Imaging studies in rodents have shown how just a single dose of the psychedelic drug, psilocybin—the compound found in “magic mushrooms”—prompts structural remodeling of neurons in the brain that could help to explain the drug’s reported antidepressant effects. The studies, by researchers at Yale University, found that administering psilocybin to mice led to an immediate and long-lasting increase in the number and strength of connections between neurons in a specific region of the cortex. Interestingly, they pointed out, other research has shown that subanesthetic doses of the drug ketamine cause similar rapid increases in spine density and elevation of spine formation rate in the medial frontal cortex.
“We not only saw a 10% increase in the number of neuronal connections, but also they were on average about 10% larger, so the connections were stronger as well,” said Yale’s Alex Kwan, PhD, associate professor of psychiatry and of neuroscience, describing results from their psilocybin study. Kwan is senior author of the team’s published paper in Neuron, which is titled, “Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo.”
Psilocybin is a serotonergic psychedelic that displays “untapped therapeutic potential,” the authors suggested. Serotonergic psychedelics produce “an atypical state of consciousness characterized by altered perception, cognition, and mood,” but it has also long been thought that such compounds may have therapeutic potential against neuropsychiatric disorders including depression, obsessive-compulsive disorder (OCD), and addiction. “Among serotonergic psychedelics, psilocybin is recently shown to relieve depression symptoms rapidly and with sustained benefits for several months,” the authors wrote. In fact, psilocybin was granted “breakthrough therapy” designation by the FDA in 2019, and clinical trials have now been initiated to test the compound as a potential treatment for major depressive disorder.
While it’s still unclear how psilocybin might work in the brain, and how long any beneficial results might last, a few studies have provided “clues” linking serotonergic psychedelic drugs with structural and functional neuroplasticity in certain regions of the brain, the investigators noted. However, they acknowledged, “… there has been no direct demonstration of psilocybin-induced structural plasticity at cellular resolution in a mammalian brain.” Also, it is not known for how long any synaptic rewiring may occur in vivo.
Kwan and first author Ling-Xial Shao, PhD, a postdoctoral associate in the Yale School of Medicine, and colleagues, were particularly interested in the effects of psilocybin in the prefrontal cortex. A loss of neuronal connections—synaptic atrophy—has been found in the prefrontal cortex of patients with depression, and also in the prefrontal cortex of rodent models of chronic stress. “It is well established that structural neuroplasticity in the frontal cortex is key to the action of antidepressants,” the team wrote.
Using a laser-scanning, two-photon microscopy technique, Kwan and Shao imaged dendritic spines in high resolution and tracked them over several days in living mice. Dendritic spines are small protrusions found on nerve cells that aid in the transmission of information between neurons. They found increases in the number, and the size of these dendritic spines within 24 hours of the animals receiving a single dose of psilocybin. The dendritic rewiring was accompanied by increased excitatory neurotransmission. These changes to spinal density and size were still present a month later.
The data also indicated that the long-term increase in spine density was due to an initial boost of enhanced spine formation. Interestingly, administering psilocybin to mice that had been subjected to stress resulted in behavioral improvements and increased neurotransmitter activity.
The authors put forward two explanations as to why the neural modifications observed following psilocybin administration might relate to its therapeutic effects. First, they suggested, depression is associated with a loss of synapses in the frontal cortex, and so restoring the number of neuronal connections may correct the deficit, “ … providing a biological mechanism for alleviating symptoms of depression.” Second, the authors noted, structural remodeling is integral to learning and facilitates the storage of lifelong memories. “Psilocybin-induced neural plasticity could prime the brain for integrating new psychological experiences.”
For some people, psilocybin can produce a profound mystical experience. The psychedelic was a staple of religious ceremonies among indigenous populations of the New World and is also a popular recreational drug. It may be the novel psychological effects of psilocybin itself that spurs the growth of neuronal connections, Kwan noted.
“It was a real surprise to see such enduring changes from just one dose of psilocybin,” he said. “These new connections may be the structural changes the brain uses to store new experiences.”
“By showing that the time course for psilocybin-induced structural remodeling is rapid and persistent in vivo, our study suggests that synaptic rewiring may be a mechanism shared by compounds with rapid antidepressant effects,” the authors concluded. “Of note, the timing of psilocybin’s effect on the neural architecture is reminiscent of ketamine, which at subanesthetic dose causes similar rapid increase in spine density and elevation of spine formation rate in the medial frontal cortex.” However, the investigators commented, it’s still not known how drugs that act on different molecular targets can result in comparable changes to neural architecture and behavior. “Elucidating the mechanisms will be crucial toward unraveling the neurobiology of rapid-acting antidepressants,” they stated.