The brain's neuropathways are illuminated by psychedelics, according to microscope pictures.

From ancient indigenous ceremonies to the often-caricatured counterculture of the 1960s to their recent reemergence as a potential therapeutic, psychedelic drugs have been embraced by very different communities for very different reasons. Scientists, however, have never fully understood how these drugs function on the brain.

Associate professor Alex Kwan of the Meinig School of Biomedical Engineering in the College of Engineering is mapping the brain’s neural response to these psychoactive chemicals using optical microscopy and other technologies. This approach might eventually lead to the development of fast-acting antidepressants and treatments for substance-use disorders and cluster headaches.

At the neural circuit level, psychedelics affect how the brain responds to certain stimuli, according to Kwan. However, he says we are still in the dark about how they work and what they do to the brain. We also know far more about their pharmacology and how they interact with brain receptors. The biggest gap, he says, is in understanding what they do to the brain itself.

Research on psychedelics was conducted in the 1950s and 60s with relatively rudimentary methods, according to Kwan. Despite the renewed interest in these drugs from popular figures such as environmentalist and author Michael Pollan, much of the research was done in these decades.

To bring together the disparate scientific research on the neural basis of psychedelic action and update it, Kwan et al. published a review paper on Oct. 24 in Nature Neuroscience entitled “The Neural Basis of Psychedelic Action.” In it, they examine the chemical, molecular, neuronal, and network levels of how psychedelic drugs function and raise questions for further study, such as the consequences of various compound psychedelics on brain cells of different types.

Kwan's research focuses on psilocybin, the active ingredient in magic mushrooms. As psilocybin is being tested in Phase II clinical trials, it is the most promising candidate for pharmaceutical development. Kwan's lab is also studying other substances, such as 5-methoxy-N,N-dimethyltryptamine (5-Me0-DMT),which is produced by the glands of the Sonoran Desert Toad as a defence mechanism.

“There are thousands of different variations and analogues of these chemicals that are fascinating,” Kwan said. “The reason we study them is because they vary slightly in their characteristics in terms of how they bind to different brain receptors. We have a very fine-tuned knob by which we can change the chemical structure in order to see what it does to the brain differently.”

The new technologies at Kwan’s disposal have grown together with the science. The use of two-photon microscopy, viral tracing, and optogenetic techniques, which can target functional neurons in the cortical and subcortical regions of a living mouse brain, is just one of the new strategies at Kwan’s disposal. After nine years at Yale University, Kwan returned to Cornell in 2021 after developing these tools at Cornell.

Neuroscientists used to record one neuron at a time in a rat’s brain. However, neuroscience has developed tremendously over the last few decades, Kwan said. Now we can record tens of thousands of neurons at the same time, we can control neural activity, we have more sophisticated methods to measure animal behaviour, and so forth.

In last year’s research, Kwan used two-photon microscopy to see that a single dose of psilocybin increased neuronal connections in a mouse brain by about 10%. In addition to generating several follow-up questions—why are new neuronal connections being formed, which pathways are enhanced, and do these changes produce psilocybin’s therapeutic effects?—Kwan was able to investigate these questions after receiving the 2022 One Mind Rising Star Award for Mental Health Research in August. The $300,000 three-year grant supports early-career scientists in neuroscience, psychiatry, and related disciplines who are investigating high-risk, high-return research that address mental health.

Because scientists know which pathways are involved, they might be able to identify new drugs for drug discovery, says Kwan. They are equally excited about the potential of psychedelics in conjunction with targeted drugs to increase the drugs’ effects.

The researchers say the findings have implications for future research.