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

3. 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

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

5. MTHFR
Dopamine
deficiency
Folate
SAM-e
Serotonin
B12
Acetylcholine

6. 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

7. 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:

8. 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:

9. 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:

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

11. 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.

12. 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. 

13. 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

14. 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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