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SAMe (S-Adenosyl Methionine)

Acting as a universal methyl donor for neurotransmitter synthesis and supporting liver detoxification processes.

nutrient
Evidence · Grade BSafety · Use with caution
Human trial evidenceTraditional useSafety cautionInteraction risk

SAMe is a naturally occurring methyl donor investigated for its role in treating depression, liver disease, and inflammatory pain. It is recognized in clinical guidelines as a potential adjunctive or monotherapy for mood disorders.

Last reviewed June 13, 2026 · AI-assisted, human-reviewed
S-Adenosyl Methionine (SAMe) is a naturally occurring compound found in almost every tissue and fluid in the human body. It is a universal methyl donor derived from the amino acid methionine and adenosine triphosphate (ATP). In the context of mental health, SAMe has been evaluated as a nutraceutical for the management of depressive disorders. Clinical guidelines from the World Federation of Societies of Biological Psychiatry (WFSBP) and CANMAT suggest it may play a role in psychiatric treatment, though evidence levels vary by condition. Beyond psychiatry, SAMe is investigated for its potential role in liver health, specifically regarding non-alcoholic steatohepatitis (NASH), and as a supportive agent in chronic inflammatory conditions like fibromyalgia and rheumatoid arthritis. Its biological relevance is closely tied to the folate and one-carbon cycles, which are essential for DNA methylation and gene expression.

Quick answer

What it is: S-Adenosyl Methionine (SAMe) is a naturally occurring compound found in almost every tissue and fluid in the human body.

May support:PMDD, Seasonal Affective Disorder, Rheumatoid Arthritis, Liver Disease, Depression, Fibromyalgia

Evidence:Evidence · Grade B

Safety:Safety · Use with caution

Evidence Summary

Evidence · Grade B

Clinical guidelines (WFSBP/CANMAT) categorize SAMe as a relevant nutraceutical for psychiatric disorders based on human clinical trials showing efficacy in mood regulation. In liver research, randomized controlled trials have compared its efficacy against other agents like pentoxifylline for treating non-alcoholic steatohepatitis (NASH) with fibrosis, focusing on its ability to reduce hepatic inflammation.

Last reviewed · Jun 2026

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Why It Works

SAMe facilitates methylation, a biochemical process essential for the synthesis of neurotransmitters (serotonin, dopamine, norepinephrine) and the regulation of gene expression through epigenetic modification.

How it works in more detail

SAMe serves as a primary methyl group donor in the one-carbon cycle. By donating a methyl group, it permits the conversion of precursors into active neurotransmitters and supports the maintenance of cell membranes. In liver health, it acts as a precursor to glutathione, the body's primary antioxidant, helping to mitigate oxidative stress. Research indicates that mutations affecting the folate cycle can impact SAMe availability, thereby influencing DNA and histone methylation which are critical for cell division and embryo development.

How to use

Always consult a qualified clinician.

Editorial guidance

Suggested dosage
400–1600 mg/day on empty stomach
Research dosage range
Commonly studied doses in clinical trials for depression range from 400 mg to 1600 mg daily, often divided into two doses.
Typical onset
1–2 weeks
Typical forms
capsule, tablet
Quality markers
When purchasing SAMe, look for products that are enteric-coated to protect the compound from stomach acid, ensuring better absorption. Check for third-party testing for purity and potency, and ensure the product is stored in a cool, dry place as SAMe is sensitive to heat and moisture.
Medication interactions
  • Antidepressants (SSRIs, MAOIs, tricyclics)
  • Levodopa (L-Dopa)
  • Dextromethorphan
  • Tramadol
  • St. John's Wort
Avoid if
  • Bipolar disorder (risk of mania)
  • Taking antidepressant medications (without medical supervision)
  • Parkinson's disease (potential interaction with L-Dopa)
  • Pregnant or breastfeeding (insufficient safety data)

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Suggested dosage

400–1600 mg/day on empty stomach

General guidance — discuss specifics with a clinician.

Active medicinal compounds

The primary active compound is S-Adenosyl Methionine itself.

Traditional use

SAMe is a naturally occurring compound in the body and does not have a history of traditional use as a botanical remedy in herbal medicine systems. Its therapeutic applications are a result of modern biochemical research and clinical studies.

Safety

Safety warnings

SAMe may trigger mania in individuals with bipolar disorder. Potential side effects include gastrointestinal distress, anxiety, or insomnia. It should be used under medical supervision, especially when combined with other serotonergic medications to avoid serotonin syndrome.

Avoid if

  • Bipolar disorder (risk of mania)
  • Taking antidepressant medications (without medical supervision)
  • Parkinson's disease (potential interaction with L-Dopa)
  • Pregnant or breastfeeding (insufficient safety data)

Medication interactions

  • Antidepressants (SSRIs, MAOIs, tricyclics)
  • Levodopa (L-Dopa)
  • Dextromethorphan
  • Tramadol
  • St. John's Wort

Reported side effects

  • Nausea
  • Diarrhea
  • Constipation
  • Dry mouth
  • Headache
  • Insomnia
  • Anxiety
  • Mild gastrointestinal upset

General guidance — discuss specifics with a clinician.

Evidence ecosystem

Scientific literature, clinical guidance, government sources, ongoing research, traditional use, and lived experience — grouped by source type and quality.

Overall grade (B)

Clinical guidelines (WFSBP/CANMAT) categorize SAMe as a relevant nutraceutical for psychiatric disorders based on human clinical trials showing efficacy in mood regulation. In liver research, randomized controlled trials have compared its efficacy against other agents like pentoxifylline for treating non-alcoholic steatohepatitis (NASH) with fibrosis, focusing on its ability to reduce hepatic inflammation.

Filter by source type

Observational Studies(3)

Cohort, case-control, and cross-sectional human studies.

Moderate Quality
  • Folic Acid, Folinic Acid, 5 Methyl TetraHydroFolate Supplementation for Mutations That Affect Epigenesis through the Folate and One-Carbon Cycles.

    Menezo Y, Elder K, Clement A, Clement P · Biomolecules · 2022

    Methylation is an essential biochemical mechanism that is central to the transmission of life, and crucially responsible for regulating gametogenesis and continued embryo development. The methylation of DNA and histones drives cell division and regulation of gene expression through epigenesis and imprinting. Brain development and its maturation also depend on correct lipid methylation, and continued neuronal function depends on biogenic amines that require methylation for their synthesis. All methylation processes are carried out via a methyltransferase enzyme and its unique co-factor S-adenosylmethionine (SAM); the transfer of a methyl group to a target molecule results in the release of SAH (SA homocysteine), and then homocysteine (Hcy). Both of these molecules are toxic, inhibiting methylation in a variety of ways, and Hcy recycling to methionine is imperative; this is achieved via the one carbon cycle, supported by the folates cycle. Folate deficiency causes hyperhomocysteinaemia,

    Observational StudyPubMedLow Quality
  • Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce.

    Sarris J, Ravindran A, Yatham LN, Marx W, Rucklidge JJ, McIntyre RS · The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry · 2022

    The therapeutic use of nutrient-based 'nutraceuticals' and plant-based 'phytoceuticals' for the treatment of mental disorders is common; however, despite recent research progress, there have not been any updated global clinical guidelines since 2015. To address this, the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Disorders (CANMAT) convened an international taskforce involving 31 leading academics and clinicians from 15 countries, between 2019 and 2021. These guidelines are aimed at providing a definitive evidence-informed approach to assist clinicians in making decisions around the use of such agents for major psychiatric disorders. We also provide detail on safety and tolerability, and clinical advice regarding prescription (e.g. indications, dosage), in addition to consideration for use in specialised populations. The methodology was based on the WFSBP guidelines development process. Evidence was assessed based on th

    Observational StudyPubMedLow Quality
  • Nutritional psychiatry: the present state of the evidence.

    Marx W, Moseley G, Berk M, Jacka F · The Proceedings of the Nutrition Society · 2017

    Mental illness, including depression, anxiety and bipolar disorder, accounts for a significant proportion of global disability and poses a substantial social, economic and heath burden. Treatment is presently dominated by pharmacotherapy, such as antidepressants, and psychotherapy, such as cognitive behavioural therapy; however, such treatments avert less than half of the disease burden, suggesting that additional strategies are needed to prevent and treat mental disorders. There are now consistent mechanistic, observational and interventional data to suggest diet quality may be a modifiable risk factor for mental illness. This review provides an overview of the nutritional psychiatry field. It includes a discussion of the neurobiological mechanisms likely modulated by diet, the use of dietary and nutraceutical interventions in mental disorders, and recommendations for further research. Potential biological pathways related to mental disorders include inflammation, oxidative stress, th

    Observational StudyPubMedLow Quality

Clinical Trial Registries(2)

Registered ongoing or completed trials (ClinicalTrials.gov).

Moderate Quality
  • A Randomized Controlled Trial to Study the Efficacy of S-adenosyl Methionine (SAMe) Versus Pentoxiphylline in Patients With Non-alcoholic Steatohepatitis With Fibrosis.

    n=122 · NCT02231333 · COMPLETED · COMPLETED

    Nonalcoholic fatty liver disease is one the most commonly encountered conditions in a daily outpatient Hepatology clinic. Secondly our country is the diabetic capital of the world and so the incidence of NAFLD (Non Alcoholic Fatty Liver Disease) is expected to rise in the future. It is a spectrum of hepatic pathology, ranging from simple steatosis, steatohepatitis, to cirrhosis. Nonalcoholic steatohepatitis (NASH) is a more advanced form of disease where steatosis is accompanied by hepatocyte injury as well as infiltration of inflammatory cells. Approximately 10-20% of patients with NASH may progress to cirrhosis. NASH is felt to be a major etiology of cryptogenic cirrhosis. Around 6230 human studies out of which 49 RCTs have been done till date to define the appropriate treatment of nonalcoholic steatohepatitis. However, still a controversy and no recommended treatment available till date. Recently published PIVENS trial has shown that Vitamin E has proven benefit in NASH. Other trials have also shown that pentoxiphylline has shown benefit in the form of histological improvement and biochemical improvement in the form of liver enzymes. Role of SAMe has been studied in alcoholic liver disease and showed to improve in both biochemical and histological features. However the usefulness of SAMe in NAFLD is not known till now. Hence this study has been designed.

    Clinical TrialClinicalTrials.govModerate Quality
  • Alcohol Abuse, Oxidative Stress, and Zinc Deficiency in Lung Disease

    n=113 · NCT01899521 · COMPLETED · COMPLETED

    This is a randomized, placebo controlled trial of dietary zinc and S-adenosylmethionine (SAMe) in otherwise healthy alcoholic US Veterans. The primary goal is to determine if either dietary zinc or S-adenosylmethionine (SAMe) can augment lung immune defenses in alcoholics and thereby decrease the risk of lung injury and infection.

    Clinical TrialClinicalTrials.govModerate Quality

Limitations: While mood-related studies are promising, more large-scale, long-term human trials are needed to standardize its use across different populations. Data regarding its efficacy in treating lung disease or specific mutations in the folate cycle remains observational or requires further clinical validation.

This page is educational. Statements use phrases like "may support" and "has been studied for"because no remedy here is approved to cure, treat, or reverse any condition. Discussion happens on the ailment pages — community statistics here are derived from those reports. Always consult a qualified clinician.

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