Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers

TLDR

Psychedelics such as LSD possess anti‑inflammatory effects mediated by 5‑HT₂A receptor signaling, making them candidates for treating neurodegeneration. The study aimed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of repeated oral doses of 5 µg, 10 µg, and 20 µg LSD in older healthy adults. In a phase‑I, double‑blind, placebo‑controlled, randomized trial, 48 participants were assigned to one of four groups (5 µg, 10 µg, 20 µg LSD, or placebo) and received six doses every four days. Results showed that LSD was well tolerated, with adverse‑event rates comparable to placebo, no cognitive or balance impairment, plasma peaks at 30 min for 10 µg and 20 µg, and support for further clinical development in Alzheimer’s disease.

Abstract

Abstract Abstract Research has shown that psychedelics, such as lysergic acid diethylamide (LSD), have profound anti-inflammatory properties mediated by 5-HT 2A 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).