A new analysis of brain imaging data reveals that lysergic acid diethylamide, commonly known as LSD, reduces the synchronization of local brain activity to produce its mind-altering effects. Published in the European Journal of Neuroscience, the research suggests the hallucinogenic drug interacts with a wider array of brain receptors than previously assumed. These insights help map the biological mechanisms underlying altered states of consciousness and could inform future therapeutic uses of psychedelics.
Over the past decade, medical researchers have renewed their focus on classic psychedelic drugs as potential treatments for psychiatric conditions. Compounds like LSD and psilocybin produce profound changes in perception, mood, and thought. Researchers largely attribute these effects to how the chemical binds to a specific type of serotonin receptor in the brain. But the drug structurally mimics several other chemical messengers, including dopamine and different subtypes of serotonin.
Paolo La-Torraca-Vittori, a researcher at the University of Pavia, and Livio Tarchi of the University of Florence led the current investigation. They aimed to fill a gap in current neuroimaging literature. Most brain scans of people on psychedelics look at large-scale, long-distance communication between widespread brain networks. Few studies have examined what happens to the tiny, localized clusters of brain cells when someone is under the influence of LSD.
The research team focused on two specific metrics that measure the resting state of the brain. The first metric captures the amplitude of low-frequency fluctuations. This assesses the power of slow, spontaneous brain waves in a very localized area. When a person is resting, their brain usually produces stable, low-frequency rhythms. A drop in this amplitude means the brain activity is becoming noisier, faster, and more desynchronized.
The second metric evaluates regional homogeneity. This assesses how well a tiny patch of brain tissue synchronizes its electrical activity with its immediate neighboring cells. High regional homogeneity indicates that a small cluster of neurons is firing together in unison. A drop in regional homogeneity suggests that local neurons are operating independently of one another.
To explain why this matters, scientists point to the entropic brain hypothesis. Entropy is a physics concept related to disorder and randomness. In neuroscience, higher entropy means a richer, less predictable pattern of brain states. The entropic brain hypothesis proposes that psychedelics push the brain into a state of higher entropy, increasing disorder in a way that allows for more flexible and dynamic thought processes.
The investigators utilized an open-access database containing the brain scans of 15 healthy adults. Because it involved fewer than 50 participants, this was a small study. During the original data collection, each participant underwent two brain scanning sessions held at least two weeks apart. On one day, they received an intravenous saline placebo. On the other day, they received a moderate, hallucinogenic dose of LSD.
The scanning took place roughly an hour after the drug was administered, capturing the peak of the psychedelic experience. The participants rested inside the scanner with their eyes closed. The scanning device tracked changes in blood flow to map neural activity. La-Torraca-Vittori, Tarchi, and their colleagues computed the two localized metrics for both the placebo and the LSD states. The researchers then overlaid these results onto established brain maps showing the typical distribution of various chemical receptors.
The analysis revealed widespread reductions in both the amplitude of low-frequency fluctuations and regional homogeneity when participants were under the influence of LSD. These drops were particularly pronounced in the visual and somatosensory cortices, the brain areas that process sight and incoming touch. The researchers noted that this local fragmentation forces the brain to abandon its normal hierarchical processing setup.
Normally, the human brain operates in a strict functional hierarchy. Sensory regions process basic inputs and then send that data up the chain to associative regions, which interpret the information. Under LSD, this structured hierarchy flattens. Instead of local clusters processing sensory information in specialized silos, the brain integrates information broadly across the entire cortex, blending visual and physical sensations.
The two metrics also highlighted distinct changes in other brain regions. The low-frequency fluctuation metric dropped heavily in areas associated with the default mode network. This network is a group of brain areas active during passive rest, daydreaming, and self-reflection. Disruptions in this network are strongly associated with the breakdown of the conscious self commonly reported by users of psychedelics.
At the same time, regional homogeneity decreased notably in deep subcortical regions like the thalamus and amygdala. These structures act as central hubs for sensory relay and emotional processing. When local synchronization drops in these relay centers, it likely changes how sensory information gets routed to the rest of the brain.
When linking these functional changes to brain chemistry, the team found robust correlations that expanded beyond the primary target of LSD. As expected, some localization related to the primary 5-HT2A serotonin receptor. Yet the drops in both brain metrics consistently mirrored the distribution patterns of dopamine D2 receptors and an alternative serotonin receptor known as 5-HT1A.
A receptor is a protein structure on the surface of a cell that receives chemical signals. When a chemical locks into a receptor, it triggers a biological response inside the cell. Brain areas with fewer of these specific dopamine and serotonin receptors experienced the greatest decreases in local synchronization and low-frequency rhythms under LSD.
This alignment dictates that LSD initiates a cascade of neurochemical events spanning multiple messenger systems. The authors suggest that regions enriched with certain dopamine and serotonin receptors might actually be shielded from the desynchronizing effects of the drug. Alternatively, the drug might indirectly activate these adjacent pathways, leading to the varied sensory and emotional shifts that characterize the experience.
While the data offers new perspectives on the physical mechanics of psychedelics, the researchers acknowledged several limitations. The analysis relied on a small sample size, requiring replication in broader populations to ensure the ultimate reliability of the findings. The team also used standardized maps of receptor density from a general population rather than maps of the actual participants’ brains, which limits the precision of the chemical correlations.
In addition, the resting scans analyzed in this project took place after a music-listening session. The researchers caution that the lingering emotional or neurological effects of listening to music could have shaped the resting state data independently of the chemical infusion. A slight difference in head motion between the placebo and LSD groups remained even after data filtering, leaving open the possibility of minor scanning artifacts.
Future investigations will likely compare these localized measures with other brain monitoring technologies. By mapping both the physical location and the precise timing of these neural changes, scientists hope to fully decode how altered brain chemistry reshapes the human mind. The exploration of localized dynamics offers a key stepping stone toward developing safe, targeted psychedelic therapies in the future.
The study, “Knocking at the Doors of Perception: Relating LSD Effects on Low-Frequency Fluctuations and Regional Homogeneity to Receptor Densities in fMRI,” was authored by Paolo La-Torraca-Vittori, Livio Tarchi, Elisa Arrigo, Stefano Lanterna, Eleonora Tosi, Arne Doose, Fulvia Palesi, Doris Pischedda, Valdo Ricca, Paolo Fusar-Poli, and Stefano Damiani.