Glycine plays a dual role in the central nervous system as a fast inhibitory neurotransmitter and a co-agonist at N-methyl-D-aspartate receptors (NMDARs). Its extracellular levels are tightly regulated by two glycine transporters (GlyTs): GlyT1, which modulates glycine near excitatory synapses to influence glutamatergic transmission. Among GlyT1 inhibitors, sarcosine continues to demonstrate potential as a viable therapeutic option, especially in schizophrenia and in treating depressive symptoms across both mood disorders and PD.

Figure 1. Structural and Functional Insights into GlyT1 and Sarcosine Modulation^[1]

Clinical studies

Sarcosine is a proven selective GlyT1 inhibitor. The positive effects of sarcosine administration are well described in pre-clinical studies, for example, by effectively reversing ketamine-induced behavioral, oxidative, and neuroinflammatory alterations in a rat model of schizophrenia, potentially by modulating oxidative stress, mitochondrial dysfunction, and neuroinflammation. Similarly, pre-clinical in vivo imaging studies suggests that injections of sarcosine (500 mg or 1000 mg/kg) can reverse hippocampal neuronal dysfunction and impaired spatial encoding, under conditions of NMDA receptor hypofunction induced by MK801, indicating its potential relevance for treating cognitive and disorganization symptoms in schizophrenia, confirming previous studies. Positive effects have been reported also in restoring impaired long-term potentiation (LTP) in mice models.

Clinically, a meta-analysis of seven randomized controlled trials (n = 326) found that sarcosine significantly improved overall clinical symptoms in patients with schizophrenia, particularly in those with stable symptoms or lower baseline severity but showed no statistically significant benefit for cognitive function compared to controls. A subsequent meta-analysis further clarified that while sarcosine did not produce uniform benefits across all patients with schizophrenia, it significantly improved symptoms in individuals with chronic and non-refractory illness, particularly those not treated with clozapine, suggesting its therapeutic efficacy may depend on specific patient subtypes. In line with these findings, a 6-month randomized controlled trial demonstrated that sarcosine significantly ameliorates negative symptoms, general psychopathology, and overall symptom severity when added to stable antipsychotic treatment in patients with chronic schizophrenia. Furthermore, a recent network meta-analysis of 50 randomized controlled trials (n = 2,384) further reinforced sarcosine's clinical potential, identifying it as one of the most effective and promising nutraceutical augmentation strategies in stable schizophrenic patients, with demonstrated benefits for both total and negative symptom domains, and good tolerability.

Mechanism

Mechanistically, sarcosine was found to activate the AMPAR–mTOR signaling pathway. Pretreatment with either the mTOR inhibitor rapamycin or the AMPAR antagonist NBQX blocked both the behavioral effects and molecular activation induced by sarcosine. Additionally, sarcosine increased phosphorylation of the AMPAR subunit GluR1 at the PKA site, suggesting enhanced AMPAR membrane trafficking. Similar antidepressive effects have been reported in clinical data, in which sarcosine led to greater improvements than citalopram in measures such as the Hamilton Depression Rating Scale, Clinical Global Impression, and Global Assessment of Function. Patients receiving sarcosine showed a higher and faster remission rate and had lower dropout rates.

Reference

[1] Pinna, A., & Pa?asz, A. (2026). Modulation of glycine transporters as a novel therapeutic strategy in neuropsychiatry. Psychopharmacology, 495–512. https://doi.org/10.1007/s00213-025-06915-7