Acute Effects and Pharmacokinetics of LSD after Paroxetine or Placebo Pre-Administration in a Randomized, Double-Blind, Cross-Over Phase I Trial

Introduction

Classic psychedelics such as LSD and psilocybin act principally via serotonin 5-HT2A receptor activation and are under investigation as treatments for depressive and anxiety disorders. Because many patients eligible for psychedelic-assisted therapies are already taking selective serotonin reuptake inhibitors (SSRIs), concerns exist that SSRIs might modulate the acute effects of psychedelics via effects on 5-HT2A receptor number or function; case reports and survey data have suggested attenuation of psychedelic responses during SSRI treatment. Prior controlled work from this group showed reduced acute response to psilocybin after escitalopram, and clinical trials commonly discontinue SSRIs before psychedelic dosing despite withdrawal and relapse risks associated with discontinuation. Becker and colleagues designed the present trial to test whether six weeks of paroxetine (a strong CYP2D6 inhibitor) versus placebo would alter the acute subjective, adverse and autonomic responses to a single 100 μg dose of LSD in healthy volunteers. The study also aimed to characterise pharmacokinetic interactions and the role of CYP2D6 genotype in LSD metabolism, and to test the primary hypotheses that overall mind-altering effects (3D-OAV/5D-ASC total score) and peak "good drug effect" VAS ratings would be similar after paroxetine and placebo, while "bad drug effect" and "anxiety" would be reduced after paroxetine. The paroxetine manipulation additionally allowed investigation of whether increased LSD exposure via CYP2D6 inhibition would offset any SSRI-related pharmacodynamic attenuation.