RESEARCH MONOGRAPH · KDC-MN-211
Trazodone
Trazodone is an old antidepressant from 1981 that almost nobody uses for depression anymore, because at the doses needed for mood (300 to 600 mg) it is unpleasantly sedating. What it gets prescribed for instead, by enormous margins, is sleep. At 25 to 100 mg it acts as a clean hypnotic by blocking the histamine receptor and the 5-HT2A serotonin receptor, both of which promote arousal. It is non-controlled, has no dependence potential, does not produce the next-day cognitive hangover of older sleep drugs, and is preferred for older adults specifically because it lacks the fall risk of benzodiazepines. The active leftover mCPP is a serotonin receptor activator that occasionally causes brief mood disturbance. Not stocked by Kodiac. This monograph is provided for research and educational reference.
Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.
Serotonin antagonist and reuptake inhibitor (SARI)
A triazolopyridine antidepressant repurposed at low dose as a hypnotic via potent H1 and 5-HT2A antagonism.
Abstract
Trazodone (2-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; CAS 19794-93-5; molecular formula C19H22ClN5O; molecular weight 371.86) is a triazolopyridine SARI developed at Angelini and approved by the FDA in 1981. The compound is a weak SERT inhibitor (Ki approximately 160 nM) but a potent 5-HT2A and H1 antagonist (5-HT2A Ki approximately 36 nM, H1 Ki approximately 220 nM). The active metabolite mCPP (m-chlorophenylpiperazine) is a 5-HT2C agonist contributing to anxiogenic side effects in some patients. Pharmacological profile distinguishes trazodone from SSRIs: at antidepressant doses the SERT inhibition contributes meaningfully, but at the more common hypnotic doses the H1 and 5-HT2A antagonism dominates, producing pronounced sedation without the GABAergic dependency profile of benzodiazepine hypnotics. Plasma half-life is bimodal: 3 to 6 hours alpha phase, 5 to 9 hours beta phase. Adverse events include orthostatic hypotension and the rare but serious priapism (1 in 1000 to 1 in 10000 incidence). Used as a low-dose hypnotic and as a reference compound for 5-HT2A receptor pharmacology.
Mechanism of action
Weak SERT inhibition; potent 5-HT2A and H1 antagonism. Active metabolite mCPP is a 5-HT2C agonist.
Reported research dose ranges
Reported research dose ranges in the literature.
References
- Stahl SM. Mechanism of action of trazodone: a multifunctional drug. CNS Spectr 2009.
- Mendelson WB. A review of the evidence for the efficacy and safety of trazodone in insomnia. J Clin Psychiatry 2005.
- Haria M, et al. Trazodone. A review of its pharmacology. Drugs Aging 1994.
Read the full monograph
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The full reference document is provided strictly for research use only. It reports research dose ranges from the published literature, not instructions for use in humans or animals.
FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.