164. PSILOCYBIN DURING THE POSTPARTUM PERIOD INDUCES LONG-LASTING ADVERSE EFFECTS IN BOTH MOTHERS AND OFFSPRING

Abstract Background Peripartum mood disorders (PMDs) are a major public health concern; they present in 20% of birthing parents and are responsible for 1 in 4 maternal deaths in the United States. The psychedelic antidepressant psilocybin (PSI) increases social connectedness, self-compassion, and has strong clinical transdiagnostic efficacy for mental illness – making it a candidate treatment to reduce maternal disconnect, personal shame, and blunted affect seen in peripartum mood disorders (PMDs). Despite phase 2 clinical trials actively recruiting postpartum parents to determine if a novel PSI analogue could address peripartum mood disorders [NCT06342310], to date there remains no clinical nor preclinical data describing the safety of psychedelic use during the postpartum period. Aims & Objectives We aimed to examine the efficacy of psilocybin in a preclinical mouse model of PMD. We further assessed the long-term behavioral consequences of PSI exposure on parous mice and their offspring. Method Our group recently developed a model in C57BL6/J mice that examines social stress and limited resources as factors that interfere with mother-infant infant bonding in the early postpartum period. In this model, limited bedding and repeated exposure to an infanticidal male mouse destabilizes maternal care and triggers prolonged stress-related behaviors that remain even in the absence of a social threat. Using this paradigm, we investigated the effects of a single PSI dose on maternal care behaviors, as well as long-term anxiety- and depressive-like behaviors in a standardized behavioral battery after offspring were weaned two weeks later (N=11-16 mice/group). This was compared to the behaviors of virgin female mice two weeks after a single dose of PSI (N=10 mice/group). Finally, we examined the long-term behavioral consequences of adult male and female mice reared by dams exposed to maternal stress and/or PSI using a standardized test battery of social, emotional and cognitive behaviors (N=7-14 mice/sex/group). Results PMD model-exposed mice displayed dramatically impaired caregiving behavior, maternal withdrawal and avoidance from pups, and increased anxiety-like behaviors – none of which were ameliorated by PSI treatment. In fact, two weeks following injection, PSI-treated dams were more anxious and had increased risk of overall behavioral impairments. This was specific to the postpartum period as, by stark contrast, virgin female mice treated with a single dose of PSI exhibited an anxiolytic phenotype and decreased risk of overall behavioral impairments – consistent with previous descriptions of PSI in the literature. Furthermore, just a single postnatal exposure to PSI through breastmilk increased the risk of behavioral phenotypes related to mood and sociability disorders in both male and female mice when aged to adulthood. Discussion & Conclusions Altogether, these data suggest that while PSI has been consistently shown to be safe and effective for treating depression in the general human patient population, as well as in preclinical models of mental health disorders, the same may not be true for exposure during the postpartum period. PSI may pose a major risk for both parous mums and their offspring, and as such, these data highlight the importance of including lactating females and their offspring in preclinical efficacy and safety testing of drugs aimed to be delivered postpartum.