Serotonin, psychedelics and psychiatry
Carhart-Harris, R. L.
This commentary (2018) proposes a theoretical model wherein 5-HT2A receptor stimulation-the primary mechanism of psychedelics-relaxes prior beliefs and heightens sensitivity to context, contrasting with the stabilising role of the 5-HT1A receptor. It suggests that this mechanism facilitates effective therapeutic change by enabling the revision of rigid assumptions and behaviours during periods of uncertainty.
Abstract
A simple and plausible model of therapeutic mechanisms of psychedelic treatments would greatly complement this ongoing clinical work. The thesis is put forward here that serotonin differentially encodes behavioral and physiological responses to uncertainty. More specifically, it is proposed that the limbic-rich inhibitory postsynaptic 5-HT1A receptor subtype provides basal control during normal conditions, via moderating emotion and anxiety, and promoting a generalized patience. On the other hand, the cortically-rich 5-HT2A receptor subtype is hypothesized to engage more during conditions of crisis, when the above-mentioned default mechanism becomes suboptimal, e.g. when an individual's internal and/or external milieu becomes so changeable and/or inconsistent with his/her prior beliefs and behaviors that significant revisions become mandated. Viewed through a Bayesian lens, it is proposed that the principal functional effect of 5-HT2A receptor stimulation is to relax prior assumptions or beliefs, held at multiple levels of the brain's functional hierarchy: perceptually, emotionally, cognitively and philosophically (e.g., in terms of biases). In so doing, it opens a door to heightened sensitivity to context, an ideal pre-condition for effective change.