Drugs that activate the serotonergic 5-HT2A receptor (e.g. LSD, psilocybin, mescaline) are notorious for causing psychedelic experiences and I would like to know the neurochemical mechanism behind this.


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Broadband cortical desynchronization "begins at the cellular level with excitation of layer 5 pyramidal neurons, and extends to the macroscopic level with cortical desynchronization and decreased brain network integrity."

"Stimulation of the 5-HT2A receptor has been shown to enhance spontaneous EPSPs/EPSCs (excitatory postsynaptic potential / excitatory postsynaptic current) in neocortical layer 5 pyramidal cells by reducing outward potassium currents (Aghajanian and Marek, 1997; Lambe et al., 2000) and to cause increased glutamatergic recurrent activity in layer 5 of the cortex."

"Speculatively, if deep-layer pyramidal cells were to become hyperexcitable during the psychedelic state, information processing would be biased in the direction of inference—such that implicit models of the world become spontaneously manifest—intruding into consciousness without prior invitation from sensory data. This could explain many of the subjective effects of psychedelics."



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