Written by Kyle Proffitt
Psychedelic medications are receiving increasing attention for their ability to treat various mental health conditions. Just this week, A Executive order The FDA, DEA, and US Department of Health and Human Services signed a directive to facilitate, fund, and accelerate clinical research and review of psychedelics.
Earlier this month, a new study, described as “the most comprehensive synthesis of psychedelic brain functioning to date,” appeared in Natural medicine Comparison of patterns of brain signals evoked in hundreds of patients experiencing different drug effects (DOI: 10.1038/s41591-026-04287-9). Using a unified processing platform and advanced statistical analysis, the researchers were able to identify both common elements of the restructured brain connections as well as unique differences between the scope and magnitude of these changes between the two different drugs. First author Manish Giren, who conducted the research at the University of California, San Francisco, explained that there were “commonalities between these drugs,” such that “the usual hierarchy in the brain that separates abstract thinking from sensory perception has kind of collapsed.” Beyond this overview, there were a lot of additional nuances.
Huge study
Jern’s explained The world of bioinformation technology Their study was motivated by the disjointed nature of brain imaging studies with psychedelics. He said that since 2012, this field has witnessed significant development, but many laboratories have conducted independent studies using independent protocols. “When different groups get results that appear to be inconsistent, it is difficult to know whether it is the analysis that is causing this, or whether it is actually the data?” he asked. An international consortium (27 authors) led by Jern and together with Danilo Bazduk, McGill University, Canada, and Emmanuel Stamatakis, University of Cambridge, has been established to share resting-state functional magnetic resonance imaging (fsMRI) data from individuals exposed to one of four different classical serotonergic drugs – psilocybin (the active ingredient in “magic” mushrooms), and lysergic acid diethylamide. (LSD), dimethyltryptamine (DMT), or mescaline—or one natural mixture, ayahuasca, which contains both DMT and additional alkaloids. The work involved seven laboratories in five countries for a total of 11 datasets, including four drugs and more than 250 people, Jern summarized.
Raw data were obtained, subjected to a standardized processing platform to remove variables in the processing of different laboratories, and then analyzed. The primary data are rsfMRI brain scans, obtained in different centers, for different doses and different exposures, but all in the acute stages of the psychedelic experience. This technology is blood oxygen level-dependent imaging, which differentially detects oxygenated and deoxygenated blood based on its magnetic properties. When neurons activate, the surrounding area becomes flooded with oxygenated blood after a few seconds, and this signal is detected as a change in ratio and is considered an indicator of neuronal activity. Imaging data is collected over several minutes, and the processing pipeline specifically identifies the correlations of this signal within and between different specific brain regions. All included placebo control measurements were designed in the study (most in a double-blind, randomized, controlled format), so each measurement is a comparison of induced connectivity changes compared to placebo. In this way, the researchers were able to see whether one or more drugs consistently changed the signals associated between any two brain regions.
Joint signatures
After applying the standardized treatment pipeline, researchers first calculated means for comparisons of drug with placebo. They analyzed the brain based on a division into 17 pre-defined cortical areas (the wrinkled outer surface, which has more to do with perception, complex thinking, language, etc.), eight subcortical areas (evolutionarily older inner parts focused on movement, emotion, memory, reward, etc.), the cerebellum, which is involved in fine motor movement and more.
Even averaged across all subjects, a picture emerges of connected joint areas that light up. For example, enhanced coupling was seen between cortical visual networks and the subcortical putamen, an area associated with habitual, routine behavior. At the same time, the average correlation of within-network signals for several regions, such as visual networks, decreased across treatments. In other words, the normally synchronized signals that occur within subregions of the visual networks and many other specific regions begin to go out of whack upon psychedelic drug administration. At a descriptive level, these findings suggested that psychedelics were stimulating some common brain reorganization, a change in the pattern of who talks to whom, but the goal was more detail.
Bayesian statistics provide a richer picture
Although averaging responses across all agents or within individual anesthetic treatments provided descriptive analyses, the primary focus of this report was to measure statistical certainty of results. For this reason, the group applied a Bayesian hierarchical modeling framework. This approach looks at each network pair, such as virtual network B (DN B).–For example, Visual Cortex A (VIS A) calculates the probability distribution of the effect of this drug on this particular association for each drug, weighting the values taking into account sample size and treatment sites. This changes the analysis from the typical probability value approach of asking whether one incremental connection to another gives “a sort of graded sense of confidence in that effect,” Jerne explained. Pooling results from multiple sites and using this modeling technique can significantly reduce confidence in the results, if there is consistency between studies.
The resulting plots contain bell-shaped curves for each treatment. In D.N.B–In the VIS diagram, for example, all four psychedelic compounds show curves indicating increased connectivity, because they are distributed to the right of zero. The width and height of these curves reflect the degree of certainty based on the distribution of results. In this connection between networks, as a rule, the curves of psilocybin and LSD are narrow and long, indicating greater certainty, while the curves of DMT and mescaline are often of similar size, but with wider and flatter distributions, and thus lower certainty. The authors state that this is largely a reflection of the larger sample sizes for LSD and psilocybin. Ayahuasca seemed more specific and showed broader probability distributions, related to sample size and inherent mixture of compounds. “The strong affinity between LSD and psilocybin is a bit surprising,” Jern said. “You would expect more differences…because LSD has more complex pharmacological properties and hits more dopamine receptors, for example.”
Jern explained that in general, across all drugs, there was “increased connectivity between what we call high-level association areas, and networks like the default mode network…that are involved in more abstract cognition, recollection of past experiences, language, conceptual thinking, our internal narrative, and sense of self…those parts of the brain became more connected to what we call low-level sensory cortex (regions): visual, somatomotor, and auditory.” He said increased engagement between cognitive and higher-level networks could explain psychedelic-induced feelings such as increased connection to our environment, blurred distinctions between internal and external experience, and ego dissolution. The article also describes these changes as “hierarchical compromise.” Normally (unimodal) sensorimotor signals have to cross heterogeneous networks to reach abstract (cross-modal) cognitive processing networks such as the default mode network highlighted by Jern, but when these hierarchical barriers collapse, the systems gain direct connectivity.
Nuance and model modification
Jern explained how their study confirmed some previous findings and provided some additional color and detail. “A common narrative or finding that has been claimed in previous studies is that individual networks of the brain disintegrate under the influence of anesthesia, including the default mode network,” he said. “This is a big story, you know, the disintegration of the network in default mode.”
Bayesian analysis of signals within the network showed results similar to the global average, but with greater detail and quantification to challenge this model. All five treatments showed a reduction in VIS B synchronization within the network, for example, but again, confidence in this effect was higher for LSD and psilocybin. “We actually found that these network dissociation effects were not very reliable across drugs… This particular claim may have been an exaggeration, and it is more complex and nuanced than that,” Jerne explained.
As a summary of increased connectivity, Jerne said: “We’ve extended previous findings to show more nuance in the specific areas that connect with others, and it suggests that it’s not just that the entire brain is becoming interconnected, it’s very subtle and there are specific patterns that we’re detecting.”
The drug is for more than just trips
On some level, scientists just want to understand what happens in the brain during these hallucinogenic experiences. All agents in this study primarily targeted serotonin 2A (5-HT2A) future. “If you block that receptor, people won’t really get stuck, and you won’t see the brain effects,” Jerne said, but there is variability when it comes to relative interactions with dopamine receptors or the serotonin 1A receptor. Psychedelics are also being increasingly explored in the mainstream for conditions such as depressionanxiety, Substance abuse disordersor even Avoid agingThese imaging efforts may be useful in understanding how reorganization of brain signals affects efficacy.
“Reduced brain modularity, which means the brain is more interconnected as a whole, has been linked to positive outcomes in two different depression trials,” Jerne said. He explained that the longer this connection continues, the better the results will be. So these maps of brain reorganization may provide a useful framework for monitoring the continuity of changes. It is worth noting that this study relies on healthy volunteers, usually those who are not naive to the drug. There may be additional complexity in the effects of these agents on the brain of someone with depression or other conditions and first-time users, and future studies will be needed to investigate this further.
In a different direction, Jern is now the co-founder and CEO of Five Discovery, a company seeking to treat neurological diseases like Parkinson’s and Alzheimer’s, and even traumatic brain injuries. Jern says this arose from the realization that psychedelics also have beneficial effects on brain plasticity and inflammation. To this end, they are designing molecules based on 5-MeO-DMT, the most effective 5-HT.2A agonist. However, they are designing variants that are gentler stimulants, aiming to produce anti-inflammatory and pro-resilience effects while getting through the ride. “It still stimulates serotonin 2A, but not enough to make people trip,” Jerne said.
What’s next
“There are a lot of nuances that we have to figure out,” Jerne said, noting that it is still early days. One way involves moving away from averages. He explained that each individual scan result is itself an average over 10 minutes of scanning. “What about all the dynamics?” In addition, he is interested in differences between individuals which will be important to understand when looking toward therapeutic intervention. “There are studies underway now using the same large-scale data set; we’re looking more at individual variation and then that will better inform potential treatment personalization, predictive biomarkers, etc.” Jiren said.
