D-Serine

D-Serine is an amino acid that plays a role in cognitive enhancement and schizophrenia treatment.

This page features 158 unique references to scientific papers.


Research analysis by and verified by the Examine.com Research Team. Last updated on Apr 29, 2017.

Summary of D-Serine

Primary Information, Benefits, Effects, and Important Facts

D-Serine is an amino acid found in the brain. Derived from glycine, d-serine is a neuromodulator, meaning it regulates the activities of neurons.

D-Serine supplementation can reduce symptoms of cognitive decline. It is also able to reduce symptoms of diseases characterized by reduced N-methyl-D-aspartate (NMDA) signaling, which includes cocaine dependence and schizophrenia.

D-Serine’s effect on schizophrenia is well researched, and though it shows promise, it is also unreliable, since d-serine does not always reach the blood after supplementation. Sarcosine may be a more reliable treatment.

D-Serine is a coagonist at NDMA receptors, which means it improves the effects of other compounds that bind with the receptor. These compounds include glutamate and NMDA itself.

D-Serine is often categorized as a nootropic.

How to Take

Recommended dosage, active amounts, other details

The usual dose used in D-serine studies is 30mg/kg of bodyweight. This correlates to an approximate dosage range of 2,045 – 2,727mg for people between 150 – 200 lbs. This dose appears to be the minimal effective dose for improving cognition in people suffering from a variety of diseases.

Preliminary evidence suggests that doubling or quadrupling the dosage to 60mg/kg and 120mg/kg, respectively, will cause additional benefits for people suffering from schizophrenia.

Human Effect Matrix

The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects d-serine has on your body, and how strong these effects are.

Grade Level of Evidence
Robust research conducted with repeated double-blind clinical trials
Multiple studies where at least two are double-blind and placebo controlled
Single double-blind study or multiple cohort studies
Uncontrolled or observational studies only
Level of Evidence
? The amount of high quality evidence. The more evidence, the more we can trust the results.
Outcome Magnitude of effect
? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.
Consistency of research results
? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.
Notes
Cognition Minor High See all 3 studies
There may be an improvement in cognitive performance secondary to reducing symptoms of schizophrenia, and while there is mechanistic plausibility that this can also work in normal controls it has not yet been demonstrated
Symptoms of Schizophrenia Minor Moderate See all 6 studies
D-Serine supplementation is able to reduce symptoms of schizophrenia (more efficacy on negative and cognitive symptoms rather than positive) in a dose-dependent manner between 30-120mg/kg, but possibly due to the unreliable increases in blood D-serine its benefits are also unreliable
Anxiety Minor - See study
When taken 2 hours prior to testing, 2.1g D-serine seems effective in reducing anxiety during testing in otherwise healthy humans
Attention Minor - See study
There was an increase in sustained attention during cognitive testing in otherwise healthy subjects given 2.1g D-serine prior to testing, as assessed by CPT-IP.
Subjective Well-Being Minor - See study
Reported sadness during cognitive testing appears to be reduced with D-serine supplementation when compared to placebo
Symptoms of Parkinson's Disease Minor - See study
Preliminary evidence suggests that the standard dosage of D-Serine can alleviate some symptoms of Parkinson's disease
Symptoms of Post-Traumatic Stress Disorder Minor - See study
One study using 20mg/kg D-serine in subjects with PTSD noted benefits with supplementation when compared to placebo.
Working Memory Minor - See study
Immediate recall appears to be increased from D-serine when 2.1g is supplemented 2 hours prior to testing.
Reaction Time - - See study
When 2.1g D-serine is taken two hours prior to cognitive testing, there does not appear to be an increase in reaction time when compared to placebo
Serum BDNF - - See study
2.1g D-serine in otherwise healthy humans does not acutely influence serum BDNF concentrations
Verbal Fluency - - See study
In a category fluency test, 2.1g D-serine taken two hours earlier appears to improve fluency. The increase was larger than seen with placebo, but comparing the two groups did not yield a significant benefit with D-serine over placebo statistically

Scientific Research

Table of Contents:

  1. 1 Sources and Structure
    1. 1.1 Sources
    2. 1.2 Structure
    3. 1.3 Biological Significance
    4. 1.4 Other Glycinergics
  2. 2 Pharmacology
    1. 2.1 Serum
    2. 2.2 Neural
  3. 3 Neurology
    1. 3.1 Regulation and Distribution
    2. 3.2 Glutaminergic Signalling
    3. 3.3 Glycinergic Signalling
    4. 3.4 Oxidation
    5. 3.5 Memory and Learning
    6. 3.6 Depression
    7. 3.7 Alzheimer's and Dementia
    8. 3.8 Schizophrenia
    9. 3.9 Parkinson's Disease
    10. 3.10 Stress and Trauma
    11. 3.11 Amyotrophic lateral sclerosis
    12. 3.12 Addiction
  4. 4 Safety and Toxicity
    1. 4.1 General


1Sources and Structure

1.1. Sources

D-Serine is known to be a glial cell-derived neuromodulator, being produced in glial cells to support transmission from one neuron to another, being one of the first D-isomer amino acids to be found to have biological relevance in the human body[1] (shortly followed by D-Aspartic Acid). Due to being derived from glial cells, it is sometimes called a gliotransmitter or gliomodulator.[1]

D-Serine is an endogenous ligand at the glycine binding sites of NMDA receptors,[2] and despite being named after glycine it is not sure which ligand is more biologically relevant in vivo; in vitro, D-serine appears to have similar binding potency[3][4][5] yet is more effective at signalling (possible due to more exposure time), being active at 1μM.[6] Furthermore, D-serine seems to have its action localized at synaptic NMDA receptors whereas glycine is an agonist at extrasynaptic[7] although it still seems possible to induce excitotoxicity[8] (which is historically thought to be due to extrasynaptic receptors due to the N2B subunit[9][10][11] and synaptic having more N2A[7]).

D-Serine is a neuromodulator that is secreted from the support cells of the nervous system (glial cells) which then modulates transmission from one neuron to another. It appears to be an endogenous ligand of the glycine binding site of NMDA receptors
While not commonly found in the diet, it is synthesized from dietary Glycine (an amino acid)

1.2. Structure

1.3. Biological Significance

L-Serine (a dietary amino acid) is racemized into D-serine via the enzyme serine racemase, present in neurons[12] and glial cells[13] although relatively speaking the glial cells known as astrocytes express the highest levels of serine racemase.[14][15][16] most notably in the forebrain; serine racemase expression correlates well with D-serine location.[14][15] The rate of D-serine synthesis from serine racemase requires the cofactors of ATP and Magnesium[17][18] and is positively affecte by calcium[19] while it is inhibited by both glycine and L-aspartic acid.[20][21]

Activation of AMPA receptors, possibly through encouraging glutamate-receptor-interacting protein (GRIP) to interact with serine racemase, causes a 5-fold increase in D-serine concentrations when activated.[22] Finally, this enzyme is not specific for this conversion as it also converts L-serine into pyruvate (3:1 ratio relative to D-serine production) and ammonia.[23]

D-Serine is produced mostly in astrocytes (some in neurons) via the serine racemase enzyme, produced from L-serine

D-serine is degraded by the d-amino acid oxidase (DAAO) enzyme which is exclusive to astrocytes.[24][25][26] D-Serine concentrations are inversely related to expression/activity of the DAAO enzyme[4][27][24] and ablating the enzyme causes a rise in D-serine in all tested brain regions.[28] D-serine can be converted back into L-serine via the serine racemase enzyme as well, but this reaction has lower affinity than the opposite.[1]

The primary mechanism that degrades D-serine is its reaccumulation in astrocytes and subsequent degradation by DAAO (major pathway) or conversion back into L-serine (minor pathway)

1.4. Other Glycinergics

When looking at the degree of symptom reduction in schizophrenia, the general 17-30% range seen with 30mg/kg D-Serine[29] is somewhat comparable to glycine when used at the dosage of 800mg/kg[30] when investigated under similar conditions, suggesting that D-serine is more potent on a weight basis.

Supplementation of similar doses of D-serine and sarcosine (2,000mg) daily for six weeks noted that D-serine failed to be significantly better than placebo while sarcosine was, and concluded sarcosine more efficacious.[31] This has been noted elsewhere, with sarcosine at the same dose of D-serine causing significantly more symptom reduction.[32]

While D-serine appears to be more potent than glycine at the same signalling properties and interventions, the limited comparative evidence suggests that D-serine underperforms relative to sarcosine (a glycine transport inhibitor)


2Pharmacology

2.1. Serum

Supplementation of 30-120mg/kg (in schizophrenic patients) has been noted to increase serum D-serine concentrations with a Tmax of 1-2 hours[33] and Cmax values have been reported at 120.6+/-34.6nmol/mL (30mg/kg), 272.3+/-62nmol/mL (60mg/kg), and 530.3+/-266.8nmol/mL (120mg/kg).[33]

D-Serine supplementation peaks in the blood 1-2 hours after oral ingestion and follows linear dose-dependence up to 120mg/kg oral intake (highest tested dose)

Six weeks supplementation of D-Serine (30mg/kg) in persons with Parkinson's disease has been noted to increase serum D-serine from less than 10µM to 120.0+/-52.4µM[34] and in persons with PTSD a similarly large increase (10-fold) has been seen with the same oral dose, reaching serum concentrations of 146+/-126.26µM.[35]

In schizophrenics, the same dose has been noted to increase serum levels from 102.0+/-30.6nmol/mL to 226.8+/-72.8nmol/mL (122% increase)[29] and mean serum levels at rest appear to increase in a dose-depedent fashion between 30-120mg/kg oral D-serine intake over 4 weeks.[33]

Basal levels of D-serine appear to be increased following supplementation of D-serine, with 30mg/kg causing around a 10-fold increase in some studies but a lesser (and still present) spike in schizophrenics. There is quite a fairly bit of unreliability in the degree of increase

Supplemental D-serine does not appear to affect serum glycine, glutamate, or alanine concentrations[29][35] and serum L-serine also appears unaffected.[35]

D-Serine does not appear to significantly influence other amino acids in serum that may be related to serine metabolism

2.2. Neural

D-serine concentrations in the brain appear to be between 66+/-41nmol/g wet weight[36] or 2.18+/-0.12nmol/mg[37] which is somewhere between 10-15% of the total serine pool (being outnumbered by L-serine).[36][37] D-serine is at higher concentrations in the prefrontal and parietal cortex relative to cerebellum and spinal cord.[38] D-serine also possesses a half-life of 16 hours in the brain[39] and increases in brain D-serine concentrations are seen with doses as low as 58mg/kg (mice).[40]

D-serine has been detected in the cerebrospinal fluid (CSF) of control persons (2.72+/-0.32μM)[41][42] and varying amounts have been found in persons with postherpetic neuralgia (1.85+/-0.21μM) and degenerative osteoarthritis (3.97+/-0.44μM)[41] while in schizophrenics D-serine concentrations are lower than control (median value of 1.26μM versus 1.43μM; ranges not significantly different) despite L-serine being higher (22.8+/-8.01μM versus 18.2+/-4.78μM) and the ratio of L-serine to D-serine.[42]

D-Serine is detected in cerebrospinal fluid (CSF) and the brain, where it is in lower concentrations in the CSF than in the blood and has a longer half-life in the brain than in the blood

Chronic supplementation of D-Serine may increase levels of L-serine in the cortex of mice.[40]


3Neurology

3.1. Regulation and Distribution

It is thought that D-serine is stored alongside glutamate in neurons and astrocytes[1] since D-serine is released when stimuli that are known to release glutamate are used[43][44] while D-serine has been detected in neurons expressing a glutamate transporter.[44] This colocalization and release has been noted elsewhere with glutamate and glycine.

D-Serine is possible released along with glutamate in neurons to activate NDMA receptors, as activation of two distinct sites (one of which requires either glycine or serine) is co-required. Neuronal release contibutes some, but not a majority, of D-serine to the synapse

D-Serine is known as a gliotransmitter, a neuromodulatory agent that is release from glial cells.[45][14][46] It is thought that D-serine is release via some form of vesicular exocytosis[47] (as these vesicles have been detected in glia[48][43]). Synaptic vesicles have been found to coexpress glycine, glutamate, and GABA (but not D-serine)[49][50][51] whereas D-serine is thought to have its own vesicular storage;[52][49][47] vesicles may not be the only method of D-serine release, as the Asc-1[51] and TRPA1[53] transporters have been implicated (direct transport and supporting calcium influx, respectively) and inhibiting vesicular storage does not abolish D-serine release.[50]

Astrocyte release of D-serine appears to be vital to NDMA-dependent processes (removing astrocytes from hippocampal cultures suppress long term potentiation, and this is restored with D-serine)[54]

D-Serine is release from astrocytes (glial cells) appears to be the predominant form of D-serine release in the brain (neuronal release being a smaller total amount) and the mechanisms mediating the release are not well known at this point in time. It is known to be vital to glutaminergic signalling, however

It has been noted that nitric oxide (NO) can suppress serine racemase activity[55] and enhance DAAO activity[56] and thus negatively regulates D-serine concentrations (which may be mutual, as D-serine is a Nitric oxide synthase (NOS) enzyme inhibitor[55]). This is potentially a negative feedback loop[1] as activation of NMDA receptors causes NOS activation and elevates NO concentrations.[57]

Activation of nitric oxide metabolism due to glutaminergic signalling may negatively regulate D-serine production and thus limit the signal enhancement from D-serine

Peripheral injections of D-serine (50mg/kg) to mice have been noted to increase hippocampal D-serine concentrations from 96.9nmol/g to 159.4nmol/g (64.5% increase) which correlates with improvements in memory.[58] These changes were without influence on glutamate or L-serine concentrations.[58]

D-Serine in systemic circulation is known to increase hippocampal concentrations of D-Serine, suggesting that it crosses the blood brain barrier

It has been noted that while glycine is likely the main agonist of the glycine binding site of NMDA receptors in spinal cord and in the hindbrain, the forebrain is likely most influenced by D-serine due to higher serine racemase expression (and thus more D-serine synthesis)[4][14][45][22] and higher expression of glycine transporters that take glycine up into astrocytes.[59][60] D-Serine has directly been measured to be higher in the forebrain area[61] in association with where NMDA receptors are expressed.[4][45][62]

D-Serine is likely more biologically relevant in the forebrain region than glycine is

3.2. Glutaminergic Signalling

D-Serine shares many mechanisms similar to Glycine, in the sense that it can bind to the glycine-dependent binding site on NMDA receptors (the subtype of NR1,[63][64] as NR2 binds glutamate[65] and any one NMDA receptor is a tetramer made of usually two of each) which then potentiates signalling through these NMDA receptors initially caused by glutamate or other agonists.[63][6][66] Unlike glycine, D-Serine appears to be more effective and is active at a concentration as low as 1µM (Glycine requiring 10µM)[6] which may not be related to their acting on the receptor itself (the two are quite comparable[3][4][5]) but may be due to less glial cell reuptake of serine than there is with glycine.[67]

Similar to glycine (or anything that can activate the glycine binding site), any increase in synaptic concentrations of D-serine is also accompanied by an increase in NMDAergic signalling[59][68][69] which is thought to be due to activity at the glycine binding site being rate-limiting. Several brain regions such as the hippocampus, thalamus, neocortex, brain stem and retina have been noted to have the glycine binding site not saturated and thus respond to additional glycine or D-serine.[6][70][59][71][72]

D-Serine, similar to Glycine, is a ligand at the NMDA receptor's glycine binding site and has the ability to potentiate glutaminergic signalling through these NMDA receptors. They are equally potent at the level of the receptor, but D-Serine appears to be more biologically relevant and overall potent

D-Serine appears to have a concentration-dependent inhibitory effect on AMPA receptors (induced by kainate acid) with an IC50 of 3.7+/-0.1mM.[73] L-Serine does not have this effect,[73] but this concentration may be too high to be relevant.

Although there may be inhibitory effects on AMPA receptors, the concentration appears to be very high and may not be practically relevant

In regards to excitotoxicity, D-serine and glycine appear to potentiate glutamate induced excitotoxicity with ED50 values of 47µM and 27µM (respectively) which are concentrations and 50-100fold higher than the dosages required to activate the glycine binding sites on NMDA receptors.[74]

This enhancement of excitotoxicity is mediated not by NMDA receptors, but by activation of glycinergic receptors. Since GABA (acting via GABAA receptors) was also able to potentiate NMDA-induced excitotoxicity, it was thought to be due to the chloride influx in the neuron.[74]

Excessive signalling through glycincergic receptors appears to potentiate NDMA induced toxicity, although the concentrations of which this occurs seem to be higher than those required to activate NMDA receptors. Practical significance of this data is unknown

3.3. Glycinergic Signalling

Glycinergic signalling (inhibitory and via glycine receptors[75] and causes chloride influx into neurons) can also occur with D-serine supplementation

In studies that compare glycinergic signalling between the two amino acids, glycine tends to be more potent as evidenced by lower EC50 values (27µM v. 47µM[74]).

The transporters that mediate glycine reuptake (Glycine transporter-1 and 2)[76][77] as well as the more general alanine–serine–cysteine transporter-1 (AscT1)[78][79] can mediate both glycine and serine (both isomers). Due to this, both D-serine and glycine are affected by sarcosine.

D-Serine also shares signalling properties on glycinergic receptors and is subject to the same transporters that glycine is

3.4. Oxidation

D-Serine can be used experimentally to induce oxidation secondary to overexciting NMDA receptors of which hyperexcitation and the resulting calcium influx induce oxidative damage,[80] and this oxidative damage from D-serine induced hyperexcitation has been noted in vitro[81] and in vivo at 50-200mg/kg (rats)[82][83] by a mechanism that is attenuated with COX2 inhibitors.[81]

COX2 tends to be overexpressed following stressors that cause NMDA hyperexcitation such as ischemia,[84][85] traumatic brain injury,[86] and Alzheimer's[87] and as this induction mediates the production of reactive oxygen species it is thought that COX2 inhibitors can be neuroprotective against NDMA toxicity.[88]

Although these mechanisms are thought to be related to some pathological conditions such as Alzheimer's, the interactions of supplemental D-serine and oxidative damage is uncertain.

Overdoses or excessive administration of D-serine can cause oxidative damage (enhancing NMDA signalling too much, resulting in excitotoxicity) and it is thought that overactive D-serine metabolism also plays a role in some disease states.
The effect of nutritional supplementation is not ascertained, but oxidative damage has been induced at doses that are not too much over the standard supplemental dosages

3.5. Memory and Learning

Glutaminergic signalling is known to enhance memory formation, as activation of the NMDA receptors causes calcium influx and mobilization of calmodulin dependent kinase (CaMK) and CREB binding protein which work to induce long term potentiation (LTP) that is known as the mechanisitic basis of memory formation[89][90] and causing an increase in NMDA signalling (particularly via the NR2B subunit) causes an increase in memory and LTP[91][92] (This is also the memory enhancing mechanism seen with Magnesium L-Threonate). Due to the ability for D-serine to enhance signalling via the NMDA receptor (52+/-16% enhancement at 1μM and increasing activity up to 30μM)[6] paired with the vitality of D-serine in this process[54] and known sensitivity of hippocampal cells to D-Serine stimulation,[70] it is thought that supplemental D-serine can promote memory and learning.[58]

There is another phenomena known as long term depression (LTD; not the opposite of LTP) that mediates synaptic plasticity[93] and can influence LTP indirectly,[94] and D-serine can activate at 600-1000mg/kg injections[95][96] with in vitro studies noting it effective at increasing LTD magnitude at 5μM (from 19.3% in control to 58.3%) which was more effective than both 3μM and 10μM concentrations.[96] It seems that LTD from D-serine is mediated via its glutaminergic actions as well,[96] and during LTD more D-serine is released from astrocytes.[96]

D-Serine may play a role in promoting memory formation, and does so secondary to augmenting glutaminergic neurotransmission via the NMDA receptors (as D-serine can activate the glycine binding site)

The aging related process, at least as it pertains to the hippocampus, is related to a reduced ability to drive calcium-dependent neuronal plasticity[97][98] which seems to be related to subactive glutaminergic receptor signalling (specifically NMDA[99][100]). Due to the reduced D-serine concentrations in the brain during the aging process[101] (possibly related to reduced expression of serine racemase)[102] and the failure of the previous theory (the age-related decline in NMDA receptor expression[103][104] may not be relevant as reduced NMDA receptor expression does not per se cause cognitive decline,[105]) it is now thought that reduced activity at the glycinergic binding site of the NMDA receptor contributes to age-related decline (by reducing NMDA signalling and thus synaptic plasticity). This is further supported by studies noting that age-related cognitive impairment is preserved with D-serine[106][107] and that NMDA-dependent plasticity is D-serine dependent.[13][108]

The aging process causes a reduction in D-serine production (not exactly known why) and the lower levels of D-serine reducing NMDA signalling and thus may contribute to age-related cognitive decline

In regards to interventions, a study in otherwise normal mice given 50mg/kg D-serine daily noted that D-serine was able to improve memory formation after a single dose and after multiple doses.[58] The potency of 50mg/kg D-Serine appears to be comparable to 20mg/kg D-Cycloserine[58] which is known to be a cognitive enhancer.[109][110]

D-serine is effective when given 30 minutes after training, suggesting it aids in memory consolidation. It was ineffective when given 6 hours later.[58]

The impairment of MK-801 induced amnesia appears to be attenuated with D-serine.[58]

It is possible that D-Serine supplementation can enhance memory formation in otherwise healthy rodents, but the studies are currently those using injections and some with quite large dosages (although the 50mg/kg has a human equivalent of 3mg/kg and is quite reasonable)

One study using 2.1g D-serine in otherwise healthy adult subjects acutely (two hours prior to cognitive testing) found improved performance in the continous performance test (CPT-IP) for sustained attention and an improvement in immediate word recall; there was an improvement in the digits forward task, but not digits backwards.[111]

There may be minor improvements in cognition when otherwise healthy adults subjects are given D-serine supplementation

3.6. Depression

Genetic overexpression of D-serine synthesis or chronic supplementation to mice (58mg/kg over five weeks) appears to confer antidepressant effects in mice that were otherwise normal at baseline.[40]

There may be some minor anti-depressive effects of D-serine supplementation which need to be further investigated

3.7. Alzheimer's and Dementia

NMDA-mediated neurotransmission appears to be perturbed in Alzheimer's disease and is thought to be related to the decline in memory[112][113] and synaptic formation[114] resulting in behavioural deficits.[115] Unlike schizophrenic patients, the signalling in Alzheimer's may be hyperfunctional as Beta-amyloid peptides (β-amyloid) can accumulate both glutamate and D-serine in the synapse[114] and both encourage their release[116][117] while promoting serine racemase expression,[117][118] all of which may contribute to excitotoxicity (excessive glutaminergic signalling resulting in cellular damage).

D-serine concentrations do not appear to be significantly perturbed in persons with Alzheimer's relative to control.[36]

D-serine may be involved in the pathology of Alzheimer's disease secondary to beta-amyloid pigmentation

3.8. Schizophrenia

Symptoms of schizophrenia (particularly negative symptoms) are currently thought to be related to glutaminergic hypofunction (a reduced total signalling capacity via glutamate receptors), and recent pharmacological therapies that aim to restore glutaminergic firing include serine/glycine restoration[119][120] (as despite total elevated serine and glycine being higher in schizophrenics versus control,[121][122] D-serine itself is reduced[123] suggesting problems with serine racemase[124][125]) since impairing glycine binding to NMDA receptors causes negative symptoms of schizophrenia[126] and serine racemase knockout mice (or anything to reduce production of D-serine) have schizophrenic symptoms as well[127][128] yet knocking out D-amino acid oxidase (and preventing degradation of D-serine) is rehabilitative.[129] Finally, clinical remission of schizophrenia is accompanied by an increase in D-serine concentrations independent of supplementation.[130]

Other possible therapeutic options include AMPAkines that enhance signalling via AMPA receptors (this includes Piracetam and Aniracetam),[131] and indirectly supporting the aforementioned NMDA signalling via inhibiting glycine uptake into cells and promoting their synaptic effects (seen with sarcosine[132]). Enhancing AMPA signalling will inherently increase glutaminergic signalling and can remove the magnesium block from NMDA receptors[133][134]

Negative symptoms of schizophrenia refer to affective flattening and social isolation whereas hallucinations, delusions, and thought disorder are referred to as 'positive' symptoms and the cognitive impairment that is associated with schizophrenia in neither category.[135][136]

D-Serine administration, via affecting the NMDA glycine binding site and thus positively regulating signalling through NDMA receptors, is thought to be able to reduce symptoms of schizophrenia. This is somewhat supported by the fact that schizophrenia appears to be a D-serine deficiency state (role in cause or effect not established)

Limited positive studies tend to note 17-30% improvements in negative symptoms of schizophrenia with 30mg/kg (2.12+/-0.6g overall) D-serine as assessed by the Positive and Negative Syndrome Scale (PNSS)[29] which is a potency similar to 800mg/kg Glycine under similar research conditions.[30] Studies that measure negative symptom progression over time note beneficial effects within 2 weeks of supplementation, which increases in potency over 6 weeks of observation[137][29] and is more apparent with higher doses in the 60-120mg/kg range.[33] When looking specifically at positive symptoms, 30mg/kg (2.12+/-0.6g overall) D-serine has noted significant improvement after 6 weeks although the trend noted at weeks 2 and 4 was not statistically significant.[29] Improvements have been noted with 60-120mg/kg to a higher degree than 30mg/kg, and benefits on both positive and negative symptoms are correlated with serum exposure to D-serine.[33]

2,000mg of D-serine daily for 16 weeks in schizophrenics in addition to standard anti-psychotic medication failed to find a significant benefit of supplementation over placebo, although the authors cautioned that the larger than normal placebo response could in part explain the results[138] although D-serine has elsewhere failed to be any significantly different than placebo at the 30mg/kg or 2,000mg dosage.[31][32][139] These studies do note that individuals get benefit albeit not consistenly enough to reach statistical significance, and this paired with the correlation between D-serine in the blood and the benefits to symptoms[33] suggest that the established variance in serum D-serine from oral therapy may underlie the null effects observed.

D-Serine appears to be effective at reducing all symptoms of schizophrenia (mostly negative and cognitive, with less effects on positive) but the standard recommended dose of 30mg/kg seems unreliable. This may be due to a large variability in how much D-serine reaches the blood, and taking higher doses seems to be more reliable based on limited evidence

3.9. Parkinson's Disease

Parkinson's disease seems to have some symptoms (impairments in motivation, drive, and initiation/emotional reactivity[140][141]) that are similar to the negative symptoms in schizophrenia (apathy, flat affect and isolation), and due to the similarities it is thought that D-serine could be useful.[34] Furthermore, dopaminergic neurons in the striatum are involved in NMDA signalling[142] while NMDA receptors in persons with Parkinson's are known to be altered.[143]

Supplementation of D-serine at 30mg/kg for six weeks in a small pilot study with 13 persons with Parkinson's disease (ended up being in the range of 1,600-2,600mg daily) was able to reduce symptoms as assessed by the Unified Parkinson’s Disease Rating Scale, Simpson-Angus scale, and Positive and Negative Syndrome Scale.[34] This study noted that when looking at subjects with a 20% improvement in symptoms, 50-70% of persons in the D-serine group met this criteria while 10-20% in placbo did.[34]

Preliminary evidence suggests that D-serine could be useful for treatment of Parkinson's disease

3.10. Stress and Trauma

NMDA receptors appear to be somewhat involved in some symptoms of PTSD including dissociation and perceptual alterations[144] and since ketamine (NMDA antagonist) can also cause these particular symptoms[145] it is thought they are caused by NMDA underfiring, particularly in the hippocampus or amygdala.[35]

D-Cycloserine (partial agonist at the glycine binding site of NMDA receptors, whereas D-serine is a full agonist) has previously shown benefit in a pilot study for reducing symptoms of post-traumatic stress disorder (PTSD; numbing, avoidance, and anxiety symptoms mostly)[146] and following that study one using D-serine at 30mg/kg for six weeks noted improvements on anxiety symptoms (HAMA; 95% CI of 13.4–46.7% symptom reduction), depressive (HAMD; 95% CI of 2.0–43.3% symptom reduction) and CAPS score (95% CI of 10.9-31% reduction).[35]

Preliminary evidence suggests benefit in treating symptoms of Post Traumatic Stress Disorder (PTSD), although the observed benefits seem fairly unreliable

3.11. Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) in mice (mSOD1 strain) is associated with 50-100% elevation in D-serine concentrations of spinal fluid[147][148] which can predict how susceptible neurons from ALS are to NMDA-mediated excitotoxic damage.[147] Although this suggests that elevated D-serine contributes to ALS pathology, it has also been noted that hindering the serine racemase enzyme accelerates disease onset (described as paradoxical) but slowed disease progression[148] which was mimicked by D-serine supplementation in the chow.[148][149]

D-Serine has unclear influences on the pathology and onset of ALS

3.12. Addiction

Cocaine addiction is known to result in alterations to glutamatergic synaptic plasticity which precedes addictive behaviour[150][151] which are thought to be related to NMDA receptors (both long term potentiation (LTP) and long term depression (LTD) are implicated).[152][153][154]

D-Serine has been noted to be reduced in the nuclear accumbens core (where it is the coagonist of synaptic receptors) of rats undergoing cocaine withdrawal,[155] which is thought to contribute to NMDA hypoactivity and relapse as incubation with their neuronal slices with D-serine normalizes the cocaine-induced changes in LTP and LTD.[155] This was confirmed when 10-100mg/kg of D-serine oral ingestion (or 100mg/kg injections) to cocaine dependent rats reduced their drug-seeking behaviour.[156][157][158]

The study to assess how D-serine affects sucrose preference failed to find a significant benefit of supplementation.[156]

Cocaine addiction is associated with alterations in synaptic plasticity from alterations in NMDA function, and D-serine has been noted to be reduced in rats undergoing cocaine withdrawal. Preliminary evidence suggests that D-serine has anti-addictive properties


4Safety and Toxicity

4.1. General

Human studies that tend to use 30mg/kg of D-serine (around 2,000mg total) daily for periods of up to six weeks do not tend to notice any side-effects[138][29][33][35][34] with one preliminary study using 120mg/kg (around 8,000mg) also failing to find significant side-effects relative to control.[33]

The standard supplemental dosages of D-serine do not note any significant side-effects associated with treatment in the standard dosage range

Scientific Support & Reference Citations

References

  1. Martineau M, Baux G, Mothet JP. D-serine signalling in the brain: friend and foe. Trends Neurosci. (2006)
  2. Schell MJ. The N-methyl D-aspartate receptor glycine site and D-serine metabolism: an evolutionary perspective. Philos Trans R Soc Lond B Biol Sci. (2004)
  3. Monahan JB, et al. Characterization of a {3H}glycine recognition site as a modulatory site of the N-methyl-D-aspartate receptor complex. J Neurochem. (1989)
  4. D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release.
  5. Watson GB, et al. D-cycloserine acts as a partial agonist at the glycine modulatory site of the NMDA receptor expressed in Xenopus oocytes. Brain Res. (1990)
  6. Berger AJ, Dieudonné S, Ascher P. Glycine uptake governs glycine site occupancy at NMDA receptors of excitatory synapses. J Neurophysiol. (1998)
  7. Papouin T, et al. Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell. (2012)
  8. Radzishevsky I, Sason H, Wolosker H. D-serine: physiology and pathology. Curr Opin Clin Nutr Metab Care. (2013)
  9. Thomas CG, Miller AJ, Westbrook GL. Synaptic and extrasynaptic NMDA receptor NR2 subunits in cultured hippocampal neurons. J Neurophysiol. (2006)
  10. Groc L, et al. NMDA receptor surface mobility depends on NR2A-2B subunits. Proc Natl Acad Sci U S A. (2006)
  11. Martel MA, et al. The subtype of GluN2 C-terminal domain determines the response to excitotoxic insults. Neuron. (2012)
  12. Yasuda E, Ma N, Semba R. Immunohistochemical evidences for localization and production of D-serine in some neurons in the rat brain. Neurosci Lett. (2001)
  13. Yang Y, et al. Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine. Proc Natl Acad Sci U S A. (2003)
  14. Wolosker H, Blackshaw S, Snyder SH. Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission. Proc Natl Acad Sci U S A. (1999)
  15. Xia M, et al. Characterization and localization of a human serine racemase. Brain Res Mol Brain Res. (2004)
  16. Williams SM, et al. Immunocytochemical analysis of D-serine distribution in the mammalian brain reveals novel anatomical compartmentalizations in glia and neurons. Glia. (2006)
  17. De Miranda J, et al. Cofactors of serine racemase that physiologically stimulate the synthesis of the N-methyl-D-aspartate (NMDA) receptor coagonist D-serine. Proc Natl Acad Sci U S A. (2002)
  18. Neidle A, Dunlop DS. Allosteric regulation of mouse brain serine racemase. Neurochem Res. (2002)
  19. Cook SP, et al. Direct calcium binding results in activation of brain serine racemase. J Biol Chem. (2002)
  20. Strísovský K, et al. Dual substrate and reaction specificity in mouse serine racemase: identification of high-affinity dicarboxylate substrate and inhibitors and analysis of the beta-eliminase activity. Biochemistry. (2005)
  21. Dunlop DS, Neidle A. Regulation of serine racemase activity by amino acids. Brain Res Mol Brain Res. (2005)
  22. Kim PM, et al. Serine racemase: activation by glutamate neurotransmission via glutamate receptor interacting protein and mediation of neuronal migration. Proc Natl Acad Sci U S A. (2005)
  23. Strísovský K, et al. Mouse brain serine racemase catalyzes specific elimination of L-serine to pyruvate. FEBS Lett. (2003)
  24. Urai Y, et al. Gene expression of D-amino acid oxidase in cultured rat astrocytes: regional and cell type specific expression. Neurosci Lett. (2002)
  25. Molla G, et al. Characterization of human D-amino acid oxidase. FEBS Lett. (2006)
  26. Horiike K, et al. D-amino-acid oxidase is confined to the lower brain stem and cerebellum in rat brain: regional differentiation of astrocytes. Brain Res. (1994)
  27. Moreno S, et al. Immunocytochemical localization of D-amino acid oxidase in rat brain. J Neurocytol. (1999)
  28. Hamase K, et al. Sensitive determination of D-amino acids in mammals and the effect of D-amino-acid oxidase activity on their amounts. Biol Pharm Bull. (2005)
  29. Heresco-Levy U, et al. D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry. (2005)
  30. Heresco-Levy U, et al. High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biol Psychiatry. (2004)
  31. Lane HY, et al. A randomized, double-blind, placebo-controlled comparison study of sarcosine (N-methylglycine) and D-serine add-on treatment for schizophrenia. Int J Neuropsychopharmacol. (2010)
  32. Lane HY, et al. Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study. Arch Gen Psychiatry. (2005)
  33. Kantrowitz JT, et al. High dose D-serine in the treatment of schizophrenia. Schizophr Res. (2010)
  34. Gelfin E, et al. D-serine adjuvant treatment alleviates behavioural and motor symptoms in Parkinson's disease. Int J Neuropsychopharmacol. (2012)
  35. Heresco-Levy U, et al. Pilot controlled trial of D-serine for the treatment of post-traumatic stress disorder. Int J Neuropsychopharmacol. (2009)
  36. Nagata Y, et al. Free D-serine concentration in normal and Alzheimer human brain. Brain Res Bull. (1995)
  37. Chouinard ML, Gaitan D, Wood PL. 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. (1993)
  38. Kumashiro S, Hashimoto A, Nishikawa T. Free D-serine in post-mortem brains and spinal cords of individuals with and without neuropsychiatric diseases. Brain Res. (1995)
  39. Foltyn VN, et al. Serine racemase modulates intracellular D-serine levels through an alpha,beta-elimination activity. J Biol Chem. (2005)
  40. Otte DM, et al. Effects of Chronic D-Serine Elevation on Animal Models of Depression and Anxiety-Related Behavior. PLoS One. (2013)
  41. Sethuraman R, et al. Simultaneous analysis of D- and L-serine in cerebrospinal fluid by use of HPLC. Clin Chem. (2007)
  42. Hashimoto K, et al. Reduced D-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry. (2005)
  43. Bezzi P, et al. Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat Neurosci. (2004)
  44. Mothet JP, et al. Glutamate receptor activation triggers a calcium-dependent and SNARE protein-dependent release of the gliotransmitter D-serine. Proc Natl Acad Sci U S A. (2005)
  45. Schell MJ, et al. D-serine as a neuromodulator: regional and developmental localizations in rat brain glia resemble NMDA receptors. J Neurosci. (1997)
  46. Van Horn MR, Sild M, Ruthazer ES. D-serine as a gliotransmitter and its roles in brain development and disease. Front Cell Neurosci. (2013)
  47. Sild M, Van Horn MR. Astrocytes use a novel transporter to fill gliotransmitter vesicles with d-serine: evidence for vesicular synergy. J Neurosci. (2013)
  48. Bergersen LH, et al. Immunogold detection of L-glutamate and D-serine in small synaptic-like microvesicles in adult hippocampal astrocytes. Cereb Cortex. (2012)
  49. Storage and Uptake of D-Serine into Astrocytic Synaptic-Like Vesicles Specify Gliotransmission.
  50. Rosenberg D, et al. Neuronal release of D-serine: a physiological pathway controlling extracellular D-serine concentration. FASEB J. (2010)
  51. Rosenberg D, et al. Neuronal D-serine and glycine release via the Asc-1 transporter regulates NMDA receptor-dependent synaptic activity. J Neurosci. (2013)
  52. Kang N, et al. Astrocytes release D-serine by a large vesicle. Neuroscience. (2013)
  53. Shigetomi E, et al. TRPA1 Channels Are Regulators of Astrocyte Basal Calcium Levels and Long-Term Potentiation via Constitutive D-Serine Release. J Neurosci. (2013)
  54. Long term potentiation depends on release of D-serine from astrocytes.
  55. Shoji K, et al. Regulation of serine racemase activity by D-serine and nitric oxide in human glioblastoma cells. Neurosci Lett. (2006)
  56. Shoji K, et al. Mutual regulation between serine and nitric oxide metabolism in human glioblastoma cells. Neurosci Lett. (2006)
  57. Alagarsamy S, Johnson KM. Voltage-dependent calcium channel involvement in NMDA-induced activation of NOS. Neuroreport. (1995)
  58. Bado P, et al. Effects of low-dose D-serine on recognition and working memory in mice. Psychopharmacology (Berl). (2011)
  59. Chen L, Muhlhauser M, Yang CR. Glycine tranporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo. J Neurophysiol. (2003)
  60. Lim R, Hoang P, Berger AJ. Blockade of glycine transporter-1 (GLYT-1) potentiates NMDA receptor-mediated synaptic transmission in hypoglossal motorneurons. J Neurophysiol. (2004)
  61. Hashimoto A, et al. The presence of free D-serine in rat brain. FEBS Lett. (1992)
  62. Endogenous d-Serine in Rat Brain: N-Methyl-d-Aspartate Receptor-Related Distribution and Aging.
  63. Johnson JW, Ascher P. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature. (1987)
  64. Clements JD, Westbrook GL. Activation kinetics reveal the number of glutamate and glycine binding sites on the N-methyl-D-aspartate receptor. Neuron. (1991)
  65. Kalia LV, Kalia SK, Salter MW. NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol. (2008)
  66. Mothet JP, et al. D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A. (2000)
  67. Supplisson S, Bergman C. Control of NMDA receptor activation by a glycine transporter co-expressed in Xenopus oocytes. J Neurosci. (1997)
  68. Wilcox KS, et al. Glycine regulation of synaptic NMDA receptors in hippocampal neurons. J Neurophysiol. (1996)
  69. Depoortère R, et al. Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic. Neuropsychopharmacology. (2005)
  70. Martina M, Krasteniakov NV, Bergeron R. D-Serine differently modulates NMDA receptor function in rat CA1 hippocampal pyramidal cells and interneurons. J Physiol. (2003)
  71. Thomson AM, Walker VE, Flynn DM. Glycine enhances NMDA-receptor mediated synaptic potentials in neocortical slices. Nature. (1989)
  72. Stevens ER, et al. D-serine and serine racemase are present in the vertebrate retina and contribute to the physiological activation of NMDA receptors. Proc Natl Acad Sci U S A. (2003)
  73. Gong XQ, Zabek RL, Bai D. D-Serine inhibits AMPA receptor-mediated current in rat hippocampal neurons. Can J Physiol Pharmacol. (2007)
  74. McNamara D, Dingledine R. Dual effect of glycine on NMDA-induced neurotoxicity in rat cortical cultures. J Neurosci. (1990)
  75. The glycinergic inhibitory synapse.
  76. Betz H, et al. Glycine transporters: essential regulators of synaptic transmission. Biochem Soc Trans. (2006)
  77. Aragón C, López-Corcuera B. Glycine transporters: crucial roles of pharmacological interest revealed by gene deletion. Trends Pharmacol Sci. (2005)
  78. Hayashi F, Takahashi K, Nishikawa T. Uptake of D- and L-serine in C6 glioma cells. Neurosci Lett. (1997)
  79. Ribeiro CS, et al. Glial transport of the neuromodulator D-serine. Brain Res. (2002)
  80. Coyle JT, Puttfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders. Science. (1993)
  81. Armagan G, Kanit L, Yalcin A. Effects of non-steroidal antiinflammatory drugs on D-serine-induced oxidative stress in vitro. Drug Chem Toxicol. (2012)
  82. Armagan G, Kanit L, Yalcin A. D-serine treatment induces oxidative stress in rat brain. Drug Chem Toxicol. (2011)
  83. Leipnitz G, et al. d-Serine administration provokes lipid oxidation and decreases the antioxidant defenses in rat striatum. Int J Dev Neurosci. (2010)
  84. Kinouchi H, et al. Induction of cyclooxygenase-2 messenger RNA after transient and permanent middle cerebral artery occlusion in rats: comparison with c-fos messenger RNA by using in situ hybridization. J Neurosurg. (1999)
  85. Collaço-Moraes Y, et al. Cyclo-oxygenase-2 messenger RNA induction in focal cerebral ischemia. J Cereb Blood Flow Metab. (1996)
  86. Dash PK, Mach SA, Moore AN. Regional expression and role of cyclooxygenase-2 following experimental traumatic brain injury. J Neurotrauma. (2000)
  87. Pasinetti GM. Cyclooxygenase and inflammation in Alzheimer's disease: experimental approaches and clinical interventions. J Neurosci Res. (1998)
  88. Hewett SJ, et al. Cyclooxygenase-2 contributes to N-methyl-D-aspartate-mediated neuronal cell death in primary cortical cell culture. J Pharmacol Exp Ther. (2000)
  89. Silva AJ. Molecular and cellular cognitive studies of the role of synaptic plasticity in memory. J Neurobiol. (2003)
  90. Matynia A, Kushner SA, Silva AJ. Genetic approaches to molecular and cellular cognition: a focus on LTP and learning and memory. Annu Rev Genet. (2002)
  91. Tang YP, et al. Genetic enhancement of learning and memory in mice. Nature. (1999)
  92. Hawasli AH, et al. Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. Nat Neurosci. (2007)
  93. Panatier A, et al. Glia-derived D-serine controls NMDA receptor activity and synaptic memory. Cell. (2006)
  94. Braunewell KH, Manahan-Vaughan D. Long-term depression: a cellular basis for learning. Rev Neurosci. (2001)
  95. Duffy S, Labrie V, Roder JC. D-serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning. Neuropsychopharmacology. (2008)
  96. Zhang Z, et al. Bell-shaped D-serine actions on hippocampal long-term depression and spatial memory retrieval. Cereb Cortex. (2008)
  97. Landfield PW, Pitler TA, Applegate MD. The effects of high Mg2+-to-Ca2+ ratios on frequency potentiation in hippocampal slices of young and aged rats. J Neurophysiol. (1986)
  98. Landfield PW, Lynch G. Impaired monosynaptic potentiation in in vitro hippocampal slices from aged, memory-deficient rats. J Gerontol. (1977)
  99. Foster TC. Calcium homeostasis and modulation of synaptic plasticity in the aged brain. Aging Cell. (2007)
  100. Thibault O, Gant JC, Landfield PW. Expansion of the calcium hypothesis of brain aging and Alzheimer's disease: minding the store. Aging Cell. (2007)
  101. Billard JM. Serine racemase as a prime target for age-related memory deficits. Eur J Neurosci. (2013)
  102. Turpin FR, et al. Reduced serine racemase expression contributes to age-related deficits in hippocampal cognitive function. Neurobiol Aging. (2011)
  103. Magnusson KR, Nelson SE, Young AB. Age-related changes in the protein expression of subunits of the NMDA receptor. Brain Res Mol Brain Res. (2002)
  104. Adams MM, et al. Hippocampal dependent learning ability correlates with N-methyl-D-aspartate (NMDA) receptor levels in CA3 neurons of young and aged rats. J Comp Neurol. (2001)
  105. Alliot J, et al. The LOU/c/jall rat as an animal model of healthy aging. J Gerontol A Biol Sci Med Sci. (2002)
  106. Mothet JP, et al. A critical role for the glial-derived neuromodulator D-serine in the age-related deficits of cellular mechanisms of learning and memory. Aging Cell. (2006)
  107. Junjaud G, et al. Age-related effects of the neuromodulator D-serine on neurotransmission and synaptic potentiation in the CA1 hippocampal area of the rat. J Neurochem. (2006)
  108. Long term potentiation depends on release of D-serine from astrocytes.
  109. Assini FL, Duzzioni M, Takahashi RN. Object location memory in mice: pharmacological validation and further evidence of hippocampal CA1 participation. Behav Brain Res. (2009)
  110. Zlomuzica A, et al. NMDA receptor modulation by D-cycloserine promotes episodic-like memory in mice. Psychopharmacology (Berl). (2007)
  111. Levin R1, et al. Behavioral and cognitive effects of the N-methyl-d-aspartate receptor co-agonist d-serine in healthy humans: Initial findings. J Psychiatr Res. (2014)
  112. Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med. (1994)
  113. Farber NB, Newcomer JW, Olney JW. The glutamate synapse in neuropsychiatric disorders. Focus on schizophrenia and Alzheimer's disease. Prog Brain Res. (1998)
  114. Paula-Lima AC, Brito-Moreira J, Ferreira ST. Deregulation of excitatory neurotransmission underlying synapse failure in Alzheimer's disease. J Neurochem. (2013)
  115. Huang YJ, et al. NMDA Neurotransmission Dysfunction in Behavioral and Psychological Symptoms of Alzheimer's Disease. Curr Neuropharmacol. (2012)
  116. Brito-Moreira J, et al. Aβ oligomers induce glutamate release from hippocampal neurons. Curr Alzheimer Res. (2011)
  117. Wu S, Basile AS, Barger SW. Induction of serine racemase expression and D-serine release from microglia by secreted amyloid precursor protein (sAPP). Curr Alzheimer Res. (2007)
  118. Wu SZ, et al. Induction of serine racemase expression and D-serine release from microglia by amyloid beta-peptide. J Neuroinflammation. (2004)
  119. Nunes EA, et al. D-serine and schizophrenia: an update. Expert Rev Neurother. (2012)
  120. Labrie V, Roder JC. The involvement of the NMDA receptor D-serine/glycine site in the pathophysiology and treatment of schizophrenia. Neurosci Biobehav Rev. (2010)
  121. Waziri R, Baruah S, Sherman AD. Abnormal serine-glycine metabolism in the brains of schizophrenics. Schizophr Res. (1993)
  122. Waziri R, et al. Abnormal serine hydroxymethyl transferase activity in the temporal lobes of schizophrenics. Neurosci Lett. (1990)
  123. Hashimoto K, et al. Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen Psychiatry. (2003)
  124. Hashimoto K. Glycine transport inhibitors for the treatment of schizophrenia. Open Med Chem J. (2010)
  125. Dysfunction of Glia-Neuron Communication in Pathophysiology of Schizophrenia.
  126. Labrie V, Lipina T, Roder JC. Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia. Psychopharmacology (Berl). (2008)
  127. Balu DT, et al. Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction. Proc Natl Acad Sci U S A. (2013)
  128. Ma TM, et al. Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion. Mol Psychiatry. (2013)
  129. Labrie V, et al. Genetic loss of D-amino acid oxidase activity reverses schizophrenia-like phenotypes in mice. Genes Brain Behav. (2010)
  130. Ohnuma T, et al. Changes in plasma glycine, L-serine, and D-serine levels in patients with schizophrenia as their clinical symptoms improve: results from the Juntendo University Schizophrenia Projects (JUSP). Prog Neuropsychopharmacol Biol Psychiatry. (2008)
  131. Buchanan RW. Novel pharmacologic targets for the treatment of negative symptoms in schizophrenia. J Clin Psychiatry. (2013)
  132. Tsai G, et al. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. (2004)
  133. Dingledine R, et al. The glutamate receptor ion channels. Pharmacol Rev. (1999)
  134. Traynelis SF, et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev. (2010)
  135. Lewis DA, Gonzalez-Burgos G. Pathophysiologically based treatment interventions in schizophrenia. Nat Med. (2006)
  136. Ross CA, et al. Neurobiology of schizophrenia. Neuron. (2006)
  137. Tsai G, et al. D-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. (1998)
  138. Weiser M, et al. A multicenter, add-on randomized controlled trial of low-dose d-serine for negative and cognitive symptoms of schizophrenia. J Clin Psychiatry. (2012)
  139. Tsai GE, et al. D-serine added to clozapine for the treatment of schizophrenia. Am J Psychiatry. (1999)
  140. Isella V, et al. Clinical, neuropsychological, and morphometric correlates of apathy in Parkinson's disease. Mov Disord. (2002)
  141. Pluck GC, Brown RG. Apathy in Parkinson's disease. J Neurol Neurosurg Psychiatry. (2002)
  142. Chéramy A, et al. Direct and indirect presynaptic control of dopamine release by excitatory amino acids. Amino Acids. (1998)
  143. Hallett PJ, Standaert DG. Rationale for and use of NMDA receptor antagonists in Parkinson's disease. Pharmacol Ther. (2004)
  144. Chambers RA, et al. Glutamate and post-traumatic stress disorder: toward a psychobiology of dissociation. Semin Clin Neuropsychiatry. (1999)
  145. Newcomer JW, Krystal JH. NMDA receptor regulation of memory and behavior in humans. Hippocampus. (2001)
  146. Heresco-Levy U, et al. Pilot-controlled trial of D-cycloserine for the treatment of post-traumatic stress disorder. Int J Neuropsychopharmacol. (2002)
  147. Sasabe J, et al. D-serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis. EMBO J. (2007)
  148. Thompson M, et al. Paradoxical roles of serine racemase and D-serine in the G93A mSOD1 mouse model of amyotrophic lateral sclerosis. J Neurochem. (2012)
  149. Crow JP, Marecki JC, Thompson M. D-Serine Production, Degradation, and Transport in ALS: Critical Role of Methodology. Neurol Res Int. (2012)
  150. Lüscher C, Malenka RC. Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron. (2011)
  151. Kauer JA, Malenka RC. Synaptic plasticity and addiction. Nat Rev Neurosci. (2007)
  152. Transition to Addiction Is Associated with a Persistent Impairment in Synaptic Plasticity.
  153. Martin M, et al. Cocaine self-administration selectively abolishes LTD in the core of the nucleus accumbens. Nat Neurosci. (2006)
  154. Moussawi K, et al. N-Acetylcysteine reverses cocaine-induced metaplasticity. Nat Neurosci. (2009)
  155. Curcio L, et al. Reduced D-serine levels in the nucleus accumbens of cocaine-treated rats hinder the induction of NMDA receptor-dependent synaptic plasticity. Brain. (2013)
  156. Kelamangalath L, Seymour CM, Wagner JJ. D-serine facilitates the effects of extinction to reduce cocaine-primed reinstatement of drug-seeking behavior. Neurobiol Learn Mem. (2009)
  157. Kelamangalath L, Wagner JJ. D-serine treatment reduces cocaine-primed reinstatement in rats following extended access to cocaine self-administration. Neuroscience. (2010)
  158. Hammond S, et al. D-Serine facilitates the effectiveness of extinction to reduce drug-primed reinstatement of cocaine-induced conditioned place preference. Neuropharmacology. (2013)

(Common misspellings for D-Serine include Serine, serin, D-serin)