Negative cognitive biases—where mood colors learning and memory—are a core feature of major depressive disorder, and reversing them may be key to how rapid-acting antidepressants work. In rats, a single dose of ketamine, scopolamine, or psilocybin selectively weakened a negative affective bias induced in an associative learning task. Low doses of ketamine and psilocybin, but not high doses, reversed the valence of the bias 24 hours later. Only psilocybin produced a lasting positive bias that depended on new learning. Ketamine's relearning effects required protein synthesis in the medial prefrontal cortex and could be altered by cue reactivation, pointing to experience-dependent neural plasticity as a shared mechanism for both the rapid and sustained effects of these drugs.
Serotonergic psychedelic drugs are being studied as treatments for psychiatric disorders like major depression. All such drugs activate the 5-HT2A receptor, but some 5-HT2A receptor agonists are not psychedelic. This investigation tested six psychedelic drugs (psilocin, 5-MeO-DMT, LSD, mescaline, 25B-NBOMe, and DOI) and three non-psychedelic drugs (lisuride, TBG, and IHCH-7079) for their effects on Gq-coupled and β-arrestin2 signaling pathways in cells expressing human 5-HT2A receptors. All psychedelic drugs were unbiased partial agonists at both pathways. The non-psychedelic drugs were not distinguished by signaling bias but showed the lowest signaling efficacy among all drugs tested, a finding confirmed in rat C6 cells. Low 5-HT2A receptor signaling efficacy may explain why some agonists lack psychedelic effects.
In a mouse model of autism spectrum disorder (ASD) created by prenatal exposure to valproic acid, the acute response to the serotonergic psychedelic psilocybin was reduced compared to controls. However, psilocybin treatment reversed the social behavior deficits that are characteristic of the ASD model. These findings suggest that psilocybin may have therapeutic potential for improving social interaction in ASD.
All psychedelic drugs tested were unbiased, partial agonists at the 5-HT2A receptor, activating G-protein and β-arrestin2 pathways equally. Non-psychedelic drugs lisuride and TBG were not biased either, but they showed the lowest signalling efficacy among all compounds. Low efficacy at the 5-HT2A receptor, not biased signalling, may explain why some 5-HT2A agonists are not psychedelic.