Psilocybin has captured attention for its potential to ease depression and anxiety. But new findings from the University of California (UC), Davis, caution that psilocybin may not be a one-size-fits-all solution. In Nature Communications, researchers report that psilocybin heightened rather than relieved postpartum depression–like symptoms in mice, with negative effects persisting in both mothers and their offspring.
Psilocybin may not be the answer for postpartum depression, according to evidence from a study titled “Psilocybin during the postpartum period induces long-lasting adverse effects in both mothers and offspring,” where researchers discovered that this substance amplified anxiety and depressive-like behaviors in mouse mothers subjected to a validated model of postpartum stress. “The IPN has done a lot of work demonstrating that a single dose of a psychedelic can lead to long-lasting, beneficial effects,” said senior author David E. Olson, PhD, director of UC Davis’ Institute for Psychedelics and Neurotherapeutics (IPN). “But it’s a little more nuanced than that in terms of who can really benefit and who might be at risk.”
A closer look at the model
The team used an innovative “two-cage” mouse system developed by co-author Danielle Stolzenberg, PhD, that “enables quantification of active maternal avoidance, which is a hallmark of postpartum depression. Repeated exposure to a social threat experience destabilizes maternal behavior, induces pup avoidance, and triggers prolonged stress-related behaviors,” the authors wrote. As expected, stressed dams withdrew from their offspring, but psilocybin failed to reverse those behaviors. Instead, the psychedelic worsened maternal avoidance, reduced pup grooming, and increased stress-related behaviors.
Virgin female mice, by contrast, did not show these impairments—suggesting that reproductive status and ovarian hormone shifts may alter the brain’s response to psilocybin. With peripartum mental illness responsible for one in four maternal deaths in the United States, the authors wrote, there is an urgent need for treatments in the postpartum period, said Stolzenberg, adding: “I think most importantly what we’ve learned is that the effects of psychedelics can differ based on the ovarian hormone context.”
Analyses revealed reduced serotonin receptor activity in postpartum dams, blunting psilocybin’s expected therapeutic effects and instead driving adverse outcomes. “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. The findings highlight how rapidly shifting hormones after childbirth may create a unique neurochemical landscape.
The authors wrote, “Given that ovarian hormones directly regulate serotonergic systems, the dramatic rise and fall of estrogens and progestins substantially alters the physiological landscape, including the pharmacokinetics and/or pharmacodynamics of drugs that impact serotonin signaling.”
Lasting impact on offspring
Perhaps most striking were the intergenerational effects. Offspring of psilocybin-treated mothers displayed higher levels of anxiety and depression-like behaviors long after weaning. Their brains contained psilocin, psilocybin’s active metabolite, indicating that exposure had been passed through breastmilk.
“We now know that even low doses of exposure can impact offspring for long periods of time,” Stolzenberg noted.
Implications and next steps
A trial testing a psilocybin analog for postpartum depression is already underway (NCT06342310). However, most safety data come from male participants, leaving a critical gap.
“These could be really important therapeutics, but we also realize they have limitations,” Olson said. “We have to conduct rigorous science to understand what those limitations are.”
The authors acknowledge that mouse models cannot capture the full complexity of human psychedelic experiences and that effects in breastfeeding mothers might be mitigated by carefully timed dosing or avoiding lactation. Still, the work underscores the need for tailored approaches rather than assuming psychedelics are universally beneficial.