Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide in healthy subjects
This analysis of data from two double-blind, placebo-controlled studies (n=40) on the pharmacokinetics of LSD (100 and 200µg) found dose-proportional effects. The effects lasted on average 8.2 and 11.6 hours, there was a strong correlation between the blood-plasma level of LSD and subjective effects, but this was only found within-subjects (over time), not between subjects.
Authors
- Yasmin Schmid
- Patrick Dolder
- Matthias Liechti
Published
Abstract
Background and Objective: Lysergic acid diethylamide (LSD) is used recreationally and in clinical research. The aim of the present study was to characterize the pharmacokinetics and exposure-response relationship of oral LSD.
Methods
We analyzed pharmacokinetic data from two published placebo-controlled, double-blind, cross-over studies using oral administration of LSD 100 and 200 µg in 24 and 16 subjects, respectively. The pharmacokinetics of the 100-µg dose is shown for the first time and data for the 200-µg dose were reanalyzed and included. Plasma concentrations of LSD, subjective effects, and vital signs were repeatedly assessed. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-effect relationships were described using pharmacokinetic-pharmacodynamic modeling.
Results
Geometric mean (95% confidence interval) maximum plasma concentration values of 1.3 (1.2-1.9) and 3.1 (2.6-4.0) ng/mL were reached 1.4 and 1.5 h after administration of 100 and 200 µg LSD, respectively. The plasma half-life was 2.6 h (2.2-3.4 h). The subjective effects lasted (mean ± standard deviation) 8.2 ± 2.1 and 11.6 ± 1.7 h for the 100- and 200-µg LSD doses, respectively. Subjective peak effects were reached 2.8 and 2.5 h after administration of LSD 100 and 200 µg, respectively. A close relationship was observed between the LSD concentration and subjective response within subjects, with moderate counterclockwise hysteresis. Half-maximal effective concentration values were in the range of 1 ng/mL. No correlations were found between plasma LSD concentrations and the effects of LSD across subjects at or near maximum plasma concentration and within dose groups.
Conclusions
The present pharmacokinetic data are important for the evaluation of clinical study findings (e.g., functional magnetic resonance imaging studies) and the interpretation of LSD intoxication. Oral LSD presented dose-proportional pharmacokinetics and first-order elimination up to 12 h. The effects of LSD were related to changes in plasma concentrations over time, with no evidence of acute tolerance.
Research Summary of 'Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide in healthy subjects'
Introduction
Lysergic acid diethylamide (LSD) is a prototypical classic hallucinogen with renewed interest for basic pharmacology, recreational use and potential therapeutic applications. Earlier human data on LSD pharmacokinetics are sparse: small intravenous and limited oral studies provided rough estimates of elimination half-life and time courses, but systematic concentration–time profiles after controlled oral dosing and linked pharmacokinetic–pharmacodynamic (PK–PD) analyses have been largely missing. In particular, prior functional imaging and other experimental studies often did not measure plasma LSD, leaving the relationship between exposure and effects at the time of outcome assessment uncertain. Dolder and colleagues set out to characterise the plasma pharmacokinetics of oral LSD at two commonly used doses (100 µg and 200 µg) and to quantify the exposure–response relationship for subjective and autonomic effects. The study combined data from two double-blind, placebo-controlled, cross-over trials to (1) describe concentration–time profiles and compartmental pharmacokinetic parameters, (2) derive EC50 (half-maximal effect) and effect-site equilibration parameters using PK–PD link modelling, and (3) examine whether plasma concentrations predict between-subject differences in pharmacodynamic responses at matched time points.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Dolder, P. C., Schmid, Y., Steuer, A. E., Kraemer, T., Rentsch, K. M., Hammann, F., & Liechti, M. E. (2017). Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide in healthy subjects. Clinical Pharmacokinetics, 56(10), 1219-1230. https://doi.org/10.1007/s40262-017-0513-9
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