Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers
In a phase 1 double‑blind, placebo‑controlled trial in 48 healthy older volunteers (mean age 62.9), oral low doses of LSD (5, 10 and 20 μg) given every fourth day for 21 days produced undetectable plasma levels at 5 μg and 30‑minute peak concentrations at 10 and 20 μg. The regimen was well tolerated with adverse event rates similar to placebo and no detectable impairment of cognition, balance or proprioception, supporting further evaluation of LSD for prevention or treatment of Alzheimer’s disease.
Authors
- Robin Carhart-Harris
- Thomas Williams
- David Nichols
Published
Abstract
Abstract Research has shown that psychedelics, such as lysergic acid diethylamide (LSD), have profound anti-inflammatory properties mediated by 5-HT2A receptor signaling, supporting their evaluation as a therapeutic for neuroinflammation associated with neurodegenerative disease.
Objective
This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of orally repeated administration of 5 μg, 10 μg, and 20 μg LSD in older healthy individuals. In the current paper, we present safety, tolerability, pharmacokinetics, and pharmacodynamic measures that relate to safety, tolerability, and dose response.
Methods
This was a phase 1 double-blind, placebo-controlled, randomized study. Volunteers were randomly assigned to 1 of 4 dose groups (5 μg, 10 μg, 20 μg LSD, and placebo), and received their assigned dose on six occasions (i.e., every 4 days).
Results
Forty-eight older healthy volunteers (mean age = 62.9 years) received placebo (n = 12), 5 μg (n = 12), 10 μg (n = 12), or 20 μg (n = 12) LSD. LSD plasma levels were undetectable for the 5 μg group and peak blood plasma levels for the 10 μg and 20 μg groups occurred at 30 min. LSD was well tolerated, and the frequency of adverse events was no higher than for placebo. Assessments of cognition, balance, and proprioception revealed no impairment.
Conclusions
Our results suggest safety and tolerability of orally administered 5 μg, 10 μg, and 20 μg LSD every fourth day over a 21-day period and support further clinical development of LSD for the treatment and prevention of Alzheimer’s disease (AD).
Research Summary of 'Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers'
Introduction
Classic serotonergic psychedelics such as lysergic acid diethylamide (LSD) act primarily via the serotonin 2A (5-HT2A) receptor and have been implicated in modulation of cognition, mood, and immune function. Converging preclinical and clinical evidence suggests 5-HT2A receptor agonism can produce anti-inflammatory and neuroprotective effects, reduce soluble amyloid-beta species in animal models, and relate to cognitive and affective processes that are relevant to Alzheimer's disease (AD). However, the psychoactive and behavioural effects of high doses of psychedelics pose therapeutic limitations; some preclinical data indicate that anti-inflammatory effects may occur at sub-perceptual doses, prompting interest in assessing safety and pharmacology at very low doses in humans. Family and colleagues designed the present study to evaluate whether periodic, low oral doses of LSD (5 μg, 10 μg, and 20 μg) could be administered to older healthy volunteers without causing cognitive or functional impairment, and to characterise pharmacokinetics (PK) and selected pharmacodynamic (PD) dose–response relationships. The primary aims were safety, tolerability, and PK; secondary objectives included selected validated cognitive, sensory, and motor measures and subjective drug-effect assessments. The regimen tested six doses given every fourth day over 21 days, a schedule informed by anecdotal microdosing patterns and prior dose-threshold data.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Family, N., Maillet, E. L., Williams, L. T. J., Krediet, E., Carhart-Harris, R. L., Williams, T. M., Nichols, C. D., Goble, D. J., & Raz, S. (2020). Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers. Psychopharmacology, 237(3), 841-853. https://doi.org/10.1007/s00213-019-05417-7
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