This rodent study (2022) shows that the activation of serotonin receptors (5-HT) by mescaline derivatives via 5-HT2CR, alone or in concert with 5-HT2AR, produces comparable hallucinogenic effects to activation via divergent 5-HT2CR- and/or 5-HT2AR signalling pathways. Given that many believe 5-HT2AR activation is the route through which psychedelics exert their effects, these findings show that 5-HT2CR is as important as 5-HT2AR in inducing these effects.
Abstract
“Serotonergic psychedelics exert their hallucinogenic properties via their high affinity for serotonin (5-HT) receptors, particularly through the activation of 5-HT2A receptors (5-HT2AR), by means of the frontal cortex-dependent head-twitch response. Although universally believed to be so, studies have not yet been able to fully ascertain whether 5-HT2AR activation is the sole initiator of the psychedelic effects of hallucinogens. This is because not all 5-HT2AR agonists exhibit hallucinogenic activities. In the present study, we extended our previous bio-behavioural studies on two mescaline derivatives, with 3,4,5 (MAL) and 2,4,5 (BOD) tri-substitutions. The results showed that the activation of 5-HT via 5-HT2CR, alone or in concert with 5-HT2AR, produces comparable hallucinogenic effects (at a dose of 1 mg·kg-1), with divergent 5-HT2CR- and/or 5-HT2AR-Gqα11-mediated signalling and enhanced neurotoxic properties (at a dose of 30 mg·kg-1) coupled with activated pro-inflammatory cytokines. These findings confirmed the psychedelic and neurotoxic effects in mice. Overall, these findings showed that 5-HT2CR is as important as 5-HT2AR in inducing the hallucinogenic effects of serotonergic compounds.”
Authors: Ray J. Custodio, Darlene M. Ortiz, Hyun J. Lee, Leandro V. Sayson, Danilo Buctot, Mikyung, Yong S. Lee, Kyeong-Man Kim, Jae H. Cheong & Hee J. Kim