Principal Proposed Uses | Other Proposed Uses

S-Adenosylmethionine (SAMe)

Supplement Forms/Alternate Names

  • Ademetionine
  • S-Adenosylmethionine
  • SAM

Uses

Principal Proposed Uses

Other Proposed Uses

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.

Sources

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.

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.

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. 1,71
A moderate amount of evidence suggests that SAMe might be helpful for depression . 2,69
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 may help the painful muscle condition known as fibromyalgia . 11,12
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

What Is the Scientific Evidence for S-Adenosylmethionine?

Osteoarthritis

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

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. 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.

Fibromyalgia

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.

Parkinson's Disease

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 Issues

SAMe appears to be quite safe, according to both human and animal studies. 52-56 The most common side effect is mild digestive distress. However, SAMe does not actually damage the stomach. 57
Like other substances with antidepressant activity, SAMe might trigger a manic episode in those with bipolar disease (manic-depressive illness). 58-60
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.

Interactions You Should Know About

If you are taking:
  • Standard antidepressants, including MAO inhibitors , SSRIs , and tricyclics : Do not take SAMe except on a physician's advice.
  • Levodopa for Parkinson's disease: SAMe might help relieve the side effects of this drug. However, it might also reduce its effectiveness over time.

References

1 di Padova C. S-adenosylmethionine in the treatment of osteoarthritis. Review of the clinical studies. Am J Med. 1987;83(5A):60-65.

2 Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol Scand Suppl. 1994;154:7-14.

3 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.

4 Bombardieri G, Milani A, Bernardi L, et al. Effects of S-adenosyl-methionine (SAMe) in the treatment of Gilbert’s syndrome. Curr Ther Res. 1985;37:580-585.

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.

6 Frezza M, Pozzato G, Pison G, et al. S-adenosylmethionine counteracts oral contraceptive hepatotoxicity in women. Am J Med Sci. 1987;293:234-238.

7 Frezza M, Pozzato G, Chiesa L, et al. Reversal of intrahepatic cholestasis of pregnancy in women after high dose S-adenosyl-L-methionine administration. Hepatology. 1984;4:274-278.

8 Barak AJ, Beckenhauer HC, Tuma DJ. Betaine, ethanol, and the liver: a review. Alcohol. 1996;13:395-398.

9 Barak AJ, Beckenhauer HC, Badakhsh S, et al. The effect of betaine in reversing alcoholic steatosis. Alcohol Clin Exp Res. 1997;21:1100-1102.

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.

11 Jacobsen S, Danneskiold-Samsoe B, Andersen RB. Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scand J Rheumatol. 1991;20:294-302.

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.

14 Liu X, Lamango N, Charlton C. L-dopa depletes S-adenosylmethionine and increases S-adenosyl homocysteine: Relationship to the wearing-off effects [abstract]. Soc Neurosci Abstracts. 1998;24:1469.

15 Bottiglieri T, Hyland K, Reynolds EH. The clinical potential in ademetionine (S-adenosylmethionine) in neurological disorders. Drugs. 1994;48:137-152.

16 Laudanno OM, Finkelstein D, Capdepon E. Complete cytoprotective action on the gastroduodenal mucosa induced by SAMe against damage provoked by ethanol in man. Panminerva Med. 1987;29:75-78.

17 di Padova C. S-adenosylmethionine in the treatment of osteoarthritis. Review of the clinical studies. Am J Med. 1987;83:60-65.

18 Kalbhen DA, Jansen G. Pharmacological studies on the antidegenerative effect of ademetionine in experimental osteoarthritis [in German]. Arzneimittelforschung. 1990;40:1017-1021.

19 Barcelo HA, Wiemeyer JCM, Sagasta CL, et al. Experimental osteoarthritis and its course when treated with S-adenyl-L-methionine (SAMe) [in Spanish]. Rev Clin Esp. 1990;187:74-78.

20 Caruso I, Peitrogrande V. Italian double-blind multicenter study comparing S-adenosylmethionine, naproxen and placebo in the treatment of degenerative joint disease. Am J Med. 1987;83:66-71.

21 Maccagno A. Double-blind controlled clinical trial of oral S-adenosylmethionine versus piroxicam in knee osteoarthritis. Am J Med. 1987;83:72-77.

22 Glorioso S, Todesco S, Mazzi A, et al. Double-blind multicentre study of the activity of S-adenosylmethionine in hip and knee osteoarthritis. Int J Clin Pharmacol Res. 1985;5:39-49.

23 Muller-Fassbender H. Double-blind clinical trial of S-adenosylmethionine versus ibuprofen in the treatment of osteoarthritis. Am J Med. 1987;83:81-83.

24 Vetter G. Double-blind comparative clinical trial with S-adenosylmethionine and indomethacin in the treatment of osteoarthritis. Am J Med. 1987;83:78-80.

25 Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol Scand Suppl. 1994;154:7-14.

26 Echols JC, Naidoo U, Salzman C. SAMe (S-adenosylmethionine). Harv Rev Psychiatry. 2000;8:84-90.

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.

29 Bell KM, Plon L, Bunney WE Jr, et al. S-adenosylmethionine treatment of depression: a controlled clinical trial. Am J Psychiatry. 1988;145:1110-1114.

30 De Vanna M, Rigamonti R. Oral S-adenosyl-L-methionine in depression. Curr Ther Res. 1992;52:478-485.

31 Bell KM, Potkin SG, Carreon D, et al. S-adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Suppl. 1994;154:15-18.

32 Echols JC, Naidoo U, Salzman C. SAMe (S-adenosylmethionine). Harv Rev Psychiatry. 2000;8:84-90.

33 Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol Scand Suppl. 1994;154:7-14.

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.

36 Bombardieri G, Milani A, Bernardi L, et al. Effects of S-adenosyl-methionine (SAMe) in the treatment of Gilbert’s syndrome. Curr Ther Res. 1985;37:580-585.

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.

38 Frezza M, Pozzato G, Pison G, et al. S-adenosylmethionine counteracts oral contraceptive hepatotoxicity in women. Am J Med Sci. 1987;293:234-238.

39 Frezza M, Pozzato G, Chiesa L, et al. Reversal of intrahepatic cholestasis of pregnancy in women after high dose S-adenosyl-L-methionine administration. Hepatology. 1984;4:274-278.

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.

41 Barak AJ, Beckenhauer HC, and Tuma DJ. Betaine, ethanol, and the liver: a review. Alcohol. 1996;13:395-398.

42 Barak AJ, Beckenhauer HC, Badakhsh S, et al. The effect of betaine in reversing alcoholic steatosis. Alcohol Clin Exp Res. 1997;21:1100-1102.

43 Tavoni A, Vitali C, Bombardieri S, et al. Evaluation of S-adenosylmethionine in primary fibromyalgia. A double-blind crossover study. Am J Med. 1987;83:107-110.

44 Tavoni A, Jeracitano G, Cirigliano G. Evaluation of S-adenosylmethionine in secondary fibromyalgia: a double-blind study. Clin Exp Rheumatol. 1998;16:106-107.

45 Jacobsen S, Danneskiold-Samsoe B, Andersen RB. Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scand J Rheumatol. 1991;20:294-302.

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.

47 Jacobsen S, Danneskiold-Samsoe B, Andersen RB. Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scand J Rheumatol. 1991;20:294-302.

48 Bottiglieri T, Hyland K, Reynolds EH. The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs. 1994;48:137-152.

49 Liu X, Lamango N, Charlton C. L-dopa depletes S-adenosylmethionine and increases S-adenosyl homocysteine: Relationship to the wearing-off effects [abstract]. Soc Neurosci Abstracts. 1998;24:1469.

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.

52 Cozens DD, Barton SJ, Clark R, et al. Reproductive toxicity studies of ademetionine. Arzneimittelforschung. 1988;38:1625-1629.

53 Berger R, Nowak H. A new medical approach to the treatment of osteoarthritis: report of an open phase IV study with ademetionine (Gumbaral). Am J Med. 1987;83:84-88.

54 Konig B. A long-term (two years) clinical trial with S-adenosylmethionine for the treatment of osteoarthritis. Am J Med. 1987;83(5A):89-94.

55 Caruso I, Peitrogrande V. Italian double-blind multicenter study comparing S-adenosylmethionine, naproxen and placebo in the treatment of degenerative joint disease. Am J Med. 1987;83:66-71.

56 Pezzoli C, Galli-Kienle M, Stramentinoli G. Lack of mutagenic activity of ademetionine in vitro and in vivo. Arzneimittelforschung. 1987;37:826-829.

57 di Padova C. S-adenosylmethionine in the treatment of osteoarthritis. Review of the clinical studies. Am J Med. 1987;83:60-65.

58 Carney MW, Chary TK, Bottiglieri T, et al. The switch mechanism and the bipolar/unipolar dichotomy. Br J Psychiatry. 1989;154:48-51.

59 Carney MW, Chary TK, Bottiglieri T, et al. Switch and S-adenosylmethionine. Ala J Med Sci. 1988;25:316-319.

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

61 Liu X, Lamango N, Charlton C. L-dopa depletes S-adenosylmethionine and increases S-adenosyl homocysteine: Relationship to the wearing-off effects [abstract]. Soc Neurosci Abstracts. 1998;24:1469.

62 Iruela LM, Minguez L, Merino J, et al. Toxic interaction of S-adenosylmethionine and clomipramine [letter]. Am J Psychiatry. 1993;150:522.

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.

65 Avezov SA, Mansurova FKh. Efficacy of combined use of ursodeoxycholic acid and heptral in the treatment of primary biliary cirrhosis. Klin Med (Mosk). 2004;82:46-49,55-58.

66 Binder T, Salaj P, Zima T et al. Ursodeoxycholic acid, S-adenosyl-L-methionine and their combinations in the treatment of gestational intrahepatic cholestasis (ICP). Ceska Gynekol. 2006;71:92-98.

67 Burrows RF, Clavisi O, Burrows E. Interventions for treating cholestasis in pregnancy. Cochrane Database Syst Rev. 2001;CD000493.

68 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. 2003;111:17-21.

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.

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