Cortical 5HT2A receptors are largely expressed in layer 5 pyramidal neurons and gate top-down inputs to local cortical microcircuits. Their number is increased in some people with depression, and blockade of these receptors partly explains the augmenting action of atypical antipsychotics. Agonists at these receptors—the psychedelic drugs psilocybin and LSD—profoundly reduce brain activity, especially in regions that highly express the 5HT2A receptor such as the default mode network (DMN). Since the DMN is overactive in depression, this reduction may explain improvements in mood that users of psychedelics often report. A study of psilocybin in resistant depression has been funded by the UK MRC and will start in early 2015.
Under LSD, people update their beliefs more quickly in response to surprising outcomes, and this behavioral marker of relaxed beliefs correlates with specific brain changes: lower alpha brainwave power and greater disintegration of the default mode network, particularly in the medial prefrontal cortex. These neural signatures support the REBUS model, which proposes that psychedelics relax the confidence in prior beliefs, making the brain more sensitive to prediction errors. The findings link a computational measure of surprise sensitivity to objective brain activity patterns, providing evidence for how psychedelics may alter belief updating and cognitive flexibility.