S-adenosylmethionine is quite a mouthful; the abbreviation SAMe (pronounced samm-ee ) is easier to say. Its chemical structure and name are derived from two materials you may have heard about already: 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—a kind of positive side effect.
Unfortunately, SAMe is an extraordinarily expensive supplement at present. Full dosages can easily cost more than $200 per month.
The body makes all the SAMe it needs, so there is no dietary requirement. However, deficiencies in methionine , folate , or vitamin B 12 can reduce SAMe levels. SAMe is not found in appreciable quantities in foods, so it must be taken as a supplement.
It's been suggested that the supplement trimethylglycine (TMG) might indirectly increase SAMe levels and provide similar benefits, but this effect has not been proven.
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.
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. 3-10,65-68
SAMe has undergone some investigation as a possible supportive treatment for Parkinson's disease . One study suggests that it may reduce the depression so commonly associated with the disease. 13 In addition, the drug levodopa , used for Parkinson's disease, depletes the body of SAMe. 14,15 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.
Highly preliminary evidence suggests that SAMe can protect the stomach against damage caused by alcohol. 16
A substantial body of scientific evidence supports the use of SAMe to treat osteoarthritis . 17,71 Double-blind studies involving a total of more than 1,000 participants suggest that SAMe is about as effective as standard anti-inflammatory drugs. In addition, animal evidence suggests that SAMe may help protect cartilage from damage. 18,19
For example, a double-blind, placebo-controlled Italian study tracked 732 people taking SAMe, naproxen (a standard anti-inflammatory drug), or placebo. 20 After 4 weeks, participants taking SAMe or naproxen showed about the same level of benefit as compared to each other, and a superior level of benefit as compared to those in the placebo group.
A more recent double-blind study compared SAMe to celecoxib (Celebrex), a member of the newest class of non-steroidal anti-inflammatory drugs. 64 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. 21 A total of 45 individuals were followed for 84 days. The two treatments proved equally effective. However, the SAMe-treated individuals 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 we have 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 equivalent benefits to various doses of indomethacin, ibuprofen, and naproxen. 22-24
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. 25,26 Furthermore, a double-blind, placebo-controlled study of 133 depressed patients, failed to find intravenous SAMe more effective than placebo. Researchers resorted to questionable statistical manipulation of the data to show benefit. 27
Other trials compared SAMe to standard antidepressants rather than to placebo. The best of these was a 6-week, double-blind trial of 281 people with mild depression that compared oral SAMe to imipramine. 28 The results indicated that the two treatments were about 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 design (such as too limited a treatment interval) mar the meaningfulness of the reported outcomes. 29-34,63
Researchers have also studied the effectiveness of oral SAMe in combination with antidepressants. Seventy-three patients with treatment-resistant major depression were randomized to take SAMe (800 mg twice daily) or a placebo. 69 Both groups continued to take their selective serotonin reuptake inhibitor (SSRI). Adding SAMe to the treatment increased the rate at which patients responded to their antidepressant medication.
Four double-blind trials have studied the use of SAMe for fibromyalgia , 43-46 three of them finding it to be helpful. Unfortunately, most of these studies used SAMe given either intravenously or as an injection into the muscles, sometimes in combination with oral doses. When you inject a medication, the effects can be quite different than when you take it orally. For that reason, these studies are of questionable relevance.
Nonetheless, the one double-blind study that used only oral SAMe did find positive results. 47 In this trial, 44 people with fibromyalgia took 800 mg of SAMe or placebo for 6 weeks. Compared to 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 isn't clear whether SAMe is helping fibromyalgia through its antidepressant effects, or by some other mechanism.
Evidence suggests that levodopa (the drug used to treat Parkinson's disease ) can reduce brain levels of SAMe. 48-50 This depletion may contribute to the side effects of levodopa treatment, as well as the depression sometimes seen with Parkinson's disease. One study found that SAMe taken orally improved depression without changing the effectiveness of levodopa. 51 However, it is also possible that over time taking extra SAMe could interfere with levodopa's effectiveness. (See Safety Issues.)
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. 61 In addition, there may also be risks involved in combining SAMe with standard antidepressants. 62 For this reason, you shouldn't try either combination except under physician supervision.
If you are taking:
5. Frezza M, Surrenti C, Manzillo G, et al. Oral S-adenosylmethionine in the symptomatic treatment of intrahepatic cholestasis. A double-blind, placebo-controlled study. Gastroenterology. 1990;99:211-215.
10. Nicastri P, Diaferia A, Tartagni M, et al. A randomised placebo-controlled trial of ursodeoxycholic acid and S-adenosylmethionine in the treatment of intrahepatic cholestasis of pregnancy. Br J Obstet Gynaecol. 1998;105:1205-1207.
12. Volkmann H, Norregaard J, Jacobsen S, et al. Double-blind, placebo-controlled cross-over study of intravenous S-adenosyl-L-methionine in patients with fibromyalgia. Scand J Rheumatol. 1997;26:206-211.
13. Carrieri PB, Indaco A, Gentile S, et al. S-adenosylmethionine treatment of depression in patients with Parkinson's disease. A double-blind, crossover study versus placebo. Curr Ther Res. 1990;48:154-160.
27. Delle Chiaie R, Pancheri P. Combined analysis of two controlled, multicentric, double blind studies to assess efficacy and safety of sulfo-adenosyl-methionine (SAMe) vs. placebo (MC1) and SAMe vs. clomipramine (MC2) in the treatment of major depression [in Italian; English abstract]. G Ital Psicopatol. 1999;5:1-16.
28. Delle Chiaie R, Pancheri P, Scapicchio P. MC3: multicentre, controlled efficacy and safety trial of oral S-adenosyl-methionine (SAMe) vs. oral imipramine in the treatment of depression [abstract]. Int J Neuropsychopharmcol. 2000;3(suppl 1):S230.
34. Delle Chiaie R, Pancheri P, Scapicchio P. MC4: multicentre, controlled efficacy and safety trial of intramuscular S-adenosyl-methionine (SAMe) vs. oral imipramine I the treatment of depression [abstract]. Int J Neuropsychopharmcol. 2000;3(suppl 1):S230.
35. Mato JM, Camara J, Fernandez de Paz J, et al. S-adenosylmethionine in alcoholic cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol. 1999;30:1081-1089.
37. Frezza M, Surrenti C, Manzillo G, et al. Oral S-adenosylmethionine in the symptomatic treatment of intrahepatic cholestasis. A double-blind, placebo-controlled study. Gastroenterology. 1990;99:211-215.
40. Nicastri P, Diaferia A, Tartagni M, et al. A randomised placebo-controlled trial of ursodeoxycholic acid and S-adenosylmethionine in the treatment of intrahepatic cholestasis of pregnancy. Br J Obstet Gynaecol. 1998;105:1205-1207.
46. Volkmann H, Norregaard J, Jacobsen S, et al. Double-blind, placebo-controlled cross-over study of intravenous S-adenosyl-L-methionine in patients with fibromyalgia. Scand J Rheumatol. 1997;26:206-211.
50. Charlton CG, Crowell B Jr. Striatal dopamine depletion, tremors, and hypokinesia following the intracranial injection of S-adenosylmethionine: a possible role of hypermethylation in parkinsonism. Mol Chem Neuropathol. 1995;26:269-284.
51. Carrieri PB, Indaco A, Gentile S, et al. S-adenosylmethionine treatment of depression in patients with Parkinson's disease: a double-blind, crossover study versus placebo. Curr Ther Res. 1990;48:154-160.
63. Pancheri P, Scapicchio P, Chiaie RD. A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. Int J Neuropsychopharmacol. 2002;5:287-294.
64. Najm WI, Reinsch S, Hoehler F, et al. S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: A double-blind cross-over trial. BMC Musculoskelet Disord. 2004;5:6.
69. Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry. 2010;167(8):942-948.
70. Strous RD, Ritsner MS, Adler S, Ratner Y, Maayan R, Kotler M, Lachman H, Weizman A. Improvement of aggressive behavior and quality of life impairment following S-adenosyl-methionine (SAM-e) augmentation in schizophrenia. Eur Neuropsychopharmacol. 2009;19(1):14-22.
71. De Silva V, El-Metwally A, Ernst E, Lewith G, Macfarlane GJ. Evidence for the efficacy of complementary and alternative medicines in the management of osteoarthritis: a systematic review. Rheumatology. 2010 Dec 17.
Last reviewed December 2015 by EBSCO CAM Review Board
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