Special Feature

SAMe: Cautious Optimism

By Andrew L. Stoll, MD

Sadenosylmenthionine, or SAMe, has received recent publicity as an effective and "natural" antidepressant with few, if any, side effects. SAMe is an endogenous compound that functions as a methyl donor in many cellular process. 1 It is not an essential dietary supplement, since humans can synthesize SAMe from readily available precursors. 2 Reports on the antidepressant activity of SAMe date back more than 30 years. A recent media account 3 report that more than 12 controlled trials of SAMe in depression have been conducted. However, a Medline search revealed only three small double-blind controlled trials. 4,5,6 The same media article reported that more than 40 "clinical studies" of approximately 1,400 patients have been published. Again, a Medline search revealed at most 10 open-label trials of SAMe in depression. Notwithstanding these discrepancies, a critical review of the literature indicates that SAMe is likely an effective antidepressant.

However, these enthusiastic reports have wholly ignored several real dangers associated with the use of SAMe. The most serious hazard associated with SAMe is the extremely high rate of induction of mania in bipolar patients. This is highly significant in primary care practice, where antidepressant agents are widely prescribed. While only approximately one in 10 depressed persons in the community at-large have bipolar disorder, the rate of bipolar disorder may be as high as one in four depressed patients who seek treatment. Thus, without careful screening for a history of bipolar symptoms, many cases of mania associated with the use of SAMe can be expected. While all antidepressants can induce mania in susceptible patients, SAMe appears to induce mania more rapidly and at a much higher frequency than conventional prescription antidepressants. For example, less than 25% of bipolar patients receiving SSRIs over one year can be expected to "switch" into mania. For SAMe, the rate of mania induction is at least 50% within two-three weeks.

Another concern associated with SAMe has been the instability of the molecule and problems with tablet dissolution in some commercial preparations used in some of the early controlled trials of SAMe in depression5. Due to the unregulated nature of the dietary supplement industry, concern over the integrity, stability, and bioavailability of SAMe preparations appropriately persist. Finally, SAMe has never undergone the rigorous safety testing required for prescription medications, and although the existing data suggests that SAMe appears safe in short-term trials, no long-term data exists.

The usage of SAMe is fairly straightforward. SAMe is indicated as monotherapy in mild unipolar major depression, should the clinician and patient choose this agent over conventional prescription antidepressants or other natural mood-elevating substances, such as St John's wort or omega-3 fatty acids. In moderate or severe depression or where suicidal ideation or safety is an issue, SAMe could be used as an adjunct to more standard prescription antidepressant therapies. SAMe is generally contraindicated in patients with bipolar disorder, or in seemingly unipolar depressed patients under age 25,where the rate of occult bipolar disorder is quite high.

There are at least seven retail distributors of SAMe products made by only several manufacturers. Currently available preparations usually contain 200 mg SAMe per capsule or tablet. The proper dosage of SAMe for major depression is not clear, but ranges from 400 to 1600 mg per day, given in a BID schedule. SAMe is very expensive, and insurers generally will not pay for this dietary supplement. The cost of SAMe generally ranges from $2 to $5 per day at 400 mg/day all the way up to $8 to $20 per day at 1600 mg/day. Thus, the price of SAMe could be prohibitive for many patients.

In summary, SAMe may be a safe and effective antidepressant agent or adjunct in selected patients with unipolar depression. However, SAMe should be avoided in patients with bipolar disorder or a suspected bipolar diathesis.


1.Carney MWP, et al. S-adenosylmethionine and affectivedisorder. Am J Medicine 1987;104-106.

2. Cantoni GL. Biological methylation; selected aspects. Ann Rev Biochem 1975;890:435-451.

3. Cowley G, et al. What is SAMe. Newsweek. July 5, 1999. pp 46-50.

4. Carney MWP, et al. The switch mechanism and the bipolar/unipolar dichotomy. Br J Psychiatry. 1989;154:48-51.

5. Kagan BL, Sultzer, et al. Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 1990;147:591-595.

6. Bell KM, et al. A-adenosyl methionine treatment of depression: a controlled clinical trial. 1988;145:1110-1114.