SAM-e

Common Names

  • SAM-e
  • SAMe
  • SAM
  • Adomet

For Patients & Caregivers

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. More study is needed to determine safety and 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.

  • To treat arthritis
    A few studies show that SAM-e is as effective as conventional treatments in treating osteoarthritis.
  • 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, and one large study did not find benefit in major depressive disorder. 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 larger studies are needed to confirm this.
  • 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 without other supplements for Alzheimer’s disease are lacking.

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 the 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.

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

You are immunocompromised: There is a hypothetical 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 tricyclic antidepressants, 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.

  • Headache
  • Mild stomach upset
  • Flatulence
  • Nausea and vomiting
  • Patients with bipolar disorder may develop manic phase
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For Healthcare Professionals

S-adenosylmethionine

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 a large trial did not find benefit with SAM-e over escitalopram or placebo for major depressive disorder (37). Another study suggests benefit compared with escitalopram or placebo (20), but its therapeutic potential may be greater in men (21). A Cochrane review cites an absence of quality evidence (22), while a meta-analysis suggests adjunctive potential (23). Other 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 results are mixed, a few clinical trials of SAM-e for osteoarthritis suggest benefit comparable with NSAIDs (14) (15) (38). For hot flashes, SAM-e was ineffective compared with historical placebo (39). It also did not significantly improve neurological measures in patients with AIDS-associated myelopathy (32). Preliminary trials suggest some benefit in fibromyalgia patients (40) (41), but larger studies are needed.

Some trials have suggested benefit with oral SAM-e in patients with chronic liver disease (42). Addition of oral SAM-e to injected pegylated interferon alpha (pegIFN 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). A small open-label study suggests oral SAM-e may be useful as adjunctive palliative therapy in patients with advanced biliary tract carcinoma (25). Other preliminary analyses suggest protective effects with SAM-e 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.

  • AIDS-related myelopathy
  • Alzheimer’s disease
  • Arthritis
  • Chronic liver disease
  • Drug-induced liver toxicity
  • Depression
  • Fibromyalgia
  • Hot flashes

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 (GSH) 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).

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).

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).

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 (tricyclic antidepressants, 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).

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


  1. Baldessarini RJ. Neuropharmacology of S-adenosyl-L-methionine. Am J Med 1987;83:60-5.

  2. Bell KM, et al. S-adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Suppl 1994;154:15-8.

  3. Reynolds EH, Carney MW, Toone BK. Methylation and mood. Lancet 1984;2:196-8.

  4. Bottiglieri T, Hyland K, Reynolds EH. The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs 1994;2:137-52.

  5. Cohen BM, Satlin A, Zubenko GS. S-adenosyl-L-methionine in the treatment of Alzeheimer’s disease. J Clin Psychopharmacol 1988;8:43-7.

  6. Osman E, Owen JS, Burroughs AK. S-adenosyl-L-methionine — a new therapeutic agent in liver disease? Aliment Pharmacol Ther 1993;7:21-8.

  7. Iruela LM, et al. Toxic interaction of S-adenosylmethionine and clomipramine. Am J Psychiatry 1993;150:522.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  21. 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.

  22. 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.

  23. Abeysundera H, Gill R. Possible SAMe-induced mania. BMJ Case Rep. Jun 27 2018;2018.

  24. Lu SC, Mato JM. S-adenosylmethionine in liver health, injury, and cancer. Physiol Rev. Oct 2012;92(4):1515-1542.

  25. Merali S, Vargas D, Franklin M, et al. S-adenosylmethionine and Pneumocystis carinii. J Biol Chem. May 19 2000;275(20):14958-14963.

  26. 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.

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