D-serine activates NMDA receptors, which are involved in synapse formation

D-Serine

  • Vitamins & Supplements
  • Updated January 31, 2018

D-serine is an amino acid found in the brain that activates a type of neurotransmitter receptor called NMDA receptors. NMDA receptors are involved in the formation of new synapses, which are important for learning and memory. D-serine has been tested in schizophrenia patients, as that disease is characterized by reduced NMDA receptor signaling. The evidence of benefit was mixed and inconsistent. However, excessive NMDA receptor activation can damage neurons and may contribute to Alzheimer's disease. Thus, D-serine may theoretically worsen cognitive function in such conditions.

Evidence

D-serine has been tested in multiple clinical trials, though most included patients with schizophrenia. Our search identified:

  • 9 double-blind randomized controlled trials (6 in schizophrenia patients, 1 in people at risk for schizophrenia, and 2 in healthy adults)
  • 1 open-label trial in schizophrenia patients
  • 3 observational studies examining levels of D-serine (2 in the spinal fluid, 1 in blood)
  • 2 postmortem studies examining D-serine levels
  • Numerous preclinical studies on possible mechanisms of action

Potential Benefit

The clinical evidence for cognitive benefits of D-serine is mixed and inconsistent. In a double-blind randomized controlled trial of 35 healthy adults, a single dose of D-serine improved attention compared to placebo [1]. A different study in 50 older adults also showed that D-serine treatment significantly decreased errors on a spatial memory test, but this effect was not compared to placebo and may have been a practice effect [2]. D-serine did not have any effect on working memory, cognitive flexibility, visual attention, or mood scores.

All other clinical trials tested the effects of D-serine in people with schizophrenia or those at risk. A few studies showed cognitive benefit with D-serine [3-5], while others reported no benefit over placebo [6-9]. Potential benefit of D-serine for cognitive functions is likely higher for people with suboptimal NMDA receptor activation, such as schizophrenia patients. In older adults with cognitive problems, D-serine may overactivate NMDA receptors, which can damage neurons.

For Dementia Patients

No clinical studies have tested the effects of D-serine in dementia patients. Theoretically, it may be harmful in Alzheimer's disease patients due to excessive activation of NMDA receptors, which can lead to neuronal toxicity [10]. Memantine, one of the drugs used to treat Alzheimer's disease, inhibits prolonged activation of NMDA receptors.

Safety

Based on numerous randomized controlled trials, D-serine is well-tolerated with few side effects [7][9][15][16]. The largest double-blind randomized controlled study of 195 schizophrenia patients reported that D-serine was well-tolerated; mouth sores were more prevalent in the D-serine group, while dizziness and headache were more common in the placebo group [9]. In one small double-blind randomized controlled trial of 35 people at risk for schizophrenia, one participant expressed suicidal thoughts and two participants withdrew because of possible liver problems related to treatment [5]. In this study, the incidence of proteinuria (protein in the urine) was higher in the D-serine group compared to placebo.

Because D-serine activates NMDA receptors, it is likely to interfere with actions of other drugs targeting NMDA receptors, such as memantine, ketamine, dextromethorphan, and nitrous oxide (all are NMDA receptor inhibitors).

NOTE: This is not a comprehensive safety evaluation or complete list of potentially harmful drug interactions. It is important to discuss safety issues with your physician before taking any new supplement or medication.

How to Use

D-serine is available as a dietary supplement in capsule or powder forms. One clinical trial in healthy adults that showed cognitive benefits used a dose of 2.1 g (single dose) [1] and another one used a dose of 30 mg/kg (mixed in orange juice)[2]. The most commonly tested dose has been 30 mg/kg (e.g., 2.7 g for someone weighing 200 lbs), but higher doses (60-120 mg/kg) have been used in schizophrenia patients [3-5].

Learn More

Evaluation of D-serine's potential biological effects from Examine.com

Quality Control of Sources: United States Pharmacopeial Convention (USP) and FDA Information on Dietary Supplements offer information on the quality of specific supplements and can assist in finding a trusted brand

References

  1. Levin R, Dor-Abarbanel AE, Edelman S et al. (2015) Behavioral and cognitive effects of the N-methyl-D-aspartate receptor co-agonist D-serine in healthy humans: initial findings. J Psychiatry Res 61, 188-195.
  2. Avellar M, Scoriels L, Madeira C et al. (2016) The effect of D-serine administration on cognition and mood in older adults. Oncotarget 7, 11881-11888.
  3. Kantrowitz JT, Epstein ML, Beggel O et al. (2016) Neurophysiological mechanisms of cortical plasticity impairments in schizophrenia and modulation by the NMDA receptor agonist D-serine. Brain 139, 3281-3295.
  4. Kantrowitz JT, Malhotra AK, Cornblatt B et al. (2010) High dose D-serine in the treatment of schizophrenia. Schizophr Res 121, 125-130.
  5. Kantrowitz JT, Woods SW, Petkova E et al. (2015) D-serine for the treatment of negative symptoms in individuals at clinical high risk of schizophrenia: a pilot, double-blind, placebo-controlled, randomised parallel group mechanistic proof-of-concept trial. Lancet Psychiatry 2, 403-412.
  6. D'Souza DC, Radhakrishnan R, Perry E et al. (2013) Feasibility, safety, and efficacy of the combination of D-serine and computerized cognitive retraining in schizophrenia: an international collaborative pilot study. Neuropsychopharmacology 38, 492-503.
  7. Lane HY, Lin CH, Huang YJ et al. (2010) A randomized, double-blind, placebo-controlled comparison study of sarcosine (N-methylglycine) and D-serine add-on treatment for schizophrenia. Int J Neuropsychopharmacol 13, 451-460.
  8. Tsai GE, Yang P, Chung LC et al. (1999) D-serine added to clozapine for the treatment of schizophrenia. Am J Psychiatry 156, 1822-1825.
  9. Weiser M, Heresco-Levy U, Davidson M et al. (2012) A multicenter, add-on randomized controlled trial of low-dose d-serine for negative and cognitive symptoms of schizophrenia. J Clin Psychiatry 73, e728-734.
  10. Monahan JB, Corpus VM, Hood WF et al. (1989) Characterization of a [3H]glycine recognition site as a modulatory site of the N-methyl-D-aspartate receptor complex. J Neurochem 53, 370-375.
  11. Madeira C, Lourenco MV, Vargas-Lopes C et al. (2015) d-serine levels in Alzheimer's disease: implications for novel biomarker development. Transl Psychiatry 5, e561.
  12. Biemans EA, Verhoeven-Duif NM, Gerrits J et al. (2016) CSF d-serine concentrations are similar in Alzheimer's disease, other dementias, and elderly controls. Neurobiol Aging 42, 213-216.
  13. Chouinard ML, Gaitan D, Wood PL (1993) Presence of the N-methyl-D-aspartate-associated glycine receptor agonist, D-serine, in human temporal cortex: comparison of normal, Parkinson, and Alzheimer tissues. J Neurochem 61, 1561-1564.
  14. Nagata Y, Borghi M, Fisher GH et al. (1995) Free D-serine concentration in normal and Alzheimer human brain. Brain Res Bull 38, 181-183.
  15. Ermilov M, Gelfin E, Levin R et al. (2013) A pilot double-blind comparison of d-serine and high-dose olanzapine in treatment-resistant patients with schizophrenia. Schizophr Res 150, 604-605.
  16. Gelfin E, Kaufman Y, Korn-Lubetzki I et al. (2012) D-serine adjuvant treatment alleviates behavioural and motor symptoms in Parkinson's disease. Int J Neuropsychopharmacol 15, 543-549.