Whole-brain drug distribution profiles of psychedelic drugs provide insights into rapid antidepressant action
Benjamin Hänisch, Tobias Kaufmann, Sofie L. Valk
bioRxiv (Cold Spring Harbor Laboratory) April 7, 2026 Peer reviewed DOI: 10.64898/2026.04.04.715307 via OpenAlex
Summary
Classic hallucinogens have high action strengths in association cortices, while Ketamine shows similar neuroanatomical trends due to its affinity for certain receptor subtypes. The study combines pharmacodynamic profiles and receptor density data to illustrate how these drugs may exert rapid antidepressant effects, particularly in regions involved in emotion processing. This work enhances the understanding of the mechanisms behind rapid-acting antidepressants.
Study at a glance
| Key finding | Classic hallucinogens exhibit high action strengths in association cortices, contributing to a mechanistic understanding of their rapid antidepressant effects. |
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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.