S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major…
If my antidepressant is only partly working, how does adding SAMe compare with the augmentation options you'd normally reach for first?
Reasonable evidence with real limitations. how we score evidence
Caveat on this rating: 73 participants across two arms is small enough that a handful of responders moves the result, and the trial has not been independently replicated in the sixteen years since — the Cochrane review, published six years later, still cites it as a single study. No funding statement or disclosure statement was read, so both funding and conflicts are recorded conservatively.
SAMe is sold in the US as a dietary supplement under DSHEA. The FDA has not approved it for depression, osteoarthritis, liver disease, or any other condition, and no premarket review of its safety or effectiveness applies.
73 people whose depression had not responded to an SRI kept taking it and were randomised to add SAMe (800 mg twice daily) or placebo for six weeks. Response was 36.1% on added SAMe versus 17.6% on added placebo, and remission 25.8% versus 11.7% — a number needed to treat of about one in six for response and one in seven for remission. Dropout for any reason (20.6% versus 29.5%) and for adverse events (5.1% versus 8.8%) did not differ. The authors called the results preliminary and explicitly said they warrant replication; this remains the single positive augmentation trial that the Cochrane review's add-on analysis rests on.
Worth asking
If my antidepressant is only partly working, how does adding SAMe compare with the augmentation options you'd normally reach for first?
Source
S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. — Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. (2010)
Top-tier peer-reviewed journal
Read the source: https://doi.org/10.1176/appi.ajp.2009.09081198
DOI: 10.1176/appi.ajp.2009.09081198
How this was scored
- Study design
- Randomised controlled trial
- Funding
- Funding not disclosed
- Published in
- Top-tier peer-reviewed journal
- Sample size
- 73
- Preregistered
- No
- Conflicts disclosed
- No
- Independent of proponent
- not recorded
- Retracted
- No
Read the full scoring rubric, including what it can't tell you.
Published August 19, 2026.
Questions
How strong is the evidence behind this?
Resolv rates this source "moderate evidence". Reasonable evidence with real limitations. It scores 60 out of 100 on our published rubric. One caveat travels with that badge: 73 participants across two arms is small enough that a handful of responders moves the result, and the trial has not been independently replicated in the sixteen years since — the Cochrane review, published six years later, still cites it as a single study. No funding statement or disclosure statement was read, so both funding and conflicts are recorded conservatively. The score is calculated from recorded facts about the source — study design, funding, publication venue, sample size, preregistration — not typed in by an editor.
What is the source for this?
S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. — Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. (2010). Published in: Top-tier peer-reviewed journal. DOI: 10.1176/appi.ajp.2009.09081198. The full source is linked on this page so you can read it yourself.
Who paid for this research, and does that matter?
Study design: Randomised controlled trial. Funding: Funding not disclosed. Independence from the proponent is not recorded. Industry sponsorship is one of the most reliably measured biases in medicine, which is why funding carries real weight in the score rather than sitting in a footnote.
Is same, s-adenosyl methionine, s-adenosyl-l-methionine, sam-e, ademetionine FDA approved for this use?
No. Its current status is: Not FDA-evaluated for this use. SAMe is sold in the US as a dietary supplement under DSHEA. The FDA has not approved it for depression, osteoarthritis, liver disease, or any other condition, and no premarket review of its safety or effectiveness applies.
Is this medical advice?
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.