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What does an LSD or psilocybin ‘trip’ actually look like on a brain scan? How do these drugs affect brain activity? And how large a dose is required to achieve an effect on depression, anxiety and other mental health disorders? These are some of the questions addressed by Drummond McCulloch, a PhD fellow, in the Neurobiology Research Unit at Rigshospitalet, Copenhagen’s university hospital. He sees great therapeutic potentials in these drugs.

“These drugs are transformative, and quite distinct from all other therapies within psychiatry,” he says.

For his research and dedication, McCulloch is among this year’s recipients of the Lundbeck Foundation Talent Prize.

“It’s a nice surprise when someone outside the field notices what you’re doing. It makes you feel that it’s actually important,” he says.

Sending study volunteers on a ‘trip’

McCulloch always pictured himself doing research. But he first explored human biology, biochemistry and philosophy at the University of Glasgow before settling on neuropharmacology, and later deep-diving into research on psychedelic drugs.

“There had been no significant advances in psychopharmaceuticals for years, so I felt these drugs held promising potential,” he says.

A deciding factor was when a couple of his friends, affected by depression, talked about their positive experiences with LSD. And a meeting at a conference with Danish researchers in the field later resulted in McCulloch now living and researching in Copenhagen.

Part of his research is controversial because he sends study participants on a ‘trip’ using mind-altering drugs like LSD or psilocybin. And in some cases, he puts them in a brain scanner, using specialised techniques to investigate how the drugs affect brain activity.

One study participant drew a picture of the experience as an explosion of colour and shapes in the brain. And that matches what McCulloch sees on the scanner images.

“These brain scans are unique. They show connectivity criss-crossing the brain’s networks unlike anything else usually observed,” he says. 

The experiments are carried out in a reassuring setting, under controlled conditions and with clinical psychologists as guides. The aim is to gain new knowledge of the medicinal potential of these drugs.

“The effect differs a lot from one person to the next, but from just a single dose some people can be expected to achieve a crucial and lasting effect on mental disorders such as depression, alcohol addiction and anxiety,” McCulloch explains.

Constructed a digital toolbox

The hallucinogenic substances act on a specific serotonin receptor in the brain, and the theory is that they work by altering the brain’s entropy, meaning its level of disorder or randomness. Normally, our brain operates within orderly, well-defined networks with no connectivity between them. The psychedelic drugs, however, cause neurones to make connections that criss-cross the networks, and this may be linked to changes in brain entropy.

One problem for scientists seeking to test this hypothesis is that they lack a metric for brain entropy.

“The hypothesis is not expressed mathematically, so many researchers have tried to test it using their own mathematical models, based on various imaging techniques,” McCulloch explains.

He reviewed the scientific literature and found 12 articles describing changes in brain entropy, but each using their own mathematical model.

Next, in collaboration with Anders S. Olsen, a mathematician from the Technical University of Denmark – DTU, he tested all the mathematical models on a single dataset consisting of brain scans from 28 individuals. The test shows that the models measure different phenomena and consequently do not arrive at the same result.

“This is naturally disappointing, because it means we can’t compare them. On the other hand, having different models helps us understand the complexity,” says McCulloch.

He has now compiled all the models in a single piece of software named Copenhagen Brain-Entropy Toolbox, CopBET, which is available for free. Using CopBET, researchers can test their hypotheses in different models, and also test each other’s hypotheses using the same models, and thereby corroborate the reliability and validity of the studies. McCulloch is also involved in international collaborations in both an academic context, and with the European Medicines Agency, which approves therapeutic drugs. In all contexts, he is an advocate for high standards of research.

“There was a time when researchers attracted a lot of media attention for hyping their research findings. That was disappointing and caused distrust. Which is why I want to disseminate research results that may be seen as ‘boring’, but are more reliable.”

Two clinical studies ongoing

McCulloch himself is currently conducting two clinical studies that are anything but boring.

In one study, the aim is to find the optimum dose of LSD.

“We administer a dose of LSD followed by a radioactive agent, which also binds to the serotonin receptors, which we can see on the scan. We can then draw a map of the serotonin receptors that take up LSD at different doses. And we can then use that in clinical studies going forward.”

He expects to publish the results next year.

In the other study, conducted in association with the Department of Psychology and Behavioural Sciences, Aarhus University, 120 healthy participants are taking psilocybin for the first time – or placebo. They have never tried psychedelic drugs or MDMA, which has some of the same effects.

This experimental research follows up on another of McCulloch’s studies, which demonstrated that healthy study participants experienced lasting positive effects such as heightened well-being and mindful awareness for up to three months after being treated with psilocybin.

“Some of the study participants wrote to us for weeks and months after the experience saying how it had changed their lives. And the fact that they have these insightful and emotionally overwhelming experiences is fascinating because it tells us something about how the brain works.”

The researchers will now be investigating what healthy study participants experience during their first ‘trip’, which induces these lasting changes. McCulloch expects to publish the results of this study in 2026.