SAMe – S-adenosyl-methionine

Peter ForsterMajor Depression, Treatments of Depression

S Adenosyl Methionine

S-adenosylmethionine, or SAM-e for short, is one of the few nutritional supplements that has good clinical research to support its safety and effectiveness. Although SAM-e is used for many purposes, we are particularly interested in it as a compound that may have antidepressant properties.

S-adenosylmethionine (SAMe) is involved in many reactions that involve methylating chemicals (transferring a methyl group to the chemical to change its properties).

Two types of methylation reactions are particularly significant for psychiatry:

  • Reactions involving Catechol-O-Methyl-Transferase (COMT)
  • DNA Methyl-Transferase reactions


COMT is one of the main enzymes involved in the breakdown of monoamine neurotransmitters which play a key role in depression (dopamine, norepinephrine, epinephrine). Either monoamine oxidase Catechol O Methyl Transferase(MAO) or COMT are involved in the first steps in the breakdown of these neurotransmitters. See the diagram on the right.

For COMT to function there must be enough SAMe present.

There is some evidence to suggest that people with a particular form of the COMT enzyme (COMT Val158Met) may be more prone to fearfulness (paranoia) and excessive risk-taking (gambling, drug use), particularly when they are in exposed to high stress situations (“COMT Val158Met polymorphism interacts with stressful life events and parental warmth to influence decision making.” Qinghua He, Gui Xue, Chuansheng Chen, Zhong-Lin Lu, Chunhui Chen, Xuemei Lei, Yuyun Liu, Jin Li, Bi Zhu, Robert K. Moyzis, Qi Dong & Antoine Bechara. Nature Scientific Reports 2, Article number: 677 (2012) doi:10.1038/srep00677). Since this form of COMT is less active, people with this form of the enzyme who are experiencing these symptoms might respond to supplementation with SAMe which could overcome some of the reduced COMT activity.

COMT is one of the ten genes that is assayed in the Genecept assay that we often use in people with depression who have not responded to initial treatments.

DNA Methyl-Transferase

DNA Methyl-Transferases play a key role in regulating gene expression. Basically, at birth, a set of these enzymes apply methyl groups to selected locations on your genes. The methylation of the genes determines which genes are active and how active they are and thus plays a huge role in who you are as a person. Since the methylation of genes can be reversed, there is another set of these enzymes that maintain the methylation pattern. All of these DNA methyl-transferase reactions depend on SAMe.

Low Vitamin B12, Folate or Methionine

People with low vitamin B12 (fairly common in the elderly) or low folate or low levels of folate activity (which can be related to having a particular form of the enzyme methylenetetrahydrofolate reductase (MTHFR) may benefit from supplementation with SAMe since B12 and folate are all essential factors in the formation of SAMe in the body. MTHFR is also part of the Genecept assay previously mentioned.

For more on this subject read here about the use of methylfolate supplements.

Clinical Effectiveness

Aside from the interesting possibility that SAMe may play a unique role in the treatment of irritability, paranoia and impulsiveness in people with the COMT Val158Met polymorphism, the use of SAMe that most people are interested in is its potential role in the treatment of depression.

SAMe is one of the most studied natural therapies for treating major depression. Several studies have shown that it is as effective as tricyclic antidepressants in treating major depression (Delle Chiaie, Am J Clin Nutr 2002, Salmaggi, Psychother Psychosom 1993, Kagan, Am J Psychiatry 1990). A more recent study (Papakostas, Am J Psychiatry 2010 clarified in Fleish, Am J Psychiatry 2010) found that it may be helpful in patients with major depressive disorder who did not respond to prescription treatment with a serotonin reuptake inhibitor (SRI). In the study, SAMe was given along with an SRI and 46.1% of patients receiving the combination benefited, versus 35.8% receiving an SRI and a placebo supplement. The results suggest that SAMe may be an effective and safe adjunctive treatment for SRI non-responders.

A recent article summarizing the literature on SAMe had this to say:

“SAMe is a methyl donor and is involved in the synthesis of various neurotransmitters in the brain. Derived from the amino acid L-methionine, SAMe has been postulated to have antidepressant properties. A small number of clinical trials with injected or oral SAMe have shown that, at doses of 200-1600 mg/d, SAMe is superior to placebo and is as effective as tricyclic antidepressants in alleviating depression, although some individuals may require higher doses. SAMe may have a faster onset of action than do conventional antidepressants and may potentiate the effect of tricyclic antidepressants. SAMe may also protect against the deleterious effects of Alzheimer disease. SAMe is well tolerated and relatively free of adverse effects, although some cases of mania have been reported in bipolar patients. Overall, SAMe appears to be safe and effective in the treatment of depression, but more research is needed to determine optimal doses.

“Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Mischoulon D, Fava M. Am J Clin Nutr. 2002 Nov;76(5):1158S-61S.Harvard Medical School, Depression Clinical and Research Program, Massachusetts General Hospital, Boston 02114, USA.

Our own experience is that SAMe is not entirely free of one side effect that can be of significant concern for those with bipolar (or manic depressive) disorder: It can definitely induce mania.

Therapeutic Dosages

A typical full dosage of SAMe is 400 mg taken 3 to 4 times per day If this dosage works for you, take it for a few weeks and then try reducing the dosage. As little as 200 mg twice daily may suffice to keep you feeling better once the full dosage has “broken through” the symptoms. However, some people develop mild stomach distress if they start full dosages of SAMe at once. To get around this, you may need to start low and work up to the full dosage gradually.

Recently, SAMe has come on the US market at a recommended dosage of 200 mg twice daily This dosage labeling makes SAMe appear more affordable (if you’re only taking 400 mg per day, you’ll spend only about a third or a fourth of what you’d pay for the proper dosage), but it is unlikely that SAMe will actually work when taken at such a low dosage.

Good sources of SAMe include: GNC, Natrol, Nature Made, Puritan’s Pride, Twinlab and the Vitamin Shoppe . It is often recommended that one start at 200 mg a day and then increase gradually to around 800 mg a day. SAMe should be taken in divided doses (at least 2 times a day and preferably 3 times a day) and improvement can be seen in a few days to 3-4 weeks.

Buyer beware! In its most recent review of these products, Consumer Lab found that almost half of all formulations were unacceptable. For one product the amount was below detectable.

Nature Made SAM-e MoodPlus 200mg Value Size , 60 Tablets

These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease I am providing you with specific brand information as a courtesy. Gateway Psychiatric Services receives no reimbursement from these companies.