Could magic mushrooms be a window into treating depression? This is the question a Cornell professor and his team seek to answer by studying the effects of psychedelics on the brain and how they could be replicated to create more effective depression medications.
Prof. Alex Kwan Ph.D. ’09, biomedical engineering, researches how the brain’s response to drugs like psilocybin — the mind-altering chemical found in magic mushrooms — could help researchers develop more specialized treatments for depression.
Kwan began his career studying engineering physics as an undergraduate at Simon Fraser University. He went on to get his Ph.D. in applied physics from Cornell University. After a postdoctoral fellowship at U.C. Berkeley and a stint as a professor of psychiatry at Yale Medical School, he landed back in Ithaca in 2022, where he now investigates how psychiatric drugs affect brain cells.
Kwan said his research is driven by asking why. Even though psychiatric medications are widely used, how and why they work remains a mystery.
“Shockingly, we still don’t quite know why they are efficacious,” Kwan said.
His strategy is to take a late-stage or recently approved antidepressant drug and investigate what it’s doing to the brain. Psilocybin, one such drug, is now in its third phase of clinical trials for general depression, as well as treatment-resistant depression, a type of depression that is highly resistant to medication, Kwan said.
Specifically, Kwan focuses on the effect of these drugs on the connections between neurons, nerve cells responsible for signaling in the brain.
Depression and its symptoms are closely associated with a loss in brain volume, says Kwan, but this is not because neurons are dying, but because the connections between these cells begin to deteriorate.
The branch-like extensions of neurons responsible for cell communication throughout the brain are referred to as dendrites. As dendrites weaken, so does the brain’s capacity to process emotional and cognitive signalling throughout, manifesting as symptoms of depression, says Kwan.
Drugs such as Psilocybin appear to encourage the growth of neural connections, and understanding why could be a key to uncovering the why behind depressive symptoms and the mechanisms behind their treatment, Kwan said.
“We want to, in a way, reverse engineer and figure out: we know this thing works, but what does it actually do in the brain?” Kwan said. This can then help researchers develop future drugs that target changes known to be effective.
Kwan uses mice as subjects in his lab, where a typical experiment may examine the effects of psilocybin on a group of mice, compared to another group that is treated with an inert substance like saline.
Using two-photon microscopy, a visualization technique that Kwan uses on the mice’s brain, the team monitors and visualizes the neurons and connections in the mice’s brains to observe the structural effects of the drug.
A group of mice treated with psilocybin will hold the chemical in their system for only a few hours, during which they exhibit head twitches, which indicate to the researchers that the mouse is under the influence of the psychedelic. Then, for up to two months following the initial treatment, Kwan’s team observes the remodeled brain. They have found that the mice’s brains begin to remodel and rewire within one to three days of the trip, despite the drug already being out of their systems.
“A common theme with these drugs is they all have some type of short-acting effect, and then also some longer-term therapeutic effect,” Kwan said.
Kwan and his team have found that drugs like psilocybin cause sustained growth of neural connections over time, which could mean that patients don’t have to take them as often as daily medications like Prozac or Lexapro.
Knowing that these drugs spur growth of brain cell connections raises a second question: where are connections growing? Kwan’s lab also studies the directionality of this cell connectivity.
During experiments, shortly after the mice are given psychiatric drug treatments, they are infected with a fluorescent engineered rabies virus that the team can visually trace as it moves through the brain.
When the virus jumps from one cell to the next, it fluoresces, or lights up, indicating that the two cells are signalling to each other. This technique allows Kwan and his team to track where the dendrites are growing during the remodeling, kind of like creating a map of the brain. This can help inform which areas of the brain are involved in symptom recovery or are involved in the response to treatments.
“That could be quite useful [for] figuring out what areas of the brain are now more connected that might then be therapeutic and lead to these improvements in behavior,” Kwan said.
By reverse-engineering existing drugs to better understand what they are actually doing in the brain, Kwan hopes to help scientists more easily create new drugs. Instead of having to rely on the time-consuming process of trial and error, future scientists can draw on his research to learn what changes in the brain are actually contributing to a drug’s therapeutic effects.
“If you can have those insights, then it will help us quite a lot in terms of drug discovery and drug developments,” Kwan said. “We can find other compounds that can do those things.”
Differences in genetics, brain chemistries and individual biologies can all influence how a treatment affects someone, Kwan said. But by having more options out for patients to choose from, their treatment can become more specialized and personalized, hopefully evoking better patient outcomes.
