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Scientific Name(s):S-adenosylmethionine, S-adenosyl-L-methionine, ademetionine (as toluenedisulfate or 1,4-butanedisulfonate), ADE-SD4

Common Name(s): SAMe , SAM


SAMe has been studied for the treatment of depressive disorders, osteoarthritis, and liver disorders.

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Depression: 200 mg to 1,600 mg/day. Liver disease: 800 to 1,000 mg/day. Osteoarthritis: 1,200 mg/day initially, then maintenance 400 mg/day.


SAMe should not be used in patients with bipolar depression because of reports of increased anxiety and mania.


Trials conducted in pregnant women documented no harmful effects.


None well documented.

Adverse Reactions

Available data indicate nausea, diarrhea, constipation, mild insomnia, dizziness, and sweating to be the most commonly reported adverse reactions of SAMe. Data from long-term use of SAMe are lacking.


Toxicological studies concluded that SAMe is safe even at the highest doses.

SAMe is found in all living cells. It is a naturally occurring molecule produced by a reaction of the amino acid methionine with adenosine triphosphate. SAMe acts as a substrate in many biological reactions and is the precursor of certain essential amino acids. 1 , 2 SAMe is not a botanical, but is a supplement or biochemical commercially produced in yeast cell cultures. One manufacturing process utilizes fermentation of the yeast Saccharomyces cerevisiae , enriched by the Schlenk method in the presence of methionine. 1


SAMe was discovered in Italy in 1952. Since that time, numerous clinical studies have been performed to determine its efficacy. SAMe has been used in Europe, where it has been available by prescription since 1975, to treat arthritis and depression. It has been available in the United States as a supplement under the Dietary Supplement and Health Education Act since 1999. 2


SAMe is the principle contributor of methyl in a number of biochemical reactions involving enzymatic transmethylation. It is a precursor of the amino acids cysteine, taurine, and glutathione. SAMe initiates 3 metabolic pathways in the human body: transmethylation, transsulfuration, and polyamine synthesis.

Transmethylation is the methyl-group transfer to other molecules, enabling them to proceed to certain anabolic or catabolic reactions. Transsulfuration is the exchange resulting in sulfates and reduced glutathione, an important antioxidant, that provides sulfhydryl groups to bind to and detoxify certain compounds. Eighty-five percent of all transmethylation reactions occur in the liver. SAMe, after donating the methyl group, is converted to cysteine, which is important for synthesis of glutathione and other sulfur-containing compounds. 1 , 2 , 3

Determination of SAMe using high performance liquid chromatography has been reported. 4 The native form of SAMe is labile and rapidly degrades. Stable toluenedisulfonate and 1,4-butanedisulfonate salts have been developed, and stable enteric-coated forms are now used in clinical studies. 2 , 5

Uses and Pharmacology

Experiments found that oral SAMe crosses the intestinal wall, leading to increased plasma concentrations. Oral and parenteral SAMe have been demonstrated to cross the blood brain barrier and increase concentrations in cerebrospinal fluid. 2 The relative safety of SAMe and the widespread availability of human trials renders animal experiments largely irrelevant.


Despite showing a positive effect, many of the earlier trials conducted in depression had methodological limitations. 6 However, several meta-analyses of quality trials and newer multicenter trials 2 , 7 , 8 , 9 , 10 have confirmed the efficacy of SAMe in depression to be equivalent to that of the tricyclic antidepressants and greater than placebo. 2 , 7 , 8 A more rapid SAMe onset of action compared with conventional antidepressants has been suggested, the effect generally seen within a few days to 2 weeks. Doses of 200 to 1,600 mg/day have been used in some trials, while others have suggested efficacy with doses up to 3,000 mg/day. 7

Studies comparing SAMe and selective serotonin reuptake inhibitors have not been conducted. 7

The exact mechanism of action is unclear, but preclinical studies demonstrated that SAMe treatment had an effect on monoamine metabolism, as well as increasing norepinephrine and serotonin levels. Vitamin B 12 or folate deficiency are also known to decrease the levels of SAMe, with an associated link to depression. 2 , 7 , 8 , 11

Trials reported few adverse reactions with SAMe except increased anxiety and mania in patients with bipolar disorder. Methionine has increased symptoms of schizophrenia when administered in large doses. 7

Other uses of SAMe include the treatment of depression in opioid detoxification, Parkinson disease, and alcoholism. 7 , 12

Liver disease

The liver is the main organ involved in the conversion of methionine to SAMe. Oral and parenteral SAMe increase hepatic glutathione, the primary antioxidant involved in hepatic detoxification. 2 , 13 Studies suggest a link between abnormal SAMe synthesis and chronic liver disorders. SAMe may act through multiple mechanisms, including inhibition of normal hepatocytes apoptosis. 14

The majority of SAMe trials in hepatic disease and cholestasis resulted in improved biochemical markers (eg, serum bilirubin, alkaline phosphatase) and subjective clinical symptoms (pruritus, fatigue). 12 , 14 , 15 Improvements in mortality and time to liver transplant have not been clearly demonstrated, 5 , 12 , 14 although a subgroup analysis of patients with mild and moderate alcohol liver cirrhosis (Child-Pugh class A and B) found a trend toward improvement. 12 , 15

The few trials evaluating the efficacy of SAMe versus placebo in gestational cholestasis show improvement in laboratory indices and measures of pruritus, but it appears to be less effective than ursodeoxycholic acid. Synergism between these 2 agents has been suggested. 16 , 17 Trial methodology has been too variable to allow for meta-analysis. 16


SAMe's efficacy in osteoarthritis was noted in earlier depression trials. 2 SAMe appears to enhance native proteoglycan synthesis and secretion in human chondrocyte cultures in the cartilage of patients with osteoarthritis. 18 It also restored basal conditions after cytokine-induced cell damage in in vitro experiments, but no clinical studies have validated this observation. 2 , 19 The antidepressant activity of SAMe is a possible mechanism of action for the effects seen in osteoarthritis. 20

Meta-analyses, primarily involving trials in Italy, have been published describing the efficacy of SAMe in reducing pain and improving function compared with nonsteroidal anti-inflammatory drugs (eg, aspirin, ibuprofen, sulindac, piroxicam, celecoxib). 2 , 19 , 20 , 21 , 22

In some studies, the recommended dosage of 1,200 mg/day was exceeded for 2 weeks and was followed by a maintenance dosage of 400 mg/day. 23 Oral administration of 400 mg/day for 7 days resulted in increases in synovial SAMe concentrations. 2 However, a trial of SAMe versus celecoxib reported a slower onset of action for SAMe. At least 30 days of treatment were required for the onset of efficacy. 20

Other uses

The role of SAMe in the management of cognitive function in Alzheimer disease and remyelination in diseases of the spinal cord have been studied. 2

Decreased concentrations of SAMe in the cerebrospinal fluid of HIV-infected patients may play a role in HIV-related myelopathy. 2 However, a trial among HIV-patients found L-methionine 6 g/day ineffective in reducing symptoms of myelopathy. 24

Older trials have explored the potential for SAMe in migraines, aging, fibromyalgia, and sleep modulation. 25 , 26 , 27 , 28


Doses of 200 to 1,600 mg/day have typically been used in depression trials, but doses of up to 3,000 mg/day have been administered. 7 In osteoarthritis trials, 1,200 mg/day has been used, with a maintenance dose of 400 mg/day (recommended). 23 Doses of 800 to 1,000 mg/day intramuscularly, intravenously, and orally have been used in trials investigating liver disease and gestational cholestasis. 12 , 16 , 17


Trials conducted in pregnant women documented no harmful effects. 16


None well documented.

Adverse Reactions

Available data indicate nausea, diarrhea, constipation, mild insomnia, dizziness, and sweating to be the most commonly reported adverse reactions of SAMe. No serious adverse reactions have been reported. 3 , 7 , 9 , 23 , 24

Data from long-term use of SAMe are lacking. Increased anxiety and mania have been reported in patients with bipolar disorder; therefore, SAMe should not be used in people with this condition. 7


Mutagenicity and carcinogenicity studies conducted in the 1980s and 1990s resulted in no safety concerns. 1 More recent studies are lacking.


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9. 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;76(5):1172S-1176S.
10. Bell KM, Potkin SG, Carreon D, Plon L. S-adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Suppl . 1994;154:15-18.
11. Young SN. The use of diet and dietary components in the study of factors controlling affect in humans: a review. J Psychiatry Neurosci . 1993;18(5):235-244.
12. Rambaldi A, Gluud C. S-adenosyl-L-methionine for alcoholic liver diseases. Cochrane Database Syst Rev . 2006 April 19;(2):CD002235.
13. Kaplowitz N. The importance and regulation of hepatic glutathione. Yale J Biol Med . 1981;54(6):497-502.
14. Purohit V, Abdelmalek MF, Barve S, et al. Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium. Am J Clin Nutr . 2007;86(1):14-24.
15. Martínez-Chantar ML, García-Trevijano ER, Latasa MU, et al. Importance of a deficiency in S-adenosyl-L-methionine synthesis in the pathogenesis of liver injury. Am J Clin Nutr . 2002;76(5):1177S-1182S.
16. Roncaglia N, Locatelli A, Arreghini A, et al. A randomised controlled trial of ursodeoxycholic acid and S-adenosyl-l-methionine in the treatment of gestational cholestasis. BJOG . 2004;111(1):17-21.
17. Burrows RF, Clavisi O, Burrows E. Interventions for treating cholestasis in pregnancy. Cochrane Database Syst Rev . 2001;(4):CD000493.
18. Harmand MF, Vilamitjana J, Maloche E, Duphil R, Ducassou D. Effects of s-adenosylmethionine on human articular chondrocyte differentiation. An in vitro study. Am J Med . 1987;83(5A):48-54.
19. Morelli V, Naquin C, Weaver V. Alternative therapies for traditional disease states: osteoarthritis. Am Fam Physician . 2003;67(2):339-344.
20. Glass GG. Osteoarthritis. Dis Mon . 2006;52(9):343-362.
21. Montrone F, Fumagalli M, Sarzi Puttini P, et al. Double-blind study of S-adenosyl-methionine versus placebo in hip and knee arthrosis. Clin Rheumatol . 1985;4(4):484-485.
22. Caruso I, Pietrogrande V. Italian double-blind multicenter study comparing s-adenosylmethionine, naproxen, and placebo in the treatment of degenerative joint disease. Am J Med . 1987;83(5A):66-71.
23. Soeken KL, Lee WL, Bausell RB, Agelli M, Berman BM. Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis. J Fam Pract . 2002;51(5):425-430.
24. Di Rocco A, Werner P, Bottiglieri T, et al. Treatment of AIDS-associated myelopathy with L-methionine: a placebo-controlled study. Neurology . 2004;63(7):1270-1275.
25. Baldessarini RJ, Kopin IJ. S-adenosylmethionine in brain and other tissues. J Neurochem . 1966;13(8);769-777.
26. Bohuon C, Caillard L. S-Adenosylmethionine in human blood. Clin Chim Acta . 1971;33(1):256.
27. Stramentinoli G. Ademetionine, a new candidate for nutraceutical. Scandinavica . 1994;(suppl 154)59:5-41.
28. Volkmann H, Norregaard J, Jacobsen S, Danneskiold-Samsol B, Knoke G, Nehrdich D. Double-blind, placebo-controlled cross-over study of intravenous S-adenosyl-L-methionine in patients with fibromyalgia. Scand J Rheumatol . 1997;26(3):206-211.

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