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SAMe (S-Adenosyl-L-Methionine)

Evidence Level
Limited
4 Clinical Trials
2 Documented Benefits
2/5 Evidence Score

SAMe (S-adenosyl-L-methionine) is a methyl donor that occurs naturally in the body, where it takes part in everyday cell metabolism. As a supplement it is mostly studied for mood and, to a lesser extent, for joint comfort. The mood evidence is mixed: one recent pooled analysis found SAMe taken alone did better than placebo in adults with diagnosed depression, while a Cochrane review, which rated the evidence very low quality, and a second recent analysis found no clear difference. Added to antidepressants, one small trial was positive and two larger ones were not. For knee and hip joints, a review of four placebo-controlled trials found only a small, uncertain effect on pain. Stomach upset is common. SAMe can trigger mania in some people and may interact with antidepressants and levodopa, so people with bipolar disorder or on those drugs should use it only with their doctor's guidance.

Studied Dose Mood trials: 800 mg/day added to antidepressants, up to 1,600 mg/day (800 mg twice daily); pooled trials ranged from 200 to 3,200 mg/day for 2 to 12 weeks. Knee trial: 1,200 mg/day.
Active Compound S-adenosyl-L-methionine (SAMe), a methyl donor that the body also makes on its own.

Benefits

Mood support

In adults with diagnosed depression, one recent pooled analysis of 11 placebo-controlled trials found SAMe taken alone lowered symptom scores, but a Cochrane review, rating the evidence very low quality, and a second recent analysis found no clear difference from placebo, so the effect is uncertain. Added to antidepressants, one 73-person trial was positive while trials of 234 and 107 adults were not.

Supported by Trial 3, Trial 2

Joint comfort

A review of four placebo-controlled trials in 656 people with knee or hip osteoarthritis found a small, uncertain drop in pain, about 0.4 cm on a 10 cm scale, and no change in function; the reviewers judged the trials poor in quality and advised against routine use. A 61-person knee trial compared SAMe with a prescription pain reliever but had no placebo group.

Supported by Trial 4, Trial 1

Mechanism of action

1

Methyl donor

SAMe is a methyl donor that occurs naturally in the body: it hands methyl groups to other molecules during normal cell metabolism, which is why it is studied as a supplement.

2

Mood pathways (proposed)

How SAMe might act on mood is unknown. In an 8-week trial in 107 adults, SAMe did not change homocysteine, red cell folate or BDNF, and none of the gene variants tested, such as COMT, predicted who responded.

Clinical trials

1
SAMe added to antidepressants in people who had not responded
PubMed

Six-week randomized, double-blind trial of SAMe (target 800 mg twice daily) or placebo added to a serotonin reuptake inhibitor (Papakostas et al. 2010, Am J Psychiatry).

73 adults with major depressive disorder who had not responded to a serotonin reuptake inhibitor.

Response and remission rates on the Hamilton depression scale were 36.1% and 25.8% with SAMe versus 17.6% and 11.7% with placebo. Dropout rates did not differ significantly. The authors called the results preliminary.

2
SAMe added to antidepressants: no difference from placebo (Horizon Study)
PubMed

Six-week double-blind, placebo-controlled add-on trial of MSI-195, a proprietary SAMe formulation, 800 mg/day, run by the manufacturer, MSI Methylation Sciences (Targum et al. 2018, J Psychiatr Res).

234 adults with major depressive disorder who had responded inadequately to their antidepressant (118 SAMe, 116 placebo).

There was no significant difference between SAMe and placebo on any of three depression scales in the main analysis. A benefit appeared only in a post-hoc look at people enrolled in the first nine months. Side effects were mostly mild and digestive.

3
SAMe added to antidepressants: no difference from placebo over 8 weeks
PubMed

Eight-week double-blind, randomized, placebo-controlled trial of SAMe 800 mg/day added to antidepressants (Sarris et al. 2018, Eur Neuropsychopharmacol).

107 outpatients with major depressive disorder who had not reached remission on antidepressants.

Depression scores fell in both groups with no significant difference (p = 0.51). Response was 54.3% on SAMe and 50.0% on placebo, and remission 43.5% and 38.3%, all not significant. One participant had serotonin syndrome-like symptoms attributed to SAMe.

4
SAMe compared with celecoxib for knee osteoarthritis
PubMed

Randomized, double-blind crossover trial of SAMe 1,200 mg/day versus celecoxib 200 mg/day over 16 weeks, with no placebo arm (Najm et al. 2004, BMC Musculoskelet Disord).

61 adults with knee osteoarthritis, 56 of whom completed.

Celecoxib reduced pain more in the first month (p = 0.024); by the second month the two did not differ. Because there was no placebo group, the trial cannot show how much of the improvement SAMe itself caused.

Side effects and drug interactions

Common Potential side effects

Side effects are uncommon and usually minor, such as nausea or digestive upset (NCCIH); in the 234-person add-on trial they were mostly mild and digestive.
Mania: SAMe may worsen mania. A Cochrane review counted two cases of mania or hypomania among 441 people taking SAMe, and a case report describes mania with psychotic features in a person taking SAMe with an antidepressant.
Anxiety: in a 10-week open-label study in 13 people with Parkinson's disease, two stopped early because of increased anxiety; others had mild nausea or diarrhea.
Information on long-term safety is limited, and safety in pregnancy has not been established (NCCIH).
NCCIH notes a theoretical concern for people with weakened immunity, because SAMe enhances the growth of the Pneumocystis organism.

Important Drug interactions

Antidepressants and other serotonin-raising products (including L-tryptophan and St. John's wort): SAMe might interact with them. One person in an add-on trial had serotonin syndrome-like symptoms, so combine only under medical supervision.
Levodopa: SAMe may decrease the effect of levodopa, a Parkinson's disease drug (NCCIH).
Bipolar disorder: do not take SAMe for low mood except under a clinician's supervision, because it may worsen mania (NCCIH).

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Frequently asked questions about SAMe (S-Adenosyl-L-Methionine)

What is SAMe used for?

SAMe (S-adenosyl-L-methionine) is a compound the body makes naturally. As a supplement it is mostly taken for mood and, less often, for joint comfort.

Does SAMe help with mood and joints?

The research is mixed. For mood, one pooled analysis found a benefit over placebo when SAMe was taken alone, but a Cochrane review rated the evidence low to very low quality, and adding SAMe to antidepressants failed in two larger trials. For joints, a review of four trials found only a small, uncertain effect on pain and advised against routine use.

How much SAMe should I take?

Mood trials used 800 to 1,600 mg a day, and pooled trials ranged from 200 to 3,200 mg a day for 2 to 12 weeks. A knee trial used 1,200 mg a day. Follow the product label and talk to your doctor before starting it for low mood.

Is SAMe safe?

Side effects are usually mild, mostly digestive upset. SAMe may worsen mania, so people with bipolar disorder should avoid it unless a clinician is supervising. It may interact with antidepressants, St. John's wort, L-tryptophan and levodopa, and its long-term and pregnancy safety is not established.

What is SAMe?

SAMe (S-adenosyl-L-methionine) is a methyl donor that occurs naturally in the body, where it takes part in everyday cell metabolism. As a supplement it is mostly studied for mood and, to a lesser extent, for joint comfort.

Does SAMe interact with any medications?

Possible interactions include: Antidepressants and other serotonin-raising products (including L-tryptophan and St. John's wort): SAMe might interact with them. One person in an add-on trial had serotonin syndrome-like symptoms, so combine only under medical supervision. If you take prescription medication, check with a pharmacist or doctor before using it.

How strong is the scientific evidence for SAMe?

NutraSmarts rates the evidence for SAMe as Limited (2 out of 5). It is backed by 4 study summaries and 11 cited references summarized on this page. A higher rating reflects more, larger, and better-designed human studies.

References(11 citations)

Evidence ratings on NutraSmarts are based on the totality of human clinical research, with emphasis on randomized controlled trials, meta-analyses, and systematic reviews. The references below directly support claims made throughout this page.

  1. Limveeraprajak N, Nakhawatchana S, Visukamol A, Siripakkaphant C, Suttajit S, Srisurapanont M. Efficacy and acceptability of S-adenosyl-L-methionine (SAMe) for depressed patients: A systematic review and meta- analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2024;132:110985. doi: 10.1016/j.pnpbp.2024.110985.PubMedUsed to support: Systematic review and meta-analysis of 23 randomized trials (2,183 participants). Against placebo in 11 trials, SAMe taken alone reduced depressive symptoms (SMD -0.58, 95% CI -0.93 to -0.23), rated moderate certainty. Added to antidepressants (5 trials) it did not differ from placebo, and it did not differ from antidepressants (7 trials). Dropout rates did not differ.
  2. Galizia I, Oldani L, Macritchie K, Amari E, Dougall D, Jones TN, Lam RW, Massei GJ, Yatham LN, Young AH. S-adenosyl methionine (SAMe) for depression in adults. Cochrane Database Syst Rev. 2016;10(10):CD011286. doi: 10.1002/14651858.CD011286.pub2.PubMedUsed to support: Cochrane review of 8 trials in 934 adults with major depression. SAMe alone did not clearly differ from placebo (SMD -0.54, 95% CI -1.54 to 0.46; 2 studies, very low quality evidence). Low quality evidence from one 73-person trial favored SAMe added to an SSRI. Two cases of mania or hypomania were recorded among 441 people on SAMe. The authors drew no firm conclusions.
  3. Peng TR, Cheng HY, Wu TW. S-Adenosylmethionine (SAMe) as an adjuvant therapy for patients with depression: An updated systematic review and meta-analysis. Gen Hosp Psychiatry. 2024;86:118-126. doi: 10.1016/j.genhosppsych.2024.01.001.PubMedUsed to support: Systematic review and meta-analysis of 14 trials (1,522 participants) using 200 to 3,200 mg/day for 2 to 12 weeks. SAMe did not differ significantly from placebo as monotherapy or as an add-on, nor from imipramine or escitalopram. The authors urge caution because of the small number of studies and wide dose range.
  4. Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. 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;167(8):942-8. doi: 10.1176/appi.ajp.2009.09081198.PubMedUsed to support: Six-week randomized, double-blind trial in 73 adults with major depressive disorder who had not responded to a serotonin reuptake inhibitor. Adding SAMe (target 800 mg twice daily) gave response and remission rates of 36.1% and 25.8% versus 17.6% and 11.7% with placebo. Dropouts did not differ significantly.
  5. Targum SD, Cameron BR, Ferreira L, MacDonald ID. An augmentation study of MSI-195 (S-adenosylmethionine) in Major Depressive Disorder. J Psychiatr Res. 2018;107:86-96. doi: 10.1016/j.jpsychires.2018.10.010.PubMedUsed to support: Manufacturer-run six-week trial (Horizon Study) in 234 adults with major depressive disorder and an inadequate antidepressant response. SAMe (MSI-195) 800 mg/day added to ongoing treatment showed no significant difference from placebo on any of three depression scales; a benefit appeared only in a post-hoc first-half subgroup. Side effects were mainly mild and digestive.
  6. Sarris J, Byrne GJ, Bousman C, Stough C, Murphy J, MacDonald P, Adams L, Nazareth S, Oliver G, Cribb L, Savage K, Menon R, Chamoli S, Berk M, Ng C, Mischoulon D. Adjunctive S-adenosylmethionine (SAMe) in treating non-remittent major depressive disorder: An 8-week double-blind, randomized, controlled trial. Eur Neuropsychopharmacol. 2018;28(10):1126-1136. doi: 10.1016/j.euroneuro.2018.07.098.PubMedUsed to support: Eight-week double-blind trial in 107 non-remitted outpatients with major depressive disorder. SAMe 800 mg/day added to antidepressants did not differ from placebo (p = 0.51; response 54.3% vs 50.0%, remission 43.5% vs 38.3%). It did not change homocysteine, red cell folate or BDNF, and was implicated in one case of serotonin syndrome-like symptoms.
  7. Rutjes AW, Nüesch E, Reichenbach S, Jüni P. S-Adenosylmethionine for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2009;2009(4):CD007321. doi: 10.1002/14651858.CD007321.pub2.PubMedUsed to support: Cochrane review of 4 placebo-controlled trials in 656 people with knee or hip osteoarthritis. Pain fell slightly (SMD -0.17, 95% CI -0.34 to 0.01, about 0.4 cm on a 10 cm scale) and function did not change. Trial quality was poor, the review was inconclusive, and the authors advised against routine use.
  8. Najm WI, Reinsch S, Hoehler F, Tobis JS, Harvey PW. S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: a double-blind cross-over trial. [ISRCTN36233495]. BMC Musculoskelet Disord. 2004;5:6. doi: 10.1186/1471-2474-5-6.PubMedUsed to support: Randomized double-blind crossover trial in 61 adults with knee osteoarthritis (56 completed) comparing SAMe 1,200 mg/day with celecoxib 200 mg/day for 16 weeks. Celecoxib reduced pain more in month one; by month two the two did not differ. There was no placebo arm.
  9. Di Rocco A, Rogers JD, Brown R, Werner P, Bottiglieri T. S-Adenosyl-Methionine improves depression in patients with Parkinson's disease in an open-label clinical trial. Mov Disord. 2000;15(6):1225-9. doi: 10.1002/1531-8257(200011)15:6<1225::aid-mds1025>3.0.co;2-a.PubMedUsed to support: Open-label pilot study in 13 depressed patients with Parkinson's disease given 800 to 3,600 mg/day for 10 weeks. Of 11 completers, 10 improved by at least 50% on the Hamilton scale, but there was no control group. Two stopped early because of increased anxiety, one had mild nausea and two had mild diarrhea.
  10. Abeysundera H, Gill R. Possible SAMe-induced mania. BMJ Case Rep. 2018;2018. doi: 10.1136/bcr-2018-224338.PubMedUsed to support: Case report of a patient who developed mania with psychotic features while taking SAMe together with a selective serotonin reuptake inhibitor.
  11. National Center for Complementary and Integrative Health S-Adenosyl-L-Methionine (SAMe): In Depth NCCIH, National Institutes of Health. ;Web page (not PubMed-indexed)..SourceUsed to support: Not PubMed-indexed: US government fact sheet. It states that evidence for SAMe in depression is not conclusive and for osteoarthritis is mixed; that side effects are uncommon and usually minor, such as nausea; that SAMe may worsen mania in bipolar disorder; that it may decrease the effect of levodopa and might interact with antidepressants, L-tryptophan and St. John's wort; that pregnancy and long-term safety are not established; and that there is a theoretical Pneumocystis concern in immunocompromised people.