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Ser4.5
L-Serine Research
Likely helps
26 peer-reviewed studies
What the evidence says
Likely helps
L-Serine appears to help in 6 of 6 studies with measurable effects — the evidence leans clearly favourable.
Most evidence is from high-quality meta-analyses and randomised trials published 2011–2026 with a typical study size of 46 participants.
Based on 26 studies · 1 meta-analysis · 11 RCTs · 2,625 total participants
Patients with developmental and epileptic encephalopathies1
Major depressive disorder patients1
Patients with serine metabolism disorders1
Active research area
20 studies in the last 5 years · Latest meta-analysis: 2021
201120182026
1Treatable variants in hereditary peripheral neuropathiesSystematic ReviewCited 16×n=2,046 · very large study2021
The 'treatable' variants highlighted in this project will be flagged in the treatabolome database to alert clinicians at the time of the diagnosis and enable timely treatment of patients with hereditary peripheral neuropathies.
Jennings MJ et al. · Journal of neuromuscular diseases (2021)
The 'treatable' variants highlighted in this project will be flagged in the treatabolome database to alert clinicians at the time of the diagnosis and enable timely treatment of patients with hereditary peripheral neuropathies.
2Precision therapies for developmental and epileptic encephalopathiesSystematic ReviewCited 15×2025
Additionally, the importance of enhancing access to genetic testing, conducting robust natural history studies, and employing innovative clinical trial designs is emphasized.
Samanta D et al. · Pediatric neurology (2025)
Additionally, the importance of enhancing access to genetic testing, conducting robust natural history studies, and employing innovative clinical trial designs is emphasized.
Future directions focus on addressing the challenges in developing and implementing gene-based therapies, integrating systems biology, leveraging artificial intelligence for data analysis, and fostering collaboration among stakeholders.
The rapidly advancing field of precision therapeutics for DEEs holds promise to improve outcomes through tailored, equitable, and patient-centered care.
3Peripheral blood metabolites in major depressive disorderMeta-AnalysisCited 171×n=46 · small study2021
MDD patients were characterized by higher levels of asymmetric dimethylarginine, tyramine, 2-hydroxybutyric acid, phosphatidylcholine (32:1), and taurochenodesoxycholic acid and lower levels of L-acetylcarnitine, creatinine, L-asparagine, L-glutamine, linoleic acid... compared with controls.
Pu J et al. · Molecular psychiatry (2021)
Pathway and network analyses revealed altered amino acid metabolism and lipid metabolism, especially for the tryptophan-kynurenine pathway and fatty acid metabolism, in the peripheral system of MDD patients.
Our findings may facilitate biomarker development and the elucidation of the molecular mechanisms that underly MDD.
4L-serine homeostasis in health and diseaseSystematic ReviewCited 42×2023
A serine tolerance test may provide a quantitative readout of l-serine homeostasis that identifies patients who may be susceptible to neuropathy or responsive to therapy.
Handzlik MK et al. · Annual review of nutrition (2023)
Compromised regulation or activity of l-serine synthesis and disposal occurs in the context of genetic diseases as well as chronic disease states, leading to low circulating l-serine levels and pathogenesis in the nervous system, retina, heart, and aging muscle.
Dietary interventions in preclinical models modulate sensory neuropathy, retinopathy, tumor growth, and muscle regeneration.
A serine tolerance test may provide a quantitative readout of l-serine homeostasis that identifies patients who may be susceptible to neuropathy or responsive to therapy.
This review aims to summarize the research progress of serine in diseases, propose the problems that need to be solved in the future, and provide guidance for subsequent research and development.
Li P, Wu X, Huang Y, Qin R, Xiong P, Qiu Y. · Frontiers in cellular and infection microbiology (2025)
An increasing number of studies have demonstrated that L-serine is widely used in the adjuvant therapy of many diseases (e.g., inflammation, infections, fibrosis, and tumors).
Here, we summarize the synthesis and metabolism of serine followed by its functions in health and disease.
Moreover, we delineate the potential mechanisms whereby L-serine is involved in the occurrence and progression of respiratory diseases.
6SLC1A4 role in neurodevelopment and neurodegenerationReview2025
This review examines the role of SLC1A4 in neurodevelopment and neurodegeneration and assesses the therapeutic potential of serine supplementation to treat neurodevelopmental symptoms associated with mutations in SLC1A4 , as well as schizophrenia, depression, traumatic brain injury, and Alzheimer's and Parkinson's diseases.
Elazar D, Alvarez N, Drobeck S, Gunn TM. · International journal of molecular sciences (2025)
In the brain, SLC1A4 plays an important role in transporting levo (L) and dopa (D) isomers of serine.
L-serine is required for many cellular processes, including protein and sphingolipid synthesis, while D-serine is a co-agonist required for normal neurotransmission through N -methyl-D-aspartate receptors.
Through its roles transporting L-serine across the blood-brain barrier and regulating synaptic D-serine levels, SLC1A4 helps establish and maintain brain health across the lifespan.
l-Serine and EPA were effective for pain relief in adults with low-back and knee pain after multiplicity adjustment.This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as UMIN000035056.
Sasahara I et al. · The Journal of nutrition (2020)
l-Serine and EPA were effective for pain relief in adults with low-back and knee pain after multiplicity adjustment.This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as UMIN000035056.
This study suggests the possibility of personalizing sleep-support supplementation based on personal life habits, sleep conditions, and sleep problems, in addition to the known efficacy of dietary supplements.
Imafuku F et al. · Nutrients (2023)
All the tested supplements were found to ameliorate sleep problems significantly (Analysis 1).
In Analysis 2, the PCs specific to improved subjects were found to differ depending on the dietary supplements and sleep problems.
In addition, subjects who consumed dairy products often showed improvement in their sleep problems with all the tested supplements.
9Clinical improvement in GRIN2B-NDD patientsRCT2025
These pioneering n-of-1 trials provide insights into l-serine's potential for GRIN2B-NDD, with improvements in two of four patients, though no clear distinguishing responder-characteristics were identified.
den Hollander B et al. · Molecular genetics and metabolism (2025)
Huge benefit
← WorseNo effectBetter →
These pioneering n-of-1 trials provide insights into l-serine's potential for GRIN2B-NDD, with improvements in two of four patients, though no clear distinguishing responder-characteristics were identified.
Future trials should focus on refining patient selection, the use of multiple baseline designs, establishing a core outcome set and pooling treatment data to better understand patient-specific responses.
10ADAS-Cog score improvementRCTCited 65×n=12 · very small study2023
Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis.
Yulug B et al. · Translational neurodegeneration (2023)
Large benefit
← WorseNo effectBetter →
Likely real
We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P = 0.00001, 29% improvement) in the CMA group.
Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment.
Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis.
11Clinical improvement in GRIN-related encephalopathyRCTCited 24×2024
L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity.
Juliá-Palacios N et al. · Brain : a journal of neurology (2024)
Noticeable benefit
← WorseNo effectBetter →
Likely real
Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy.
Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group.
The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points.
In terms of intestinal metabolites, the levels of acylcarnitine18:0 (ACar.18:0), cotinine, N-arachidonoyl-L-serine, phosphatidylcholine ... changed after FMT.
Zhi W et al. · Scientific reports (2024)
Flow cytometry analysis showed the absolute count of plasma B cells decreased in subjects, and this change correlated with alterations in the intestinal microbiota and metabolites.
This study preliminarily evaluates the safety and efficacy of FMT in patients with IgAN.
No significant adverse reactions were observed, and the administration of FMT alongside ACEI/ARB therapy was effective in reducing urinary protein levels in patients with IgAN, a process that may be associated with B-cell immunity.
The protocol called for enrollment of patients with a diagnosis of probable or definite ALS, age 18-85 years, disease duration of less than three years and forced vital capacity (FVC) ≥ 60%.
Of 20 patients enrolled, one withdrew before receiving study drug and two withdrew with gastro-intestinal problems.
15Cognition and mood in older adultsRCTCited 36×n=50 · small study2016
D-serine administration may be a strategy to improve spatial memory, learning and problem solving in healthy older adults.
Avellar M et al. · Oncotarget (2016)
Noticeable benefit
← WorseNo effectBetter →
Likely real
D-serine administration improved performance in the Groton Maze learning test of spatial memory and learning and problem solving (F(3, 38)= 4.74, p = 0.03).
Subjects that achieved higher increases in plasma D-serine levels after administration improved more in test performance (r2=-0.19 p = 0.009).
Future studies should evaluate the impact of long-term D-serine administration on cognition in older adults.
The results show that treating patients infected with COVID-19 with CMAs lead to a more rapid symptom-free recovery, suggesting a role for such a therapeutic regime in the treatment of infections leading to respiratory problems.
Altay O et al. · Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2021)
Plasma levels of proteins and metabolites associated with inflammation and antioxidant metabolism are significantly improved in patients treated with CMAs as compared to placebo.
A comprehensive analysis of the plasma metabolome and proteome reveals major metabolic changes.
The results show that treating patients infected with COVID-19 with CMAs lead to a more rapid symptom-free recovery, suggesting a role for such a therapeutic regime in the treatment of infections leading to respiratory problems.
17CMTNS improvementRCTCited 96×n=18 · very small study2019
High-dose oral l-serine supplementation appears safe in patients with HSAN1 and is potentially effective at slowing disease progression.
Fridman V et al. · Neurology (2019)
Noticeable benefit
← WorseNo effectBetter →
Likely real
After 1 year, the l-serine group experienced improvement in CMTNS relative to the placebo group (-1.5 units, 95% CI -2.8 to -0.1, p = 0.03), with evidence of continued improvement in the second year of treatment (-0.77, 95% CI -1.67 to 0.13, p = 0.09).
Concomitantly, deoxysphinganine levels dropped in l-serine-treated but not placebo-treated participants (59% decrease vs 11% increase; p < 0.001).
High-dose oral l-serine supplementation appears safe in patients with HSAN1 and is potentially effective at slowing disease progression.
18L-serine metabolism in intestinal mucosal homeostasisReview2026
Finally, we highlight directions for future research to target L-serine as a promising therapy.
Devaux A et al. · Communications biology (2026)
Prokaryotic cells, including Escherichia coli, have developed mechanisms to exploit L-serine to support their growth, virulence, inflammatory and/or carcinogenic properties.
In this review, we summarize current findings on L-serine metabolism in the intestinal mucosal homeostasis, its interactions with microbiota, and its modulation in digestive diseases.
Finally, we highlight directions for future research to target L-serine as a promising therapy.
Understanding these pathways could highlight new therapeutic targets to mitigate brain injury.
Carretero VJ, Álvarez-Merz I, Hernández-Campano J, Kirov SA, Hernández-Guijo JM. · Neural regeneration research (2025)
Blocking N-methyl-D-aspartate receptors prevented neuronal damage in the presence of these amino acids during hypoxia.
Thus, previously unrecognized mechanisms involving non-excitatory amino acids may contribute to the progression and expansion of brain injury in neurological emergencies such as stroke and traumatic brain injury.
Understanding these pathways could highlight new therapeutic targets to mitigate brain injury.
Well-controlled studies in subjects without glycine deficit are required to examine the potential benefits of high doses of glycine as a pharmaconutrient.
Holeček M. · Metabolism: clinical and experimental (2025)
It can, therefore, be assumed that, rather than glycine alone, its coadministration with l-serine is more appropriate in glycine-deficient conditions.
Replacing a part of the glycine with l-serine should avoid (i) glycine flux through SHMT towards l-serine associated with the loss of methylenetetrahydrofolate, a substance essential for methylation reactions, and (ii) ammonia formation due to glycine flux through the glycine cleavage system.
Unfortunately, studies comparing the effects of separate administration of glycine and its coadministration with l-serine do not exist.