This re-analysis of a Phase I RCT (n=80) examines the pharmacokinetics (how the body affects a drug) of LSD microdosing (10µg; 14x; 6w) in healthy adult males. The study established a one-compartment pharmacokinetic model showing an elimination half-life of 3.08h, found minimal physiological effects (<15% change in heart rate), noted possible influence of CYP enzymes on drug metabolism, and reported no changes in peripheral BDNF levels.
Abstract of Pharmacokinetics and pharmacodynamics of sublingual microdosed LSD in healthy adult volunteers
“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 Two of the participants withdrawn from the study due to anxiety had intermediate-weak CYP2D6 activity.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.”
Summary of Pharmacokinetics and pharmacodynamics of sublingual microdosed LSD in healthy adult volunteers
Lysergic acid diethylamide (LSD) is a classic psychedelic whose effects stem primarily from partial agonism at the serotonin 5‑HT₂A receptor, although it also interacts with other serotonergic, dopaminergic and histaminergic sites. A receptor agonist is a molecule that binds to a receptor and activates it, and partial agonists produce a sub‑maximal response even when fully occupying the receptor. The study of how a drug’s concentration changes over time within the body is termed pharmacokinetics, while the relationship between concentration and its physiological or psychological effects is pharmacodynamics.
Microdosing involves administering sub‑perceptual doses of psychedelics—typically 10 µg of LSD versus a full “psychedelic” dose of 100–200 µg—so as to produce minimal subjective effects. Community practitioners claim benefits ranging from enhanced mood and cognition to relief from depression, anxiety and substance misuse. Earlier research in healthy volunteers has shown dose‑dependent changes in blood pressure, sleep architecture, neural connectivity, social cognition, mood and time perception at 5–26 µg doses. No clinical trials have yet evaluated therapeutic applications of microdosing. Morse and colleagues conducted a Phase I double‑blind, placebo‑controlled, parallel‑group trial to characterise the pharmacokinetics and pharmacodynamics of a 10 µg sublingual LSD microdose in healthy male volunteers. Secondary aims included development of a high‑sensitivity LC‑MS/MS assay for low LSD concentrations, exploration of cytochrome P450 (CYP) genotype effects on pharmacokinetics and assessment of peripheral brain‑derived neurotrophic factor (BDNF) as a biomarker of neuroplasticity.
Methods
Participants
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https://doi.org/10.1177/02698811251330747
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Cite this paper (APA)
Morse, J. D., Jeong, S. H., Murphy, R. J., Muthukumaraswamy, S. D., & Sumner, R. L. (2024). Pharmacokinetics and pharmacodynamics of sublingual microdosed lysergic acid diethylamide in healthy adult volunteers. Journal of Psychopharmacology, 02698811251330747.
Study details
Topics studied
Microdosing
Healthy Subjects
Study characteristics
Original Re-analysis
Placebo-Controlled
Double-Blind
Randomized
Follow-up
Participants
80
Humans
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Linked Clinical Trial
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