Psychedelics, a class of psychoactive drugs that typically induce peculiar mental states and hallucinations, are still prohibited for recreational use in most countries worldwide. In recent years, some neuroscientists and medical researchers have been exploring the potential therapeutic effects of these drugs, focusing on the treatment of depression, anxiety and various substance use disorders.
Researchers at the University of Bristol, Compass Pathways plc and other institutes recently carried out a new study involving rats, exploring the effects of the psychedelic compound on the activity of neurons in the medial prefrontal cortex, a brain region that supports decision-making, attention and the regulation of emotions. Their paper, published in Molecular Psychiatry, outlines some of the neural patterns associated with the intake of this compound, which had not yet been observed in human experiments.
“Psychedelic drugs like psilocybin have profound effects on our brains and minds,” Matt Jones, Professor of Neuroscience at the University of Bristol and senior author of the paper, told Medical Xpress. “These effects are fascinating and—as a long history of psychedelic use and recent clinical trials attest—potentially beneficial. This study was driven by two interrelated questions. Firstly, how does a relatively simple, small molecule alter brain activity to completely change our mental model of the world? Secondly, can those effects be harnessed to help treat mental illness?”
Designing and executing studies aimed at safely exploring the effects of drugs on the human brain is typically challenging. Jones and his colleagues thus decided to perform their experiment with rats, as this would also allow them to collect more precise neural recordings.
To monitor the activity of neurons in the rat brain, they used “Neuropixels,” neural probes developed by researchers at HHMI, UCL and other institutes. These tiny electrodes can monitor electrical activity in the brain of rodents while they are moving around in their surroundings, with high precision and temporal resolution.
“Neuropixels are 12um thin blades of silicon, printed with thousands of recording sites, precisely targeted to defined brain regions,” explained Jones. “This allowed us to record the activity of up to 600 neurons simultaneously, measuring the immediate effects of psilocybin over 1-hour timescales, plus hunting for longer-term effects of single injections over several days.”
While psilocybin is a naturally occurring compound found in some mushrooms, for the purpose of their study, the researchers used a synthetic analog developed by the biotechnology company Compass Pathways, called COMP360 psilocybin. The doses of the drug that they administered to the rats resembled those given to human patients diagnosed with depression during past clinical trials.
“We observed that psilocybin’s effects were more pronounced during quiet wakefulness than during cognitive task performance,” said Jones. “This is interesting because it aligns with anecdotal and clinical experience that psychedelic benefits are best achieved when participants are in a calm, restful state.”
Jones and his colleagues found that one region appeared to be the epicenter of psilocybin-induced 100Hz oscillations in the rat medial prefrontal cortex. This region is the infralimbic cortex, which is believed to play a similar role to the subgenual anterior cingulate cortex in the human brain. Notably, the same region was previously identified as a promising target for deep-brain stimulation interventions aimed at treating depression.
“Perhaps psilocybin induces a kind of localized, chemical electroconvulsive therapy (ECT)?” said Jones. “Moreover, we observed that 6 days following a single, low dose of psilocybin, infralimbic network oscillations were enhanced, but not oscillations in neighboring brain regions. These oscillations reflect coordinated neural information processing, and their emergence may indicate psilocybin-induced network plasticity.”
As part of their study, the researchers recorded the activity of over 2,000 neurons in the rat medial prefrontal cortex in response to the psychedelic compound. This led to the observation of specific neural activity patterns associated with psilocybin in rats.
Nonetheless, the responses of the neurons they recorded appeared to be very mixed, with some increasing their activity after psilocybin was administered, others decreasing it and others seeming unaffected. Jones and his colleagues would now like to pinpoint variations between the neurons that are differentially affected.
“In our next studies, we would like to relate these varied responses to neuron types and connectivity,” added Jones. “We would also like to extend our recordings to other brain regions implicated in depression, including circuits signaling memory, emotion and reward.
“Finally, there are strong and important interrelationships between sleep and mental health—so we are analyzing the effects of psilocybin on sleep architecture, and on the sleep-dependent brain activity that supports processing of memory and emotion.”
Written for you by our author Ingrid Fadelli, edited by Gaby Clark, —this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive.
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More information:
Ross J. Purple et al, Short- and long-term modulation of rat prefrontal cortical activity following single doses of psilocybin, Molecular Psychiatry (2025). DOI: 10.1038/s41380-025-03182-y.
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