Pharmacokinetics and Concentration-Effect Relationship of Oral LSD in Humans

Abstract

Background: The pharmacokinetics of oral lysergic acid diethylamide are unknown despite its common recreational use and renewed interest in its use in psychiatric research and practice.

Methods: We characterized the pharmacokinetic profile, pharmacokinetic-pharmacodynamic relationship, and urine recovery of lysergic acid diethylamide and its main metabolite after administration of a single oral dose of lysergic acid diethylamide (200 μg) in 8 male and 8 female healthy subjects.

Results: Plasma lysergic acid diethylamide concentrations were quantifiable (>0.1 ng/mL) in all the subjects up to 12 hours after administration. Maximal concentrations of lysergic acid diethylamide (mean±SD: 4.5±1.4 ng/mL) were reached (median, range) 1.5 (0.5-4) hours after administration. Concentrations then decreased following first-order kinetics with a half-life of 3.6±0.9 hours up to 12 hours and slower elimination thereafter with a terminal half-life of 8.9±5.9 hours. One percent of the orally administered lysergic acid diethylamide was eliminated in urine as lysergic acid diethylamide, and 13% was eliminated as 2-oxo-3-hydroxy-lysergic acid diethylamide within 24 hours. No sex differences were observed in the pharmacokinetic profiles of lysergic acid diethylamide. The acute subjective and sympathomimetic responses to lysergic acid diethylamide lasted up to 12 hours and were closely associated with the concentrations in plasma over time and exhibited no acute tolerance.

Conclusions: These first data on the pharmacokinetics and concentration-effect relationship of oral lysergic acid diethylamide are relevant for further clinical studies and serve as a reference for the assessment of intoxication with lysergic acid diethylamide.

Keywords: LSD; O-H-LSD; pharmacodynamics; pharmacokinetics; plasma; urine.

Figure 1.

Pharmacokinetics (PK) of lysergic acid diethylamide (LSD) and 2-oxo-3-hydroxy-LSD (O-H-LSD). (a) Individual LSD plasma concentration-time curves with the geometric mean shown in the inset. Filled circles indicate male subjects, and open circles indicate female subjects. (b) Semilogarithmic plot of the individual concentrations of LSD. Curves are shown separately for each individual in the supplementary Material (supplementary Figure S1). First-order kinetics were observed in all 16 subjects up to 12 hours. LSD levels fell below the lower limit of quantification (0.1ng/mL) in 2 subjects at 16 hours and 5 subjects at 24 hours. Slower elimination was observed between 12 and 24 hours. (c) Individual O-H-LSD plasma concentration-time curves in 8 subjects in whom metabolite concentrations could be determined, with the geometric mean shown in the inset. (d) Semilogarithmic plot of the individual concentrations of O-H-LSD. Curves are shown separately in supplementary Figure S2. LSD was administered at t = 0 hours.

Figure 2.

Lysergic acid diethylamide (LSD) effects plotted against LSD plasma concentrations (geometric means). The pharmacodynamic values are the mean±SEM differences from placebo at each time point in 16 subjects. The time of sampling is noted next to each point (in hours after LSD administration). Heart rate (a), mean arterial pressure (b), and bad drug effect (g) showed no hysteresis. Counterclockwise hysteresis was observed for body temperature (c), pupil size (d), any drug effect (e), and good drug effect (f), consistent with a delay between plasma concentration and effect. For most dynamic variables, maximal plasma concentrations (at approximately 2 hours) coincided with maximal dynamic effects. The dynamic changes then gradually decreased over time with decreasing plasma levels. No evidence of acute tolerance (clockwise hysteresis) was observed for any of the dynamic effects of LSD.