Benefits
Mood support
In pooled data from 23 randomized trials in 2,183 adults with depression, SAMe taken on its own improved symptoms more than placebo, a moderate effect rated moderate certainty, but showed no clear added benefit when taken with antidepressants. A separate review of 8 trials judged the evidence low quality. Use it for mood only with a doctor.
Joint comfort
Results are inconclusive. A review of 4 placebo-controlled trials in 656 people with knee or hip osteoarthritis found a small pain difference (0.4 cm on a 10 cm scale) that was not statistically certain and no difference in function, and advised against routine use. A 16-week crossover trial without placebo found improvement that took about a month to build.
Pain, fatigue and morning stiffness comfort
In a 6-week double-blind trial in 44 people with fibromyalgia, 800 mg a day improved pain, fatigue, morning stiffness and mood on a face scale more than placebo, but not tender points, muscle strength or a depression questionnaire. It is a single trial and has not been repeated.
Mechanism of action
Methyl donation
SAMe is the body's main methyl donor, handing off methyl groups for the methylation of nucleic acids, phospholipids, histones, biogenic amines and proteins, reactions involved in gene regulation and cell signaling.
Transsulfuration and glutathione
After donating its methyl group, SAMe feeds the transsulfuration pathway that produces glutathione, the main antioxidant inside cells. SAMe production is lower in chronic liver disease, which is why it has been studied for the liver, but no large, high-quality trial has shown a clinical liver benefit.
Clinical trials
Systematic review and meta-analysis of randomized trials comparing SAMe with placebo or antidepressants, searched to July 2023. (Limveeraprajak et al. 2024, Prog Neuropsychopharmacol Biol Psychiatry)
23 trials with 2,183 adults with depression: 11 SAMe vs placebo, 5 SAMe added to antidepressants vs placebo added, and 7 SAMe vs antidepressants.
SAMe alone reduced depressive symptoms more than placebo (SMD -0.58, 95% CI -0.93 to -0.23), with moderate-certainty evidence. Added to antidepressants it did not differ significantly from placebo (SMD -0.22), and it did not differ from antidepressants alone. Dropout rates did not differ in any comparison.
Analysis of a 144-person subsample from one site of a two-site double-blind randomized trial of SAMe, the antidepressant escitalopram, or placebo for 12 weeks. (Sarris et al. 2014, J Affect Disord)
144 adults with major depressive disorder.
At this site, improvement on the Hamilton depression scale differed between groups (p=0.039). Response rates were 45% with SAMe, 31% with escitalopram and 26% with placebo; remission rates were 34%, 23% and 6%. The authors noted that the full two-site study found no significant difference between groups.
Double-blind randomized placebo-controlled trial of oral SAMe (target 800 mg twice daily) added to an ongoing 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 rates were 36.1% with SAMe vs 17.6% with placebo, and remission rates 25.8% vs 11.7%. Dropouts did not differ significantly. The authors called the results preliminary and in need of replication.
Cochrane systematic review of randomized trials comparing SAMe, oral or injected, with placebo or antidepressants, searched to February 2016. (Galizia et al. 2016, Cochrane Database Syst Rev)
8 trials with 934 adults with major depression.
There was no strong evidence of a difference between SAMe alone and placebo (2 trials, very low quality evidence). Low-quality evidence favored SAMe over placebo when added to SSRIs (1 trial). Two cases of mania or hypomania were reported among 441 people on SAMe. The authors called for large, high-quality trials.
Cochrane systematic review and meta-analysis of randomized trials comparing SAMe with placebo or no treatment, searched to August 2008. (Rutjes et al. 2009, Cochrane Database Syst Rev)
4 placebo-controlled trials with 656 people with knee or hip osteoarthritis.
Pain showed a small difference (SMD -0.17, 95% CI -0.34 to 0.01, about 0.4 cm on a 10 cm scale) that was not statistically certain, and function did not differ (SMD 0.02). Trial quality was poor. The review was inconclusive and advised against routine use.
Randomized double-blind crossover trial of SAMe 1,200 mg/day vs the prescription pain reliever celecoxib 200 mg/day over 16 weeks, with no placebo group. (Najm et al. 2004, BMC Musculoskelet Disord)
61 adults with knee osteoarthritis; 56 completed.
In the first month celecoxib reduced pain significantly more than SAMe; by the second month the difference was gone. Most function measures improved from baseline in both groups without a significant difference between them. Without a placebo group, the size of any SAMe effect is unclear.
Double-blind placebo-controlled trial of oral SAMe 800 mg daily for 6 weeks. (Jacobsen et al. 1991, Scand J Rheumatol)
44 people with primary fibromyalgia.
Compared with placebo, SAMe improved clinical disease activity, pain over the last week, fatigue, morning stiffness and mood on a face scale. Tender point score, muscle strength, the Beck Depression Inventory and side effects did not differ.