7458 Eight Weeks Intranasal Oxytocin vs. Placebo Does Not Impact Circulating Oxytocin or Arginine-Vasopressin Levels in Adults With Obesity

Abstract Disclosure: A. Aulinas: None. F. Galbiati: None. M. Wronski: None. C.S. Carter: None. J. Davis: None. H.P. Nazarloo: None. K. Holman: None. G. Julia: None. E. Asanza: None. S.E. Smith: None. L. Kerem: None. F. Plessow: None. E.A. Lawson: Research Investigator; Self; received research funding and study drug from Tonix Pharmaceuticals. Background: Oxytocin (OXT)–based therapeutics, most commonly intranasal (IN) OXT, are under investigation for treating disorders ranging from obesity to osteopenia/osteoporosis, anxiety, and depression. OXT and arginine vasopressin (AVP) are structurally similar hypothalamic-pituitary “sister” peptides with physiologic actions that are shared (e.g. both suppress food intake) and opposing (e.g., OXT is anabolic while AVP is catabolic to bone; OXT reduces and AVP increases anxiety and depressive symptoms). However, the effect of chronic IN OXT administration on endogenous release of OXT and AVP into the circulation, where they can have peripheral and (through the vagus nerve) central actions, is not well established. Preclinical and short-term human studies (mostly single-dose IN OXT) suggest that exogenous OXT increases circulating OXT levels, and limited data on OXT effects on AVP levels report mixed results. Determining the effect of chronic IN OXT administration on endogenous levels of OXT and AVP is important to improve our understanding of underlying mechanisms and potential adverse effects. Leveraging a clinical trial of 8 weeks IN OXT vs. placebo in adults with obesity, we hypothesized that IN OXT would increase endogenous OXT and AVP levels. Since relative levels of OXT and AVP may impact balance of the OXT-AVP system, we also explored effects of IN OXT on the OXT:AVP ratio. Methods: We performed a randomized, double-blind, placebo-controlled trial of 8 weeks IN OXT (24 IU) 4x/day in 61 adults with obesity (stratified by sex and obesity class). Fasting plasma OXT and AVP levels were drawn prior to the morning dose of IN OXT at baseline, and weeks 4, 6, and 8. Fifty-eight participants (53% female, mean age±SD 33.6±5.8 years, body mass index 36.8±4.9 kg/m2) had plasma AVP and/or OXT measurements available at two or more timepoints and were included in our analyses. All endpoints were analyzed with linear mixed effect models including factors Time, Treatment and the interaction term Time*Treatment, controlled for biological sex and obesity class. Results: IN OXT did not impact levels of plasma OXT (coefficient, 0.45 pg/mL; 95% CI, -7.05 to 7.96), AVP (coefficient 0.59 pg/mL; 95% CI -2.81 to 4.01), or the OXT:AVP ratio (coefficient, 0.10; 95% CI, -0.17 to 0.38). Conclusions: Our data suggest that endogenous OXT and AVP levels are not impacted by 8 weeks IN OXT 4x/day, consistent with reassuring safety and tolerability data reported in clinical trials of chronic IN OXT. Effects of IN OXT are likely not mediated by changes in endogenous circulating OXT or AVP levels. Since OXT has a short half-life, it is possible that transient effects on endogenous OXT and AVP production could occur. To determine this, future studies could measure OXT and VP levels with chronic use of IN OXT closer to drug administration.Trial registration number: NCT03043053 Presentation: 6/2/2024