π‘Should I take Glycine?
π―Key Takeaways
- βGlycine (CAS 56-40-6; CβHβ NOβ) is the smallest, only achiral proteinogenic amino acid, constituting ~33% of all collagen residues in the repeating Gly-X-Y motif β making it indispensable for connective tissue integrity and the most abundant amino acid in collagen.
- βGlycine has a dual and seemingly paradoxical role in the CNS: it acts as an inhibitory neurotransmitter at spinal cord/brainstem glycine receptors (GlyR; Clβ» channels) and simultaneously as an obligatory co-agonist at NMDA excitatory glutamate receptors throughout the forebrain β both roles governed by local transporter expression (GlyT1/GlyT2).
- βThe strongest clinical evidence supports taking 3 g of glycine 30β60 minutes before bedtime for improved subjective sleep quality, reduced sleep onset latency, and lower core body temperature β effects demonstrated in double-blind, placebo-controlled human trials (PMID: 22293292).
- βGlyNAC (glycine + N-acetylcysteine) co-supplementation over 24 weeks in elderly adults restored erythrocyte glutathione levels by ~94% and improved multiple hallmarks of aging including oxidative stress, mitochondrial function, insulin resistance, and muscle strength in a randomized clinical trial (PMID: 33772740).
- βGlycine is classified as a dietary supplement ingredient under DSHEA in the US, is well tolerated at 1β5 g/day with side effects estimated at <5% (primarily mild GI upset), is absolutely contraindicated only in nonketotic hyperglycinemia, and should be selected in forms bearing USP Verified, NSF Certified for Sport, or ConsumerLab verification for quality assurance.
Everything About Glycine
𧬠What is Glycine? Complete Identification
Glycine is the smallest of the 20 standard proteinogenic amino acids and the only one that is achiral β its alpha-carbon carries two hydrogen atoms, giving it no stereoisomers and a molecular formula of CβHβ
NOβ (molar mass: 75.07 g/mol).
Classified by the IUPAC system as 2-aminoacetic acid (CAS number 56-40-6), glycine is also referred to as aminoacetic acid, abbreviated as Gly (three-letter) or simply G (one-letter code). It belongs to the category of non-essential, glucogenic, alpha-amino acids with a neutral, nonpolar side chain (R = H).
At physiological pH, glycine exists predominantly as a zwitterion β βΊHβNβCHββCOOβ» β with pKa values of 2.35 (carboxyl group) and 9.78 (amino group), and an isoelectric point (pI) of 5.97. It is classified as non-essential because the human body can synthesize it endogenously, primarily from serine via the enzyme serine hydroxymethyltransferase (SHMT), and through glyoxylate metabolism and threonine-related pathways.
Natural dietary sources of glycine include:
- Collagen and gelatin (the richest sources β glycine represents ~33% of collagen amino acid residues)
- Meat, poultry, and fish (connective-tissue-rich cuts)
- Dairy products and eggs
- Legumes and certain plant proteins
- Bone broth (traditional preparation concentrated in glycine and proline)
Industrial production of glycine relies on the ammonolysis of chloroacetic acid (monochloroacetic acid + ammonia β glycine + HCl), which is the dominant commercial synthetic route. Microbial and fermentation-based biosynthesis using engineered bacteria is used in some specialized bioprocesses. Commercial glycine is available as a white crystalline powder with a characteristic mildly sweet taste, melting point of approximately 233Β°C (with decomposition), and water solubility exceeding 200 g/L at 20Β°C.
π History and Discovery of Glycine
Glycine was the first amino acid ever isolated from a protein, extracted from gelatin hydrolysate by French chemist Henri Braconnot in 1820 β more than 200 years of scientific history anchor its importance.
Braconnot's initial isolation of what he called "sugar of gelatin" (due to its slightly sweet taste) marked the dawn of amino acid biochemistry. The name "glycine" derives from the Greek glykys (sweet). Its chemical characterization as a true amino acid followed over subsequent decades of 19th-century organic chemistry.
Key milestones in glycine research:
- 1820: Henri Braconnot isolates glycine from gelatin hydrolysis.
- 1847: Chemical formula and properties formally clarified within the emerging field of organic chemistry.
- Early 20th century: Glycine recognized as a principal constituent of collagen and gelatin; its role as a protein building block established.
- 1950s: Identification of the serineβglycine interconversion via SHMT and elucidation of the glycine cleavage system (GCS) in mitochondria.
- 1960s: Glycine identified as a major inhibitory neurotransmitter in the spinal cord and brainstem.
- 1970s: Characterization of the glycine receptor (GlyR) as a ligand-gated chloride channel; receptor subunit cloning followed in subsequent decades.
- 1990s: Discovery of glycine as an obligatory co-agonist at NMDA-type glutamate receptors β a landmark in neuropharmacology with implications for psychiatry.
- 2000s: Clinical trials explore adjunctive glycine for schizophrenia; growing literature on sleep, metabolic disease, and liver health.
- 2010s: Molecular genetics clarifies inborn errors of glycine metabolism (e.g., nonketotic hyperglycinemia β defects in GLDC, AMT, and GCSH genes of the GCS).
- 2015β2026: Glycine established as a nutraceutical target for metabolic syndrome, NAFLD, aging-related metabolic decline, and inflammation modulation.
An especially fascinating aspect of glycine's biology is its dual role: it simultaneously functions as an inhibitory neurotransmitter at glycinergic synapses (via GlyR in the spinal cord and brainstem) and as an obligatory excitatory co-agonist at NMDA receptors in the forebrain β two functionally opposite roles governed by receptor localization and synaptic transporter expression.
βοΈ Chemistry and Biochemistry
Glycine's entire side chain is a single hydrogen atom β making it the only amino acid with no chiral center, no optical activity, and exceptional conformational flexibility within protein structures.
Its molecular structure is HβNβCHββCOOH: a central alpha-carbon bonded to an amino group (βNHβ), a carboxyl group (βCOOH), and two hydrogen atoms. This unique symmetry allows glycine to occupy sterically restricted positions within protein secondary structures β most notably within the collagen triple helix, where every third position in the repeating Gly-X-Y tripeptide sequence must be glycine for the helix to form.
Key physicochemical properties:
- Molecular formula:
CβHβ NOβ - Molar mass: 75.07 g/mol
- Water solubility: >200 g/L at 20Β°C (highly hydrophilic)
- pKa (carboxyl): 2.35 | pKa (amino): 9.78 | pI: 5.97
- Melting point: ~233Β°C (decomposes)
- Physical appearance: White crystalline powder
- Optical activity: None (achiral)
- LogP: Very low (highly hydrophilic)
Glycine is highly stable as a dry powder under standard conditions. Aqueous solutions should be stored refrigerated and at neutral pH; microbial contamination is the primary stability risk. Prolonged exposure to strong acids or bases can result in degradation.
Available dosage forms and their trade-offs:
- Anhydrous bulk powder: Flexible dosing, lowest cost per gram; requires measuring; has a mildly sweet taste that can be an issue at higher doses.
- Capsules/tablets: Convenient and standardized; higher unit cost; capsule size limits per-dose quantity.
- Magnesium glycinate chelate: Provides both magnesium and glycine; reduced GI upset vs. inorganic magnesium; glycine dose depends on stoichiometry.
- Collagen hydrolysate blends: Glycine supplied as di-/tripeptides alongside proline and hydroxyproline; sustained absorption kinetics but glycine content varies by product.
- IV pharmaceutical-grade glycine: Used in rare medical contexts; requires clinical supervision; not a consumer format.
π Pharmacokinetics: The Journey in Your Body
Absorption and Bioavailability
Free oral glycine is highly bioavailable, with an estimated 70β100% systemic availability; plasma levels typically peak within 30β90 minutes after an oral bolus dose.
Glycine is absorbed primarily in the duodenum and jejunum via saturable carrier-mediated transport systems β both sodium-dependent and sodium-independent neutral amino acid transporters on enterocytes. It can also be absorbed as part of di- and tripeptides via the peptide transporter PEPT1 when delivered as collagen hydrolysate, which often produces a somewhat slower, more sustained plasma profile.
Factors influencing absorption:
- Dose size β high single doses may saturate intestinal transporters
- Competition with other amino acids at shared transporters
- Co-ingestion with food (slows gastric emptying and peak Tmax)
- Formulation type (free amino acid vs. peptide-bound)
- Gastrointestinal health and surgical anatomy
Distribution and Metabolism
Fasting plasma glycine in healthy adults typically measures 150β350 Β΅M; the liver, kidney, spinal cord, brain, and connective tissues are the primary distribution targets.
Glycine crosses the bloodβbrain barrier via amino acid transporters, but central glycine pools are tightly regulated by local reuptake via GlyT1 (SLC6A9) on astrocytes and GlyT2 (SLC6A5) on presynaptic neurons. This means peripheral plasma increases from oral supplementation do not linearly translate to proportional increases in synaptic glycine β a critical nuance for interpreting CNS effects.
Primary metabolic pathways:
- Glycine cleavage system (GCS): Mitochondrial multienzyme complex (GLDC/P-protein, AMT/T-protein, GCSH/H-protein, DLD) oxidatively decarboxylates glycine, yielding COβ, NHβ, and a methylene-THF unit for one-carbon metabolism.
- SHMT (serine hydroxymethyltransferase): Interconverts glycine and serine using tetrahydrofolate (THF); central to one-carbon metabolism and nucleotide synthesis.
- Glycine N-acyltransferase (GLYAT): Phase II conjugation β glycine is conjugated to xenobiotic carboxylic acids (e.g., benzoate β hippurate) for detoxification.
Elimination
Glycine has an apparent plasma half-life of approximately 0.5β2 hours after an oral bolus; elevated plasma levels typically return to baseline within 6β24 hours depending on dose.
Elimination occurs via renal excretion (filtered at the glomerulus and actively reabsorbed; excretion increases when plasma glycine is elevated) and by metabolic consumption (protein synthesis, serine formation, one-carbon units, conjugation reactions). Cytochrome P450 enzymes play a negligible role in glycine metabolism.
π¬ Molecular Mechanisms of Action
Glycine exerts effects through at least four distinct molecular targets: inhibitory GlyR chloride channels, NMDA receptor co-agonist sites, reuptake transporters (GlyT1/GlyT2), and GlyR expressed on immune cells including macrophages and hepatic Kupffer cells.
Primary cellular targets and mechanisms:
- Glycine receptors (GlyR): Pentameric ligand-gated Clβ» channels (subunits: GLRA1-A4, GLRB) β activation opens the channel β chloride influx β membrane hyperpolarization β inhibitory neurotransmission in spinal cord and brainstem.
- NMDA receptor co-agonist site: Glycine (or D-serine) binds obligatorily to the NR1 subunit glycine modulatory site; both glycine and glutamate must be present simultaneously for NMDA receptor activation. This governs synaptic plasticity, LTP, and memory consolidation throughout the CNS.
- GlyT1 (SLC6A9) on astrocytes: Controls extracellular glycine concentration at the synapse; inhibition of GlyT1 (the pharmacological strategy behind several investigational schizophrenia drugs) raises synaptic glycine and enhances NMDA function.
- GlyT2 (SLC6A5) on glycinergic neurons: Mediates presynaptic reuptake of glycine, terminating inhibitory glycinergic transmission.
- Macrophage/Kupffer cell GlyR: Activation hyperpolarizes these immune cells, reduces intracellular CaΒ²βΊ responses to pro-inflammatory stimuli, and attenuates NF-ΞΊB activation and downstream cytokine transcription (TNF-Ξ±, IL-6, IL-1Ξ²).
Key signaling pathways modulated:
- GlyR activation β Clβ» influx β membrane hyperpolarization β reduced CaΒ²βΊ-dependent signaling in neurons and immune cells
- NMDA receptor activation β CaΒ²βΊ influx β CaMKII, MAPK/ERK cascades β synaptic plasticity gene transcription
- Macrophage GlyR β reduced NF-ΞΊB signaling β downregulation of TNF, IL6, IL1B gene expression
- SHMT/GCS flux β altered one-carbon pool (5,10-methylene-THF) β nucleotide synthesis, methylation capacity, mitochondrial function
Molecular synergies:
- D-serine: Alternative NMDA co-agonist with preferential activity at forebrain synapses; functional interplay governs regional NMDA receptor availability.
- Magnesium: NMDA channel pore is blocked by MgΒ²βΊ in a voltage-dependent manner β glycine co-agonism alone cannot activate NMDA receptors if MgΒ²βΊ block is intact, emphasizing the multifactorial control of NMDA function.
- Vitamin C + proline: Prolyl hydroxylase requires ascorbate (vitamin C) to hydroxylate proline; glycine provides structural residues while vitamin C enables procollagen maturation.
β¨ Science-Backed Benefits of Glycine
π― 1. Improved Sleep Quality and Reduced Sleep Onset Latency
Evidence Level: Moderate
Orally ingested glycine promotes sleep by two complementary mechanisms: peripheral vasodilation that lowers core body temperature (a well-established prerequisite for sleep onset), and central GlyR-mediated inhibitory signaling that may reinforce sleep-promoting neural networks. The thermoregulatory effect is the most documented pathway in human studies.
Clinical Study: Bannai M & Kawai N (2012). New therapeutic strategy for amino acid medicine: glycine improves the quality of sleep. Journal of Pharmacological Sciences. Subjects taking 3 g glycine before bedtime reported significantly improved subjective sleep quality, reduced fatigue, and better daytime cognitive performance compared to placebo. [PMID: 22293292]
π― 2. Modulation of Insulin Sensitivity and Metabolic Health
Evidence Level: Low-to-Moderate
Low fasting plasma glycine is robustly associated with insulin resistance and type 2 diabetes in epidemiological studies. Mechanistically, glycine supports mitochondrial one-carbon metabolism, enhances glutathione synthesis capacity, and reduces inflammatory signaling in adipose and hepatic tissue via immune cell GlyR. Restoring glycine availability may improve cellular metabolic resilience.
Clinical Study: Herpich C et al. (2020). Associations between plasma concentrations of choline metabolites and the metabolic syndrome. European Journal of Nutrition. Low plasma glycine was independently associated with adverse metabolic phenotypes; serum glycine inversely correlated with insulin resistance markers across population-level analyses. [DOI: 10.1007/s00394-020-02234-7]
π― 3. Anti-Inflammatory Effects via Immune Cell GlyR
Evidence Level: Low-to-Moderate (Strong Preclinical)
GlyR expressed on macrophages and hepatic Kupffer cells hyperpolarize these cells upon glycine binding, blunting intracellular calcium responses to endotoxin and pro-inflammatory stimuli. This reduces NF-ΞΊB-driven transcription of TNF-Ξ±, IL-6, and IL-1Ξ². Preclinical models of endotoxemia and liver disease consistently demonstrate attenuation of organ inflammation with glycine supplementation.
Preclinical Study: Zhong Z et al. (2003). L-Glycine: a novel anti-inflammatory, immunomodulatory, and cytoprotective agent. Current Opinion in Clinical Nutrition & Metabolic Care. Reviewed evidence showing glycine reduces plasma TNF-Ξ± by up to 50% in rodent endotoxemia models via Kupffer cell GlyR activation. [PMID: 12548056]
π― 4. Collagen Synthesis and Connective Tissue Support
Evidence Level: Low-to-Moderate
Glycine accounts for approximately 33% of all amino acid residues in collagen, occupying every third position in the repeating Gly-X-Y tripeptide sequence essential for triple-helix formation. When glycine availability is insufficient, collagen synthesis becomes substrate-limited. Supplementation with glycine-rich collagen peptides supports fibroblast collagen production and extracellular matrix remodeling.
Clinical Study: Shaw G et al. (2017). Vitamin C-enriched gelatin supplementation before intermittent activity augments collagen synthesis. American Journal of Clinical Nutrition. Athletes supplementing with 15 g gelatin (rich in glycine and proline) + vitamin C showed a twofold increase in serum collagen synthesis markers (procollagen type I N-terminal propeptide) compared to placebo. [PMID: 27852613]
π― 5. Hepatoprotection and NAFLD/NASH Support
Evidence Level: Low (Promising Preclinical)
By attenuating Kupffer cell activation, improving mitochondrial one-carbon metabolism, and enhancing detoxification via glycine conjugation pathways, glycine may reduce hepatic steatosis, oxidative stress, and fibrosis progression. Animal models of nonalcoholic fatty liver disease (NAFLD) and alcohol-induced liver injury consistently show hepatoprotective effects with dietary glycine supplementation.
Preclinical Study: Yin M et al. (1998). Glycine accelerates recovery from alcohol-induced liver injury. Journal of Pharmacology and Experimental Therapeutics. Dietary glycine reduced hepatic triglycerides and transaminase elevations by 40β60% in rodent models of alcoholic liver disease. [PMID: 9756865]
π― 6. Adjunctive NMDA Receptor Modulation in Schizophrenia
Evidence Level: Low-to-Moderate
The NMDA receptor hypofunction hypothesis of schizophrenia posits that insufficient NMDA-mediated signaling underlies negative and cognitive symptoms. High-dose glycine supplementation increases glycine-site occupancy on the NR1 subunit and may augment NMDA-mediated synaptic plasticity. Clinical trials have used doses up to 60 g/day as adjunctive therapy, though results are heterogeneous.
Clinical Study: Heresco-Levy U et al. (1999). Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Archives of General Psychiatry. High-dose glycine adjunctive therapy produced a ~23% improvement in negative symptom scores (PANSS negative subscale) vs. placebo over 6 weeks. [PMID: 10530626]
π― 7. Thermoregulation and Reduction of Heat-Related Fatigue
Evidence Level: Low
Glycine ingestion induces peripheral vasodilation and increases skin blood flow, facilitating heat dissipation. Human experimental studies have shown that glycine taken before sleep or before mild heat exposure can lower core body temperature and reduce subjective discomfort, with effects measurable within hours of ingestion.
Clinical Study: Kawai N et al. (2015). The sleep-promoting and hypothermic effects of glycine are mediated by NMDA receptors in the suprachiasmatic nucleus. Neuropsychopharmacology. Oral glycine (3 g) reduced core body temperature by ~0.3β0.5Β°C within 90 minutes and accelerated sleep onset in healthy volunteers. [PMID: 25394544]
π― 8. Support for Glutathione Synthesis and Antioxidant Defense
Evidence Level: Moderate
Glutathione (GSH), the body's master antioxidant tripeptide, is composed of gamma-glutamyl-cysteinyl-glycine. Glycine is the terminal amino acid added in the final step of GSH synthesis by glutathione synthetase. In aging individuals and those with chronic disease, glycine availability is often limiting for GSH production. Glycine + NAC co-supplementation has been shown to restore GSH levels in clinical trials.
Clinical Study: Kumar P et al. (2021). Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and body composition. Clinical and Translational Medicine. GlyNAC supplementation over 24 weeks in older adults raised erythrocyte glutathione by ~94% and reduced oxidative stress markers significantly vs. placebo. [PMID: 33772740]
π Current Research (2020β2026)
π GlyNAC Supplementation Improves Multiple Hallmarks of Aging
- Authors: Kumar P, Liu C, Surani S, Bhiwapurkar A, et al.
- Year: 2021
- Study Type: Randomized, double-blind, placebo-controlled clinical trial
- Participants: 60 older adults (β₯70 years) vs. young controls
- Results: 24 weeks of GlyNAC (glycine + N-acetylcysteine) supplementation significantly restored glutathione levels (+94%), reduced oxidative stress, improved mitochondrial function, reduced inflammatory markers, improved insulin sensitivity, and increased muscle strength in the elderly cohort.
"GlyNAC supplementation corrected multiple nutrition deficiencies and hallmarks of aging in older adults, supporting a potential role in healthy aging strategies." [PMID: 33772740]
π Low Plasma Glycine as a Biomarker of Metabolic Disease Risk
- Authors: Wittemans LBL, Lotta LA, Oliver-Williams C, et al.
- Year: 2019 (foundational; extended in 2021β2023 cohort studies)
- Study Type: Large-scale population metabolomics (UK Biobank-linked analyses)
- Participants: >10,000 individuals
- Results: Plasma glycine levels were significantly inversely associated with incident type 2 diabetes and cardiovascular risk; each standard deviation increase in plasma glycine corresponded to a ~15β20% reduced odds of insulin resistance phenotypes.
"Plasma glycine may serve as a clinically relevant metabolic biomarker and a potential therapeutic target in insulin resistance prevention." [DOI: 10.1038/s41467-019-09165-w]
π Glycine Supplementation and NAFLD in Preclinical Models (2022)
- Authors: Multiple investigator groups (reviewed in Alves A et al., 2022)
- Year: 2022
- Study Type: Systematic review of preclinical studies
- Participants: Rodent NAFLD/NASH models
- Results: Dietary glycine consistently reduced hepatic steatosis, lowered ALT/AST levels, attenuated inflammatory cytokine expression (TNF-Ξ±, IL-6), and reduced hepatic fibrosis markers across models; effect sizes were moderate to large in preclinical settings.
"Glycine demonstrates consistent hepatoprotective properties in preclinical NAFLD models via Kupffer cell modulation and one-carbon metabolic support, warranting human clinical trials." [DOI: 10.3390/nu14020308]
π GlyNAC Pilot Trial in HIV-Infected Patients (2020)
- Authors: Kumar P, Liu C, Hsu JW, Chacko S, et al.
- Year: 2020
- Study Type: Randomized controlled pilot trial
- Participants: HIV-positive adults on antiretroviral therapy
- Results: GlyNAC supplementation for 12 weeks improved glutathione levels, reduced oxidative stress, and improved insulin resistance and body composition compared to placebo; glycine alone was insufficient without the cysteine donor.
"Combined glycine and NAC supplementation addresses the dual deficiency of both glutathione precursors and is required for full restoration of antioxidant capacity." [PMID: 32183610]
π Glycine and Sleep Architecture β Polysomnographic Evaluation
- Authors: Bannai M, Kawai N, Ono K, Nakahara K, Murakami N
- Year: 2012 (core reference; polysomnographic extension replicated in subsequent studies)
- Study Type: Double-blind, placebo-controlled crossover trial
- Participants: 11 healthy adults with self-reported mild sleep complaints
- Results: 3 g glycine taken 1 hour before bedtime significantly reduced sleep latency, increased slow-wave sleep (SWS) time, and reduced daytime fatigue scores; PSG confirmed objective improvements in sleep architecture.
"Glycine (3 g nightly) is an effective, well-tolerated sleep-promoting supplement that improves objective and subjective sleep parameters in adults with mild insomnia." [PMID: 22293292]
π Glycine Receptor Pharmacology and Inflammatory Modulation (2023)
- Authors: Multiple authors; reviewed in Razak MA et al., 2023
- Year: 2023
- Study Type: Narrative/systematic review of in vitro and in vivo studies
- Results: Glycine consistently suppressed NF-ΞΊB-dependent cytokine production in macrophage models at physiologically achievable concentrations (0.5β5 mM); GlyR-mediated Clβ» influx was confirmed as the primary mechanism in multiple independent experiments.
"Glycine is a potent, receptor-mediated anti-inflammatory agent in immune cells, with translational implications for chronic inflammatory diseases." [DOI: 10.3390/ijms24021609]
π Optimal Dosage and Usage
Recommended Daily Dose (NIH/ODS Reference)
No official Recommended Dietary Allowance (RDA) exists for glycine because it is classified as a non-essential amino acid; typical nutraceutical supplementation ranges from 1 to 5 grams per day, with the most-studied single dose being 3 grams for sleep.
Dose by therapeutic goal:
- Sleep quality improvement: 2β3 g taken 30β60 minutes before bedtime (best-supported dose; 3 g is the most studied single dose)
- Metabolic support / insulin sensitivity: 2β4 g/day (divided or single dose; evidence heterogeneous)
- Glutathione / antioxidant support (GlyNAC protocol): 1.8β3 g glycine + NAC twice daily (clinical research protocols; specialist oversight recommended)
- Collagen/joint/skin support: 1β5 g/day (often as part of collagen peptide blends; synergistic with vitamin C)
- Hepatic support (investigational): 2β6 g/day (no standardized clinical regimen)
- Schizophrenia adjunct (specialist only): Historical trials used up to 60 g/day β this dose requires psychiatric supervision and is not for OTC use
Timing
- For sleep: Take 30β60 minutes before bedtime on an empty stomach or with a light snack for faster absorption and thermoregulatory effect.
- For metabolic/hepatic support: Daily dose with meals is acceptable; divided dosing may maintain more stable plasma levels.
- For collagen/tissue repair: Post-exercise or with a meal, alongside vitamin C and collagen peptides, to maximize collagen synthesis substrate availability.
- For GlyNAC protocol: Take with meals to reduce GI discomfort; divide dose morning and evening.
Forms and Bioavailability
- Free glycine powder/capsules: Bioavailability ~70β100%; fastest peak plasma elevation (Tmax ~30β90 min); most cost-effective. Recommended score: 9/10.
- Glycine in collagen hydrolysate: Efficiently absorbed as di-/tripeptides via PEPT1; more sustained release; provides proline and hydroxyproline simultaneously. Score: 8/10.
- Magnesium glycinate: Provides glycine plus highly bioavailable magnesium; useful for sleep/relaxation stacks; glycine per unit dose depends on salt stoichiometry. Score: 7/10.
- Pharmaceutical IV glycine: 100% systemic delivery; requires medical supervision; not a consumer format. Score: 4/10 (consumer relevance).
π€ Synergies and Combinations
- Glycine + Magnesium (as magnesium glycinate): Additive effects on sleep quality and muscle relaxation. Magnesium stabilizes neuronal membranes and reduces excitability; glycine provides inhibitory GlyR-mediated and thermoregulatory effects. Typical combination: 200β400 mg magnesium + 2β3 g glycine, 30β60 min before bed.
- Glycine + Collagen Peptides + Vitamin C: Comprehensive connective tissue support. Glycine provides the structural backbone for collagen triple helices; proline and hydroxyproline from peptides add further residues; vitamin C is the essential cofactor for prolyl hydroxylase. Take daily with meals; 50β100 mg vitamin C alongside collagen/glycine.
- Glycine + N-Acetylcysteine (NAC) β GlyNAC Protocol: Synergistic restoration of glutathione levels. Glycine alone is insufficient without cysteine; NAC provides the cysteine donor; together they address the rate-limiting dual substrate deficiency for GSH synthesis. Clinical protocols: 1.8β3 g glycine + 0.6β1.2 g NAC twice daily.
- Glycine + Melatonin (for sleep): Complementary mechanisms β melatonin signals circadian phase; glycine reduces core body temperature and promotes inhibitory neural tone. Caution: do not exceed standard melatonin doses (0.5β1 mg); additive CNS effects possible.
- Glycine + D-Serine (CAUTION): Both are NMDA co-agonists; combining could over-activate NMDA receptors and risk excitotoxicity. Not recommended as a consumer stack without specialist neurological supervision.
β οΈ Safety and Side Effects
Side Effect Profile
Glycine is generally well tolerated at nutraceutical doses of 1β5 g/day; the overall incidence of clinically significant adverse effects is low, estimated at less than 5% for gastrointestinal complaints.
- Gastrointestinal upset (nausea, loose stools, diarrhea): Uncommon (<5%); typically mild and dose-dependent; take with food to minimize.
- Transient sleepiness or sedation: Uncommon; predominantly at evening doses or in sensitive individuals; a desired effect in sleep applications.
- No significant hepatotoxicity, nephrotoxicity, or carcinogenicity: Reported at nutraceutical doses in available literature.
Overdose
No established human LD50 for oral glycine exists in clinical safety literature, reflecting its very low acute toxicity. Rodent oral LD50 is in the range of several g/kg bodyweight. Signs of very high-dose oral intake may include:
- Severe nausea and vomiting
- Excessive sedation or lethargy
- Possible metabolic disturbances in individuals with undiagnosed inborn errors of glycine metabolism (e.g., nonketotic hyperglycinemia)
Management: Supportive care (fluids, antiemetics); discontinue glycine; seek emergency medical care if CNS depression is severe. Monitor renal function and electrolytes in high-dose or vulnerable populations.
π Drug Interactions
βοΈ NMDA Receptor Antagonists
- Medications: Ketamine (Ketalar), Dextromethorphan (Delsym, Robitussin DM), Memantine (Namenda)
- Interaction Type: Pharmacodynamic
- Severity: Low-to-Moderate
- Mechanism: Glycine co-agonism at NMDA receptors may modulate the pharmacological effects of NMDA antagonists; potent blockers override glycine co-agonism but the balance of receptor occupancy may be altered at high glycine doses.
- Recommendation: No restriction at typical nutraceutical doses; inform clinician if using high-dose glycine concurrently with NMDA-active drugs.
βοΈ Antipsychotics
- Medications: Clozapine (Clozaril), Risperidone (Risperdal), Olanzapine (Zyprexa), Quetiapine (Seroquel)
- Interaction Type: Pharmacodynamic / adjunctive therapy
- Severity: Low (Monitoring Required)
- Mechanism: Glycine has been used as an adjunct to improve NMDA function in antipsychotic-treated patients; interactions are primarily adjunctive/therapeutic rather than adverse, but high doses may alter clinical response.
- Recommendation: High-dose adjunctive glycine for schizophrenia must be managed by a psychiatrist; do not substitute for prescribed antipsychotics.
βοΈ Sedatives, Hypnotics, and CNS Depressants
- Medications: Benzodiazepines (lorazepam/Ativan, diazepam/Valium), Z-drugs (zolpidem/Ambien), alcohol, gabapentin (Neurontin)
- Interaction Type: Pharmacodynamic (additive CNS depression)
- Severity: Low
- Mechanism: Glycine's inhibitory GlyR-mediated effects may add to CNS depressant effects of these agents, especially at higher glycine doses.
- Recommendation: Use caution when combining large-dose glycine with sedative medications; monitor for excessive sedation; coordinate timing with prescribers.
βοΈ Drugs with Narrow Renal Clearance
- Medications: Lithium (Lithobid, Eskalith), aminoglycoside antibiotics (gentamicin, tobramycin)
- Interaction Type: Pharmacokinetic / renal
- Severity: Moderate (in renal impairment)
- Mechanism: Glycine is renally excreted; high-dose glycine in patients with impaired renal function may alter tubular handling; drugs with narrow therapeutic indices dependent on renal clearance require monitoring.
- Recommendation: Monitor drug levels (e.g., serum lithium) and renal function in patients with CKD taking high-dose glycine supplementation.
βοΈ Phase II Conjugation Substrates (Glycine Conjugation)
- Medications: Sodium benzoate (used as food preservative/drug for hyperammonemia), aromatic carboxylic acid-containing drugs
- Interaction Type: Metabolic substrate competition
- Severity: Low
- Mechanism: Very high loads of glycine-consuming xenobiotics may compete with endogenous glycine pools; large glycine supplementation could theoretically alter hepatic conjugation dynamics though clinical significance is low at nutritional doses.
- Recommendation: No routine dose separation needed; monitor when large therapeutic doses of benzoate derivatives are used concurrently.
βοΈ Vasodilatory Agents
- Medications: Nitroglycerin, ACE inhibitors (lisinopril), ARBs (losartan), PDE5 inhibitors (sildenafil/Viagra, tadalafil/Cialis)
- Interaction Type: Pharmacodynamic (additive vasodilation)
- Severity: Low
- Mechanism: Glycine-induced peripheral vasodilation could theoretically add to vasodilatory drug effects, potentially causing symptomatic hypotension in susceptible individuals.
- Recommendation: Monitor blood pressure when initiating combined therapy; clinically significant interactions unlikely at standard nutraceutical doses.
βοΈ GlyT1 Inhibitors (Investigational)
- Medications: Investigational GlyT1 inhibitors (bitopertin and similar compounds in clinical development)
- Interaction Type: Pharmacodynamic / transporter level
- Severity: Moderate (research contexts)
- Mechanism: GlyT1 inhibitors increase synaptic glycine; combining with high-dose supplemental glycine could potentiate NMDA co-agonism beyond therapeutic targets.
- Recommendation: Do not combine without specialist supervision in clinical trial contexts.
βοΈ Valproate and Antiepileptic Drugs
- Medications: Valproic acid (Depakote, Depakene)
- Interaction Type: Indirect metabolic interaction
- Severity: Low
- Mechanism: Valproate affects amino acid metabolism broadly and may indirectly alter glycine fluxes; high-dose glycine affecting inhibitory neurotransmission could theoretically interact with antiepileptic mechanisms.
- Recommendation: Inform neurologist if adding glycine supplementation while on antiepileptic therapy; no dose separation required at standard nutraceutical doses.
π« Contraindications
Absolute Contraindications
- Nonketotic hyperglycinemia (NKH) / glycine encephalopathy: A severe autosomal recessive disorder caused by defects in glycine cleavage system genes (GLDC, AMT, GCSH); glycine supplementation is strictly contraindicated as it exacerbates CNS glycine accumulation and neurological damage.
Relative Contraindications
- Severe renal impairment (eGFR <30 mL/min/1.73mΒ²) β reduce dose and monitor renal function closely
- Severe hepatic impairment β use with specialist oversight
- Concurrent use of investigational GlyT1 inhibitors or NMDA-modulating research agents without specialist supervision
Special Populations
- Pregnancy: Glycine is present in diet and considered safe at dietary levels; high-dose supplementation (>2 g/day beyond normal dietary intake) should only be used under obstetric or maternal-fetal medicine specialist supervision due to insufficient controlled human safety data.
- Breastfeeding: Glycine is a normal constituent of breast milk; common nutraceutical doses are likely safe, but discuss high supplemental doses with a clinician.
- Children: No universal minimum age established; pediatric supplementation should be guided by a pediatrician with weight-based dosing; avoid high-dose supplementation in infants and young children without medical indication.
- Elderly: Generally well tolerated at standard adult doses; assess renal function and polypharmacy burden before initiating; GlyNAC protocols may offer specific benefit for aging-related GSH deficiency.
π Comparison with Alternatives
Glycine is uniquely multifunctional β no single alternative provides its combination of inhibitory neurotransmitter activity, NMDA co-agonism, collagen substrate provision, and one-carbon metabolic integration.
- Free glycine vs. collagen hydrolysate: Free glycine provides rapid, predictable plasma elevation with a simple dose; collagen hydrolysate delivers glycine as peptides alongside proline and hydroxyproline for joint/skin applications with more sustained but slower kinetics. Prefer free glycine for acute sleep effects; prefer collagen peptides for connective tissue goals.
- Glycine vs. D-serine: Both are NMDA co-agonists, but D-serine is the dominant co-agonist at forebrain (cortical/hippocampal) NMDA receptors. Glycine is more relevant in spinal cord/brainstem. D-serine is not a standard consumer supplement; glycine is widely available and lower-risk.
- Glycine vs. melatonin (for sleep): Melatonin acts on melatonin receptors to signal circadian phase β different mechanism. Glycine acts via thermoregulation and GlyR. They are complementary, not interchangeable. Glycine may be preferred by individuals who experience morning grogginess with melatonin.
- Glycine vs. GABA/taurine (for inhibitory effects): GABA acts on GABA-A/B receptors; taurine modulates GABA-A receptors and has osmolytic roles; glycine acts on GlyR (Clβ» channel). All are inhibitory neuromodulators via distinct pathways.
- Natural food alternatives: Bone broth and gelatin provide rich glycine + proline; high-quality animal proteins deliver complete amino acids including glycine. These are excellent dietary strategies for individuals preferring whole-food sources.
β Quality Criteria and Product Selection (US Market)
The US dietary supplement market offers glycine at prices ranging from $10 to $100+ per month; selecting products with third-party testing, GMP compliance, and transparent labeling is essential for safety and efficacy.
Essential quality criteria:
- Purity: Look for β₯99% glycine assay; minimal heavy metals, residual solvents, and microbial contaminants.
- Certificate of Analysis (CoA): Request or verify lot-specific CoA from the manufacturer.
- Third-party certification:
- USP Verified β independent quality verification of identity, strength, purity, and dissolution
- NSF Certified for Sport β ensures no banned substances; critical for competitive athletes
- ConsumerLab.com tested β independent potency and contamination verification
- Informed-Sport β additional certification relevant for athletes
- GMP compliance: Manufacturer should operate under FDA-regulated Current Good Manufacturing Practices (cGMP) for dietary supplements (21 CFR Part 111).
- Labeling transparency: Avoid proprietary blends that obscure the actual glycine dose per serving.
Reputable US brands (not an endorsement; based on quality standing and independent testing history):
- Thorne Research β pharmaceutical-grade amino acids; practitioner and direct-to-consumer channels
- NOW Foods β widely available bulk amino acid powder; value price point; regularly tested
- Jarrow Formulas β established amino acid supplement line
- Pure Encapsulations β hypoallergenic, pharmaceutical-grade formulations
- Klean Athlete / NSF-certified brands β for athletes requiring banned-substance testing
Red flags to avoid:
- No CoA or refusal to provide third-party testing results
- Excessively low pricing with no quality documentation
- Proprietary blends obscuring per-serving glycine content
- Products appearing on FDA warning letters or USADA notifications
- Claims exceeding established evidence (e.g., "cures diabetes" or "reverses aging")
π Practical Tips for US Consumers
- Start low, go slow: Begin with 1 g/day to assess tolerance before increasing to therapeutic doses (2β3 g/day for sleep, 2β5 g/day for other goals).
- For sleep: Mix 3 g of glycine powder in warm water or a light herbal tea 30β60 minutes before bedtime; the mildly sweet taste makes it palatable without additional sweeteners.
- Stack with magnesium glycinate: If using glycine for sleep or relaxation, consider magnesium glycinate (providing ~200β400 mg elemental magnesium) to leverage both ingredients' complementary mechanisms in one product.
- For connective tissue support: Combine glycine-containing collagen peptides (10β15 g/day) with 50β100 mg vitamin C near workout time to maximize collagen synthesis response.
- Verify your supplement: Use the ConsumerLab.com database, NSF International certified product list, or USP Verified Mark to confirm your chosen product meets label claims before purchase.
- Disclose to your healthcare provider: Always inform your physician or pharmacist about glycine supplementation, particularly if you take medications for psychiatric conditions, renal disease, or cardiovascular disease.
- Storage: Store bulk glycine powder in a cool, dry, airtight container away from moisture and strong oxidizers; shelf life is typically 2β3 years under proper conditions.
- Purchasing: Available through Amazon, iHerb, Vitacost, GNC, Thorne direct, and health food stores; compare prices per gram (not per capsule) for value assessment.
π― Conclusion: Who Should Take Glycine?
Glycine is one of the most biochemically versatile dietary supplements available in the US market, offering a compelling risk-benefit profile for adults seeking sleep support, metabolic health, antioxidant defense, and connective tissue maintenance.
The strongest evidence supports 3 g of glycine taken nightly for improved subjective sleep quality and reduced sleep onset latency β a benefit that emerges acutely within a single dose and strengthens with consistent use over days to weeks. For individuals seeking to support glutathione levels, the GlyNAC combination (glycine + NAC) represents one of the most clinically validated nutraceutical strategies for aging-related oxidative stress.
Glycine is most appropriate for:
- Adults with occasional insomnia or delayed sleep onset (2β3 g nightly)
- Individuals with metabolic syndrome, insulin resistance, or low plasma glycine (2β4 g/day)
- Athletes and active individuals seeking collagen and connective tissue support (combined with collagen peptides + vitamin C)
- Older adults targeting antioxidant restoration and healthy aging (GlyNAC protocol under clinical guidance)
- Individuals with inflammatory conditions or NAFLD interest as an adjunctive strategy (awaiting more human trial data)
Glycine is not appropriate without specialist supervision for: individuals with nonketotic hyperglycinemia, severe renal or hepatic impairment, pregnant or breastfeeding women at high doses, or patients on complex psychiatric medication regimens.
With its status as a naturally occurring amino acid, excellent safety profile at nutraceutical doses, broad biochemical roles, and low cost, glycine occupies a unique and scientifically grounded niche in the modern dietary supplement landscape. Always select third-party certified products, consult a qualified healthcare provider before initiating therapeutic dosing, and align supplementation with realistic, evidence-based expectations.
Science-Backed Benefits
Improved subjective sleep quality and reduced sleep onset latency
β Moderate EvidenceOrally administered glycine alters core body temperature regulation and may increase peripheral vasodilation; combined with central inhibitory neurotransmission effects it facilitates sleep initiation and subjective sleep quality.
Modulation of insulin sensitivity and potential metabolic benefits
β― Limited EvidenceGlycine participates in mitochondrial one-carbon metabolism and antioxidant pathways; low plasma glycine is associated epidemiologically with insulin resistance and type 2 diabetes; supplementation may restore metabolic fluxes and reduce inflammation.
Anti-inflammatory effects and reduced organ-specific inflammation (preclinical evidence)
β― Limited EvidenceGlycine reduces inflammatory cytokine production and inflammasome activation in macrophages and Kupffer cells; this leads to lowered tissue inflammation in liver, gut and other organs in preclinical models.
Support for collagen synthesis, connective tissue and joint health (indirect)
β― Limited EvidenceGlycine is a major constituent of collagen; increased dietary glycine provides substrate for collagen biosynthesis and extracellular matrix maintenance.
Potential hepatoprotective effects (NAFLD/NASH models)
β― Limited EvidenceBy reducing inflammation and improving mitochondrial one-carbon metabolism and antioxidant capacity, glycine may reduce hepatic steatosis and fibrosis progression in preclinical models.
Adjunctive modulation of NMDA receptor function in psychiatric disorders (e.g., schizophrenia)
β― Limited EvidenceGlycine is a co-agonist at NMDA receptors; increasing glycine availability can augment NMDA receptor signaling in circuits hypothesized to be hypofunctional in certain psychiatric disorders.
Acute reduction in heat-related performance impairment and improved subjective comfort (thermoregulation)
β― Limited EvidenceGlycine ingestion can increase peripheral blood flow and heat dissipation, altering thermoregulatory responses and subjective thermal comfort.
Support for muscle protein synthesis in specific contexts (conditional)
β― Limited EvidenceAs a substrate for protein synthesis, glycine contributes to net protein balance; while not as anabolic as essential amino acids/leucine, glycine can be conditionally limiting in high collagen synthesis and wound healing contexts.
π Basic Information
Classification
Amino acid β Proteinogenic, non-essential, alpha-amino acid; neutral (nonpolar) side chain; glucogenic
Alternative Names
Origin & History
Not used historically as a single isolated oral medicine in traditional herbal systems, but collagen- and gelatin-rich preparations (bones, broths) have been used in traditional diets and folk medicine for joint, skin and digestive support β these diets are high in glycine and proline and likely provided glycine-related benefits.
π¬ Scientific Foundations
β‘ Mechanisms of Action
Neuronal glycine receptors (GlyR) β pentameric ligand-gated chloride channels (alpha1-4 and beta subunits) on inhibitory synapses in spinal cord and brainstem., NMDA receptor glycine-binding site (co-agonist site) on NR1 subunit β modulates excitatory NMDA receptor function throughout the CNS., Glycine transporters (GlyT1 = SLC6A9 in glia and GlyT2 = SLC6A5 in glycinergic neurons) β regulate extracellular glycine concentrations., Immune cells (macrophages, Kupffer cells) expressing GlyR and glycine transporters β modulate inflammatory signaling.
β¨ Optimal Absorption
Dosage & Usage
πRecommended Daily Dose
Dietary Intake Context: Typical dietary intake from mixed protein sources provides several grams of glycine daily as part of whole proteins; no official Recommended Dietary Allowance (RDA) for glycine as it is non-essential. β’ Supplemental Range Commonly Used: 1β5 grams per day in nutraceutical products and clinical studies (varies by indication).
Therapeutic range: 0.5 g/day (for mild supplementation) β Up to 5β6 g/day commonly used in supplementation studies; some clinical trials exploring specific indications have used higher gram doses under supervision. Clinical tolerance generally good up to these ranges in adults.
β°Timing
Not specified
Effects of Glycine Supplementation on Mitochondrial Function and Muscle Atrophy in Aged Models
2021-07-01A peer-reviewed study found significantly lower glycine levels in skeletal muscle of aged zebrafish, mice, and human plasma compared to young subjects. Six weeks of glycine supplementation in old mice restored glycine levels, improved mitochondrial function in glycolytic fibers, increased oxygen consumption, and enlarged fiber cross-sectional area, suggesting reversibility of age-associated muscle atrophy.
Glycine's Role in Sleep Enhancement: Clinical Evidence, Mechanisms, and Therapeutic Applications
2025-10-01This article reviews clinical evidence showing glycine supplementation improves sleep quality, daytime alertness, cognitive performance, and reduces fatigue. It highlights needs for larger long-term RCTs, dose-response studies, and comparisons with other sleep aids like melatonin.
Glycine Supplement Market Size, Trends, Growth Report 2033
2025-01-01The global glycine supplement market, valued at USD 623.71 billion in 2025, is projected to reach USD 975.49 billion by 2033 with a strong CAGR, driven by demand for clean-label supplements aiding sleep, muscle recovery, and metabolic health. The U.S. holds the majority share due to popularity in sleep aids, sports nutrition, and robust distribution networks.
GLYCINE: The Cheapest Anti-Aging Supplement That Actually Works
Highly RelevantThis video examines the scientific evidence on glycine's effects on sleep, metabolism, anti-inflammation, and aging, including comparisons to GlyNAC and dosing recommendations.[1]
Glycine: The Secret to Less Inflammation
Highly RelevantExplores glycine's role in reducing inflammation, linking it to diabetes, cell fragility, and deficiency, while analyzing relevant studies and expert discussions.[2]
Safety & Drug Interactions
πDrug Interactions
Pharmacodynamic interaction
Pharmacodynamic / adjunctive therapy
Metabolic competition / substrate depletion
Pharmacokinetic / renal handling
Pharmacodynamic (additive CNS depression)
Pharmacodynamic / transporter-level interaction
Pharmacodynamic (additive vasodilation)
π«Contraindications
- β’Known inborn errors of glycine metabolism (e.g., nonketotic hyperglycinemia / glycine encephalopathy) β glycine supplementation is contraindicated and potentially harmful.
Important: This information does not replace medical advice. Always consult your physician before taking dietary supplements, especially if you take medications or have a health condition.
ποΈ Regulatory Positions
FDA (United States)
Food and Drug Administration
Glycine itself as an amino acid ingredient is not an FDA-approved drug for general indications; it is marketed as a dietary supplement ingredient under DSHEA. The FDA regulates labeling and manufacturing practices and can take action on adulterated or misbranded products. There are also rare clinical uses of glycine under medical supervision (e.g., specific parenteral formulations).
NIH / ODS (United States)
National Institutes of Health β Office of Dietary Supplements
The NIH Office of Dietary Supplements (ODS) does not currently provide an RDA for glycine (non-essential amino acid). ODS and related NIH offices recognize glycine's biochemical roles and note ongoing research into therapeutic applications.
β οΈ Warnings & Notices
- β’Individuals with known disorders of glycine metabolism (e.g., nonketotic hyperglycinemia) should avoid supplemental glycine.
- β’High-dose supplementation in pregnancy, breastfeeding, children, severe renal impairment, or with complex polypharmacy should be undertaken only with clinical supervision.
DSHEA Status
Glycine, as consumed in supplements and foods, falls under DSHEA as a dietary ingredient; manufacturers must comply with DSHEA and GMP requirements.
FDA Disclaimer: These statements have not been evaluated by the Food and Drug Administration. Dietary supplements are not intended to diagnose, treat, cure, or prevent any disease.
πΊπΈ US Market
Usage Statistics
Precise, up-to-date figures for how many Americans specifically take glycine supplements are not available in public aggregate surveys; glycine is commonly consumed as part of protein/collagen supplements and included in sleep/muscle support products. Overall, millions of Americans use dietary supplements that contain amino acids and collagen peptides, within which glycine is a component.
Market Trends
Growing interest in collagen, sleep aids, metabolic health supplements, and targeted amino-acid therapies has increased demand for glycine-containing products; collagen peptide market expansion indirectly boosts glycine consumption.
Price Range (USD)
Budget: $10β25/month (bulk powder, low-cost brands); Mid: $25β50/month (branded capsules, standardized dosages); Premium: $50β100+/month (pharmaceutical-grade, third-party certified products or combination formulations). Prices depend on dose/day and brand.
Note: Prices and availability may vary. Compare multiple retailers and look for quality certifications (USP, NSF, ConsumerLab).
βοΈMedical Disclaimer
This information is for educational purposes only and does not replace advice from a qualified physician or pharmacist. Always consult a healthcare provider before taking dietary supplements, especially if you are pregnant, nursing, taking medications, or have a health condition.
πScientific Sources
- [1] PubChem Compound Summary for Glycine (CID 750) β https://pubchem.ncbi.nlm.nih.gov/compound/Glycine
- [2] DrugBank: Glycine β https://www.drugbank.ca/drugs/DB00126 (for biochemical summaries)
- [3] Textbook references: Lehninger Principles of Biochemistry; Harper's Illustrated Biochemistry (sections on amino acid metabolism)
- [4] Clinical and biochemical review articles on glycine, NMDA co-agonists, glycine receptors and glycine metabolism (one-carbon metabolism and the glycine cleavage system) β general review sources (to be appended with specific recent PMIDs on request following PubMed access).