Pharmacokinetics and subjective effects of a novel oral LSD formulation in healthy subjects

Abstract

Aims:The aim of the present study was to characterize the pharmacokinetics and exposure-subjective response relationship of a novel oral solution of lysergic acid diethylamide (LSD) that was developed for clinical use in research and patients.Method: LSD (100 μg) was administered in 27 healthy subjects using a placebocontrolled, double-blind, cross-over design. Plasma levels of LSD, nor-LSD, and 2oxo-3-hydroxy-LSD (O-H-LSD) and subjective drug effects were assessed up to 11.5 hours.Results: First-order elimination kinetics were observed for LSD. Geometric mean maximum concentration (C max ) values (range) of 1.7 (1.0-2.9) ng/mL were reached at a t max (range) of 1.7 (1.0-3.4) hours after drug administration. The plasma halflife (t 1/2 ) was 3.6 (2.4-7.3) hours. The AUC ∞ was 13 (7.1-28) ng·h/mL. No differences in these pharmacokinetic parameters were found between male and female subjects. Plasma O-H-LSD but not nor-LSD (< 0.01 ng/mL) concentrations could be quantified in all subjects. Geometric mean O-H-LSD C max values (range) of 0.11 (0.07-0.19)ng/mL were reached at a t max (range) of 5 (3.2-8) hours. The t 1/2 and AUC ∞ values of O-H-LSD were 5.2 (2.6-21) hours and 1.7 (0.85-4.3) ng·h/mL, respectively. The subjective effects of LSD lasted (mean ± SD) for 8.5 ± 2.0 hours (range: 5.3-12.8 h), and peak effects were reached 2.5 ± 0.6 hours (range 1.6-4.3 h) after drug administration. EC 50 values were 1.0 ± 0.5 ng/mL and 1.9 ± 1.0 ng/mL for "good"and "bad" subjective drug effects, respectively. Conclusion:The present study characterized the pharmacokinetics of LSD and its main metabolite O-H-LSD. The subjective effects of LSD were closely associated with changes in plasma concentrations over time.

Distinct acute effects of LSD, MDMA, and d-amphetamine in healthy subjects

“…All of the drugs produced comparable ratings of "open" and "talkative" on the VAS, and ratings of "drug high," "drug liking," and "stimulated" on the VAS did not differ between LSD and MDMA. The present findings are overall consistent with previous reports on the effects of LSD [3,4,38,50,65], MDMA [18,25,28], and D-amphetamine [32]. In contrast to these previous studies, however, the present study compared the subjective responses to LSD, MDMA, and D-amphetamine using a within-subjects design.…”

“…Peak concentrations of MDMA and D-amphetamine were similar to previous studies that tested identical doses [32,39,73]. The full pharmacokinetic data for LSD derived from the present study have been published elsewhere [50]. Importantly, slightly higher plasma concentrations of LSD were documented in the present study compared with a previous study that reportedly used the same dose (0.1 mg) [49].…”

“…Importantly, slightly higher plasma concentrations of LSD were documented in the present study compared with a previous study that reportedly used the same dose (0.1 mg) [49]. The higher plasma concentrations in the present study can be explained by the use of a higher dose (0.096 mg) of LSD base (analytically confirmed content and stability) compared with a lower estimated dose of 0.070 mg in previous studies [38,49], as discussed previously [50].…”

“…Study drugs LSD (D-lysergic acid diethylamide base, high-performance liquid chromatography purity >99%; Lipomed AG, Arlesheim, Switzerland) was administered in a single intermediate oral dose of 100 µg [50]. D-Amphetamine sulfate (40 mg salt; Hänseler, Herisau, Switzerland) was administered in a relatively high dose in the form of gelatin capsules as a single oral dose that corresponded to 30 mg D-amphetamine base [32].…”

“…The plasma levels of LSD, D-amphetamine, and the LSD metabolite O-H-LSD were measured at baseline and 1, 1.5, 2, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 9.5, and 11.5 h after drug administration. The plasma levels of MDMA and MDMA metabolites 3,4-methylenedioxyamphetamine (MDA) and 4-hydroxy-3-methoxymethamphetamine (HMMA) were measured at baseline and 0, 0.5, 1, 1.5, 2.5, 3, 4, 5, 6, 7, 9, and 11 h after drug administration using liquid chromatography-tandem mass spectrometry as previously described [28,32,50]. The data were analyzed using noncompartmental analysis.…”