Pharmacokinetics and pharmacodynamics of sublingual microdosed lysergic acid diethylamide in healthy adult volunteers
In a double‑blind Phase 1 trial in 80 healthy male volunteers, a one‑compartment population pharmacokinetic model and LC‑MS/MS assay characterised 10 µg sublingual LSD (Cmax 0.20 µg/L, Tmax 1.51 h, t1/2 3.08 h, clearance 7.78 L/h/70 kg, Vc 32.9 L/70 kg). Microdosing produced minimal cardiovascular and subjective effects, no change in peripheral BDNF, and suggested qualitative influences of CYP genotypes (notably CYP2D6) on concentrations, indicating the need for larger genotype studies and more sensitive pharmacodynamic measures.
Authors
- Suresh Muthukumaraswamy
- Rebecca Sumner
- Robin Murphy
Published
Abstract
Introduction
Microdosing is the practice of taking psychedelic drugs at doses that produce no or minimal perceptible subjective or behavioural effects. This study investigated the pharmacokinetics and pharmacodynamics of microdosed lysergic acid diethylamide (LSD).
Methods
This was a Phase 1 double-blind placebo-controlled parallel-groups trial with 80 healthy male volunteers (four withdrawals due to anxiety). Plasma samples were taken at 0.5, 1, 2, 4 and 6 h after 10 µg sublingual LSD and analysed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). LSD pharmacokinetics were modelled. Population analyses were performed using nonlinear mixed effects models. Heart rate and a visual analogue scale (‘feel effect’) were used to describe LSD pharmacodynamics. The effect of the relevant cytochrome P450 (CYP) genotype on LSD pharmacokinetics was qualitatively assessed. Plasma and serum levels of brain-derived neurotrophic factor (BDNF) were evaluated.
Results
A one-compartment model best described LSD pharmacokinetics. Mean (95% confidence interval): elimination clearance = 7.78 L/h/70 kg (6.75–8.77), central volume of distribution = 32.9 L/70 kg (30.1, 36.0). Maximal concentration (0.20 µg/L), time to maximal concentration (1.51 h) and elimination half-life (3.08 h). The maximal increase in heart rate and visual analogue scale was small (<15%) compared to baseline estimates limiting the modelling. Two of the participants withdrawn from the study due to anxiety had intermediate-weak CYP2D6 activity. CYP2D6, CYP1A6, CYP2B6 and CYP2C9 qualitatively appeared to influence concentration. No evidence of alterations of peripheral BDNF with microdosing was found.
Conclusion
This study provides a population pharmacokinetic model and LC-MS/MS assay that can inform clinical and bioequivalence studies. Relevant CYP genotypes should be studied in larger samples as combined potential biomarkers of response. Microdose-sensitive and reliable pharmacodynamic measures are needed.
Research Summary of 'Pharmacokinetics and pharmacodynamics of sublingual microdosed lysergic acid diethylamide in healthy adult volunteers'
Introduction
Microdosing with LSD refers to repeated administration of sub‑perceptual doses (commonly about 10 µg) that users report may improve mood, cognition and other symptoms. Earlier experimental work in healthy volunteers has shown dose-dependent effects of low doses (5–26 µg) on physiological and behavioural measures, but pharmacokinetic (PK) characterisation at microdose levels, especially for sublingual administration, is limited. There are no published population PK models for sublingual microdoses of LSD, and uncertainty remains about concentration–effect relationships, appropriate pharmacodynamic (PD) endpoints sensitive to microdoses, and the influence of metabolic genotype (notably CYP2D6) on exposure and subjective effects. Morse and colleagues set out to describe the pharmacokinetics and pharmacodynamics of a 10 µg sublingual LSD microdose in healthy adult male volunteers, develop and validate a high‑sensitivity LC‑MS/MS assay for low plasma concentrations (including the major metabolite O‑H‑LSD and iso‑LSD), and to explore whether CYP genotype and peripheral brain‑derived neurotrophic factor (BDNF) concentrations change acutely or after a 6‑week microdosing regimen. The study aimed to provide a population PKPD model that could inform dose selection, bioequivalence studies and future clinical development of LSD microdosing.
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Study Details
- Study Typeindividual
- Journal
- Compound
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- Authors
- APA Citation
Morse, J. D., Jeong, S. H., Murphy, R. J., Muthukumaraswamy, S. D., & Sumner, R. L. (2025). Pharmacokinetics and pharmacodynamics of sublingual microdosed lysergic acid diethylamide in healthy adult volunteers. Journal of Psychopharmacology, 39(9), 976-989. https://doi.org/10.1177/02698811251330747
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