Ketanserin Reverses the Acute Response to LSD in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Participants

Abstract

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.

Comparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited

“…In accordance with previous studies from our laboratory, pretreatment with 0.01 mg/kg M100907 did not induce any effect on body temperature or locomotor activity before or after LSD administration (Figure S7A – C, Figure S8A – B, Table S5, Table S6). , The finding that LSD-induced HTR is 5-HT 2A -dependent is consistent with many other studies using pharmacological and genetic manipulations in mice, as well as clinical studies where the subjective effects of psilocybin or LSD are attenuated by pretreatment with ketanserin. ,,− …”

Synergistic, Multi-level Understanding of Psychedelics: Three Systematic Reviews and Meta-analyses of Their Pharmacology, Neuroimaging and Phenomenology

“…While LSD does display moderate affinity for dopamine receptors, the 5-HT 2A receptor plays a much more essential role in the hallucinogenic effects of not only LSD but also all other psychedelics. Blocking the receptor with a 5-HT 2A antagonist such as ketanserin has repeatedly been shown to attenuate or abolish the subjective experience in humans (Becker et al, 2023; Preller et al, 2017; Preller, Burt, et al, 2018; Vollenweider et al, 1998). In our meta-analysis, we find that LSD and psilocin bind with higher affinity to 5-HT 2A than to any of the other receptors we examined (the fact that we do not also find this for DMT may be attributable to the small number of studies).…”

Lysergic Acid Diethylamide Alters the Effects of Brain Stimulation in Rodents

“…There is evidence that the acute changes in subjective experience and brain activity as well as the the long-term enhanced neuroplasticity are mediated by the 5HT-2A receptor such that antagonists like ketanserin are able to significantly attenuate if not ablate these effects. [43][44][45][46] Although the subjective experience, the changes in brain activity, and the enhanced neuroplasticity are related to one-another through their dependence on 5HT-2A receptor activation, whether any of these effects of psychedelic drugs are causally related or parallel processes remains to be elucidated.…”