Acute Effects and Pharmacokinetics of LSD after Paroxetine or Placebo Pre-Administration in a Randomized, Double-Blind, Cross-Over Phase I Trial
Avedisian, I., Becker, A. M., Erne, L., Grünblatt, E., Humbert-Droz, M., Jelusic, A., Liechti, M. E., Luethi, D., Meyer zu Schwabedissen, H. E., Mueller, L., Straumann, I., Thomann, J., Tolev, A.
This randomised, double-blind, cross-over study (n=23) investigates LSD (100μg) effects after daily paroxetine (SSRI) or placebo administration in healthy participants. It finds paroxetine reduced negative LSD effects (bad drug effect, anxiety, nausea) while maintaining pleasant effects, and caused higher LSD concentrations (1.4-1.5x) due to CYP2D6 inhibition, suggesting no LSD dose adjustment is needed when combined with CYP2D6-inhibiting SSRIs.
Abstract
Psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), are being investigated for the treatment of depressive and anxiety disorders, for which concomitant treatment with selective serotonin reuptake inhibitors (SSRIs) is prevalent. The present study investigated the acute response to single doses of LSD (100μg) after daily administration of paroxetine (10mg for 7days, followed by 20mg for 35days) or placebo (42days) using a randomized, double-blind, cross-over design in 23 healthy participants. Paroxetine did not alter pleasant subjective effects of LSD but significantly reduced “bad drug effect,” “anxiety,” and “nausea.” No differences in autonomic effects or QTc interval after LSD administration were found between both conditions. The strong cytochrome P450 2D6 (CYP2D6) inhibitor paroxetine led to higher maximal concentrations and total exposures of LSD (geometric mean ratios of 1.4 and 1.5, respectively) indicating relevant involvement of CYP2D6 in its metabolism. The extent of this inhibition was nominally highest in genetic CYP2D6 normal metabolizers and lowest in poor metabolizers. The present findings suggest that add-on treatment with LSD to an SSRI is well-tolerated. The pharmacokinetic and pharmacodynamic interactions indicate that no dose adjustment of LSD seems necessary in the presence of an SSRI that inhibits CYP2D6. For SSRIs that do not relevantly inhibit CYP2D6, a dose increase of LSD might be appropriate, but due to lacking data and potential other pharmacokinetic interactions with these compounds, no definitive dose recommendation can be made.