Glycine is a safe amino acid that may be beneficial in reducing negative symptoms in schizophrenia.

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Description

• Glycine is the smallest amino acid in the body.
• It is a nonessential amino acid consisting of a single carbon molecule attached to an amino and carboxylic group.

Food Sources

• Most protein-containing foods.
• Endogenously, serine and glycine are readily interconverted by the addition or removal of a hydroxymethyl group (1).

Main Functions/Pharmacokinetics

• Glycine is a major constituent of collagen. Glycine conjugation is important for detoxifying drugs. Glycine may also regulate glutamine metabolism within hepatocytes (1). In the central nervous system, glycine functions as an inhibitory neurotransmitter; also, a glycine site within the N-methyl-D-aspartate (NMDA) receptor complex must be activated in order for the receptor complex to function properly.
• A precursor for glutathione, creatine, and purine biosynthesis, glycine is also incorporated into porphyrins (hemoglobin and cytochromes) and may have a role in protecting tissues from ischemia, hypoxia, and reperfusion injury (2).

[Outline]

• DDescription
• FFood Sources
• MMain Functions/Pharmacokinetics

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Clinical Trials

• Schizophrenia
  • No trials have shown a beneficial effect of glycine on positive symptoms (hallucinations, disorganized thought); studies are mixed on negative symptoms (alogia, flat affect, anhedonia, apathy, motor retardation).
  • A double-blind, placebo-controlled, crossover trial was performed in 22 treatment-resistant schizophrenic patients to assess the effect of a glycine solution (0.8 g/kg/day, a mean dose of approximately 60 g/day) or a taste-matched placebo solution as adjunctive treatment to antipsychotic medication (3). In this 6-week trial, glycine treatment resulted in a 30% (± 16%) decline in negative symptoms [measured by the Positive and Negative Symptom Scale (PANSS]; no significant changes in negative symptoms were observed during placebo treatment. Cognitive symptoms improved by 16% and depression improved by 17% during glycine treatment; no improvements were seen with placebo treatment. Changes in positive symptoms were not significantly different between treatment and placebo. Both glycine and serine serum levels increased.
  • Another placebo-controlled 8-week study of 14 male schizophrenic patients found that 0.4 g/kg body weight (about 30 g/day) of glycine dissolved in juice as adjunctive treatment to neuroleptic and anticholinergic medications improved negative symptoms in all seven patients; only two of seven placebo-treated patients improved in negative symptoms (4). Neither group improved on positive symptoms, general psychopathology, or extrapyramidal side effects. After this study, all patients received glycine for an additional 8 weeks, in an open-label phase; those previously treated with glycine showed no further improvement, but those previously treated with placebo showed significant improvement in negative symptoms.
  • A double-blind, placebo-controlled 12-week study of 19 patients with chronic, treatment-resistant schizophrenia tested the effect of glycine (30 g/day) as adjunctive treatment to optimal doses of clozapine (400 to 1,200 mg/day) (4a). Evaluations were done biweekly using the Brief Psychiatric Rating Scale, the Scale for the Assessment of Negative Symptoms, and the Simpson-Angus movement scale. Glycine was ineffective for decreasing positive or negative symptoms. In addition, it appeared to interfere with clozapine; patients treated with clozapine alone experienced a 35% reduction in positive symptoms.
  • Earlier clinical trials using lower doses of glycine (5 to 15 g/day) either found no effect of glycine on schizophrenia or found some effect only on negative symptoms (5). Cycloserine, a partial glycine agonist, is currently undergoing study and appears promising.

Animal/In Vitro

• In animal models, glycine has cytoprotective effects in the stomach, kidney, liver and cardiovascular system against a variety of chemical insults (1). Representative studies follow. A study in rats given the liver carcinogen W Y-14,643 found that glycine (as 5% of the diet) did not inhibit early foci formation but significantly decreased their ability to progress to tumors (6).
• Intravenous glycine improved survival after hemorrhagic shock in rats in a dose-dependent manner. Although 20% of saline-treated rats survived 72 hours after shock, glycine administered in a dose of 45 mg/kg increased survival to 78% (7).
• Two studies have found that dietary glycine prevents cyclosporine A-induced nephrotoxicity in rats. Rats fed a diet containing glycine (5%) for 3 days before cyclosporine treatment were compared with rats maintained on a control diet. Dietary glycine prevented or significantly reduced kidney damage resulting from cyclosporine in all parameters studied (8). Another study found similar results and noted that glycine minimized hypoxia and blocked free radical reduction without altering cyclosporine A blood levels (9).
• Alcohol-induced liver injury
  • In rats exposed to ethanol continuously to cause alcoholic liver injury, administration of glycine after cessation of alcohol resulted in about a 30% more rapid recovery of liver enzyme level levels (serum aspartate aminotransferase and alanine amino-transferase), lower hepatic pathology scores and lower rates of steatosis than rats fed a controlled diet (10).

[Outline]

• CClinical Trials
  • Schizophrenia
• AAnimal/In Vitro
  • Alcohol-induced liver injury

Adverse Reactions

• None identified. There have been several clinical trials using glycine orally or parenterally; no safety concerns have been identified.

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Factors Decreasing Availability/Absorption

• Several hereditary collagen diseases (osteogenesis imperfecta, Ehlers-Danlos syndrome type IV, and epidermolysis bullosa pruriginosa) are due to the substitution of other residues for glycine in collagen; mutations in glycine receptors can also cause hereditary motor disorders (1).
• Glycine synthesis is marginal in early life; it may be conditionally essential in the neonate (1).

Laboratory Tests

• Free amino acid concentration in blood plasma is 179 to 587 µmol/L in venous blood and 226 µmol/L in arterial blood. Urinary output of glycine is 1,380 µmol/24 hours. Its half-life in plasma is 12 hours (11).

[Outline]

• FFactors Decreasing Availability/Absorption
• LLaboratory Tests

Common Dosage Forms

• Clinical trials have used doses of 5 to 30 g/day.

Q: Why haven’t there been more clinical trials of glycine?

A: Probably because it is widely viewed as having no pharmacologic effect. Glycine is often used as a placebo in amino acid studies, especially as a nitrogen source in control solutions. The possible activity of glycine makes it an inappropriate control. Some researchers have recommended that it be replaced by a mixture of nonessential amino acids (1).

1. Hall JC. Glycine. J Parenter Enteral Nutr 1998;22:393–398.
2. Shils ME, Olson JA, Shike M et al, eds. Modern nutrition in health and disease, 9th ed. Baltimore: Williams & Wilkins, 1999.
3. Heresco-Levy U, Javitt DC, Ermilov M et al. Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry 1999;56:29–36.
4. Javitt DC, Zylberman I, Zukin SR et al. Amelioration of negative symptoms in schizophrenia with glycine. Am J Psychiatry 1994;151:1234–1236.
4. (a) Potkin SG, Jin Y, Bunney BG et al. Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia. Am J Psych 1999;156:146–147.
5. Farber NB, Newcomer JW, Olney JW. Glycine agonists: what can they teach us about schizophrenia? Arch Gen Psychiatry 1999;56:13–17.
6. Rose ML, Cattley RC, Dunn C et al. Dietary glycine prevents the development of liver tumors caused by the peroxisome proliferator WY-14,643. Carcinogenesis 1999;20:2075–2081.
7. Zhong Z, Enomoto N, Connor HD et al. Glycine improves survival after hemorrhagic shock in the rat. Shock 1999;12:54–62.
8. Thurman RG, Zhong Z, von Frankenberg M et al. Prevention of cyclosporine-induced nephrotoxicity with dietary glycine. Transplantation 1997;63:1661–1667.
9. Zhong Z, Arteel GE, Connor HD et al. Cyclosporin A increases hypoxia and free radical production in rat kidneys: prevention by dietary glycine. Am J Physiol 1998;275:F595–604.
10. Yin M, Ikejima K, Arteel GE et al. Glycine accelerates recovery from alcohol-induced liver injury. J Pharmacol Exp Ther 1998;286:1014–1019.
11. Linder MC. Nutritional biochemistry and metabolism, with clinical applications, 2nd ed. East Norwalk, CT: Appleton & Lange, 1991.