We’ve gotten used to talking about LSD and psilocybin as if they’re variations on the same theme. Both are classic psychedelics. Both act on serotonin receptors. Both can produce startling changes in perception, emotion, and a person’s sense of self.
But underneath those similarities, the brain may be doing quite different things.
In a new Nature Neuroscience paper, researchers in Copenhagen combined two kinds of brain scans to watch what happened as volunteers experienced LSD. They then compared their results with earlier measurements from a separate group given psilocybin. One finding was especially strange: blood flow through the brain increased after LSD, while the psilocybin group showed a decrease. A measure of how strongly signals across the brain were correlated also moved in opposing directions.
That’s an intriguing contrast. It isn’t proof that one drug is safer, better for depression, or even more powerful. And it comes with a sample-size warning big enough to put on the front page.
Seven people, two kinds of scan
The experiment wasn’t a treatment trial. The volunteers were healthy, and the researchers weren’t measuring whether anyone recovered from depression or anxiety. They wanted to see how a psychedelic interacts with the living human brain, from the receptor molecules it binds to, all the way out to blood flow and the changing patterns of activity picked up by a scanner.
Eleven people took part in the LSD arm and completed baseline imaging. Seven produced usable combined scans during the drug’s peak effects. The investigators used PET imaging to estimate how much LSD occupied a particular serotonin receptor, 5-HT2A, and MRI techniques to measure blood flow and changes in functional connectivity.
These are different measurements. A PET scan can help show where a drug is engaging its molecular target. An MRI blood-flow measurement tells researchers about circulation through brain tissue. Functional MRI looks at the relationship between signals in different regions. None of them provides a direct camera feed of what somebody thinks or feels.
The 5-HT2A receptor is central to the effects of classic psychedelics, but drugs that engage the same receptor need not set off identical cascades in the brain. That is part of what makes this study worth reading.
The numbers are striking. So is the small print.
In the seven participants with usable peak scans, LSD was associated with about a 19% increase in global cerebral blood flow and a 28% increase in flow through the internal carotid arteries. The team did not observe a corresponding increase in the diameter of those arteries.
Meanwhile, a whole-brain measure of signal correlation, known as GCOR, decreased across much of the cortex. Areas involved in vision and parts of the default-mode network were among those showing changes.
The comparison with psilocybin came from a different group: 25 people who had participated in an earlier study. In that cohort, the direction of the average findings was reversed. Psilocybin was associated with lower cerebral blood flow and higher global correlation.
It would be tempting to turn this into a tidy diagram: LSD makes the brain flow faster and talk less; mushrooms make it flow slower and talk more. Biology doesn’t really cooperate with that kind of slogan. Blood flow is not a meter for intelligence, consciousness, or the richness of an experience. And a statistical measure of global correlation is not a simple measure of how well your neurons are communicating.
There is another complication. This was not a randomized head-to-head experiment assigning participants to LSD or psilocybin under identical conditions. The teams compared two datasets, with their own participants and measurement contexts. Differences between the groups, timing, and methods could matter.
What the researchers could see for the first time
For decades, scientists have known that LSD acts strongly at serotonin receptors. But measuring a drug’s occupation of those receptors in a living human brain, while also measuring changes in circulation and network activity, has been a harder problem.
By combining PET and MRI during the same experimental sessions, the researchers built an unusually detailed picture of what happens at several levels. They reported high-affinity binding to 5-HT2A receptors and a dose–occupancy relationship that gives researchers something more concrete than guessing from the amount swallowed.
They also noticed that blood concentrations of LSD and the intensity of the experience didn’t rise and fall in lockstep. The strongest subjective effects could lag behind the peak concentration measured in blood. Pharmacologists call that sort of delayed relationship hysteresis. For the rest of us, it means the amount of drug circulating at one moment doesn’t perfectly tell you how intense the experience feels at that moment.
This matters for psychedelic research because it’s another warning against assuming that dose, blood concentration, receptor engagement, brain imaging, and subjective experience are all interchangeable. They’re related, but they’re not the same thing.
Could the blood vessels be distorting our picture of psychedelic brains?
Here’s the question I keep coming back to. Functional MRI doesn’t record electrical activity from neurons directly. It tracks blood-oxygen-related signals that researchers use as an indirect window into brain activity.
But psychedelics can affect blood vessels as well as neurons. If a drug changes the circulation itself, how confidently can scientists interpret an altered MRI signal as a change in neural communication?
The new study doesn’t fully answer that question. It does make it harder to ignore. Across the LSD and psilocybin data, changes in blood flow and the global connectivity measure tended to relate negatively to one another, even though each drug moved those measures in different directions overall. That could point to important differences in neurovascular coupling—the relationship between neural activity and the blood flow that supports it.
In other words, when a psychedelic brain scan lights up or quiets down, part of the story may be happening in the blood vessels. That doesn’t make earlier brain-scan research worthless. It means we should be precise about what the instrument is actually measuring.
Does this mean LSD and psilocybin work differently as medicines?
Possibly. But this particular research can’t tell us how their benefits compare.
No one in the experiment was being treated for depression. There was no clinical outcome to compare with blood flow. A physiological difference between two drugs doesn’t necessarily turn into a meaningful difference in their usefulness for patients. It might. Or it might be incidental, context-dependent, or less important than some other mechanism we haven’t isolated yet.
That distinction is easy to lose in a field where every new scan is sometimes framed as evidence of a breakthrough. The imaging results are the finding. Claims about lasting therapeutic benefit would be a separate question requiring a separate kind of study.
It’s also worth remembering how tiny the LSD imaging sample was. Seven people can reveal a signal worth chasing, particularly with sophisticated techniques, but they can’t establish how widely that signal applies across ages, health conditions, medications, or doses. Two LSD participants were unable to complete scanning because of adverse effects, and another two because of scanner failures, leaving that usable sample of seven. Those missing observations matter when interpreting the results.
The more interesting story isn’t a contest
For readers used to comparing the substances through trip reports, this research offers a refreshing change of scale. Instead of asking which trip is more visual or spiritually profound, it asks what is happening when the same broad family of drugs meets a very complicated organ.
The answer, so far, is that sharing a famous receptor doesn’t guarantee sharing the same full-body physiology. That’s scientifically interesting without making one drug a winner and the other a loser.
We previously looked at how psilocybin’s effects on brain activity can depend on context. The Copenhagen findings add another layer: even two closely related psychedelic substances may alter the measurements behind our favorite brain-scan narratives in different ways.
The researchers now have a better foundation for asking how receptor engagement, circulation, and neural activity interact. What they don’t have—and don’t pretend to have—is a clinical verdict.
For now, the useful takeaway is modest but fascinating: LSD and psilocybin may look like cousins from the outside, but the brain’s response is much more complicated than a shared psychedelic label suggests.
Editorial note: This article is about basic neuroscience research, not medical advice or a recommendation to use psychedelic drugs. The two compounds were not tested against one another as treatments in this study.
There’s a very unglamorous problem with psychedelic therapy: somebody has to book the room.
Long sessions don’t just ask patients to clear their calendars. They require trained staff, monitoring, space, and a way to pay for all of it. A promising treatment that’s too expensive or difficult to deliver can stay out of reach for the people who need it.
So when a study claims that a psychedelic experience may be over relatively quickly while the improvement in depression lasts for weeks, it deserves attention. It also deserves a closer read than the inevitable “two-hour trip cures depression” headlines.
On October 26, JAMA published a phase 2b trial of intranasal mebufotenin—the clinical name for 5-MeO-DMT—in people with treatment-resistant depression. The findings were encouraging. They weren’t quite the neat story a headline might suggest.
The treatment wasn’t a mushroom trip in a bottle
If you’ve read our earlier piece on 5-MeO-DMT and its “God Molecule” mythology, you know the compound comes with a considerable amount of cultural baggage. Stories of ego dissolution, transcendent encounters, and the Colorado River toad tend to drown out the less cinematic questions.
This study wasn’t testing a ceremony, a toad secretion, or a recreational dose. Researchers used a pharmaceutical nasal-spray formulation of mebufotenin benzoate, given by trained clinicians in a monitored setting, with psychological support before, during, and after treatment. The distinction matters. A drug tested under careful clinical conditions is not evidence that taking an unregulated substance on your own produces the same results—or carries the same risks.
Researchers enrolled adults whose major depression had not improved adequately after two to five antidepressant treatments in their current episode. The trial ran at 38 sites across the United States, Australia, and Europe. Of 196 participants randomized, 193 were included in the main analysis.
People were assigned to receive a single nasal dose of 8 milligrams, 12 milligrams, or a very small 0.3-milligram comparison dose. Those groups weren’t equal in size: 46 people received 8 mg, 73 received 12 mg, and 74 received the comparator. Researchers followed participants for eight weeks.
What actually improved?
The trial used the Montgomery–Åsberg Depression Rating Scale, a clinician-rated measure of depression severity. It’s a structured assessment, not a question about whether someone had a meaningful or profound experience.
Twenty-nine days after dosing, the people given 12 mg had improved by an average of 11.1 points from their starting score, compared with 5.5 points in the low-dose group. After adjusting for the study design, the difference between the groups was 5.3 points in favor of 12 mg. That met the trial’s prespecified primary statistical test.
Here’s where the story gets interesting. The 8-mg group also did better than the low-dose comparison, with an average 12.5-point drop from baseline and an adjusted between-group difference of 6.2 points at day 29. A stronger dose didn’t obviously mean a better outcome.
The response and remission figures tell a similar story. At day 29, roughly 35% of the 8-mg group and 34% of the 12-mg group met the study’s definition of response, compared with 12% of the comparison group. The remission proportions were 26%, 18%, and 8%, respectively. These are group-level results, not a prediction of what will happen to any particular person.
Scores also favored the active doses at later assessments through day 57. That’s promising after a single administration. But “durable” is a relative word here. Eight weeks of follow-up cannot tell us whether someone will feel better in six months, whether a second treatment is needed, or who might relapse.
About that two-hour claim
It’s the finding most likely to make its way into a breathless social post: 85% of the 8-mg group and 78% of the 12-mg group met discharge-readiness criteria within two hours.
Notice the word readiness.
The team began checking participants against predetermined discharge criteria 90 minutes after dosing. But the protocol did not actually allow anyone to leave before four hours had passed. So this was not a trial of clinics sending people home after a two-hour appointment.
What the result does suggest is that the acute drug effects may subside quickly enough to make shorter monitoring arrangements worth investigating. Compared with the long psychedelic sessions associated with substances such as psilocybin or LSD, that could eventually change the logistics of providing care.
Could it lower costs? Maybe. Could it let more patients access treatment? Possibly. But this study didn’t measure real-world staffing costs, insurance coverage, or the safety of a shorter release protocol. Before anyone starts selling the convenience angle, those questions need proper answers.
More intensity didn’t guarantee more benefit
There’s a longstanding tendency in psychedelic culture to treat a more overwhelming experience as a more transformative one. The results here complicate that assumption.
The lower active dose appeared to deliver similar antidepressant benefit, with a tolerability profile the authors considered more favorable. And researchers did not find evidence that scores on a questionnaire measuring mystical-type experiences correlated with improvement in depression at day 29.
That doesn’t mean the experience itself is irrelevant. A questionnaire can’t capture everything a person feels, and no single trial can settle how drug action, personal expectations, and psychological support interact. It simply means we shouldn’t assume that the intensity of a trip is a reliable measure of therapeutic success.
It’s one reason the researchers identified 8 mg as a dose to evaluate further. That’s a decision about the balance of results and tolerability in this study, not a recommended dose for the general public.
And the risks?
They’re part of the story, not a footnote.
Treatment-emergent adverse events were reported by 76% of people in the 8-mg group, 85% in the 12-mg group, and 73% in the low-dose group. Nearly all recorded events were classified as mild or moderate, and common complaints included nausea, headache, and discomfort at the administration site. Heart rate and blood pressure rose temporarily in some participants.
One participant receiving 12 mg experienced severe panic-attack events considered related to the treatment. It’s worth remembering that “generally well tolerated” in a research paper describes a particular sample under supervision. It isn’t a blanket safety guarantee.
People were screened, monitored, and supported. Some stopped taking antidepressants under medical supervision before dosing. The trial was too small to reliably detect rare harms, and its participants don’t represent everyone who might eventually seek treatment. Nor should anyone interpret these findings as an invitation to stop prescribed medication or experiment with 5-MeO-DMT outside clinical care.
“Double-blind” sounds wonderfully reassuring. In theory, neither participants nor the people evaluating treatment know who received which dose. In practice, that’s hard to maintain when one group experiences a powerful alteration of consciousness and another doesn’t.
In this trial, participants and on-site clinicians were often able to guess which treatment was given. Independent raters evaluating depression symptoms were better shielded from that information, which helps, but doesn’t make expectation effects disappear.
Other limitations matter too. The 8-mg group was comparatively small. Participants were not especially ethnically diverse. Some had to discontinue antidepressants, which can complicate how results apply in everyday medicine. And the study included psychological support without testing its contribution separately from the medication.
The research was funded by Beckley Psytech, an AtaiBeckley company associated with developing the formulation. Industry backing doesn’t make results false. It does make independent replication and transparent follow-up particularly important.
What happens next
The next meaningful test is larger phase 3 research. Researchers need to see whether the improvement survives stricter comparisons, whether the apparent benefits last, how rare or delayed harms emerge, and whether a clinical program built around a shorter experience is actually practical.
It’s easy to be cynical about psychedelic medicine’s promises. It’s just as easy to get swept up in them. Neither reaction does the research much justice.
What this trial offers is more specific, and more useful: evidence that a single, medically supervised dose of a short-acting psychedelic formulation improved depression ratings for some people with treatment-resistant illness over the following weeks. It also reveals how much work remains between a positive clinical trial and a treatment people can reliably access.
Maybe the long psychedelic session won’t be the only model. That’s an important possibility. Just don’t confuse a patient being ready to leave at two hours with a treatment that’s already ready for the world.
Editorial note: This is an evidence-based report on a clinical study, not medical advice. 5-MeO-DMT remains an investigational treatment in this context. Don’t use this article to guide self-medication or changes to prescribed treatment.
