Psychedelics elicit their effects by 5-HT_2A receptor-mediated G_i signalling

Area of Science:

• Neuroscience
• Pharmacology
• Psychiatry

Background:

• Psychedelics are being investigated for psychiatric disorders, with over 200 clinical trials worldwide.
• The serotonin 2A receptor (5-HT2AR) is considered the primary target for psychedelics.
• The exact mechanisms of psychedelic action and their clinical risks are not fully understood.

Purpose of the Study:

• To investigate the signaling mechanisms of psychedelics at the serotonin 2A receptor (5-HT2AR).
• To differentiate between signaling pathways responsible for therapeutic effects and hallucinogenic effects.
• To guide the development of novel psychedelic-based therapeutics with reduced hallucinogenic potential.

Main Methods:

• In vitro and in vivo studies comparing psychedelics and non-hallucinogenic analogues (nHAs).
• Cryo-electron microscopy to determine structures of 5-HT2AR in complex with psychedelics/nHAs.
• Pharmacological analysis to identify signaling bias and functional mechanisms.

Main Results:

• 5-HT2AR-mediated non-canonical G_i signaling is essential for hallucinogenic effects.
• Structural and pharmacological analysis revealed a specific interaction mediating signaling bias by nHAs.
• A novel G_q-biased compound, DOI-NBOMe, demonstrated therapeutic effects in mouse models without hallucinations.

Conclusions:

• Uncovered the functional mechanisms of 5-HT2AR G_i signaling in psychedelic-induced hallucinations.
• Provided structural insights into psychedelic-receptor interactions.
• Identified a pathway for designing safer psychedelic-based drugs by targeting G_q-biased signaling.