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S-Adenosyl Methionine (SAM-e) David Mischoulon, MD, PhD Director, Depression Clinical and Research Program Massachusetts General Hospital Professor of Psychiatry Harvard Medical School

Functions as a methyl donor Mechanism Important in various physiologic processes e.g. neurotransmitter synthesis SAM-e levels are dependent on folate and B12 Methyl group Functions as a methyl donor

Depression Folate B12 B12 Bypasses any MTHFR* polymorphisms Dopamine SAM-e Serotonin B12 B12 Acetylcholine *MTHFR: methylenetetrahydrofolate reductase

MTHFR Dopamine deficiency Folate SAM-e Serotonin B12 Acetylcholine

Efficacy More effective than placebo More than 50 clinical trials Equivalent efficacy to tricyclic antidepressants Administered orally, intramuscularly or intravenously Doses: 200 – 1600 mg/day, up to 3200 mg/day  Sharma, A. et al. (2017). S-Adenosylmethionine (SAMe) for Neuropsychiatric Disorders: A Clinician-Oriented Review of Research. The Journal of Clinical Psychiatry, 78(6), e656–e667

Double-Blind Randomized Controlled Study ..  SAM-e Vs SSRIs Vs Placebo  Up to 3200 mg day (escitalopram  up to 20 mg/day)  189 patients with depression 12 weeks No advantage for SAM-e or for escitalopram over placebo Mischoulon D et al. (2014). A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-l-methionine (SAMe) vs. escitalopram in major depressive disorder. J Clin Psychiatry; 75:370-376

not responding to SSRIs Efficacy 2004 open study 6 weeks 800 – 1600 mg/day  Positive results 30 people not responding to SSRIs  Alpert JE 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 (2004). J Clin Psychopharmacol; 24:661-664

Efficacy 2010 study 6 weeks Significant advantage 73 patients SAM-e 800 mg twice / day  not responding to SSRIs or SNRIs  Placebo Recommended dose: 400 – 3200 mg / day Papakostas GI et al. (2010). S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors (SRIs) for SRI-non-responders with major depressive disorder: a double-blind, randomized clinical trial. Amer J Psychiatry 167:942-948

Drug Interactions Combined safely with Tricyclic antidepressants Serotonin reuptake inhibitors Serotonin-norepinephrine reuptake inhibitors

Side Effects Mild side effects Insomnia Mania or hypomania in patients with bipolar depression Loss of appetite Constipation Nausea Use carefully Dry mouth in combination with mood stabilizer Sweating Dizziness Anxiety Alpert JE et al. (2008) One-Carbon Metabolism and the Treatment of Depression: Roles of S-Adenosyl Methionine (SAMe) and Folate. Natural Medications for Psychiatric Disorders: Considering the Alternatives. Philadelphia: Lippincott Williams & Wilkins, pp.68-83   Sharma, A. et al (2017). S-Adenosylmethionine (SAMe) for Neuropsychiatric Disorders: A Clinician-Oriented Review of Research. The Journal of Clinical Psychiatry, 78(6), e656–e667.

Pregnancy Methylation activity and SAM-e levels SAM-e for intrahepatic cholestasis, positive results Safe in pregnancy More studies needed Advise caution in pregnant women Zhou F et al. (2014) Meta-analysis of ursodeoxycholic acid and S-adenosylmethionine for improving the outcomes of intrahepatic cholestasis of pregnancy. Zhonghua Gan Zang Bing Za Zhi ;22:299–304. 

Among the more expensive of the natural remedies Financial Factors Among the more expensive of the natural remedies 400 mg tablet  $0.75 – $1.25

Key Points Evidence supports antidepressant efficacy as well as safety. SAM-e can be used by itself as monotherapy or in combination with standard antidepressants. The cost of SAM-e may be prohibitive to some individuals.

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