Life Extension Magazine April 2007
By Tiesha D. Johnson, BSN, RN
SAMe is most frequently available in 200-mg or 400-mg tablets. The typical oral dose for depression is 400-1600 mg daily. For bone and joint health, the typical dose is 200-1200 mg a day, in divided doses. For liver problems, up to 1600 mg may be taken daily in divided doses. Some of the scientific literature suggests that once positive effects are achieved, the dose of SAMe can be reduced. SAMe’s effects often manifest in two weeks or sooner.56
For optimal effects, stable, enteric-coated SAMe tablets are recommended. SAMe should be consumed on an empty stomach, either one hour before or two hours after meals.56
SAMe has a well-established track record of safe use, with minimal side effects. Some researchers, however, have worried that it may contribute to elevated levels of homocysteine, one of the products of SAMe’s chemical cycle in the body.26 Elevated homocysteine is a risk factor for cardiovascular disease.
Fortunately, a 2004 study provides powerful reassurance about this concern. Researchers studied 15 healthy volunteers who took oral SAMe supplements (1600 mg/day) for four weeks.57 None of the subjects experienced any increase in homocysteine levels during the treatment. Nonetheless, to prevent the possibility of elevated homocysteine, the Physician’s Desk Reference® recommends taking supplemental vitamins B6, B12, and folic acid, and possibly trimethylglycine (TMG), while using supplemental SAMe.56
People with bipolar disorder (previously known as manic-depressive illness) can develop mania (excitability, grandiose thinking, excessive energy, etc.) in response to supplementation with SAMe, and should therefore not use SAMe unless under medical supervision.14,58 Individuals taking antidepressant medications should likewise consult their physicians before taking SAMe in place of or in addition to those medications.56
SAMe is not recommended for use in children or nursing mothers. Pregnant women should use SAMe only under a physician’s recommendation.56
When Life Extension introduced SAMe to American consumers over 10 years ago, few recognized it as a major step forward in the science of natural health care. Yet decades of accumulating studies show that this remarkable natural compound matches the efficacy of many popular prescription drugs in combating conditions as varied as depression and arthritis—with minimal or no side effects.
SAMe was a relatively expensive nutrient when introduced to the US market a decade ago. Since then, the cost of synthesizing pharmaceutical-quality SAMe has been greatly reduced. Its affordability, enviable safety record, and growing number of diverse health applications—including promoting the health of the liver and endothelium—make SAMe worthy of inclusion in every well-rounded supplement regimen.
1. Vedantum S. Antidepressants a suicide risk for young adults. The Washington Post. December 14, 2006:A16
2. Friedel HA, Goa KL, Benfield P. S-adenosyl-L-methionine. A review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism. Drugs. 1989 Sep;38(3):389-416.
3. 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 Dec;5(4):287-94.
4. 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 Jan;111(1):17-21.
5. Soeken KL, Lee WL, Bausell RB, Agelli M, Berman BM. Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis. J Fam Pract. 2002 May;51(5):425-30.
6. Mischoulon D, Fava M. Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr. 2002 Nov;76(5):1158S-61S.
7. 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 Jul;99(1):211-5.
8. Kagan BL, Sultzer DL, Rosenlicht N, Gerner RH. Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 1990 May;147(5):591-5.
9. Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant prescription rates and rate of early adolescent suicide. Am J Psychiatry. 2006 Nov;163(11):1898-904.
10. Rihmer Z, Akiskal H. Do antidepressants t(h)reat(en) depressives? Toward a clinically judicious formulation of the antidepressant-suicidality FDA advisory in light of declining national suicide statistics from many countries. J Affect Disord. 2006 Aug;94(1-3):3-13.
11. Monaco P, Quattrocchi F. Study of the antidepressive effects of a biological transmethylating agent (S-adenosyl-methione or SAM). Riv Neurol. 1979 Nov;49(6):417-39.
12. Papakostas GI, Alpert JE, Fava M. S-adenosyl-methionine in depression: a comprehensive review of the literature. Curr Psychiatry Rep. 2003 Dec;5(6):460-6.
13. Carney MW, Edeh J, Bottiglieri T, Reynolds EM, Toone BK. Affective illness and S-adenosyl methionine: a preliminary report. Clin Neuropharmacol. 1986;9(4):379-85.
14. Carney MW, Toone BK, Reynolds EH. S-adenosylmethionine and affective disorder. Am J Med. 1987 Nov 20;83(5A):104-6.
15. Bottiglieri T, Godfrey P, Flynn T, et al. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry. 1990 Dec;53(12):1096-8.
16. Bell KM, Potkin SG, Carreon D, Plon L. S-adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Suppl. 1994;154:15-8.
17. Lipinski JF, Cohen BM, Frankenburg F, et al. Open trial of S-adenosylmethionine for treatment of depression. Am J Psychiatry. 1984 Mar;141(3):448-50.
18. Rosenbaum JF, Fava M, Falk WE, et al. The antidepressant potential of oral S-adenosyl-l-methionine. Acta Psychiatr Scand. 1990 May;81(5):432-6.
19. Delle CR, 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 Nov;76(5):1172S-6S.
20. Alpert JE, Papakostas G, Mischoulon D, et al. S-adenosyl-L-methionine (SAMe) as an adjunct for resistant major depressive disorder: an open trial following partial or nonresponse to selective serotonin reuptake inhibitors or venlafaxine. J Clin Psychopharmacol. 2004 Dec;24(6):661-4.
21. Fava M, Giannelli A, Rapisarda V, Patralia A, Guaraldi GP. Rapidity of onset of the antidepressant effect of parenteral S-adenosyl-L-methionine. Psychiatry Res. 1995 Apr 28;56(3):295-7.
22. Shippy RA, Mendez D, Jones K, Cergnul I, Karpiak SE. S-adenosylmethionine (SAM-e) for the treatment of depression in people living with HIV/AIDS. BMC Psychiatry. 2004 Nov 11;438.
23. Berlanga C, Ortega-Soto HA, Ontiveros M, Senties H. Efficacy of S-adenosyl-L-methionine in speeding the onset of action of imipramine. Psychiatry Res. 1992 Dec;44(3):257-262.
24. Jacobsen S, nneskiold-Samsoe B, Andersen RB. Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scand J Rheumatol. 1991;20(4):294-302.
25. Tavoni A, Vitali C, Bombardieri S, Pasero G. Evaluation of S-adenosylmethionine in primary fibromyalgia. A double-blind crossover study. Am J Med. 1987 Nov 20;83(5A):107-10.
26. Miller AL. The methionine-homocysteine cycle and its effects on cognitive diseases. Altern Med Rev. 2003 Feb;8(1):7-19.
27. Bottiglieri T. Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev. 1996 Dec;54(12):382-90.
28. Bottiglieri T, Laundy M, Crellin R, et al. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry. 2000 Aug;69(2):228-32.
29. Colell A, Garcia-Ruiz C, Miranda M, et al. Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor. Gastroenterology. 1998 Dec;115(6):1541-51.
30. Fernandez-Checa JC, Kaplowitz N, Garcia-Ruiz C, et al. GSH transport in mitochondria: defense against TNF-induced oxidative stress and alcohol-induced defect. Am J Physiol. 1997 Jul;273(1 Pt 1):G7-17.
31. Patrick L. Toxic metals and antioxidants: Part II. The role of antioxidants in arsenic and cadmium toxicity. Altern Med Rev. 2003 May;8(2):106-28.
32. Chawla RK, Bonkovsky HL, Galambos JT. Biochemistry and pharmacology of S-adenosyl-L-methionine and rationale for its use in liver disease. Drugs. 1990;40 Suppl 3:98-110.
33. Sofia HJ, Chen G, Hetzler BG, Reyes-Spindola JF, Miller NE. Radical SAM, a novel protein superfamily linking unresolved steps in familiar biosynthetic pathways with radical mechanisms: functional characterization using new analysis and information visualization methods. Nucleic Acids Res. 2001 Mar 1;29(5):1097-106.
34. Fernandez-Checa JC, Colell A, Garcia-Ruiz C. S-Adenosyl-L-methionine and mitochondrial reduced glutathione depletion in alcoholic liver disease. Alcohol. 2002 Jul;27(3):179-83.
35. Arias-Diaz J, Vara E, Garcia C et al. S-adenosylmethionine protects hepatocytes against the effects of cytokines. J Surg Res. 1996 Apr;62(1):79-84.
36. Dhiman RK, Chawla YK. Is there a link between oestrogen therapy and gallbladder disease? Expert Opin Drug Saf. 2006 Jan;5(1):117-29.
37. Richardson WS, Carter KM, Helm B, et al. Risk factors for gallstone disease in the laparoscopic era. Surg Endosc. 2002 Mar;16(3):450-2.
38. Di PC, Tritapepe R, Di PF, Frezza M, Stramentinoli G. S-adenosyl-L-methionine antagonizes oral contraceptive-induced bile cholesterol supersaturation in healthy women: preliminary report of a controlled randomized trial. Am J Gastroenterol. 1984 Dec;79(12):941-4.
39. Look MP, Riezler R, Reichel C, et al. Is the increase in serum cystathionine levels in patients with liver cirrhosis a consequence of impaired homocysteine transsulfuration at the level of gamma-cystathionase? Scand J Gastroenterol. 2000 Aug;35(8):866-72.
40. Yu J, Sauter S, Parlesak A. Suppression of TNF-alpha production by S-adenosylmethionine in human mononuclear leukocytes is not mediated by polyamines. Biol Chem. 2006 Dec;387(12):1619-27.
41. Loguercio C, Nardi G, Argenzio F, et al. Effect of S-adenosyl-L-methionine administration on red blood cell cysteine and glutathione levels in alcoholic patients with and without liver disease. Alcohol Alcohol. 1994 Sep;29(5):597-604.
42. Diaz BA, Dominguez HR, Uribe AF. Parenteral S-adenosylmethionine compared to placebos in the treatment of alcoholic liver diseases. An Med Interna. 1996 Jan;13(1):9-15.
43. Mato JM, Camara J, Fernandez de PJ, et al. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol. 1999 Jun;30(6):1081-9.
44. Purohit V, Russo D. Role of S-adenosyl-L-methionine in the treatment of alcoholic liver disease: introduction and summary of the symposium. Alcohol. 2002 Jul;27(3):151-4.
45. Podymova SD, Nadinskaia MIu. Clinical trial of heptral in patients with chronic diffuse liver disease with intrahepatic cholestasis syndrome. Klin Med (Mosk). 1998;76(10):45-8.
46. Polli E, Cortellaro M, Parrini L, Tessari L, Cherie LG. Pharmacological and clinical aspects of S-adenosylmethionine (SAMe) in primary degenerative arthropathy (osteoarthrosis). Minerva Med. 1975 Dec 5;66(83):4443-59.
47. Stramentinoli G, Pezzoli C, Catto E. Anti-inflammatory and analgesic action of S-adenosyl-L-methionine (SAMe) in experimental tests on laboratory animals. Minerva Med. 1975 Dec 5;66(83):4434-42.
48. Barcelo HA, Wiemeyer JC, Sagasta CL, Macias M, Barreira JC. Effect of S-adenosylmethionine on experimental osteoarthritis in rabbits. Am J Med. 1987 Nov 20;83(5A):55-9.
49. Barcelo HA, Wiemeyer JC, Sagasta CL, Macias M, Barreira JC. Experimental osteoarthritis and its course when treated with S-adenosyl-L-methionine. Rev Clin Esp. 1990 Jun;187(2):74-8.
50. Gutierrez S, Palacios I, Sanchez-Pernaute O, et al. SAMe restores the changes in the proliferation and in the synthesis of fibronectin and proteoglycans induced by tumour necrosis factor alpha on cultured rabbit synovial cells. Br J Rheumatol. 1997 Jan;36(1):27-31.
51. 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(1):39-49.
52. 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 Nov 20;83(5A):66-71.
53. Maccagno A, Di Giorgio EE, Caston OL, Sagasta CL. Double-blind controlled clinical trial of oral S-adenosylmethionine versus piroxicam in knee osteoarthritis. Am J Med. 1987 Nov 20;83(5A):72-7.
54. Vetter G. Double-blind comparative clinical trial with S-adenosylmethionine and indomethacin in the treatment of osteoarthritis. Am J Med. 1987 Nov 20;83(5A):78-80.
55. Najm WI, Reinsch S, Hoehler F, Tobis JS, Harvey PW. S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: a double-blind cross-over trial. BMC Musculoskelet Disord. 2004 Feb 26;5:6.
56. Available at: http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/sad_0231.shtml. Accessed February 5, 2007.
57. Goren JL, Stoll AL, Damico KE, Sarmiento IA, Cohen BM. Bioavailability and lack of toxicity of S-adenosyl-L-methionine (SAMe) in humans. Pharmacotherapy. 2004 Nov;24(11):1501-7.
58. Carney MW, Chary TK, Bottiglieri T, Reynolds EH. The switch mechanism and the bipolar/unipolar dichotomy. Br J Psychiatry. 1989 Jan;154:48-51.
59. Han SH, Quon MJ, Koh KK. Reciprocal relationships between abnormal metabolic parameters and endothelial dysfunction. Curr Opin Lipidol. 2007 Feb;18(1):58-65.
60. Martens FM, Visseren FL. The operative risk factors in the metabolic syndrome: is it lipids and high BP or are there direct vascular effects of insulin resistance and obesity. Curr Diab Rep. 2007 Feb;7(1):74-81.
61. Wassink AM, Olijhoek JK, Visseren FL. The metabolic syndrome: metabolic changes with vascular consequences. Eur J Clin Invest. 2007 Jan;37(1):8-17.
62. Purushothaman KR, Meerarani P, Moreno PR. Inflammation and neovascularization in diabetic atherosclerosis. Indian J Exp Biol. 2007 Jan;45(1):93-102.
63. Soucy KG, Lim HK, Benjo A, et al. Single exposure gamma-irradiation amplifies xanthine oxidase activity and induces endothelial dysfunction in rat aorta. Radiat Environ Biophys. 2007 Jan 26.
64. Spijkerman AM, Smulders YM, Kostense PJ, et al. S-adenosylmethionine and 5-methyltetrahydrofolate are associated with endothelial function after controlling for confounding by homocysteine: the Hoorn Study. Arterioscler Thromb Vasc Biol. 2005 Apr;25(4):778-84.
65. Net M, Valero R, Almenara R, et al. Hepatic preconditioning after prolonged warm ischemia by means of S-adenosyl-L-methionine administration in pig liver transplantation from non-heart-beating donors. Transplantation. 2003 Jun 27;75(12):1970-7.