A new analysis of brain imaging data reveals that lysergic acid diethylamide, commonly known as LSD, reduces the synchronization of local brain activity, producing mind-altering effects. The study, published in the European Journal of Neuroscience, suggests that psychedelics interact with a wider range of brain receptors than previously thought. These insights may help map the biological mechanisms underlying altered states of consciousness and inform future therapeutic uses of psychedelics.
Over the past decade, medical researchers have renewed their focus on classic psychedelic drugs as potential treatments for mental illness. Compounds such as LSD and psilocybin cause significant changes in perception, mood, and thinking. Researchers believe these effects are primarily due to how the chemical binds to specific types of serotonin receptors in the brain. However, the drug structurally mimics several other chemical messengers, including various subtypes of dopamine and serotonin.
Researchers Paolo La Toracca Vittori from the University of Pavia and Livio Tarchi from the University of Florence led the current study. They aimed to fill a gap in the current neuroimaging literature. Most brain scans of people taking psychedelic drugs observe extensive long-range communication between widespread brain networks. Few studies have investigated what happens to small local clusters of brain cells when someone is under the influence of LSD.
The research team focused on two specific indicators that measure the brain’s resting state. The first metric captures the amplitude of low frequency fluctuations. It assesses the power of slow spontaneous brain waves in very localized areas. When a person is at rest, the brain normally generates a steady, low-frequency rhythm. This decrease in amplitude means that brain activity is louder, faster, and more asynchronous.
The second indicator assesses the homogeneity of the region. This assesses how well a small patch of brain tissue synchronizes its electrical activity with its immediate neighbors. High field homogeneity indicates that small clusters of neurons are firing in unison. The reduction in local uniformity suggests that local neurons are operating independently of each other.
To explain why this is important, scientists point to the entropic brain hypothesis. Entropy is a concept in physics related to disorder and randomness. In neuroscience, higher entropy means richer and less predictable patterns of brain states. The entropic brain hypothesis proposes that psychedelic substances increase disorder in a way that pushes the brain into a state of higher entropy, allowing for more flexible and dynamic thought processes.
The researchers used an open-access database containing brain scans from 15 healthy adults. This was a small study as there were less than 50 participants. During the original data collection, each participant underwent two brain scanning sessions at least 2 weeks apart. One day, they were given a saline placebo intravenously. One day, they were given a moderately hallucinogenic dose of LSD.
The scans were taken about an hour after the drug was administered and captured the peak of the psychedelic experience. Participants rested with their eyes closed inside the scanner. Scanning devices tracked changes in blood flow and mapped neural activity. La-Torraca-Vittori, Tarchi, and their colleagues calculated two local indices for both the placebo and LSD conditions. The researchers then superimposed these results onto established brain maps showing the typical distribution of different chemoreceptors.
Analysis revealed that both the amplitude and regional homogeneity of low-frequency fluctuations were broadly reduced when participants were under the influence of LSD. These declines were particularly pronounced in the visual and somatosensory cortex, the brain regions that process vision 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 based on a strict hierarchy of functions. Sensory areas process basic input and send that data up the chain to associative areas, where the information is interpreted. Under LSD, this structured hierarchy is flattened. Rather than local clusters processing sensory information in specialized silos, the brain integrates information broadly across the cortex, merging visual and bodily sensations.
The two indicators also highlighted distinct changes in other brain regions. The low frequency variation metric was significantly reduced in regions associated with the default mode network. This network is a group of brain regions that are active during passive rest, daydreaming, and reflection. Disruption of this network is strongly associated with the disruption of the conscious self commonly reported by users of psychedelic drugs.
At the same time, local homogeneity was markedly reduced in deep subcortical regions such as the thalamus and amygdala. These structures serve as central hubs for sensory relay and emotional processing. Decreased local synchronization at these relay centers can alter the way sensory information is sent to other parts of the brain.
By linking these functional changes to brain chemistry, the research team discovered a strong correlation that extends beyond LSD’s primary targets. As expected, some localizations were associated with primary 5-HT2A serotonin receptors. However, the decline in both brain indicators consistently reflected the distribution pattern of dopamine D2 receptors and an alternative serotonin receptor known as 5-HT1A.
Receptors are protein structures on the surface of cells that receive chemical signals. When a chemical is fixed on a receptor, it triggers a biological reaction within the cell. Brain regions with fewer of these specific dopamine and serotonin receptors had the greatest reductions in local synchrony and low-frequency rhythms under LSD.
This agreement indicates that LSD initiates a cascade of neurochemical events that span multiple messenger systems. The authors suggest that certain dopamine and serotonin receptor-enriched regions may actually be protected from the drug’s asynchronous effects. Alternatively, drugs may indirectly activate these adjacent pathways, causing the various sensory and emotional changes that characterize the experience.
Although this data provides a new perspective on the physical mechanisms of psychedelics, the researchers acknowledged some limitations. This analysis relied on a small sample size and required replication in a broader population to ensure ultimate reliability of the results. The research team also used a standardized map of receptor density in the general population rather than a map of the brains of actual participants, which limited the accuracy of the chemical correlations.
Furthermore, the resting state scans analyzed in this project were taken after a music listening session. The researchers cautioned that lingering emotional or neurological effects from listening to music could have shaped the resting-state data independently of the chemical injections. Small differences in head movements between the placebo and LSD groups remained after data filtering, leaving the possibility of minor scanning artifacts.
Future studies may compare these local measurements with other brain monitoring techniques. By mapping both the physical location and precise timing of these neural changes, scientists hope to fully decipher how altered brain chemistry reshapes the human mind. Exploration of local dynamics provides an important stepping stone towards the development of future safe and targeted psychedelic therapies.
The study, “Knocking on the door of perception: The association of LSD effects with receptor density on low-frequency fluctuations and regional homogeneity in fMRI,” was authored by Paolo La-Torraca-Vittori, Livio Tarchi, Elisa Arrigo, Stefano Lanterna, Eleonora Tosi, Arne Doose, Fulvia Palesi, Doris Pischedda, and Valdo. Ricca, Paolo Fusar-Poli, and Stefano Damiani.
