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Ketanserin reverses the acute response to LSD in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects

https://academic.oup.com/ijnp/advance-article/doi/10.1093/ijnp/pyac075/6808755?login=false

Anna M Becker, Aaron Klaiber, Friederike Holze, Ioanna Istampoulouoglou, Urs Duthaler, Nimmy Varghese, Anne Eckert, Matthias E Liechti

International Journal of Neuropsychopharmacology, pyac075, https://doi.org/10.1093/ijnp/pyac075

Published: 07 November 2022 Article history

Background
Lysergic acid diethylamide (LSD) is currently being investigated in psychedelic-assisted therapy. LSD has a long duration of acute action of 8-11 h. It produces its acute psychedelic effects via stimulation of the serotonin 5-hydroxytryptamine-2A (HT2A) receptor. Administration of the 5-HT2A antagonist ketanserin before LSD almost fully blocks the acute subjective response to LSD. However, unclear is whether ketanserin can also reverse the effects of LSD when administered after LSD.

Methods
We used a double-blind, randomized, placebo-controlled, crossover design in 24 healthy subjects who underwent two 14-h sessions and received ketanserin (40 mg p.o.) or placebo 1 h after LSD (100 µg p.o.). Outcome measures included subjective effects, autonomic effects, acute adverse effects, plasma brain-derived neurotrophic factor (BDNF) levels, and pharmacokinetics up to 12 h.

Results
Ketanserin reversed the acute response to LSD, thereby significantly reducing the duration of subjective effects from 8.5 h with placebo to 3.5 h. Ketanserin also reversed LSD-induced alterations of mind, including visual and acoustic alterations and ego dissolution. Ketanserin reduced adverse cardiovascular effects and mydriasis that were associated with LSD but had no effects on elevations of BDNF levels. Ketanserin did not alter the pharmacokinetics of LSD.

Conclusions
These findings are consistent with an interaction between ketanserin and LSD and the view that LSD produces its psychedelic effects only when occupying 5-HT2A receptors. Ketanserin can effectively be used as a planned or rescue option to shorten and attenuate the LSD experience in humans in research and LSD-assisted therapy.

LSD, ketanserin, interaction, subjective effects, pharmacokinetics
Issue Section: Regular Research Article