r/anhedonia

Glycine

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• 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