Bioavailability of S-adenosyl methionine and impact on response in a randomized, double-blind, placebo-controlled trial in major depressive disorder

J Clin Psychiatry. 2012 Jun;73(6):843-8. doi: 10.4088/JCP.11m07139. Epub 2012 May 15.


Objective: To characterize the impact of S-adenosyl methionine (SAMe) on homocysteine and potential risk of adverse cardiovascular effects by examining plasma levels of SAMe, S-adenosyl homocysteine (SAH), total homocysteine (tHCY), methionine (MET), and 5-methyltetrahydrofolate (5-MTHF) in 35 of 73 patients from a 6-week randomized double-blind, placebo-controlled trial of SAMe augmentation in serotonin reuptake inhibitor partial responders with DSM-IV major depressive disorder (MDD), published in 2010.

Method: Subjects were randomized from June 4, 2004, until August 8, 2008, to adjunctive placebo or SAMe 800-1600 mg/d for 6 weeks. Primary outcome measures included changes in one-carbon cycle intermediates within each treatment arm (by paired t test) and between treatment arms (by independent samples t test). Univariate analysis of variance and Fisher Protected Least Significant Difference were carried out to compare posttreatment levels of each one-carbon cycle intermediate. Secondary outcome measures included associations between clinical improvement and change in plasma intermediate levels, examined by linear regression (for change in Hamilton Depression Rating Scale scores) and logistic regression (for response or remission).

Results: We found significant differences in pretreatment plasma levels of tHCY (P = .03) between the SAMe and placebo arms. Following 6 weeks of treatment, plasma SAMe (P = .002) and SAH (P < .0001) levels increased significantly in the SAMe arm; no intermediates in the placebo group changed significantly. Posttreatment plasma SAMe (P = .0035), SAH (P < .0001), and tHCY (P = .0016) levels differed significantly between the SAMe and placebo groups. No significant associations were found between plasma intermediate levels and clinical improvement, response, or remission.

Conclusions: Despite concerns about the impact that SAMe therapy may have on homocysteine levels and risk of adverse cardiovascular effects, the lack of significant increase in tHCY levels after treatment suggests that no toxic effects from SAMe should be expected. Our findings, however, have some significant limitations and should be interpreted with caution.

Trial registration: identifier: NCT00093847.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Biological Availability
  • Depressive Disorder, Major / blood
  • Depressive Disorder, Major / drug therapy*
  • Dietary Supplements / statistics & numerical data*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Therapy, Combination / psychology
  • Drug Therapy, Combination / statistics & numerical data
  • Female
  • Homocysteine / blood
  • Humans
  • Male
  • Methionine / blood
  • Middle Aged
  • Psychiatric Status Rating Scales / statistics & numerical data
  • S-Adenosylhomocysteine / blood
  • S-Adenosylmethionine / administration & dosage
  • S-Adenosylmethionine / blood
  • S-Adenosylmethionine / pharmacokinetics*
  • S-Adenosylmethionine / therapeutic use*
  • Serotonin Uptake Inhibitors / administration & dosage
  • Serotonin Uptake Inhibitors / therapeutic use
  • Tetrahydrofolates / blood


  • Serotonin Uptake Inhibitors
  • Tetrahydrofolates
  • Homocysteine
  • S-Adenosylmethionine
  • S-Adenosylhomocysteine
  • Methionine
  • 5-methyltetrahydrofolate

Associated data