Glycine

NMDA co-agonist / glutamate modulation. Glycine is an endogenous co-agonist at the NMDA glutamate receptor (it binds the “glycine modulatory site” and helps NMDA receptor activation). A long-standing hypothesis of schizophrenia implicates NMDA hypofunction in negative symptoms and some cognitive deficits. Increasing glycine availability (by giving glycine or by inhibiting glycine reuptake) can enhance NMDA receptor function and thereby may improve negative symptoms and some cognitive measures when used in addition to antipsychotics. JAMA Network

Two pharmacologic approaches used in research:

1. Direct glycine supplementation (high-dose oral glycine) to raise glycine levels in the brain enough to act at NMDA receptors. JAMA Network
2. GlyT-1 (glycine transporter 1) inhibitors or glycine-related compounds (e.g., sarcosine/N-methylglycine, bitopertin, BI 425809) which increase synaptic glycine indirectly by blocking reuptake — a more “drug-like” approach tested in modern trials. The Lancet

Common trial doses (direct glycine):

• ~0.8 g/kg/day (the widely cited crossover trials used ~0.8 g/kg/day — roughly 60 g/day for a 75 kg person). This was given orally as divided doses and used as an adjunct to existing antipsychotic medication in double-blind trials (durations typically 6 weeks). Example: a 6-week, double-blind, placebo-controlled crossover study of 0.8 g/kg/day showed improvements in negative symptoms. JAMA Network
• 30 g/day and 60 g/day were also used in earlier/additional studies; some trials began at 15 g/day and titrated upward (schemes differ between studies). (See trial protocols below.) Schizophrenia.com

Titration approaches reported in non-trial guidance / trial summaries:

• Some protocols started at ~15 g/day and increased by 15 g every 2–3 days up to a target (reports vary; some patients were taken up to 60 g/day) — this reflects older clinical trial regimens rather than a universally accepted clinical guideline. Do not attempt without medical supervision. Schizophrenia.com

Administration context:

• Glycine was used as an add-on (adjunct) to existing antipsychotic regimens, not as a replacement for antipsychotics. Most positive effects in trials were for negative symptoms (social withdrawal, flat affect) rather than positive symptoms (hallucinations/delusions). BMJ Mental Health

GlyT-1 inhibitors / sarcosine (N-methylglycine):

• These are prescription or investigational agents with their own dosing regimens (e.g., sarcosine trials have used ~2 g/day oral). Newer GlyT-1 inhibitors (bitopertin, BI 425809, PF-03463275 etc.) have been evaluated in randomized trials with specific doses — results have been mixed and some large trials failed to meet primary endpoints for negative symptom improvement. See clinical trial citations below. JAMA Network

Summary on “how to use” from the literature: trials used high-dose glycine (tens of grams daily), given orally as an adjunct to antipsychotic therapy for several weeks. There is no regulatory-approved standard dosing regimen for over-the-counter glycine to treat schizophrenia — the dosages used in trials should only be attempted in a supervised clinical/research context. JAMA Network

Randomized controlled trials / crossover trials (direct glycine supplementation):

• Heres et al. / JAMA Psychiatry (1994) — “Efficacy of High-Dose Glycine…” — double-blind, placebo-controlled, crossover trial using 0.8 g/kg/day glycine added to antipsychotics in treatment-resistant patients; reported improvements in negative symptoms. JAMA Network
• Double-blind, placebo-controlled crossover trial (British Journal of Psychiatry / Cambridge source) — 6-week crossover with 0.8 g/kg/day showing benefit for negative symptoms. Cambridge University Press & Assessment
• Adjunctive high-dose glycine trial (International Journal of Neuropsychopharmacology / earlier trials) — observations of improved negative and cognitive symptoms in several small trials. Oxford Academic

Trials and studies of glycine-related compounds (GlyT-1 inhibitors / sarcosine / bitopertin):

• Sarcosine (N-methylglycine) trials and meta-analyses — several RCTs of sarcosine as an adjunct showed benefit in some trials; meta-analyses show mixed but promising results for negative symptoms and some total psychopathology measures. Biological Psychiatry Journal
• Bitopertin (RG1678) phase 2/3 trials — large RCTs (e.g., JAMA Psychiatry report) tested bitopertin as add-on for predominant negative symptoms; phase 2 showed some promise but later phase 3 trials failed to show consistent benefit — illustrating mixed outcomes for glycine-transporter targeting approaches. JAMA Network
• BI 425809 (GlyT-1 inhibitor) — randomized clinical development program; some trials examined cognition; results have been variable. The Lancet

Systematic reviews & meta-analyses:

• Tuominen HJ, Tiihonen J, Wahlbeck K. (2005) — Systematic review & meta-analysis (Schizophrenia Research): evaluated glutamatergic drugs and found that glycine and D-serine produced modest decreases in negative symptoms, while overall effects on positive symptoms were inconsistent. BMJ Mental Health
• More recent meta-analyses on sarcosine/GlyT1 inhibitors — show mixed results: some improvement on negative symptoms/cognition in short trials; larger, later trials of some GlyT1 inhibitors were negative. See the Lancet Psychiatry and other systematic analyses for details. The Lancet