r/anhedonia

Creatine

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• 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.