A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-L-methionine (SAMe) versus escitalopram in major depressive disorder.
In the largest placebo-controlled SAMe trial, SAMe, escitalopram and placebo all landed in the same place — does that tell us SAMe doesn't work, or that the trial couldn't detect anything?
Well-supported by good-quality research. how we score evidence
Caveat on this rating: This is a failed trial, not simply a negative one: escitalopram, a drug with established efficacy, also failed to beat placebo, which means the study lacked assay sensitivity and cannot cleanly rule SAMe out. Two later papers re-analysed subsets of the same dataset and reported positive findings — a single-site subsample (Sarris 2014, J Affect Disord, PMID 24856557, n=144, SAMe superior to placebo) and a male-only subgroup (Sarris 2015, Pharmacopsychiatry, PMID 26011569, significant in 51 men, not in 62 women). Post-hoc subgroups from a failed trial are hypotheses, not results.
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. There is no prescription SAMe product in the US, though in some other countries SAMe has been available as a prescription medicine — which is part of why much of the older trial literature used intravenous or intramuscular SAMe at doses that do not map onto the oral tablets on a US shelf. Oral SAMe is chemically unstable and depends on enteric coating and salt form (tosylate, butanedisulfonate) for absorption, so the number on the label and the amount that reaches the bloodstream are not the same thing, and no regulator verifies either before sale.
189 outpatients with major depressive disorder were randomised for 12 weeks to SAMe (1,600-3,200 mg/day), escitalopram (10-20 mg/day), or placebo. All three arms improved by about 5-6 points on the 17-item Hamilton scale and none separated from any other: response was 36% on SAMe, 34% on escitalopram, and 30% on placebo; remission was 28%, 28%, and 17%. The authors' own conclusion is that the results fail to support an advantage over placebo for SAMe — or, notably, for the standard antidepressant used as the active comparator, which marks this as a failed trial rather than a clean negative. Gastrointestinal effects were the commonest complaint on SAMe (19% stomach discomfort, 20% diarrhoea).
Worth asking
In the largest placebo-controlled SAMe trial, SAMe, escitalopram and placebo all landed in the same place — does that tell us SAMe doesn't work, or that the trial couldn't detect anything?
What to watch for
Evidence quality tells you whether to trust the finding — not whether the treatment is safe. These are the risks this research reports.
- Psychosis & mania
- Interactions with other medicines
- Sleep disruption
- Stomach & digestion
Source
A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-L-methionine (SAMe) versus escitalopram in major depressive disorder. — Mischoulon D, Price LH, Carpenter LL, Tyrka AR, Papakostas GI, et al. (2014)
Reputable peer-reviewed journal
Read the source: https://doi.org/10.4088/JCP.13m08591
DOI: 10.4088/JCP.13m08591
How this was scored
- Study design
- Randomised controlled trial
- Funding
- Mixed public and industry funding
- Published in
- Reputable peer-reviewed journal
- Sample size
- 189
- Preregistered
- Yes
- Conflicts disclosed
- No
- Independent of proponent
- Yes
- Retracted
- No
Read the full scoring rubric, including what it can't tell you.
Published August 19, 2026. Last verified September 10, 2026.
Where we put this study in context
Questions
How strong is the evidence behind this?
veisund rates this source "strong evidence". Well-supported by good-quality research. It scores 72 out of 100 on our published rubric. One caveat travels with that badge: This is a failed trial, not simply a negative one: escitalopram, a drug with established efficacy, also failed to beat placebo, which means the study lacked assay sensitivity and cannot cleanly rule SAMe out. Two later papers re-analysed subsets of the same dataset and reported positive findings — a single-site subsample (Sarris 2014, J Affect Disord, PMID 24856557, n=144, SAMe superior to placebo) and a male-only subgroup (Sarris 2015, Pharmacopsychiatry, PMID 26011569, significant in 51 men, not in 62 women). Post-hoc subgroups from a failed trial are hypotheses, not results. 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?
A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-L-methionine (SAMe) versus escitalopram in major depressive disorder. — Mischoulon D, Price LH, Carpenter LL, Tyrka AR, Papakostas GI, et al. (2014). Published in: Reputable peer-reviewed journal. DOI: 10.4088/JCP.13m08591. 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: Mixed public and industry funding. The researchers were independent of whoever benefits from the result. 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. There is no prescription SAMe product in the US, though in some other countries SAMe has been available as a prescription medicine — which is part of why much of the older trial literature used intravenous or intramuscular SAMe at doses that do not map onto the oral tablets on a US shelf. Oral SAMe is chemically unstable and depends on enteric coating and salt form (tosylate, butanedisulfonate) for absorption, so the number on the label and the amount that reaches the bloodstream are not the same thing, and no regulator verifies either before sale.
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.