IngredientsSarcosine, also known as N-methylglycine, or monomethylglycine, is a non-proteinogenic amino acid with the formula CH3N(H)CH2CO2H. It is the N-methyl derivative of glycine, with a secondary amine in place of the primary amine, and occurs naturally in muscles and other body tissues as an intermediate in the metabolism of choline to glycine. Its CAS registry number is 107-97-1. Sarcosine has the molecular formula C3H7NO2 and a molecular weight of 89.09 g/mol. It appears as deliquescent crystals or powder with a sweetish taste and is highly soluble in water, approximately 1480 mg/mL at 20°C. Chemically, it is 2-(methylamino)acetic acid and exists primarily as a zwitterion at neutral pH.
Sarcosine is an achiral, colourless crystalline solid. Common synonyms used in research literature include: N-methylglycine, monomethylglycine, methylglycine, sarcosin, and the chemical abbreviation Sar. Sarcosine is a nonproteinogenic amino acid that occurs as an intermediate product in the synthesis and degradation of amino acid glycine.
Sarcosine is ubiquitous in biological materials. Sarcosine, also known as N-methylglycine, is ubiquitous in biological materials and is present in such foods as egg yolks, turkey, ham, vegetables, legumes, etc. The concentration of sarcosine in blood serum of normal human subjects is 1.4 ± 0.6 micromolar.
Sarcosine, like the related compounds dimethylglycine (DMG) and trimethylglycine (betaine, TMG), is formed via the metabolism of nutrients such as choline and methionine, which both contain methyl groups used in a wide range of biochemical reactions. Sarcosine is rapidly degraded to glycine, which, in addition to its importance as a constituent of protein, plays a significant role in various physiological processes as a prime metabolic source of components of living cells such as glutathione, creatine, purines and serine.
As a dietary supplement, sarcosine is available as a crystalline powder or in capsule/tablet form, typically in doses ranging from 500 mg to 2 g. Sarcosine and DMG are widely distributed in food and used as dietary supplements. It is used in manufacturing biodegradable surfactants and toothpastes as well as in other applications. In research settings, it is provided as a pure powder for oral administration in aqueous solution. It is also used as a chemical reagent in organic synthesis.
Sarcosine was first isolated and named by the German chemist Justus von Liebig in 1847. Prior to the synthesis of sarcosine, it had long been known to be a hydrolysis product of creatine, a compound found in meat extract. Jacob Volhard first synthesized it in 1862 while working in the lab of Hermann Kolbe. Under this assumption, by preparing the compound with methylamine and monochloroacetic acid, Volhard proved that sarcosine was N-methylglycine.
Sarcosine does not have a documented tradition of deliberate medicinal use in any specific ethnobotanical or historical healing system — it is not a botanical extract or classical herbal remedy but rather a naturally occurring amino acid derivative found in animal and plant foods. Its identity as a distinct, isolatable compound emerged from nineteenth-century organic chemistry and its pharmacological properties were characterized only in the twentieth and twenty-first centuries through modern biochemical and clinical research.
Sarcosine is primarily biosynthesized in mammalian tissues through the methylation of glycine, catalyzed by the enzyme glycine N-methyltransferase (GNMT), a member of the class I S-adenosylmethionine-dependent methyltransferase family. GNMT transfers a methyl group from S-adenosylmethionine (SAM) to glycine, yielding sarcosine and S-adenosylhomocysteine (SAH) as the byproduct. This reaction is a key regulatory step in cellular methylation, helping to maintain SAM homeostasis by diverting excess methyl groups when intracellular SAM levels are high.
A second biosynthetic route proceeds via the choline pathway: choline of endogenous or dietary origin is first converted into betaine aldehyde and betaine (trimethylglycine), a donor of a methyl group to homocysteine to form methionine and dimethylglycine, which is by oxidative demethylation converted to sarcosine (N-methylglycine). Sarcosine is then converted to glycine by sarcosine dehydrogenase.
Biologically, sarcosine functions as a key intermediate in one-carbon metabolism, particularly in the degradation pathway of choline to glycine. It is synthesized from glycine by glycine N-methyltransferase (GNMT) and metabolized back to glycine by sarcosine dehydrogenase (SARDH), an enzyme in the mitochondrial matrix. The major enzymes regulating metabolism of sarcosine are glycine N-methyltransferase (GNMT), sarcosine dehydrogenase (SARDH), and L-pipecolic acid oxidase (PIPOX).
In the mitochondria, serine, glycine, dimethylglycine, and sarcosine undergo catabolism under the action of mitochondrial serine hydroxymethyltransferase (SHMT), aminomethyltransferase, dimethylglycine dehydrogenase, and sarcosine dehydrogenase, respectively. This process depends on tetrahydrofolate (THF) and produces 5,10-methylene-THF. THF plays a crucial role in a number of reactions that generate methyl groups from the catabolism of sarcosine, serine, dimethylglycine.
Glycine and sarcosine are part of a futile cycle in which glycine-N-methyltransferase (GNMT), expressed primarily in the liver, pancreas, and prostate, removes excess S-adenosylmethionine (SAMe) to maintain a constant SAMe/S-adenosylhomocysteine ratio and avoid aberrant methylation.
Pharmacologically, sarcosine functions as a competitive inhibitor of the glycine transporter type 1 (GlyT1), a co-agonist at the glycine binding site of the NMDA receptor, and, at higher concentrations, an agonist at the strychnine-sensitive glycine receptor. By blocking GlyT1, sarcosine elevates the extracellular concentration of glycine in the vicinity of NMDA receptors, thereby augmenting NMDA receptor-mediated neurotransmission.
Sarcosine's main mechanism involves inhibiting a transporter, called GlyT1, which takes up glycine and D-serine into cells. This increases the levels of glycine and D-serine in the body and increases their effects.
N-methylglycine (sarcosine) is an endogenous antagonist of glycine transporter-1, which potentiates glycine's action on N-methyl-D-aspartate (NMDA) glycine site and can have beneficial effects on schizophrenia. Hypofunction of N-methyl-D-aspartate glutamate receptor had been implicated in the pathophysiology of schizophrenia. Treatment with D-serine or glycine, endogenous full agonists of the glycine site of N-methyl-D-aspartate receptor, or D-cycloserine, a partial agonist, improve the symptoms of schizophrenia. N-methylglycine (sarcosine) is an endogenous antagonist of glycine transporter-1, which potentiates glycine's action on the NMDA glycine site and can have beneficial effects on schizophrenia.
Moreover, sarcosine not only inhibits glycine transporter 1 but also regulates the surface trafficking of NMDA receptors, coactivates glycine modulatory sites, and enhances synaptic glycine levels. Additionally, sarcosine may act as an agonist at the glycine modulatory site on NMDA receptors, potentially activating downstream BDNF/AKT/mTOR signaling pathways. This action could stabilize calcium influx and neural excitability.
In experimental tissue studies, glycine, sarcosine and DMG alone did not alter the NMDA receptor-mediated excitatory field potentials, but in combination with glutamate, glycine and its N-methyl derivatives significantly increased the frequency and amplitude of excitatory field potentials. The enhancing effects of glycine analogs in combination with glutamate on excitatory field potentials were remarkably reduced by the glycine binding site antagonist 7-chlorokynurenate.
In practice, the high effective dosage of direct administration of glycine is still a problem because of its poor ability to cross the blood–brain barrier, which results in a high effective dose and aversive effect for patients. In contrast, inhibition of glycine transporter 1 is another potential way to treat schizophrenia.
It has been hypothesized that NMDA receptor hypofunction plays a role in the mechanism for negative symptoms and cognitive dysfunction in patients with schizophrenia. The NMDA hypofunction may be reversed with increased synaptic glycine availability. Sarcosine is a GlyT-1 and System A transport inhibitor, actions which could be expected to increase the availability of glycine in the synaptic space.
The pivotal early clinical study by Tsai and colleagues (published in 2004 in Biological Psychiatry) demonstrated the following: thirty-eight schizophrenic patients were enrolled in a 6-week double-blind, placebo-controlled trial of sarcosine (2 g/d), which was added to their stable antipsychotic regimens. Twenty of them received risperidone. Measures of clinical efficacy and side effects were determined every other week. Patients who received sarcosine treatment revealed significant improvements in their positive, negative, cognitive, and general psychiatric symptoms. Sarcosine treatment can benefit schizophrenic patients treated by antipsychotics including risperidone. The significant improvement with sarcosine further supports the hypothesis of N-methyl-D-aspartate receptor hypofunction in schizophrenia.
A subsequent study of acute-phase schizophrenia examined sarcosine as a standalone (non-adjunctive) agent: twenty acutely symptomatic drug-free patients with schizophrenia were randomly assigned under double-blind conditions to receive a 6-week trial of 2 g or 1 g of sarcosine daily. Overall, patients in the 2-g group were more likely to respond as defined by a 20% or more reduction of the Positive and Negative Syndrome Scale (PANSS) total score, particularly among antipsychotic-naïve patients. Although patients receiving the 2-g daily dose were more likely to respond, it requires further clarification whether the effect is limited to the antipsychotic-naive population. Future placebo- or active-controlled, larger-sized studies are needed to fully assess sarcosine's effects.
A 6-month randomized, double-blind, placebo-controlled study (the PULSAR study) further confirmed benefits for negative symptoms: fifty-eight individuals with schizophrenia with predominantly negative symptoms completed a 6-month randomized, double-blind placebo-controlled prospective study. Patients received 2 g of sarcosine (n = 29) or placebo (n = 30) daily per os. IL-6 levels and severity of symptoms were measured at the beginning, after 6 weeks, and 6 months, using the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia. Only the sarcosine group showed a significant improvement in negative symptoms, general psychopathology subscales and the overall PANSS score.
A 2020 systematic review and meta-analysis published in the Journal of Psychopharmacology (Chang et al.) pooled double-blind randomised controlled trial data and reported: sarcosine use achieved more significant effects than the use of its comparators in relieving overall clinical symptoms (SMD = 0.51, CI = 0.26–0.76, p < 0.01).
A separate systematic review and meta-analysis published in Expert Opinion on Drug Metabolism & Toxicology examined the evidence differently, reporting a more cautious conclusion: six independent randomized controlled trials of sarcosine as add-on treatment to current antipsychotic medication, involving 234 adult participants with schizophrenia and reporting data on symptom severity, were included. Standardized mean differences (SMDs) were used to assess continuous outcomes. In all of the trials, sarcosine was administered orally at 2 g/day. Treatment with sarcosine did not show a significant effect size at any of the pre-established time points (2, 4, 6, or >6 weeks), due to marked quantitative heterogeneity. Despite this, the authors concluded: people with chronic and non-refractory schizophrenia may benefit from the use of sarcosine as an add-on treatment to antipsychotic medication. Due to the good tolerability of this compound, future trials with larger sample sizes appear worthwhile.
An earlier meta-analysis of seven randomized controlled trials (n = 326) reported that sarcosine significantly improved overall clinical symptoms in patients with schizophrenia, particularly in those with stable symptoms or lower baseline symptom severity.
A clinically important finding across several trials is that sarcosine appears ineffective — and may even be counterproductive — when combined with clozapine. Previous studies suggested that sarcosine may not be effective when used as an augmentation agent with clozapine. Combining glutamatergic modulators such as glycine or sarcosine with clozapine was not effective or led to worsening of mental state by increasing positive symptoms.
The evidence base for sarcosine in schizophrenia consists of multiple small-to-medium-sized randomised controlled trials and several meta-analyses. Findings for negative symptoms are the most consistent; results for positive and cognitive symptoms are more mixed. All clinical trials have used 2 g/day orally. Key limitations include small sample sizes, heterogeneous patient populations, short study durations in most trials, and the open question of whether benefits apply equally across all antipsychotic co-treatments. Evidence quality is moderate and the totality of data supports further investigation rather than definitive clinical endorsement.
Antidepressants, aiming at monoaminergic neurotransmission, exhibit delayed onset of action, limited efficacy, and poor compliance. Glutamatergic neurotransmission is involved in depression. However, it is unclear whether enhancement of the N-methyl-D-aspartate (NMDA) subtype glutamate receptor can be a treatment for depression. Sarcosine, as a GlyT1 inhibitor that potentiates NMDA receptor function, has been investigated as a potential antidepressant mechanism distinct from classical monoamine-based approaches.
The landmark clinical study of sarcosine in depression was a 6-week randomised, double-blinded, citalopram-controlled trial (Huang et al., 2013, Biological Psychiatry): we investigated sarcosine's effects in forced swim test, tail suspension test, elevated plus maze test, novelty-suppressed feeding test, and chronic unpredictable stress test in rats and conducted a 6-week randomized, double-blinded, citalopram-controlled trial in 40 patients with major depressive disorder. Clinical efficacy and side effects were assessed biweekly, with the main outcomes of Hamilton Depression Rating Scale, Global Assessment of Function, and remission rate. Sarcosine has shown promising results as an antidepressant in several animal experiments, where long-term administration considerably lessened the effects of induced depression.
A more recent randomised, double-blind clinical trial (NCT04975100) examined sarcosine as an add-on to SSRI therapy: in this randomized, double-blind clinical trial, 60 eligible participants with major depressive disorder (MDD) were randomly assigned to either the test group (SSRI + sarcosine) or the control group (SSRI + placebo). Clinical and biochemical parameters including the Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression (CGI), serum BDNF, and serum glycine were assessed at baseline and eight weeks. The mean reduction in MADRS score was significant in both the control (−8.7, 95% CI: −11.0 to −6.4, p < 0.001) and the test group (−13.3, 95% CI: −14.9).
Evidence for sarcosine in major depressive disorder is preliminary. Only a small number of clinical trials have been conducted, and earlier studies were not placebo-controlled (using an active comparator instead). One-third of the patients with major depressive disorder do not respond to conventional antidepressants that act through the mono-aminergic system, underscoring the clinical motivation, but the existing human evidence for sarcosine in depression remains insufficient to draw firm conclusions and constitutes an early-phase signal requiring replication in larger, well-controlled trials.
Based on its enhancing effects on NMDA receptors, sarcosine has been studied for its efficacy in ameliorating negative and cognitive symptoms in patients with schizophrenia, showing promising results. Accumulating animal and clinical studies show that sarcosine (N-methylglycine), a glycine transporter-1 inhibitor, is effective in ameliorating the negative and cognitive symptoms of schizophrenia. The efficacy of sarcosine and other GlyT-1 inhibitors in the treatment of schizophrenia has been under investigation in recent years. It is considered that these compounds may have beneficial effects on the negative, affective, and cognitive symptomatology in schizophrenia. Cognitive outcomes have been measured as secondary endpoints in schizophrenia trials, with some studies showing improvement; however, evidence for cognition enhancement in healthy individuals is not established by clinical data.
Sarcosine has been identified as an oncometabolite in prostate cancer, where elevated levels correlate with disease progression and metastatic potential. The field was substantially advanced by a 2009 metabolomics study published in Nature: using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, researchers profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer and metastatic disease.
In the initial metabolomics study, approximately 1,126 metabolites were profiled across 262 prostate-derived clinical samples and levels of sarcosine, an N-methyl derivative of the amino acid glycine, were found to increase progressively in benign, localized prostate cancer, and metastatic disease. Metabolomic profiling of prostate cancer progression identified markedly elevated levels of sarcosine (N-methyl glycine) in metastatic prostate cancer and modest but significant elevation of the metabolite in prostate cancer urine.
At the enzymatic level, the expression of sarcosine biosynthetic enzyme, glycine N-methyltransferase (GNMT), was elevated in prostate cancer tissues, while sarcosine dehydrogenase (SARDH) and pipecolic acid oxidase (PIPOX), which metabolize sarcosine, were reduced in prostate tumors. Consistent with this, GNMT promoted the oncogenic potential of prostate cells by facilitating sarcosine production, while SARDH and PIPOX reduced the oncogenic potential of prostate cells by metabolizing sarcosine. Sarcosine levels were significantly elevated in prostate cancer urine sediments compared to controls, with a modest area under the receiver operating characteristic curve of 0.71.
Subsequent research has challenged the utility of urinary sarcosine as a reliable diagnostic biomarker. Sarcosine and uracil in urine samples of patients with prostate cancer were not found to be significant biomarkers for the diagnosis of prostate cancer. None of the three metabolites studied could be used reliably for monitoring the progress of the disease. Similarly, another study found that the difference in concentration of sarcosine in analyzed urine samples after creatinine normalization between the prostate cancer group and the control group was not statistically significant, suggesting that sarcosine has to be rejected as a urinary biomarker of prostate cancer.
The overall state of the evidence is therefore mixed. Sarcosine was initially reported as the most promising biomarker of cancer cell invasion and aggressivity, although its significance has been doubted by newer data. Importantly, sarcosine may be a biomarker for prostate cancer, which means that if sarcosine levels in the blood are higher than normal, it could be an indicator of prostate cancer. This does not mean that sarcosine itself causes cancer. More research is needed to confirm this relationship.
Increased sarcosine concentrations in plasma are associated with multiple diseases, primarily prostate, colorectal, and stomach cancer. This association is understood through sarcosine's deep integration into one-carbon metabolism. Two major enzymes, glycine N-methyl-transferase (GNMT) and sarcosine dehydrogenase (SARDH), regulate the biosynthesis and degradation of sarcosine, processes which involve folate metabolism and DNA methylation. Because sarcosine catabolism by SARDH requires folate (THF) as a cofactor, folate status influences sarcosine homeostasis; sarcosinemia may also occur in some people with glutaric acidemia type II or severe folic acid deficiency.
All clinical studies to date have administered sarcosine orally. The following dosages are reported in published trials:
No established pharmaceutical dose has been approved by any regulatory body; all dosing information originates from research settings.
Across completed clinical trials, sarcosine has demonstrated a generally favorable tolerability profile. People with chronic and non-refractory schizophrenia may benefit from the use of sarcosine as an add-on treatment to antipsychotic medication. Due to the good tolerability of this compound, future trials with larger sample sizes appear worthwhile.
Chronic elevation of sarcosine in humans can be studied through the lens of the inherited metabolic disorder sarcosinemia. Sarcosinemia (also called hypersarcosinemia or SARDH deficiency) is a rare metabolic disorder characterized by elevated sarcosine in blood plasma and increased urinary excretion. Biochemically, sarcosine is produced from dimethylglycine by dimethylglycine dehydrogenase and is normally converted to glycine by sarcosine dehydrogenase (SARDH; EC 1.5.99.1). Many cases result from deficiency of sarcosine dehydrogenase due to homozygous or compound heterozygous pathogenic variants in the SARDH gene (located at chromosome 9q34.2); inheritance is autosomal recessive.
Sarcosinemia is a rare inborn error of metabolism characterized by increased concentrations of sarcosine in plasma and urine due to sarcosine dehydrogenase deficiency. The condition is considered benign and not associated with any specific clinical phenotype. It is reportedly most likely benign, unrelated to significant signs or symptoms. A number of children have been detected by newborn screening and have remained symptom-free.
Originally described in 1966 in a child with mental retardation, it was assumed that sarcosinemia was responsible for neurologic symptoms. In the following years, it was subsequently proposed that the finding of sarcosinemia in individuals with neurologic symptoms most likely occurred because of ascertainment bias, i.e., only persons with clinical problems routinely underwent evaluation for alterations in plasma or urine amino acid concentrations. This concept of sarcosinemia being a benign condition is currently the most prevalent belief, but some doubt remains. Some reports have associated sarcosinemia with various symptoms including intellectual disability and other neurologic problems; growth failure; enlarged liver; cardiomyopathy; vision or hearing problems; and skeletal abnormalities. Whether symptoms were attributable to sarcosinemia or were coincidental is controversial.
The most clinically significant interaction documented in the literature involves concurrent use with clozapine. Combining glutamatergic modulators such as glycine or sarcosine with clozapine was not effective or led to worsening of mental state by increasing positive symptoms. All major trials of sarcosine in schizophrenia have excluded patients receiving clozapine on this basis.
A single case report from the PULSAR trial described a rare adverse event: a 34-year-old woman with a diagnosis of schizophrenia with persistent moderate negative and cognitive symptoms, treated with olanzapine and venlafaxine, was administered sarcosine at 2 g per day. During ten weeks of sarcosine administration, the patient's activity and mood improved, but in the following 2 weeks, the patient reported decreased need for sleep, elevated mood, libido and general activity, consistent with a hypomanic episode. The hypomanic state occurred, which had not been previously noted and described in any patient taking sarcosine. This is an isolated report and the generalizability remains uncertain.
Sarcosine is a key intermediate in 1-carbon metabolism, and its elevation in blood and urine could reflect a deficient pool size of activated 1-carbon units. Because sarcosine catabolism by SARDH is folate-dependent, sarcosinemia may also occur in some people with severe folic acid deficiency, suggesting that folate status may influence sarcosine pharmacodynamics. The practical implications of this interaction for supplemental sarcosine users have not been directly studied.
Sarcosine is a metabolite of glycine. It shares properties with both glycine and D-serine, though its effects are weaker. Sarcosine supplementation can be used to alleviate symptoms of depression and schizophrenia, or improve cognition. It is absorbed more reliably by the body than D-serine, which can also treat similar conditions.
The following table summarises, in narrative form, the overall evidence quality for each studied area:
Health conditions that Sarcosine may help support.
Body systems that Sarcosine may help support.
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