Psilocybin alters how rats balance risks and rewards, researchers find

New research published in Neurobiology of Learning and Memory sheds light on how psilocybin, a compound found in certain psychedelic mushrooms, affects behaviors involving the balance of reward and punishment. Conducted on male and female rats, researchers at Oregon Health & Science University found that psilocybin influenced how these animals learned and responded to situations involving potential risks.

Psilocybin is a naturally occurring psychedelic compound found in certain types of mushrooms. Once ingested, it is converted in the body into psilocin, which interacts with the brain by activating serotonin-2A receptors. These receptors play a key role in regulating mood, cognition, and perception.

Over the past decade, psilocybin has gained significant attention for its potential as a treatment for mental health conditions like depression and anxiety, particularly in cases where traditional therapies have been ineffective. Clinical studies have shown that even a single dose of psilocybin can lead to rapid and lasting improvements in mood, making it a promising option for conditions that are notoriously difficult to treat.

Despite its therapeutic potential, much about how psilocybin works remains unclear. Most research to date has focused on its effects in reducing fear and anxiety or enhancing emotional processing. However, real-life decision-making often involves balancing rewards and risks. For instance, individuals might need to decide whether pursuing a goal is worth the potential negative consequences—a process often disrupted in mental health disorders.

People with anxiety might avoid potentially rewarding situations out of fear, while those with addictive behaviors might take excessive risks despite knowing the possible harm. Understanding how psilocybin influences this type of conflict between reward and punishment is essential for uncovering its broader therapeutic mechanisms.

To better understand how psilocybin affects the learning and execution of behaviors that involve weighing risks against rewards, the researchers conducted a controlled experimental model with rats. Fifty-five adult Long-Evans rats, both male and female, were trained to perform tasks in specially designed operant chambers. These chambers included two illuminated “nose-poke” stations and a food dispenser.

Rats were tasked with earning food rewards (sucrose pellets) by completing a sequence of two actions: a “seek” action followed by a “take” action. The “seek” action carried a risk of a mild footshock, while the “take” action was always safe and resulted in a reward.

The study was divided into two phases. In the first phase, researchers investigated the effects of psilocybin during the initial learning of risk-punishment associations. Rats were randomly assigned to receive either psilocybin or a saline solution (control) before starting their tasks. The second phase examined the effects of psilocybin after the rats had already learned the associations. In this phase, rats were again given psilocybin or, for comparison, another psychedelic compound called ±DOI. Researchers measured several outcomes, including how many tasks the rats completed (indicating their willingness to take risks), how long they hesitated before acting, and whether these behaviors changed under varying levels of risk.

During the learning phase, psilocybin produced different effects depending on the rats’ sex. Female rats treated with psilocybin were more cautious, showing greater suppression of the risky “seek” action compared to males and saline-treated females. This heightened sensitivity to punishment persisted even when the task was safe, suggesting that psilocybin may have enhanced the females’ ability to associate risk with specific actions. In contrast, males treated with psilocybin displayed behaviors similar to the control group during this phase.

After the learning phase, the effects of psilocybin shifted. When given psilocybin after the rats had already learned the task, both males and females became less inhibited, completing more tasks despite the risk of punishment. This reduction in cautious behavior was not observed in rats treated with ±DOI, indicating that the effects might be specific to psilocybin.

Interestingly, the decrease in cautiousness did not appear to be due to reduced sensitivity to the footshocks, as psilocybin did not significantly alter the threshold at which the rats reacted to shocks. Instead, it appeared to change their willingness to act despite the risks.

In addition to task performance, researchers conducted supplementary tests to evaluate whether psilocybin affected the rats’ sensitivity to footshocks or their natural tendency to explore risky situations using an elevated plus maze. This maze included two open arms (perceived as riskier by rats) and two enclosed arms (perceived as safer). Time spent in the open arms was used as a measure of the rats’ willingness to engage in risky exploration.

In the elevated plus maze, psilocybin-treated rats spent less time in the open arms compared to controls, indicating an increase in cautious behavior in a novel, risky environment. However, this effect was accompanied by reduced overall movement, suggesting that the observed behavior might also reflect a general reduction in exploratory activity.

These findings suggest that psilocybin’s effects on behavior are dynamic and context-dependent. By increasing caution during the learning phase and reducing it afterward, psilocybin may help individuals adapt to challenging situations more flexibly. This dual role could have implications for its therapeutic use, particularly in conditions like anxiety, where individuals often overestimate risks, or in depression, where risk-taking may be impaired.

Future studies could explore the long-term effects of psilocybin on behavior and its potential to reshape learned associations over time. Understanding how psilocybin interacts with other factors, such as stress or environmental cues, could also provide deeper insights into its therapeutic potential.

The study, “Effects of psilocybin on uncertain punishment learning,” was authored by David S. Jacobs, Alina P. Bogachuk, Chloé L. Le Moing, and Bita Moghaddam.