LSD, psilocybin, and 2C-B are often classified together as psychedelics—but new brain imaging research in rats shows that each compound produces its own distinct pattern of brain activity.

These differences appeared during both the drugs‘ active effects and in brain scans taken one week later, according to a study published in Nature Communications.

Interest in psychedelic medicine has increased rapidly, with several compounds now being tested in clinical trials for conditions such as depression, PTSD, and addiction. Most previous studies have focused on individual drugs, leaving it unclear how the effects of different psychedelics actually overlap. To address this, researchers at the University of Southern Denmark designed a study to directly compare the effects of different psychedelics side by side.

Different Drugs, Different Fingerprints

Each drug produced its own distinct pattern of brain activity, and only a handful of changes showed up across all three.

“Psychedelic drugs are often discussed as if they work in the same way. But when we look at the brain, the differences are clear,” said Mikael Palner, associate professor at the University of Southern Denmark’s Department of Clinical Research and senior author of the study. “Each drug appears to affect its own networks, and that is new knowledge.”

2C-B and LSD drove the most changes while the drugs were active, but the more striking result showed up after the drugs had worn off. At the one-week mark, 2C-B primarily affected regions of the brain associated with reward, while LSD showed effects in areas involved in habits and motivation. Meanwhile, psilocybin primarily affected regions associated with emotion.

“What is interesting is that the differences do not only appear while the drugs are active. We can also see different traces in the brain afterwards,” said Frederik Gudmundsen, the study’s first author, who completed his PhD at the University of Southern Denmark and now works as a postdoc at Aarhus University’s Translational Neuropsychiatry Unit.

Not Better, Just Different: and Still a Long Way From the Clinic

None of this means one drug is better than another, but it does suggest psychedelics may not be one interchangeable category when it comes to developing them for medical practice.

“If the drugs affect the brain differently, it is also possible that they may eventually prove better suited to different disorders,” Palner said. “We do not know that yet, but our study provides a biological starting point for investigating it.”

Despite these intriguing findings, the research does not determine if these distinct patterns of brain activity from different psychedelic substances apply to human patients. The researchers acknowledge this limitation, noting that the results are based on animal models and that further studies in humans are necessary to determine if the same differences apply.

The authors also disclosed that Mikael Palner holds shares in the psychedelic drug companies Compass Pathways and AtaiBeckley, but neither company was involved in the research.

The study still offers a detailed biological picture of how different psychedelic substances alter brain metabolism and network activity and could help researchers investigate whether specific compounds might eventually prove better suited to particular disorders.

For now, researchers have yet to determine whether LSD, psilocybin, and 2C-B will ultimately have distinct roles in medicine or whether the differences between them are less important in humans.

Austin Burgess is a writer and researcher with a background in sales, marketing, and data analytics. He holds an MBA, a Bachelor of Science in Business Administration, and a data analytics certification. His work focuses on breaking scientific developments, with an emphasis on emerging biology, cognitive neuroscience, and archaeological discoveries.

Psychedelic drugs are often described as throwing the brain into a state where the usual rules begin to break down. Under psilocybin, neural networks that normally organize perception, thought, and our sense of self loosen, blurring the boundaries between the mind and what we perceive as reality.

Close your eyes, and colors and shapes may appear from nowhere. Music can feel almost physical. Even the familiar boundary between where the self ends and the rest of the world seemingly begins to melt away.

From the outside, this altered state can look a lot like a neurological disorder—a brain becoming less synchronized, less structured, and increasingly chaotic.

But a major new brain-imaging study suggests an unexpected order may be hidden within that apparent chaos. Rather than simply scrambling the brain, psilocybin appears to reorganize its activity, making it unusually sensitive to what a person is experiencing in the moment.

Published in Nature, the study used functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and machine learning to examine 62 adults before and after receiving psilocybin.

Researchers say their results uncover a previously hidden form of organization within the psychedelic brain that helps explain why setting and subjective experience can have such a powerful influence on the psychological effects of psychedelics.

“Under psilocybin, brain networks that help us process our inner world and the world around us became less distinct, but reorganized into patterns that reflected what people were experiencing,” lead author and Research Fellow at the Turner Institute for Brain and Mental Health in the Monash School of Psychological Sciences, Dr Devon Stoliker, said in a statement. “We uncovered hidden order within that disruption.”

Past studies have shown that psychedelics disrupt the brain’s usual organization. Psilocybin acts primarily on serotonin 5-HT2A receptors, reshaping communication between sensory regions and higher-level networks involved in cognition, perception, and our sense of self. Researchers have frequently characterized the resulting brain state as more entropic, desynchronized, and disordered.

The new study does not necessarily contradict those findings. Instead, it suggests conventional measurements may have been missing another layer of organization unfolding over time.

Participants, none of whom had previously used psychedelics, underwent both fMRI and EEG while experiencing four different conditions: resting with their eyes closed, guided meditation, listening to music, and watching a silent movie of moving clouds. Researchers recorded their brain activity during a baseline session and again after participants received a 19-milligram dose of psilocybin.

Standard brain-imaging measurements initially produced results consistent with previous psychedelic research. Psilocybin reduced the degree to which the brain remained divided into distinct functional networks. During eyes-closed conditions, connectivity between sensory areas and the wider brain decreased while integration involving associative regions increased.

One especially intriguing change involved the difference between eyes open and eyes closed. Normally, those states produce clearly distinguishable patterns of brain connectivity.

Under psilocybin, however, that distinction narrowed dramatically. In the visual network, the gap in global functional connectivity between eyes-open and eyes-closed conditions fell by 85 percent.

EEG measurements independently showed a similar convergence. Alpha-band activity, normally associated with suppressing visual information while the eyes are closed, decreased under psilocybin, while brain-wide signal complexity increased. Because the effect appeared using two different methods of measuring brain activity, the researchers argue that psychedelic-induced changes in blood flow cannot simply explain it.

Researchers also used machine-learning techniques to follow changes in brain activity over time. Instead of becoming increasingly random, the brain activity of participants experiencing stronger psychedelic effects formed tighter, more clearly distinguishable patterns corresponding to whether they were resting, meditating, listening to music, or watching the movie.

In other words, as the psychedelic experience intensified, researchers became better able to identify what participants were doing simply from the structure of their brain activity. That is essentially the opposite of what would be expected if psilocybin were merely introducing neural noise.

“This shows that context is not just background to the psychedelic experience,” co-author and researcher at the Turner Institute for Brain and Mental Health in the Monash School of Psychological Sciences,  Dr. Adeel Razi, explained. “What a person is doing and focusing on shapes how their brain responds.”

The effect was particularly strong among people reporting positive experiences involving unity, bliss, self-dissolution, and the disappearance of boundaries between themselves and their surroundings. It was weaker for purely sensory or hallucinatory effects and largely absent for negative experiences, such as anxiety or impaired cognition.

Researchers call this phenomenon “context alignment” and describe the corresponding subjective experience as “embeddedness.”

Embeddedness differs subtly from simply feeling connected to something. The researchers use the term to describe an experience in which the distinction itself begins disappearing—a feeling that the person is continuous with, rather than separate from, the surrounding environment.

Two brain systems appeared especially important. The default mode network, heavily involved in internally directed and self-referential processing, and the visual network, representing the opposite end of a broad gradient toward externally directed sensory processing. Together, changes in these systems accounted for nearly half of the machine-learning model’s improvement in distinguishing different contexts under psilocybin.

Those findings could influence psilocybin and psychedelic-assisted therapy, where a person’s mental state and surrounding environment have long been considered important.

Half of the participants later ranked their psilocybin session among the most meaningful experiences of their lives. One month later, the group also showed improvements in measures of personal meaning, acceptance of death, and bond with nature, although there was considerable variation between individuals.

However, the findings also come with important caveats. The study involved healthy volunteers rather than patients being treated for psychiatric disorders, meaning the results do not establish whether “embeddedness” itself contributes to the therapeutic benefits reported in clinical psychedelic research. Participants also knew they were receiving psilocybin.

While the researchers identified machine-learning signatures associated with subjective experience and subsequent psychological changes, they acknowledge that additional research is needed to determine whether those patterns hold across populations.

Nevertheless, the results present a different way of thinking about what psychedelics do to the brain. Psilocybin may loosen ordinary neural boundaries without eliminating organization. Beneath what looks like disorder when averaged across time, the brain may actually be reorganizing itself around the person’s immediate experience.

“Until now, brain-imaging studies have mainly told us what happens on average across a group. Using artificial intelligence, we could measure this reorganization in each person,” Dr. Razi notes. “If translated to patients, this could eventually help clinicians understand how someone is responding and predict who is most likely to benefit.”

The recent study, “Psychedelics Align Brain Activity with Context,” appeared in the journal Nature.

Tim McMillan is a retired law enforcement executive, investigative reporter and co-founder of The Debrief. His writing typically focuses on defense, national security, the Intelligence Community and topics related to psychology. You can follow Tim on Twitter: @LtTimMcMillan.  Tim can be reached by email: tim@thedebrief.org or through encrypted email: LtTimMcMillan@protonmail.com