Glicina

Glycine

1. Identity

Chemical and Botanical Names

Glycine, denoted by the symbol Gly or G, is the simplest amino acid found in nature. With a chemical formula of C₂H₅NO₂, it is characterized by its single hydrogen atom as its side chain. It is the only achiral amino acid, in that the carbon atom bearing the carboxylate and amino groups is not a stereogenic center. Because it lacks a chiral center, glycine has no L- or D-designation in the conventional sense: glycine is the simple amino acid with no L or D chemical configuration. Its IUPAC name is 2-aminoacetic acid; its CAS registry number is 56-40-6. The name derives from the Greek word glykys, reflecting its sweet taste.

Classification

Glycine is one of several so-called nonessential amino acids for mammals; that is, they can synthesize it from the amino acids serine and threonine and from other sources, and do not require dietary sources. However, although generally viewed as a non-essential amino acid because it can be endogenously synthesized to a certain extent, glycine has also been suggested as a conditionally essential amino acid. This perspective has gained traction because generally in common feeding conditions, glycine is not sufficiently synthesized in humans, animals, and birds.

Natural Sources

Sweet-tasting, glycine was among the earliest amino acids to be isolated from gelatin (1820), and especially rich sources include gelatin and silk fibroin. In the diet, the richest dietary sources of glycine are animal-derived proteins, particularly gelatin, bone broth, and collagen-containing foods, followed by meat, poultry, fish, and dairy products. Animal connective tissue is particularly notable: cuts like brisket, short ribs, and pork belly are rich in glycine because they contain a lot of connective tissue, such as tendons, cartilage, and ligaments — parts that are high in collagen, which breaks down into gelatin and glycine during slow cooking. Plant-based contributions exist but are modest: plant-based foods such as beans, vegetables like spinach, kale, cauliflower, cabbage, and pumpkin, and fruits like banana and kiwi also provide some glycine.

Endogenous biosynthesis is the dominant source for most adults. Glycine is a non-essential amino acid, and mammals can produce sufficient amounts via de novo synthesis; in humans, approximately 45 g of endogenous glycine is synthesized, and 3–5 g of glycine is ingested from the daily diet. Generally, glycine is synthesized from choline, serine, hydroxyproline, and threonine through interorgan metabolism in which the kidneys and liver are primarily involved.

Industrial Synthesis and Supplement Forms

Although glycine can be isolated from hydrolyzed proteins, this route is not used for industrial production, as it can be manufactured more conveniently by chemical synthesis. The two main processes are amination of chloroacetic acid with ammonia, giving glycine and hydrochloric acid, and the Strecker amino acid synthesis, which is the main synthetic method in the United States and Japan. About 15 thousand tonnes are produced annually in this way. As a dietary supplement, glycine is available as a free-form powder (often sold in bulk), capsules, tablets, and as part of combination formulas. It is also present at high concentrations in collagen peptide and hydrolyzed gelatin supplements. In pharmaceutical and medical contexts, glycine functions as a bidentate ligand for many metal ions, forming amino acid complexes; representative complexes include iron glycinate, copper glycinate, and zinc glycinate. These chelated mineral forms are widely used in mineral supplement products.

---

2. Historical and Traditional Use

Scientific Discovery

French chemist H. Braconnot was the first to isolate glycine from acid hydrolysates of protein in 1820. Glycine's name was derived from the Greek word glykys owing to its sweet taste. A. Cahours subsequently chemically synthesized glycine from monochloroacetic acid and ammonia and established the structure of glycine. In 1924, Hilda Louise Kingston and Samuel Barnett Schryver at the Imperial College of Science and Technology (London) isolated glycine from the hydrolysis products of gelatin. The following year, two laboratory syntheses of glycine were published in Organic Syntheses. In the subsequent 30 years, additional biological sources were identified and lab syntheses were developed.

Traditional Dietary Context

Unlike many botanical supplements, glycine has no tradition as an isolated, extracted preparation in pre-modern medicine. Its traditional human exposure has been entirely dietary, through foods rich in connective tissue, skin, and bones. Historically, humans consumed the entire animal — skin, joints, tendons, connective tissue, and bones — which naturally balanced methionine intake with glycine. Today, that balance is often lost: modern diets tend to emphasize muscle meat while leaving out the collagen-rich parts of the animal that ancestors relied upon.

Across cultures, long-simmered broths made from bones and cartilage have been a staple preparation for millennia. Bone broth is made by slowly simmering bones, skin, and connective tissue from animals, and can be used for soups, stews, sauces, and gravies, or drunk on its own. Gelatin is produced from the breakdown of collagen when cooking bone broth, and contains many amino acids, including glycine, proline, glutamic acid, and arginine. This preparation — known variously across European, East Asian, Middle Eastern, and other culinary traditions as stock, consommé, pho base, tonkotsu, bone broth, and similar forms — was historically used as a nutritive preparation for the sick, convalescent individuals, the elderly, and young children, though the specific attribution of benefit to glycine is a modern scientific interpretation rather than an explicit historical claim.

Gelatin derived from animal connective tissue has also had longstanding pharmaceutical use as a medium for drug delivery — a use that persists today in the form of gelatin capsule shells. In aqueous solutions, glycine exists predominantly as a zwitterion (H₃N⁺CH₂COO⁻), a polar molecule with both a positive and negative charge, stabilized by hydrogen bonding with solvent water molecules. This chemical property makes it a valuable pharmaceutical excipient and stabilizer in parenteral preparations.

Glycine's role as an isolated dietary supplement is an entirely modern development, emerging from 20th-century biochemical research into amino acid metabolism.

---

3. Key Constituents and Mechanisms of Action

Glycine itself is the sole biologically active compound when the supplement is consumed. Its actions arise from its participation in multiple biochemical and receptor-mediated pathways.

Inhibitory Neurotransmitter

Amino acid glycine is a major component in proteins like collagen and functions as an inhibitory neurotransmitter in the spinal cord and brainstem. In both the peripheral and central nervous system, glycine acts as an inhibitory neurotransmitter via glycine receptors. When glycine receptors are activated, chloride enters the neuron via ionotropic receptors, causing an inhibitory postsynaptic potential. The termination of the action of glycine is mediated by rapid reuptake into the presynaptic terminal or surrounding glial cells; two glycine transporters, GLYT1 and GLYT2, are known.

NMDA Receptor Co-agonism

Glycine functions as an obligatory co-agonist at NMDA receptors through its action at a strychnine-insensitive binding site on the NMDA receptor complex. Glycine-induced augmentation of NMDA receptor-mediated neurotransmission may thus offer a potentially safe and feasible approach for ameliorating persistent negative symptoms of schizophrenia. These agonists act by enhancing NMDA receptor-mediated neurotransmission, thereby restoring synaptic plasticity and neural circuitry function.

Precursor to Critical Metabolites

Glycine acts as a precursor for several key metabolites of low molecular weight, including creatine, glutathione, haem, purines, and porphyrins. Glycine is utilized to synthesize serine, sarcosine, purines, creatine, heme group, glutathione, and collagen. Of particular relevance to its health effects is its role in glutathione synthesis: theoretical calculations have estimated that glutathione synthesis represents approximately 38% of the glycine flux necessary for the synthesis of the metabolites mentioned above; this flow amounts to approximately 1.5 g of glycine per day.

Collagen Structural Role

The extracellular structural proteins such as elastin and collagen are made up of glycine. Quantitatively, it has been estimated that 12 g per day of glycine is needed for collagen synthesis and 1 g per day for the synthesis of other proteins in the body. Glycine comprises roughly one-third of the amino acids in collagen and is essential for the triple-helix structure of the collagen molecule.

Anti-inflammatory and Glycine-Gated Chloride Channels

Supplemental glycine, via activation of glycine-gated chloride channels that are expressed on a number of types of cells — including Kupffer cells, macrophages, lymphocytes, platelets, cardiomyocytes, and endothelial cells — has been found to exert anti-inflammatory, immunomodulatory, cytoprotective, platelet-stabilizing, and antiangiogenic effects in rodent studies that may be of clinical relevance. The plasma concentration of glycine in normally nourished individuals — around 200 µM — is near the Km for activation of these channels, implying that the severalfold increases in plasma glycine achievable with practical supplementation can be expected to further activate these channels in vivo.

Glycine decreases the expression of proinflammatory cytokines through the inhibition of NF-κB and favors the expression of anti-inflammatory cytokines, thus reducing the feedback of the chronic inflammatory process that occurs in some diseases. Mechanistically, glycine shapes macrophage polarization via cellular signaling pathways such as NF-κB, NRF2, and Akt, and microRNAs.

Thermoregulatory Mechanism in Sleep

Research in animal models has shed light on how glycine promotes sleep. In acute sleep disturbance, oral administration of glycine induced non-REM sleep and shortened NREM sleep latency with a simultaneous decrease in core temperature. Oral and intracerebroventricular injection of glycine elevated cutaneous blood flow at the plantar surface in a dose-dependent manner, resulting in heat loss. This peripheral vasodilation and heat dissipation are thought to facilitate the drop in core body temperature that is necessary for sleep initiation.

One-Carbon Metabolism

In addition to being a building block for proteins, glycine is required for multiple metabolic pathways, such as glutathione synthesis and regulation of one-carbon metabolism. The glycine cleavage system catalyzes glycine degradation to carbon dioxide and ammonium while tetrahydrofolate is converted into 5,10-methylene-tetrahydrofolate, linking glycine metabolism directly to folate-dependent methylation processes.

Methionine Balance

A growing body of research describes glycine as a functional counterpart to methionine. The elimination of excess methionine requires two to three molar equivalents of glycine per mole of methionine. This stoichiometric relationship has led some researchers to propose that high-methionine diets (typical of muscle-meat-heavy Western diets) may increase relative glycine demand.

---

4. Scientific Evidence by Area of Use

4.1 Sleep Quality

Glycine's effects on sleep represent one of the most clinically studied areas in humans, with both subjective and objective (polysomnographic) evidence available.

Given that insomnia causes many problems, amelioration of the symptoms is crucial. A non-essential amino acid, glycine, was found to subjectively and objectively improve sleep quality in humans who have difficulty sleeping. A further study evaluated the effects of glycine on daytime sleepiness, fatigue, and performance in sleep-restricted healthy subjects. Sleep was restricted to 25% less than the usual sleep time for three consecutive nights. Before bedtime, 3 g of glycine or placebo were ingested; in subjects given glycine, the VAS data showed a significant reduction in fatigue and a tendency toward reduced sleepiness.

The positive effects reported on healthy populations included improved sleep and decreased daytime fatigue. The nervous system demonstrated the most positive effects, including improved psychiatric symptoms from longer-term glycine administration in psychiatric populations. While longer-term glycine administration improved sleep in healthy populations, these studies had small sample sizes with a high risk of bias.

Evidence strength: Preliminary-to-moderate. The clinical trials showing benefit used 3 g of glycine taken before bedtime. The studies are small, and the 2024 systematic review published in GeroScience explicitly noted high risk of bias and small sample sizes. Larger, blinded, controlled trials are needed to confirm and generalize these findings.

4.2 Psychiatric Disorders (Schizophrenia)

Glycine's role as an obligatory NMDA receptor co-agonist has generated considerable research interest in schizophrenia, where NMDA receptor hypofunction is thought to contribute to negative and cognitive symptoms.

Glycine-induced augmentation of NMDA receptor-mediated neurotransmission may offer a potentially safe and feasible approach for ameliorating persistent negative symptoms of schizophrenia. Twenty-two treatment-resistant schizophrenic patients participated in a double-blind, placebo-controlled, 6-week, crossover treatment trial with 0.8 g/kg per day of glycine added to their ongoing antipsychotic medication, with clinical assessments performed biweekly using the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), and other scales.

The studies varied in sample size and glycine dosage, but the majority reported significant improvements in negative symptoms and cognitive deficits of schizophrenia with glycine treatment. However, several studies did not find any significant effects on symptoms. Notably, inconsistent results have been reported, and data indicate that glycine administered with clozapine had no effect on patients with schizophrenia. In a 16-week randomized double-blind, double-dummy, parallel-group clinical trial conducted at four sites in the United States and one site in Israel, no significant differences were found between total average scores on the Scale for the Assessment of Negative Symptoms (SANS) of patients treated with glycine or placebo, and no change in average cognitive scores was apparent.

The lack of consistency across trials could be due to small sample sizes, different doses of glycine, different trial durations, and different clinical ratings. Notably, glycine is an inhibitory neurotransmitter in glycinergic neurons, and it has been reported to have poor CNS penetration (i.e., rate of permeation across the blood-brain barrier).

Evidence strength: Mixed and inconsistent. High-dose glycine as an adjunct to antipsychotics (other than clozapine) has shown benefit in some trials, but results are not uniform. The poor blood-brain barrier penetration of exogenous glycine is a recognized limitation. Indirect approaches using glycine transporter inhibitors (GlyT1 inhibitors) are under active pharmaceutical investigation.

4.3 Metabolic Syndrome, Insulin Resistance, and Type 2 Diabetes

A robust body of research links low plasma glycine levels to insulin resistance and metabolic disease. In metabolic disorders associated with obesity, type 2 diabetes (T2DM), and non-alcoholic fatty liver disease (NAFLDs), lower circulating glycine levels have been consistently observed, and clinical studies suggest the existence of beneficial effects induced by glycine supplementation.

Plasma glycine concentration is lower in the lean offspring of parents with type 2 diabetes compared to healthy subjects. Among patients with type 2 diabetes, hypoglycinemia occurs before clinical manifestations of the disease, but the pathophysiological mechanisms underlying glycine deficit and its potential clinical repercussions are unclear.

In terms of intervention evidence, acute glycine supplementation (5 g per day) was reported to improve insulin response and glucose tolerance. Positive effects included decreased systolic blood pressure with an oral glycine dose of 5 g × 3/day over 3 months in metabolic syndrome patients. In T2DM patients, significant positive immune system effects were observed after 3 months of 5 g × 3/day oral glycine ingestion, including decreased proinflammatory cytokines such as interleukin-6 (IL-6), interferon-gamma (IFN-γ), tumour necrosis factor-receptor 1 (TNF-RI), resistin, and interleukin-1 beta (IL-1β).

The mechanistic basis for improved insulin sensitivity involves glycine's role in glutathione synthesis and reduction of oxidative stress: the hypothesis that correction of glutathione levels by glycine treatment leads to reduced oxidative stress is associated with improved insulin signaling and insulin resistance; glycine treatment was found to decrease the levels of oxidative stress markers in the liver of sucrose-fed rats and increase the concentrations of glutathione (GSH) and γ-glutamylcysteine. (This is a preclinical model, not human data.)

As a cautionary note, current conclusions cannot extend beyond a dose of 15 g of glycine per day, which is the highest dose well tolerated in adult humans.

Evidence strength: Promising but primarily observational (plasma glycine association with T2DM risk) and small-scale interventional. Human clinical trials are predominantly short-term with small sample sizes. A 2022 review concluded that glycine supplementation improves various components of metabolic syndrome including diabetes, obesity, hyperlipidemia, and hypertension, and that in the future the use of glycine may have a significant clinical impact on the treatment of patients with metabolic syndrome.

4.4 Glutathione Deficiency and Aging (GlyNAC Research)

A significant line of human clinical research has investigated glycine in combination with N-acetylcysteine (NAC) under the label "GlyNAC," as both amino acids are precursors of glutathione. This research has been largely conducted by Rajagopal Sekhar and colleagues at Baylor College of Medicine.

The first randomized clinical trial of GlyNAC supplementation in older humans found that a wide variety of age-associated abnormalities, including notable hallmarks of aging, improved in older adults supplemented with GlyNAC, while no improvements were seen in those receiving placebo. The improvements included oxidative stress, glutathione deficiency, and multiple aging hallmarks affecting mitochondrial dysfunction, mitophagy, inflammation, insulin resistance, endothelial dysfunction, genomic damage, stem cell fatigue, and cellular senescence.

GlyNAC supplementation for 24 weeks in older adults corrected RBC-GSH deficiency, oxidative stress, and mitochondrial dysfunction, and improved inflammation, endothelial dysfunction, insulin resistance, genomic damage, cognition, strength, gait speed, and exercise capacity, and lowered body fat and waist circumference. However, benefits declined after stopping GlyNAC supplementation for 12 weeks. Conclusions confirmed that GlyNAC supplementation for 24 weeks in older adults was well tolerated.

A subsequent larger randomized clinical trial published in The Journals of Gerontology: Series A in 2023 confirmed these findings in 24 older adults and extended them, further validating the glutathione-restoration hypothesis.

Evidence strength: Encouraging early-phase clinical data. These trials are small (8–24 participants) and use glycine in combination with NAC, making it impossible to attribute results to glycine alone. Larger replication trials are needed.

4.5 Cardiovascular System

Results from in vitro work show that glycine can inhibit NF-κB activation, IκBα degradation, CD62E expression, and IL-6 production in human coronary arterial endothelial cells (HCAECs), suggesting that glycine may exhibit anti-inflammatory effects during endothelial inflammation. In human clinical data, decreased systolic blood pressure was observed with an oral glycine dose of 5 g × 3/day over 3 months in metabolic syndrome patients.

Evidence strength: Primarily preclinical and mechanistic. Human cardiovascular outcome data are limited and derived from small studies not specifically designed to measure cardiovascular endpoints.

4.6 Body Composition and Muscle in Renal Disease

A randomized double-blind crossover trial examined glycine supplementation in malnourished hemodialysis patients. Low plasma glycine concentrations have been associated with increased insulin resistance, an aetiological factor of protein-energy wasting. The mechanisms leading to increased lean components are unclear, but oral glycine could affect fat-free mass directly and/or through changes at the gut barrier level. Glycine has been proposed to decrease cell damage, oxidative stress, and the production of pro-inflammatory cytokines; overcome the anabolic resistance to leucine in wasting models; and increase protein synthesis in many cell types including skeletal muscle cells.

Evidence strength: Preliminary. The clinical evidence for muscle preservation and body composition benefit with glycine supplementation alone is limited; most data come from animal models or combination supplement trials.

4.7 Physical Performance and Ergogenic Use

This area of research critically explores glycine's potential as an ergogenic aid and its relevance to muscle regeneration, muscle strength, endurance exercise performance, and sleep quality, but it concludes that more randomized controlled clinical trials in humans are needed to confirm glycine's potential as a dietary supplement to support muscle function, recovery, and overall athletic performance. There are no rigorous clinical studies on its nutritional or ergogenic safety and efficacy in humans or its systematic use in the sports environment.

Evidence strength: Insufficient. No robust human RCTs specifically addressing ergogenic outcomes have been published.

4.8 Liver (NAFLD/NASH)

Glycine receptors as well as glycine transporters are found in macrophages, and glycine shapes macrophage polarization via cellular signaling pathways including NF-κB, NRF2, and Akt. Glycine has beneficial effects in preventing and/or treating macrophage-associated diseases such as colitis, NAFLD, and ischemia-reperfusion injury. Plasma glycine levels were reported to be 9 to 13% lower in patients with NAFLD, whether obese or not, compared to controls.

Evidence strength: Primarily preclinical (rodent models) and observational in humans. Clinical intervention trials in NAFLD patients are lacking.

4.9 Longevity and Aging in Animal Models

Dietary glycine increases healthy lifespan in model organisms and might decrease inflammation in humans, suggesting its geroprotective potential. Glycine results strengthen the idea that modulation of dietary amino acid levels can increase healthy lifespan in mice, and provide a foundation for further investigation of dietary effects on aging and late-life diseases.

Evidence strength: Animal data only for lifespan extension. Human longevity data do not yet exist, though the GlyNAC trials provide indirect support through the correction of aging hallmarks.

---

5. Body Systems Associated with Glycine

• Nervous system: Inhibitory neurotransmitter (spinal cord, brainstem); NMDA receptor co-agonism; sleep regulation via NMDA receptors in the suprachiasmatic nucleus; studied in schizophrenia, depression, and cognitive function.
• Musculoskeletal system: Structural component of collagen (approximately one-third of collagen amino acid content); required for connective tissue, cartilage, tendons, bone matrix, and skin integrity.
• Metabolic/endocrine system: Associated with insulin sensitivity; lower plasma levels linked to T2DM, obesity, and metabolic syndrome; precursor to creatine (relevant to muscle energy metabolism).
• Immune system: Modulates macrophage polarization; suppresses NF-κB-driven inflammation; reduces proinflammatory cytokines (IL-6, TNF-α, IFN-γ, IL-1β) in clinical studies of diabetic patients.
• Cardiovascular system: Anti-inflammatory effects on coronary endothelium in vitro; blood pressure-lowering in small clinical trials; platelet-stabilizing effects identified in preclinical research.
• Hepatic system: Glycine-gated chloride channels on Kupffer cells; protective effects in NAFLD and ischemia-reperfusion models in animals.
• Antioxidant system: Rate-limiting precursor to glutathione (with cysteine and glutamate); critical for correcting glutathione deficiency observed in aging and metabolic disease.
• Renal system: Synthesized partly in the kidney; glycine conjugation is a route for bile acid and xenobiotic metabolism.

---

6. Dosage Forms and Dosages Reported in Studies

Glycine is administered almost exclusively by the oral route in dietary supplement research. The following dosages are drawn directly from published human studies and clinical trials:

• Sleep quality: 3 g of glycine ingested before bedtime in studies of sleep-restricted healthy volunteers and those with subjective sleep complaints (Yamadera et al., 2007; Bannai et al., 2012).
• Metabolic syndrome / blood pressure / inflammatory cytokines: Oral glycine dose of 5 g × 3/day (15 g/day total) over 3 months in metabolic syndrome patients.
• Insulin response: Acute glycine supplementation at 5 g per day reported to improve insulin response and glucose tolerance.
• Schizophrenia adjunct therapy: 0.8 g/kg per day of glycine added to ongoing antipsychotic medication in a 6-week double-blind, placebo-controlled crossover trial.
• Maximum well-tolerated oral dose in adults: Current conclusions cannot extend beyond a dose of 15 g of glycine per day, which is the highest dose well tolerated in adult humans.
• GlyNAC trials (older adults): The older participants in Sekhar's pilot trial took GlyNAC for 24 weeks, then stopped for 12 weeks. Specific dosing of the glycine component in published GlyNAC trials has been weight-adjusted (approximately 1.33 mmol/kg/day glycine based on published protocols).
• Cystic fibrosis trial: A daily oral supplement of glycine at a dose of 0.5 g/kg divided in three doses during 8 weeks, dissolved in any liquid.
• Schizophrenia prodrome trials: Glycine dosing was fixed at an initial dose of 0.2 g/kg once at bedtime for 3 days, then 0.2 g/kg twice daily for 4 days, then escalating to 0.4 g/kg twice daily; subjects weighing more than 100 kg were limited to a total daily dose of 80 g daily.

Animal studies have used up to 3% glycine supplementation while clinical studies in humans have ranged between 3 g per day and 0.8 g/kg body weight per day with no adverse side effects reported.

---

7. Safety Considerations and Interactions

General Safety Profile (Oral Supplementation)

Glycine has a well-established safety profile at orally administered doses used in clinical research. Once-daily oral administration of glycine at 500, 1,000, or 2,000 mg/kg/day for 4 weeks in rats caused no toxicologically significant change; no animals died, and no glycine-related changes were observed in body weight, food consumption, water consumption, hematology, organ weight, gross pathological examination, or histopathological examination. The no-observed-adverse-effect level (NOAEL) of glycine was determined to be at least 2,000 mg/kg under the conditions of that study.

Nausea and Gastrointestinal Effects

Negative effects were mainly reported in studies giving a higher glycine dose in a single bolus. At high single doses, nausea and gastrointestinal discomfort have been observed. Adverse reactions may result from intravascular absorption of glycine; large intravenous doses of glycine are known to cause salivation, nausea, and lightheadedness. These intravenous safety notes are specifically relevant to the clinical context of glycine irrigation solutions (used in urological surgery), not to oral supplementation.

Intravenous / Irrigation Safety (Distinct from Oral Use)

Glycine 1.5% irrigation solutions (used during transurethral resection procedures) carry specific and serious risks from inadvertent systemic absorption that are entirely distinct from oral supplement use. Adverse reactions may include fluid and electrolyte disorders such as acidosis, electrolyte loss, marked diuresis, urinary retention, edema, and dehydration; cardiovascular/pulmonary disorders such as pulmonary congestion, hypotension, tachycardia, angina-like pain, and thrombophlebitis. Literature includes reports on hyponatremia, hyperammonemia, transient blindness, coma (immediate or delayed), and digitalis toxicity in digitalized patients.

Ammonia Accumulation and Liver Impairment

Care should be exercised if impaired liver function is known or suspected. Under such conditions, ammonia resulting from the metabolism of glycine may accumulate in the blood. This is a pharmacologically relevant concern for patients with hepatic encephalopathy or significant liver disease, particularly at high doses.

Interactions

High-dose glycine (at the g/kg range used in schizophrenia trials) has shown absent or reduced efficacy when co-administered with clozapine. Inconsistent results have been reported, including data indicating that glycine administered with clozapine had no effect on patients with schizophrenia. The mechanistic basis for this interaction is not fully established but may relate to clozapine's own glycinergic or glutamatergic effects.

No well-characterized pharmacokinetic interactions between oral glycine supplementation and common pharmaceutical agents have been established in controlled human studies at the doses used in dietary supplementation (3–15 g/day). Glycine is a natural constituent of the diet and endogenous metabolic pool, which limits the likelihood of conventional drug-drug interactions at typical supplement doses.

Clairifcation on Evidence Limitations

Functional decline of physiological systems during aging leads to age-related diseases. Dietary glycine increases healthy lifespan in model organisms and might decrease inflammation in humans, suggesting its geroprotective potential. A 2024 systematic review summarized the evidence of glycine administration on the characteristics of eleven physiological systems in adult humans. Across most areas, the overall evidence base is characterized by small sample sizes, short durations, and heterogeneous dosing regimens. A total of 50 human clinical studies were included in that review, and most — 42 studies — were randomized controlled trials; of the 50 studies, 18 involved healthy populations while 34 involved diseased populations. The breadth of physiological systems studied is notable, but effect sizes and consistency of findings vary considerably by outcome and population.

---

References

• Razak MA et al. "Multifarious Beneficial Effect of Nonessential Amino Acid, Glycine: A Review." Oxidative Medicine and Cellular Longevity, 2017. PMC5350494.
• Lee JH et al. "The effect of glycine administration on the characteristics of physiological systems in human adults: A systematic review." GeroScience, 2024. PMC10828290.
• Imenshahidi M, Hosseinzadeh H. "Effects of glycine on metabolic syndrome components: a review." Journal of Endocrinological Investigation, 2022. PubMed 35013990.
• Consolidate H et al. "Glycine Metabolism and Its Alterations in Obesity and Metabolic Diseases." Nutrients, 2019. PMC6627940.
• Bannai M et al. "The Effects of Glycine on Subjective Daytime Performance in Partially Sleep-Restricted Healthy Volunteers." Frontiers in Neurology, 2012. PMC3328957.
• Kawai N et al. "The sleep-promoting and hypothermic effects of glycine are mediated by NMDA receptors in the suprachiasmatic nucleus." Neuropsychopharmacology, 2015. PubMed 25533534.
• Javitt DC et al. "Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia." Archives of General Psychiatry, 1999. PubMed 9892253.
• Yuen EY et al. "Directly and Indirectly Targeting the Glycine Modulatory Site to Modulate NMDA Receptor Function to Address Unmet Medical Needs of Patients With Schizophrenia." Frontiers in Psychiatry, 2021.
• Advances in the Treatment of Cognitive Impairment in Schizophrenia: Targeting NMDA Receptor Pathways. PMC11477438.
• Kumar P et al. "Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation…" Clinical and Translational Medicine, 2021. PubMed 33783984.
• Kumar P et al. "Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency…" The Journals of Gerontology: Series A, 2023.
• McCarty MF et al. "The cardiometabolic benefits of glycine: Is glycine an 'antidote' to dietary fructose?" Open Heart, 2014. PMC4195924.
• Pérez-Torres I et al. "Glycine: The Smallest Anti-Inflammatory Micronutrient." International Journal of Molecular Sciences, 2023. PubMed 37510995.
• Hasegawa S et al. "Cysteine, histidine and glycine exhibit anti-inflammatory effects in human coronary arterial endothelial cells." Clinical and Experimental Immunology, 2012. PMC3278693.
• Zhong X et al. "Glycinergic Signaling in Macrophages and Its Application in Macrophage-Associated Diseases." Frontiers in Immunology, 2021. PMC8523992.
• Tsuji M et al. "A 4-week Repeated Dose Toxicity Study of Glycine in Rats by Gavage Administration." Journal of Toxicological Sciences, 2014. PMC3921923.
• Adeva-Andany M et al. "Insulin resistance and glycine metabolism in humans." Amino Acids, 2018. PubMed 29094215.
• Miller RA et al. "Glycine supplementation extends lifespan of male and female mice." Aging Cell, 2019. PubMed 30916479.
• Encyclopaedia Britannica. "Glycine." Britannica.com.
• NIH PubChem. "Glycine | C2H5NO2 | CID 750."
• NIH DailyMed. "Label: GLYCINE solution — 1.5% Glycine Irrigation, USP."
• An Update of the Promise of Glycine Supplementation for Enhancing Physical Performance and Recovery. PMC11510825.
• Alvarado-Vásquez N. "Glycine Increases Insulin Sensitivity and Glutathione Biosynthesis and Protects against Oxidative Stress in a Model of Sucrose-Induced Insulin Resistance." PMC5841105.
• Wikipedia. "Glycine." (chemical synthesis section; industrial production data).