New Insight Into Psilocybin’s Therapeutic Potential

A single high dose of psilocybin results in dramatic, acute, and persistent changes to the brain’s functional networks in healthy adults, results of a small randomized controlled trial show. 

The new findings enhance the understanding of psychedelics’ effects on human brain activity and offer insights into their therapeutic potential. By revealing mechanisms that increase brain malleability, these findings could benefit patients with rigid, maladaptive patterns of thought and behavior. 

The observed brain changes with psilocybin were more than threefold larger than the effects of the control drug, methylphenidate (generic Ritalin).

“Compared to methylphenidate, the effects of psilocybin were massive in terms of how much it was changing brain activity and connectivity,” Joshua S. Siegel, MD, PhD, an instructor in psychiatry, Washington University School of Medicine in St. Louis, Missouri, told Medscape Medical News. “For one thing, psilocybin is erasing boundaries between brain networks.”

The findings were published online on July 17 in Nature. 

Desynchronization Drives Change

As previously reported by Medscape Medical News, in clinical trials, a single dose of p silocybin rapidly reduces the symptoms of treatment-resistant depression, major depressive disorder, as well anorexia nervosa. 

In animal models, transient activation of the serotonin 5-HT2A receptors by psychedelics, such as psilocybin and ketamine, induces persistent plasticity-related phenomenon.

What’s happening in brain networks that connect the cellular and molecular level to the clinical level is not well understood, said Siegel. 

To address this gap, the researchers employed precision functional MRI (fMRI) mapping to track brain changes in seven healthy adults aged 18-45 years who had prior experience with psychedelics. The investigators monitored brain activity before, during, and 3 weeks after the participants ingested 25 mg of psilocybin followed by 4src mg of methylphenidate 1-2 weeks later. 

The average number of fMRI visits per participant was 18. One participant was unable to complete the MRI while on psilocybin.

The results indicated that association networks, responsible for higher cognitive functions, were more affected by psilocybin than primary networks, which handle sensory and motor function. 

Psilocybin significantly increased normalized global spatial complexity, a measure of brain signal synchrony, acutely with values returning to pre-drug baseline by the following session. 

“The entire idea of a resting functional MRI is that we can see these networks functioning in synchrony,” Siegel said. “There was just this very large desynchronization.”

Performing a simple audio-visual matching test while in the scanner significantly reduced the magnitude of psilocybin-associated network disruption and desynchronization. 

This finding may explain why grounding techniques, or directing a person’s attention externally, may lessen overwhelming or distressing effects of psilocybin during psychedelic-associated psychotherapy, the investigators suggested.

Altered Connectivity

Psilocybin produced the largest changes in functional connectivity in the default mode network, which is connected to the anterior hippocampus and thought to be associated with a sense of self, space, and the present moment.

“The simple answer for why that is, is because that’s where there’s the highest density of the serotonin 2A receptor,” Siegel said.

When the acute effects of the psychedelic wore off, most brain networks normalized except for connections between the default mode network and the anterior hippocampus, where small differences from pre-psilocybin scans persisted for up to 3 weeks. 

“We hypothesized that connectivity from the hippocampus would be altered because in animal studies showing a plasticity effect, the hippocampus is one of the areas where you see the biggest plasticity and where it’s been tied to the clinical or at least the antidepressant phenotype of psilocybin,” Siegel said. 

“There seems to be a reset basically of connectivity between the hippocampus and the default mode network and, in fact, the cortex in general,” he added. 

The findings extend the observation from a PNAS 2src16 neuroimaging study by co-author Robin Carhart-Harris, PhD, that lysergic acid diethylamide (LSD) desynchronizes brain activity within the default mode network and correlates with profound changes in consciousness, typified by ego dissolution.

Participants in the current study were asked about their psychedelic experience, including feelings of transcendence, connectedness, and awe, using the 3src-item Mystical Experience Questionnaire. Across psilocybin sessions, the magnitude of whole-brain changes in functional connectivity tracked with the intensity of the participants’ subjective experience.

Temporary desynchronization creates the psychedelic experience, but the longer-term consequence is that it may make the brain more flexible and enable recovery, said Siegel. 

“It also suggests the therapy that is done surrounding these treatments is probably very important. Because I don’t think it’s fundamentally a positive thing to increase plasticity or adaptability of the brain,” he added. “It potentially can be a dangerous thing but combined with a therapist who can enable a positive change in behavior and a positive change in cognitive habits, I think those are the two pieces that can enable recovery.”

‘Excruciatingly’ Small Sample Size

Reached for comment, Bertha Madras, PhD, professor of psychobiology, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, said that “this is a very well-executed paper, [but] the N is excruciatingly small for trying to understand brain changes.” 

“An N of six just does not provide the variability that one would anticipate based on people’s own mindset of whether or not they are attracted to this class of drugs,” she said. “The response is hugely variable within their own data.”

To draw any global conclusions, one would need to recruit a much larger number of participants without prior experience then compare different types of hallucinogens, some of which don’t act on the 5-HT2A receptor, Madras said. 

“I just don’t think that methylphenidate was a reasonable comparator, frankly, just because it increases heart rate,” she said. “From my perspective, it’s a puzzling choice.”

Still, the study is an important addition to the neurobiology of how psilocybin functions and “offers a road map towards future studies,” Madras concluded.

Clear Clinical Implications

However, in contrast to Madras’s remarks, an accompanying commentary, by Petros D. Petridis, MD, department of psychiatry, New York University Langone Center for Psychedelic Medicine, New York City, said that the finding of acute and persistent desynchronized brain activity has “clear clinical implications because it suggests that psilocybin could make connections in the brain more malleable, which could be beneficial for people who experience rigid maladaptive patterns of thought.

“It also seems plausible that this malleability is what therapists are harnessing to promote lasting change after a person has a psychedelic experience. In other words, psilocybin could open the door to change, allowing the therapist to lead the patients through.”

Petridis also called for larger clinical trials in diverse patient populations and noted that a better mechanistic understanding of the treatment targets engaged by psychedelic-induced desynchrony could lead to the development of medications with fewer side effects compared with existing therapeutics.

The study was funded by the Taylor Family Institute Fund for Innovative Psychiatric Research; Healthy Mind Lab; McDonnell Center for Systems Neuroscience; Washington University Institute of Clinical and Translational Science; National Institutes of Health; National Spasmodic Dysphonia Association; the Ralph Metzner Professorship; the Tianqiao and Chrissy Chen Institute, Washington University Intellectual and Developmental Disabilities Research Center; the Kiwanis Foundation; Washington University Hope Center for Neurological Disorders; and Mallinckrodt Institute of Radiology. Within the last year, Siegel has been an employee of Sumitoma Pharma America and received consulting fees from Longitude Capital. Siegel and co-authors Timothy O. Laumann and Evan M. Gordon have submitted a provisional patent for the use of precision functional mapping for measuring target engagement by experimental therapeutics. Madras reports as a consultant for IMS Legal Consulting. Petridis decla