SAMe (S-adenosyl-L-methionine)
Summary
SAMe is a methyl donor made from methionine. A 2024 meta-analysis of 23 trials found it beat placebo for depressive symptoms (grade C), but a Cochrane review rated the evidence very low quality and a 189-person trial found no difference from placebo. For hip and knee osteoarthritis, a Cochrane review found only a tiny pain effect. It can trigger mania in bipolar disorder.
Key facts
- A methyl donor the body makes from the amino acid methionine and ATP[7]
- Depressive symptoms (C, mixed trials); add-on to SSRIs in non-responders (D); hip or knee osteoarthritis pain (no clear effect, C)[1][2][3][4][5]
- 23 trials, 2,183 people: better than placebo (SMD −0.58), with high heterogeneity; no clear benefit as an add-on to antidepressants[2]
- 4 placebo-controlled trials, 656 people: pain difference of 0.4 cm on a 10 cm scale; Cochrane advises against routine use[4]
- May worsen mania in bipolar disorder and may interact with serotonergic drugs and levodopa[7]
- 5 graded human outcomes on this page
- October 11, 2026
How it works
ProposedSAMe donates methyl groups for the synthesis of neurotransmitters, phospholipids and other molecules; whether oral SAMe changes these pathways enough to affect mood is not established.[7]
What the human research says
Human trials only, one row per outcome. The form column shows what each trial actually tested. Grades follow our evidence-grading policy.
At a glance: strongest evidence per outcome
| Outcome | Grade | Effect | Strongest evidence | Rows |
|---|---|---|---|---|
| Stress | Grade C | Improved | Meta-analysis · n = 2,183 · 2024 | 4 rows |
| Bones & joints | Grade C | No effect | Meta-analysis · n = 656 · 2009 | 1 row |
Every graded row
| Outcome | Effect | Grade | Best evidence | PMID |
|---|---|---|---|---|
| Depressive symptoms versus placebo | Improved | Grade C | Meta-analysis · n = 2,183 · 2024 Adults with depression in 23 randomized trials Form: SAMe (oral and injected) · Dose: Varied across trials · Duration: Varied across trials 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. | 38423354 (opens PubMed)Source [2] |
| Depressive symptoms (Cochrane review) | Mixed | Grade C | Systematic review · n = 934 · 2016 Adults with depression, inpatients and outpatients Form: SAMe · Dose: Varied across trials · Duration: Varied across trials 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). | 27727432 (opens PubMed)Source [1] |
| Hip or knee osteoarthritis pain and function | No effect | Grade C | Meta-analysis · n = 656 · 2009 Adults with knee or hip osteoarthritis, 4 placebo-controlled trials Form: SAMe · Dose: Varied across trials · Duration: Varied across trials 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. | 19821403 (opens PubMed)Source [4] |
| Depression versus escitalopram and placebo | No effect | Grade C | RCT · n = 189 · 2014 Outpatients with major depressive disorder Form: SAMe · Dose: 1,600–3,200 mg/day · Duration: 12 weeks All three arms improved by about 5–6 points on the Hamilton scale; neither SAMe nor escitalopram separated from placebo. | 24500245 (opens PubMed)Source [3] |
| Add-on to SSRIs in non-responders | Improved | Grade D | RCT · n = 73 · 2010 Adults with major depressive disorder not responding to an SSRI Form: SAMe · Dose: Target 800 mg twice daily · Duration: 6 weeks Response (36% vs 18%) and remission (26% vs 12%) rates were higher with SAMe than placebo added to the SSRI. | 20595412 (opens PubMed)Source [5] |
Forms
| Form | Elemental % | Absorption (human data) | GI tolerance | Studied for |
|---|---|---|---|---|
| SAMe tablets (salt forms vary by brand) | Varies[7][3] | No head-to-head human absorption data between salts in our sources.[7][3] | Generally well tolerated in trials; mania has been reported in people with bipolar disorder.[7][3] | Depression (1,600–3,200 mg/day) and osteoarthritis |
Studied doses
Doses studied in human trials ranged from 1,600 to 3,200 mg of SAMe a day in the depression trials cited here, for 6 to 12 weeks; the osteoarthritis trials pooled by Cochrane used varying doses.[3][5][4]
Interactions
Published interactions only: each row cites a source. No row means none was found in our sources, not that a combination is safe.
Who should be careful
- Bipolar disorder
- SAMe may worsen mania; NCCIH says it should only be used under medical supervision in bipolar disorder.[7]
- Pregnancy
- Safety in pregnancy has not been established.[7]
- Weakened immune system
- NCCIH notes a theoretical risk that SAMe could promote Pneumocystis infection in immunocompromised people.[7]
Talk to your pharmacist or clinician before starting a supplement, especially if you take prescription medicines.
Where to buy SAMe (S-adenosyl-L-methionine)
Products from brands we partner with that contain SAMe (S-adenosyl-L-methionine). Listing a product is not a claim that it works; check the amount per serving against the doses studied above, and the label for other ingredients.
- SupersmartPaid linkSAM-e (S-Adenosyl-Methionine) 400 mg2 tablets: 800 mg SAMe (400 mg per tablet); 30 servingsShop at Supersmart (opens in new tab)Price and label checked 2026-10-11 on the brand’s site.
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Frequently asked questions
Does SAMe work for depression?
A 2024 meta-analysis found it beat placebo, but a Cochrane review rated the evidence very low quality and a 189-person trial found no difference from placebo.[2][1][3]
Does SAMe help arthritis?
A Cochrane review of 4 trials found only a tiny pain effect and advised against routine use.[4]
Who should not take SAMe?
People with bipolar disorder, because it may worsen mania; safety in pregnancy is not established.[7]
Sources
- [1]S-adenosyl methionine (SAMe) for depression in adults.. Cochrane Database Syst Rev, 2016. systematic-review
- [2]Efficacy and acceptability of S-adenosyl-L-methionine (SAMe) for depressed patients: A systematic review and meta- analysis.. Prog Neuropsychopharmacol Biol Psychiatry, 2024. meta-analysis
- [3]A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-L-methionine (SAMe) versus escitalopram in major depressive disorder.. J Clin Psychiatry, 2014. RCT
- [4]S-Adenosylmethionine for osteoarthritis of the knee or hip.. Cochrane Database Syst Rev, 2009. meta-analysis
- [5]S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial.. Am J Psychiatry, 2010. RCT
- [6]Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis.. J Fam Pract, 2002. meta-analysis
- [7]S-Adenosyl-L-Methionine (SAMe): In Depth. National Center for Complementary and Integrative Health (NCCIH), 2017. fact-sheet
What changed
- Independent review: dose range corrected to the cited trials (1,600–3,200 mg/day; the 800 mg/day figure was a single dose, not a daily total); osteoarthritis and escitalopram-comparison rows regraded from no-effect to C because neither was an adequately powered null result; key-fact grade made consistent with the table.
- First draft. Every PMID checked against NCBI E-utilities (title, year and journal taken from the PubMed record; retraction and expression-of-concern flags checked: none) and abstracts read for each cited row. Product details in Where to buy read from the brand page on the date shown.