S-Adenosyl-L-Methionine

SAMe is said to be effective for treatment of depression (1–3) osteoarthritis (4–6), cholestasis (7), and liver disorders (8). In addition, mechanistically SAMe has been shown to be a platelet inhibitor (9).

A 2016 Cochrane review of 8 trials (934 subjects) found lack of high-quality evidence to support SAMe use in depression treatment and recommended further evaluation in high-quality randomized controlled trials (1). An 8-week randomized control trial of SAMe for depression (a pilot study of 49 patients) reported that SAMe use resulted in a reduction of depression symptoms per the Montgomery-Asberg Depression Rating Scale (MADRS) that was clinically but not statistically significant (2). Per exploratory analysis in this trial, SAMe reduced symptoms of milder depression. In a different study, when SAMe was used adjunctively with antidepressants, although depression scores decreased over time, there were no differences between SAMe treated and untreated groups (3). In a small study, SAMe appeared to improve symptoms of depression that did not abate with treatment using a selective serotonin reuptake inhibitor (SSRI) (10). However, another study of SAMe plus an antidepressant compared to placebo plus an antidepressant showed an improvement in response and remission rates that was not statistically significant (3).

Another large meta-analysis of 14 randomized trials with 1522 patients reported that SAMe may offer relief of depression symptoms comparable to the relief provided by escitalopram or imipramine. However, there was no consistency in doses used or study duration (Another large meta-analysis of 14 randomized trials with 1522 patients reported that SAMe may offer relief of depression symptoms comparable to the relief provided by escitalopram or imipramine. However, there was no consistency in doses used or study duration (11). Clinical practice guidelines from the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) indicate that lower doses of SAMe monotherapy may not be of benefit in the treatment of depression, but higher doses may be beneficial as an adjunct (12).

A meta-analysis including patients with osteoarthritis indicated that SAMe was more effective than placebo in reducing functional limitations associated with osteoarthritis (6). In addition, in 2 studies evaluated in this analysis, SAMe was as efficacious as nonsteroidal anti-inflammatory drugs (NSAIDs) but without the adverse effects common with NSAID use. However, a subsequent Cochrane review of 4 trials with 656 patients yielded inconsistent results for knee or hip osteoarthritis (4).

More high-quality studies are needed with standardized supplements before recommendations can be made for the supplementation of SAMe for the treatment of depression, liver disorders, or osteoarthritis.

No serious adverse effects have been reported unless higher doses are used.

Adverse effects of SAMe are uncommon, and when they do occur, they are usually minor problems such as nausea, gas, diarrhea, constipation, dry mouth, or headache.

SAMe is contraindicated in patients with bipolar disorder because SAMe can precipitate manic episodes.

Some care should be taken with antidepressant medications taken in combination with SAMe, as both will increase serotonin levels, potentially resulting in adverse effects such as serotonin syndrome.

SAMe may also methylate levodopa, thus decreasing levodopa levels and diminishing the effectiveness of medications that aim to treat Parkinson disease by increasing levodopa levels.SAMe may also methylate levodopa, thus decreasing levodopa levels and diminishing the effectiveness of medications that aim to treat Parkinson disease by increasing levodopa levels.

1. 1. Galizia I, Oldani L, Macritchie K, et al. S-adenosyl methionine (SAMe) for depression in adults (review). Cochrane Database Syst Rev. 10:CD011286, 2016. doi: 10.1002/14651858.CD011286.pub2

2. 2. Sarris J, Murphy J, Stough C, et al. S-adenosylmethionine (SAMe) monotherapy for depression: an 8-week double-blind, randomised, controlled trial. Psychopharmacology (Berl). 237(1):209-218, 2020. doi: 10.1007/s00213-019-05358-1 

3. 3. Sarris, 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. Eur Neuropsychopharmacol. 28(10):1126-1136, 2018. doi: 10.1016/j.euroneuro.2018.07.098

4. 4. Rutjes AW, Nüesch E, Reichenbach S, et al. S-Adenosylmethionine for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. (4) CD007321, 2009. doi: 10.1002/14651858.CD007321.pub2

5. 5. De Silva V, El-Metwally A, Ernst E, et al; Arthritis Research UK Working Group on Complementary and Alternative Medicines. Evidence for the efficacy of complementary and alternative medicines in the management of osteoarthritis: a systematic review. Rheumatology (Oxford). 50(5):911-920, 2011. doi: 10.1093/rheumatology/keq379

6. 6. Soeken KL, Lee WL, Bausell RB, et al. Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis. J Fam Pract. 51(5):425-430, 2002.

7. 7. Walker KF, Chappell LC, Hague WM, Middleton P, Thornton JG. Pharmacological interventions for treating intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev. 2020 Jul 27;7(7):CD000493. doi: 10.1002/14651858.CD000493.pub3

8. 8. Rambaldi A, Gluud C. S-adenosyl-L-methionine for alcoholic liver diseases. . S-adenosyl-L-methionine for alcoholic liver diseases.Cochrane Database Syst Rev. (2):CD002235, 2006. doi: 10.1002/14651858.CD002235.pub2

9. 9. De la Cruz JP, Mérida M, González-Correa JA, et al. Effects of S-adenosyl-L-methionine on blood platelet activation. . Effects of S-adenosyl-L-methionine on blood platelet activation.Gen Pharmacol. 29(4):651-655, 1997. doi:10.1016/s0306-3623(96)00571-x

10. 10. 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. Am J Psychiatry. 167(8):942-948, 2010. doi:10.1176/appi.ajp.2009.09081198

11. 11. 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 Jan-Feb;86:118-126. doi: 10.1016/j.genhosppsych.2024.01.001

12. 12. Sarris J, Ravindran A, Yatham LN, et al. Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce. World J Biol Psychiatry. 2022 Jul;23(6):424-455. doi: 10.1080/15622975.2021.2013041. Epub 2022 Mar 21. PMID: 35311615.

The following English-language resource may be useful. Please note that The Manual is not responsible for the content of this resource.

1. National Institutes of Health (NIH), National Center for Complementary and Integrative Health: S-Adenosyl-L-Methionine (SAMe): In Depth