Last Updated: September 28 2022

Sarcosine is a product of glycine. It can be used as a cognitive enhancer and to treat schizophrenia.

Sarcosine is most often used for.

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Sources and Structure





Biological Significance

Sarcosine is synthesized by the glycine N-methyltransferase (GMNT) enzyme which uses a methyl group from S-Adenosyl methionine to donate to glycine, creating sarcosine and S-adenosylhomocysteine.[1][2]

It can be metabolized by either the sarcosine dehydrogenase (SARDH) enzyme or pipecolic acid oxidase (PIPOX),[3][4] the former of which is highly expressed in the liver but not brain and converts sarcosine into glycine.[5]

Sarcosine is synthesized by one enzyme (which appears to modulate sarcosine concentrations in the body) and is degraded by one of two other enzymes

Due to being able to facilitate a conversion from SAMe into S-adenosylhomocysteine, sarcosine is involved in methyl donation and homeostasis[6] and the one-carbon cycle.[7] This pathway, and particularly the enzyme of synthesis (GMNT), appear to be fairly important as the enzyme constitutes more than 1% of all cytosolic proteins in the liver[8] and is upregulated in response to excess methionine.[9]

Sarcosine is involved in the one-carbon cycle alongside other methyl donating molecules, and the enzyme that creates sarcosine appears to be involved with regulating methionine concentrations in the body





Serum sarcosine concentrations independent of supplementation have been noted to be 102.3ng/mL and 80.8ng/mL in men and women respectively.[10]



Mean urine concentrations of sarcosine have been noted to be 138.5ng/mL and 94.8ng/mL (men and women)[10] and urinary sarcosine has been correlated to both age and serum sarcosine in women (but not men) and is independent of BMI.[10] Urinary sarcosine is known to be correlated with urinary creatinine.[11]




Glutaminergic Neurotransmission

NMDA receptors (a subset of glutaminergic receptors) have a glycine binding site which has become a favorable target for enhancing glutaminergic function as it carries a lower risk for excitotoxicity than other pharmaceutical interventions.[12]

Sarcosine appears to be a co-agonist at the NMDA receptor (glycine binding site) similar to both glycine and D-serine although it has a potency of 26+/-3µM (ED50 value).[13] Previous research[14][15] failed to find such an effect, and relative to glycine (EC50 of 61+/-8nM) sarcosine appears much weaker as 300µM of sarcosine is less potent than 3µM of glycine in vitro.[13]

When matched at the EC50 value, sarcosine appears to induce less desensitization than does glycine (did not extend to EC20 nor saturation, desensitization was 48+/-6% with sarcosine and 85+/-3% with glycine) and produces a larger calcium influx than does glycine.[13] This calcium influx from NMDA receptors is vital to signalling through the neuron[16][17]

Sarcosine is an agonist at the glycine binding site of NMDA receptors, and while it may be more potent when matched for the EC50 values it is practically weaker since it requires a much larger EC50 value to induce signalling. If the value is matched, however, then sarcosine is better at enhancing glutaminergic signalling


Glycinergic Neurotransmission

Sarcosine appears to be a glycine transporter 1 inhibitor (GlyT1; present on glial cells and helps regulate glycine concentrations[18]), blocking the reuptake of glycine.[19][20][21] This inhibition occurs somewhere in the range of 40-150µM, and although the increased amount of glycine can enhance glycinergic signalling inhibition does not appear to explain all the signalling from sarcosine.[22]

Sarcosine can act on glycinergic receptors with an EC50 value of 3.2+/-0.7mM (3,200µM), which is significantly less potent than glycine (60μM).[22] 100μM sarcosine failed to elicit any activation.[22]

Appears to prevent glycine reuptake into glial cells and thus increase the exposure of glycine to the synapse, which appears to be the main mechanism. Although sarcosine can directly act on glycine receptors, it is quite weak at doing so relative to glycine


Memory and Learning

Activity at the glycine binding site of the NMDA receptors appears to enhance cognition secondary to enhancing NMDA signalling which can affect both youth and older rats, which is evident with synthetic agonists,[23][24] mice lacking the Gly1T transporter (which sarcosine inhibits) and thus having higher glycine levels in the synapse,[25][26] as well as both glycine and D-serine supplementation. Sarcosine's inhibition of Gly1T is thought to underlie cognitive promoting effects secondary to increasing synaptic levels of glycine and D-serine, since although sarcosine can directly act as a coagonist[13] it is significantly less potent than the other two.

Secondary to increasing synaptic levels of D-serine and glycine, sarcosine is thought to possess cognitive promoting effects in otherwise healthy and young rodents and humans

Social memory performance has been noted to be enhanced with GlyT1 transportation inhibitors (a deriviative of sarcosine in this study) and D-serine.[27] Sarcosine is also able to attenuate the impairments of social memory,[27] motor coordination,[28] and novel object recognition[29] induced by NMDA antagonists.

GlyT1 inhibitors seem to have similar cognitive enhancing properties as D-serine (as they increase synaptic D-serine concentrations), although it is fairly underresearched



NMDA signalling itself is thought to be perturbed in schizophrenic persons[30][31][32][33] (and antagonists such as PCP cause or exacerbate schizophrenic symptoms[34]) and since agonists of the glycine modulatory site such as D-serine are reduced in schizophrenic persons[35] it is thought that the reduced NMDA function may be indirectly through reduced glycine binding site activity.

Glycine transport inhibitors (of which sarcosine is[20][21]) appear to be useful in the treatment of schizophrenia secondary to increasing glycine and D-serine concentrations in the synapse, which encourages glycinergic and NMDA signalling.[36][37] There are two main glycine transporters (GlyT1 and GlyT2) with 50% homology, with GlyT1 being the target of sarcosine and the more prominent one expressed on glial cells[38][39][40] and possibly colocalized with NMDA receptors[40][41] whereas GlyT2 is localized to neurons and less expressed overall[41] and tends to be localized with the glyinergic receptors.[42][38][43] Since GlyT1 is more apparently involved with NMDA signalling, it is thought to be more relevant to the treatment of schizophrenia.

Similar to the theory behind SSRIs (which block reuptake of serotonin), glycine transport inhibitors can block the uptake of glycine and leave more present in the synapse to signal. The subsequently enhanced NMDA signalling from the higher glycine levels appears to be therapeutic for schizophenia

When looking at studies using sarcosine, 2,000mg sarcosine daily for six weeks in addition to antipsychotics noted improvements in symptoms in the range of 14-16% (BPRS and PANSS rating scales)[44] reaching up to around 20% symptom reduction relative to control.[45][46]

One study in persons on clozapine failed to find a benefit with sarcosine therapy at 2,000mg[47] which is similar to null results seen with D-serine.[48] Since clozapine is thought to be antipsychotic via D-serine signalling[49] this signalling pathway may already be saturated in persons on clozapine.

This magnitude of response seen with sarcosine is somewhat comparable to D-Serine at a similar dose,[50] Glycine at a higher dose (800mg/kg),[51][52] and D-cycloserine.[53][54] In direct comparative studies, however, sarcosine has been twice noted to outperform D-serine[45][46] which may be due to the unreliability seen with D-serine supplementation.

It should be noted that some studies by the author Guochuan Tsai have potential conflicts of interest due to the aforementioned being the creator of sarcosine (US patent 6228875[55]) alongside Joseph Coyle. These studies include the following,[44][45][47][46] although publication bias does not seem likely as the authors have published negative results previously.[47]

Sarcosine at 2,000mg appears to be just as effective as D-serine for treating symptoms of schizophrenia when looking at the magnitude of benefit, but sarcosine seems to be more reliable and is thus currently seen as being a better therapeutic alternative



Inhibition of GlyT1 is thought to be a novel treatment for depression, and has been implicated in preliminary evidence as being more potent than the reference drug citalopram.[56] Antidepressant effects have previously been noted with D-serine,[57] thought to be related to enhancing glutaminergic neurotransmission.

Although it is not currently well researched, sarcosine may have anti-depressant properties secondary to enhancing glutaminergic neurotransmission



D-Serine has been well investigated for its usage in treating cocaine dependency, and this appears to extend to both other agonsits at the glycine binding site of NMDA receptors (cycloserine) and to sarcosine as well.[58]

May hold the same anti-addictive properties as D-serine in response to cocaine


Interactions with Cancer Metabolism



Sarcosine appears to be elevated in the urine of persons with prostate cancer and thus potentially useful as a biomarker[59][60] and also appears to be elevated in the tumor itself[61] which is likely related to an increase in the enzyme that synthesizes sarcosine (GMNT) with reductions in degratory enzymes.[60] Its usage as a biomarker of prostate cancer rivals that of prostate specific antigen (PSA)[62][63][64] and is useful in persons with low PSA[65] although it does not show a relation to stage of cancer.[11][66]

Sarcosine is elevated in persons with prostate cancer, and the elevation is thought to be reflective of prostate cancer (as a biomarker). While it may be able to detect the presence of prostate tumors, it does not appear to be reliable in predicting the stage of prostate cancer

The oncogenic protein HER2/neu (overexpression of which is associated with tumor development in various cancers[67][68] including prostate,[69] and may promote disease progression via NF-kB[70]) appears to have its protein content upregulated after exposure to sarcosine of 25-100μM although there were no changes in the phosphorylation thereof.[71] In vitro studies have noted that application of high levels of sarcosine (1,500µM) can increase intracellular concentrations in this concentration (106µM) although lower extracellular levels of sarcosine (10µM) are not large enough (270nM).[72]

In benign prostate cells, increasing sarcosine concentrations seems to induce an invasive phenotype[59] thought to be indepedent of the androgen receptor (not affected elsewhere[71]). In PC-3 prostatic cancer cells, sarcosine (10-1,500µM) showed time-dependent changes in antioxidant status of these cells (reduction at 24 hours yet an increase at 48 hours) with the higher concentrations;[72] the implications of these changes for cancer progression are not clear.

It is unclear what mediates these pro-oncogenic effects as sarcosine does not appear to be inhernetly mutagenic,[73] although sarcosine has been noted to interact with the TMEFF2 protein[74] and it is also involved in the one-carbon cycle (of which an insufficiency of activity, resulting in hypomethylation, is known to be pro-oncogenic and causes cell division[75][76]).

Sarcosine may have pro-oncogenic effects without apparent mutagenic effects (furthers cancer growth when present without inherently causing cancer), yet this information is currently based of cell cultures. There are currently no animal models to support this hypothesis although it seems plausible

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