On a cold November day in 1957, Laika made history as she rode into orbit on a Soviet spaceship, withstanding tremendous acceleration to become the first living being to circle the Earth. Laika wasn’t a trained astronaut—she was a dog, a former stray from the streets of Moscow chosen for this historic, but ultimately fatal, mission.
In the name of science, humans have since launched hundreds of different animals into space. Now, however, scientists are sending mice on a very different kind of trip—one that doesn’t require them to leave the laboratory, much less the Earth.
Rather, they’re on a mushroom trip.
Research into the neurological effects of psilocybin, the hallucinogenic compound found in so-called “magic mushrooms,” has experienced a powerful revival in recent years. Psilocybin is a serotonergic psychedelic, meaning that it has a high affinity for serotonin receptors and produces altered states of consciousness, including positive mood. Clinicians and academics have long been interested in the potential of these substances as therapies for neuropsychiatric disorders, including depression and addiction, but their clinical implementation has faced considerable challenges.
The frontal cortex’s neuroplasticity, or its ability to adapt over time, has proven fundamental to the efficacy of antidepressant therapies. Results of previous studies suggested a potential relationship between psychedelics and neuroplasticity, but the particulars remained unknown. To address some of these uncertainties, researchers from Yale School of Medicine’s Department of Psychiatry examined psilocybin’s effect on the brain and demonstrated psilocybin-induced structural neuroplasticity at cellular resolution for both short and long timescales.
Structural and Behavioral Effects of Psilocybin
Psilocybin has a centuries-long tradition of medicinal and spiritual use, particularly among Indigenous peoples. Despite this, however, psilocybin has not been extensively studied in the context of Western medicine, leaving many questions about its neurological functions unanswered. “Psychedelic compounds like psilocybin produce temporary psychedelic experiences that last for four to six hours, but it’s a mystery as to how those short-term actions translate to longer-lasting therapeutic effects on mental illnesses,” said Alex Kwan, associate professor of Psychiatry and Neuroscience at Yale and senior author of the paper. By studying how psilocybin affects neuron structure, researchers could bridge this gap and offer a structural explanation behind its well-observed lasting therapeutic effects, which include a substantial reduction in depression and anxiety symptoms according to early but promising clinical trials.
In this study, the researchers administered various doses of psilocybin to mice and evaluated the neurological effects through a series of tests. “One of our focuses is on neuronal structure. We used two-photon imaging, a fluorescence imaging technique used for live tissues, and confocal imaging, an optical laser imaging technique with high resolution, to see the structural changes caused by single-dose psilocybin,” said Ling-Xiao Shao, first author of the paper and a postdoctoral associate researcher in Kwan’s lab. The researchers used the two-photon imaging technique to longitudinally track the dendritic spines—protrusions from the membranes of dendrites, the branch-like appendages of neurons that receive communications from other cells—in neurons within the mice’s medial frontal cortex. These spines play a vital role in receiving and processing electrical impulses.
The study’s results suggest that a single dose of psilocybin was sufficient to enhance the formation of dendritic spines in the medial frontal cortex of the mouse, increase spine head width, and boost spine protrusion length. A month after administration of psilocybin, approximately a third of psilocybin-induced new dendritic spines remained. These results are especially promising for potential therapeutic use, as conditions like depression are associated with a loss of synapses in the frontal cortex region. Psilocybin’s stimulation of lasting dendritic growth may offer a solution.
While imaging neural modifications clarifies the physical effects of psilocybin, it does not fully account for the functional outcomes of the compound. To understand the impact of these structural changes on behavior, the researchers applied footshocks to the mice and assessed if single-dose psilocybin improved their ability to escape stressful conditions. The results demonstrated that mice exposed to psilocybin exhibited healthier stress-response behavior.
While this study provides compelling evidence in support of the enduring actions of psilocybin in the brain, it is still unclear whether the compound’s therapeutic potential can be isolated from its hallucinogenic effects. Kwan and Shao’s study found that suppressing psilocybin’s hallucinogenic effects by knocking out a key serotonin receptor, 5-HT2A, did not interfere with the therapeutically promising changes in neuron structure. However, further research is needed to determine if this separation of function is possible in humans.
The Rise (and Fall) of Psychedelic Psychiatry
Kwan and Shao’s recent foray into the world of hallucinogens is representative of a larger, ongoing renaissance in psychedelic research after decades of fluctuating acclaim and condemnation. When Swiss researcher Albert Hofmann first discovered LSD’s potent hallucinogenic effects in the early 1940s, he was not alone in his excitement about the drug’s psychiatric potential. Hundreds of academic articles expounding psychedelics’ effects appeared in medical journals throughout the 1950s. So began a brief and initially promising affair between psychedelics and clinical psychiatry in the United States. Various clinics and institutions, including Harvard, devoted significant resources to researching the therapeutic potential of psilocybin and LSD. Psychedelic researchers, such as Timothy Leary and Richard Alpert, became household names.
However, growing backlash against the free-loving, acid-tripping counterculture of the 1960s—facilitated by psychedelics’ association with anti-war dissidence—began to turn the political tide. In 1965, the passage of the Drug Abuse Control Amendments Bill banned the unlicensed individual manufacturing and sale of hallucinogenic drugs, signaling a strengthened political and legal resistance to hallucinogens and ringing a death knell for psilocybin. In 1970, the Controlled Substances Act explicitly designated psilocybin a Schedule I drug, the most restrictive classification, indicating a high potential for abuse and no accepted medical use. In so doing, the Act not only subjected psilocybin to extremely prohibitive regulations, but also heavily stigmatized its use, taking the wind out of the sails of psilocybin research for years.
By Kwan’s own recollection, the landscape of psychedelic research was nearly barren even just a decade ago. “Reading from other labs who were studying this fifteen years ago, the culture was very different, very restrictive,” Kwan said. “There were no suppliers of these compounds… there were only a few labs who would [synthesize psychedelic compounds] in the United States.”
The Psychedelic Revival
In recent years, however, the research landscape has shifted. With greater knowledge of how drugs function on a molecular level, further research into the science of addiction, and growing recognition of the failures of the War on Drugs, popular conceptions of drug use are shifting. While much of the mainstream drug debate focuses on recreational use, these changing perspectives have opened up the academic and clinical fields as well.
Kwan and Shao’s study adds to a growing body of research into the therapeutic potential of psilocybin and other psychedelics to treat mental disorders. As a compound used in conjunction with psychotherapy, psilocybin has a number of uniquely appealing characteristics—it’s non-addictive, has low risk of overdose, and may require less frequent dosing than selective serotonin reuptake inhibitors, the most common class of antidepressants.
Financial support for research from activist organizations, academic institutions, and commercial entities has accompanied this growing recognition of psilocybin’s potential. Echoing the academic enthusiasm of the 1950s, centers dedicated to the study of psychedelic drugs have opened at a number of research institutions in recent years, among them Johns Hopkins, Massachusetts General Hospital, and New York University. Promising clinical psilocybin trials in the U.S. led the FDA to designate psilocybin a “breakthrough therapy” in 2018, indicating significant institutional optimism about the drug’s therapeutic potential. Kwan and Shao’s own study reflects the growing acceptance of psychedelic research, given its publication in Neuron, a prestigious peer-reviewed research journal.
Even in today’s more liberal environment, however, obstacles remain for those interested in conducting research with psychedelics. “Even though the public perception is changing quickly, the funding is still slow,” Kwan explained. “We had a pilot grant from Yale, but [this research] is not funded right now at the federal level, so it’s tricky.” The National Institutes of Health has abstained from funding psychedelic research, even as commercial interest in psychedelic psychiatry grows.
Moreover, while Kwan and Shao are optimistic about the therapeutic potential of psilocybin, they caution against framing psychedelics as a panacea for mental illness. Noting “the possibility of adverse effects,” Kwan described particular risks for people with a history of psychosis or cardiovascular issues. “There’s a lot of hype in terms of what these compounds can do, but they’re definitely not going to be a solve-all,” Kwan cautioned.
In the meantime, though, Kwan and Shao intend to remain an integral part of this research. The results of their study offer fertile ground for further exploration of psilocybin. After observing the neurological changes induced by psilocybin, Kwan and Shao are eager to address new questions regarding the particular molecular signals, brain receptors, and neural cell types involved.
Five decades on from the initial criminalization of psilocybin, the psychedelic research landscape again appears bright. While we may not be “turning on, tuning in, and dropping out” any time soon, researchers like Kwan and Shao remind us that the future of psychiatry may well be psychedelic after all.
About the Authors
Anna Calame is a junior in Davenport College studying the history of science, medicine, and public health. Outside of her work with the YSM, Anna is involved with Yale UAID, YaleBleeds, and the club tennis team.
Rayyan Darji is a sophomore in Grace Hopper interested in studying neuroscience on the pre-med track. In addition to writing for YSM, Rayyan is involved with Yale Muslim Students Association, Alzheimer’s Buddies, and YNEURO.
The authors would like to thank Alex Kwan and Ling-Xiao Shao for discussing their research process and findings with them, and the research team would like to acknowledge the non-profit Usona Institute for providing psilocybin for research.
Shao, L.X., Liao, C., Gregg, I., Davoudian, P.A., Savalia, N.K., Delagarza, K., & Kwan, A.C. (2021). Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron, 109(16).