Abstract

Rationale: Psychedelics such as lysergic acid diethylamide (LSD) and psilocybin have returned into psychiatric research for indications such as anxiety, depression, cluster headache, and many more. Modern experimental studies with psilocybin‐assisted therapy for anxiety and depression show promising results. However, finding the right dose of the right psychedelic is crucial and data on dosing is scarce. There are remaining questions especially on the definition and characterization of microdoses and psychoactive doses and regarding dose equivalence of psilocybin and LSD. It is still unclear to what extent psilocybin and LSD differ, and there is currently no modern data available.

Methods: Acute pharmacokinetic and pharmacodynamics effect data from three double‐blind, randomized, placebo‐controlled, crossover trials in healthy volunteers using different doses of LSD ﴾5, 10, 20, 25, 50, 100 and 200 μg﴿ and psilocybin ﴾15 and 30mg﴿ was compared using psychometric tools, such as the five‐dimensions of Altered States of Consciousness ﴾5D‐ASC﴿, the Mystical Experience Questionnaire ﴾MEQ﴿, and visual analogue scales ﴾VASs﴿. Furthermore, autonomic effects, plasma concentrations and concentration‐effect relationships using PK‐PD modeling were assessed.

Results: LSD showed increasing subjective effects starting at 10 μg LSD. A ceiling effect was observed for good drug effects at 100 μg. The 200 μg dose induced greater ego‐dissolution compared to 100 μg dose and induced significant anxiety. Average effect durations increased dose‐dependently from 4 to 11 hours with increasing doses of 10‐200 μg. Further, LSD showed dose‐proportional pharmacokinetics and first‐order elimination. LSD concentrations decreased with an average half‐life of 3 hours. For doses of 25‐200 μg, LSD moderately increased blood pressure and heart rate. Final data from the dose‐response analysis of psilocybin and the comparison with LSD are not yet available but will be presented at the conference.

Conclusions: These studies provide an acute effect characterization of well‐defined doses useful for dose selection in future substance‐assisted studies.