A single dose of psilocybin leads to long-lasting optimism boost in animal study

A recent study published in Translational Psychiatry suggests that psilocybin, a compound found in certain psychedelic mushrooms, could increase optimism and engagement in tasks, offering potential insights into its benefits for treating depression. Using computational modeling, researchers demonstrated that rats given psilocybin showed a sustained increase in optimism, motivating them to engage more with their environment.

Depression is often characterized by withdrawal, pessimism, and a lack of motivation to engage with the world, making it difficult for affected individuals to benefit from rewarding experiences. Psilocybin has shown promise as a treatment for depression, but the specific mechanisms driving its therapeutic effects remain unclear. By using a controlled environment and animal models, the researchers aimed to uncover how psilocybin influences decision-making processes and optimism.

Understanding these processes could help refine treatments, ensuring they target the underlying mechanisms of depression. Unlike human trials, which can be influenced by participants’ expectations, studies on rats offer a way to examine pure pharmacological effects in a controlled setting.

“We were interested in the post-acute effects of psilocybin on the brain’s mechanisms. By understanding the mechanisms of psilocybin treatment, we can begin to determine who might benefit from psilocybin treatment for depression and who may not. Psychedelic therapies don’t work for everyone but are amazing for some; hopefully, understanding the mechanisms can help us learn why,” explained study author Beth Fisher, a PhD student at the Monash Centre for Consciousness and Contemplative Studies.

To explore the effects of psilocybin on optimism, the researchers used a combination of behavioral testing and computational modeling to identify changes in the rats’ decision-making processes. The sample included 22 female Sprague-Dawley rats, divided into two groups: one received a single dose of psilocybin, and the other was given a saline placebo.

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The experiment centered on a reversal learning task, designed to measure the rats’ ability to adapt to changing reward contingencies. Each rat’s home cage was equipped with a device offering two nose-poke ports. Poking the correct port resulted in a reward (a sucrose pellet), while poking the incorrect port did not.

After 10 consecutive correct responses, the reward shifted to the opposite port, requiring the rats to adjust their behavior. The task was conducted for three hours daily over 14 consecutive days, allowing the rats to engage or remain inactive as they chose. The setup ensured that motivation and engagement could be assessed independently of other factors, such as hunger, since the rats had free access to standard food.

To better understand the cognitive processes underlying the rats’ behavior, the researchers applied computational models, including reinforcement learning and active inference models. These models evaluated decision-making parameters, such as optimism bias (how strongly the rats updated their beliefs after rewards versus losses) and loss aversion (the degree to which the rats avoided losses compared to seeking rewards).

The researchers found notable differences between the psilocybin-treated rats and the control group in both their behavior and underlying decision-making processes. Rats that received psilocybin displayed increased engagement with the reversal learning task, choosing to participate more frequently than the control group. This heightened engagement led to more rewards for the psilocybin group over time, particularly during the second week of testing. Despite engaging more, the psilocybin-treated rats also experienced more losses, suggesting they were less deterred by potential negative outcomes.

The computational modeling revealed two primary mechanisms driving this behavior. First, psilocybin-treated rats exhibited a stronger optimism bias, meaning they updated their expectations more after receiving rewards than after experiencing losses. This bias likely made the rats more inclined to anticipate positive outcomes, encouraging them to persist in the task. Second, psilocybin reduced the rats’ loss aversion, making them less sensitive to the negative impact of losses. This reduction in loss aversion helped sustain their motivation to engage with the task, even when they encountered setbacks.

“Our work found that psilocybin increased optimism over time in rats, which led to them engaging more with their environment,” Fisher told PsyPost. “Engaging with the world more can help people with depression who may be withdrawn.”

Interestingly, these effects became more pronounced over time. By the second week of testing, the psilocybin-treated rats consistently outperformed the control group in terms of task engagement and reward acquisition. This gradual increase in engagement aligns with previous research suggesting that psilocybin’s effects on brain plasticity and behavior may peak days or weeks after administration.

Importantly, the observed changes in engagement were not accompanied by increased general activity levels or reduced anxiety-like behaviors, indicating that the effects were specific to decision-making processes related to optimism and reward.

Although promising, the study has limitations. First, it was conducted in rats, and while animal models offer valuable insights, the findings may not directly translate to humans. Human decision-making is influenced by more complex factors, such as emotions and social contexts, which are difficult to replicate in animal studies.

“We would love to start translating this study to a human study! We would need to make adjustments to the time points and methods of collecting data after treatment, but this is all possible,” Fisher said. “Our work found that psilocybin increased optimism, but we are also working on other interventions that can increase optimism as well. The dream is to find a range of treatments that can help treat depression by increasing optimism and engagement with the world.”

The study, “Psilocybin increases optimistic engagement over time: computational modelling of behaviour in rats,” was authored by Elizabeth L. Fisher, Ryan Smith, Kyna Conn, Andrew W. Corcoran, Laura K. Milton, Jakob Hohwy, and Claire J. Foldi.