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.
The development of sleep medicines has evolved from ancient herbal sedatives to modern synthetic drugs, driven by deeper understanding of sleep mechanisms. Barbiturates and bromides in the 19th century gave way to benzodiazepines, which promote gamma-amino butyric acid release to inhibit brain signaling. Newer therapies more specifically target the wake-inducing neurotransmitter orexin, reducing side effects. Kinases are predicted to be the next targets for breakthroughs in sleep medicine. Sleep disruptions contribute to the buildup of pathological neuronal proteins in neurodegenerative disorders, so sleep medicine could improve prognosis in such conditions, but medicines that do not fully mimic sleep might worsen disease progression.