Abstract

Lysergic acid diethylamide (LSD) is being investigated in substance-assisted therapy. Therapy sessions with LSD are long, due to its duration of acute action of 8-11 h. LSD acutely produces an altered state of mind primarily through serotonin i.e. 5-hydroxytryptamine-2A (5-HT2A) receptor agonism (Holze et al., 2021). However, it is not clear whether its effect duration can be shortened using the 5-HT2A receptor antagonist ketanserin. Molecular dynamics simulations hypothesized that a lid is formed by an extracellular loop at the entrance to the 5-HT2A binding pocket (Wacker et al., 2017), which could therefore trap LSD at the receptor.

On the other hand, the time course of the acute subjective action of LSD indicates that it acts only as long as it is present in the body (Holze et al., 2021). Therefore, no special mechanisms at the receptor would be needed to explain its duration of action in humans. The present study hypothesis was that ketanserin (40 mg p.o.) administered 1 h after LSD shortens the acute subjective and autonomic effects of LSD (100 μg p.o.) compared with LSD (100 μg p.o.) followed by placebo in healthy humans. The study used a randomized double-blind, placebo-controlled, cross-over design with two experimental test sessions in 24 healthy volunteers. Psychometric data were assessed, as well as autonomic effects and plasma concentrations.

Ketanserin strongly and significantly reduced the LSD effect duration from 8.5 ± 2.2 h to 3.5 ± 1.3 h (mean ± SD; t(23) = -1.6, p = 0.001) compared with placebo. Similarly, ketanserin significantly reversed LSD-induced overall autonomic effects such as rate pressure product (t(23) = -3.7, p = 0.001), and mydriasis (t(23) = 3.1, p = 0.005). Pharmacokinetic parameters of LSD and its main metabolite 2-oxo-3-hydroxy LSD (O-H-LSD) remained unaffected by ketanserin administration.

Conclusions: The study findings are consistent with a competitive interaction of ketanserin and LSD at the 5-HT2A receptor and the view that LSD produces its effects only when present at the receptor. Moreover, ketanserin can be used clinically, as a planned or as a rescue option to shorten the effect duration of LSD in humans.

References
Holze, F. et al. Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects. Neuropsychopharmacology 46, 537-44 (2021).
Wacker, D. et al. Crystal structure of an LSD-bound human serotonin receptor. Cell 168, 377-89.e12 (2017)