400–1,600 mg/day (depression); 600–1,200 mg/day (osteoarthritis). Best with an enteric coating.
Efficacy comparable to some antidepressants in several studies.
View the study (meta-analysis) →Relieves pain similarly to an anti-inflammatory, but with a slower onset.
View the study (RCT) →⏱ 3 min read
SAMe, or S-adenosyl-L-methionine, is an endogenous molecule central to mammalian metabolism: it is synthesized from methionine and ATP in practically all cells of the body and acts as a universal methyl group donor in more than 100 biosynthetic reactions, including the synthesis of monoaminergic neurotransmitters (serotonin, dopamine, norepinephrine), membrane phospholipids, nucleic acids, and articular cartilage proteins; this metabolic centrality explains the unusually broad clinical profile it has shown in controlled trials in three main indications: depression, osteoarthritis, and liver disease.
As an oral supplement, SAMe presents the technical challenge of being a very unstable molecule that tends to degrade rapidly with moisture and heat; the clinically effective products are enteric-coated formulations with stable salts (tosylate disulfate or butanedisulfonate) that allow reasonable bioavailability; cheap products in unprotected packaging often contain a significant proportion of degraded SAMe and are therapeutically ineffective, an important feature for understanding the variability of clinical results with commercial products.
The indication with the best clinical evidence is mild to moderate major depression: several randomized trials and meta-analyses have shown efficacy comparable to classic tricyclic antidepressants (imipramine, amitriptyline) at doses of 800-1,600 milligrams per day for 4-8 weeks, with a significantly more favorable adverse-effect profile, without the anticholinergic, sedative, or sexual effects typical of pharmacological antidepressants.
A meta-analysis published by the U.S. Agency for Healthcare Research and Quality in 2002 concluded that SAMe was significantly superior to placebo and comparable to tricyclic antidepressants in major depression; subsequent studies have evaluated it as an enhancer of the effect of SSRIs in patients with a partial response, an indication with positive data in a randomized trial published in the American Journal of Psychiatry in 2010.
In symptomatic osteoarthritis (knee, hip, spine), several randomized trials have shown efficacy comparable to nonsteroidal anti-inflammatory drugs (ibuprofen, naproxen) at doses of 1,200 milligrams per day for 12-24 weeks, with a significantly better adverse-effect profile (without the gastrointestinal, renal, or cardiovascular risk of conventional anti-inflammatories); the onset of action is slower than that of anti-inflammatories (several weeks vs. hours), but the sustained effects are comparable or superior.
In cholestatic liver disease (especially cholestasis of pregnancy, alcoholic hepatitis, and primary biliary cholangitis), SAMe at doses of 1,600 milligrams orally per day or 800 milligrams intravenously has shown improvements in hepatic biochemical parameters and in clinical prognosis in several trials, an indication recognized in some countries such as Italy and Spain, where SAMe is available as a medication (Adometionine).
The doses studied range from 400 to 1,600 milligrams per day, divided into 2-3 doses on an empty stomach to improve absorption; for depression, escalate gradually from 400 mg/day to 800-1,600 mg/day over 1-2 weeks; for osteoarthritis, 1,200 mg/day for at least 12 weeks; enteric-coated formulations are significantly more effective than unprotected tablets.
Generally well tolerated; the most frequent adverse effects are mild digestive discomfort (nausea, dyspepsia), insomnia (especially if taken in the afternoon, which is why taking it in the morning is recommended), and anxiety or irritability in predisposed people; people with bipolar disorder should use great caution because SAMe can precipitate a switch to hypomania or mania, a well-documented complication; those taking serotonergic antidepressants (SSRIs, SNRIs, MAOIs) should use it only under medical supervision because of the theoretical risk of serotonin syndrome; in pregnancy it has been used for cholestasis without significant problems, but medical supervision is advisable.
Information, not medical advice. Scientific evidence reflects the quality of the studies.