Pharmacological characterisation of psilocybin and 5-MeO-DMT discriminative cues in the rat and their translational value for identifying novel psychedelics

Drug discrimination procedures in rats confirm that hallucinogenic effects of psychedelics like psilocybin, LSD, DMT, and 5-MeO-DMT are mediated primarily by 5-HT2A and 5-HT1A receptors. Plasma levels of psilocin required for generalization in rats (5–52 ng/mL) overlapped with human perceptual effects, while DMT and LSD needed higher exposures in rats than in humans. The duration of drug-lever generalization followed LSD > psilocybin > 5-MeO-DMT ≥ DMT, matching clinical experience. LSD showed a disconnect between plasma exposure and generalization, similar to clinical findings. These results support the translational value of drug discrimination assays for studying psychedelics.

Study at a glance

Abstract

Background and aims: Drug discrimination procedures have made important contributions to the pre-clinical investigation of psychedelic drugs, such as psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). One of the most important being to highlight the critical role of central 5-HT2A receptor agonism as a mediator of hallucinogenic activity, and secondly, drugs that fully generalise to a 5-HT2A receptor agonist cued drug discrimination in rodents, may elicit hallucinogenic activity in humans, showing a forward translational value. However, there is relatively little information about how clinical exposures associated with hallucinations back-translate to generalisation profiles in the rat. Methods: The present series of experiments utilised two cohorts of male Sprague-Dawley rats, one trained to a psilocybin (0.5 mg/kg SC) cue, and the second trained to a 5-MeO-DMT (1 mg/kg SC) cue. Results: Tests of substitution and antagonism supported the primary role of 5-HT2A and 5-HT1A receptors, respectively, in the mediation of each cue. Plasma exposures of psilocin required for generalisation to the psilocybin cue (5–52 ng/mL) overlapped with clinical exposures associated with perceptual effects in humans. With respect to DMT and LSD, higher exposures were required in the rat compared to humans. Time-course studies using an approximate ED90 dose of each psychedelic showed differing temporal profiles in terms of duration of drug-lever generalisation, with LSD > psilocybin > 5-MeO-DMT ⩾ DMT, showing good agreement with clinical experience. With the exception of LSD, there was a good temporal association between plasma exposure and drug lever generalisation. The disconnect noted for LSD is mirrored by similar findings in the clinic. Conclusions: In summary, the present studies both support and extend the value of the drug discrimination assay as a translational approach to the pre-clinical study of psychedelic drugs.