🧠 Neuroscience

How psychedelics work in the brain

The Serotonin 5-HT2A Receptor

Classic psychedelics (psilocybin, LSD, DMT, mescaline) are all partial agonists at the serotonin 5-HT2A receptor. This receptor is densely expressed in the cortex, particularly in layer V pyramidal neurons. Blocking 5-HT2A with ketanserin abolishes the subjective effects of psilocybin, confirming this receptor as the primary mediator.

The Default Mode Network

One of the most robust findings in psychedelic neuroscience: classic psychedelics decrease activity and functional connectivity in the default mode network (DMN) — a set of brain regions active during self-referential thought, mind-wandering, and rumination. The magnitude of DMN disruption correlates with the intensity of ego dissolution. Robin Carhart-Harris has proposed that psychedelics work therapeutically by "relaxing" the precision weighting of top-down priors — the REBUS (Relaxed Beliefs Under Psychedelics) model.

Increased Global Connectivity

While the DMN loses internal coherence, the brain as a whole becomes more interconnected. Regions that don't normally communicate begin to do so. This "entropic brain" state may underlie synesthesia, novel associations, and the sense of expanded awareness. Functional connectivity studies show the brain moves toward a more flexible, less modular configuration.

Neuroplasticity

Psychedelics promote structural neuroplasticity — increased dendritic spine density, synaptogenesis, and neurite growth. This has been demonstrated in vitro and in animal models. A single dose of psilocybin increases spine density in mouse frontal cortex for at least a month. This may explain lasting therapeutic effects from single or few-session interventions.

Ketamine: A Different Mechanism

Ketamine works on the glutamate system via NMDA receptor antagonism, not serotonin. Its rapid antidepressant effects appear to involve a burst of glutamate signaling, AMPA receptor activation, and downstream BDNF release and mTOR-dependent synaptogenesis. It's mechanistically distinct but converges on a shared theme: rapid plasticity.