Introduction: Treatment of hypoactive sexual desire disorder (HSDD) remains unfulfilled. The only approved medication, flibanserin (FLI), is highly underused owing to concerns about central nervous system (CNS) depression and interactions. Trazodone (TRZ), which is not often used for sexual problems, has evidence suggesting efficacy but similar concerns.

Aim: To explore whether the pharmacologic similarities between TRZ and FLI could allow treatment of HSDD without CNS depression.

Methods: A literature search on TRZ was performed for clinical effects and to facilitate pharmacologic considerations relating to doses for HSDD and CNS depression.

Main outcome measure: The main measures were threshold doses for sedative-hypnotic effects, and calculated doses for occupy 20% of agonist receptors and 70% of antagonist receptors, considering 5HT1A, 5HT2A, 5HT2C, and α1 receptors for sexual benefits and 5HT2A, α1, and histamine type 1 receptors for CNS depression.

Results: 3.5-19.2-mg extended-release (XR) TRZ daily (bioequivalent to 1.2-6.4-mg immediate-release [IR] TRZ 3 times a day) is estimated to be the minimum effective dose for improving sexual desire and arousal; 75 mg (25-mg IR) appears to be the threshold dose for CNS depression.

Conclusion: Although tested only in much larger dose strengths, the optimal dose of XR TRZ for HSDD according to receptor and PK data appears to be about 4-20 mg. HSDD or arousal problems might be treated without over-sedation with XR 150-mg TRZ matrix tablets quartered to 37.5 mg daily or 50-mg IR TRZ tablets quartered to 12.5 mg given 2-3 times daily or as needed for arousal problems. Interindividual sensitivity might require varying the dose. Mechanistically rational adjuncts (eg, bupropion or dopaminergics) might augment response. Pyke RE. Trazodone in Sexual Medicine: Underused and Overdosed? Sex Med Rev 2020;8:206-216.