The universal methyl donor of human metabolism, formed from methionine and ATP. It participates in the methylation of neurotransmitters, phospholipids, DNA and many drugs.
SAMe is a prescription medicine in several European countries and a supplement in the US, and it has more genuine clinical evidence than most things in this category. Systematic reviews find it superior to placebo in depression and broadly comparable to tricyclic antidepressants in the trials that made that comparison, and it has been studied as an adjunct in people who did not respond to SSRIs. Osteoarthritis reviews are more cautious, describing the evidence as inconclusive. Two safety issues matter more than the efficacy debate: SAMe can precipitate mania in people with bipolar disorder, and its serotonergic activity creates a serotonin syndrome risk with antidepressants.
Sold as
Enteric-coated tablet, Capsule, Injectable (clinical use in some countries)
Standardised to
mg of the ion, as tosylate disulfate or butanedisulfonate salts — salt weight is much higher than ion weight — a product without this marker may not resemble what was studied.
Regulation: A prescription medicine in Italy, Spain, Germany and elsewhere, and a dietary supplement in the US with no pre-market efficacy review. SAMe is unstable and requires enteric coating and careful storage, so product quality varies considerably.
What the research used
The amounts, forms and durations published trials of SAMe (S-adenosylmethionine) actually administered.
These are the amounts published trials administered — not a recommendation, and not a dose to copy. Trial participants were screened, supervised and given a characterised preparation. What is in a retail bottle is frequently not what was studied, and the amount that suits one person is not general advice.
Studied for Depression
400–1600 mg
Moderate
Divided oral doses daily · 2–12 weeks
Trials commonly used 800–1,600 mg/day, either alone or added to an SSRI in people who had not responded. Doses refer to the active ion rather than to the salt.
Studied for Osteoarthritis
600–1200 mg
Limited
Divided doses daily · 4–24 weeks
Trials compared SAMe with non-steroidal anti-inflammatory drugs. A Cochrane review judged the evidence inconclusive and the trials small and of uncertain quality.
This is general information about food, not medical advice. It cannot diagnose, treat or replace guidance from a clinician who knows your history.
When it was taken
Each window says whether a trial compared it against an alternative, or whether it is convention and pharmacology. Most timing advice is the second kind.
None of the timings below were directly compared in a trial. They reflect how the research happened to dose, or what the pharmacology implies — which is not the same as a timing being better.
⏳On an empty stomach
Not enough
Taken between meals in most trial protocols because absorption is better fasted, and often earlier in the day because it can be activating. The absorption point is pharmacological; the morning convention is not tested.
Timing was not directly compared. This reflects convention or how the compound behaves in the body, not a trial showing this window works better.
The evidence in depth
Best supported: Moderate
What each association actually rests on, and the papers behind it. A rating describes the state of the research, not how promising the supplement sounds. How we rate evidence.
Systematic reviews find SAMe more effective than placebo in depression and comparable to tricyclic antidepressants in head-to-head trials, with some evidence as an add-on for people who did not respond to SSRIs. Trials are mostly short, sample sizes modest, and dosing and preparations vary.
What may be going on: As the principal methyl donor, SAMe participates in the synthesis and metabolism of monoamine neurotransmitters and in phospholipid methylation affecting membrane fluidity.
Moderate evidence. Several human studies point the same way, with real caveats.
SAMe has been studied in intrahepatic cholestasis and in alcohol-related liver disease, including as an injectable in some countries. Reviews describe the evidence as insufficient to establish benefit on clinically important outcomes.
Limited evidence. Early human work, or mostly lab and animal research.
Trials in osteoarthritis report pain reduction comparable to non-steroidal anti-inflammatory drugs, but a Cochrane review concluded the evidence was inconclusive and the included studies small and heterogeneous.
Not enough evidence. Not enough human research to say anything useful yet.
No source is attached to this association yet, so it is rated not enough evidenceby default. It is listed because people commonly ask about it — not because there is evidence for it.
Things to know
Interactions, contraindications and dose limits, most serious first. Concentrated extracts interact with medication in ways the whole plant does not, so this section carries more weight here than it does on a food page.
Avoid
Mania in bipolar disorder
SAMe has precipitated hypomania and mania in people with bipolar disorder, including in people whose diagnosis was not known at the time. Anyone with bipolar disorder, or with a family history and unexplained mood elevation, should not take it outside psychiatric supervision. This is the most important caution on this entry.
Interaction
Serotonin syndrome
Interacts withSSRIs, SNRIs, MAO inhibitors, tricyclic antidepressants, tramadol, triptans, St John’s wort
Combining SAMe with SSRIs, SNRIs, MAO inhibitors, tricyclics, tramadol, triptans or St John’s wort can precipitate serotonin syndrome. Trials that added SAMe to an SSRI did so under supervision with monitoring.
Worth knowing
Homocysteine and B vitamin status
SAMe metabolism generates homocysteine, which is remethylated using folate, vitamin B12 and vitamin B6. Adequate status of those vitamins is generally considered necessary during use, particularly in people with an existing homocysteine problem.
Too much
Gastrointestinal upset, insomnia and anxiety
Nausea, dry mouth, restlessness, insomnia and anxiety are the common complaints, more likely at higher doses and when taken late in the day.