NutriStack
SAMe and Trazodone, a caution.
SAMe has independent serotonergic and antidepressant activity. Combined with trazodone (a serotonin reuptake inhibitor whose active metabolite mCPP also agonizes serotonin receptors), the additive serotonergic load raises the risk of serotonin syndrome.
One pair, every claim cited. The two substances, the type, the mechanism, the recommendation, and the primary literature.
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At a glance
- Pair type
- Caution
- Evidence (highest tier)
- Emerging
- Source citations
- 2 sources
- Stack Score effect
- −5 to your Stack Score (per scored caution row).
- Scope
- Supplement × Prescription
- Last verified
- May 30, 2026
Caution · Emerging evidence
Caution
What is happening. SAMe has independent serotonergic and antidepressant activity. Combined with trazodone (a serotonin reuptake inhibitor whose active metabolite mCPP also agonizes serotonin receptors), the additive serotonergic load raises the risk of serotonin syndrome.
Mechanism. SAMe modulates monoamine neurotransmission. Trazodone blocks SERT and forms mCPP, a serotonin agonist. Combined serotonergic effects can drive postsynaptic toxicity.
Recommendation. Avoid starting SAMe alongside trazodone without explicit prescriber approval. If used together, start SAMe at the lowest effective dose and watch for tremor, sweating, restlessness, or fast heart rate.
Sources (2)
- Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-20. PMID 15784664
- Sarris J, Murphy J, Mischoulon D, et al. Adjunctive S-adenosylmethionine (SAMe) in treating non-remittent major depressive disorder: An 8-week double-blind, randomized, controlled trial. Eur Neuropsychopharmacol. 2018;28(10):1126-1136. PMID 30115553
Stack Score
How this pair moves the number.
Effect on the composite score
If both SAMe and Trazodone are in the same stack, this pair applies −5 to your Stack Score (per scored caution row).
The full algorithm, the clamping rules, and four worked stacks are documented at /methodology/stack-score.
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