S-Adenosyl methionine (SAMe) as a nutritional supplement

• PRINCIPAL PROPOSED USES: Depression, osteoarthritis

• OTHER PROPOSED USES: Chronic viral hepatitis, cirrhosis and other forms of liver disease, fibromyalgia, Parkinson’s disease

DEFINITION: Natural substance used as a dietary supplement for specific health benefits

Overview

The chemical structure and name of S-adenosylmethionine, usually called SAMe, are derived from two materials—methionine, a sulfur-containing amino acid, and adenosine triphosphate (ATP), the body’s main energy molecule. SAMe was discovered in Italy in 1952. It was first investigated as a treatment for depression, but along the way, it was accidentally noted to improve arthritis symptoms.

Sources

The body makes all the SAMe it needs, so there is no dietary requirement. However, deficiencies in methionine, folate, or vitamin B₁₂ can reduce SAMe levels. SAMe is not found in appreciable quantities in foods, so it must be taken as a supplement. It has been suggested that the supplement trimethylglycine might indirectly increase SAMe levels and provide similar benefits, but this effect has not been proven.

Therapeutic Dosages

A typical full dosage of SAMe is 400 milligrams (mg), taken three to four times per day. As little as 200 mg twice daily may suffice to keep a person 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 avoid this side effect, one may need to start low and work up to the full dosage gradually.

SAMe is on the market in the US at a recommended dosage of 200 mg twice daily. This dosage labeling makes SAMe appear more affordable, but it is unlikely that SAMe will actually work when taken at such a low dosage.

Therapeutic Uses

A substantial amount of evidence suggests that SAMe can be an effective treatment for osteoarthritis, the “wear and tear” type of arthritis that many people develop as they get older. Also, a moderate amount of evidence suggests that SAMe might be helpful for depression.

Weak and inconsistent evidence hints that SAMe might be helpful for a variety of liver conditions, such as cirrhosis, chronic viral hepatitis, pregnancy-related jaundice, and Gilbert’s syndrome. SAMe also may help the chronic, painful muscle condition known as fibromyalgia.

SAMe has undergone investigation as a possible supportive treatment for Parkinson’s disease. One study suggests that it may reduce depression, which is commonly associated with the disease. Additionally, the drug levodopa, used for Parkinson’s disease, depletes the body of SAMe. This suggests that taking extra SAMe might be helpful. However, it is also possible that SAMe could interfere with the effect of levodopa, requiring an increase in dosage. Finally, preliminary evidence suggests that SAMe can protect the stomach against damage caused by alcohol.

Scientific Evidence

Osteoarthritis. A substantial body of scientific evidence supports using SAMe to treat osteoarthritis. Double-blind studies involving more than one thousand participants suggest that SAMe is about as effective as standard anti-inflammatory drugs like ibuprofen. In addition, evidence from studies of animals suggests that SAMe may help protect cartilage from damage.

For example, a double-blind, placebo-controlled Italian study tracked 732 people taking SAMe, the standard anti-inflammatory drug naproxen, or placebo. After four weeks, participants taking SAMe or naproxen showed about the same level of benefit compared with each other and a superior level of benefit compared with those in the placebo group.

A later double-blind study compared SAMe with celecoxib (Celebrex), a member of a class of nonsteroidal anti-inflammatory drugs. Celecoxib produced more rapid effects than SAMe, but over time, SAMe appeared to catch up. However, the lack of a placebo group makes these results less than fully reliable.

Another double-blind study compared SAMe with the anti-inflammatory drug piroxicam. Forty-five people were followed for eighty-four days. The two treatments proved equally effective. However, the SAMe-treated persons maintained their improvement long after the treatment was stopped, whereas those on piroxicam quickly started to hurt again.

Similarly long-lasting results have been seen with glucosamine and chondroitin. This pattern of response suggests that these treatments are somehow making a deeper impact on osteoarthritis than simply relieving symptoms. However, while there is some direct evidence that glucosamine and chondroitin can slow the progression of osteoarthritis, the evidence regarding SAMe is more hypothetical. In other double-blind studies, oral SAMe has shown benefits equivalent to those of various doses of indomethacin, ibuprofen, and naproxen. However, SAMe must be taken regularly for about one month before most individuals see results.

Depression. The evidence for SAMe for the treatment of depression is provocative but far from definitive. Several double-blind, placebo-controlled studies have found SAMe effective in relieving depression, but most were small and poorly reported, and many used an injected form of the supplement. Furthermore, a late trial, a double-blind, placebo-controlled study of 133 people with depression, failed to find intravenous SAMe more effective than placebo. Unfortunately, researchers resorted to questionable statistical manipulation of the data to show benefit.

Other trials compared SAMe to standard antidepressants rather than to placebo. The best of these trials was a six-week, double-blind trial of 281 people with mild depression that compared oral SAMe to imipramine. The results indicated that the two treatments were almost equally effective. However, the absence of a placebo group makes this study less than fully definitive.

Other studies have also compared the benefits of oral or intravenous SAMe to those of tricyclic antidepressants and have also found generally equivalent results. However, again, poor reporting and inadequacies of study designsuch as too limited a treatment intervalmarred the meaningfulness of the reported outcomes.

Fibromyalgia. Four double-blind trials have studied the use of SAMe for fibromyalgia, three of them finding it to be helpful. Most of these studies, however, used SAMe given either intravenously or as an injection into the muscles, sometimes in combination with oral doses. Injected medication has effects that can be quite different from those of the same medications taken orally. For this reason, these studies are of questionable relevance.

Nonetheless, the one double-blind study that used only oral SAMe did find positive results. In this trial, forty-four people with fibromyalgia took 800 mg of SAMe or placebo for six weeks. Compared with the group taking placebo, those taking SAMe had improvements in disease activity, pain at rest, fatigue, and morning stiffness, and in one measurement of mood. In other respects, such as the amount of tenderness in their tender points, the group taking SAMe did no better than those taking the placebo. It is not clear whether SAMe is helping fibromyalgia through its antidepressant effects or by some other mechanism.

Parkinson’s disease. Evidence suggests that levodopa, the drug used to treat Parkinson’s disease, can reduce brain levels of SAMe. This depletion may contribute to the side effects of levodopa treatment and to the depression sometimes seen with Parkinson’s disease. One study found that SAMe taken orally improved depression without changing the effectiveness of levodopa. However, it is also possible that over time, taking extra SAMe could interfere with levodopa’s effectiveness.

Dementia. SAMe has been shown in several studies to have potential applications for dementia patients, though large, randomized-controlled studies in humans are needed. Those who participated in the study found that the use of SAMe improved cognitive symptoms, such as the ability to recall words. Further research confirmed SAMe's ability to cross the blood-brain barrier and possibly limit Alzheimer's disease biomarkers. In animal studies, using SAMe in aging rats improved cognitive function.

Safety Issues

SAMe appears to be quite safe, according to both human and animal studies. The most common side effect is mild digestive distress. However, SAMe does not damage the stomach.

Like other substances with antidepressant activity, SAMe might trigger a manic episode in those with bipolar disease. Also, safety in young children, pregnant or nursing women, or those with severe liver or kidney disease has not been established.

SAMe might interfere with the action of the Parkinson’s drug levodopa (L-dopa). Additionally, there may be risks involved in combining SAMe with standard antidepressants. For this reason, one should not try either combination without physician supervision.

Individuals with bipolar disorder should avoid SAMe supplements, as they have been linked to episodes of mania. Additionally, individuals with Lesch-Nyhan syndrome may experience worsened symptoms if they take SAMe.

Important Interactions

One should not take SAMe except on a physician’s advice if already taking standard antidepressants, including monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, and tricyclics. This combination may lead to a dangerous condition called serotonin syndrome. Also, SAMe might help relieve the side effects of levodopa (L-dopa) for Parkinson’s disease. However, it might also reduce levodopa’s effectiveness over time.

Bibliography

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Hosea Blewett, H. J. “Exploring the Mechanisms Behind S-adenosylmethionine (SAMe) in the Treatment of Osteoarthritis.” Clinical Reviews in Food Science and Nutrition, vol. 48, 2008, pp. 458-63.

Najm, W. I., et al. “S-adenosyl Methionine (SAMe) Versus Celecoxib for the Treatment of Osteoarthritis Symptoms.” BMC Musculoskeletal Disorders, vol. 5, 2004, p. 6.

"S-adenosylmethionine." Icahn School of Medicine at Mount Sinai, www.mountsinai.org/health-library/supplement/s-adenosylmethionine. Accessed 20 Sept. 2024.

"S-Adenosyl-L-Methionine (SAMe): In Depth." National Center for Complementary and Integrative Health, www.nccih.nih.gov/health/sadenosyllmethionine-same-in-depth. Accessed 20 Aug. 2023.

Zhao, Yan, et al. “Effects of S-Adenosylmethionine on Cognition in Animals and Humans: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.” Journal of Alzheimer's Disease, vol. 94, no. s1, 2023, pp. S267-87. doi:10.3233/JAD-221076.