At present, major depression is most commonly treated with selective serotonin reuptake inhibitors (SSRIs), yet these pharmaceuticals have demonstrated poor treatment response in certain populations and occasionally exacerbate comorbidities in the endocrine, lipid, or gastrointestinal systems. For this reason, many depressed patients seek natural agents to take instead of, or alongside, SSRIs. S-adenosylmethionine (SAMe) is a well-tolerated nutritional supplement synthesized from methionine that has been shown to produce therapeutic effects similar to antidepressants.
An Australian pilot study published in the journal Advances in Integrative Medicine explored the relationship between SAMe and depression in a cohort of 36 participants (age range=28 y-70 y) who had been prescribed SSRIs yet experienced suboptimal response to the medication. All participants had a primary diagnosis of major depressive disorder with 98% of them diagnosed with a variety of comorbidities. They were randomized to receive either 800mg SAMe or 1600mg SAMe (Life Extension brand) daily for 15 weeks. The SAMe was taken as 400mg doses (twice daily in the 800mg group and four times daily in the 1600mg group). To measure changes in depressive symptoms from baseline to end of study, participants were administered the Mini International Neuropsychiatric Interview, Beck Depression Inventory (BDI), Depression Anxiety Stress Scale, Structured Clinical Interview for DSM, Outcome Questionnaire 45 (OQ45), Warwick-Edinburgh Mental Well-being Scale, and Quality of Life (QOL) Scale.
After 15 weeks, 35% of the participants taking SAMe saw significant improvement in their symptoms as indicated by BDI, OQ45, and QOL scores. Surprisingly, a higher dose of SAMe did not signify greater improvement: participants taking the lower dose of SAMe (800 mg) had the same results as those taking the higher dose (1600 mg). What’s more, SAMe at either dose did not aggravate any of the participants’ comorbid conditions.
In a substudy, the researchers tested magnesium orotate in 8 participants who did not respond to SAMe. After a 2-week washout period, these participants were supplemented with 1600 mg magnesium orotate (brand unspecified) for 8 weeks. They saw significant clinical improvement as measured by BDI, OQ45, and QOL, but because the cohort was so small, the results were considered preliminary.
The authors of this study are the first to admit that its small numbers warrant caution in drawing conclusions—and yet the results are intriguing enough to consider both SAMe and magnesium ororate in future research on depressed adults.
Bambling M, Parham SC, Coulson S, Vitetta L. S-adenosylmethionine (SAMe) and magnesium orotate as adjunctives to SSRIs in sub-optimal treatment response of depression in adults: A pilot study. Adv Integr Med. 2015;2:56-62.

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*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.