Psilocybin induces different behavioral responses depending on the age of the rat and the reproductive cycle of the female. However, treating young rats with this drug does not change their behavior later in life. These results indicate that psychedelic therapies may need to be customized for different patient populations to work safely and effectively. The research results were published in a magazine neuropharmacology.
Rates of mood and anxiety disorders continue to increase worldwide. Standard medications such as selective serotonin reuptake inhibitors serve as the most common first line of defense against these health problems. These daily medications can take weeks or even months to provide noticeable symptom relief. Additionally, psychedelic drugs do not alleviate the symptoms of most people who take them, forcing medical researchers to explore psychedelic drugs as alternative treatments.
Clinical trials suggest that psilocybin works faster than standard antidepressants, requires lower doses, and may provide long-lasting symptom relief. When a person or animal ingests psilocybin, the body rapidly breaks it down into a chemical called psilocin, which enters the brain and binds to specific docking stations on brain cells called serotonin receptors. Activating these receptors changes consciousness, mood, and perception and promotes neuroplasticity. Neuroplasticity is the brain’s physical ability to form new cell connections and rewire old pathways.
Historically, most studies exploring these potential treatments have relied almost entirely on adult male subjects. This blind spot exists even though major depressive episodes are significantly more common in women than in men. These mental illnesses also frequently occur during human adolescence, and the teenage years represent a unique period of extensive brain development.
During this period of development, the brain undergoes a remodeling process in which vast numbers of connections between neurons are formed and then intentionally cut out. The serotonin system plays a major role in guiding this body remodeling. The introduction of potent drugs that alter serotonin signaling could theoretically disrupt typical growth trajectories. AL Zylko, Matthew S. McMurray, and their colleagues at the University of Miami designed a study to evaluate these overlooked areas in psychedelic medicine.
The research team looked at how rats of different ages responded to a single dose of psilocybin. The particular psilocybin used in this study was synthesized in the lab using bioengineered bacteria. They gave adolescent rats either a harmless aqueous solution or a manufactured drug. They also administered the exact same substance to fully grown adult rats to provide a baseline for comparison.
After administering the substance through a feeding tube, the researchers placed each animal in a transparent observation cage and videotaped its behavior for 30 minutes. They observed rapid side-to-side rocking movements of the head and body. This behavior is similar to a wet dog shaking off water and is a standard marker used to measure hallucination-like states in rodents. Activating the specific serotonin receptors that psilocybin targets reliably cause this unique trembling motion.
Adult rats showed a significant increase in this behavior within 5 minutes of being administered the substance. Adolescent rats, on the other hand, showed little response. They did not exhibit the typical rapid head movements associated with drugs. This result was consistent across test days for both early and late adolescent test groups.
The researchers then allowed all the young rats to grow to adulthood. They wanted to see whether short-term exposure to the drug during a sensitive developmental period would produce significant changes in the adult brain. Once the rats were mature, the research team put them through a series of behavioral testing paradigms.
In one test, animals were placed in an elevated zero maze and anxiety was measured. The device is a raised circular track featuring an open section without walls and an enclosed protected section. Mice instinctively fear exposed heights. This means that rats that spend more time exploring open areas have lower anxiety levels. The researchers found that rats given the psychedelic substance beforehand explored the footprints just as well as rats given only water.
Another evaluation tested how well rats could adapt to changes in rules. This task measures behavioral flexibility, a cognitive trait that is often impaired in individuals suffering from severe depression. The researchers restricted the animals’ food intake and then taught the hungry rats to press a specific lever in a test chamber to receive a sugar pellet. One lever almost always delivered a sweet reward, while the other rarely dispensed items.
Once the rats learned to prefer reliable levers, the experimenters changed the rules to make rare levers highly rewarding. The animals recognized that their environment had changed and had to change their strategies. Rats exposed to psilocybin at a young age learned new rules as quickly as unexposed rats.
Finally, the researchers gave these adult rats a new dose of the psychedelic. They recorded their behavior to see if exposure during early adolescence permanently altered the brain’s sensitivity to chemicals. Again, there was no difference in physical response with early exposure. Adult rats responded similarly to adults experiencing the drug for the first time.
While analyzing a test group of adults, the researchers noticed a clear distinction between men and women. Adult female rats exhibited trembling movements much more frequently than adult male rats. To understand this difference, researchers began a secondary study focused entirely on the female reproductive cycle.
In female rodents, this process is called the estrous cycle, and it has a major impact on the structure and chemistry of the mammalian brain. This cycle involves rising and falling levels of hormones such as estrogen. Researchers tracked the menstrual cycles of adult female rats for two weeks to establish their individual biological rhythms. Psilocybin was then administered at two different stages of the cycle.
They tested rats during a stage called estrus, which is characterized by relatively low estrogen levels. They also tested during the period when estrogen levels peak, known as proestrus. The results showed clear variations in drug sensitivity that directly tracked hormonal changes. Females in the low estrogen phase showed more tremor responses compared to the high estrogen phase.
Researchers note that hormonal changes can alter the function of serotonin receptors in the brain. Estrogen levels can change the precise location of these receptors, pulling them away from the cell surface and hiding psychedelic chemicals inside cells where they can’t be easily reached. Estrogens can also alter the cellular chain reactions that normally occur immediately after a drug binds to a receptor.
The researchers outline several limitations to their experimental results. The lack of tremor behavior in young rats does not guarantee that the young rats were completely unaffected by the drug. Adolescent rats may physically process drugs faster and may develop neurological effects through entirely different physical movements than adults. Preliminary testing suggested that the overall baseline number of serotonin receptors did not vary significantly between age groups, but there were technical limitations to the measurement method used.
While finding that early exposure does not cause long-term behavioral harm is a positive result, the researchers note that the developing brain naturally has high levels of plasticity. These naturally high levels may mask subtle structural rewiring typically caused by drugs in the adult brain. Future studies should test different doses and examine alternative behavioral markers in developing animals.
Extensive monitoring of how developmental age and hormonal cycles change receptor function allows us to map laboratory studies to real-world situations. Understanding these specific biological parameters will help medical professionals optimize future psychiatric drug dosing for a more diverse set of patients.
The study, “Age- and oestrus-dependent effects of psilocybin in rats,” was authored by AL Zylko, RJ Rakoczy, BF Roberts, M. Wilson, A. Powell, A. Page, M. Heitkamp, D. Feist, JA Jones, and MS McMurray.
