New research published in Molecular Psychiatry provides insight into how psilocybin, a compound found in psychedelic “magic” mushrooms, influences the brain and behavior. By observing the effects of psilocybin on larval zebrafish, scientists uncovered that it not only stimulates exploratory behavior but also buffers against stress-induced changes in activity patterns.
This investigation sheds light on the complex interplay between psychedelic compounds and the serotonergic system — the part of the brain that helps regulate mood, anxiety, and happiness.
What is Psilocybin, and Why Focus on It?
Psilocybin is a naturally occurring psychedelic compound found in certain species of mushrooms, renowned for its ability to induce profound changes in perception, mood, and thought. It operates primarily by activating serotonin receptors in the brain, particularly those in regions involved with mood regulation and perception.
This substance has been the subject of increasing scientific interest, especially in the field of psychiatry, due to its potential to offer therapeutic benefits for a range of mood-related disorders. Unlike traditional antidepressants, which often take weeks to show effects and come with various side effects, research suggests that psilocybin might provide rapid and lasting relief after just a few doses.
But how does this compound work in the brain? To answer this question, researchers turned to larval zebrafish. The choice of zebrafish stems from their transparent bodies and the remarkable similarity of their serotonergic system to that of humans, which makes them an invaluable tool for studying brain activity and behavior in response to pharmacological treatments.
“Our laboratory mainly studies the functions of the endogenous serotonergic systems in the brain, which is not easy to study in mammals but is more accessible in fish,” said study author Takashi Kawashima, an assistant professor in the Department of Brain Sciences at Weizmann Institute of Science. “Hence, the recent psychedelic boom in psychiatry naturally caught our attention. Psychedelics act on serotonin receptors, and we thought we might be able to contribute some basic research insight from our background of serotonin research.”
The Research Methodology
For their study, the researchers developed a high-resolution tracking system specifically developed to monitor the movements and behaviors of these tiny aquatic creatures in a controlled environment. The system was capable of capturing the nuanced body kinematics of zebrafish larvae with extraordinary detail, thanks to a custom-built setup featuring a high-speed camera and specialized lighting. This allowed for the precise observation of spontaneous exploration behaviors and responses to visual stimuli, which are critical for understanding the innate and drug-induced behavioral patterns of zebrafish.
To assess the impact of psilocybin, researchers conducted a series of experiments where larval zebrafish were exposed to varying concentrations of the compound, as well as to other pharmacological treatments for comparison, including traditional antidepressants (SSRIs). The experimental design also incorporated stress-inducing conditions, such as changes in water temperature, to evaluate how psilocybin influenced stress-related behaviors
The Findings: Psilocybin’s Dual Effects
The study revealed that psilocybin had a dual effect on larval zebrafish: it enhanced spontaneous exploration but also shielded against stress-induced behavioral disruptions.
Psilocybin-treated zebrafish demonstrated a marked increase in spontaneous movement and exploration, suggesting a stimulatory effect of the compound on these behaviors. Furthermore, when subjected to stress, these same fish maintained normal swimming patterns, in stark contrast to the erratic “zig-zag” movements observed in control fish under similar conditions. This indicated a significant anxiolytic effect, with psilocybin helping to mitigate the behavioral manifestations of stress.
“The action of psychedelics has been mostly studied in the cognitive domains of brain functions,” Kawashima told PsyPost. “However, we found that psychedelics is at least acutely anxiolytic in fish, which shares evolutionarily old structures with humans. This indicates that psychedelics may also modulate a primitive functionality of the brain.”
Through behavioral analyses, the study also revealed that psilocybin’s effects were distinct from those of traditional antidepressants, which tended to suppress overall movement rather than stimulate exploratory behavior.
“We are very surprised by the dramatic, visible effects of psilocybin in fish,” Kawashima said. “Behavioral phenotypes in these types of model organisms are usually subtle and bar graphs. We did quantify the effects using cutting-edge machine-learning algorithms. Nonetheless, I can easily explain our findings, how the fish change their trajectories under stress and psilocybin, to our preschool daughters.”
Further analysis showed that psilocybin’s impact extends deep into the brain’s serotonergic system, specifically affecting the dorsal raphe nucleus, a key area involved in mood regulation. Here, psilocybin appeared to suppress the activity of serotonergic neurons, offering a clue to its calming effect on stress-induced behaviors.
Limitations and Future Directions
While the findings from this study are compelling, they also highlight the complexity of psilocybin’s actions and the need for further research. The larval zebrafish model, though powerful, is a simplified system. Human brains are vastly more complex, and how these findings translate to humans remains to be fully understood.
“First and foremost, this is a study of fish behavior,” Kawashima explained. “I studied medicine before turning into a basic researcher and am cautious about direct translation into clinical insights. Second, we haven’t demonstrated persistent effects of psychedelics that last for weeks and months, which is the most interesting clinical finding in humans. We are working on this.”
Future research will need to explore the long-term effects of psilocybin, its efficacy across different types of stressors and mood disorders, and its potential side effects. Additionally, studies will benefit from incorporating more advanced imaging techniques to observe changes in neural activity and connectivity in real-time, providing a more detailed map of psilocybin’s impact on the brain.
This study is a step toward demystifying the mechanisms behind psilocybin’s promising effects on mood and behavior. By leveraging the simplicity of the zebrafish model, researchers have begun to unravel the intricate dance between psychedelic compounds and the brain’s serotonergic system.
“Zebrafish’s brain is entirely accessible for methodologies of circuit studies in neuroscience,” Kawashima added. “We intend to clarify which part of the serotonin system psilocybin acts on using whole-brain neural activity imaging that we have expertise in. Also, zebrafish have been used at the first level of drug screening for various biomedical goals. We hope our machine learning approach will advance such industrial aspects of zebrafish use.”
The study, “High-resolution tracking of unconfined zebrafish behavior reveals stimulatory and anxiolytic effects of psilocybin,” was authored by Dotan Braun, Ayelet M. Rosenberg, Elad Rabaniam, Ravid Haruvi, Dorel Malamud, Rani Barbara, Tomer Aiznkot, Berta Levavi-Sivan, and Takashi Kawashima.
