L-Serine & D-Serine: Health Benefits and Safety

Answer:

Serine is an amino acid that the body can produce either as L-serine or, to a lesser extent, D-serine. Since the body can produce these, serine is considered non-essential from the diet; however, both forms are sold as supplements, work differently in the body, have different safety profiles, and dosage is typically larger with L-serine than D-serine.

Although both L- and D-serine have been evaluated to aid cognitive function, L-serine works by releasing proteins that enhance blood flow in the brain, reduce inflammation, and support regeneration of myelin — a layer around nerves that allows electrical impulses to transmit quickly and efficiently. It has been tried in trials to treat aspects of Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and hereditary sensory neuropathy type I (HSN1). On the other hand, D-serine can increase activity at NMDA receptors in the brain, which plays a role in mediating learning and memory, as well as neurotransmission, and it has been studied in treating schizophrenia, as people with that disease may have declining NMDA receptor activity. It has also been studied in treating Parkinson's disease.

Learn below if supplementing with L-serine or D-serine is beneficial for treating any condition, if these forms are safe, and how dosage differs.

What is L-serine?

L-serine is the form of serine that is naturally found in foods such as soy, seaweed, sweet potatoes, eggs, and meats. It can also be produced in the body by certain cells of the central nervous system, which is why it is not an essential amino acid. It is involved in the production of DNA and RNA as well as the production of phosphatidylserine, a component of brain cell membranes (den Hollander, Contemp Clin Trials Commun 2023; Ye, Front Mol Neurosci 2021).

What is D-serine?

D-serine is produced in the body from L-serine, although only a small portion of L-serine is converted to D-serine (Myint, Biomedicines 2023; Ye, Front Mol Neurosci 2021). D-serine is generally not found in significant quantities in food, although food processing techniques can increase the conversion of L-serine to D-serine in foods (Bastings, Nutrients 2019).

Potential Health Benefits

Possible Benefits of L-serine

Cognitive function

Healthy adults
Although intake of L-serine has been associated with better memory and cognitive function, these observational studies do not prove cause and effect and there do not appear to be any clinical studies of L-serine for improving these conditions.

An observational study in the U.S. among 1,837 adults found that highest dietary intake of serine (average intake: 6.44 grams/day, mainly from meat, grains, and milk) was associated with improved short-term memory compared to lowest intake (1.76 grams/day), although higher intake of serine was not linked with other measures of cognition, including attention, psychomotor speed, and executive function (Chen, Food Funct 2024). Similarly, other research among adults with chronic kidney disease has linked lower brain and blood levels of L-serine with declined cognitive function (Iwata, Kidney Dis (Basel). 2023). However, these studies do not prove cause and effect, so more research is needed to determine the benefit, if any, of L-serine for cognitive function.

Alzheimer's disease
Based on its neuroprotective effects, there is interest in L-serine supplementation for Alzheimer's disease. However, there does not appear to be any published evidence to support this use. A study evaluating L-serine for Alzheimer's disease was terminated early.

The study, which was conducted in New Hampshire among 21 adults with early-stage Alzheimer's disease, intended to assess the effects of taking 15 grams of L-serine gummies twice daily for 9 months on cognitive function, but the study was terminated early as the manufacturer could not confirm that the supplement was stable over the duration of the study (ClinicalTrials.gov, NCT03062449).

An early study analyzing brain tissue from people with intermediate and advanced Alzheimer's disease found that levels of an enzyme called PHGDH, which is involved in the production of L-serine, was reduced in Alzheimer's disease patients compared to those without Alzheimer's disease (Le Douce, Cell Metab 2020). The researchers speculated that, because of this, L-serine production in the brain might also be low, and therefore boosting L-serine levels may be beneficial. However, subsequent research found opposite results: Levels of PHGDH in brain tissue were increased in people with Alzheimer's disease, even among those with early stage disease, suggesting that L-serine production in the brain may already be elevated in people with Alzheimer's disease and supplementation may not be beneficial (Chen, Cell Metab 2022; Yan, Curr Biol 2020).

Amyotrophic lateral sclerosis (ALS)

Based on the neuroprotective effects of L-serine demonstrated in laboratory research, there has been interest in L-serine supplementation to slow the progression of ALS, although preliminary results suggest only limited benefit, if any.

A study among 18 people with ALS showed that supplementing with 0.5 to 15 grams of L-serine twice daily (in the morning and evening; total daily dose 1 to 30 grams) for 6 months was generally well tolerated, with only mild side effects such as bloating, nausea, and loss of appetite, but L-serine supplementation did not significantly slow decline in breathing ability (based on forced vital capacity testing) compared to a historical placebo group. Also, decline in overall functionality was not significantly reduced with L-serine supplementation compared to historical placebo, although those receiving the highest dose (30 grams/day) showed a slower rate of physical function decline compared to the control (Bradley, Neurotox Res 2018; Levine, Amyotroph Lateral Scler Frontotemporal Degener 2017). More research is needed to confirm the benefit, if any, of L-serine for ALS.

Hereditary sensory neuropathy type I (HSN1)

HSN1 is a genetic disorder characterized by peripheral neuropathy (nerve damage in the hands and feet) that leads to sensory impairment, nerve pain, limb weakness and skin ulceration. The disease is caused by mutations in an enzyme that uses serine to produce a certain class of lipids (sphingolipids). The disease mutation causes the enzyme to use alanine and glycine instead of serine, leading to production of a class of neurotoxic lipids in the blood (Dawkins, Nat Genet 2001). Research in a mouse model of this condition suggested that supplementation with high doses of L-serine may reduce the formation of these neurotoxic lipids in the blood and improve motor performance (Garofalo, J Clin Invest 2011).

A placebo-controlled study in Boston among 18 adults (average age 48) with HSN1 showed that high-dose L-serine — 400 mg/kg/day (about 28 grams/day for a person weighing 155 lbs) — divided into three daily doses for one year, slightly reduced the overall severity of disease by 1.5 points (on a scale of 0 to 36) compared to placebo. However, there were no statistically significant improvements in nerve conduction, function of the autonomic nervous system (the part of the peripheral nervous system that controls involuntary bodily functions), neuropathy pain, or self-reported physical or social functioning. The L-serine group showed a decrease in blood levels of certain neurotoxic lipids, but not others, compared to placebo. L-serine was administered as a powder dissolved in water (Fridman, Neurology 2019).

Other uses

L-serine is sometimes promoted for conditions such as schizophrenia, Parkinson's disease, or depression. However, the "evidence" supporting these uses appears to be based on results from clinical trials evaluating the effects of D-serine. There do not appear to be any clinical studies evaluating L-serine for these conditions (Longoni, Biomedicines 2023; Ye, Front Mol Neurosci 2021).

Possible Benefits of D-serine

Schizophrenia

Schizophrenia has been linked with reduced NMDA receptor activity, which can be increased by D-serine. D-serine has shown possible benefit for improving positive and negative symptoms of schizophrenia, although its effects may depend on other medication being taken at the same time. There is mixed evidence regarding the benefit of D-serine on cognition among people with schizophrenia.

A study in Israel among 38 adults (average age 45) with schizophrenia and on a stable dose of olanzapine or risperidone showed that taking about 2 grams per day of D-serine for 6 weeks modestly decreased negative symptoms (e.g., wanting to avoid people, feeling disconnected from feelings or emotions, not wanting to take care of themselves, etc.) by 13.3% to 16.3%, positive symptoms (e.g., hallucinations or delusions) by 13%, cognitive symptoms by 11.7%, and depression symptoms by 14.7% compared to baseline, and these improvements were statistically significant compared to the placebo group, which showed no improvements (Heresco-Levy, Biol Psychiatry 2005).

These results differed from that of an earlier study in Taiwan among 20 adults (average age 41) with schizophrenia and on a stable dose of clozapine, which found that taking the same dose of D-serine for 6 weeks did not improve positive or negative symptoms, depression, or cognition compared to placebo (Tsai, Am J Psychiatry 1999). Research has shown that, among people with schizophrenia, who tend to have lower blood levels of D-serine and ratio of D- to L-serine compared to healthy individuals, clozapine can increase blood levels of D-serine (Yamamori, Neurosci Lett 2014). Consequently, additional D-serine supplementation may not have added benefit.

Several studies have evaluated D-serine for improving cognition among people with schizophrenia, but results are mixed. Among the studies that showed possible benefit, which were conducted by the same research group, one found that taking a high-dose of D-serine (about 4 grams) 30 minutes before testing improved auditory plasticity (the ability of synaptic connections of the auditory system to adapt to changes in the environment) compared to placebo. Schizophrenia has been linked with reduced auditory plasticity (Kantrowitz, Brain 2016). Another showed that taking the same dose of D-serine daily for 4 weeks modestly improved overall cognition (based on the MATRICS battery), as well as subscores for processing speed and verbal learning but not attention, working memory, visual learning, or reasoning, compared to baseline among a small group of people with schizophrenia. However, because this study lacked a placebo group, it is not possible to draw conclusions from the results (Kantrowitz, Schizophr Res 2010).

Several other studies have shown no cognitive benefit of D-serine, although all used lower dosages. One found that taking a lower doses of D-serine (about 2 grams/day) for 12 weeks did not significantly improve cognitive function among people with schizophrenia, nor did it have additive effects when taken in combination with cognitive retraining (D'Souza, Neuropsychopharmacology 2013). Another study showed that taking 2 grams of D-serine daily for 16 weeks did not significantly improve cognitive function based on the MATRICS battery compared to placebo (Weiser, J Clin Psychiatry 2012). Also, a third study found that taking 2 grams/day of D-serine for 6 weeks did not improve mental function based on the Global Assessment of Functioning scale compared to placebo (Lane, Int J Neuropsychopharmacol 2010).

Parkinson's disease

Because of its role in improving certain neurotransmission (communication between nerve cells), there is some interest in D-serine for improving symptoms of Parkinson's disease. A very small clinical study among 10 people with Parkinson's disease (average age 64) showed that taking about 2 grams/day of D-serine for 6 weeks modestly reduced the severity of Parkinson's disease by 8.6 points (on a scale of 0 to 272) compared to baseline, and these improvements were statistically significant compared to the placebo group. Specifically, the severity of motor symptoms (e.g., gait, facial expressions, finger tapping, etc.) and mental function and mood (e.g., forgetfulness, depressed mood, sleep problems, etc.) improved with D-serine compared to placebo. D-serine also reduced extrapyramidal symptoms (such as rigidity and delayed movement) compared to placebo (Gelfin, Int J Neuropsychopharmacol 2012). While these results are promising, larger studies are needed to confirm a benefit, if any.

Cognitive function

NMDA receptor function also plays a role in synaptic plasticity (the ability of synapses — the place where nerve cells connect and communicate — to strengthen or weaken over time), memory and learning. However, D-serine appears to have very limited benefit, if any, for boosting cognitive performance among healthy adults, and it does not appear to have been evaluated among people with Alzheimer's disease or dementia.

A study in Brazil among 50 older adults (average age 73) showed that taking a single dose of D-serine (about 2 grams) diluted in orange juice 1.5 hours prior to cognitive testing did not improve measures of working memory, cognitive flexibility, visual attention, or mood compared to placebo (orange juice only), although there were fewer errors made in following the rules of the test (Avellar, Oncotarget 2016).

An earlier study in Israel among 35 healthy younger adults (average age 27) showed that taking a single dose of about 2 grams of D-serine 2 hours prior to cognitive testing modestly improved just one measure of attention compared to placebo but did not significantly improve reaction time, ability to recall items, verbal fluency, or visual memory and perception compared to placebo (Levin, J Psychiatr Res 2015).

There are no clinical studies assessing the effects of D-serine among people with Alzheimer's disease or dementia.

Side Effects & Safety Concerns

L-Serine

In healthy adults, L-serine appears to be safe when taken short-term (up to 4 weeks) at doses up to 12 grams/day, with no side effects reported at this dosage (Miura, Nutrients 2021).

At higher doses (up to 30 grams/day), L-serine may cause side effects including bloating, nausea, and loss of appetite (Levine, Amyotroph Lateral Scler Frontotemporal Degener 2017).

D-Serine

D-serine has been generally well tolerated in clinical research in doses of about 2 to 4 grams/day for up to 6 weeks (Kantrowitz, Schizophr Res 2010; Heresco-Levy, Biol Psychiatry 2005). However, in one study, one participant taking about 4 grams daily experienced suicidal thoughts but continued with the study, and two other participants were withdrawn after showing abnormal test results for kidney function (which was deemed to be possibly related to D-serine). Taking D-serine at a dose of about 8.4 grams/day for 4 weeks was linked with one case of proteinuria (too much protein in the urine, which is a sign of kidney injury) that resolved after stopping the supplement (Kantrowitz, Schizophr Res 2010).

Since D-serine activates NMDA receptors, there is some concern that it may reduce the effects of drugs that inhibit NMDA receptors, although this has not been reported in any clinical studies. Examples of drugs that target NMDA receptors include memantine (a drug used to treat Alzheimer's disease), ketamine (an anesthetic sometimes used for pain or depression), dextromethorphan (Robitussin), and nitrous oxide (i.e., laughing gas).