Investigating molecular and hemodynamic effects of LSD in the human brain.

Abstract

Lysergic acid diethylamide (LSD) is a potent psychedelic with increasing therapeutic interest, yet qualification of target engagement using in vivo neuroimaging has not yet been performed. Using simultaneous positron emission tomography-magnetic resonance imaging technology, we describe multiple brain actions of LSD in seven healthy volunteers blinded to LSD dose received. Here we show that LSD occupies 5-HT2AR with a high affinity and increases both global cerebral blood flow (CBF) and internal carotid artery flow. LSD also decreases global connectivity, which was negatively associated with changes in CBF. We observe an anticlockwise hysteresis loop between plasma drug levels and subjective effects, suggesting atypical pharmacodynamic mechanisms. We contrast our CBF and global connectivity findings and their relation in a separate cohort of 25 participants administered psilocybin, highlighting key consistencies and differences. By establishing the dose-occupancy relation of LSD in humans, our findings provide insights for the clinical development of psychedelic compounds and demonstrate unique neurophysiological effects that distinguish LSD from psilocybin.

In the evidence

This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.

• State of the evidence: LSD ↑Supports

  LSD occupied 5-HT2A receptors with high affinity, increased global cerebral blood flow and carotid flow, decreased global connectivity, and showed hysteresis between plasma levels and subjective effects.

  Synthesized October 19, 2026

Comparable studies

Other experimental studies on LSD, most cited first.