My experience with the supplement SAMe


SAMe (S-adenosyl-L-methionine) is a molecule made naturally by the body. It is involved in a number of reactions such as the synthesis and activation of hormones, neurotransmitters and proteins.

Mechanism of action:

The antidepressant mechanism is not completely understood. It may be involved in the production of neurotransmitters as its synthesis is closely linked to vitamin B12 and folate metabolism. It causes increased serotonin turnover and elevated dopamine and norepinephrine levels.

SAMe may also alter cell membrane fluidity. This could cause an increase in signal efficiency. Post treatment phosphocreatine levels are higher and beta nucleoside triphosphate levels are lower. This suggests that SAMe alters bioenergetic status.


SAMe is typically dosed to treat depression between 800-1600mg in two divided doses. Taking on an empty stomach is best.


(1) A study in 144 patients compared SAMe (1600-3200mg/daily), escitalopram (10-20mg/daily), or matching placebo for 12 weeks. The Hamilton Depression Rating Scale was used to assess changes in depression. Response rate, defined as a 50% reduction in depression scores was seen in 45% of SAMe patients, in 31% of escitalopram patients and in 26% of placebo patients. Remission rates were seen in 34% of SAMe patients, in 23% of escitalopram patients and in 6% of placebo patients.

(2) A trial compared 143 patients receiving SAMe with 138 patients receiving Imipramine for 6 weeks and 147 patients received intramuscular SAMe to 148 patients that received Imipramine. The efficacy between Imipramine and SAMe did not differ but SAMe was associated with significantly better tolerability.

(3) A re-analysis of data from a trial of 189 patients showed that SAMe reduced depression scores in males by 4.3 points more than placebo, but did not show significant change in females. The underlying cause of this difference is unknown, but SAMe may be effective for males over females.

(4) A study examined if SAMe added to SSRI/SNRI nonresponders would improve sexual dysfunction. The men treated with adjunctive SAMe demonstrated significantly lower arousal dysfunction than those treated with adjunctive placebo.

(5) A secondary analysis of a trial examined if SAMe can improve cognitive impairment in patients with depression. 46 patients were enrolled in a double-blind randomized trial of adjunctive SAMe. There was a greater improvement in the ability to recall information and a treat towards significant increases in word finding.


SAMe is likely safe when used orally. No serious toxicity has been reported in studies of more than 22,000 patients. It is possibly safe in children and in pregnancy, more data is needed.

Medication interactions:

1. Antidepressant medications: SAMe seems to have serotonergic effects and using SAMe with prescription anti-depressants can lead to serotonin syndrome. This is characterized by agitation, tremors, anxiety, tachycardia, shivering and sweating.

2. Levodopa: SAMe methylates levodopa which could reduce the anti-Parkinson’s effects of Levodopa

Side effects:

SAMe is generally well tolerated. It can cause nausea, vomiting and diarrhea. It can cause sweating, dizziness, and anxiety. It may also be associated with mania in rare cases.


SAMe is difficult to formulate in a stable salt. The tosylate formulation is 1% bioavailable compared to 5% of the butanedisulfonate salt. There are concerns about the tosylate stability, while the butanedisulfonate salt is stable for 2 years at room temperature.

My experience:

I purchased a 400mg per tablet SAMe butanedisulfonate product. Each tablet is in foil to maintain stability as shelf life is a concern with SAMe. I started low and slow to ensure tolerability. I started with just one 400mg tablet daily for a few days with a goal to slowly titrate up to 1600mg daily (800mg twice daily). I noticed a sulfur smell, but it was not too bad. I did not notice any physical side effects while taking the SAMe. I did notice an increase in anxiety after taking SAMe for a few days, which can happen with serotonergic medications and supplements. My mood then seemed to fall for a bit, but then after a few weeks, I did notice some mild improvements in my mood, motivation and hope for the future. One of the potential benefits for SAMe is that is may work more quickly than prescription antidepressants. Unfortunately for me, I did not notice a quick benefit.



1. Sarris J, Papakostas G, Vitolo O, et al. S-adenosyl methionine (SAMe) versus escitalopram and placebo in major depression RCT: efficacy and effects of histamine and carnitine as moderators of response. J Affect Disord. 2014 Aug;164:76-81.

2. Delle Chiaie R, Pancheri P, Scapicchio P. Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. Am J Clin Nutr. 2002 Nov;76(5):1172S-6S.

3. Sarris J, Price L, Carpenter L, et al. Is S-Adenosyl Methionine (SAMe) for Depression Only Effective in Males? A Re-Analysis of Data from a Randomized Clinical Trial. Pharmacopsychiatry. 2015 Jul;48(4-5):141-4.

4. Dording C, Mischoulon D, Shyu I, et al. SAMe and sexual functioning. Eur Psychiatry. 2012 Aug;27(6):451-4.

5. Levkovitz Y, Alpert J, Brintz, et al. Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder. Eur Psychiatry. 2012 Oct;27(7):518-21.


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