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Research · Supplements

SAM-e

A Cochrane review of 8 trials found no clear difference from placebo for depression as a stand-alone treatment. Results were similar to imipramine and escitalopram. Add-on trials to antidepressants disagree. Osteoarthritis pain differed by 0.4 cm on a 10 cm scale, not significantly. Mortality in alcoholic liver disease did not change significantly. Mania and stomach upset were reported.

Add to Bio HackChecked 2026-11-09
Status
Dietary supplement in the US. Not FDA-approved for any condition.
Also called
SAMe, S-adenosylmethionine, S-adenosyl-L-methionine, ademetionine, AdoMet, SAM
Taken for
depression, mood, osteoarthritis, joint pain, liver health, alcoholic liver disease

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help0

No benefit shown in research yet.

Reported risks3

What people take it for, and what was found

Mixed results1

Limited

Depression added to an antidepressant

Small trials found mixed results added to an antidepressant. One raised response to 36% against 18% on placebo, and another found no difference.

The numbers and sources
Effect
In 73 people not responding to a serotonin reuptake inhibitor, adding 800 mg twice a day for 6 weeks raised response to 36.1% against 17.6% on placebo, and remission to 25.8% against 11.7% [3]. In 107 non-remitting outpatients, adding 800 mg a day for 8 weeks did not differ from placebo (response 54.3% against 50.0%, p 0.51 for symptom scores) [4]. A 2020 review of 8 trials (1,011 subjects) found SAMe better than placebo in 3 of 5 placebo comparisons [5].
Population
Adults with major depression on antidepressants [3][4]. Trials of 2 to 12 weeks at 200 to 3,200 mg a day [5].
Sources
[3], [4], [5]
Caveats
The two add-on trials disagree and used different doses. [3] was funded by NIMH and [4] by Australia's NHMRC. Europe PMC lists Mylan as a funder of [5].

Not shown to help3

Moderate

Depression as a stand-alone treatment

Not shown to lower depression symptoms more than placebo in adults with major depression. Results were similar to imipramine and escitalopram, in mostly low-quality evidence.

The numbers and sources
Effect
A Cochrane review of 8 trials (934 adults) found no strong evidence of a difference from placebo in depressive symptoms (SMD -0.54, 95% CI -1.54 to 0.46, 2 studies, 142 participants, very low quality). Results were similar to imipramine (SMD -0.04, 95% CI -0.34 to 0.27, 4 studies, 619 participants) and escitalopram (MD 0.12, 95% CI -2.75 to 2.99, 1 study) [1]. In a 12-week trial of 189 outpatients, response was 36% on SAMe, 34% on escitalopram and 30% on placebo, and no group differed from the others [2].
Population
Adults with major depression, oral or injected SAMe [1]. 189 outpatients in the US [2].
Sources
[1], [2]
Caveats
Most evidence was rated low or very low quality [1]. The 12-week trial was funded by NIH's NCCIH, and escitalopram also did not separate from placebo [2].
Moderate

Osteoarthritis pain and function

Not shown to lower pain or improve function more than placebo in adults with knee or hip osteoarthritis.

The numbers and sources
Effect
In 4 trials (656 patients), pain was slightly lower than placebo, but not significantly (SMD -0.17, 95% CI -0.34 to 0.01), equal to 0.4 cm on a 10 cm scale. Function did not differ (SMD 0.02, 95% CI -0.68 to 0.71) [6].
Population
Adults with knee or hip osteoarthritis [6].
Sources
[6]
Caveats
The review rated trial quality and reporting as poor and called itself inconclusive [6].
Moderate

Alcoholic liver disease

Not shown to lower death or liver transplant in adults with alcoholic liver disease. One trial's after-the-fact subgroup, excluding the most advanced cases, found fewer.

The numbers and sources
Effect
Across 9 trials (434 patients), SAMe did not significantly change all-cause mortality (RR 0.62, 95% CI 0.30 to 1.26), liver-related mortality (RR 0.68) or death or transplant (RR 0.55, 95% CI 0.27 to 1.09) [7]. In the largest trial, 123 people with alcoholic cirrhosis on 1,200 mg a day for 2 years had death or transplant in 16% against 30% on placebo (p 0.077). Excluding the most advanced cases, rates were 12% against 29% (p 0.025) [8].
Population
Adults with alcoholic liver disease [7]. 123 adults with cirrhosis in Spain [8].
Sources
[7], [8]
Caveats
The pooled analysis rests mostly on one trial [7]. The subgroup result in [8] excluded Child class C patients after the fact.

Doses studied

Depression trials used 200 to 3,200 mg a day for 2 to 12 weeks [5]. The escitalopram comparison used 1,600 to 3,200 mg a day [2]. Add-on trials used 800 mg twice a day [3] and 800 mg a day [4]. The cirrhosis trial used 1,200 mg a day by mouth for 2 years [8].

Risks

Reported risks2

LimitedHow often is not known

Mania and hypomania

Limited evidence: 2 of 441 people given SAMe in depression trials had mania or hypomania.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Two cases of mania or hypomania were recorded among 441 participants given SAMe across the depression trials [1].
Population
Adults with major depression [1].
Sources
[1]
Caveats
Most trials did not detail specific adverse effects. The review authors flagged induction of mania as of particular interest for future trials [1].
LimitedHow often is not known

Serotonin syndrome-like symptoms with antidepressants

One trial found one case of serotonin syndrome-like symptoms with SAMe added to an antidepressant. Other side effects were no higher than on placebo.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
In the 8-week add-on trial, SAMe was implicated in one case of serotonin syndrome-like symptoms. Adverse effects otherwise did not exceed placebo [4].
Population
107 adults taking antidepressants [4].
Sources
[4]
Caveats
A single case in one trial.

Mixed results1

LimitedVery common

Stomach discomfort and diarrhea

Limited evidence: stomach discomfort and diarrhea each affected about 1 in 5 on SAMe in one trial. Side effects did not differ significantly from placebo in other trials.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
In the 12-week trial, stomach discomfort (19%) and diarrhea (20%) were the most common side effects on SAMe [2]. In osteoarthritis trials, any adverse event did not differ significantly from placebo (RR 1.27, 95% CI 0.94 to 1.71) [6]. In alcoholic liver disease trials, non-serious adverse events did not differ significantly (RR 4.92, 95% CI 0.59 to 40.89) [7].
Population
189 outpatients with depression [2]. 656 people with osteoarthritis [6]. 434 people with liver disease [7].
Sources
[2], [6], [7]
Caveats
No osteoarthritis trial reported on serious adverse events [6].

Claims tested and not found

  1. That SAMe alone treats major depression better than placebo. Pooled symptom change did not clearly differ from placebo [1], and a 12-week trial found no group differences [2].
  2. That 800 mg a day added to an antidepressant improves depression. In 107 outpatients over 8 weeks, scores did not differ from placebo [4].
  3. That SAMe lowers deaths in alcoholic liver disease. Pooled mortality did not change significantly [7].

Sources

  1. Galizia I, Oldani L, Macritchie K, et al. S-adenosyl methionine (SAMe) for depression in adults. Cochrane Database of Systematic Reviews. 2016. https://doi.org/10.1002/14651858.CD011286.pub2
  2. Mischoulon D, Price LH, Carpenter LL, et al. A Double-Blind, Randomized, Placebo-Controlled Clinical Trial of S-Adenosyl-L-Methionine (SAMe) Versus Escitalopram in Major Depressive Disorder. The Journal of Clinical Psychiatry. 2014. https://doi.org/10.4088/jcp.13m08591
  3. Papakostas GI, Mischoulon D, Shyu I, et al. 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. 2010. https://doi.org/10.1176/appi.ajp.2009.09081198
  4. Sarris J, Byrne GJ, Bousman C, et al. Adjunctive S-adenosylmethionine (SAMe) in treating non-remittent major depressive disorder: An 8-week double-blind, randomized, controlled trial. European Neuropsychopharmacology. 2018. https://doi.org/10.1016/j.euroneuro.2018.07.098
  5. Cuomo A, Beccarini Crescenzi B, Bolognesi S, et al. S-Adenosylmethionine (SAMe) in major depressive disorder (MDD): a clinician-oriented systematic review. Annals of General Psychiatry. 2020. https://doi.org/10.1186/s12991-020-00298-z
  6. Rutjes AW, Nüesch E, Reichenbach S, et al. S-Adenosylmethionine for osteoarthritis of the knee or hip. Cochrane Database of Systematic Reviews. 2009. https://doi.org/10.1002/14651858.CD007321.pub2
  7. Rambaldi A, Gluud C. S-adenosyl-L-methionine for alcoholic liver diseases. Cochrane Database of Systematic Reviews. 2006. https://doi.org/10.1002/14651858.CD002235.pub2
  8. Mato JM, Cámara J, Fernández de Paz J, et al. S-Adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. Journal of Hepatology. 1999. https://doi.org/10.1016/s0168-8278(99)80263-3

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