A Pilot Randomized Clinical Trial of Intranasal Oxytocin to Promote Weight Loss in Individuals With Hypothalamic Obesity

**Background:** Hypothalamic obesity is a rare, treatment-resistant form of obesity that develops after damage to the hypothalamus from tumors such as craniopharyngioma. Affected individuals have low resting energy expenditure and uncontrolled appetite, leading to excess mortality from obesity-related comorbidities. No therapies are specifically approved for this condition. The hypothalamic neuropeptide oxytocin (OXT) regulates appetite and energy balance, and OXT deficiency is plausible in patients with hypothalamic/pituitary tumors. Preliminary studies suggested OXT could promote weight loss, including a case report of sustained BMI reduction in a 13-year-old with craniopharyngioma and a small study showing 9% body weight loss in adults with common obesity after 8 weeks of intranasal OXT.

**Methods:** This was a randomized, double-blind, placebo-controlled, crossover pilot trial conducted at an outpatient academic medical center (Children's Hospital of Philadelphia). Eligible participants were aged 10–35 years with obesity (BMI ≥85th percentile for age/sex or BMI ≥25 kg/m²) after treatment for a hypothalamic/pituitary brain tumor, with at least one hypothalamic/pituitary hormone disorder and excess weight gain associated with tumor diagnosis/treatment. Exclusion criteria included QTc interval >460 msec, use of QTc-prolonging medications, and insulin/insulin secretagogue use. Participants received intranasal OXT (Syntocinon, 40 USP units/mL, 4 IU/spray) or excipient-matched placebo, 16–24 IU three times daily at mealtimes, in two 8-week treatment blocks separated by a 4-week washout. Dosing was weight-based: 20 IU (escalating to 24 IU) three times daily for those ≥70 kg, and 16 IU (escalating to 20 IU) for those 50–<70 kg. The primary outcome was within-subject difference in body weight change attributable to OXT vs placebo. Secondary outcomes included BMI, waist circumference, and safety. Exploratory outcomes included test meal energy intake, hyperphagia questionnaire scores, Eating Inventory subscales, Stop-Signal Task performance, physical activity, and Neuro-QOL measures. Linear mixed-effects regression was used for analysis, accounting for baseline weight and treatment order.

**Key Results:** Of 18 individuals screened, 13 were randomized (54% female, median age 15.3 years, IQR 13.3–20.6), and 10 completed the entire study. Etiology included craniopharyngioma (n=9), germinoma (n=2), optic glioma (n=1), and pilocytic astrocytoma (n=1). Median time since diagnosis was 7.5 years (IQR 4.3–8.7). The primary analysis showed a nonsignificant within-subject weight change of −0.6 kg (95% CI: −2.7, 1.5) attributable to OXT vs placebo. No significant effects were found for BMI (β = −0.2 kg/m²; 95% CI: −1.1, 0.7), BMI Z-score (β = 0.02; 95% CI: −0.03, 0.06), or waist circumference (β = 0.6 cm; 95% CI: −1.9, 3.1). Sensitivity analyses adjusting for age, sex, and adherence did not change results. OXT was well-tolerated with no adverse events higher than Grade 2. Common side effects included epistaxis (23% OXT vs 15% placebo), nasal congestion/irritation (31% vs 0%), headache (23% vs 31%), and nausea/vomiting (8% vs 23%). Notably, 5 of 13 randomized participants had prolonged QTc interval (>450 msec) on ECG, and 2 were withdrawn due to QTc prolongation. In exploratory analyses, OXT was associated with improved response inhibition on the Stop-Signal Task (43 msec shorter stop-signal reaction time; 95% CI: 1–85; P < .01) and a reduction in anxiety T-score of 3.7 points (95% CI: 0.8–6.6). No significant effects were detected on eating behaviors, hyperphagia, or test meal energy intake.

**Clinical Implications:** This pilot study did not find a significant effect of 8 weeks of intranasal OXT on body weight in individuals with hypothalamic obesity, though the 95% CI (−2.7 to 1.5 kg) does not exclude a clinically meaningful effect that might be detectable in a larger trial. The high prevalence of prolonged QTc interval (38% of randomized participants) highlights a potentially under-recognized cardiac comorbidity in this population that warrants screening. The exploratory findings of reduced anxiety and improved impulse control suggest OXT may have psychosocial benefits that could indirectly support weight management efforts. Future studies should consider different dosing strategies, longer treatment duration, combination therapies, and enrichment for patients with significant hyperphagia. The crossover design proved valuable for studying this rare condition, and larger adaptive trials are needed to identify predictors of OXT response.