Estrogen levels may dictate how the brain reacts to psychedelics, new animal study indicates

Psilocybin induces different behavioral responses in rats depending on their age and female reproductive cycles. Treating young rats with the drug, however, does not alter their behavior later in life. These outcomes indicate that psychedelic therapies may need to be customized for different patient demographics to ensure they work safely and effectively. The findings were published in the journal Neuropharmacology.

Rates of mood disorders and anxiety disorders continue to rise globally. Standard medications, like selective serotonin reuptake inhibitors, act as the most common first line of defense for these health issues. These daily medications can take weeks or even months to provide noticeable relief. They also fail to alleviate symptoms for a large portion of the people taking them, pushing medical researchers to investigate psychedelic drugs as alternative treatments.

Clinical trials suggest psilocybin might act faster, require fewer doses, and offer longer lasting relief than standard antidepressants. When a person or animal consumes psilocybin, the body rapidly breaks it down into a chemical called psilocin, which enters the brain and attaches to specific docking stations on brain cells called serotonin receptors. Activating these receptors alters consciousness, mood, and perception while promoting neuroplasticity, which is the brain’s physical ability to form new cell connections and rewire old pathways.

Historically, most studies exploring these potential therapies rely almost entirely on adult male test subjects. This blind spot exists even though major depressive episodes are notably more common in women than in men. These psychiatric conditions also frequently emerge during human adolescence, and the teenage years represent a unique period of massive brain development.

During this developmental window, brains undergo a restructuring process where massive numbers of connections between neurons are formed and then intentionally pruned away. Serotonin systems play a massive role in guiding this physical restructuring. Introducing a potent drug that alters serotonin signaling could theoretically disrupt a typical growth trajectory. A.L. Zylko, Matthew S. McMurray, and their colleagues at Miami University designed a study to evaluate these overlooked areas in psychedelic medicine.

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The research team observed how rats of different ages reacted to a single dose of psilocybin. The specific psilocybin used in the study was synthesized in a laboratory using bioengineered bacteria. They gave adolescent rats either a harmless water solution or the manufactured drug. They also administered the exact same substances to fully grown adult rats to provide a baseline for comparison.

After administering the substances through a feeding tube, the researchers placed each animal in a clear observation cage and recorded their behavior on video for half an hour. They watched for a rapid, side-to-side shaking movement of the head and body. This behavior, resembling a wet dog shaking off water, is a standard marker used to measure hallucination-like states in rodents. Activating the specific serotonin receptors targeted by psilocybin reliably triggers this distinct shaking motion.

The adult rats displayed a robust increase in this behavior within five minutes of receiving the substance. The adolescent rats, on the other hand, barely reacted at all. They did not show the typical rapid head movements associated with the drug. This outcome was consistent across testing days for both early adolescent and late adolescent test groups.

The researchers then let all the young rats grow to adulthood. They wanted to see if brief exposure to the drug during a sensitive developmental period would change their adult brains in noticeable ways. Once the rats reached maturity, the team ran the subjects through a series of behavioral testing paradigms.

One test placed the animals on an elevated zero maze to measure their anxiety. This apparatus is a raised, circular track featuring open sections without walls alongside enclosed, sheltered sections. Rats instinctively fear exposed heights, meaning animals spending more time exploring the open sections show lower anxiety levels. The team found that rats previously given the psychedelic explored the track exactly like the rats given only water.

Another assessment tested how well the rats could adapt to changing rules. This task measures behavioral flexibility, a cognitive trait often impaired in individuals suffering from severe depression. The researchers restricted the animals’ food intake, then taught the hungry rats to press specific levers inside a testing chamber to receive a sugar pellet. One lever provided a sweet reward most of the time, while the other rarely dispensed an item.

Once the rats learned to favor the reliable lever, the experimenters switched the rules, making the rare lever the highly rewarding one. The animals had to figure out that the environment had changed and alter their strategy. The rats exposed to psilocybin during their youth learned the new rules just as quickly as their unexposed peers.

Finally, the researchers gave these grown rats a fresh dose of the psychedelic. They recorded their behavior to see if early adolescent exposure permanently altered their brain’s sensitivity to the chemical. Again, the early exposure made no difference in their physical response. The matured rats reacted just like adults experiencing the drug for the exact first time.

While analyzing the adult test groups, the research team noticed a clear division between the sexes. Adult female rats exhibited the shaking motion much more frequently than the adult male rats. To understand this difference, the researchers launched a secondary study focusing entirely on the female reproductive cycle.

In female rodents, this process is called the estrous cycle, and it heavily influences the structure and chemistry of the mammalian brain. The cycle involves rising and falling levels of hormones like estrogen. The researchers tracked the cycles of adult female rats for two weeks to establish their individual biological rhythms. Then, they administered psilocybin during two distinct phases of the cycle.

They tested the rats during a phase characterized by relatively low estrogen levels, called diestrus. They also tested them during a phase with peak estrogen levels, known as proestrus. The results showed a clear fluctuation in drug sensitivity that tracked directly with the hormonal shifts. Females in the low-estrogen phase displayed a higher number of shaking responses compared to when they were in the high-estrogen phase.

The researchers note that hormonal changes may alter how serotonin receptors function inside the brain. Estrogen levels might change the exact location of these receptors, pulling them off the cell surface and hiding them inside the cells where the psychedelic chemicals cannot easily reach them. Estrogen might also alter the cellular chain reactions that usually happen immediately after the drug binds to the receptor.

The researchers outline several limitations to their experimental findings. The lack of shaking behavior in the younger rats does not guarantee that the youngsters experienced no effects from the drug at all. Adolescent rats might process the drug physically faster or express the neurological effects through entirely different physical movements than adults. Preliminary tests hinted that the overall baseline number of serotonin receptors does not change drastically between age groups, but the measurement methods used had technical limitations.

Discovering that early exposure does not cause long lasting behavioral harm is a positive result, but the researchers note that developing brains naturally possess high levels of plasticity. These naturally high levels might hide the subtle structural rewiring usually triggered by the drug in adult brains. Future research should test different dosages and examine alternative behavioral markers in developing animals.

Extensively monitoring how developmental age and hormonal cycles change receptor function allows laboratory work to map onto real world conditions. Understanding these specific biological parameters will help medical professionals optimize future psychiatric drug doses for a wider diversity of patients.

The study, “Age- and estrous-dependent effects of psilocybin in rats,” was authored by A.L. Zylko, R.J. Rakoczy, B.F. Roberts, M. Wilson, A. Powell, A. Page, M. Heitkamp, D. Feist, J.A. Jones, and M.S. McMurray.