Whole-brain drug distribution profiles of psychedelic drugs provide insights into rapid antidepressant action

Combining pharmacodynamic profiles of four classic hallucinogens and ketamine with receptor density distributions from PET and autoradiography studies produces anatomical distribution profiles of drug action strength. Classic hallucinogens show high action strengths in association cortices and, based on autoradiography, in supragranular layers and multimodal temporal areas. Ketamine's affinity for high-affinity subtypes of 5-HT2a and D2 receptors generates classic hallucinogen-like neuroanatomical trends. High rapid-acting antidepressant action strengths in emotion-processing regions contribute to understanding the mechanism of rapid antidepressant action.

Study at a glance

Abstract

Recent studies pioneered the use of classic hallucinogens as Rapid-Acting Antidepressants (RAAD). To further understand the link between their neuromodulatory and antidepressant effects, we combine pharmacodynamic profiles of four classic hallucinogens and the anaesthetic Ketamine with receptor density distributions from both Positron Emission Tomography (PET) and layer-resoluted autoradiography studies to develop anatomical distribution profiles of drug action strengths giving a comparative measure how strong a drug would act in a region of interest. PET-based, we find high action strengths in association cortices for classic hallucinogens, which we contextualise anatomically using functional and cytoarchitectural measures. Autoradiography-based, we observe high action strengths in the supragranular layer and multimodal temporal areas. Finally, we show how Ketamine's affinity to high-affinity subtypes of 5-HT2a and D2 receptors produce classic hallucinogen-like neuroanatomical trends. Through highlighting high RAAD action strengths in regions with emotion processing functionality, our results contribute to a mechanistic understanding of rapid antidepressant action.