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 preprint DOI: 10.64898/2026.04.04.715307 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Pharmacological modeling study |
|---|---|
| Topics | Ketamine |
| Keywords | Antidepressant Drug action Action physics Pharmacodynamics Hallucinogen Distribution mathematics Pharmacology Mechanism of action Receptor Drug development |
| Key points | Classic hallucinogens and ketamine show high action strengths in brain regions involved in emotion processing, suggesting a mechanistic link to rapid antidepressant effects. |
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.