The Science of Serotonin: Psychedelics and Brain Plasticity
Una Meistere
An interview with Gitte Moos Knudsen, Professor in Clinical Neurobiology at the University of Copenhagen
Gitte Moos Knudsen is a Danish translational neurobiologist and clinical neurologist. She is Chairman of the Neurobiology Research Unit at Rigshospitalet and Professor of Clinical Neurobiology at the University of Copenhagen. Her main area of research is the neurobiology of neurotransmission, with particular emphasis on multimodal brain imaging and neuropharmacology.
Over the past decade, her work has focused on experimental medicine and neuropharmacology, addressing fundamental questions about human brain disease mechanisms and predicting brain responses to different categories of neuromodulatory — particularly serotonergic — interventions, as well as treatment efficacy. For this purpose, she employs PET brain scanning to image serotonin receptors and receptor occupancy, and fMRI to evaluate drug effects on brain hemodynamic responses and regional interactions, i.e., functional connectivity.
According to PubMed, Dr. Knudsen has published more than 200 papers on serotonin. She was instrumental in developing and validating the first 5-HT₂A receptor agonist PET radioligand, which has since been used in multiple studies, especially of psychedelic compounds. One of her most cited papers is Beliveau V. et al., “A high-resolution in vivo atlas of the human brain's serotonin system” (Journal of Neuroscience, 2017). This atlas laid the foundation for many subsequent discoveries, such as Hansen J. et al., “Mapping neurotransmitter systems to the structural and functional organization of the human neocortex” (Nature Neuroscience, 2022), and Kringelbach M. et al., “Dynamic coupling of whole-brain neuronal and neurotransmitter systems” (PNAS, 2020).
Professor Knudsen was one of the keynote speakers at the international hybrid conference “New Approaches in Regulating Psycho-Emotional States: Perspectives from Human and Life Sciences,” organized by the NGO Veselīga Latvija (Healthy Latvia) in collaboration with the Faculty of Medicine and Life Sciences and the Faculty of Humanities at the University of Latvia. The event was part of the 83rd International Scientific Conference of the University of Latvia and took place on March 4, 2025, in Riga, Latvia.
Our conversation took place after the conference and explored how different serotonin receptors and transporters respond to a psychedelic dose of classical compounds, and what might make psilocybin and other psychedelics distinct — especially in the treatment of patients with treatment-resistant depression.
Throughout your career, you have focused on the brain’s serotonin system, particularly the 5-HT₂A receptor. What sparked your interest in this field, and why serotonin specifically?
Well, my background is as a neurologist, and the serotonin system is obviously involved in many different brain disorders and is an important neurotransmitter system. When I began my research in molecular brain imaging — specifically PET imaging, where you can scan the brain for molecular targets such as receptors or transporters — there was a lot of emphasis on dopamine. There still is, but at that time, there was much less focus on serotonin. That’s why I chose to concentrate on the serotonin system.
Serotonin is involved in a wide range of functions — things like appetite, sleep, mood, seasonality, and reward — so it plays a role in many different disorders. We also wanted to image serotonin release in vivo in the human brain, much like what had already been done for dopamine, where researchers measured dopamine release after a pharmacological or behavioral challenge.
So, we began searching for a PET radioligand that could enable imaging of serotonin release, because we felt it was important to have that capability in the research toolbox. We eventually homed in on the serotonin 5-HT₂A receptor, partly because it is so abundantly expressed — it’s one of the most densely represented serotonin receptors in the brain.
We realized that, to image serotonin release effectively, we might need to develop a PET agonist radiotracer. That’s what we did, and we succeeded — we published our first human studies in 2014. That work sparked our continued interest in serotonin 5-HT₂A agonists, which include the classical psychedelics.
Since then, we’ve conducted many studies not only on serotonin release but increasingly on serotonergic 5-HT₂A agonists such as psilocybin, DMT, and LSD. This line of work has also led us to explore other ways of imaging the brain under the influence of psychedelics, including MRI.
Serotonin is involved in a wide range of functions — things like appetite, sleep, mood, seasonality, and reward — so it plays a role in many different disorders.
What do we currently know for sure about the serotonin system, and what remains unknown—especially in relation to psychedelics?
We know that many psychedelic compounds don’t act solely on the serotonin 5-HT₂A receptor — they also interact with other serotonergic receptors. Right now, we’re trying to understand how various serotonin receptors and transporters are affected by a psychedelic dose of the classical compounds. Our main focus is on psilocybin, but we’re also studying other substances.
One important question is whether receptors beyond 5-HT₂A, such as 5-HT1A, also contribute to the effects of psychedelics. Some researchers believe they might, and there are subtle differences in how people experience different psychedelics. It’s difficult to know whether those differences are due to variations in dose or to distinct receptor profiles. That’s one of the areas we’re currently exploring.
Right now, we’re trying to understand how various serotonin receptors and transporters are affected by a psychedelic dose of the classical compounds.
We also have some interesting observations suggesting that the number of serotonin 5-HT₂A receptors in a person’s brain may influence how strongly they experience the effects of a psychedelic. Our data so far come from small samples, but it’s a promising avenue for future research.
Another major open question concerns neuroplasticity — specifically, how the serotonin 5-HT₂A receptor might be involved in the long-lasting effects of psychedelics. One of the most fascinating aspects of these compounds is that a single dose can sometimes lead to sustained changes in mood and behavior lasting for months. We don’t see that kind of enduring effect with most other drugs, so understanding the mechanisms behind it — and whether serotonin 5-HT₂A plays a central role — remains a key focus of ongoing research.
One of the most fascinating aspects of these compounds is that a single dose can sometimes lead to sustained changes in mood and behavior lasting for months.
Is that connected with the so-called “opening of critical periods” in the brain when taking psychedelic drugs?
There’s a theory from Gül Dölen’s lab in the U.S. suggesting that psychedelics may reopen critical periods in the brain. She’s studying this in mice using a social learning paradigm and has found that certain drugs seem to affect how easily mice can learn social interactions, depending on which compound is administered. However, her work doesn’t really distinguish between the specific molecular targets of these psychedelics. For example, she compares compounds like ibogaine, LSD, and I believe also MDMA — all of which have quite different pharmacological mechanisms of action.
It’s important to emphasize that all of this work has been done in mice, and we currently have no evidence that the same phenomenon occurs in humans. What we can say is that if psychedelics promote synaptic multiplication — meaning that more synapses are formed following a psychedelic session — this process will not continue indefinitely. At some point, there will be enough synapses, and the next step is likely synaptic pruning, where the brain eliminates weaker or dysfunctional connections.
This pruning process might be relevant to conditions like depression, where certain neural circuits or synapses may be overactive or malfunctioning. Pruning could help restore a healthier balance in those networks.
From both our animal (pig) studies and human data, we’ve seen indications that synaptic density increases after a psychedelic dose of psilocybin. But we also expect that over time, this density decreases again — which is likely a healthy and adaptive process.
So, whether this has anything to do with the so-called “critical window” findings from the mouse studies is still unclear. We’re obviously more interested in understanding what happens in the human brain. Animal studies are valuable for generating hypotheses, but they always need to be translated and tested to determine whether they truly apply to humans.
From both our animal (pig) studies and human data, we’ve seen indications that synaptic density increases after a psychedelic dose of psilocybin. But we also expect that over time, this density decreases again — which is likely a healthy and adaptive process.
But how far are we now from studies that could explore this topic in humans?
Right now, most of the ongoing work is focused on clinical trials using different psychedelic compounds for different disorders. The most advanced program is from Compass Pathways, which has recently completed its Phase III trial in patients with treatment-resistant depression. The results were positive — perhaps not with as large an effect size as some had hoped — but that’s not unexpected. As clinical trials scale up, effect sizes often decrease somewhat.
The main clinical question now is how to identify which patients are most likely to benefit from a psychedelic intervention. That’s something we still don’t fully understand.
Beyond that, many other studies are underway, investigating predictive factors and examining how the brain changes in response to a psychedelic dose of psilocybin. The whole field has really burgeoned — it’s been remarkable to watch. For example, at the Gordon Research Conference in the U.S. this summer, a wealth of new data were presented.
So finally, we’re moving beyond speculation and reviews based on limited evidence. We’re now beginning to see more informative, data-driven results that will help us understand the mechanisms of action — how these compounds work, when they should be given, and to whom they might be most beneficial.
Speaking about major depression or treatment-resistant depression — we know that existing therapies are limited and often ineffective. What makes psilocybin and other psychedelics different, especially compared to traditional antidepressants?
I think the main advantage is their very rapid onset of action. With traditional antidepressants, we’re used to seeing effects only after several weeks of treatment — that’s not the case with psychedelics. Their effects can appear within hours or days.
Another important difference is that psychedelics are typically administered only once, rather than daily. We don’t yet know whether repeat dosing is necessary — perhaps after six or twelve months —in some individuals, the effects appear to be quite sustained, while in others they may fade more quickly.
So, in these two respects — the speed of onset and the potential durability of their effects — the classical psychedelics are quite distinct from traditional antidepressants.
With traditional antidepressants, we’re used to seeing effects only after several weeks of treatment — that’s not the case with psychedelics. Their effects can appear within hours or days.
One of the outcomes of your research is precision medicine and its potential role in treating brain disorders. On a scale from 1 to 100, how much do we truly know about how the brain functions — how its different parts work together — and what is still unknown?
Well, I think there’s still a lot we need to learn. I would hardly want to put a number on it, because it’s really hard to quantify knowledge, but there’s still a great deal that remains to be uncovered. It’s one of the fastest-expanding fields of science — at least within biology — so we still have a lot to do.
And if we speak more concretely about depression?
One of the main challenges with depression is how we make the diagnosis of major depressive disorder. It’s really based on an interview with the patient, who reports their own symptoms, and then — based on those symptoms and their relation to what’s considered “normal” — a diagnosis of depression can be made.
But people can be depressed in many different ways. For instance, some individuals eat less, while others eat more. Some sleep less, while others sleep more. So it’s an extremely heterogeneous group.
I think one of our shortcomings in the past has been failing to recognize that depression might be more of a symptom — much like fever. You can have a fever for many different reasons, but it’s ultimately just a symptom of an underlying condition. Depression may work in a similar way — as a symptom of various brain disorders. That means that to treat it effectively, we need to identify and target the underlying mechanisms causing a person’s depressive symptoms.
I think one of our shortcomings in the past has been failing to recognize that depression might be more of a symptom — much like fever.
This idea isn’t entirely new — people have tried before to classify depression based on biological markers — but it’s been difficult to find consistent biomarkers across patients. That’s something we’re working on in my group, as are many others.
I think what’s needed now is to increase the number of patients in studies, so that we can better understand the heterogeneity of depression. Once we can identify and classify different subtypes and match them with the right treatments, I believe that will be key to truly understanding depression itself.
How important is an interdisciplinary approach to these medicines—and to medicine in general? For example, while psychedelics can make cognitive and emotional systems more flexible, psychotherapy is crucial for integrating and reinforcing new patterns. In that sense, psychedelics act as catalysts for developing new pathways through psychotherapy. Does this also represent a paradigm shift in healthcare? Perhaps this is one reason why, despite all the research and scientific evidence, there is still such stigma around psychedelics as medicines?
My experience is that I’ve never seen a field as divided and polarized as this one. On one side, there are people who believe psychedelics can treat almost everything — that they’re some kind of magic cure. On the other side, there are people who are afraid of them and want to have nothing to do with the field. And of course, that kind of polarization doesn’t help progress.
I’m a scientist, and I strongly believe that what everything needs to be substantiated by data. When it comes to psychotherapy and how to implement it alongside psychedelic treatment, there are three distinct phases in a psychedelic intervention:
The first is the preparatory phase, which mainly focuses on aligning expectations — helping participants understand what they might experience during the psychedelic session. That’s not really psychotherapy; it’s more about preparation and information.
Then comes the psychedelic session itself. During the session, there usually isn’t much talking. Participants are generally very quiet. The role of the therapists or guides is to provide support and ensure that people feel comfortable and safe, especially if the experience becomes challenging. It’s not talk therapy in that moment — it’s about containment and care.
Finally, there’s the integration phase, which can vary quite a bit between studies. According to our psychologist, who leads those sessions in our projects, some participants don’t need very much integration at all. They may already have gained insights during their experience that they feel are helpful for their recovery. Others might need more time and space to process what happened — and that’s where talking therapy can be important.
My key point here is that we still know far too little about what is actually needed — how these compounds work without psychotherapy, what kind of psychotherapy is most effective, and for how long or how intensively it should be provided. To move the field forward, we need psychotherapists and medical doctors to work together, not in opposition. We need interdisciplinary research to clarify what really makes a difference in psychedelic treatment.
There’s also data suggesting that some of the rapid-acting psychedelics can have therapeutic effects even when no psychotherapy or integration sessions are included in the clinical protocol. So, I’m not saying psychotherapy is unimportant or should be omitted — far from it. What I’m saying is that we need a more evidence-based approach to understanding its role.
This is also important from a practical perspective. If we insist on very intensive and resource-heavy treatment programs — without strong evidence that every component is necessary — psychedelic therapy will remain accessible to only a very small number of people simply due to capacity limits.
To move the field forward, we need psychotherapists and medical doctors to work together, not in opposition.
Considering ongoing clinical trials, how long will it take to introduce psilocybin and other psychedelics into the healthcare system in Denmark?
We’re seeing now is that several countries are beginning to move in that direction. Switzerland, for instance, has had a compassionate use program for many years. Germany is now opening up for that as well, and I’ve heard that Australia — and possibly the Czech Republic — are also getting closer to implementing similar programs.
These compassionate use programs essentially allow certified psychiatrists to provide psychedelic-assisted treatment in special cases, under controlled conditions. Once that model starts to gain momentum, I wouldn’t be surprised to see it adopted in many other European countries — and eventually in the U.S. as well.
And also in Denmark?
Yes, I think Denmark will probably follow the same path as other European countries. We already have quite an active research program here, which I think is helpful in that regard. If there’s a request from psychiatrists to provide this kind of treatment — and I can see that beginning to happen — it will likely support the process of introducing psychedelic-assisted therapies into the Danish healthcare system.
