Psychedelics amplify brain connectivity through serotonin receptors, study suggests

Psychedelics like psilocybin, LSD, DMT and mescaline have garnered renewed scientific interest due to their potential therapeutic applications in treating mental disorders. However, the exact mechanisms by which these substances alter perception, thought and consciousness remain poorly understood. Most studies have focused on the aggregate brain activity during psychedelic experiences, but a new study published in Neuroscience & Biobehavioral Reviews proposes a bottom-up explanation grounded in cellular neurobiology and electrophysiology.

The framework posits that psychedelics exert their effects primarily through the serotonin 2A receptor (5-HT2A), which is most abundant in the cortex, particularly on layer V pyramidal neurons. These neurons serve as the brain's key integrators and primary output stream from the cortex to deeper structures. The apical dendrites of these neurons, which extend towards the topmost layer of the cortex and gather input from distant cortical regions and the thalamus, are particularly affected by the 5-HT2A receptor.

The study suggests that psychedelics tip layer V pyramidal neurons towards their apical, context-gathering side. Normally, these neurons balance direct, local input with wider contextual input. Psychedelics weaken the local input and strengthen the contextual input, causing the neurons to be driven more by relations and associations rather than the raw stimulus. This results in the contextual signal being broadcast widely across the brain, leading to the global brain activity observed in neuroimaging studies.

In summary, psychedelics amplify brain connectivity by enhancing the contextual processing of information in layer V pyramidal neurons via the 5-HT2A receptor. This leads to a loosening of boundaries between mental objects, resulting in the global brain activity and altered perception, thought, and consciousness associated with psychedelic experiences.