Absolute Oral Bioavailability and Bioequivalence of LSD Base and Tartrate in a Double-Blind, Placebo-Controlled, Crossover Study

Lysergic acid diethylamide (LSD) is currently being investigated as a potential treatment for psychiatric and neurological disorders. Different LSD formulations (base or tartrate, oral or intravenous) are being used. Unclear is whether LSD base and tartrate pharmacokinetics are equivalent. Additionally, LSD's absolute oral bioavailability is unknown. Therefore, we tested the bioequivalence of different oral LSD base and tartrate formulations and defined LSD's absolute oral bioavailability at a dose of ~80 μg freebase equivalent. We used a randomized, double‐blind, placebo‐controlled, five‐period crossover design in 20 healthy participants to investigate an ethanolic drinking solution of LSD base, a watery drinking solution of LSD tartrate, a rapid dissolvable tablet of LSD base, an intravenous formulation of LSD tartrate, and corresponding placebos. We assessed pharmacokinetic parameters and acute subjective, autonomic, and adverse effects up to 24 hours. All oral formulations were bioequivalent, with the ethanolic base solution as a reference. The area under the concentration–time curve from zero to infinity and maximum plasma concentration were within a 90% confidence interval of 80–125%. The absolute bioavailability of oral LSD was 80% and similar for all tested formulations. Overall, the oral formulations showed comparable pharmacokinetic and pharmacodynamic parameters. Intravenous LSD administration produced higher “any drug effect,” “good drug effect,” and “ego dissolution” compared with oral LSD tartrate, more “anxiety” compared with all oral formulations, and more “nausea” and “bad drug effect” compared with oral LSD base and tartrate. In conclusion, dosing with LSD base and tartrate can be considered bioequivalent with high and similar oral bioavailability.