Molecular, haemodynamic and functional effects of LSD in the human brain
Drummond E-Wen Mcculloch, Kristian Larsen, Annette Johansen, Kristian H. R. Jensen, Charlotte H. Nykjær, Friederike Holze, Nora Falck, Victor August Backer Neufeld, Emilia Steenstrup, Peter Moltke Skov-Andersen, Anders Spangaard, Maria Geisler, Paw Patrick Randrup, P.s. Jensen, Vladimir Shulganov, Sys Stybe Johansen, Marie Katrine Klose Nielsen, Thomas Lund Andersen, Dea Siggaard Stenbæk, Claus Svarer, Patrick M. Fisher, Gitte M. Knudsen
medRxiv June 18, 2025 preprint DOI: 10.1101/2025.06.17.25329677 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Within-subjects, blinded, simultaneous PET-MRI study |
|---|---|
| Sample size | 7 |
| Population | Healthy volunteers |
| Intervention | Lysergic acid diethylamide (LSD) |
| Topics | LSD Serotonin |
| Keywords | Neuroimaging Pharmacodynamics Hallucinogen Electroencephalography Pharmacology Receptor Pharmacokinetics |
| Key points | LSD increases global cerebral blood flow and internal carotid artery flow without affecting artery diameter, decreases global connectivity, and shows an anticlockwise hysteresis loop between plasma drug levels and subjective effects. |
Abstract
In this study, we provide the first study to integrate molecular and functional neuroimaging during psychedelic drug effects in humans. Using simultaneous PET-MRI technology, we describe multiple brain actions of lysergic acid diethylamide (LSD) in healthy volunteers. We quantify the occupancy of LSD at cerebral serotonin 2A receptors and show that LSD increases global cerebral blood flow and internal carotid artery flow without affecting the diameter of the internal carotid artery, opposite effects to those observed In this study, we provide the fi rst study to integrate molecular and functional neuroimaging during psychedelic drug eff ects in humans. Using simultaneous PET-MRI technology, we describe multiple brain actions of lysergic acid diethylamide (LSD) in seven healthy volunteers blinded to LSD dose received. We quantify the occupancy of LSD at cerebral serotonin 2A receptors and show that LSD increases global cerebral blood fl ow (CBF) and internal carotid artery fl ow without aff ecting the diameter of the internal carotid artery, opposite eff ects to those observed following psilocybin. Functional connectivity analyses show decreases in global connectivity (GCOR). Change in GCOR is negatively correlated with change in CBF. We observe an anticlockwise hysteresis loop between plasma drug levels and subjective eff ects, suggesting atypical pharmacodynamic mechanisms. We contrast our CBF and GCOR fi ndings and their relation in a separate cohort of 25 participants administered psilocybin, highlighting key consistencies and diff erences in their neural eff ects. By establishing the dose-occupancy relation of LSD in humans, our fi ndings provide critical insights for the clinical development of psychedelic compounds and demonstrate unique neurophysiological eff ects that distinguish LSD from related psychedelics.
Comparable studies
Other experimental studies on LSD, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Neural correlates of the LSD experience revealed by multimodal neuroimaging. Human participants | 2016 | Experimental study | |
| Crystal structure of an LSD-bound human serotonin receptor | 2017 | Experimental study with structural biology and molecular dynamics simulations | |
| Lysergic Acid Diethylamide: Sensitive Neuronal Units in the Midbrain Raphe Midbrain neurons containing serotonin | 1968 | Experimental study | |
| Connectome-harmonic decomposition of human brain activity reveals dynamical repertoire re-organization under LSD. Human brain | 2017 | Experimental study | |
| LSD-Assisted Psychotherapy in Patients with Terminal Cancer Cancer patients | 1973 | Experimental study | n = 60 |