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).

The clinical studies evaluating the health benefits of SAMe either are very small, lacking in proper methodology, or yield conflicting results among different trials.

A 2002 meta-analysis of osteoarthritis patients (6) indicated that SAMe was more effective than placebo in reducing functional limitations associated with osteoarthritis. More importantly, in 2 studies evaluated in this analysis, SAMe (1200 mg/day, eg, at 600 mg orally twice a day) was as efficacious as nonsteroidal anti-inflammatory drugs (NSAIDs) but without the adverse effects common with NSAID use.

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 with dosages between 200 and 1200 mg a day.

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 drugs taken in combination with SAMe, as both will increase serotonin levels, potentially resulting in adverse effects such as serotonin syndrome.

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. Gurung V, Middleton P, Milan SJ, et al: Interventions for treating cholestasis in pregnancy. Cochrane Database Syst Rev 6:CD000493, 2013. doi: 10.1002/14651858.CD000493.pub2

8. 8. Rambaldi A, Gluud CCochrane Database Syst Rev (2):CD002235, 2006. doi: 10.1002/14651858.CD002235.pub2

9. 9. De la Cruz JP, Mérida M, González-Correa JA, et alGen 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

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: Information on research regarding the use of SAMe for depression, osteoarthritis, and liver diseases