So what has science been able to offer since Shulgin?
There have been at least two contributions to the field: The first is the structural determination of a psychedelic-bound 5-HT2A receptor at near-atomic resolution. These reconstructions have enabled detailed computer simulations to identify thousands of candidate compounds which can be tested to evaluate their kinetic binding properties. The second has been major advances in tracing the signal transduction pathways that are activated by receptor binding. In this case, the established canonical pathway involves the G-protein Gαq, which dissociates from the receptor and from its Gβγ partners and activates other downstream effector proteins upon receptor activation. But there is also another parallel, G-protein-independent pathway mediated by β-arrestins that has come to be viewed with increasing relevance for these drugs. “Some psychedelics appear to be biased ligands such that they preferentially engage 5-HT2A receptors in conformations that favor β-arrestin signaling over the G-protein pathway. In contrast to 5-HT2A receptors, the 5-HT1A receptors are Gi/o-protein coupled and activate other signaling proteins.” These kinds of observations now form the basis of more recent and sometimes dubious efforts to deconvolve desirable antidepressant effects of receptor activation from any of the undesirable hallucinogenic effects.
Original Article (Medicalxpress):
The struggle to define psychedelics
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