SAMe — The Universal Methyl Donor
S-adenosylmethionine (SAMe) is the body's primary methyl donor, participating in over 100 biochemical reactions including DNA methylation, neurotransmitter synthesis, and phospholipid production. It is one of the most clinically studied supplements for depression, liver disease, and osteoarthritis, with multiple RCTs and meta-analyses supporting its efficacy.
Mechanism of Action
SAMe donates methyl groups to DNA, RNA, proteins, and lipids via methyltransferases. In the brain, it is required for synthesis of dopamine, serotonin, and norepinephrine. In the liver, it supports glutathione synthesis and phosphatidylcholine production. SAMe levels decline with age, B12/folate deficiency, and liver disease. It is the intersection of the methionine cycle and the folate cycle.
Human Trial Evidence
A 2002 Agency for Healthcare Research and Quality systematic review found SAMe equivalent to NSAIDs for osteoarthritis pain with fewer GI side effects. A 2002 American Journal of Clinical Nutrition meta-analysis confirmed efficacy for depression comparable to tricyclic antidepressants. Multiple RCTs support liver-protective effects in alcoholic and non-alcoholic liver disease.
Dosing Protocol
400–1,600 mg/day in divided doses, taken on an empty stomach (30 min before meals). Start at 400 mg/day and titrate. Enteric-coated forms have better stability. Take with B12 and folate to support the methionine cycle. Best taken in the morning — may cause insomnia if taken late.
Safety & Contraindications
Generally well-tolerated. GI side effects (nausea, diarrhoea) at higher doses. May trigger mania in bipolar disorder — contraindicated without mood stabiliser. Mild anxiety or insomnia possible. Avoid with MAOIs (serotonin syndrome risk). Monitor homocysteine with long-term use.