Negative behavioral effects of psilocybin persist in mouse mothers and offspring

Magic mushrooms may not be the answer to postpartum depression, new research from the University of California, Davis suggests. 

In a first-of-its-kind study appearing in Nature Communications, an interdisciplinary team from the university's Institute for Psychedelics and Neurotherapeutics (IPN) dosed mouse mothers with psilocybin and found that the drug amplified anxiety and depressive-like symptoms associated with perinatal mood disorders - mental health conditions that can arise during or after pregnancy.

While psilocybin and its ability to promote neuronal growth have been previously shown to benefit those with mental health conditions, the new research indicates that it's not a one-size-fits-all therapy.

The IPN has done a lot of work demonstrating that a single dose of a psychedelic can lead to long-lasting, beneficial effects. But it's a little more nuanced than that in terms of who can really benefit and who might be at risk. There are different patient populations." 

David E. Olson, study co-author, director of the IPN and professor of chemistry, biochemistry and molecular medicine at UC Davis

With mental illness being the leading cause of pregnancy-related deaths in the United States, the research lays a critical foundation in the search for a viable therapeutic.

"There is an urgent need for treatments in the postpartum period," said study co-author and IPN affiliate Danielle Stolzenberg, an associate professor of psychology at UC Davis. "I think most importantly what we've learned is that the effects of psychedelics can differ based on the ovarian hormone context and that is a critically important finding." 

Not only were psylocibin's negative impacts long-lasting in mouse mothers (persisting for two weeks after a single dose), but the researchers also found that offspring raised by psylocibin-treated mothers also exhibited anxiety and depression-like symptoms long into adulthood. 

The finding suggests that the mothers passed on those negative effects via lactation, permanently stunting the offspring's neurodevelopment. 

A one-of-a-kind mouse model for postpartum depression

The study was built around Stolzenberg's innovative mouse model of postpartum depression.

In the model, mouse mothers live with their offspring in a two-cage system that allows them to escape from the demands of motherhood. Stolzenberg found that repeated exposure to a social threat (a male mouse) destabilizes maternal behavior, leading to infant avoidance and triggering other stress responses. These symptoms are hallmarks of postpartum depression in humans. 

"One of the things that's discussed consistently in the clinical literature is that moms often feel like they have trouble bonding with their infants when they're experiencing depressive symptoms," Stolzenberg said. "The mouse moms in the social stress paradigm spend significantly more time in the cage without the pups. They will often run back and forth to check on them but tend to actively avoid their infants for long periods of time." 

The team initially thought the treatment might help alleviate postpartum depression symptoms. 

"Psilocybin was of such interest for us because it's been demonstrated to be useful across a whole host of mental disorders, including addressing anxiety and depression," said study first-author Cassandra Hatzipantelis, a postdoctoral fellow at the IPN. "We thought it could have the ability to address things that go wrong in postpartum depression like parent-infant connection." 

Instead, psilocybin induced the opposite effect, having both negative behavioral impacts on mothers and their offspring. Mouse mothers continued avoiding their offspring and displaying anxiety and depressive-like symptoms. These symptoms persisted after mice were separated from their offspring. 

"Two weeks after a single dose of psylocibin, the mothers were dramatically impaired," Hatzipantelis said. "We were shocked." 

Psilocybin-treated mice, the researchers found, were at higher risk for behavioral impairments and depressive-like symptoms. 

"I was very surprised that we saw the moms getting worse," Olson said. 

Virgin female mice did not show such effects. The findings indicate that there may be distinct neurochemical differences in the brains of mouse mothers that led to psilocybin producing adverse effects. 

"We know that ovarian hormones regulate serotonergic signaling, but we understand very little about the interaction between ovarian hormones and drugs that impact serotonin," said Stolzenberg, noting that the latter is critical to how psychedelics affect the brain.

Passing on negative effects to offspring

The team also found that behavioral effects were passed to the offspring. Nine weeks after weaning, both male and female offspring exhibited pronounced measures of anxiety and depression compared to the control groups. Their brains also showcased traces of psilocin - a metabolite of psilocybin. 

"We now know that even low doses of exposure can impact offspring for long periods of time," Stolzenberg said. 

The study highlights the IPN's commitment to studying both the positive and negative effects of psychedelics. 

"These could be really important therapeutics, but we also realize they have limitations, and we have to conduct rigorous science to understand what those limitations are," Olson said. 

Since its launch in 2023, the IPN has attracted nearly 80 UC Davis faculty affiliates spanning diverse fields from anthropology and chemistry to neuropharmacology and genomics. 

"UC Davis has incredible experts across a breadth of fields and in specialized domains," Olson said. "That's why we can do this type of high impact, interdisciplinary science. It's really the people."

Additional study authors include Min Liu, Adam Love, Sadie J. Leventhal, Hero Maera, Srinidhi Viswanathan, Emily Avetisyan, Liana Belinsky, McKenna M. Rangel, Nina J. Jain, Max Kelly, Claire Copeland, Yara A. Khatib and Oliver Fiehn.^.

The research reported here was supported by funding from the National Institutes of Health (R01HD087709, R35GM148182), the W. M. Keck Foundation, the University of California at Davis Pilot Project Program Award from the Perinatal Origins of Disparities Center, and the University of California at Davis Academic Senate Large Grant Award.