can you take same with an antidepressant?

it has mostly been studied that way: the one positive trial added same to a serotonin reuptake inhibitor that was not working, with response 36.1% against 17.6% on added placebo and no more dropouts for side effects. combining is not itself unusual, but starting it alongside an antidepressant is a prescriber’s decision, the result has never been replicated, and the tranylcypromine (maoi) label lists same among the products not to combine with that drug.

does same cause mania?

it can. the cochrane review recorded two reports of mania or hypomania among 441 people who received same, and the american psychiatric association review documents that mania seen in early studies is why later trials excluded bipolar disorder and enrolled only unipolar depression. anyone with bipolar disorder, a past manic or hypomanic episode, or a strong family history has a reason to involve a psychiatrist before taking it.

is same fda approved?

no. it is sold in the united states as a dietary supplement under dshea, with no fda review of safety or effectiveness before sale, and has not been approved for depression, osteoarthritis, liver disease or any other condition. there is no prescription same product in the united states, though some other countries have sold it as a prescription medicine, often by injection, which is why many older trials used doses and routes that do not match oral tablets.

Supplement evidence

SAMe

The depression trials, and the mania and interaction signals.

page first published 2026-09-08 · last updated 2026-10-06

Not an FDA-approved treatmentSold as a dietary supplement4 studies on this page

What Its Legal Status Actually Means

Read this before anything below it. Legal to sell is not the same fact as reviewed, verified, or approved.

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.

Quoted whole from the 2026-08-18 study harvest. Not summarized, not shortened.

does same work for depression? what the trials say

there is no fda label for same, because it is sold as a dietary supplement and has never been reviewed for effectiveness. the regulatory facts below come from the legal-status paragraph above, written from the regulator’s documents in the 2026-08-18 study harvest; every trial figure is from a study record on this page or a library row linked at the end. every source is linked at the end of this section. last checked 2026-10-06.

same, s-adenosyl methionine, is a compound the body makes and uses in methylation reactions, sold in tablets for depression, osteoarthritis and liver disease. it is unusual among supplements in having a real trial literature, including a cochrane review, a 189-person placebo-controlled trial against an ssri, and a trial as an add-on in people whose antidepressant had not worked. this section says what its legal status means, what the trials measured and in whom, what they found in both directions, the one risk the trials themselves changed their design around, and who wrote the reviews. every number is from a study record on this page or a library row, and each source is linked at the end.

this is information to take to a prescriber or pharmacist. nothing here tells anyone to take same or to stop, and nothing here is a reason to put off treatment that works.

what its legal status means, and does not mean

same is sold in the united states as a dietary supplement under the 1994 dietary supplement health and education act. the fda has not approved it for depression, osteoarthritis, liver disease or any other condition, and no premarket review of safety or effectiveness applies [status]. there is no prescription same product in the united states, though in some other countries it 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 [status].

one fact about the product itself belongs here. oral same is chemically unstable and depends on its 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 [status]. legal to sell is not the same fact as reviewed, verified or approved.

what the trials measured, in whom, and for how long

the cochrane review of 2016 pooled eight trials in 934 adults with major depression, comparing same with placebo, with standard antidepressants, and as an add-on to an ssri [galizia-2016]. the largest placebo-controlled trial randomised 189 outpatients with major depressive disorder for 12 weeks to same at 1,600 to 3,200 mg a day, escitalopram at 10 to 20 mg, or placebo [mischoulon-2014]. the add-on trial randomised 73 people whose depression had not responded to a serotonin reuptake inhibitor to keep taking it and add same at 800 mg twice daily or placebo for six weeks [papakostas-2010]. a work group of the american psychiatric association’s council on research screened 174 records and reviewed 132 studies, 115 of them clinical trials, across psychiatric and medical conditions [sharma-2017].

the trials ran six to twelve weeks. the parenteral trials from the 1970s and 1980s are pooled inside the reviews rather than listed here, because their dosing does not correspond to oral tablets [exclusions]. two re-analyses of subsamples from the failed 189-person trial, one single-site and one men-only, reported positive results and are excluded as study records because reporting them separately would count one negative trial three times [exclusions].

what the research says, in both directions

in favour. in the add-on trial, response was 36.1% on added same against 17.6% on added placebo and remission 25.8% against 11.7%, a number needed to treat of about six for response and seven for remission, with no difference in dropouts for any reason or for adverse events [papakostas-2010]. the american psychiatric association work group concluded that the evidence for major depressive disorder is "promising but limited" for both monotherapy and augmentation [sharma-2017]. in the 189-person trial, remission was 28% on same against 17% on placebo, the same 28% as on escitalopram [mischoulon-2014]. the cochrane review found same no different from two standard antidepressants [galizia-2016].

against, or smaller than it sounds. on its own, same did not clearly beat placebo in the cochrane review; its one positive signal, the add-on use, "came from a single study of seventy three people, rated low quality" [galizia-2016]. that study’s authors called their own results preliminary and said they warranted replication, and in the sixteen years since no one has replicated it; the cochrane review still cites it as a single study [papakostas-2010]. in the 189-person trial, same, escitalopram and placebo all improved by about five to six points on the 17-item hamilton scale and none separated from any other: response was 36%, 34% and 30%. that makes it a failed trial rather than a clean negative, because escitalopram, a drug with established efficacy, also failed to beat placebo, so the trial could not have detected a same effect either; the two post-hoc subsample analyses that found an effect are hypotheses, not results [mischoulon-2014; exclusions]. "no different from two standard antidepressants" in a review where the drug also did not clearly beat placebo is not the same finding as "works as well as an antidepressant" [galizia-2016]. the american psychiatric association review pools trials of widely varying quality, dose and route without a meta-analysis, so "promising but limited" is a judgement rather than an effect size, and two of its authors have direct commercial ties to same: one chaired the advisory board of and holds stock options in a same manufacturer and advises another, and one receives book royalties covering same [sharma-2017].

the mania signal, the side effects, and the interactions

the risk that changes decisions is mania. the cochrane review recorded two reports of mania or hypomania among 441 participants who received same, and the american psychiatric association review documents that mania seen in the early same studies is the reason later trials confined themselves to unipolar depression and excluded bipolar disorder [galizia-2016; sharma-2017; risks]. that is the clearest statement in the literature of why anyone with bipolar disorder, a past manic or hypomanic episode, or a strong family history has a reason to involve a psychiatrist before starting same [risks].

beyond that, the profile in the 189-person trial was mostly gastrointestinal: 19% on same reported stomach discomfort and 20% diarrhoea [mischoulon-2014]. anxiety, restlessness and insomnia are also reported, which is why it is usually taken earlier in the day [risks]. on interactions, same has most often been studied as an add-on to an ssri rather than instead of one, so combining is not itself unusual, but starting it alongside an antidepressant is a prescriber’s decision rather than a solo experiment, and levodopa in parkinson’s disease is a known interaction area [risks]. the clearest regulator statement is on an maoi label: the tranylcypromine prescribing information lists same by name among the products not to be combined with the drug [maoi-label].

questions for a prescriber or pharmacist about same

each one comes from a warning or a study above. they are questions, not instructions; the answers depend on a history nobody here has.

the one positive trial was same added to an antidepressant that was not working, in 73 people, never replicated. if my antidepressant is only partly working, how does adding same compare with the augmentation options you would normally reach for first?
same was linked to mania in the early studies, which is why later trials excluded bipolar disorder. is there anything in my history, or my family’s, that makes that a risk for me?
the largest placebo-controlled trial could not tell same, escitalopram or placebo apart. does that tell us same does not work, or that the trial could not detect anything, and how do you read it?
i take levodopa, an maoi, or another antidepressant. the maoi label names same; is anything i take a reason not to combine?
oral same is unstable and depends on its coating and salt form, and no regulator checks what reaches the blood. does that change which product, if any, you would be comfortable with?
the trials ran six to twelve weeks. if my mood has not improved in that time, what happens next?

questions people ask

does same work for depression?: not clearly on its own. the 2016 cochrane review of eight trials in 934 adults found same did not clearly beat placebo as a single treatment and was no different from two standard antidepressants; its one positive signal was same added to an ssri, from a single 73-person study rated low quality. the largest placebo-controlled trial, 189 people over 12 weeks, found same, escitalopram and placebo indistinguishable (response 36%, 34% and 30%), a failed trial rather than a clean negative because the comparator antidepressant also did not beat placebo. an american psychiatric association review called the evidence "promising but limited"; two of its authors have commercial ties to same.
can you take same with an antidepressant?: it has mostly been studied that way: the one positive trial added same to a serotonin reuptake inhibitor that was not working, with response 36.1% against 17.6% on added placebo and no more dropouts for side effects. combining is not itself unusual, but starting it alongside an antidepressant is a prescriber’s decision, the result has never been replicated, and the tranylcypromine (maoi) label lists same among the products not to combine with that drug.
does same cause mania?: it can. the cochrane review recorded two reports of mania or hypomania among 441 people who received same, and the american psychiatric association review documents that mania seen in early studies is why later trials excluded bipolar disorder and enrolled only unipolar depression. anyone with bipolar disorder, a past manic or hypomanic episode, or a strong family history has a reason to involve a psychiatrist before taking it.
is same fda approved?: no. it is sold in the united states as a dietary supplement under dshea, with no fda review of safety or effectiveness before sale, and has not been approved for depression, osteoarthritis, liver disease or any other condition. there is no prescription same product in the united states, though some other countries have sold it as a prescription medicine, often by injection, which is why many older trials used doses and routes that do not match oral tablets.
what are the side effects of same?: in the 189-person placebo-controlled trial, 19% on same reported stomach discomfort and 20% diarrhoea. anxiety, restlessness and insomnia are also reported, which is why it is usually taken earlier in the day. the serious one is mania or hypomania, recorded in two of 441 people on same in the cochrane review.

sources for this section

the library rows link to our one-page summary of each study, with the original paper, its funding and our evidence grade on that page.

What the Research Shows

4 records from the 2026-08-18 harvest, each checked against PubMed and Europe PMC on that date. How a study was designed, how many people were in it, and who paid for it are printed above what it found, because those three facts decide how much the finding is worth.

Study 1 · 2016
- Systematic review of randomized trials
- 934 participants
- Top-tier journal
- Independently funded
- Preregistered
- Declared conflicts of interest
gold standard95/100
Top of the evidence hierarchy, independently funded.
Eight trials involving 934 adults with major depression produced no strong evidence that SAMe beats placebo as a standalone treatment (SMD -0.54, 95% CI -1.54 to 0.46, P=0.29; 142 participants, 2 studies; very low quality evidence) and no evidence it differs from imipramine (SMD -0.04, 95% CI -0.34 to 0.27; 619 participants) or from escitalopram (mean difference 0.12 points, 95% CI -2.75 to 2.99; 129 participants). The one positive signal was SAMe added on top of an SSRI, where a single 73-person study showed a 3.9-point advantage (95% CI 0.87 to 6.93) — low quality evidence from one trial. Two cases of mania or hypomania were recorded among 441 SAMe recipients.
Galizia I, Oldani L, Macritchie K, Amari E, Dougall D, Jones TN, Lam RW, Massei GJ, Yatham LN, Young AH. (2016). S-adenosyl methionine (SAMe) for depression in adults. Cochrane Database of Systematic Reviews. PMID 27727432.
How this record was checked
PubMed record 27727432 fetched via NCBI efetch 2026-08-18; title, all ten authors, journal (Cochrane Database Syst Rev 2016;10(10):CD011286), year, DOI, 8 trials, N=934 adults, and every effect estimate quoted above confirmed from the abstract, which also carries a per-author conflict-of-interest statement (hence conflicts true). PMC full text PMC6457972 read 2026-08-18: "CRG Funding Acknowledgement — The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Common Mental Disorders Group", hence funding INDEPENDENT; the PubMed record's "Update of doi:10.1002/14651858.CD011286" confirms a previously published protocol, hence preregistered true.
Study 2 · 2014
- Randomized trial
- 189 participants
- Reputable journal
- Mixed funding
- Preregistered
strong72/100
Well-supported by good-quality research.
Read this first: 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.
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).
Mischoulon D, Price LH, Carpenter LL, Tyrka AR, Papakostas GI, et al. (2014). A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-L-methionine (SAMe) versus escitalopram in major depressive disorder. Journal of Clinical Psychiatry. PMID 24500245.
How this record was checked
PubMed record 24500245 fetched via NCBI efetch 2026-08-18; title, authors, journal (J Clin Psychiatry 2014;75(4):370-376), year, DOI, N=189, the 12-week design, response and remission rates, and registration NCT00101452 (hence preregistered true) confirmed from the abstract. PMC full text PMC5360105 read 2026-08-18: "This study was supported by the National Institutes of Health (NIH) and the National Center for Complementary and Alternative Medicine (NCCAM), R01 grant R01AT001638... The sponsors had no further role... SAMe tosylate and matching placebo were supplied by Pharmavite LLC, CA" — public funding with industry in-kind study drug, hence MIXED. No separate financial-disclosure statement was located on that page, so conflicts is recorded false.
Study 3 · 2010
- Randomized trial
- 73 participants
- Top-tier journal
- Funding not established
moderate60/100
Reasonable evidence with real limitations.
Read this first: 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.
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.
Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. (2010). S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. American Journal of Psychiatry. PMID 20595412.
How this record was checked
PubMed record 20595412 fetched via NCBI efetch 2026-08-18; title, all five authors, journal (Am J Psychiatry 2010;167(8):942-948), year, DOI, N=73, the 800 mg twice-daily target dose, the 6-week duration, and the response/remission percentages confirmed from the abstract. Europe PMC core record fetched 2026-08-18 lists one NIH grant (NIMH 5-K23 MH-069629) but no funding statement and no PMC full text; the AJP page was not read, so per the format rule funding is recorded UNKNOWN rather than inferred from the grant linkage, conflicts false, and independence left null (unchecked). No trial registration appears in the record, so preregistered is false.
Study 4 · 2017
- Systematic review of observational studies
- Reputable journal
- No funding reported
- Declared conflicts of interest
moderate63/100
Reasonable evidence with real limitations.
Read this first: Two of the authors have direct commercial ties to SAMe: the disclosure statement records that Dr Bottiglieri chaired the advisory board of and holds stock options in Methylation Sciences Inc. and is a scientific advisor to Gnosis S.p.A., and Dr Gerbarg receives royalties from books covering SAMe. The review received no funding, and it reports the mania risk plainly, but it is not written by parties independent of the product. It also pools trials of widely varying quality, dose, and route without a meta-analysis, so "promising but limited" is a judgement rather than an effect size.
A work group of the American Psychiatric Association Council on Research screened 174 records and reviewed 132 studies (115 clinical trials, 17 preclinical) of SAMe across psychiatric and medical conditions, concluding that the evidence for major depressive disorder is "promising but limited" for both monotherapy and augmentation. The review documents that mania and hypomania seen in early SAMe studies is the reason subsequent trials confined themselves to unipolar depression — the clearest statement in the literature of why bipolar disorder is a contraindication.
Sharma A, Gerbarg P, Bottiglieri T, Massoumi L, Carpenter LL, et al. (2017). S-Adenosylmethionine (SAMe) for Neuropsychiatric Disorders: A Clinician-Oriented Review of Research. Journal of Clinical Psychiatry. PMID 28682528.
How this record was checked
PubMed record 28682528 fetched via NCBI efetch 2026-08-18; title, authors, the "as Work Group of the American Psychiatric Association Council on Research" byline, journal (J Clin Psychiatry 2017;78(6):e656-e667), year, DOI, and the 174-record/132-study counts confirmed from the abstract. PMC full text PMC5501081 read 2026-08-18: "Funding/Support: None" (hence funding NONE), a full per-author disclosure section (hence conflicts true) including the Methylation Sciences and Gnosis S.p.A. interests quoted above (hence independent false), and the passage stating that observations of SAMe-induced hypomania or mania in early studies limited subsequent trials to unipolar episodes.

The Risks

Nobody checks this purchase the way a prescription is checked. No prescriber reviews it against the rest of what you take, no pharmacist screens the interaction, and no regulator confirms the dose in the capsule before it is sold. That is why this section sits here at full length rather than as a footnote.

What the paragraph below covers:

Psychosis and mania
Drug interactions
Sleep disruption
Stomach and gut

The risk that actually changes decisions is mania. SAMe can trigger manic or hypomanic switching, and this is not hypothetical: the Cochrane review recorded two reports of mania or hypomania among 441 participants who received SAMe, and the American Psychiatric Association Council on Research review notes that mania observed in the early studies is precisely why later trials restricted enrolment to unipolar depression and excluded bipolar disorder. Anyone with bipolar disorder, a past manic or hypomanic episode, or a strong family history should not start SAMe without a psychiatrist involved. Beyond that, the profile is mostly gastrointestinal — in the 189-person placebo-controlled trial, 19% on SAMe reported stomach discomfort and 20% diarrhoea — plus anxiety, restlessness, and insomnia, which is why it is usually taken earlier in the day. SAMe has most often been studied as an add-on to an SSRI rather than instead of one, so combining is not itself unusual, but starting it alongside an antidepressant should be a prescriber's decision rather than a solo experiment, and it should be discussed before any procedure or new medication that affects mood or methylation (levodopa in Parkinson's disease is a known interaction area).

What Is Not Known

The boundaries of the section above, in the harvest’s own words. What it excluded, why, and where it looked and found nothing. An absence of evidence is not evidence of absence, and it is not evidence of benefit either.

What Was Left Out, and Why

Quoted from the harvest, where these notes sat above the study list rather than after it. Where a note says “below” it means the studies in the section above.

Sarris 2014 (J Affect Disord, PMID 24856557) and Sarris 2015 (Pharmacopsychiatry, PMID 26011569) were fetched and verified but are excluded as study records: both are post-hoc re-analyses of subsamples from the same failed trial listed here (Mischoulon 2014, NCT00101452), one reporting a positive result in a single-site subsample and one a male-only subgroup effect. Reporting them as independent findings would triple-count one negative trial. Their existence is flagged in that trial's contestedNote.
The 1970s-80s parenteral (IV/IM) SAMe trials are excluded individually; they are pooled inside the Cochrane review and the APA-affiliated review below, and their dosing does not correspond to the oral tablets sold in US stores.

The Retraction Check

PubMed efetch records for all four PMIDs inspected 2026-08-18 for "Retraction in" flags; none present, and no errata or expressions of concern.

Questions for a Prescriber or Pharmacist

This page does not tell anyone to take SAMe or to avoid it. It is not able to: it does not know what else you take, what you have tried, or what you are treating. These are the questions each study above raises, written to be asked out loud.

The only place SAMe showed a benefit was added on top of an antidepressant, in one 73-person study — given that, is it worth adding to what I'm taking, and what would you watch for?
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?
If my antidepressant is only partly working, how does adding SAMe compare with the augmentation options you'd normally reach for first?
Given that SAMe was linked to mania in the early studies, is there anything in my history — or my family's — that would make it a bad idea for me specifically?

And the one to ask at the counter, whatever the answers above turn out to be: given everything I am already taking, what would you want to know about SAMe before I put it in the same body?

Open SAMe in veisund

The app has the resources behind this page and people working through the same questions.What you post there goes to people, not to a model. If someone answers, it is a person who has been there. The one automated message is a crisis-resource reply.

Where This Page Comes From

Transcribed from the study-harvest-2026-08-18 record for same, built into this page by scripts/supplement-ingest.mjs on 2026-09-07. Nothing here is fetched at page load, and nothing here was written by a model without a citation behind it.

Source file	study-harvest/2026-08-18/same.yaml
Source repo	REPTechnologies/avalo-backend
SHA-256	3eca1336ebed9899aff65cc3f90c481332f52d20349497353fb2aa1ac4ac2e90
Also searched as	SAMe, S-adenosyl methionine, S-adenosyl-L-methionine, SAM-e, ademetionine

The Other Substances

Do any supplements actually work? asks the question across all of them. The full library has the medication records, the funding investigations, and the glossary.