Recent research published in the journal Molecular Psychiatry has provided new insights into the potential therapeutic effects of psilocybin, a psychedelic compound, on cognitive flexibility and weight maintenance in a rat model of anorexia. The study found that psilocybin not only helps maintain body weight in female rats subjected to conditions mimicking anorexia nervosa but also enhances cognitive flexibility, particularly in adapting to changes in reward contingencies.
Psilocybin is a naturally occurring psychedelic compound found in certain species of mushrooms, commonly known as “magic mushrooms.” When ingested, psilocybin is converted in the body to psilocin, which interacts with serotonin receptors in the brain to produce altered states of consciousness, including visual and auditory hallucinations, changes in perception, and a sense of expanded consciousness.
Anorexia nervosa is a severe psychiatric disorder characterized by extreme weight loss, restrictive eating, and excessive physical activity. It has the highest mortality rate among psychiatric disorders, especially affecting young women. Current pharmacological treatments, like selective serotonin reuptake inhibitors, are often ineffective in underweight individuals with anorexia.
One hallmark of anorexia is cognitive inflexibility, a trait that persists even after weight recovery and is linked to poorer quality of life. Cognitive inflexibility refers to difficulties in adapting behavior to new situations or rules, a problem also observed in other psychiatric conditions such as depression, anxiety, substance use disorders, and obsessive-compulsive disorder. Psilocybin has shown promise in improving symptoms in these conditions, which prompted researchers to investigate its effects on cognitive flexibility and weight maintenance in an anorexia model.
“Our lab is dedicated to understanding the neurobiological underpinnings of anorexia nervosa, with a view to inform the development of new treatments that actually work,” explained study author Claire Foldi, the head of the Foldi Lab at the Monash Biomedicine Discovery Institute. “When psilocybin came along as a promising treatment option, it seemed only natural that we would want to understand how it works in the brain, to inform the clinical application of psilocybin for people with anorexia nervosa.”
The researchers used the activity-based anorexia (ABA) model in female Sprague-Dawley rats to explore the effects of psilocybin on cognitive flexibility and weight maintenance. This model is particularly relevant for mimicking conditions seen in human anorexia nervosa, as it combines limited food access with increased physical activity, leading to significant weight loss in the rats.
To investigate the effects of psilocybin, the researchers administered the compound at a dose of 1.5 mg/kg, dissolved in saline. Additionally, they used selective antagonists for serotonin receptors, such as 5-HT1A and 5-HT2A, to delineate the specific receptor subtypes involved in the observed effects. These antagonists were administered 30 minutes before psilocybin treatment to examine their influence on psilocybin’s efficacy.
One of the key findings was that psilocybin-treated rats maintained their body weight more effectively compared to control rats during the ABA conditions. Psilocybin administration prior to the onset of restricted feeding helped the rats resist the severe weight loss typically induced by the ABA model. The psilocybin-treated rats spent more days above 85% of their baseline body weight and had a higher proportion of animals resistant to the ABA-induced weight loss.
Psilocybin also significantly enhanced cognitive flexibility in the rats, as evidenced by their performance on reversal learning tasks. In these tasks, the reward contingencies were altered, requiring the rats to adapt to new rules to obtain food rewards. Psilocybin-treated rats showed improved accuracy in responding to the changed contingencies, indicating enhanced cognitive flexibility. They learned to shift their behavior more quickly and efficiently compared to control rats. This improvement was characterized by a rapid shift in responding towards the new reward location and an increased proportion of rats that reached the performance criterion.
Moreover, the study found that psilocybin-induced improvements in cognitive flexibility were not driven by general increases in motivation or effortful responding. In other words, psilocybin did not simply make the rats more active or eager to obtain rewards; rather, it specifically improved their ability to learn and adapt to changing conditions.
The findings also shed light on the specific brain receptors involved in psilocybin’s effects. The researchers found that antagonism of the 5-HT1A receptor negated the cognitive-enhancing effects of psilocybin. Rats that received a 5-HT1A antagonist prior to psilocybin administration did not show the same improvements in cognitive flexibility, indicating that the 5-HT1A receptor is critical for psilocybin’s cognitive benefits.
On the other hand, antagonism of the 5-HT2A receptor did not significantly impair the cognitive benefits of psilocybin. While the 5-HT2A receptor is known to be involved in the psychedelic effects of psilocybin, this finding suggests that its role in cognitive flexibility may be less central compared to the 5-HT1A receptor.
“The most surprising thing we demonstrated was that a different subtype of serotonin receptor was responsible for the pro-cognitive effects of psilocybin than previously thought,” Foldi told PsyPost.
The molecular analysis of the rats’ brains provided further insights into the neurobiological mechanisms underlying psilocybin’s effects. Psilocybin caused a transient increase in the transcription of the 5-HT1A receptor and a decrease in the 5-HT2A receptor in the medial prefrontal cortex (mPFC). These changes were observed 6 to 12 hours after psilocybin administration, suggesting a shift in the balance of serotonin signaling that supports cognitive flexibility. The mPFC is a critical brain region for executive functions and adaptive behavior, and these molecular changes align with the observed improvements in cognitive flexibility.
In rats exposed to ABA conditions, psilocybin treatment led to similar molecular changes. There was an increase in the number of cells exclusively expressing the 5-HT1A receptor and a decrease in those expressing the 5-HT2A receptor. Additionally, psilocybin reduced the overall abundance of 5-HT2A transcripts, particularly in the ABA-exposed rats. These findings indicate that psilocybin’s effects on serotonin receptor expression are relevant to its therapeutic potential for conditions like anorexia.
“What we discovered was that there are two specific mechanisms that might underlie the efficacy of psilocybin for alleviating symptoms of anorexia nervosa – improved flexible learning and altered serotonin signalling,” Foldi explained. “We showed that psilocybin treatment curtailed the dramatic weight loss that occurs under conditions that normally elicit anorexia in female rats, improved their ability to flexibly learn new rules and altered the balance and abundance of specific serotonin receptor subtypes in part of the brain that controls complex cognitive processes.”
“Intriguingly, we also show in rats that not all individuals respond to psilocybin treatment with improved body weight or learning outcomes, which provides a basis for future studies examining the mechanisms that drive different response profiles.”
Animal models, such as the activity-based anorexia rat model used in this study, offer valuable insights into the fundamental mechanisms underlying human diseases like anorexia nervosa and allow for controlled experimentation on the effects of potential treatments like psilocybin. These models can mimic critical aspects of human conditions, enabling researchers to investigate the biological and behavioral responses to interventions in ways not feasible in humans. However, there are limitations to consider, including differences in physiology and behavior between animals and humans, which can affect the generalizability of findings to human populations.
“We only studied female animals, based in the fact that young women comprise the majority of the population of individuals with anorexia nervosa,” Foldi noted. “So, these findings need to be recapitulated in males to understand whether there are any differences in the effects of psilocybin based on biological sex.”
Regarding the longer term goals for the research, Foldi explained that her team is “now examining the brains of individuals that respond to psilocybin with improved adaptive abilities, to determine what differentiates them from ‘non-responders.’ We are also investigating how psilocybin alters neurochemical systems other than serotonin to better understand how improvements in learning are linked to changes in brain function.”
“Psilocybin is already in clinical trials for people with anorexia nervosa across four sites globally and the results from these trials will demonstrate efficacy one way or the other,” Foldi added. “Our findings will build towards a mechanism (or series of mechanisms) that underpin/s response efficacy, helping to tailor this novel (but psychologically intense) treatment to those most likely to respond with clinically significant outcomes.”
The study, “Psilocybin restrains activity-based anorexia in female rats by enhancing cognitive flexibility: contributions from 5-HT1A and 5-HT2A receptor mechanisms,” was authored by K. Conn, L. K. Milton, K. Huang, H. Munguba, J. Ruuska, M. B. Lemus, E. Greaves, J. Homman-Ludiye, B. J. Oldfield, and C. J. Foldi.