British journal of pharmacology
June 22, 2025
Aurelija Ippolito, Sridhar Vasudevan, Shaun Hurley et al.
9 citations
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.
British journal of pharmacology
May 23, 2025
Trevor Sharp, Aurelija Ippolito
8 citations
Psychedelic drugs like LSD and psilocin, once banned and stigmatized, are now being studied for their long-lasting benefits in mental illnesses such as depression, addictions, and anxiety disorders. Their powerful hallucinatory effects are thought to be mediated by agonist action at 5-HT2A receptors, but the link between the psychedelic experience and therapeutic outcomes remains uncertain. Recent research has identified a new class of 5-HT2A receptor agonists that may retain therapeutic potential without inducing hallucinations, with biased signalling, partial agonism, and increased neuroplasticity offering possible explanations for their effects. This article explores the neuropsychopharmacological properties of both hallucinogenic and non-hallucinogenic 5-HT2A receptor agonists as potential novel psychiatric treatments.
bioRxiv (Cold Spring Harbor Laboratory)
June 16, 2024
Aurelija Ippolito, Sridhar R. Vasudevan, Shaun Hurley et al.
1 citation
preprint
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.