Knocking at the Doors of Perception: Relating LSD Effects on Low‐Frequency Fluctuations and Regional Homogeneity to Receptor Densities in fMRI
Paolo La‐torraca‐vittori, Livio Tarchi, Elisa Arrigo, Stefano Lanterna, Eleonora Tosi, Arne Doose, Fulvia Palesi, Doris Pischedda, Valdo Ricca, Paolo Fusar‐poli, Stefano Damiani
European Journal of Neuroscience November 1, 2025 DOI: 10.1111/ejn.70338 (opens in new tab)
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Study at a glance
AI-extracted from the abstract| Characteristics | Within-subjects experimental study Peer reviewed |
|---|---|
| Sample size | 15 |
| Population | Healthy adults |
| Intervention | Lysergic acid diethylamide (LSD) |
| Dose | 75-μg |
| Topics | Default mode network LSD |
| Keywords | Neurochemical Homogeneity statistics Placebo Brain mapping Neurotransmitter receptor Magnetic resonance imaging Audiology Grouped data Endocrinology |
| Citations | 1 |
| Key findings | LSD decreases local brain activity and connectivity in sensory and association cortices, with changes correlated to D2 and 5-HT1A receptor densities. |
Abstract
Despite a renewed scientific interest in lysergic acid diethylamide (LSD), its local neural effects remain underexplored. This functional magnetic resonance imaging (fMRI) study explored and compared LSD-induced changes in local activity (amplitude of low-frequency fluctuations: ALFF) and local connectivity (regional homogeneity: ReHo), assessing their relationship to regional receptor density. Imaging data of 15 healthy adults from an open dataset were analyzed. For each participant, two pairs of resting-state runs were available (rest1 and rest2), one performed under placebo and one following the intravenous administration of 75-μg LSD. Voxel-wise paired t-tests compared ALFF and ReHo in the LSD versus placebo conditions. Rest1*rest2 test-retest reliability and ALFF*ReHo cross-modal associations were assessed with conjunction maps and vertex-wise correlations. Finally, neurochemical enrichment analyses related LSD-induced ALFF and ReHo changes to cortical density maps of LSD-related neurotransmitter receptors and transporters. Both ALFF and ReHo decreased in somatosensory/visual cortices under LSD compared to placebo. Specific decreases were observed for ALFF in associative regions belonging to the default mode and frontoparietal networks, and for ReHo in subcortical regions (cluster-based corrected p < 0.05). Test-retest reliability was high for ALFF (rho = 0.80, p = 0.001) and moderate for ReHo (rho = 0.46, p = 0.001). ALFF*ReHo LSD-induced changes were moderately associated (rest1: rho = 0.36, p = 0.001; rest2: rho = 0.56, p = 0.001). Neurochemical enrichment analysis showed that LSD-induced ALFF/ReHo alterations were reliably and negatively correlated with the density of D2 and 5-HT1A receptors (FDR-corrected p < 0.05). These preliminary findings suggest that LSD may engage complex and dynamic neurochemical processes beyond its known 5-HT2A receptor target, warranting further investigation.
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 |
Citations in the library
Cites 32
- The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs Frontiers in Human Neuroscience 2014
- Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences April 11, 2016
- Increased Global Functional Connectivity Correlates with LSD-Induced Ego Dissolution. Current Biology April 13, 2016
- Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor Elife October 25, 2018
- Lysergic Acid Diethylamide: Sensitive Neuronal Units in the Midbrain Raphe Science August 16, 1968
and 27 more in the library