Behavioral effects of psychedelic and non-psychedelic serotonin 2A receptor agonist drugs in pigs

By measuring brain serotonin 2A receptor occupancy with PET scans and relating it to plasma drug levels, the authors established dose-occupancy relationships for DMT, psilocybin, LSD, and lisuride in pigs. At doses producing 60–70% occupancy, all drugs elicited headshakes, a behavioral proxy for psychedelic effects. Lisuride produced the most headshakes (16.5 ± 9.4 in 30 min), while psilocybin, DMT, and LSD produced fewer (5.7–6.9). The time course of headshakes matched each drug's plasma pharmacokinetics. The authors argue that comparing 5-HT2AR agonists at similar receptor occupancy is a valid approach for assessing their biochemical and behavioral effects.

Study at a glance

Abstract

Background: Serotonergic psychedelics induce their psychoactive effects by stimulating the brain’s serotonin 2A receptor (5-HT2AR). In humans, a cerebral 5-HT2AR occupancy of ≥60% is required to elicit a profound psychedelic experience with psilocybin [1] and for pigs, a dose corresponding to ∼65% 5-HT2AR occupancy elicits headshakes [2]. We posit that in order to assess biochemical and behavioral effects of different 5-HT2AR agonists, it is compelling to compare them at similar cerebral 5-HT2AR occupancies. Here, we have determined the relationship between plasma concentration and cerebral 5-HT2AR occupancy of N,N-dimethyltryptamine (DMT), psilocybin, lysergic acid diethylamide (LSD) and lisuride in pigs, and measured psychedelic-induced behavior (headshakes) at doses generating 60-70% occupancy.Methods: 18 female pigs underwent positron emission tomography (PET) scans with 5-HT2AR agonist radiotracer [11C]Cimbi-36, including a baseline scan followed by a block scan with IV interventions of 5-HT2AR agonists. Modelling was done with Logan plot using a metabolite corrected input function. Occupancies were estimated with Lassen plot and fitted to a two-parameter Emax model. Half maximal blocking concentrations (IC50) were estimated from the fitted models. The behavioral study was done in 8 awake female pigs each receiving IV DMT, 0.4 mg/kg (injected 30 min after monoamine oxidase inhibitor, moclobemide, 0.85 mg/kg), psilocybin, 30 μg/kg, LSD, 0.6 μg/kg, and lisuride, 5.8 μg/kg, in a randomized order, with 3-4 days separating each drug. Preceding all drug sessions, saline was given alone to establish baseline behavior. The doses were based on the PET IC50 values and corresponded to ∼65% occupancy. The pigs were video recorded from 2 projections, and blinded observers scored the number of headshakes.Results: All drugs caused considerable dose-related 5-HT2AR occupancies in the pig brain. The mean plasma drug concentrations versus cerebral 5-HT2AR occupancies conformed to a single site binding model with IC50 values of 13.2 nM (psilocin), 435 nM (DMT), 0.0928 nM (LSD) and 0.207 nM (lisuride). In awake pigs, all drugs elicited headshakes. In the 30 min following administration, saline induced 1.8 ± 2.1 (mean ± SD), psilocybin induced 5.7 ± 2.8, DMT induced 5.8 ± 2.5, LSD induced 6.9 ± 3.0, and lisuride induced 16.5 ± 9.4 headshakes. The distribution of the headshakes over time corresponded well with the in vivo plasma pharmacokinetics of the drugs in pigs. For DMT and psilocybin, headshakes were most frequent within the first 5 min after administration and returned to baseline levels after 15 and 25 min for DMT and psilocybin, respectively. For LSD, the frequency of headshakes was delayed and peaked 5-10 min after administration and continued beyond the 30 min. For lisuride, headshakes were most frequent within the first 5 min after administration and continued beyond the 30 min.Conclusions: We have for the first time established relationships between cerebral 5-HT2AR occupancy, drug plasma concentrations and drug dose for 5-HT2AR agonists in vivo in pigs, and subsequently compared psychedelic-induced behavior in awake pigs on the basis of the cerebral 5-HT2AR occupancy.