SAM-e

Purported Benefits, Side Effects & More
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SAM-e

Purported Benefits, Side Effects & More
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SAM-e

Common Names

  • SAM-e
  • SAMe
  • SAM
  • Adomet

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For Patients & Caregivers

Tell your healthcare providers about any dietary supplements you’re taking, such as herbs, vitamins, minerals, and natural or home remedies. This will help them manage your care and keep you safe.

What is it?

Not enough research has been done to say whether SAM-e can treat depression, arthritis, or liver disease.

SAM-e is a compound produced naturally by the human body. It acts on a number of important molecules including hormones, neurotransmitters, fatty acids, DNA, proteins, and cell membranes. In the United States, SAM-e is marketed as a supplement to enhance mood, brain and neural function, joint mobility, and liver detoxification.

Data suggest that SAM-e has anti-inflammatory and antidepressant properties. Lower levels of SAM-e have been observed with various diseases such as depression, Alzheimer's and liver disease. However, study results on SAM-e for these conditions are mixed. In osteoarthritis, a few studies suggest benefit comparable with standard medications, but a panel could not recommend it for pain. More study is needed to determine safety and potential benefits.

SAM-e may interact with medications such as antidepressants, or other natural products that also affect serotonin levels. Therefore, patients should consult with their physician before taking this supplement.

What are the potential uses and benefits?
  • To treat arthritis

    A few studies show that SAM-e is as effective as conventional treatments in treating osteoarthritis, but a panel could not recommend it for pain because of insufficient evidence. More studies are needed.
  • To treat chronic liver disease

    Earlier studies found SAM-e helpful in chronic liver disease, but additional studies are needed to confirm this.
  • To treat drug-induced liver toxicity

    Initial studies suggest that SAM-e may help reduce liver toxicity caused by some drugs, but more studies are needed to confirm safety as well as effectiveness.
  • To treat depression

    Clinical studies produced conflicting results or were poorly designed. More studies are needed to evaluate this use.
  • To treat hot flashes

    A preliminary study suggests SAM-e is ineffective for this use.
  • To treat muscle pain

    Older studies of SAM-e for fibromyalgia suggest some benefit, but a panel could not recommend it for pain because of insufficient evidence. More studies are needed.
  • To treat AIDS-related spinal cord disease

    One study did not show significant benefits in this patient population.
  • To treat Alzheimer’s disease

    Studies that evaluate SAM-e alone without the use of other supplements for Alzheimer’s disease are lacking.
What are the side effects?
  • Headache
  • Mild stomach upset
  • Flatulence
  • Nausea and vomiting
  • Patients with bipolar disorder may develop mania
What else do I need to know?

Patient Warnings:

Patients taking selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, or other drugs that affect serotonin levels should avoid taking SAM-e without the supervision of a physician due to case reports of mania and serotonin syndrome, a serious condition, or other side effects.

Use of this supplement should be avoided if taking other supplements such as 5-HTP or St John’s wort because these products may also affect serotonin levels.

Patients who are immunocompromised should avoid this supplement due to concerns that SAM-e could enhance the growth of a microorganism called Pneumocystis carinii.

Do Not Take if:

You have bipolar disorder: There have been case reports of mania in patients with bipolar disorder.

You are immunocompromised: There is a theoretical risk that SAM-e could enhance the growth of a microorganism called Pneumocystis carinii.

You are taking clomipramine: There is a report of serotonin syndrome in a woman after simultaneous use of clomipramine and SAM-e.

You are taking antidepressants or anxiolytics (including tricyclics, MAOIs, and SSRIs): Because many of these drugs also affect serotonin levels, there is an increased risk for side effects or toxicities if you also take SAM-e. Discuss any use of this supplement with your treating physician.

You are taking levodopa: There is concern that taking SAM-e over a period of time may decrease the effectiveness of L-dopa, which is used for Parkinson’s disease. Discuss any use of this supplement with your treating physician.

You are taking St John’s wort: Because SJW may also affect serotonin levels, the use of multiple herbs that do this should be avoided to reduce risks for excess serotonin in the body, a serious condition.

You are taking 5-HTP : Because 5-HTP may also affect serotonin levels, the use of multiple herbs that do this should be avoided to reduce risks for excess serotonin in the body, a serious condition.

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For Healthcare Professionals

Scientific Name
S-adenosylmethionine
Clinical Summary

SAM-e is endogenously produced in the human body from adenosine triphosphate and methionine (1) (2). It is involved in the formation of monoamine neurotransmitters such as serotonin and norepinephrine (28). Decreased SAM-e levels in cerebrospinal fluid are thought to contribute to the etiologies of depression and Alzheimer’s disease (29) (30). SAM-e levels may also be decreased in chronic liver disease (31) and AIDS-associated myelopathy (32). In the United States, SAM-e is marketed as a supplement to enhance mood, brain and neural function, joint mobility, and liver detoxification. It is also a prescription drug in other countries.

Preclinical data suggest that SAM-e may have antidepressive (33), neuroprotective (34), anti-inflammatory (35), and chondroprotective (36) effects. Other models suggest liver injury can be exacerbated by depleted SAM-e levels, and that supplementation may have hepatoprotective effects (31).

In humans, data on whether SAM-e is an effective adjunct for major depressive disorder are mixed (16) (27), and whether it is more effective than escitalopram or placebo is also unclear (20) (37), although it may have greater therapeutic potential in men (21). Other double-blind studies have not found SAM-e, either as monotherapy or in a nutraceutical combination, helpful for major depressive disorder (50) (51), and various analyses remain mixed on its potential benefit (22) (23). Preliminary data suggest SAM-e may improve memory-related cognitive symptoms in depressed patients (17). However, studies that suggest cognitive benefits for patients with Alzheimer’s disease do not evaluate SAM-e in isolation (28).

Although preliminary trials suggest some benefit in fibromyalgia patients (40) (41), results are mixed on whether SAM-e is comparable with NSAIDs for osteoarthritis (14) (15) (38), and it did not significantly improve neurological measures in patients with AIDS-associated myelopathy (32). In addition, a steering committee examining whether dietary ingredients could help reduce pain determined there was insufficient evidence for SAM-e (52) (53). For hot flashes, SAM-e was ineffective compared with historical placebo (39).

Some trials suggest benefit in chronic liver disease (42). Addition of oral SAM-e to injected pegylated interferon alpha and oral ribavirin improved viral response in patients with chronic hepatitis C (18). Postoperative intravenous SAM-e therapy improved residual liver function in patients with cirrhosis (19). However, in patients with hepatitis C cirrhosis at elevated risk for hepatocellular carcinoma, oral SAM-e did not improve liver function or reduce injury or oxidative stress (24). Other preliminary data suggest it may be useful as adjunctive palliative therapy in advanced biliary tract carcinoma (25) or protect against chemotherapy-induced liver toxicity (43) (44) (45). Additional confirmatory studies are needed to assess efficacy and safety.

While generally well-tolerated, the therapeutic value of SAM-e in chronic liver disease is limited (26) or yet to be determined. Because it is poorly absorbed, enteric-coated tablets are preferred. Outside the United States, parenteral formulations are used to treat fibromyalgia (9), osteoarthritis, and tendonitis as well as depression. However, patients with bipolar disorder or taking serotonergic medications including antidepressants should discuss any use of this supplement with their treating physician, as cases of mania and serotonin syndrome have been reported.

Purported Uses and Benefits
  • AIDS-related myelopathy
  • Alzheimer’s disease
  • Arthritis
  • Liver disease
  • Depression
  • Fibromyalgia
  • Hot flashes
Mechanism of Action

SAM-e is endogenously produced from adenosine triphosphate and the amino acid methionine. It is a major, ubiquitous methyl donor to a wide variety of molecules (26), including catecholamines and other biogenic amines, fatty acids, neurotransmitters, nucleic acids, polysaccharides, porphyrins, proteins and membrane phospholipids. Homocysteine is formed through the transsulfuration pathway and is catabolized to cysteine and indirectly to glutathione.

In preclinical models, SAM-e protected against amyloid-beta-induced cellular injury by inhibiting oxidative stress and neuroinflammation (34). It also increased the endogenous antioxidant glutathione and potentiated antioxidant enzyme activity. Supplementation with SAM-e restores hepatic glutathione deposits and attenuates liver injury (26). The mechanism by which SAM-e might treat depression is unknown, but increased synthesis of neurotransmitters such as serotonin, norepinephrine, and dopamine, may increase responsiveness of neurotransmitter receptors and fluidity of cell membranes in the production of phospholipids (2) (3) (4).

Contraindications

Use of this supplement should be avoided if taking other supplements such as 5-HTP or St John’s wort because these products may also affect serotonin levels.

Patients on antidepressants or with bipolar disorder should avoid this supplement without the supervision of the treating physician due to case reports of mania, serotonin syndrome, or other side effects (13) (22) (46).

There is a theoretical concern that immunocompromised individuals may have an increased risk of Pneumocystis carinii infection with SAM-e (47) (48).

Adverse Reactions

Generally well tolerated (32) (37) (42) (43)

Headache, mild GI upset, flatulence, nausea, vomiting, diarrhea
Patients with bipolar disorder may develop manic phase (11) (22) (37).

Case Reports

Serotonin syndrome: In a woman after simultaneous use of clomipramine and SAM-e (13).

Mania with psychotic features: In a patient, related to concomitant use of SAM-e and the SSRI escitalopram (46).

Increase of serum homocysteine: In some patients with AIDS-associated myelopathy (32).

Herb-Drug Interactions

Clomipramine: Serotonin syndrome was reported following concomitant administration of clomipramine and intramuscular S-adenosylmethionine (13).

Levodopa: There is concern that taking SAM-e over a period of time may decrease the effectiveness of L-dopa in Parkinson’s disease (49).

Antidepressants/anxiolytics (tricyclics, MAOIs, and SSRIs): SAM-e may also raise serotonin levels, thereby increasing the risk of side effects or toxicities. A few case reports of mania and serotonin syndrome have been attributed to concomitant use of SAM-e (13) (46).

Herb Lab Interactions

Increased serum homocysteine levels: In some patients with AIDS-associated myelopathy (32).

Dosage (OneMSK Only)
References
  1. Osteoarthritis: the clinical picture, pathogenesis, and management with studies on a new therapeutic agent, S-adenosylmethionine. Proceedings of a symposium. Am J Med 1987;83:1-110.
  2. Baldessarini RJ. Neuropharmacology of S-adenosyl-L-methionine. Am J Med 1987;83:60-5.
  3. Stramentinoli G. Pharmacologic aspects of S-adenosylmethionine. Pharmacokinetics and pharmacodynamics. Am J Med 1987;83:35-42.
  4. Bell KM, et al. S-adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Suppl 1994;154:15-8.
  5. di Padova C. S-adenosylmethionine in the treatment of osteoarthritis. Review of the clinical studies. Am J Med 1987;83:95-103.
  6. Reynolds EH, Carney MW, Toone BK. Methylation and mood. Lancet 1984;2:196-8.
  7. Bradley JD, et al. A randomized, double blind, placebo controlled trial of intravenous loading with S-adenosylmethionine (SAM) followed by oral SAM therapy in patients with knee osteoarthritis. J Rheumatol 1994;21:905-11.
  8. Bottiglieri T, Hyland K, Reynolds EH. The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs 1994;2:137-52.
  9. Volkmann H, et al. Double-blind, placebo-controlled cross-over study of intravenous S-adenosyl-L-methionine in patients with fibromyalgia. Scand J Rheumatol l997;26:206-11.
  10. Cohen BM, Satlin A, Zubenko GS. S-adenosyl-L-methionine in the treatment of Alzeheimer’s disease. J Clin Psychopharmacol 1988;8:43-7.
  11. 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;38:389-416.
  12. Osman E, Owen JS, Burroughs AK. S-adenosyl-L-methionine — a new therapeutic agent in liver disease? Aliment Pharmacol Ther 1993;7:21-8.
  13. Iruela LM, et al. Toxic interaction of S-adenosylmethionine and clomipramine. Am J Psychiatry 1993;150:522.
  14. Caruso I, et al. 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.
  15. Maccagno A. Double-blind controlled clinical trial of oral S-adenosylmethionine versus piroxicam in knee osteoarthritis. Am J Med 1987;83:72-7.
  16. 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 Aug;167(8):942-8.
  17. Levkovitz Y, Alpert JE, Brintz CE, et al. Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder. J Affect Disord. 2012 Feb;136(3):1174-8.
  18. Filipowicz M, Bernsmeier C, Terracciano L, et al. S-adenosyl-methionine and betaine improve early virological response in chronic hepatitis C patients with previous nonresponse. PLoS One. 2010 Nov 8;5(11):e15492.
  19. Su ZR, Cui ZL, Ma JL, et al. Beneficial effects of S-adenosyl-L-methionine on post-hepatectomy residual liver function: a prospective, randomized, controlled clinical trial. Hepatogastroenterology. 2013 Jul-Aug;60(125):1136-41.
  20. Sarris J, Papakostas GI, Vitolo O, et al. S-adenosyl methionine (SAMe) versus escitalopram and placebo in major depression RCT: efficacy and effects of histamine and carnitine as moderators of response. J Affect Disord. Aug 2014;164:76-81.
  21. Sarris J, Price LH, Carpenter LL, et al. Is S-Adenosyl Methionine (SAMe) for Depression Only Effective in Males? A Re-Analysis of Data from a Randomized Clinical Trial. Pharmacopsychiatry. Jul 2015;48(4-5):141-144.
  22. Galizia I, Oldani L, Macritchie K, et al. S-adenosyl methionine (SAMe) for depression in adults. Cochrane Database Syst Rev. Oct 10 2016;10:Cd011286.
  23. Sarris J, Murphy J, Mischoulon D, et al. Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. Am J Psychiatry. Jun 01 2016;173(6):575-587.
  24. Morgan TR, Osann K, Bottiglieri T, et al. A Phase II Randomized, Controlled Trial of S-Adenosylmethionine in Reducing Serum alpha-Fetoprotein in Patients with Hepatitis C Cirrhosis and Elevated AFP. Cancer Prev Res (Phila). Sep 2015;8(9):864-872.
  25. Hoang BX, Tran HQ, Vu UV, et al. Palliative treatment for advanced biliary adenocarcinomas with combination dimethyl sulfoxide-sodium bicarbonate infusion and S-adenosyl-L-methionine. J Pain Palliat Care Pharmacother. Sep 2014;28(3):206-211.
  26. Guo T, Chang L, Xiao Y, et al. S-adenosyl-L-methionine for the treatment of chronic liver disease: a systematic review and meta-analysis. PLoS One. 2015;10(3):e0122124.
  27. Sarris J, Byrne GJ, Bousman C, et al. Adjunctive S-adenosylmethionine (SAMe) in treating non-remittent major depressive disorder: An 8-week double-blind, randomized, controlled trial(). Eur Neuropsychopharmacol. 2018 Oct;28(10):1126-1136.
  28. Sharma A, Gerbarg P, Bottiglieri T, et al. S-Adenosylmethionine (SAMe) for Neuropsychiatric Disorders: A Clinician-Oriented Review of Research. J Clin Psychiatry. Jun 2017;78(6):e656-e667.
  29. Mischoulon D, Fava M. Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr. Nov 2002;76(5):1158s-1161s.
  30. Linnebank M, Popp J, Smulders Y, et al. S-adenosylmethionine is decreased in the cerebrospinal fluid of patients with Alzheimer’s disease. Neurodegener Dis. 2010;7(6):373-378.
  31. Anstee QM, Day CP. S-adenosylmethionine (SAMe) therapy in liver disease: a review of current evidence and clinical utility. J Hepatol. Nov 2012;57(5):1097-1109.
  32. Di Rocco A, Werner P, Bottiglieri T, et al. Treatment of AIDS-associated myelopathy with L-methionine: a placebo-controlled study. Neurology. Oct 12 2004;63(7):1270-1275.
  33. De Berardis D, Orsolini L, Serroni N, et al. A comprehensive review on the efficacy of S-Adenosyl-L-methionine in Major Depressive Disorder. CNS Neurol Disord Drug Targets. 2016;15(1):35-44.
  34. Li Q, Cui J, Fang C, et al. S-Adenosylmethionine Attenuates Oxidative Stress and Neuroinflammation Induced by Amyloid-beta Through Modulation of Glutathione Metabolism. J Alzheimers Dis. 2017;58(2):549-558.
  35. Stramentinoli G. Pharmacologic aspects of S-adenosylmethionine. Pharmacokinetics and pharmacodynamics. Am J Med. Nov 20 1987;83(5a):35-42.
  36. Barcelo HA, Wiemeyer JC, Sagasta CL, et al. Effect of S-adenosylmethionine on experimental osteoarthritis in rabbits. Am J Med. Nov 20 1987;83(5a):55-59.
  37. Mischoulon D, Price LH, Carpenter LL, et al. A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-L-methionine (SAMe) versus escitalopram in major depressive disorder. J Clin Psychiatry. Apr 2014;75(4):370-376.
  38. Kim J, Lee EY, Koh EM, et al. Comparative clinical trial of S-adenosylmethionine versus nabumetone for the treatment of knee osteoarthritis: an 8-week, multicenter, randomized, double-blind, double-dummy, Phase IV study in Korean patients. Clin Ther. Dec 2009;31(12):2860-2872.
  39. Kadakia KC, Loprinzi CL, Atherton PJ, et al. Phase II evaluation of S-adenosyl-L-methionine (SAMe) for the treatment of hot flashes. Support Care Cancer. Mar 2016;24(3):1061-1069.
  40. Tavoni A, Vitali C, Bombardieri S, et al. Evaluation of S-adenosylmethionine in primary fibromyalgia. A double-blind crossover study. Am J Med. Nov 20 1987;83(5a):107-110.
  41. Jacobsen S, Danneskiold-Samsoe B, Andersen RB. Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scand J Rheumatol. 1991;20(4):294-302.
  42. 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. Jul 1990;99(1):211-215.
  43. Santini D, Vincenzi B, Massacesi C, et al. S-adenosylmethionine (AdoMet) supplementation for treatment of chemotherapy-induced liver injury. Anticancer Res. Nov-Dec 2003;23(6d):5173-5179.
  44. Vincenzi B, Santini D, Frezza AM, et al. The role of S-adenosyl methionine in preventing FOLFOX-induced liver toxicity: a retrospective analysis in patients affected by resected colorectal cancer treated with adjuvant FOLFOX regimen. Expert Opin Drug Saf. May 2011;10(3):345-349.
  45. Vincenzi B, Daniele S, Frezza AM, et al. The role of S-adenosylmethionine in preventing oxaliplatin-induced liver toxicity: a retrospective analysis in metastatic colorectal cancer patients treated with bevacizumab plus oxaliplatin-based regimen. Support Care Cancer. Jan 2012;20(1):135-139.
  46. Abeysundera H, Gill R. Possible SAMe-induced mania. BMJ Case Rep. Jun 27 2018;2018.
  47. Lu SC, Mato JM. S-adenosylmethionine in liver health, injury, and cancer. Physiol Rev. Oct 2012;92(4):1515-1542.
  48. Merali S, Vargas D, Franklin M, et al. S-adenosylmethionine and Pneumocystis carinii. J Biol Chem. May 19 2000;275(20):14958-14963.
  49. Muller T, Fowler B, Kuhn W. Levodopa intake increases plasma levels of S-adenosylmethionine in treated patients with Parkinson disease. Clin Neuropharmacol. Nov-Dec 2005;28(6):274-276.
  50. Sarris J, Murphy J, Stough C, et al. S-Adenosylmethionine (SAMe) monotherapy for depression: an 8-week double-blind, randomised, controlled trial. Psychopharmacology (Berl). Jan 2020;237(1):209-218.
  51. Sarris J, Byrne GJ, Stough C, et al. Nutraceuticals for major depressive disorder- more is not merrier: An 8-week double-blind, randomised, controlled trial. J Affect Disord. Feb 15 2019;245:1007-1015.
  52. Crawford C, Boyd C, Berry K, et al. Dietary Ingredients Requiring Further Research Before Evidence-Based Recommendations Can Be Made for Their Use as an Approach to Mitigating Pain. Pain Med. Aug 1 2019;20(8):1619-1632.
  53. Crawford C, Boyd C, Paat CF, et al. Dietary Ingredients as an Alternative Approach for Mitigating Chronic Musculoskeletal Pain: Evidence-Based Recommendations for Practice and Research in the Military. Pain Med. Jun 1 2019;20(6):1236-1247.
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