The impact of fluoxetine on the aversive effects of lysergic acid diethylamide.

Abstract

Serotonergic antidepressant history can reduce the subjective effects, including therapeutic efficacy, of a number of psychedelics. A related issue is the impact of traditional antidepressants with serotonergic action on the adverse effects of psychedelics. Becker et al. (2025) reported that adverse effects induced by lysergic acid diethylamide (LSD) were reduced by pretreatment with the selective serotonin reuptake inhibitor paroxetine, while "good drug effects" induced by LSD were not. The present studies examined if exposure to the selective serotonin reuptake inhibitor fluoxetine impacts the aversive effects of LSD as assessed in the taste avoidance procedure, a behavioral index of the aversive effects of drugs. After determining a dose of LSD inducing intermediate taste avoidance in male Sprague-Dawley rats (Experiment 1), a different set of subjects in Experiment 2 were exposed to fluoxetine (10 mg/kg) or vehicle every fourth day for a total of five injections prior to taste avoidance conditioning in which saccharin was followed by 50 ug/kg LSD or saline over six trials. Subjects were then assessed over extinction in which they were given saccharin alone. Although there was no overall impact of fluoxetine on LSD, consumption by a subset of subjects in the fluoxetine-LSD group that drank less than the group's mean did not overlap with consumption of subjects drinking less than the mean of the vehicle-LSD group, indicating an attenuating effect of fluoxetine. Future work should assess the generalization of such effects across different psychedelic classes and the neurobiological mediation of the effects with other combinations of antidepressants and psychedelics. (PsycInfo Database Record (c) 2026 APA, all rights reserved).