SAMe for Depression: A 2024 Meta-Analysis Found a Benefit, but a Large NIH-Funded Trial Did Not Beat Placebo
SAMe (S-adenosyl-methionine) is one of the most studied supplements for low mood. Pooled trials suggest it beats placebo, but the evidence is low quality, the largest US trial found no difference, and it can trigger mania and interact with antidepressants. Here is what each study found, who paid for it, and who should be careful.
By Kymata Health Editorial Published Last checked
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Key takeaways
From 6 sources- A 2024 meta-analysis of 23 trials (2,183 people) found SAMe reduced depressive symptoms more than placebo (standardised mean difference −0.58), but results varied widely between trials, and as an add-on to antidepressants it did not clearly beat placebo1.
- A 2016 Cochrane review rated the evidence low to very low quality and found no strong evidence of a difference from placebo when SAMe was used on its own2.
- In a 12-week NIH-funded trial of 189 outpatients, SAMe, the antidepressant escitalopram and placebo all improved by about 5 to 6 points, with no significant difference between them3.
- Added to an SSRI in 73 people who had not responded to it, SAMe roughly doubled response rates versus placebo (36.1% vs 17.6%) in a 6-week trial4.
- SAMe may worsen mania in bipolar disorder and might interact with antidepressants and levodopa, so it is not a do-it-yourself substitute for depression care5.
What this article covers
1 evidence profileThe evidence, graded
Pulled from the trial tables in our evidence profiles. Grades follow our evidence-grading policy.
Graded findings
5 rows- CGrade CDepressive symptoms versus placeboImproved SAMe reduced depressive symptoms more than placebo (SMD −0.58, 95% CI −0.93 to −0.23) with high heterogeneity (I² 68%); as an add-on to antidepressants it did not clearly beat placebo.SAMe (S-adenosyl-L-methionine) · Meta-analysis · n=2,183 · 2024 · PMID 38423354
- CGrade CDepressive symptoms (Cochrane review)Mixed No strong evidence of a difference from placebo as monotherapy (SMD −0.54, 95% CI −1.54 to 0.46; 2 trials; very low-quality evidence).SAMe (S-adenosyl-L-methionine) · Systematic review · n=934 · 2016 · PMID 27727432
- CGrade CDepression versus escitalopram and placeboNo effect All three arms improved by about 5–6 points on the Hamilton scale; neither SAMe nor escitalopram separated from placebo.SAMe (S-adenosyl-L-methionine) · RCT · n=189 · 2014 · PMID 24500245
- DGrade DAdd-on to SSRIs in non-respondersImproved Response (36% vs 18%) and remission (26% vs 12%) rates were higher with SAMe than placebo added to the SSRI.SAMe (S-adenosyl-L-methionine) · RCT · n=73 · 2010 · PMID 20595412
- CGrade CHip or knee osteoarthritis pain and functionNo effect Pain SMD −0.17 (95% CI −0.34 to 0.01), about 0.4 cm on a 10 cm scale; no effect on function. The reviewers advised against routine use.SAMe (S-adenosyl-L-methionine) · Meta-analysis · n=656 · 2009 · PMID 19821403
Where these trials agree: SAMe (S-adenosyl-L-methionine) and depression, counted row by row in the Consensus finder.
What SAMe is
SAMe is a compound the body makes from methionine, an amino acid in food, and it is sold in the US as a dietary supplement5. Low levels have been reported in depression and liver disease, which prompted research into supplements5.
NCCIH, part of the US National Institutes of Health, notes that at least 40 human studies have tested SAMe for depression, but most were short and small, and some used injected rather than oral SAMe5.
What the pooled trials show
The 2024 meta-analysis searched to July 2023 and grouped 23 randomised trials into three comparisons1. Against placebo (11 trials), SAMe reduced depressive symptoms more, with a standardised mean difference of −0.58 (95% CI −0.93 to −0.23), but heterogeneity was high (I² 68%)1. Added to antidepressants (5 trials) it did not differ significantly from placebo, and against antidepressants alone (7 trials) it performed about the same1. Dropout rates did not differ1.
Two of its authors reported speaker fees or consulting for antidepressant makers, and its PubMed record lists no funder1.
The 2016 Cochrane review, which included 8 trials and 934 adults, was more cautious2. On its own versus placebo, the difference was not significant (standardised mean difference −0.54, 95% CI −1.54 to 0.46; 2 trials, 142 people; very low-quality evidence)2. SAMe and the older antidepressant imipramine performed similarly (4 trials, 619 people; low-quality evidence)2. The reviewers recorded two reports of mania or hypomania among 441 people taking SAMe and asked future trials to track it2. Several Cochrane authors declared past fees or grants from drug companies2.
The two trials that matter most
In the largest US trial, 189 outpatients with major depression were randomised for 12 weeks to SAMe 1,600 to 3,200 mg a day, escitalopram 10 to 20 mg a day, or placebo3. All three groups improved by about 5 to 6 points on the Hamilton depression scale, and none separated from placebo: response rates were 36% on SAMe, 34% on escitalopram and 30% on placebo3. Because the standard antidepressant also failed to beat placebo, the trial may have been unable to detect a real difference3.
That trial was funded by the US National Institutes of Health (grant R01AT001638), and the SAMe and matching placebo were supplied by the supplement maker Pharmavite3. Stomach discomfort (19%) and diarrhea (20%) were the most common side effects on SAMe3.
In a 6-week add-on trial, 73 adults whose depression had not responded to an SSRI kept taking it and added SAMe (target 800 mg twice a day) or placebo4. Response (36.1% vs 17.6%) and remission (25.8% vs 11.7%) rates were higher with SAMe, and dropouts did not differ significantly4. It was small and short, its authors called the results preliminary, and its PubMed record lists a US National Institute of Mental Health grant4.
What about SAMe for joint pain?
SAMe is also sold for osteoarthritis. A 2009 Cochrane review of 4 placebo-controlled trials (656 people) found a pain difference of about 0.4 cm on a 10 cm scale that was not statistically significant, and no effect on function6. The reviewers, who declared no conflicts, said routine use should not be advised6.
For other supplements studied for low mood, see our explainers on saffron, omega-3 and St John's wort and its drug interactions. The SAMe page grades each SAMe finding.
Who should be careful
Check with a doctor or pharmacist before taking SAMe if any of these apply:
- Bipolar disorder: SAMe may worsen symptoms of mania, and NCCIH says it should only be used under a health care provider's supervision in bipolar disorder5.
- Taking antidepressants or other serotonin-raising products (SSRIs, L-tryptophan, St John's wort): SAMe might interact with them5.
- Parkinson's disease medicine levodopa: SAMe may reduce the effect of levodopa5.
- Pregnancy: safety in pregnancy has not been established5.
- Weakened immune system, including HIV: NCCIH notes a theoretical concern that SAMe could promote Pneumocystis infection5.
- Current depression: it needs a clinician's care, and SAMe results are mixed23. Anyone with thoughts of self-harm should seek urgent help rather than rely on a supplement.
Quick answers
Common questions
4 answersHow much SAMe was used in the depression trials?
Can SAMe be taken with an antidepressant?
How fast does SAMe work?
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SAMe (S-adenosyl-L-methionine) products from partner brands
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References
6 sources. Numbers in the text link here.
Sources cited in this article
6 sources- 1Efficacy and acceptability of S-adenosyl-L-methionine (SAMe) for depressed patients: A systematic review and meta-analysisProg Neuropsychopharmacol Biol Psychiatry, 2024 · PMID 38423354
- 2S-adenosyl methionine (SAMe) for depression in adultsCochrane Database Syst Rev, 2016 · PMID 27727432
- 3A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-L-methionine (SAMe) versus escitalopram in major depressive disorderJ Clin Psychiatry, 2014 · PMID 24500245
- 4S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trialAm J Psychiatry, 2010 · PMID 20595412
- 5S-Adenosyl-L-Methionine (SAMe): In DepthNational Center for Complementary and Integrative Health (NIH), 2017
- 6S-Adenosylmethionine for osteoarthritis of the knee or hipCochrane Database Syst Rev, 2009 · PMID 19821403
SAMe (S-adenosyl-L-methionine) and other dietary supplements are not intended to diagnose, treat, cure or prevent any disease, and these statements have not been evaluated by the FDA. Talk to your clinician or pharmacist before starting a supplement, especially if you take prescription medicines. Product links on this page are paid partner links.