5+ Intriguing Health Benefits of Sarcosine + Side Effects

Supplementation of Antipsychotic Treatment with the Amino Acid Sarcosine Influences Proton Magnetic Resonance Spectroscopy Parameters in Left Frontal White Matter in Patients with Schizophrenia

5+ Intriguing Health Benefits of Sarcosine + Side Effects

Open AccessArticle

byDominik Strzelecki 1,*, Michał Podgórski 2, Olga Kałużyńska 1, Oliwia Gawlik-Kotelnicka 1, Ludomir Stefańczyk 2, Magdalena Kotlicka-Antczak 1, Agnieszka Gmitrowicz 3 and Piotr Grzelak 2


Department of Affective and Psychotic Disorders, Medical University of Łódź, Central Clinical Hospital, ul. Pomorska 251, Łódź 92-213, Poland


Department of Radiology—Diagnostic Imaging, Medical University of Łódź, Łódź 92-213, Poland


Department of Adolescent Psychiatry, Medical University of Łódź, Łódź 92-213, Poland


Author to whom correspondence should be addressed.

Nutrients 2015, 7(10), 8767-8782; https://doi.org/10.3390/nu7105427

Received: 12 May 2015 / Revised: 3 September 2015 / Accepted: 29 September 2015 / Published: 22 October 2015

(This article belongs to the Special Issue Nutrition in Cognitive Function)View Full-TextDownload PDF Dysfunction of the glutamatergic system, the main stimulating system in the brain, has a major role in pathogenesis of schizophrenia. The frontal white matter (WM) is partially composed of axons from glutamatergic pyramidal neurons and glia with glutamatergic receptors. The natural amino acid sarcosine, a component of a normal diet, inhibits the glycine type 1 transporter, increasing the glycine level. Thus, it modulates glutamatergic transmission through the glutamatergic ionotropic NMDA (N-methyl-d-aspartate) receptor, which requires glycine as a co-agonist. To evaluate the concentrations of brain metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine, and γ-aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left frontal WM, Proton Nuclear Magnetic Resonance (1H-NMR) spectroscopy was used. Twenty-five patients randomly chosen from a group of fifty with stable schizophrenia (DSM-IV-TR) and dominant negative symptoms, who were receiving antipsychotic therapy, were administered 2 g of sarcosine daily for six months. The remaining 25 patients received placebo. Assignment was double blinded. 1H-NMR spectroscopy (1.5 T) was performed twice: before and after the intervention. NAA, Glx and mI were evaluated as Cr and Cho ratios. All patients were also assessed twice with the Positive and Negative Syndrome Scale (PANSS). Results were compared between groups and in two time points in each group. The sarcosine group demonstrated a significant decrease in WM Glx/Cr and Glx/Cho ratios compared to controls after six months of therapy. In the experimental group, the final NAA/Cr ratio significantly increased and Glx/Cr ratio significantly decreased compared to baseline values. Improvement in the PANSS scores was significant only in the sarcosine group. In patients with schizophrenia, sarcosine augmentation can reverse the negative effect of glutamatergic system overstimulation, with a simultaneous beneficial increase of NAA/Cr ratio in the WM of the left frontal lobe. Our results further support the glutamatergic hypothesis of schizophrenia.View Full-Text

Keywords: sarcosine; glutamate; white matter; frontal lobe; 1H-NMR spectroscopy; schizophrenia sarcosine; glutamate; white matter; frontal lobe; 1H-NMR spectroscopy; schizophrenia

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MDPI and ACS Style

Strzelecki, D.; Podgórski, M.; Kałużyńska, O.; Gawlik-Kotelnicka, O.; Stefańczyk, L.; Kotlicka-Antczak, M.; Gmitrowicz, A.; Grzelak, P. Supplementation of Antipsychotic Treatment with the Amino Acid Sarcosine Influences Proton Magnetic Resonance Spectroscopy Parameters in Left Frontal White Matter in Patients with Schizophrenia. Nutrients 2015, 7, 8767-8782.

AMA Style

Strzelecki D, Podgórski M, Kałużyńska O, Gawlik-Kotelnicka O, Stefańczyk L, Kotlicka-Antczak M, Gmitrowicz A, Grzelak P. Supplementation of Antipsychotic Treatment with the Amino Acid Sarcosine Influences Proton Magnetic Resonance Spectroscopy Parameters in Left Frontal White Matter in Patients with Schizophrenia. Nutrients. 2015; 7(10):8767-8782.

Chicago/Turabian Style

Strzelecki, Dominik; Podgórski, Michał; Kałużyńska, Olga; Gawlik-Kotelnicka, Oliwia; Stefańczyk, Ludomir; Kotlicka-Antczak, Magdalena; Gmitrowicz, Agnieszka; Grzelak, Piotr. 2015.

“Supplementation of Antipsychotic Treatment with the Amino Acid Sarcosine Influences Proton Magnetic Resonance Spectroscopy Parameters in Left Frontal White Matter in Patients with Schizophrenia.

” Nutrients 7, no. 10: 8767-8782.

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Source: https://www.mdpi.com/2072-6643/7/10/5427

5+ Intriguing Health Benefits of Sarcosine + Side Effects

5+ Intriguing Health Benefits of Sarcosine + Side Effects

Sarcosine is an amino acid currently researched as a biomarker for prostate cancer. But did you know that it is also being researched for its potential to reduce the symptoms of mental health disorders such as schizophrenia and depression? Keep reading to learn more about the health benefits and side effects of sarcosine.

What Is Sarcosine?

Sarcosine (also known as N-methylglycine) is required to produce the amino acidglycine and is also a byproduct of glycine breakdown. In the body, it is produced by turning dietary choline into glycine, or by breaking down methionine to glycine [1].

It is also produced in the laboratory (from chloroacetic acid and methylamine) [2].

Sarcosine has a distinct mild, sweet flavor. An ingredient of toothpaste for decades, one derivative of sarcosine appears to help prevent cavities and cause foaming [3].

Sarcosine has other surprising health benefits. Studies over the past 2 decades uncovered its role in treating mental health disorders, including schizophrenia and depression [4, 5, 6].

Mechanism of Action

Some researchers believe that sarcosine’s apparent effects in different mental health disorders stem from its effect on 2 important receptors in the brain. In cell studies, sarcosine:

  • Activated the NMDAR (N-methyl-D-aspartate receptor): Sarcosine increased the activity of NMDAR in the same way as glycine. Both glycine and glutamate are required for increasing the activity of NMDAR, which is thought to bring about the therapeutic effects of sarcosine in schizophrenia and other mental health disorders [7, 8].
  • Blocked the GlyT1 (type 1 glycine) transporter: GlyT1 maintains glycine levels in the brain. Sarcosine blocks this transporter leading to glycine builds up in the brain (which then may increase the activity of NMDAR). This could improve the symptoms of mental health disorders, including schizophrenia [9, 10].

Potential Benefits of Sarcosine

Sarcosine supplements have not been approved by the FDA for medical use and generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective. Speak with your doctor before supplementing.

Insufficient Evidence For

The following purported benefits are only supported by limited, low-quality clinical studies. There is insufficient evidence to support the use of sarcosine for any of the below-listed uses. Remember to speak with a doctor before taking sarcosine supplements, and never use it in place of something a doctor recommends or prescribes.

1) Schizophrenia

Schizophrenia is one of the most serious mental health disorders in the world, and still one of the most difficult to understand.

The symptoms include delusions and hallucinations (positive symptoms), flattened mood, loss of speech, and disorganized speech (negative symptoms), and difficulties with attention, memory, and decision making (cognitive symptoms) [11, 12].

About 1.5 people per 10,000 are diagnosed with schizophrenia each year. Depression, anxiety, and substance abuse often appear at the same time [13].

Multiple studies (in 20, 38, 50, 60, and 65 patients) administered sarcosine with the usual antipsychotic treatment in patients with acute or stable schizophrenia. In all studies, sarcosine greatly improved positive, negative, and cognitive symptoms of schizophrenia more than the antipsychotic drug alone [14, 15, 16, 17, 18].

In a study of 22 patients with schizophrenia, sarcosine improved symptoms and was safe [19].

In a study of 49 patients, sarcosine improved overall cognitive functioning when taken with benzoate, even if their symptoms did not improve [20].

Multiple case studies, wherein sarcosine was added to patients’ conventional therapy, have also produced promising results [21, 22].

However, in another clinical trial of 20 patients, sarcosine added to clozapine failed to improve symptoms over clozapine alone [23].

2) Depression

Although depression and schizophrenia sometimes occur together, they are distinct illnesses. Both involve malfunctioning of neurotransmitters in the brain (NMDAR [N-methyl-D-aspartate receptor]) and GlyT1 [type 1 glycine] transporter). Un schizophrenia, depression is caused by the overactivity of NMDAR [6, 24].

Since sarcosine activates NMDAR, it would follow that those with depression should avoid it. Instead, one clinical study suggests a potential benefit in depression [25].

In a study of 40 patients with depression, citalopram alone or with sarcosine was given for 6 weeks. Sarcosine improved mood, compared to citalopram alone [26].

Additionally, sarcosine improved mood faster and patients were more ly to stick to their treatment [26].

Sarcosine even improved low mood in depressed rats [26].

3) OCD

Obsessive-compulsive disorder (OCD) is another mental health disorder that causes a great deal of distress, often interfering with a person’s daily life. It is characterized by repetitive unwelcome thoughts, images, and urges until the person feels compelled to act on them to reduce feelings of anxiety and uneasiness [27].

In a trial of 26 OCD patients, sarcosine was administered alone or as an add-on treatment for 10-weeks. Sarcosine rapidly reduced OCD symptoms, particularly in patients who had not received any therapeutic drug treatment before the study [28].

4) ODD

Oppositional-defiant disorder (ODD) is a disorder where children or adolescents behave in a defiant and impulsive manner (particularly towards their parents and teachers), and are often angry or irritable. Symptoms of ODD often coexist with ADHD [29].

A 6-week study of 116 children with ADHD found that treatment with sarcosine slightly improved ODD symptoms, but not ADHD symptoms [30].

5) Anxiety

In a study of 40 depressed patients, sarcosine reduced symptoms of anxiety more effectively than an antidepressant (citalopram) [26].

In rats suffering from anxiety (mothers being separated from pups), a sarcosine derivative (ALX 5407) decreased anxious behavior. The reduction was comparable to anti-anxiety medications diazepam and escitalopram [31].

Some researchers have suggested that sarcosine could reduce anxiety through a novel pathway – that is, with a different mechanism than any antidepressant currently on the market [31].

Animal Research (Lacking Evidence)

No clinical evidence supports the use of sarcosine for any of the conditions listed in this section. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.

6) Seizures

Seizures are caused by various factors, with treatments often specific to the cause [32].

In mice with induced seizures treated with sarcosine:

  • Sarcosine was administered each time a seizure was caused. At high doses, it increased the threshold, making it more difficult for seizures to occur [33].
  • Sarcosine was effective in reducing the incidence of seizures and death by up to 72% [34].

In another study in mice, sarcosine reduced stress-induced seizures [35].

7) Neuropathic Pain

Nerve (neuropathic) pain is difficult to address. Un pain from physical trauma (nociceptive pain), nerve pain often results from underlying damage to the nervous system. Long-standing diabetes, stroke, and herpes zoster are some of the common causes [36, 37, 38, 39].

In rats with neuropathic pain in one paw, oral sarcosine reduced pain in both the injured and uninjured paw with higher doses showing greater pain reduction. This effect was lost shortly after it was stopped. It also reduced pain when injected into the spinal cord and brain of the rats [40].

8) Harm From Toluene

Toluene is a widely-used industrial solvent that is also abused as a recreational inhalant for its intoxicating effects in the brain. Exposure can affect behavior, movement, and brain function [41].

Mice exposed to toluene were pretreated with sarcosine, which reversed dangerously low body temperatures, memory loss, and lack of coordination in body movements. However, it did not change the intoxicating effects of toluene. These findings show that sarcosine may have a significant role in treating toluene exposure [41].

9) Stroke

Cerebral ischemia occurs when there is insufficient blood flow to the brain, which then results in the death of brain tissue or stroke.

In rats, pretreatment with sarcosine increased tolerance to blood shortage and reduced cell death in a brain region (hippocampus). Hence, sarcosine protected the brain from stroke [42].

Limitations and Caveats

While there are several clinical trials in humans, they are limited in sample size. Due to ethical concerns, the ability to administer sarcosine without antipsychotic drugs is limited.

The other studies were done in animals.

Hence, larger human studies are needed to confirm the beneficial effects of sarcosine.

Side Effects & Precautions

Sarcosine is generally well-tolerated, but it did produce the following side effects in clinical studies [14, 15, 16, 17, 30, 21, 22, 28]:

  • Decreased need for sleep
  • Hypomanic symptoms (elevated mood, libido, and hyperactivity)
  • Irritability
  • Unpleasant inner tension
  • Headaches

A study of 59 subjects with schizophrenia over a 6-month period did not find any side effects of sarcosine on metabolism (measured by blood pressure, level of fats in the blood, weight, BMI, percentage of body fat) [43].

Drug Interactions

Administering sarcosine as an add-on treatment in patients with schizophrenia taking clozapine did not show any improvement in symptoms. This may be because clozapine may have increased the activity of NMDAR (N-methyl-D-aspartate receptor) to the maximum possible level, so the addition of sarcosine does not have any further beneficial effects [23].

No other drug interactions for sarcosine have been reported thus far, but future studies may identify more. The best way to avoid adverse effects and unexpected interactions is to talk to your doctor before using sarcosine.

Prostate Cancer

Sarcosine is a promising biomarker for prostate cancer. Its presence may indicate and help detect prostate cancer in the early stages, with some advantages over the currently used biomarker (prostate-specific antigen or PSA) [44, 45].

However, by the same token, sarcosine supplements may increase prostate cancer risk. Sarcosine might also make harmless prostate cancer cells become more dangerous and invasive, according to animal studies. What’s more, men with prostate cancer have much higher sarcosine levels in their prostate tissue, other healthy tissues, and urine [46].

Given the possible increase in prostate cancer risk, men may want to avoid sarcosine supplements and stick to its healthy food sources unless directed otherwise by a doctor. More information about the safety of sarcosine is needed.

Natural Sources / Forms of Supplementation

Sarcosine is readily present in a variety of food products, including egg yolks, legumes, nuts, certain vegetables, turkey, ham, andother meats [1].

As a supplement, sarcosine is available in bulk powders, capsules, and sometimes liquid form.


There is no safe and effective dose of sarcosine because no sufficiently powered study has been conducted to find one. That being said, clinical studies have produced benefits at certain doses.

Clinical trials have used doses ranging from 1 g to 4 g, with 2 g being the most common [21, 22].

User Experiences

Users describe sarcosine as helpful for panic attacks, delusional thoughts, and depression, especially in combination with other supplements.

Patients with schizophrenia have reported a variety of experiences ranging from good symptom control, no change, or worsening of positive symptoms, including decreased sleep and racing thoughts.

Some people reported improvement in a matter of days, while others saw improvement in a month’s time. The improvement was usually observed in negative symptoms of schizophrenia.

Source: https://selfhacked.com/blog/sarcosine/

What is Sarcosine: Uses, How it Works and Benefits

5+ Intriguing Health Benefits of Sarcosine + Side Effects

Sarcosine is a metabolite of an amino acid (N-Methylglycine) that is found in biological tissues. It may have Nootropic and testosterone boosting properties.

This supplement is an intermediate and byproduct in glycine synthesis processes and degradation. Sarcosine is metabolized into glycine by the enzyme Sarcosine Dehydrogenase.

This supplement is found almost everywhere you look. Foods such as egg yolks, turkey, ham, vegetables, and legumes all contain Sarcosine. Also, this supplement is sweet tasting and it is actually used in the creation of products toothpaste.

It is formed from the dietary intake of Choline and the metabolism of methionine (another powerful amino acid). It is then rapidly degraded into glycine, which is an important constituent of protein and plays a role in a number of physiological processes as a prime metabolic source of components of living cells.


Mental Function Mental Function Brain Health

  • Promotes brain health & communication
  • Supports memory, reasoning & cognition
  • oosts focus, mental clarity & attention

Varies depending on supplement

Varies depending on supplement

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Sarcosine Effects:

This supplement has several different mechanisms of action stemming from the fact that it aids multiple metabolic processes within the human body.

One of the most interesting of these is its ability to raise testosterone levels naturally when combined with D-Aspartic Acid (DAA). This type of stack has also been added to a number of recent supplement products.

Sarcosine also acts as a type 1 glycine transporter inhibitor and agonist. This also means that supplementation will increase glycine concentrations in the brain and lead to NMDA receptor activation.

Many times, this action results in Nootropic effects and noticeable cognitive enhancement. To a degree, Sarcosine appears to work as a type of glycinergic re-uptake inhibitor.

Sarcosine helps to increase natural testosterone production in the body.

This happens through the stimulation of receptors located within the hypothalamus area of the brain along with the pituitary gland and the testes.

This promotes increased production of gonadotropin releasing hormone (GRH), which in turn stimulates the pituitary to release more lutenizing hormone and follicle stimulating hormone.

Together, all of these hormones stimulate the testes, leading to more testosterone. Studies indicate that these effects are even more pronounced when Sarcosine is used in combination with DAA.

There is also mounting evidence to suggest that Sarcosine may be an effective supplement in treating conditions Schizophrenia. One of the reasons for this is how glycine actually effects the NDMA receptors within the brain.

By increasing the amount of glycine available to help work, Sarcosine has been show to lead to some promising benefits helping to increase the function of these receptors.

Sarcosine is also thought to improve cognition and mental processes. This is also ly related to the effects of the glycine actually binding to the Glutamate (and other) receptors within the brain. There is evidence suggesting that this is capable of helping to increase memory, expand learning capacity and even improve the speed of memory recall.

In short, this supplement appears to work similarly to a Nootropic. This effect is also thought to help healthy adults as well as Alzheimer’s patients and those undergoing treatment for degenerative cognitive issues.

Sarcosine Dosage:

Although a recommended dose has not been established, most research on the subject suggests using between 1,500 and 3,000 mg once or twice a day.

Splitting the daily dose into two different administrations also appears to be more effective, helping to ensure a consistent supply.

Most new users should start with smaller doses in the beginning. The general principle is to begin with the lowest effective dose and then only increase after becoming more familiar with how the effects present themselves.

Of course, it is also advisable to consult with a physician before adding this to your supplementation regimen.

The research on whether Sarcosine produces side effects seems mixed at the moment. Most studies suggest that there are no significant side effects to speak of.

However, you should also keep in mind the fact that supplements do have different effects on different people; it will not work exactly the same for everyone.

This is especially true for supplements Sarcosine that influence areas of the brain.

Having said that, you may experience some general side effects. They should typically be fairly mild headache, fatigue, and possibly nausea, and gastrointestinal discomfort. Once again, the best strategy is to take things slow and carefully observe how this compound affects your body.

Sarcosine Review:

The most promising benefits for Sarcosine in a medical context seem to revolve around treatment for Schizophrenia and possibly other cognitive disorders. There is also the potential for this supplement to produce Nootropic- effects on the brain. However, there many other Nootropics which are more powerful and have a proven history of positive user reviews.

Sarcosine may be effective for increasing memory performance when used in a stack and it is known to improve testosterone production. But if you are looking for a better experience with a memory boosting supplement, consider Noopept instead of Sarcosine supplements.

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Glycinergic signaling in the human nervous system: An overview of therapeutic drug targets and clinical effects

5+ Intriguing Health Benefits of Sarcosine + Side Effects

The physiological role of glycine as a transmitter in the central nervous system (CNS) is complex, and the understanding of its processing reveals a variety of potential therapeutic targets, many of which have been explored.

Classically, glycine is considered an inhibitory neurotransmitter alongside gamma-amino butyric acid (GABA), and glutamate is the primary excitatory neurotransmitter.

1 In the brain stem and spinal cord, glycinergic neurons release glycine to act on strychnine-sensitive glycine receptors (GlyRs, also called the glycine-A binding site), which are ligand-gated ion channels structurally homologous to GABA-A, serotonin type 3 (5HT3), and nicotinic acetylcholine (nAChR) receptors.

1 Glycine also functions as a requisite coagonist on the n-methyl-d-aspartate (NMDA) subtype of ionotropic glutamate receptors and, as such, facilitates excitatory neurotransmission.2 Although this site is often called the glycine modulatory site (GMS) of the NMDA receptor (also delineated as glycineB), the primary endogenous ligand for synaptic NMDA receptors (NMDAR) has been shown to be the racemate d-serine.3

In addition to glycine receptors, 2 glycine transporters (GlyT1 and GlyT2) have been cloned and function to remove glycine from the synapse (Figure).

4 GlyT1 is located on the surface of astrocytes in both excitatory and inhibitory synapses as well as on the presynaptic side of excitatory (glutamatergic) synapses. GlyT1 maintains a subsaturating concentration of glycine in the excitatory synapse.

5 In contrast, GlyT2 is located on the presynaptic surface of inhibitory (glycinergic) synapse.6,7

View larger version (62K)Figure:Summary of receptors, enzymes, and transporters for glycine at glycinergic and glutamtergic synapses. At inhibitory glycinergic synapses, both presynaptic glycine transporter 2 (GlyT2) and GlyT1 on glial cell surfaces help to regulate extracellular concentrations of glycine. Excitatory glutamatergic synapses with N-methyl-D-aspartate receptors (NMDAR) require both glutamate binding and binding to the glycineB site, usually by d-serine. Alanine-serine-cysteine transporter 1 (Asc-1) can remove d-serine from the synapse into presynaptic terminal bouton. Kynurenine aminotransferase (KAT), d-amino acid oxidase (DAAO), and serine racemase (SRR) are present in glial cells and are involved with the metabolism of d-serine and other ligands discussed in the text.

Beyond glycine receptors and transporters, enzymes involved in the metabolism of glycine, d-serine, and kynurenic acid (an endogenous antagonist of the glycineB site) may also represent potential targets for pharmacotherapy as there is evidence that these systems may be altered in schizophrenia.8,9 These include d-amino acid oxidase (DAAO), serine racemase (SRR), alanine-serine-cysteine transporter-1 (Asc-1), and kynurinene aminotransferase (KAT).

This review focuses on the knowledge of current therapeutics' impact on glycine-related sites of action, clinical trials of glycine-specific agents (glycine, d-serine, d-alanine, and sarcosine) as both monotherapy and augmentation strategies, and phase 3 trials of agents in development, which are limited primarily to GLYT1 inhibitors. To limit the scope of this review, studies of the glycineB site partial agonist d-cycloserine (DCS) will not be reviewed in depth. Briefly, because the NMDAR plays a key role in long-term potentiation and therefore learning, DCS has been studied to augment a variety of cognitive behavioral therapies and exposure therapies to help reinforce learning during these sessions. The efficacy of this intervention is largely dependent on the effect of the individual session of psychotherapeutic intervention.10 First, an overview of glycinergic neurotransmission will prepare the reader for discussion of the clinical trial results covered by the literature review.

Biochemistry and Pharmacology of Glycinergic Neurotransmission

Inhibitory signaling via glycine takes place primarily in the spinal cord, brain stem, and caudal brain and requires action at GlyRs on postsynaptic neurons.11 Both motor and afferent sensory pathways (audition and vision) rely on glycinergic signaling.

GlyRs are ligand-gated ion channels, which are primarily permeable to chloride ions. Chloride ion influx leads to hyperpolarization of the post-synaptic cell, which inhibits propagation of an action potential.

The glycine receptor has a limited number of known endogenous agonists, which are potent in the order of glycine > β-alanine > taurine > d- or l-alanine > l-serine >> d-serine.12,13

GlyRs are antagonized by the alkaloid strychnine with high affinity, and therefore GlyRs are generally referred to as strychnine-sensitive to distinguish them from the glycine binding site on the NMDAR, which is sometimes referred to as strychnine-insensitive.14 As mentioned previously, the GlyT2 glycine transporter is localized to these inhibitory synapses, making specific inhibition of these transporters a potential influence on inhibitory glycinergic action.7

GlyR and GlyT2 are potential therapeutic targets for a number of conditions. As strychnine is a convulsant, modulating the activity of glycine receptors is an attractive target for the treatment of epilepsy.

13,15 GlyR mutations are implicated in the neurodevelopmental disorder hyperekplexia, also known as startle disease, in which unexpected auditory or visual stimuli trigger an exaggerated startle response accompanied by a brief period of muscular stiffness.

Other conditions marked by exaggerated startle (eg, anxiety disorders, post-traumatic stress disorder) may therefore be influenced by modulating this system.

16 The inhibitory role of glycine in spinal cord and brain stem neurotransmission has been exploited in efforts to treat chronic neuropathic pain as well.17,18 Abnormalities related to the neurodevelopmental role of glycine have been linked to autism and neurodegenerative disease.16

The role of glycine and related molecules acting at the glycineB site of the NMDAR has been studied extensively and has far-reaching clinical implications commensurate with the wide distribution of these receptors. The NMDAR serves key functions in cognition, learning, and memory.

19 Binding of a coagonist ligand to the glycineB site is required for the ion channel to open. The concentration of glycine in cerebrospinal fluid is high, but there is evidence that the coagonist site of NMDAR is not generally saturated in vivo due to glycine transport the synapse.

5,20 d-serine appears to be the primary coagonist for NMDARs localized to the excitatory synapse and is the predominate coagonist involved in NMDA-elicited neurotoxicity.

21,22 d-serine concentration is regulated primarily by the activity of 3 proteins: SRR, which converts l-serine into d-serine; DAAO, which is responsible for the degradation of d-serine; and Asc-1, which removes d-serine from the synapse (Figure). All 3 proteins are potential targets for therapeutics although only DAAO inhibitors have reached clinical trials.23,24

The NMDA-hypofunction hypothesis of schizophrenia is elegant in that antagonists (eg, phencyclidine, ketamine) at this receptor induce both positive and negative symptoms as well as cognitive deficits in healthy humans that mimic those seen in schizophrenia.

25 Glycine and related molecules function as positive allosteric modulators of NMDA activity and so would be expected to improve the symptoms of schizophrenia. Direct overstimulation of NMDARs is excitotoxic and leads to neuronal cell damage and death.

26 Because of this, agents designed to reduce NMDA activity have been explored to minimize the effects of excitotoxic conditions (eg, stroke or head trauma). A more recent line of research has focused on the observed antidepressant effects of the NMDAR antagonist ketamine and subsequent development of similar molecules (reviewed previously by Wijesinghe27 in this journal).

The dependence of NMDA function on glycine makes this site interesting for depression as well. Finally, because of the role of NMDARs in long-term potentiation and learning, glycineB agonists have been studied as cognitive enhancers.

Online databases MEDLINE, Web of Science, and PsycINFO were searched by lead author (R.S.

) with combinations of terms glycine, receptor, transporter, inhibitor, d-serine, d-alanine, sarcosine, serine racemase, d-amino acid oxidase, kynurenic acid, neurotransmission, and psychiatry and limited to human clinical trials in English with no date limitations.

Trials of the glycineB partial agonist DCS were not included to limit the scope of the review. Searches were conducted initially in December 2015 and repeated throughout the peer review process, ending in May of 2016.

Titles, abstracts, and related articles were examined for relevance to the current topic as were article references when appropriate. Other resources were used to expand background information when necessary and provide some preclinical information when pertinent.

Glycine-B Agonists

As a group, the endogenous glycineB agonists (glycine, d-serine, and d-alanine), when administered exogenously, are less than ideal pharmacologic agents due to poor brain penetrance.

Studies also have shown more positive results in the short term and lack of effect in longer, larger trials.

This may be related to the observation that activation of the glycineB site primes endocytosis of the NMDAR, leading to NMDAR internalization.28


Exogenous glycine has been studied in the treatment of a variety of conditions, including schizophrenia and its prodrome, obsessive-compulsive disorder, and pain syndromes. Taken as a whole, these studies have had somewhat mixed results.

This is ly related to individual differences in study design, small samples, and ranges in dose.29-32 Glycine transport across the blood-brain barrier is low, but CSF levels can be influenced in a dose-dependent manner by moderate-to-high doses.


A 2010 meta-analysis of studies with glycinergic coagonists for the treatment of schizophrenia included an analysis of the dose-response of glycine 10 studies for this indication. It has been given in doses ranging from 15 to 60 g/d, most often dosed as 0.8 g/kg of total body weight.

34 The investigators found glycine treatment to be significantly effective on measures of total psychopathology, positive symptoms, and depressive symptoms, but no dose-response relationship was found.

Regardless of indication, the large doses of glycine required for positive treatment effects may be poorly tolerated due to gastrointestinal side effects and poor taste.34,35

A report36 of 2 short-term trials of glycine monotherapy for patients identified to be at risk for developing schizophrenia (using the Criteria of Psychosis-risk Syndromes) found positive results on the Scale of Psychosis-risk Symptoms (SOPS) and Montgomery-Asberg Depression Rating Scale (MADRS).

These were an open-label trial in 10 patients for 8 weeks, followed by 16 weeks to evaluate for treatment durability and a 12-week placebo-controlled trial in 8 patients (4 per treatment arm). The dose was titrated over the course of 11 days to the target dose of 0.4 mg/kg twice daily, capped at 80 g total daily dose in both studies.

These studies incorporated microencapsulated preparations of glycine to improve palatability. The open-label trial had significant improvement in all outcome measures (SOPS-total, positive, negative, disorganized, general, and MADRS).

In the placebo-controlled trial, the only statistically significant between-group effect was an improvement on MADRS (effect size −2.06, P

Source: https://mhc.cpnp.org/doi/full/10.9740/mhc.2016.11.266

Two grams of sarcosine in schizophrenia – is it too much? A potential role of glutamate-serotonin interaction

5+ Intriguing Health Benefits of Sarcosine + Side Effects

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3921092/