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 

Scientists at the Weizmann Institute of Science have engineered Nicotiana benthamiana, a fast-growing relative of tobacco, to produce five different psychedelic compounds. 

The achievement, detailed in a study published in Science Advances, brings together biosynthetic pathways that nature distributes across three different kingdoms of life.

The five compounds (DMT, psilocybin, psilocin, bufotenin, and 5-MeO-DMT) are typically sourced from an Amazonian shrub, mushrooms, and the defensive skin glands of a desert toad. Extracting even one of these molecules from its natural source is a slow process. Producing all five in a single, easily cultivated plant had not been achieved before.

A Shared Chemical Ancestor

Despite coming from such different sources, all five of these molecules share a common origin: tryptophan, an amino acid found in every living thing. In humans, tryptophan is the building block for serotonin, which helps explain why these psychedelics interact with serotonin receptors in the brain. This shared chemistry gave the Weizmann team, led by Dr. Paula Berman and Prof. Asaph Aharoni, a logical starting point for their experiments.

The team began by focusing on DMT to address a previously unresolved question. Researchers knew the general biochemical pathway plants use to synthesize DMT, but they had not yet identified all the genes and enzymes responsible for each step. “At the heart of the study was the challenge of making DMT,” Aharoni says.

To identify the necessary genes, the team analyzed genetic material from the Amazonian chacruna shrub and an Australian acacia species. Introducing these genes into Nicotiana benthamiana allowed the plant to produce DMT within days.

Fixing a Bottleneck With One Amino Acid

The researchers applied the same gene transfer approach to the other four psychedelics, but the engineered plants initially produced only trace amounts of 5-MeO-DMT. Protein-design specialists Prof. Sarel Fleishman and Dr. Olga Khersonsky determined that the limitation was due to a poor molecular fit in one enzyme’s active site. Replacing a single amino acid resolved the issue.

“We mutated one amino acid in the sequence and got a 40-fold increase in the production of 5-MeO-DMT,” Berman says.

One Organism, Three Kingdoms

Once all five biosynthetic pathways were functioning separately, the researchers combined them within a single plant. The result was a tobacco relative capable of producing DMT from plants, psilocin and psilocybin from fungi, and bufotenin and 5-MeO-DMT from toads, all at the same time. “In effect, we created a kind of biological ‘cocktail’ — not by mixing substances externally, but by combining the underlying pathways inside one organism,” Aharoni says.

Combining all five pathways reduced the yield of each compound, as they competed for the same pool of tryptophan. The researchers also introduced bacterial enzymes to attach chlorine and bromine atoms to the psychedelic molecules, creating modified psychedelic molecules that do not naturally occur in the engineered plant. Some similar modified molecules have shown antidepressant-like effects in previous studies.

Why the Compounds Exist in the First Place

The bottleneck also highlighted a broader research question about the natural role of these compounds. These molecules likely function as defenses or as tools for interacting with microbes and insects in the organisms that produce them, rather than evolving to affect human consciousness.

“If we can move these pathways into a model plant that grows quickly and is easy to manipulate, we can start asking what these compounds actually do for the plant,” Berman explains.

A Sustainable Supply Line

There is a clear practical benefit to this approach. Plants used for ayahuasca are increasingly threatened by habitat loss and rising demand, and the Sonoran Desert toad is declining due to overcollection and habitat destruction. A fast-growing laboratory plant capable of producing these compounds within a week provides an alternative that does not rely on harvesting wild species.

The Weizmann researchers are now working on a plant that can produce the complete ayahuasca mixture, which includes both DMT and the compound required for it to be active when taken orally. They are also exploring whether these psychedelics could be produced in edible plants capable of delivering carefully regulated doses.

Whether this platform becomes a practical manufacturing system will depend on overcoming the metabolic bottleneck that currently limits production when multiple pathways operate simultaneously.

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.

Psilocybin therapy involves more than the compound itself, and a new research initiative at the University of Southern California is investigating the effects of combining psilocybin with structured mental training.

A team from the Keck School of Medicine of USC, working with the USC Dornsife Brain and Creativity Institute and the USC Norris Comprehensive Cancer Center, has begun the university’s first clinical trial of psychedelic therapy. The study will examine whether structured mindfulness meditation can boost the effects of psilocybin, the active ingredient in psychedelic mushrooms, on mental well-being and cognitive performance.

Funding for the trial comes from ARPA-H’s EVIDENT initiative, a federal program designed to accelerate the development of rapid-acting treatments for mental and behavioral health conditions. The study will investigate whether adding mindfulness training to psilocybin-assisted therapy yields outcomes distinct from those of psilocybin-assisted therapy alone.

A Schedule 1 Drug With a Breakthrough Label

Although the Controlled Substances Act still classifies psilocybin as a Schedule I substance, the FDA has granted it a breakthrough therapy designation for major depressive disorder and treatment-resistant depression. In clinical settings, psilocybin has shown promise in treating these conditions, and other studies suggest it may also help with addiction.

Psilocybin alters a person’s perception, mood, and thought processes, and can influence how individuals experience their senses and their sense of time and space. With therapeutic support, people often report emotionally meaningful or spiritual experiences during these altered states.

Testing Whether Mental Training Changes the Outcome

About 72 middle-aged adults from the Los Angeles area will take part in the study. All participants will have no psychiatric or medical conditions and no previous experience with either psychedelics or meditation. Researchers will assign participants to one of two groups: one will receive supervised psilocybin alone, while the other will receive psilocybin alongside an eight-week mindfulness training program designed to build attention and focus through structured meditation.

The study is based on the hypothesis that mindfulness training, which has demonstrated mental and physical health benefits independently, may enhance the effects of psilocybin-assisted therapy when used together.

“Mindfulness meditation practice provides people with the tools to deconstruct unhelpful narratives, a process that may be amplified by psilocybin-assisted therapy,” said Rael Cahn, MD, PhD, director of the USC Center for Mindfulness Science and the study’s co-lead. The trial, he said, is meant to clarify how combining the two approaches “may enhance both the potential immediate and longer-term effects of psychedelic medicine.”

An Unusually Deep Data Set

The team will collect extensive biological, neurological, and psychological data from participants throughout the study. Participants will undergo EEG scans, brain MRI and fMRI imaging, and provide saliva, blood, and stool samples. Researchers will administer psychological and cognitive assessments before and after treatment and will survey participants again at three, six, and twelve months.

The team will use the data to track changes across psychological, cognitive, neurological, and biological measures, including well-being, spirituality, brain activity, and markers of inflammation and brain health. The open-label design means both participants and researchers are aware of group assignments, which allows for more comprehensive data collection at the expense of some blinding rigor.

Through the EVIDENT initiative, researchers will contribute anonymized trial results to a national repository. The resource will help researchers identify broader patterns in rapid-acting mental health treatments.

“Psilocybin-assisted therapy has the potential to revolutionize how we approach mental health research,” said Caryn Lerman, PhD, director of the USC Norris Comprehensive Cancer Center and the study’s other co-lead. Beyond addiction, she said, there’s growing evidence the treatment could improve “quality of life and emotional well-being for people facing serious illness and end-of-life challenges.”

A Test Case for the Next Wave of Psychedelic Medicine

If mindfulness training is shown to enhance the effects of psilocybin therapy, future protocols for psychedelic treatment may incorporate mental training as an additional component of treatment. Regardless of the outcome, the study will generate one of the most detailed biological and psychological datasets from a psilocybin trial to date.

Whether mindfulness ultimately amplifies psilocybin’s effects remains an open question. By tracking participants’ brains, biology, and psychological well-being over the course of a year, the USC team hopes to generate some of the clearest data yet on how mindset and psychedelic medicine interact.

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.

For five years, an elderly woman with advanced Alzheimer’s disease had spoken mostly in single words, needed help walking, and showed little spontaneous interaction with the people around her. Then, roughly 19 hours after receiving a high dose of psilocybin-containing mushrooms, she emerged from a prolonged, deep sleep-like state and began talking about her life.

The striking episode, described in a new case report published in Frontiers in Neuroscience, does not show that psilocybin reverses Alzheimer’s disease. The researchers are careful to stress that this was a single patient, observed in a real-world private clinical setting without brain imaging, formal sleep monitoring, or standardized cognitive testing.

Still, the study’s authors say the case raises the interesting possibility that in late-stage dementia, some functional abilities may indeed remain dormant rather than be completely lost.

“Advanced Alzheimer’s disease is generally regarded as a stage of irreversible functional decline,” researchers write. “This case documents transient multidomain functional improvement in advanced Alzheimer’s disease following psilocybin administration.”

The case involved a Japanese-American woman in her 80s with a 10-year history of Alzheimer’s disease. The patient was described as being in an advanced stage of dementia, with the previous five years being noted for severe decline.

Her speech had become mostly monosyllabic, and she had chronic urinary incontinence, executive dysfunction, dysphagia, dependent mobility, flat affect, prolonged somnolence, and a severe reduction in spontaneous communication.

Her diagnosis had been made clinically about a decade earlier, based on a steadily progressive neurodegenerative course, memory impairment, language reduction, executive dysfunction, and functional decline.

The intervention was a single oral dose of 5 grams of psilocybin-containing mushrooms from the “Enigma” strain. Researchers note that no established psilocybin dosing framework exists for advanced dementia, and the dose was high by almost any comparison.

Recreational users commonly describe 1 to 3 grams of dried Psilocybe cubensis mushrooms as a typical range, while doses around 3.5 grams or more are generally considered strong. A 5-gram dose is often treated as an especially intense experience. However, direct comparisons are imprecise because psilocybin content can vary widely between mushroom species, strains, batches, and even different parts of the same mushroom.

The study also notes that the dose was “relatively high compared with dosing approaches commonly used in modern clinical trials,” which typically use carefully measured amounts of purified psilocybin rather than whole mushrooms.

One month later, after some improvements persisted, the patient underwent a second supervised session using 3 grams.

The first session produced a dramatic acute response. The patient experienced autonomic activation, profuse sweating, suspected hyperthermia, and what the researchers describe as a prolonged deep sleep-like state. Exact temperature measurements were not available.

The study’s timeline shows that the first 12 hours were dominated by autonomic and sleep-like effects. At about 19 hours, the patient spontaneously awakened and produced roughly four hours of autobiographical speech.

By the first day, she showed increased alertness and recognition of family. By the second day, she was independently walking. By days two and three, she was dressing herself and showing spontaneous initiative. Around the same time, her diapers remained dry, including at night.

The improvement in continence was particularly notable to researchers because urinary control depends on more than a single simple reflex. It requires awareness of bodily signals, executive inhibition, and coordination among brain networks affected by dementia. The report states that the patient remained continent one month after the initial session, which was one reason a second session was performed.

During that second session, the patient reportedly remained more verbally expressive and described positive imagery involving surfing with her son on a peaceful island.

Researchers also observed improved facial expressivity, emotional reciprocity, spontaneous humor, and greater agility while walking. At one point during follow-up, the patient spontaneously said, “It is pleasant to come here.”

The study’s broader importance is in what it may suggest about the brain in advanced neurodegenerative disease. Alzheimer’s is usually understood as a progressive condition in which neurons and networks progressively deteriorate, stripping away memory, communication, mobility, and autonomy. By the advanced stage, treatment is largely supportive, and meaningful functional recovery is generally considered unlikely.

Psilocybin, however, is known to transiently alter large-scale brain dynamics via activation of the serotonin 5-HT2A receptor. Researchers point to prior human neuroimaging studies showing changes in default mode network integrity, network segregation, and functional connectivity after psilocybin administration. They also cited preclinical research suggesting psychedelics may promote structural and functional plasticity, including dendritic growth and synaptic remodeling.

That does not mean psilocybin repaired the patient’s Alzheimer’s disease. Instead, researchers suggest a more measured interpretation. The drug may have temporarily altered brain network activity, allowing remaining functional systems to reintegrate or become accessible again, at least for a limited period.

The report does not claim that plaques, tangles, or neurodegeneration were reversed. It also does not show that other patients would experience similar results. Because this was a single case, there was no control group, no placebo comparison, no formal biomarker confirmation, and no standardized cognitive testing to measure the degree of change.

Researchers acknowledge that mixed or alternative neurodegenerative contributions, including vascular components, cannot be fully excluded. Although they found no evidence of acute delirium, intoxication, or another acute neurological diagnosis during the observation period, the case remains observational. Causality cannot be established, and fluctuations in neurodegenerative disease cannot be completely ruled out.

The safety picture is also incomplete. While no severe persistent adverse effects, prolonged agitation, clinically significant cardiovascular instability, persistent psychotic symptoms, delayed neurological deterioration, or delayed medical complications were observed during follow-up, the acute phase included suspected hyperthermia and profuse sweating. In frail elderly patients, especially those with advanced dementia, such responses could carry serious risks.

For that reason, the findings should not be read as a green light for unsupervised psychedelic use in dementia patients. Psilocybin is still a powerful psychoactive compound, and older adults with complex neurological disease may be especially vulnerable to complications.

Ultimately, the value of the report doesn’t lie in providing a treatment recommendation but in documenting an unusual clinical observation that researchers say warrants controlled investigation.

The case also lands amid a flood of scientific interest in psychedelics as tools for studying brain plasticity, perception, memory, and large-scale network dysfunction.

As The Debrief has previously reported, recent brain-imaging work has found that psilocybin can temporarily dissolve familiar brain-network patterns tied to the sense of self, while other studies suggest psychedelics may redirect visual processing toward memory-related regions. Additional research has analyzed how a single dose of psilocybin may produce lasting brain changes, how the compound can reshape neural pathways associated with depression, and how psychedelic effects may be influenced by factors such as exercise, food restriction, and immune signaling.

However, most clinical work with psilocybin has centered on psychiatric conditions such as depression, anxiety, PTSD, and substance use disorders.

More recently, researchers have begun asking whether similar neuromodulatory effects might have relevance for people with mild cognitive impairment or early Alzheimer’s disease.

Published clinical data involving advanced dementia remain extremely limited, which is why the new report is best understood not as evidence of a treatment, but as a provocative case study that may help guide future controlled research.

This recent case does not prove efficacy, but it questions assumptions about what may remain possible in a brain already deeply affected by Alzheimer’s disease.

If future studies find similar effects under supervised conditions, the implications could be significant, not only for dementia care but also regarding understanding how much latent function can persist beneath the outward appearance of severe decline.

“Residual functional capacity may persist in advanced Alzheimer’s disease and may become transiently accessible following psilocybin induced modulation of large-scale brain networks,” researchers conclude. “Systematic investigation is warranted.”

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