From Dendrites to Drug Discovery: An Interview with Dr. Alex Kwan

Dr. Alex Kwan shares his insight on the field of preclinical psychedelic research and where he thinks things are headed in the future - in his lab, in drug discovery, and beyond.


Alex Kwan, PhD, is an Associate Professor at Cornell University’s Meinig School of Biomedical Engineering. He previously held the position of Associate Professor in the Department of Psychiatry at the Yale University School of Medicine. Dr. Kwan’s pioneering research aims to uncover the psychoplastogenic effects of psychedelic drugs such as ketamine and psilocybin, and his 2021 publication won Psychedelic Science Review’s Editor’s Choice Award for Best Study on Psychedelics and Neuroplasticity. We caught up with Dr. Kwan to learn more about his past, present, and future perspectives on psychedelic neuroscience.

Your background is in engineering and physics – how did you progress into the field of psychedelic neuroscience?

I did my PhD at Cornell University in Applied Physics. I was building optical microscopes, and along the way I became interested in neuroscience. My interest in psychedelics did not begin until I started my own lab at Yale University. Yale was a pioneering institution in ketamine research, so right away I was exposed to this work. It was inspiring to see how ketamine was being advanced as a new treatment for depression, building on a strong foundation of basic research and clinical work at Yale. This led me to join the effort to initially study ketamine, and then more recently, psychedelics.

Interest in psychedelic research has really exploded over the past couple years, but before the mid 2010s it was much less popular and not as widely accepted. Did you find support for this line of research early in your career?

When we started working with psilocybin in 2019, I feel there was not much interest in psychedelics in the basic science community. I remember talking to a few colleagues who were not interested. My department chair at that time, John Krystal, was one of the few who saw the potential and supported our work. But then within a year or so, right around when we started publishing, there was a surge of interest, and everybody started talking about psychedelics. It was great timing, at least for us.

Congratulations on your move this summer from Yale to Cornell – can you talk a bit about what prompted your decision to move your lab back to your alma mater? Do you have any interesting collaborations with colleagues at Cornell in the works?

Yale was a fantastic environment for doing this research, which I probably would not be doing if I hadn’t been at Yale Psychiatry! The environment let me do what I was trained to do in optical microscopy and combine it with my new interest in drug action. Specifically, we became interested in finding out how psychedelic compounds like psilocybin affect how neurons receive their information through dendrites. Our current technology allows us to image a few dendritic branches at a time, but neurons have very complex and extensive dendritic trees for receiving inputs – we want to be able to observe drug-induced effects on the entirety of these structures. Cornell presented an interesting opportunity as they have a large optical microscopy community. Moving to Cornell allows us to collaborate and develop new tools to study drug actions in the brain.

More broadly, do you think that preclinical rodent behavioral models with relevance to psychiatric illnesses have strong translational components? Are we reading too much into them and coming to too many conclusions?

I believe that the best way we can use preclinical animal models is in drug discovery to support the identification and evaluation of new drugs. These models are fantastic for understanding what novel compounds do in the brain. For example, we can measure how the administration of a drug impacts neuronal activity in cellular resolution. We can also precisely measure how synaptic connectivity between neurons is changed. These physiological changes may be useful biomarkers for targeted drug development.  I have mixed feelings about behavioral assays – some are valuable, like the rodent head twitch response assay for measuring acute effects of psychedelics. But then there are behavioral assays that are difficult to interpret and may not be very informative for psychiatric conditions. Overall, there are strengths and limitations for preclinical research that we should all keep in mind.

There is a real push in both research and industry to explore the use of psilocybin for treatment of both mental health and physical health concerns. Do you think that this buzz will subside after some time? Can you realistically see a future where psychedelic drugs like psilocybin are used in treatment protocols for obesity, eating disorders, substance use disorders, etc?

In general, more work needs to be done. There seems to be real, promising evidence for or the use of psilocybin plus psychotherapy in treating Major Depressive Disorder and potentially for cluster headaches and substance use disorder. MDMA seems to be efficacious in treating PTSD. Beyond this, for other indications, clinical evidence is lacking – we should wait for these studies to be carried out before making broader statements. I don’t believe psychedelics are a panacea that would be appropriate for treating all illnesses.

It’s possible that there is a bit of trying to fit a square peg in a round hole, from the industry side. I can see some companies may be trying to pursue certain indications and develop their intellectual property, in the hopes that future research validates their capital interests. I am hopeful that with more research, particularly from neutral sources like the NIH, there will be a more realistic assessment of what these compounds can do and what they do not do.

Where do you see the future of your lab’s research heading? Are there any themes in psychedelic research that you are hoping to pursue, or working up to?

A long-term goal of my lab is to know exactly what happens electrically in the brain after administration of a psychedelic drug. This is because ultimately our behavior is governed by how we think, which for the brain means communication via electrical impulses passed between neurons. So if we can figure out how psychedelics impact electrical neural activity in the brain, then we may learn how these molecules can evoke such interesting behaviors.

Within this broad theme, in the short-term of the next 5 years, we want to focus first on understanding what psychedelics do to the dendrites of neurons. This stems from our earlier work showing that psilocybin can lead to changes in synaptic inputs in the dendrites. How do these compounds evoke such long-lasting neural plasticity? We suspect that it is because psychedelics cause a certain pattern of electrical activity in the dendrites. We have a guess for how this may work, and we want to test whether our model and hypotheses are correct in the next several years.

Dr. Kwan’s groundbreaking research continues to pave the path towards a greater understanding of psychedelic drugs, from cellular and molecular mechanisms to broad drug-induced changes in brain circuitry. You can find out more about Dr. Kwan’s research and view the lab’s other publications on the Kwan Lab website.


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