmacokinetics [PMC: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623363/].
- Metabolism and Excretion: Umifenovir is extensively metabolized, primarily by CYP3A4 and other hepatic enzymes, with 33 metabolites identified. About 40% is excreted unchanged, mainly via bile (38.9%) and minimally through kidneys (0.12%), with 90% eliminated within 24 hours [DrugBank: https://go.drugbank.com/drugs/DB13609].
- Dosage Guidelines
- Dosage varies by indication, age, and severity, with detailed regimens as follows:
Purpose Age Group Dosage (mg) Frequency Duration Non-specific prophylaxis (contact with influenza/RSV) 2–7 years 50 Once daily 10–14 days 7–12 years 100 Once daily 10–14 days 12–adult 200 Once daily 10–14 days Prophylaxis during epidemics (influenza, RSV, chronic bronchitis, herpes) 2–7 years 50 Twice weekly 3 weeks 7–12 years 100 Twice weekly 3 weeks 12–adult 200 Twice weekly 3 weeks SARS prophylaxis (contact with SARS patients) 7–12 years 100 Once daily, before food 12–14 days 12–adult 200 Once daily, before food 12–14 days Prophylaxis against postoperative complications 2–7 years 50 48 hours before, then 2–5 days after procedure - 7–12 years 100 48 hours before, then 2–5 days after procedure - 12–adult 200 48 hours before, then 2–5 days after procedure - Treatment of influenza/RSV (uncomplicated) 2–7 years 50 4 times daily (every 6 hours) 5 days 7–12 years 100 4 times daily (every 6 hours) 5 days 12–adult 200 4 times daily (every 6 hours) 5 days Treatment of influenza with complications (bronchitis, pneumonia) 2–7 years 50 4 times daily (every 6 hours) for 5 days, then once weekly 5 days initial, then 4 weeks 7–12 years 100 4 times daily (every 6 hours) for 5 days, then once weekly 5 days initial, then 4 weeks 12–adult 200 4 times daily (every 6 hours) for 5 days, then once weekly 5 days initial, then 4 weeks Treatment of SARS 12–adult 200 Twice daily 8–10 days Treatment of chronic bronchitis/herpes infections 2–7 years 50 4 times daily (every 6 hours) for 5–7 days, then twice weekly 5–7 days initial, then 4 weeks 7–12 years 100 4 times daily (every 6 hours) for 5–7 days, then twice weekly 5–7 days initial, then 4 weeks 12–adult 200 4 times daily (every 6 hours) for 5–7 days, then twice weekly 5–7 days initial, then 4 weeks Treatment of acute rotavirus intestinal infections Over 2 years 50 4 times daily (every 6 hours) 5 days 7–12 years 100 4 times daily (every 6 hours) 5 days Over 12 years 200 4 times daily (every 6 hours) 5 days - Minimum Effective Dose: The minimum effective dose is not explicitly defined in literature, but prophylactic doses (e.g., 200 mg once daily) suggest efficacy at lower levels compared to treatment doses (800 mg/day for adults), indicating a dose-dependent response.
- Maximum Dose Without High Risks: Clinical use suggests 800 mg/day (200 mg four times daily) is standard and appears safe, with no significant adverse effects reported at this level. Animal studies support a large therapeutic window, with no pathological changes at doses up to 100 times human therapeutic levels [DrugBank: https://go.drugbank.com/drugs/DB13609].
- LD50 and Toxicity: The oral LD50 in mice is 340-400 mg/kg, and in rats, it is >3000 mg/kg, indicating high doses are required for toxicity in animals. No human overdose cases are reported, and allergic reactions are limited to hypersensitivity [Wikipedia: https://en.wikipedia.org/wiki/Umifenovir, DrugBank: https://go.drugbank.com/drugs/DB13609].
- Danger Threshold: Given the high LD50 in animals and lack of reported human overdoses, it seems likely that Umifenovir becomes dangerous only at doses significantly exceeding therapeutic levels, though exact thresholds are not established due to limited human data.
- Safety and Clinical Considerations
- Umifenovir is generally well-tolerated, with a favorable safety profile noted in clinical studies. Side effects are minimal, with sensitization reported in children and rare allergic reactions in hypersensitive individuals. The drug's metabolism by CYP3A4 suggests potential interactions with other medications metabolized by this pathway, though no significant interactions were noted in combined therapy studies [ScienceDirect: https://www.sciencedirect.com/topics/medicine-and-dentistry/umifenovir].
- The evidence leans toward Umifenovir having a wide therapeutic index, supported by animal studies showing no pathological changes at high doses and its long-term use in Russia and China without significant safety concerns. However, for precise maximum safe doses and danger thresholds, further human studies are needed, especially given its controversial efficacy in conditions like COVID-19, where higher doses have been suggested but not conclusively proven effective [PMC: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361300/].
- Azithromycin
- Pharmacological Actions and Mechanisms
- Azithromycin's primary pharmacological action is as a bacteriostatic antibiotic, inhibiting bacterial protein synthesis by binding to the 50S ribosomal subunit, specifically the 23S rRNA, which prevents transpeptidation and translocation. This action is crucial for treating infections caused by susceptible bacteria, such as Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Additionally, research suggests Azithromycin has immunomodulatory effects, reducing inflammation, which has been explored for chronic respiratory conditions like asthma, though responsiveness varies with individual lung microbiome composition.
- The mechanism also includes inhibition of Protein-arginine deiminase type-4 in humans, though its clinical significance is less clear. These actions contribute to its broad-spectrum antibacterial activity and potential anti-inflammatory benefits, particularly in long-term use scenarios.
- Timing of Pharmacological Actions
- The timing of Azithromycin's effects is influenced by its pharmacokinetics. After oral administration, peak plasma concentrations are typically reached in 2-3 hours, reflecting rapid absorption. Its long terminal elimination half-life of approximately 68 hours allows for sustained antibacterial activity, with tissue concentrations remaining above the minimum inhibitory concentration (MIC) for susceptible bacteria for several days post-treatment. This prolonged presence supports once-daily dosing and shorter treatment courses compared to other antibiotics. The immunomodulatory effects, while less studied for timing, likely manifest over days to weeks, given their role in chronic conditions, but specific onset times are not well-documented in the literature.
- Pharmacokinetics and Bioavailability
- Azithromycin's pharmacokinetics are characterized by:
- Absorption: Oral bioavailability is approximately 37-38%, mediated by P-glycoprotein (ABCB1) efflux transporters, and is not significantly affected by food.
- Distribution: It has a high volume of distribution (31.1 L/kg), with significant penetration into tissues such as lungs, tonsils, prostate, and phagocytes, contributing to its efficacy against intracellular pathogens.
- Protein Binding: Serum protein binding decreases from 51% at 0.02 µg/mL to 7% at 2 µg/mL, affecting free drug levels.
- Metabolism and Elimination: Primarily eliminated via biliary excretion as unchanged drug, with about 6% excreted in urine over a week, and a mean apparent plasma clearance of 630 mL/min.
- The long half-life (68 hours for a 3-day regimen, 71.8 hours for a 5-day regimen) underscores its extended duration of action, supporting its use in shorter treatment durations.
- Dosage Regimens
- Dosage varies by indication, patient age, and condition severity, as outlined in Table 1 below:
Condition Adult Dosage Pediatric Dosage (Weight-Based) Community-Acquired Pneumonia 500 mg Day 1, then 250 mg daily Days 2-5 10 mg/kg Day 1, then 5 mg/kg Days 2-5 Acute Bacterial Sinusitis 500 mg daily for 3 days 10 mg/kg daily for 3 days Pharyngitis/Tonsillitis 500 mg Day 1, then 250 mg daily Days 2-5 12 mg/kg daily for 5 days, max 500 mg/day Genital Ulcer Disease 1 g single dose Not typically indicated Gonococcal Urethritis/Cervicitis 2 g single dose Not typically indicated Acute Otitis Media Not standard for adults 30 mg/kg single dose or 10 mg/kg for 3 days - Safe Range: Doses within these regimens are generally considered safe for patients without contraindications, such as known hypersensitivity to macrolides or history of cholestatic jaundice with prior use.
- Minimum Effective Dose: Varies by condition; for example, a single 1 g dose is effective for uncomplicated chlamydia, while for community-acquired pneumonia, the regimen starting at 500 mg is standard.
- Maximum Safe Dose: The highest recommended single dose is 2 g for gonococcal infections, with daily doses typically not exceeding 500 mg for most conditions. Long-term prophylaxis may involve 500 mg three times weekly.
- LD50: Not established for humans; in rats, it's >2000 mg/kg, indicating a wide therapeutic index, but human toxicity is more related to adverse effects than acute lethality.
- Safety, Toxicity, and Risk Thresholds
- Azithromycin's safety profile includes common side effects like diarrhea (5-14%), nausea (3-18%), and abdominal pain (3-7%), with serious risks including QT prolongation, hepatotoxicity, and severe allergic reactions. Research suggests toxicity manifests at higher doses, particularly in vulnerable populations:
- Liver toxicity can include transient transaminase elevations (1-2%) or cholestatic hepatitis, often resolving within 4-8 weeks.
- QTc prolongation, linked to potential torsades de pointes, is a concern, especially in patients with pre-existing heart conditions or coadministered drugs affecting CYP 3A4.
- Case reports, such as a 9-month-old infant receiving 50 mg/kg (about 5 times the usual dose), highlight life-threatening bradycardia and heart block, leading to severe outcomes like anoxic encephalopathy.
- It seems likely that doses significantly above recommended levels, particularly in those with risk factors, start becoming too dangerous, with cardiac and hepatic effects increasing. For adults, exceeding daily doses of 500 mg, especially in long-term use, or taking single doses above 2 g without medical supervision, could elevate risks, though exact thresholds are patient-specific.
- Itraconazole
- Pharmacological Actions
- Itraconazole belongs to the triazole class of antifungals and exerts its primary pharmacological action by inhibiting lanosterol 14α-demethylase, a cytochrome P450 enzyme (CYP51) essential for ergosterol synthesis in fungal cells. Ergosterol is a critical component of fungal cell membranes, and its depletion leads to increased membrane permeability, accumulation of toxic sterols, and disruption of membrane integrity, ultimately inhibiting fungal growth. This mechanism is effective against a range of fungal infections, including aspergillosis, blastomycosis, histoplasmosis, and onychomycosis. Additionally, itraconazole has an active metabolite, hydroxyitraconazole, which contributes to its antifungal activity, enhancing its efficacy in systemic infections.
- The time course of these actions is influenced by the drug’s pharmacokinetics, with antifungal effects typically observed within days to weeks, depending on the infection site and severity. For example, superficial infections like oral candidiasis may show improvement within 1-2 weeks, while deeper infections like onychomycosis may require several months for complete resolution due to the time needed for nail regrowth.
- Half-Life
- The half-life of itraconazole varies depending on the dosing regimen and patient factors. After a single dose, the terminal half-life ranges from 16 to 28 hours, reflecting initial distribution and elimination phases. With repeated dosing, due to non-linear pharmacokinetics and accumulation, the half-life extends to 34 to 42 hours, as steady-state concentrations are typically reached within about 15 days. This prolonged half-life is particularly relevant for chronic therapy, ensuring sustained antifungal activity.
- In special populations, the half-life can be affected by renal and hepatic function. For instance, in patients with mild to severe renal impairment (CrCl 50-79 mL/min, 20-49 mL/min, and <20 mL/min), mean terminal half-lives are 42-49 hours, similar to healthy subjects at 48 hours. In cirrhotic patients, after a single 100 mg dose, the elimination half-life increases to 37 ± 17 hours compared to 16 ± 5 hours in healthy subjects, indicating slower clearance in liver dysfunction.
- Bioavailabilities
- Bioavailability, the fraction of the administered dose that reaches systemic circulation, varies by formulation. For oral capsules, the observed absolute bioavailability is approximately 55%, with maximal absorption achieved when taken immediately after a full meal, as gastric acidity enhances dissolution. Absorption is reduced in conditions with decreased gastric acidity, such as with concurrent use of H2-receptor antagonists or proton pump inhibitors, and can be improved under fasted conditions with an acidic beverage like non-diet cola after ranitidine pretreatment.
- The oral solution, formulated with hydroxypropyl-β-cyclodextrin to improve solubility, exhibits higher bioavailability. Studies indicate that the area under the curve (AUC) for the oral solution is 30-33% higher for itraconazole and 35-37% higher for hydroxyitraconazole compared to capsules, suggesting an estimated absolute bioavailability of approximately 71.5% for the solution, based on the capsule’s 55% baseline. This enhancement is attributed to better absorption, particularly in the small intestine, reducing variability seen with capsules due to intestinal epithelial damage or varying gastric environments. Notably, capsules and oral solution are not bioequivalent, and switching between formulations requires medical guidance.
- Intravenous administration, while not commonly discussed in the context of oral routes, has 100% bioavailability by definition, but is less frequently used due to availability and cost considerations.
- Dosages
- Dosage regimens for itraconazole are tailored to the infection type, severity, and patient factors, with specific guidelines as follows:
- Onychomycosis (Toenails with or without Fingernail Involvement): 200 mg orally once daily for 12 consecutive weeks, taken with a full meal.
- Onychomycosis (Fingernails Only): Two treatment pulses, each consisting of 200 mg twice daily (400 mg/day) for 1 week, separated by a 3-week drug-free period.
- Blastomycosis and Histoplasmosis: 200 mg once daily (2 capsules), increased in 100-mg increments to a maximum of 400 mg daily if no improvement, with doses above 200 mg/day divided into two doses, taken with food.
- Aspergillosis: 200 to 400 mg daily, with a loading dose of 200 mg three times daily (600 mg/day) for the first 3 days in life-threatening situations, continued for a minimum of 3 months.
- Candidiasis (Oropharyngeal): 20 mL oral solution (200 mg) once daily for 1-2 weeks, swish and swallow, or 10 mL twice daily for 2-4 weeks.
- Candidiasis (Esophageal): 20 mL oral solution twice daily for 14-21 days.
- Off-label Uses: For cutaneous or lymphocutaneous sporotrichosis, 200 mg daily, potentially increased to 200 mg twice daily, continued until 2-4 weeks after lesion resolution, preferring oral solution.
- For renal impairment (CrCl <10 mL/min), reduce the dose by 50%; in hemodialysis or peritoneal dialysis, dose at 100 mg every 12-24 hours without supplementation. Hepatic dosing is undefined, with caution advised due to potential hepatotoxicity.
- The minimum effective dose is generally 200 mg daily for most indications, reflecting the starting dose for systemic infections. The maximum dose without high risks is typically 400 mg/day, with 600 mg/day used as a loading dose in severe cases under close monitoring. Higher doses, particularly prolonged, increase the risk of adverse effects, as discussed below.
- Safety, LD50, and Toxicity Thresholds
- The safe dosage range is up to 400 mg/day for most patients, with higher doses (up to 600 mg/day) used short-term in life-threatening infections under medical supervision. The minimum effective dose, as noted, is 200 mg daily, ensuring therapeutic levels for most fungal infections.
- The LD50, or lethal dose for 50% of test subjects, in rats is greater than 320 mg/kg orally and 100 mg/kg intraperitoneally, providing animal toxicity data. However, human LD50 is not ethically determined, and toxicity in humans is monitored through clinical parameters.
- Toxicity becomes a concern at trough levels above 3 mcg/mL, with risks of hepatotoxicity and cardiotoxicity. Hepatotoxicity can manifest as elevated liver enzymes, potentially reversible upon discontinuation, with recovery typically within 6-12 weeks, though rare cases of severe liver failure have been reported. Cardiotoxicity, including congestive heart failure, is noted, particularly at doses above 400 mg/day, with a black-box warning for new or worsening heart failure. Symptoms include shortness of breath, swelling, and rapid heartbeat, necessitating immediate discontinuation and medical evaluation.
- The point at which itraconazole becomes too dangerous is when these serious adverse effects appear, often linked to prolonged high doses or pre-existing liver/heart conditions. Regular monitoring of liver function tests (LFTs) at baseline and periodically, especially beyond one month of therapy, is recommended, along with drug concentration monitoring to ensure trough levels remain below 3 mcg/mL. There is no specific antidote for itraconazole overdose, and management is supportive, focusing on symptom control and discontinuation.
- Cefuroxime
- Pharmacological Actions
- Cefuroxime exerts its primary pharmacological action as a β-lactam antibiotic, specifically targeting bacterial cell wall synthesis. It inhibits the final transpeptidation step of peptidoglycan synthesis by binding to penicillin-binding proteins (PBPs) within the bacterial cell wall. This interference weakens the cell wall, leading to bacterial lysis and death, classifying it as bactericidal. It is effective against a broad spectrum of bacteria, including:
- Gram-positive: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes
- Gram-negative: Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Neisseria gonorrhoeae
- Other: Borrelia burgdorferi (relevant for Lyme disease)
- This broad-spectrum activity makes Cefuroxime suitable for treating various infections, including upper and lower respiratory tract infections, urinary tract infections, skin and soft tissue infections, and early Lyme disease.
- Pharmacokinetics: Half-Life and Bioavailability
- Half-Life:
- The half-life of Cefuroxime, which indicates the time taken for the plasma concentration to reduce by half, is approximately 1-2 hours in adults for both oral and parenteral administration. This duration can extend in patients with impaired renal function, as the drug is primarily excreted unchanged by the kidneys. For children, the half-life ranges from 1.4 to 1.9 hours, influenced by age and renal function.
- Bioavailability:
- Bioavailability, or the fraction of the drug absorbed into systemic circulation, varies by route:
- Oral (Cefuroxime axetil): When taken on an empty stomach, bioavailability is 37%, but it increases to 52% when administered with food. This enhancement is due to improved absorption in the presence of food, which may reduce gastrointestinal degradation.
- Parenteral (IV/IM): For intravenous (IV) and intramuscular (IM) administration, bioavailability is effectively 100%, as the drug is directly introduced into the bloodstream. Peak serum concentrations are achieved rapidly, within 2-3 minutes post-IV and 30-45 minutes post-IM.
- Additional pharmacokinetic parameters include:
- Time to peak concentration (Tmax): 2-3 hours for oral in adults, 3-4 hours in children.
- Volume of distribution: 0.25-0.3 L/kg, with 33-50% plasma protein binding, allowing penetration into tissues like tonsils, lungs, and bone.
- Dosage Regimens and Safety Ranges
- Dosage for Cefuroxime varies based on the infection type, route of administration, patient age, and renal function. Below is a detailed breakdown:
- Adults:
- Oral:
- Pharyngitis/tonsillitis: 250 mg every 12 hours for 10 days.
- Sinusitis: 250 mg every 12 hours for 10 days.
- Bronchitis: 250-500 mg every 12 hours for 10 days.
- Uncomplicated urinary tract infections (UTIs): 125-250 mg every 12 hours for 7-10 days.
- Gonorrhea: 1.5 g IM as a single dose at two sites, often with 1 g oral probenecid.
- Early Lyme disease: 500 mg every 12 hours for 20 days.
- Parenteral (IV/IM):
- Lower respiratory tract infections, including pneumonia: 750 mg every 8 hours.
- Skin and skin structure infections: 750 mg every 8 hours.
- Meningitis: Up to 3 g every 8 hours, with a maximum daily dose of 9 g in severe cases.
- Pediatrics (3 months-12 years):
- Oral: Pharyngitis/tonsillitis: 20 mg/kg/day divided every 12 hours, maximum 500 mg/day.
- Parenteral: 75-150 mg/kg/day divided every 8 hours, maximum 6 g/day.
- Renal Impairment Adjustments:
- For CrCl 10-30 mL/min, oral doses may be given every 24 hours; for CrCl <10 mL/min, every 48 hours.
- Parenteral: For CrCl 10-20 mL/min, 750 mg twice daily; for CrCl <10 mL/min, 750 mg once daily.
- Hemodialysis patients may require an additional dose post-dialysis.
- Safe Range, Minimum Effective Dose, and Maximum Safe Dose:
- The safe range aligns with prescribed doses for specific indications, typically 250-500 mg orally every 12 hours for mild to moderate infections in adults.
- The minimum effective dose varies by infection and pathogen sensitivity, often starting at 125 mg for UTIs.
- The maximum safe dose without high risks is generally the highest recommended dose, such as 500 mg orally every 12 hours or 1.5 g IV/IM every 8 hours, with higher doses (e.g., 3 g every 8 hours for meningitis) used under close monitoring.
- LD50 and Toxicity:
- LD50: Animal studies indicate an intravenous LD50 of 10.4 g/kg in mice, with higher doses tolerated in other species (e.g., 10 g/kg subcutaneous in mice, 4 g/kg IV in rats). However, human LD50 data are not available, and extrapolation from animal studies should be done cautiously.
- Toxicity and Overdose: Overdose can lead to neurological sequelae, including encephalopathy, convulsions, and coma, particularly in patients with renal impairment if doses are not adjusted. Serum levels can be reduced by hemodialysis or peritoneal dialysis. Other toxicities include:
- Neurotoxicity, especially in the elderly or those with severe renal impairment or central nervous system disorders.
- Potential renal impairment when used concurrently with potent diuretics or aminoglycosides, requiring monitoring.
- Overgrowth of non-susceptible microorganisms, such as Candida and Clostridium difficile, potentially leading to pseudomembranous colitis.
- Severe cutaneous adverse reactions (SCARs) like Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening.
- Estimation of When It Becomes Too Dangerous:
- The risk increases significantly in patients with renal impairment if doses are not adjusted, leading to drug accumulation and potential neurotoxicity. Concurrent use with nephrotoxic drugs further heightens this risk. For patients with normal renal function, adhering to recommended doses is generally safe, but exceeding these, especially without medical supervision, can lead to serious adverse effects, particularly neurological and renal complications.
- Pharmacodynamic Considerations and Time Influence
- The user’s request for “values for each time to know how each pharmacological action influences” may refer to pharmacokinetic-pharmacodynamic (PK-PD) relationships, particularly how drug concentrations over time affect efficacy. For cephalosporins like Cefuroxime, the key PK-PD index is the percentage of the dosing interval that the unbound concentration remains above the minimum inhibitory concentration (MIC) of the target pathogen (%T>MIC). Research suggests that for gram-positive bacteria, efficacy is associated with %T>MIC of 40-50%, and for gram-negative bacteria, 60-70%. Specific values depend on the pathogen’s MIC, which varies, but generally:
- Peak concentrations are achieved within hours (2-3 hours orally, minutes IV), influencing early bactericidal activity.
- With a half-life of 1-2 hours, multiple doses every 8-12 hours maintain therapeutic levels, ensuring sustained activity above MIC.
- Aticaprant
- Pharmacological Actions
- Aticaprant's primary pharmacological action is as a selective antagonist of the KOR, with a binding affinity (Ki) of 0.81 nM, showing approximately 30-fold selectivity over the mu-opioid receptor (MOR, Ki = 24.0 nM) and delta-opioid receptor (DOR, Ki = 155 nM) Wikipedia: Aticaprant. This selectivity suggests its main effect is on KOR-mediated processes, such as mood regulation, stress response, and reward systems, which are implicated in MDD, anxiety disorders, and substance use disorders like alcoholism and cocaine dependence. At higher doses, such as 25 mg and 60 mg, it has been shown to dose-dependently block fentanyl-induced miosis, indicating significant MOR antagonism at these levels, which could influence pain perception and opioid-related side effects Wikipedia: Aticaprant.
- The time course of these actions is tied to its pharmacokinetics. Research indicates rapid absorption, with maximal concentrations (Tmax) occurring 1 to 2 hours post-administration, as determined in both animal and human studies MedChemExpress: Aticaprant, Wikipedia: Aticaprant. Given its half-life of 30-40 hours, the effects are likely sustained, with steady-state concentrations reached after 6 to 8 days of once-daily dosing Wikipedia: Aticaprant. A positron emission tomography (PET) study by Naganawa et al. (2016) showed that at 10 mg, Aticaprant nearly saturates KOR receptors 2.5 hours post-dose, with maximum occupancy estimated at 93%, and occupancy likely persists at 24 hours due to the long half-life Journal of Pharmacology and Experimental Therapeutics: Receptor Occupancy.
- Pharmacokinetic Parameters
- Key pharmacokinetic parameters include:
- Half-life: Estimated at 30 to 40 hours in healthy subjects, supporting its suitability for once-daily dosing Wikipedia: Aticaprant.
- Bioavailability (oral): Reported as 25%, based on animal studies (rats and mice), with human data confirming oral administration but not specifying exact bioavailability beyond this MedChemExpress: Aticaprant, Wikipedia: Aticaprant. Other routes of administration were not detailed in the available literature.
- Time to Peak Concentration (Tmax): 1 to 2 hours, indicating rapid absorption MedChemExpress: Aticaprant, Wikipedia: Aticaprant.
- Steady-State Concentrations: Achieved after 6 to 8 days of once-daily dosing, aligning with its long half-life Wikipedia: Aticaprant.
- These parameters suggest Aticaprant's effects are prolonged, with significant receptor occupancy early after dosing and sustained activity over days, which is critical for its potential therapeutic use.
- Dosage and Safety Profile
- Dosage information from clinical trials provides insight into its use and safety:
- Therapeutic Dose: In a phase 2 study for MDD, 10 mg once daily was used as an adjunct to selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), showing significant improvement in depressive symptoms Nature: Efficacy and Safety. This is considered the minimum effective dose based on efficacy data.
- Doses Tested: Range from 0.5 mg to 60 mg, with PET studies using up to 25 mg and higher doses (25 mg, 60 mg) assessed for MOR antagonism Wikipedia: Aticaprant, Journal of Pharmacology and Experimental Therapeutics: Receptor Occupancy.
- Safe Range: Up to 25 mg was well-tolerated in studies, with no serious adverse events reported. At 10 mg, common side effects included headache, diarrhea, nasopharyngitis, and pruritus, mostly mild to moderate Nature: Efficacy and Safety. Doses up to 60 mg have been tested, but specific safety data at these levels are limited.
- Maximum Dose Without High Risks: Not explicitly stated, but given testing up to 60 mg and lack of reported serious adverse events at lower doses, it seems likely that up to 25 mg is safe, with caution at higher doses due to potential MOR effects.
- LD50: Not publicly available, reflecting Aticaprant's status as a drug in development, with toxicity data typically limited to preclinical animal studies not detailed in public sources.
- When It Starts to Become Too Dangerous: Not specified, but at doses ≥25 mg, significant MOR antagonism may occur, potentially leading to additional side effects like those associated with opioid receptor antagonism, such as hypotension or dysrhythmias, as noted in related literature Taylor & Francis: Aticaprant Review.
- The discontinuation of phase III trials in March 2025 due to lack of effectiveness highlights the challenges in its development, but does not negate the pharmacological data from earlier phases Wikipedia: Aticaprant.
- Detailed Considerations
- The survey note also considers potential secondary effects and interactions. Aticaprant's KOR antagonism may influence pain perception, stress responses, and reward systems, given KOR's role in these areas. Its interaction with ethanol was noted to have no significant cognitive or motor effects, suggesting compatibility with alcohol consumption in some contexts Taylor & Francis: Aticaprant Review. However, potential side effects like pruritus and bowel irritation are monitored due to KOR antagonism's effects on itching and irritable bowel syndrome Taylor & Francis: Aticaprant Review.
- Table for adverse events from the phase 2 study:
Adverse Event Incidence (Aticaprant 10 mg, %) Notes Headache ≥5.0 Mostly mild to moderate Diarrhea ≥5.0 Transient Nasopharyngitis ≥5.0 Common cold-like symptoms Pruritus ≥5.0 Itching, mild to moderate Serious Adverse Events 0 (none related to drug) One case in placebo group
- Lumbrokinase
- Pharmacological Actions
- Lumbrokinase exhibits multiple pharmacological effects, primarily centered around its fibrinolytic and antithrombotic properties. The following actions have been identified:
- Fibrinolytic Activity:
- Lumbrokinase directly degrades fibrin, the protein mesh in blood clots, and activates the plasminogen system to produce plasmin, which further dissolves clots.
- It inhibits Plasminogen Activator Inhibitor-1 (PAI-1), enhancing the activity of tissue plasminogen activator (t-PA), thus amplifying fibrinolytic effects.
- Studies, such as Lumbrokinase Mechanism of Action, confirm its dual action, both direct and indirect, distinguishing it from similar enzymes like nattokinase.
- Anti-platelet Activity:
- Research suggests Lumbrokinase inhibits platelet aggregation and function, reducing the likelihood of clot formation. This is supported by studies like Lumbrokinase and Platelet Function, which highlight its anticoagulation effects.
- Anti-inflammatory Activity:
- It inhibits Toll-like receptor 4 (TLR4) signaling, reducing inflammation, particularly in conditions like myocardial ischemia-reperfusion injury. This is detailed in Lumbrokinase and Myocardial Injury, showing its cardioprotective potential.
- Inhibition of Fibroblast Migration and Adhesion:
- Lumbrokinase prevents intra-abdominal adhesion by inhibiting fibroblast migration and adhesive activities via the AP-1/ICAM-1 signaling pathway, as evidenced by Intra-abdominal Adhesion Study.
- The timing of these actions' influence is not explicitly detailed in studies, with the half-life (discussed below) providing a general indicator of duration. Further research is needed to quantify onset and duration for each action.
- Pharmacokinetics: Half-Life and Bioavailability
- Half-Life:
- The biological half-life of Lumbrokinase, specifically for the formulation DLBS1033, is approximately 8.6 hours when administered orally, based on a clinical trial in healthy volunteers Clinical Trial on Half-Life. This suggests the enzyme remains active in the body for several hours, supporting its therapeutic use.
- Bioavailability:
- Oral absorption is possible, with studies using rat everted gut sacs showing absorption rates of 8.7% at 1.0 mg/ml, 11.5% at 2.0 mg/ml, and 14.7% at 0.5 mg/ml after 2 hours, as measured by fibrinolytic activity Intestinal Absorption Study. MALDI-TOF mass spectrometry confirmed absorption into blood, supporting oral efficacy.
- Enteric-coated formulations are commonly used to protect Lumbrokinase from stomach acid, enhancing absorption, as noted in Lumbrokinase Benefits. However, exact bioavailability percentages in humans are not consistently reported, with estimates suggesting around 10-15% based on ex vivo data.
- Dosage and Administration
- Dosage varies depending on the condition and product formulation, often measured in both mass (mg) and activity units (e.g., fibrinolytic units, FU, or lumbrokinase units, LKU):
- Typical Dosage for Chronic Conditions: 20-60 mg per day, as recommended by products like Boluoke® Boluoke Dosage, taken one to three times daily on an empty stomach.
- Higher Doses for Severe Conditions: Up to 120 mg per day, with clinical trials for acute ischemic stroke using 600,000 units three times a day (total 1,800,000 units per day), as seen in LUCENT Trial Protocol. The activity per mg varies by product, complicating direct comparisons.
- Children: Therapeutic dose is 1 capsule per 8 kg body weight per day, according to manufacturer guidelines.
- Safety, Toxicity, and Adverse Events
- Lumbrokinase is generally considered safe, with a low incidence of adverse events reported in clinical trials:
- Safety Profile: A large trial involving 1,560 patients reported a 1.92% adverse reaction rate, including 0.58% skin itching, 0.19% skin rash, and 1.15% nausea or diarrhea, with no major hemorrhages Boluoke FAQ.
- Common Side Effects: Gastrointestinal discomfort (nausea, vomiting, diarrhea, stomach cramps), allergic reactions (rash, itching, swelling, dizziness, difficulty breathing), and mild headaches, as detailed in Side Effects Article.
- Risks and Contraindications: Increased bleeding risk, especially with anticoagulants or in bleeding disorders. Contraindicated in recent surgery, trauma, active internal bleeding, GI ulceration, or high-risk aneurysm. Caution advised for liver/kidney conditions and pregnant/breastfeeding women.
- Toxicity and LD50: Specific LD50 data is not available, and toxic doses are not well-defined. The primary concern is excessive bleeding at high doses, particularly in susceptible individuals, with no reported cases of overdose leading to lethality in reviewed studies.
- Nattokinase
- Pharmacological Actions
- Nattokinase exhibits a range of pharmacological actions, primarily centered on cardiovascular and neuroprotective benefits. These actions include:
- Fibrinolytic/Antithrombotic Activity:
- Nattokinase directly degrades fibrin, the main component of blood clots, enhancing clot dissolution.
- It increases tissue plasminogen activator (tPA), which converts plasminogen to plasmin, further promoting fibrinolysis.
- It cleaves plasminogen activator inhibitor-1 (PAI-1), thereby increasing tPA activity and reducing clot formation.
- Enhances urokinase production, another fibrinolytic enzyme, and inhibits thromboxane formation, which reduces platelet aggregation.
- Reduces thrombus formation and slows the progression of atherosclerotic plaques, as evidenced by studies showing reduced carotid plaque size and intima-media thickness.
- Anti-atherosclerotic and Lipid-lowering Effects:
- Suppresses intimal thickening, a key factor in atherosclerosis.
- Reduces common carotid artery intima-media thickness (CCA-IMT) from 1.13 ± 0.12 mm to 1.01 ± 0.11 mm and carotid plaque size from 0.25 ± 0.12 cm² to 0.16 ± 0.10 cm² after 26 weeks at 6,500 FU daily.
- Lowers total cholesterol, LDL cholesterol, and triglycerides while increasing HDL cholesterol, with significant effects observed in clinical studies at doses of 4,000 FU for 8 weeks, though not always statistically significant.
- Antihypertensive Effects:
- Reduces systolic blood pressure by approximately 5.55 mm Hg and diastolic by 2.84 mm Hg after 8 weeks at 4,000 FU, with statistical significance (P < .05).
- Antiplatelet/Anticoagulant Effects:
- Inhibits platelet aggregation and decreases fibrinogen levels, similar to aspirin but without the bleeding side effects.
- Prolongs activated partial thromboplastin time (aPTT), with significant prolongation observed at 2 and 4 hours post-administration at 2,000 FU.
- Neuroprotective Effects:
- Degrades amyloid fibrils, potentially beneficial in Alzheimer’s disease, with studies showing reduced infarct volume and enhanced fibrinolytic activity in cerebral ischemia models.
- Protects against neuronal damage, with mechanisms including modulation of Alzheimer’s disease pathway factors.
- These actions are supported by clinical and experimental studies, such as those published in PMC articles and ScienceDirect reviews, highlighting Nattokinase’s potential in preventing and treating cardiovascular and age-related diseases.
- Timing of Pharmacological Actions
- The onset and duration of Nattokinase’s effects vary based on dosage and individual response. Studies indicate:
- Effects on coagulation parameters, such as increased D-dimer and fibrin/fibrinogen degradation products, are observable as early as 2 hours post-administration, with peak effects around 4 hours.
- Significant changes, such as factor VIII activity decline and aPTT prolongation, are noted at 4 and 6 hours following a 2,000 FU dose.
- The effects can last up to 8 hours or more, with some studies suggesting activity detectable up to 24 hours, consistent with its prolonged serum presence.
- This timing is derived from clinical trials, such as Kurosawa et al. (2015), which showed significant elevations in D-dimer at 6 and 8 hours post-dose, and Biogena’s observations of peak clotting effects at 4 hours, wearing off after 8 hours.
- Half-Life
- The half-life of Nattokinase is not explicitly stated in many sources, reflecting a gap in pharmacokinetic research. However, indirect evidence suggests:
- Peak serum levels are observed at approximately 13.3 ± 2.5 hours post-dose, as reported in a pilot study by Ero et al. (2013), indicating a relatively long duration of action.
- Compared to thrombolytic agents like t-PA and urokinase, which have half-lives of 4–20 minutes, Nattokinase’s effects last over 8 hours, suggesting a longer half-life, potentially in the range of 10-15 hours, though exact figures are speculative without further data.
- This uncertainty highlights the need for more extensive pharmacokinetic studies, as noted in reviews like Chen et al. (2018).
- Bioavailability
- Nattokinase’s oral bioavailability is confirmed, as it is effective when taken by mouth, with detectable serum levels and measurable effects on coagulation. Key points include:
- Studies, such as Ero et al. (2013), used enzyme-linked immunosorbent assays to detect Nattokinase in human blood following oral administration, showing activity from 2 to 24 hours post-dose.
- Animal studies, like those on rats, demonstrate effective absorption across the intestinal tract, inducing fibrinolysis after intraduodenal administration.
- However, the exact bioavailability percentage is not specified, with some sources noting a lack of convincing data on metabolism and absorption rates, indicating a need for further research.
- This oral effectiveness is supported by its long history of consumption in Japan and clinical studies, such as those referenced in PMC articles.
- Dosage and Safety
- Dosage recommendations and safety profiles are based on clinical studies and observational data:
- Common Dosage: Typically, 100 mg (2,000 FU) daily, as noted in Examine.com and WebMD, is used for cardiovascular health, with effects observed in short-term studies.
- Higher Doses: Doses up to 540 mg (10,800 FU) daily have been used for up to a year in China without adverse effects, as seen in PMC studies with 1,062 participants, showing efficacy in managing atherosclerosis and hyperlipidemia.
- Minimum Effective Dose: 2,000 FU daily is considered the minimum effective dose, based on studies showing significant fibrinolytic activity at this level.
- Maximum Safe Dose: While higher doses like 10,800 FU have been safe, caution is advised, especially for individuals on anticoagulants, with no clear upper limit defined beyond clinical study doses.
- Safe Range: Generally, 2,000 to 10,800 FU daily appears safe, with animal studies showing no toxicity at 480,000 FU/kg in mice, suggesting a high safety margin.
- Toxicity and LD50
- Specific LD50 values are not available for humans, but animal studies, such as the ScienceDirect article on acute toxicity, show no mortality or toxicological signs at doses up to 480,000 FU/kg in mice, which is 1,000 times the recommended human dose.
- This high tolerance suggests a wide therapeutic index, but human data is limited, with most studies reporting no adverse reactions at recommended doses.
- Risks and When It Becomes Dangerous
- The primary risk is an increased chance of bleeding, particularly when combined with other anticoagulants like warfarin or aspirin, as noted in Drugs.com and WebMD.
- Individuals with bleeding disorders, those undergoing surgery, or those on antihypertensive medications should use caution, with recommendations to stop at least 2 weeks before surgery.
- Excessive doses may exacerbate bleeding risks, with case reports of cerebellar hemorrhage in patients with ischemic stroke history, though such incidents are rare.
- Benzylpenicillin
- Pharmacological Actions
- The primary pharmacological action of benzylpenicillin is its bactericidal effect, achieved by inhibiting bacterial cell wall synthesis. It binds to penicillin-binding proteins (PBPs), specifically transpeptidases, preventing the cross-linking of peptidoglycan chains in the bacterial cell wall. This leads to an osmotically unstable cell wall, causing cell lysis and bacterial death, particularly effective during active bacterial multiplication. This action is rapid, occurring shortly after administration, and is most pronounced against susceptible gram-positive bacteria such as Streptococcus pneumoniae and non-penicillinase-producing Staphylococcus, as well as some gram-negative cocci like Neisseria gonorrhoeae.
- The influence over time is closely tied to its pharmacokinetics. Given its short half-life (0.4–0.9 hours for IV/IM administration), frequent dosing is necessary to maintain therapeutic levels, typically every 4–6 hours. For long-acting forms like benzathine penicillin G, the slow release from the injection site provides sustained low levels, maintaining antibacterial activity over weeks, which is crucial for conditions like syphilis requiring prolonged exposure.
- Pharmacokinetics
- The pharmacokinetic profile of benzylpenicillin varies by administration route and formulation, as detailed below:
- Absorption:
- For IV or IM administration of sodium or potassium salts, absorption is rapid, achieving high initial blood levels. Oral absorption is poor, with bioavailability estimated at 15-30% in fasting, healthy humans, primarily due to acid-catalyzed hydrolysis in the stomach, making oral administration uncommon.
- Benzathine penicillin G, administered intramuscularly, is slowly absorbed, leading to transient high initial levels followed by prolonged low concentrations due to its repository nature.
- Distribution: The volume of distribution is approximately 0.53–0.67 L/kg in adults with normal renal function, indicating good distribution throughout body tissues. It binds to serum proteins, mainly albumin, at a rate of 45-68%.
- Metabolism: About 16-30% of an IM dose is metabolized to penicilloic acid, an inactive metabolite, with small amounts converted to 6-aminopenicillanic acid and hydroxylated into active metabolites, all excreted via urine.
- Elimination: Primarily renal, with a clearance rate of 560 ml/min in healthy humans. Nonrenal clearance includes hepatic metabolism and biliary excretion. The short half-life (0.4–0.9 hours) necessitates frequent dosing for IV/IM forms.
- Half-Life:
- For sodium/potassium salts (IV/IM): 0.4–0.9 hours.
- For benzathine penicillin G: Effective levels are maintained for weeks, with studies showing detectable levels up to 4 weeks after a 1.2 million unit IM injection, with a mean apparent terminal half-life of around 189 hours in some reports.
- Bioavailability:
- IV: 100%
- IM (sodium/potassium salts): Nearly 100%
- Oral: 15-30%, not typically recommended due to poor absorption
- Benzathine penicillin G: Provides prolonged low levels via slow release, with pharmacokinetics supporting once-every-4-week dosing for some indications like rheumatic fever prophylaxis.
- Dosage Regimens
- Dosage varies significantly based on the infection, patient age, and renal function, with specific recommendations as follows:
Patient Group Condition Dosage (Units or mg) Route Frequency Adults General infections 600,000–3,600,000 units daily IV/IM Divided 4–6 doses Adults Serious infections (e.g., meningitis) Up to 24 million units/day (14.4 g) IV Divided doses Adults Bacterial endocarditis 7.2–12 g (12–20 million units) daily IV, often infusion As needed Adults Gas gangrene Up to 72 million units/day (43.2 g) IV As needed Children (1 month–12 years) General 100 mg/kg/day (not exceeding 4 g/day) IV/IM Divided 4 doses Infants (1–4 weeks) General 75 mg/kg/day IV/IM Divided 3 doses Newborns General 50 mg/kg/day IV/IM Divided 2 doses Benzathine Penicillin G Syphilis 2.4 million units IM Single dose or weekly Benzathine Penicillin G Streptococcal pharyngitis 1.2 million units IM Single dose - Safe Range: Generally, 600,000 to 24 million units daily for adults, with higher doses (up to 72 million units/day) used for severe infections under close monitoring.
- Minimum Effective Dose: Varies by infection; for example, 1.2 million units IM for streptococcal pharyngitis, but must be tailored to microbial susceptibility and condition severity.
- Maximum Dose Without High Risks: Up to 24 million units/day for most serious infections, with 72 million units/day reported for gas gangrene, though individual tolerance, especially renal function, must be considered.
- LD50 and Toxicity Thresholds: LD50 is not typically reported for humans, but research suggests a convulsant dose of approximately 5 g/kg IV, far exceeding therapeutic levels. Toxicity, particularly CNS effects like convulsions, increases at high doses, especially in renal impairment, with interstitial nephritis reported at doses >12 g/day.
- Safety and Toxicity
- Benzylpenicillin has a relatively low toxicity profile at therapeutic doses, with a high therapeutic index. However, several adverse effects and toxicity concerns exist:
- Common Side Effects: Include diarrhea, allergic reactions (urticaria, rashes, anaphylaxis), and, rarely, CNS toxicity (convulsions, especially at high doses or in severe renal impairment).
- Serious Reactions: Interstitial nephritis at doses >12 g/day, hemolytic anemia, leucopenia, thrombocytopenia, and severe cutaneous adverse reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported.
- Overdose Management: Discontinue the drug if neurotoxicity is suspected, with IV benzodiazepines and EEG monitoring for refractory cases, as it may inhibit GABA transmission.
- The evidence leans toward careful monitoring in patients with renal impairment, as the drug's renal excretion means accumulation can lead to toxicity. Allergic reactions, particularly anaphylaxis, are a significant concern and require pre-treatment assessment.
- Supporting Information
- This analysis is based on data from authoritative sources, including DrugBank [https://go.drugbank.com/drugs/DB01053], the Summary of Product Characteristics for Benzylpenicillin sodium [https://www.medicines.org.uk/emc/product/3828/smpc], and clinical guidelines from StatPearls [https://www.ncbi.nlm.nih.gov/books/NBK554560/]. Pharmacokinetic details for benzathine penicillin G were supplemented by studies like Kaplan et al. [https://pubmed.ncbi.nlm.nih.gov/2738782/], ensuring a robust foundation for the provided information.
- Tinidazole
- Pharmacological Actions and Temporal Influence
- Tinidazole’s primary pharmacological action is its antiprotozoal and antibacterial activity, achieved through the reduction of its nitro group by a ferredoxin-mediated electron transport system in organisms like Trichomonas vaginalis. This generates a free nitro radical that covalently binds to DNA, causing damage and leading to cell death. While the exact mechanism against Giardia and Entamoeba species is not fully known, it is likely similar.
- The influence over time is tied to its pharmacokinetics:
- Onset of Action: Research indicates a time to maximum concentration (Tmax) of approximately 1.6 hours under fasted conditions for a 2 g dose, suggesting the drug begins exerting effects shortly after administration.
- Duration of Action: With a half-life of 12-14 hours, Tinidazole maintains therapeutic levels for an extended period, supporting single-dose regimens for some infections like trichomoniasis (2 g once) and multi-day regimens for others, such as amebiasis (2 g/day for 3-5 days).
- The effectiveness over time is likely related to maintaining concentrations above the minimum inhibitory concentration (MIC) for the target organisms, though specific MIC values vary by pathogen and are not detailed here.
- Half-Life and Bioavailability
- Half-Life: The elimination half-life is reported as 13.2 ± 1.4 hours, with a plasma half-life of 12-14 hours, indicating the drug’s persistence in the body. This long half-life supports less frequent dosing, enhancing patient compliance.
- Bioavailability: Tinidazole exhibits nearly 100% oral bioavailability, meaning it is almost completely absorbed when taken by mouth. Studies show that food does not affect overall bioavailability, though it delays Tmax by about 2 hours and reduces peak concentration (Cmax) by approximately 10%, with an area under the curve (AUC) of 901.6 ± 126.5 mcg hr/mL at 72 hours for a 2 g dose under fasted conditions. This high bioavailability is consistent across formulations, including crushed tablets in cherry syrup, which show no pharmacokinetic differences compared to whole tablets.
- Other routes of administration are not commonly used, as Tinidazole is primarily available as oral tablets (250 mg and 500 mg), with no significant data on alternative routes in humans.
- Dosage Regimens
- Dosage varies by condition and patient age, with the following standard regimens:
Condition Adult Dose Pediatric Dose (>3 years) Amebiasis (Intestinal) 2 g/day PO for 3 days 50 mg/kg/day PO for 3 days; max 2 g Amebic Liver Abscess 2 g/day PO for 3-5 days 50 mg/kg/day PO for 5 days; max 2 g Giardiasis 2 g PO once 50 mg/kg PO once; max 2 g Trichomoniasis 2 g PO once Safety and efficacy not established Bacterial Vaginosis 2 g PO qDay for 2 days OR 1 g PO qDay for 5 days Not applicable (adult women only) - Minimum Effective Dose: For trichomoniasis, a single 2 g dose is effective, while for bacterial vaginosis, 1 g daily for 5 days is a lower effective regimen.
- Safe Range: Doses within the above guidelines are considered safe, typically up to 2 g/day for adults, with children’s doses capped at 2 g maximum based on weight.
- Maximum Dose Without High Risks: Clinical data suggest doses up to 2 g/day are standard, with no specific data on higher doses in humans. Exceeding recommended doses is not advised due to potential toxicity, though exact thresholds are unclear.
- LD50 and Toxicity: In animal studies, LD50 values are >3,600 mg/kg oral in mice and >2,000 mg/kg in rats, indicating high doses are required for toxicity in animals. Human overdose data is limited, with no reported cases, and treatment is symptomatic and supportive, including gastric lavage and hemodialysis (removing ~43% in a 6-hour session).
- Estimation of Dangerous Levels: Given the lack of human overdose data, it is difficult to specify when Tinidazole becomes too dangerous. Caution is advised with doses exceeding recommended levels, especially in patients with hepatic or renal impairment, where metabolism and elimination may be affected.
- Safety Considerations
- Tinidazole is generally well-tolerated, with common side effects including metallic taste and nausea (9-11% of recipients). It crosses the placental barrier and is secreted in breast milk, requiring caution in pregnancy and breastfeeding. In patients with severe renal impairment (CrCL < 22 mL/min), pharmacokinetics are similar to healthy subjects, but hemodialysis reduces half-life to 4.9 hours, necessitating an additional half-dose post-session if administered pre-hemodialysis. For hepatic impairment, no specific pharmacokinetic data exists, but caution is advised due to potential reduced elimination, similar to metronidazole.
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- Inosine + DMAE
- List of ME/CFS Recovery and Improvement Stories
- Homemade Isoprinosine/Immunovir
- Warning about inosine plus dmae
- Inosine and DMAE (Dimethylaminoethanol) are compounds used in various health contexts, with Inosine often part of antiviral and immunomodulatory treatments like Imunovir (Inosine Pranobex), and DMAE marketed for cognitive and skin health. The combination, termed "homemade Imunovir," is not a pharmaceutical product but is discussed in forums as a potential substitute, particularly for conditions like ME/CFS. This note synthesizes available data to provide detailed insights into their pharmacological actions, time courses, pharmacokinetics, and dosage considerations.
- Pharmacological Actions
- Inosine:
- Inosine is a nucleoside involved in purine metabolism, with significant immunomodulatory effects. It enhances T-cell lymphocyte proliferation, boosts natural killer cell activity, and increases pro-inflammatory cytokines, restoring deficient immune responses in immunosuppressed patients [PMC6822865]. It is also used in antiviral contexts, such as in Imunovir for herpes simplex and other viral infections, likely by affecting viral RNA levels and supporting immune function.
- Emerging research suggests neuroprotective, anti-inflammatory, and cardioprotective roles, with potential benefits in neurological conditions like Parkinson's disease and multiple sclerosis [DrugBank DB04335].
- DMAE:
- DMAE is structurally similar to choline and is believed to support acetylcholine production, a neurotransmitter crucial for memory and focus, though it's not a direct precursor [Nootropics Expert]. It is used in supplements for cognitive enhancement, with studies exploring benefits for ADHD, depression, and Alzheimer's, though evidence is limited and older [Healthline].
- In cosmetics, 3% DMAE gel has shown efficacy in reducing wrinkles and improving skin appearance over 16 weeks, suggesting anti-aging properties [PubMed 15675889].
- Combination (Inosine + DMAE):
- Specific studies on the combination are scarce, but forum discussions (e.g., Phoenix Rising) suggest users aim to mimic Imunovir's effects, which includes Inosine combined with dimepranol acedoben, not DMAE. User reports indicate varied experiences: some found benefits similar to Imunovir, while others reported overstimulation, dizziness, and confusion, suggesting DMAE might add cognitive or stimulatory effects not present in Imunovir [Phoenix Rising Forum 81113].
- Given Inosine's immune focus and DMAE's cognitive potential, the combination might theoretically offer both immunomodulation and brain support, but this is speculative without clinical data.
- Time Courses of Pharmacological Actions
- Inosine: Immunomodulatory effects, such as increased T-cell activity, may take days to weeks to manifest, as immune responses often require sustained exposure. Antiviral effects, when part of combinations like Imunovir, are typically seen over treatment courses of 7-14 days for herpes infections [Medicines.org.uk/emc/product/2824].
- DMAE: Cognitive effects, if present, might be noticed more quickly, potentially within hours to days, given its role in neurotransmitter support, though evidence is limited. Skin benefits from topical DMAE were observed over 16 weeks in clinical studies [PubMed 15675889].
- Combination: Without specific studies, time courses are inferred from individual components. Immune effects might lag, while cognitive effects could be quicker, but user reports suggest immediate overstimulation risks, indicating rapid onset for some effects [Phoenix Rising Forum 81113].
- Pharmacokinetics
- Half-Life:
- Inosine: Estimated at approximately 15 hours, based on its metabolism as a stable purine nucleoside, with a longer half-life compared to adenosine (about 10 seconds) [PubMed 26903141].
- DMAE: Specific half-life data is not widely available, but studies suggest a half-life of around 24 hours in fetal rat brain cell cultures, and excretion data (57–64% in urine within 24 hours in rats) implies a half-life of several hours, likely 12-24 hours [PMC7252906].
- Bioavailability:
- Inosine: Orally bioavailable, with up to 70% recovered as urinary uric acid in animal studies, indicating significant absorption [Medicines.org.uk/emc/product/2824]. Clinical trials for Parkinson's used oral doses effectively, suggesting good bioavailability [JAMA 2784144].
- DMAE: Well-absorbed orally, with animal studies showing 21–44% tissue retention at 24 hours and significant urinary excretion, indicating good oral bioavailability [PMC7252906].
- Different Bioavailabilities (Including Oral Route):
- Both compounds are primarily considered for oral administration, with no specific data on other routes for the combination. Inosine's oral bioavailability is supported by its use in oral formulations, while DMAE's is confirmed by animal studies showing absorption and distribution.
- Dosage Information
- The following table summarizes dosage details for Inosine and DMAE, based on available literature and user reports:
Aspect Inosine DMAE Typical Dose 500 mg to 2 g per day (supplements, clinical trials) 100-500 mg per day (supplements) Safe Range Up to 2 g/day, monitor uric acid levels Up to 500 mg/day, higher doses risk side effects Minimum Effective Dose Not specified, start at 500 mg/day Not specified, start at 100 mg/day Maximum Safe Dose Limited by uric acid elevation, typically 2 g/day Limited by side effects, typically 500 mg/day LD50 Not specified, likely high based on safety profile 1803 mg/kg oral in rats When It Starts to Become Dangerous High uric acid levels (gout, kidney stones) Overstimulation, insomnia, at higher doses - Combination Considerations: Start with low doses (e.g., 500 mg Inosine and 100 mg DMAE daily) and monitor for side effects, especially overstimulation or sleep issues, as reported in forums [Phoenix Rising Forum 81113]. Adjust based on individual tolerance, and consult a healthcare professional, particularly for ME/CFS patients where stimulants may be harmful.
- Safety and Side Effects
- Inosine: Main concerns include elevated uric acid levels, potentially leading to gout or kidney stones, as seen in MS trials where 4/16 patients developed kidney stones [Wikipedia Inosine]. Clinical trials for Parkinson's used doses up to 2 g/day, generally well-tolerated with monitoring [JAMA 2784144].
- DMAE: Reported side effects include insomnia, muscle tension, headaches, and overstimulation, especially at higher doses. Forum users noted dizziness and confusion with the combination, suggesting caution [Phoenix Rising Forum 81113]. The LD50 in rats (1803 mg/kg oral) indicates high toxicity thresholds, but therapeutic doses are much lower.
- Combination: User reports highlight risks of overstimulation, with some finding it intolerable, particularly in ME/CFS contexts. Dr. Ros Vallings noted 33% of ME/CFS patients benefit from Imunovir, but 10% cannot tolerate it, suggesting similar risks for the homemade version [Phoenix Rising Forum 81113].
- Green Tea + Guarana
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- PRL-8-53 + Dihexa
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- Products
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