Pharmacokinetics, pharmacodynamics and urinary recovery of oral lysergic acid diethylamide (LSD) administration in healthy participants
In 28 healthy volunteers given 85 or 170 μg oral LSD, pharmacokinetic–pharmacodynamic modelling showed dose‑proportional pharmacokinetics with mean Cmax 1.8 and 3.4 ng/mL at ~1.7 h, elimination half‑lives of ~3.7–4.0 h, and dose‑dependent subjective effects lasting ~9–11 h. The drug was extensively metabolised with only ~1% recovered unchanged and ~16% as 2‑oxo‑3‑hydroxy‑LSD in urine over 24 h, validating prior findings and providing the first detailed urinary recovery data.
Authors
- Matthias Liechti
- Friederike Holze
- Urs Duthaler
Published
Abstract
Aims
Lysergic acid diethylamide (LSD) is currently investigated for several neurological and psychiatric illnesses. Various studies have investigated the pharmacokinetics and the pharmacokinetic–pharmacodynamic relationship of LSD in healthy participants, but data on urinary recovery and confirmatory studies are missing.
Methods
The present study characterized the pharmacokinetics, pharmacokinetic–pharmacodynamic relationship and urinary recovery of LSD at doses of 85 and 170 μg administered orally in 28 healthy participants. The plasma concentrations and subjective effects of LSD were continuously evaluated over a period of 24 h. Urine was collected during 3 time intervals (0–8, 8–16 and 16–24 h after LSD administration). Pharmacokinetic parameters were determined using compartmental modelling. Concentration–subjective effect relationships were described using pharmacokinetic–pharmacodynamic modelling.
Results
Mean (95% confidence interval) maximal LSD concentrations were 1.8 ng/mL (1.6–2.0) and 3.4 ng/mL (3.0–3.8) after the administration of 85 and 170 μg LSD, respectively. Maximal concentrations were achieved on average after 1.7 h. Elimination half‐lives were 3.7 h (3.4–4.1) and 4.0 h (3.6–4.4), for 85 and 170 μg LSD, respectively. Only 1% of the administered dose was recovered from urine unchanged within the first 24 h, 16% was eliminated as 2‐oxo‐3‐hydroxy‐LSD. Urinary recovery was dose proportional. Mean (±standard deviation) durations of subjective effects were 9.3 ± 3.2 and 11 ± 3.7 h, and maximal effects (any drug effects) were 77 ± 18% and 87 ± 13% after 85 and 170 μg of LSD, respectively.
Conclusion
The present novel study validates previous findings. LSD exhibited dose‐proportional pharmacokinetics and first‐order elimination kinetics and dose‐dependent duration and intensity of subjective effects. LSD is extensively metabolized and shows dose‐proportional urinary recovery.
Research Summary of 'Pharmacokinetics, pharmacodynamics and urinary recovery of oral lysergic acid diethylamide (LSD) administration in healthy participants'
Introduction
Lysergic acid diethylamide (LSD) is a classical psychedelic whose principal pharmacology involves partial agonism at serotonin 5-HT2A receptors. Earlier human studies of oral LSD across a wide dose range (5–200 µg) have generally shown dose-proportional increases in plasma concentrations, peak levels around 1.5 hours, and first-order elimination with reported half-lives of about 2.7–4.1 hours. Subjective effects such as "any drug effect" also rose dose-proportionally up to about 100 µg, with some ceilinging at higher doses, while unpleasant effects and ego dissolution increased at higher doses. Prior work also reported that LSD is extensively metabolised and that only small fractions of an administered dose appear unchanged in urine, but those urinary data derive from a single-dose study with potential formulation stability concerns and therefore leave uncertainty about urinary recovery across doses within the same participants. This analysis aimed to fill that gap by describing urinary recovery of LSD and its primary metabolite O‑H‑LSD after two analytically confirmed oral doses (85 µg and 170 µg LSD base) administered within the same healthy participants, and to replicate and confirm prior pharmacokinetic and pharmacokinetic–pharmacodynamic (PK–PD) findings for these doses. The objective was both to characterise plasma PK and PD relationships and to quantify urinary excretion and renal clearance for each dose, providing data relevant to dosing, metabolism, and potential dose adjustments in clinical settings.
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Study Details
- Study Typeindividual
- Journal
- Compound
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- APA Citation
Holze, F., Erne, L., Duthaler, U., & Liechti, M. E. (2024). Pharmacokinetics, pharmacodynamics and urinary recovery of oral lysergic acid diethylamide (LSD) administration in healthy participants. British Journal of Clinical Pharmacology, 90(1), 200-208. https://doi.org/10.1111/bcp.15887
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Holze, F., Vizeli, P., Müller, F. et al. · Neuropsychopharmacology (2019)
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