Glycine, D-Serine, D-Cycloserine and D-Alanine Helpful for Schizophrenia

Many research studies since 1996 have found glycine or similar acting d-cycloserine (an antibiotic), d-serine, sarcosine, and d-alanine to be helpful as add-ons to anti-psychotic medication in the treatment of schizophrenia.  Glycine is especially good at decreasing negative symptoms like apathy and social withdrawal, but also has a lesser effect on positive symptoms.  It has been well tested with traditional anti-psychotics and appears helpful with risperidone (Risperdal) and olanzapine (Zyprexa), but probably not clozapine.  Indeed, it appears that atypical anti-psychotics may get their advantage over traditional anti-psychotics from working at the same NMDA glycine modulatory site as glycine itself.  It appears that adding glycine to other anti-psychotics eliminates the advantage of clozapine avoiding the hassle of biweekly blood tests.  It may also make traditional antipsychotics just as effective as atypicals.

The amino acid glycine (Gly) serves as a neurotransmitter at excitatory and inhibitory synapses in the mammalian central nervous system. Gly concentrations at post-synaptic neurotransmitter receptors are regulated by Na+/Cl(-)-dependent Gly transporters, which are expressed in neurons and in glial cells. Recent evidence suggests that these transporters are promising targets for the treatment of psychiatric and neurological disorders, such as schizophrenia and pain. (Gomeza, et al. Curr Opin Drug Discov Devel. 2003 Sep;6(5):675-82). NMDA receptor antagonists, such as phencyclidine (PCP), induce dopaminergic dysregulation that resembles the pattern observed in schizophrenia. In animal studies, glycine blocks the effects of PCP. (DC Javitts, et al. Neuropsychopharmacology. 2003 Oct 15)

D-serine levels are actually reduced in schizophrenics and L-serine levels are increased, suggesting that serine racemase, the enzyme that converts L-serine to D-serine may not be functioning well. (K Hashimoto, Arch Gen Psychiatry. 2003 Jun;60(6):572-6). Clinical and preclinical literature suggests that stimulation of AMPA-type glutamate receptors may be involved in positive symptoms of schizophrenia, whereas hypofunctionality of NMDA-type glutamate receptors may be involved in negative symptoms and cognitive deficits. Several pharmacological approaches are conceivable to prevent stimulation of AMPA receptors (AMPA receptor blockade, metabotropic glutamate receptors (mGlu(2) receptor) stimulation or lamotrigine-like Na(+)/Ca(2+) channel blockade). (HO Kalkman et al. Expert Opin Ther Targets. 2002 Oct;6(5):571-82.). As noted on this website, lamotrigine has been shown to help schizophrenia as an adjunctive medication to atypical anti-psychotics for positive symptoms only.

Unfortunately, I have never heard of a patient treated with glycine outside of research studies, even though it has been repeatedly shown to be helpful.  A new 24-week study did not find any significant harmful effects on adults.  Pregnancy tests should be done on women before treatment, since no one knows whether high dose glycine might have an adverse effect.  Glycine is used in large quantities, i.e., one-half or two ounces a day. It can be mixed in water with aspartame sweetener with or without a flavoring.  I have found L-glycine from www.dextersportscience.com for $8.50 a pound, meaning that a month's supply would cost $17-$34.  If I were schizophrenic and had negative symptoms, I might consider giving it a try.  There does not appear to be any long-term toxicity.  It is simply mixed in fruit juice and taken one or two ounces once a day.  

D-Cycloserine is sold only from chemical companies for $35 per gram or as an anti-biotic.  It is only a partial agonist of glycine sites, so may be less effective.  Glycine seems the better deal and is much better researched.

Folic Acid functions as a single carbon donor in the synthesis of serine from glycine.  There is good evidence that folic acid helps depression and a small amount of evidence that it might help schizophrenia.  Would this have the same effect as glycine?  Folic acid is very cheap and helps prevent or treat both cardiac and nervous system diseases.  It can be used in combination with glycine.

D-Alanine Helps Too: D-alanine is another endogenous agonist of the NMDA-glycine site. In a 6-week DB PC study of 36 patients with schizophrenia, D-alanine (100 mg/kg/day) added to their stable antipsychotic medications caused significant reductions in their Clinical Global Impression Scale and Positive and Negative Syndrome Scale (PANSS) total scores. The Scale for the Assessment of Negative Symptoms and PANSS subscores of positive and cognitive symptoms were improved. D-alanine was well tolerated, and no significant side effect was noted. D-Alanine Added to Antipsychotics for the Treatment of Schizophrenia. Tsai GE, at al. UCLA and Kaoshiung Medical University, Taiwan. Biol Psychiatry. 2005 Sep 8. Ed: While D-alanine is not readily available, glycine is.

Glycine Low in Schizophrenia: Plasma levels of amino acids in 94 patients with schizophrenia were compared with those in 34 age- and sex-matched normal subjects. Glycine levels and glycine-serine ratios were lower and homocysteine levels were higher in patients. Low glycine levels correlated with a greater number of negative symptoms. The glycine-serine ratios of normal subjects and patients being treated with clozapine did not differ significantly. Relation of plasma glycine, serine, and homocysteine levels to schizophrenia symptoms and medication type. Neeman G, et al. Jerusalem, Israel. Am J Psychiatry 2005 Sep;162(9):1738-40.

Glycine Site NMDA Receptor Higher in Superior Temporal Cortex and Putamen: Saturable radioligand binding to the glycine site of the N-methyl-D-aspartate (NMDA) receptor was higher bilaterally in a post-mortem study of the superior temporal cortex in schizophrenic patients but not in the prefrontal cortex.  A significant decrease in NMDA receptor density occurs in rat frontal cortex following chronic antipsychotic drug administration, indicating that prior drug treatment is unlikely to have contributed to the differences in schizophrenia. Increased density of glutamate/N-methyl-D-aspartate receptors in superior temporal cortex in schizophrenia. Nudmamud S, Reynolds GP. Neurosci Lett. 2001 May 18;304(1-2):9-12. Neurosci Lett. 2001 May 18;304(1-2):9-12; Increased density of glutamate/ N-methyl-D-aspartate receptors in putamen from schizophrenic patients. Aparicio-Legarza MI, Davis B, Hutson PH, Reynolds GP. Neurosci Lett. 1998 Jan 30;241(2-3):143-6.

Glycine: Researcher Writes:   In a 1/7/04 email to me, Dr. Daniel Javitt advises: "I have also seen the reports of in utero effects of glycine, and would be cautious in using glycine in women who could potentially become pregnant.  I do not think enough is known about its teratogenic potential.  So far, we have required pregnancy tests in all of our clinical trials.  I do not feel the in utero results are relevant to ongoing treatments in adults.  We are in the last stages of a clinical trial in which we have been treating for up to 24 weeks with glycine.  The results are blinded, so I can't say anything about effectiveness, but I can tell you that we have not seen significant adverse effects.  My sense is that glycine is safe with prudent monitoring, but since it is not a medication there is no formal approval process.  We have administered glycine dissolved in water or fruit juice.  It has a saccharine-like taste.  It is more palatable if flavored and sweetened slightly  My only caution is to make sure that you use pharmaceutical grade glycine, rather than OTC grade, since even trace impurities could be an issue."

Glycine Better Than D-Cycloserine: In a comparison of 17 schizophrenic patients who participated in DB PC trials of glycine and cycloserine, the degree of improvement was significantly larger during glycine. Similar findings are apparent when data are considered from all trials with NMDA agonists performed to date.  Comparative effects of glycine and D-cycloserine on persistent negative symptoms in schizophrenia: a retrospective analysis. Heresco-Levy U, Javitt DC. Jerusalem, Israel. Schizophr Res. 2004 Feb 1;66(2-3):89-96.

Glycine Helped Olanzapine and Risperidone: In a 6-week DB PC crossover study of 17 patients being treated with olanzapine and risperidone treatment, glycine 0.8 g/kg/day was well tolerated and resulted in a (p <.0001) 23% reduction in negative symptoms. Significant improvements were also registered in cognitive and positive symptoms. High posttreatment glycine serum levels significantly predicted (r =.60) clinical response. These atypical antipsychotics may affect NMDA receptor-mediated neurotransmission differently than clozapine. High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Heresco-Levy U, Ermilov M, et al. Hebrew University, Jerusalem, Israel. Biol Psychiatry. 2004 Jan 15;55(2):165-71. 

Glycine: Harvard Researchers Say Glycine is Good: Postmortem and genetic studies have identified several abnormalities associated with schizophrenia that would interfere with the activation of the glycine modulatory site on the NMDA receptor. Placebo-controlled clinical trials with agents that directly or indirectly activate the glycine modulatory site consistently reduce negative symptoms and frequently improve cognition in patients with chronic schizophrenia who are receiving concurrent typical antipsychotics. Harvard. Converging Evidence of NMDA Receptor Hypofunction in the Pathophysiology of Schizophrenia. Coyle JT, Tsai G, Goff D. Ann N Y Acad Sci. 2003 Nov;1003:318-327

Glycine Appears to Help Olanzapine and Clozapine Patients: 12 patients in a DB PC crossover trial were given high dose glycine and experience a 34% decrease in negative symptoms. Most patients were on olanzapine and clozapine. Serum glycine levels increased 8-fold. Benefit persisted after glycine was stopped. Adjunctive high-dose glycine in the treatment of schizophrenia. Javitt DC, Silipo G, et al. Int J Neuropsychopharmacol. 2001 Dec;4(4):385-91. Email:

Glycine: Chronic Administration Without Toxic Effect in Animal Study: Serum glycine levels increased dose dependently during glycine nutrition, whereas serine levels were not changed. In hippocampal dentate gyrus, the percentage of hypertrophied astrocytes transiently increased at 1 month. At 3 and 5 months of glycine treatment, the density of class B, N-type Ca(2+) channels was reduced in parietal cortex and hippocampus. No evidence of neuronal or glial cell excitotoxic damage or degeneration was registered at either of the treatment intervals studied. Chronic high-dose glycine nutrition: effects on rat brain cell morphology. Shoham S, Javitt DC, Heresco-Levy U. Biol Psychiatry. 2001 May 15;49(10):876-85.

Glycine: Kynurenic Acid Elevated in Schizophrenia; Antagonist at Glycine NMDA Site: Kynurenic acid is an endogenous glutamate antagonist with a preferential action at the glycine-site of the N-methyl D-aspartate-receptor. In a study of 28 male schizophrenics and 17 male controls, kynurenic acid was found to be 70% higher in the cerebral spinal fluid of the schizophrenic patients. Levels in patients tended to increase with age. It appears that kynurenic acid plays a pathophysiological role in schizophrenia. Karolinska Institute, Sweden. Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Erhardt S, Blennow K, et al. Neurosci Lett. 2001 Nov 2;313(1-2):96-8

Glycine Helps Negative: Glycine well tolerated long-term. The normal diet has 2 g/d. 8 studies with glycine. DB study with 30g/d 17% decrease negative (Kay). At 0.8g/kg or approximately 60g/d in DB placebo crossover study of 19 patients, there was a 30% decrease negative and 16% improvement in cognitive and depression with a 12% improvement in positive symptoms. In all, 79% had a greater than 20% improvement with glycine vs. 11% with placebo. One developed nausea and vomit with glycine. There was a 50% decrease in EPS on glycine. It was given three times a day and started at 4g/d and raised 4g/d. Uriel Heresco-Levy, Hadassah, Arch Gen Psychiatry 1/99 56:29-36.

Glycine Helps Schizophrenia: DB PC crossover 6 weeks each 0.8g/kg/d (mean 60g) 22 schizophrenics on meds. 30% less negative symptoms and 50% less EPS. 30% lower BPRS. Heresco-Levy, Jerusalem, Arch Gen Psych 97:54:29; At 60g/d, need almost 2 kg/month!

Glycine, Serine, and Threonine Abnormalities in Schizophrenia: In a post-mortem study of 20 areas of schizophrenic brains, glycine and serine concentration closely paralleled each other. Glycine in the orbitofrontal cortex of schizophrenics was found to be increased in schizophrenics, with a tendency to an increase in that of serine. The increase in glycine was also high in the off-drug group of schizophrenics who had not taken antipsychotics more than 40 days before death. Prominent decreases in both glycine and serine were observed in the somesthetic cortex of the on-drug schizophrenics. Serine was found to be decreased in the putamen of the off-drug schizophrenics. A marked decrease in threonine was also observed in the supramarginal cortex and posterior portion of the lateral occipitotemporal cortex of the off-drug group of schizophrenics and in the putamen of all schizophrenics. The highly similar distribution pattern of glycine and serine supports the close coupling of synthesis and metabolism between these chemicals. Tokyo. A postmortem study of glycine and its potential precursors in chronic schizophrenics. Kurumaji A, Watanabe A, Kumashiro S, Semba J, Toru M. Neurochem Int. 1996 Sep;29(3):239-45. 

Glycine: 3 Studies as of 1996 Show Helpful: 3 DB PC studies with glycine 0.8g/kg/d found 15-30% improvement as add-on to anti-psychotics. Heresco, Israel, Psychopharm Bull ’96;32:731

Glycine Helps: There was a very significant decrease (7.3% PANSS, 10.5% general psychopathology) in a DB study of 11 patients for 6 weeks in negative symptoms but no decrease in positive in treatment resistant chronic schizophrenia with 0.8g/kg/d. It also helped depression and cognitive. No side-effects were reported. Heresco-Levy U et al: Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia. Hadassah, Br J Psychiatry ’96;169:610

Glycine No Benefit or Harm with Clozapine: Double-blind, Placebo-Controlled, Crossover Trial of Clozapine Plus Glycine in Refractory Schizophrenia Negative Results. Diaz P, Bhaskara S, et al. University of Toronto. J Clin Psychopharmacol. 2005 Jun;25(3):277-278.

Glycine No Benefit or Harm with Clozapine: A DB PC 8-week 30-patient study of glycine 60 g/day of patients on glycine. No patient was harmed by glycine but there was no benefit. Placebo-controlled trial of glycine added to clozapine in schizophrenia. Evins AE, Fitzgerald SM, et al. Am J Psychiatry. 2000 May;157(5):826-8.

Glycine Patients Did Worse on Clozapine: In a DB PC of 19 patients with all on clozapine and half given glycine 30gm/d, the use of glycine as an adjunct to clozapine was not effective in decreasing positive or negative symptoms. In contrast, the patients treated with clozapine without glycine had a 35% reduction in positive symptoms. Mass General, Harvard. Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia. Potkin SG, Jin Y, Bunney BG, Costa J, Gulasekaram B. Am J Psychiatry. 1999 Jan;156(1):145-7. 

Glycine No Benefit with Clozapine: Double-blind, Placebo-Controlled, Crossover Trial of Clozapine Plus Glycine in Refractory Schizophrenia Negative Results. Diaz P, Bhaskara S, et al. J Clin Psychopharmacol. 2005 Jun;25(3):277-278.

Glycine: Hyperglycinemia May Be a Cause of Schizophrenia: There is evidence that glycine is elevated in both the periphery and brains of schizophrenic patients. To test the hypothesis that the high glycine concentrations observed in schizophrenics play an etiologic role in schizophrenia, an animal model was tested where rats were made hyperglycinic from life in utero to adulthood. The hyperglycinic rats showed abnormalities in sensory gating mechanisms, enlarged cerebral ventricles and diminished hippocampal dimensions. All of these abnormalities closely parallel observations reported in patients with schizophrenic psychoses. Univ. Iowa. A hyperglycinergic rat model for the pathogenesis of schizophrenia: preliminary findings. Waziri R, Baruah S. Schizophr Res. 1999 Jun 22;37(3):205-15.

D-Serine Helped Zyprexa and Risperdal Patients: In a DB PC 6-week study of 39 risperidone- or olanzapine-treated schizophrenia patients, 30 mg/kg/day D-serine added to their antipsychotic medication resulted in (p < .001) improvements in negative, positive, cognitive, and depression symptoms, as measured by the Positive and Negative Syndrome Scale. For approximately one third of the sample, D-serine treatment resulted in significant (>20%) reductions in Brief Psychiatric Rating Scale total scores. D-serine was well tolerated, and no detrimental changes in clinical laboratory parameters were noted. D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Heresco-Levy U, Javitt DC, et al. Hebrew University, Jerusalem, Israel. Biol Psychiatry. 2005 Mar 15;57(6):577-85.

D-Serine Helps: D-serine 30mg/kg/d use tested in an add-on DB PC study of 31 Taiwanese patients for 6 weeks. It was beneficial and the author recommends a study with D-serine alone. No significant side-effects were noted. Tsai, Harvard, Biol Psychiatry 12/98;44:1081

D-Serine No Benefit or Harm with Clozapine: A DB PC of 20 patients on clozapine found no harm or benefit from d-serine 30 mg/kg/day in a 6-week study. This suggests that clozapine may have its own agonistic effects on the NMDA system. D-serine added to clozapine for the treatment of schizophrenia. Tsai GE, Yang P, et al. Am J Psychiatry. 1999 Nov;156(11):1822-5.

Sarcosine Also Helps in DB: 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 N-methyl-D-aspartate glycine site and can have beneficial effects on schizophrenia. In a 6-week DB PC study of 38 schizophrenic patients, sarcosine (2 g/d) added to their stable antipsychotic regimens found significant positive, negative, cognitive, and general symptom improvement. Twenty of them received risperidone. Sarcosine was well-tolerated, and no significant side effect was noted. Harvard. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Tsai G, Lane HY, Yang P, Chong MY, Lange N. Biol Psychiatry. 2004 Mar 1;55(5):452-6

Sarcosine Did Better Than D-Serine: Agents that enhance N-methyl-D-aspartate (NMDA) function through the glycine modulatory site (D-serine, glycine, or D-cycloserine) or through glycine transporter 1 (sarcosine) improve the symptoms of patients with stable chronic schizophrenia. In a 6-week DB PC study of 65 schizophrenic inpatients with acute exacerbation comparing sarcosine (2 g/d), D-serine (2 g/d), or placebo and concomitant optimal risperidone therapy, the sarcosine group revealed more reductions in PANSS total scores than the placebo (P = .04) and D-serine (P<.001) groups. Thus, a glycine transporter 1 inhibitor may be more efficacious than NMDA-glycine site agonists for adjuvant treatment of schizophrenia, at least during the acute phase. Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study. Lane HY, et al. China Medical University, Taichung, Taiwan. Arch Gen Psychiatry 2005 Nov;62(11):1196-204.

D-Cycloserine Slightly Worsened Positive Symptoms and No Benefit for Negative: A DB PC study of schizophrenic patients found that high dose d-cycloserine 100 mg/day slightly worsened positive symptoms without any benefit on the negative ones. D-cycloserine increases positive symptoms in chronic schizophrenic patients when administered in addition to antipsychotics: a double-blind, parallel, placebo-controlled study. van Berckel BN, Evenblij CN, et al. Neuropsychopharmacology. 1999 Aug;21(2):203-10.

D-Cycloserine No Benefit in 6-Month DB: In a 6-month DB PC study of 55 schizophrenia patients with prominent negative symptoms treated with conventional antipsychotics, d-cycloserine treatment did not differ from placebo treatment on any primary outcome measure at 8 or 24 weeks. The researchers speculate that because d-cycloserine is a partial agonist with relatively low affinity for the glycine site, the magnitude of potential therapeutic effect may be smaller than that achieved by the higher-affinity full agonists, glycine and d-serine. A six-month, placebo-controlled trial of D-cycloserine co-administered with conventional antipsychotics in schizophrenia patients. Goff DC, Herz L, et al. MGH-Harvard. Psychopharmacology (Berl). 2005 Apr;179(1):144-50. 

D-Cycloserine No Benefit in Small Study: In a small, brief 4-week DB PC study of 22 schizophrenic males displaying prominent negative symptoms who were stabilized on typical neuroleptics, d-cycloserine 50 mg/day was no different from placebo on any symptom rating. Effects of D-cycloserine on negative symptoms in schizophrenia. Duncan EJ, Szilagyi S, et al. Emory University. Schizophr Res. 2004 Dec 1;71(2-3):239-48. 

D-Cycloserine Helps Negative Symptoms in Risperidone Patients: A Harvard DB PC crossover study of 10 schizophrenics on risperidone treated with four different doses of d-cycloserine and placebo for 2 weeks each found that D-cycloserine 50 mg/day resulted in a 10% decrease in negative symptoms. D-Cycloserine added to risperidone in patients with primary negative symptoms of schizophrenia. Evins AE, Amico E, et al. Schizophr Res. 2002 Jul 1;56(1-2):19-23

D-Cycloserine Helps Negative as Adjunct: Twenty-four patients participated in a double-blind, placebo-controlled, 6-week crossover trial with D-cycloserine, 50 mg/day, added to their fixed dose of antipsychotic medication. Clinical ratings were performed every 2 weeks. D-Cycloserine treatment was well tolerated and resulted in a significant reduction in negative symptoms (mean=15%). The degree of improvement did not differ between patients treated with conventional neuroleptics and those treated with olanzapine or risperidone. Am J Psychiatry 3/02

D-Cycloserine Helps Negative Symptoms: N-methyl-D-aspartate (NMDA) glutamate receptor has been linked to schizophrenia. Phencyclidine and ketamine are glutamate antagonists and mimic schizophrenia. You can’t treat the receptor directly due to neurotoxic effects. Therefore, you treat the glycine modulatory site of M=NMDA receptor enhancing cat-ion channel. Glycine has some difficulty with CNS penetrance. Javitt used glycine 0.4g/kg or 30g/d added to the antipsychotic. It resulted in a 15% decrease in negative symptoms. A DB crossover of glycine 60g/d to 11 patients for 6 weeks resulted in a 36% decrease. D-cycloserine is an antituberculosis drug and a relatively selective partial agonist of glycine site but readily crosses blood-brain and has a half-life of 7-15 hr. A DB study adding D-cycloserine 50 mg/d improved negative symptoms. However, clozapine patients worsened with cycloserine just like with glycine. Van Berckel found D-cycloserine 100 mg/d helped negative symptoms in 7 of 14 unmedicated schizophrenics. Rosse found no benefit 10 mg/d or 30 mg/d added to molindone. 23% decrease in negative symptoms in DB of 47 pt with 50 mg/d for 8 wk. No difference in cognitive tests or any other clinical measure. 61% D-cycloserine patients improved vs. 27% placebo. Don Goff, Harvard, Arch Gen Psych 56:21-7, 1/99

D-Cycloserine Case for Social Phobia: One reader with severe chronic social phobia e-mailed in May, 2005, to report that he had done well of d-cycloserine, but had developed diarrhea on it and was looking for an alternative.