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Background: Accumulating preclinical and preliminary translational evidence shows that the hypothalamic peptide oxytocin reduces food intake, increases energy expenditure, and promotes weight loss. It is currently unknown whether oxytocin administration is effective in treating human obesity., Methods: In this randomized, double-blind, placebo-controlled trial, we randomly assigned adults with obesity 1:1 (stratified by sex and obesity class) to receive intranasal oxytocin (24 IU) or placebo four times daily for 8 weeks. The primary end point was change in body weight (kg) from baseline to week 8. Key secondary end points included change in body composition (total fat mass [g], abdominal visceral adipose tissue [cm 2 ], and liver fat fraction [proportion; range, 0 to 1; higher values indicate a higher proportion of fat]), and resting energy expenditure (kcal/day; adjusted for lean mass) from baseline to week 8 and caloric intake (kcal) at an experimental test meal from baseline to week 6., Results: Sixty-one participants (54% women; mean age ± standard deviation, 33.6 ± 6.2 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 36.9 ± 4.9) were randomly assigned. There was no difference in body weight change from baseline to week 8 between oxytocin and placebo groups (0.20 vs. 0.26 kg; P=0.934). Oxytocin (vs. placebo) was not associated with beneficial effects on body composition or resting energy expenditure from baseline to week 8 (total fat: difference [95% confidence interval], 196.0 g [-1036 to 1428]; visceral fat: 3.1 cm 2 [-11.0 to 17.2]; liver fat: -0.01 [-0.03 to 0.01]; resting energy expenditure: -64.0 kcal/day [-129.3 to 1.4]). Oxytocin compared with placebo was associated with reduced caloric intake at the test meal (-31.4 vs. 120.6 kcal; difference [95% confidence interval], -152.0 kcal [-302.3 to -1.7]). There were no serious adverse events. Incidence and severity of adverse events did not differ between groups., Conclusions: In this randomized, placebo-controlled trial in adults with obesity, intranasal oxytocin administered four times daily for 8 weeks did not reduce body weight. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT03043053.).

Background: Obesity affects more than one-third of adults in the U.S., and effective treatment options are urgently needed. Oxytocin administration induces weight loss in animal models of obesity via effects on caloric intake, energy expenditure, and fat metabolism. We study intranasal oxytocin, an investigational drug shown to reduce caloric intake in humans, as a potential novel treatment for obesity., Methods: We report the rationale, design, methods, and biostatistical analysis plan of a randomized, double-blind, placebo-controlled clinical trial of intranasal oxytocin for weight loss (primary endpoint) in adults with obesity. Participants (aged 18-45 years) were randomly allocated (1:1) to oxytocin (four times daily over eight weeks) versus placebo. Randomization was stratified by biological sex and BMI (30 to <35, 35 to <40, ≥40 kg/m 2 ). We investigate the efficacy, safety, and mechanisms of oxytocin administration in reducing body weight. Secondary endpoints include changes in resting energy expenditure, body composition, caloric intake, metabolic profile, and brain activation via functional magnetic resonance imaging in response to food images and during an impulse control task. Safety and tolerability (e.g., review of adverse events, vital signs, electrocardiogram, comprehensive metabolic panel) are assessed throughout the study and six weeks after treatment completion., Results: Sixty-one male and female participants aged 18-45 years were randomized (mean age 34 years, mean BMI 37 kg/m 2 ). The study sample is diverse with 38% identifying as non-White and 20% Hispanic., Conclusion: Investigating intranasal oxytocin's efficacy, safety, and mechanisms as an anti-obesity medication will advance the search for optimal treatment strategies for obesity and its associated severe sequelae., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: E.A.L. served on the scientific advisory board and has a financial interest in OXT Therapeutics, Inc. E.A.L. also received funding for an investigator-initiated study by Tonix Pharmaceuticals. All other authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Context: In healthy females, oxytocin levels decrease postmeal, corresponding to increased satiety. The postprandial response of oxytocin in females with anorexia nervosa (AN)/atypical AN is unknown., Objectives: To determine the pattern of postprandial serum oxytocin levels in females with AN/atypical AN, relationship with appetite, and effect of weight, eating behavior, and endogenous estrogen status., Design: Cross-sectional., Setting: Clinical research center., Participants: 67 women (36 with AN [<85% expected body weight (EBW)]; 31 with atypical AN [≥ 85% EBW)]), age 22.4 ± 0.9 (mean ± SEM) years, categorized by weight, restricting vs binge/purge behavior, and estrogen status., Interventions: Standardized mixed meal., Main Outcome Measurements: Blood sampling for oxytocin occurred fasting and 30, 60, and 120 minutes postmeal. Subjective appetite was assessed using visual analog scales., Results: In females with AN/atypical AN, oxytocin levels decreased from fasting to 60 (P = 0.002) and 120 (P = 0.005) minutes postmeal. The decrease in oxytocin from fasting to 120 minutes was greater in females with atypical AN than AN (P = 0.027) and did not differ by restricting vs binge/purge behavior or estrogen status. Controlling for caloric intake, the decrease in oxytocin was inversely related to the decrease in hunger postmeal in females with atypical AN (P = 0.04)., Conclusions: In females with AN/atypical AN, oxytocin levels decrease postmeal, as established in healthy females. Weight, but not restricting vs binge/purging nor endogenous estrogen status, affects postprandial oxytocin levels. The postprandial change in serum oxytocin levels is related to appetite in females with atypical AN only, suggesting a disconnect between oxytocin secretion and appetite in the undernourished state., (Copyright © 2019 Endocrine Society.)

Context: Oxytocin regulates a range of physiological processes including eating behavior and oxytocin administration reduces caloric intake in males. There are few data on oxytocin and eating behavior in healthy females or on the response of endogenous oxytocin to food intake and its relationship to appetite in humans., Objectives: To determine the postprandial pattern of oxytocin levels, the relationship between oxytocin and appetite, and the impact of menstrual cycle phase and age on oxytocin levels in females., Design: Cross-sectional., Setting: Clinical research center., Participants: Fifty-five healthy females (age 10 to 45 years)., Interventions: A standardized mixed meal was administered., Main Outcome Measurements: Blood sampling for oxytocin occurred at fasting and at 30, 60, and 120 minutes postmeal. Appetite was assessed using Visual Analogue Scales pre- and postmeal., Results: Mean fasting oxytocin levels were 1011.2 ± 52.3 pg/mL (SEM) and decreased at 30 and 60 minutes postmeal (P = 0.001 and P = 0.003, respectively). Mean oxytocin levels decreased19.6% ± 3.0% from baseline to nadir. Oxytocin area under the curve was lower in the early to midfollicular menstrual cycle phase (P = 0.0003) and higher in younger females (P = 0.002). The percent change in oxytocin (baseline to nadir) was associated with postprandial hunger (rs = -0.291, P = 0.03) and fullness (rs = 0.345, P = 0.009). These relations remained significant after controlling for calories consumed, menstrual cycle status, and age (P = 0.023 and P = 0.0001, respectively)., Conclusions: Peripheral oxytocin levels in females decrease after a mixed meal and are associated with appetite independent of menstrual phase, age, and caloric intake, suggesting that endogenous oxytocin levels may play a role in perceived hunger and satiety., (Copyright © 2019 Endocrine Society.)

Purpose of Review: The neurohormone oxytocin (OXT) impacts food intake as well as cognitive, emotional, and social functioning-all of which are central to eating disorder (ED) pathology across the weight spectrum. Here, we review findings on endogenous OXT levels and their relationship to ED pathology, the impact of exogenous OXT on mechanisms that drive ED presentation and chronicity, and the potential role of genetic predispositions in the OXT-ED link., Recent Findings: Current findings suggest a role of the OXT system in the pathophysiology of anorexia nervosa. In individuals with bulimia nervosa, endogenous OXT levels were comparable to those of healthy controls, and exogenous OXT reduced food intake. Studies in other ED are lacking. However, genetic studies suggest a broad role of the OXT system in influencing ED pathology. Highlighting findings on why OXT represents a potential biomarker of and treatment target for ED, we advocate for a systematic research approach spanning the entire ED spectrum.

The hypothalamic hormone oxytocin (OXT) plays an important role in a range of physiological processes and social-emotional functioning in both sexes. In women, physiological stimuli, such as suckling and parturition, result in pulsatile release of OXT into the peripheral circulation via the posterior pituitary gland. However, data regarding OXT secretory patterns in men during a state of rest are limited. Further, the relationship between secretory dynamics of OXT and emotional measures has never been evaluated. We hypothesized a pulsatile pattern of OXT secretion in men, and explored the relationship between OXT secretory patterns and social-emotional functioning., Methods: Deconvolution analysis was performed on serum OXT levels obtained every 5min over a period of 10h in 5 healthy normal weight men. Area under the curve (AUC), average OXT values, and pulse characteristics [pulse number, inter-pulse interval, pulse height and mass (area under each pulse)] were calculated. State Adult Attachment Measure (SAAM) assessed types of human attachment. Interpersonal Support Evaluation List (ISEL) assessed perception of social support. Toronto Alexithymia Scale (TAS-20) measured the ability to express and identify one's own emotions., Results: Mean age was 22.8±1.2years, and BMI was 21.7±0.4kg/m 2 (mean±SEM). Assuming a basal secretion of zero and a half life of five to seven minutes, we demonstrated the following: OXT AUC: 5421±1331pg/ml, mean OXT level: 9.1pg/ml, mean pulse number: 22±3/10hr, mean pulse height: 1.81±0.48pg/ml, mean pulse mass: 30.34±10.29pg/ml and mean inter-pulse interval: 27±4min. The SAAM Avoidant scale correlated negatively with mean OXT pulse height (r=-0.90, p=0.04) and pulse mass (r=-0.95, p=0.01). The ISEL Belonging score correlated positively with OXT AUC (r=0.89, p=0.04) and average OXT (r=0.93, p=0.02). ISEL Appraisal score also had a positive association with mean OXT pulse height (r=0.99, p=0.0006) and pulse mass (r=0.98, p=0.003). Finally, ISEL total score had a significant correlation with average OXT values (r=0.90, p=0.04). While none of the subjects had a score in the alexithymia range, TAS-20 Difficulty describing feelings score had an inverse correlation with OXT pulse height (r=-0.96, p=0.01) and pulse mass (r=-0.99, p=0.001). TAS-20 total score also had an inverse correlation with OXT pulse height (r=-0.94, p=0.02) and pulse mass (r=-0.96, p=0.009)., Conclusion: We demonstrate a pulsatile pattern of peripheral OXT secretion in healthy men at rest. Subjects with lower OXT pulse height and pulse mass had a more avoidant style of attachment, felt less supported, and expressed greater difficulty in describing their feelings. Our findings support the concept that OXT is a key mediator of social-emotional functioning. Future studies to determine causality are warranted., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Anorexia nervosa is associated with social-emotional functioning deficits and low levels of the social neurohormone oxytocin, even after weight gain. The relationship between low oxytocin levels and social-emotional functioning impairment has not been studied., Method: We performed a cross-sectional study of 79 women (19 who were less than 85% of ideal body weight [IBW] with anorexia nervosa [AN], 26 who were 90-120% IBW with a history of AN [AN-WR], and 34 who were 90-120% IBW with no eating disorder history [H]). We administered the Eating Disorder Examination-Questionnaire (EDE-Q), Leibowitz Social Anxiety Scale-Self Report (LSAS-SR), Dimensional Assessment of Personality Pathology-Basic Questionnaire (DAPP-BQ; suspiciousness and insecure attachment subscales), and the Toronto Alexithymia Scale (TAS-20). We also analyzed fasting serum oxytocin levels., Results: Most measures of social-emotional functioning showed impairment in women with AN and AN-WR compared to H. Oxytocin levels were low in AN-WR compared to H. Across groups, low oxytocin levels were associated with difficulty identifying feelings (r = -.45, p = .008) and overall alexithymia (r = -.34, p = .0489)., Discussion: We speculate that low oxytocin levels may contribute to alexithymia in women with anorexia nervosa., (© 2017 Wiley Periodicals, Inc.)

Context: Oxytocin (OXT), an anorexigenic hypothalamic hormone anabolic to bone, may reflect energy availability. Basal serum OXT levels are lower in anorexia nervosa (AN, state of energy deficit) than healthy controls (HC) and negatively associated with spine bone mineral density (BMD). Reports are conflicting regarding OXT levels in overweight/obesity (OB, state of energy excess). Relationships between OXT and BMD in OB and hip geometry across the weight spectrum are unknown., Objective: To determine whether overnight serum OXT levels are (1) elevated in OB and (2) associated with body composition, BMD, and hip geometry across the weight spectrum., Design: Cross-sectional., Setting: Clinical research center., Participants: Fifty-nine women, ages 18 to 45 years: amenorrheic AN (N = 16), eumenorrheic HC (N = 24), eumenorrheic OB (N = 19)., Main Outcome Measures: Serum sampled every 20 minutes from 8 pm to 8 am and pooled for integrated overnight OXT levels. Body composition, BMD, and hip structural analysis measured by dual x-ray absorptiometry., Results: OXT levels were lowest in AN, higher in HC, and highest in OB (P ≤ 0.02). There were positive associations between OXT and (1) body mass index (P = 0.0004); (2) total, visceral, and subcutaneous fat (P ≤ 0.0002); (3) spine and hip BMD Z-scores (P ≤ 0.01); and (4) favorable hip geometry, namely buckling ratio (P ≤ 0.05). In a subset analysis of HC and OB, relationships between OXT and body composition, but not bone parameters, remained significant., Conclusions: These data suggest OXT is a marker of energy availability and may be a mediator of bone density, structure, and strength. OXT pathways may provide targets for obesity and osteoporosis treatment., (Copyright © 2017 Endocrine Society)

Objective: Anorexia nervosa (AN), a psychiatric disorder characterized by restriction of food intake despite severe weight loss, is associated with increased comorbid anxiety and depression. Secretion of oxytocin, an appetite-regulating neurohormone with anxiolytic and antidepressant properties, is abnormal in AN. The link between oxytocin levels and psychopathology in AN has not been well explored., Methods: We performed a cross-sectional study of 79 women aged 18-45 years (19 AN, 26 AN in partial recovery [ANPR], and 34 healthy controls [HC]) investigating the relationship between basal oxytocin levels and disordered eating psychopathology, anxiety, and depressive symptoms. AN diagnoses were based on DSM-5 criteria. Data acquisition took place between December 2008 and March 2014. Fasting serum oxytocin levels were obtained, and the following self-report measures were used to assess psychopathology: Eating Disorder Examination Questionnaire, State-Trait Anxiety Inventory, and Beck Depression Inventory-II., Results: Fasting oxytocin levels were low in ANPR compared to HC (P = .0004). In ANPR but not AN, oxytocin was negatively associated with disordered eating psychopathology (r = -0.39, P = .0496) and anxiety symptoms (state anxiety: r = -0.53, P = .006; trait anxiety: r = -0.49, P = .01). Furthermore, ANPR with significant disordered eating psychopathology, anxiety symptoms, or depressive symptoms had lower oxytocin levels compared to those with minimal or no symptoms (P = .04, .02, and .007, respectively)., Conclusions: We speculate that a dysregulation of oxytocin pathways may contribute to persistent psychopathology after partial weight recovery from anorexia nervosa., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

Objective: Anorexia nervosa, a psychiatric disorder characterized by self-induced starvation, is associated with endocrine dysfunction and comorbid anxiety and depression. Animal data suggest that oxytocin may have anxiolytic and antidepressant effects. We have reported increased postprandial oxytocin levels in women with active anorexia nervosa and decreased levels in weight-recovered women with anorexia nervosa compared to healthy controls. A meal may represent a significant source of stress in patients with disordered eating. We therefore investigated the association between postprandial oxytocin secretion and symptoms of anxiety and depression in anorexia nervosa., Method: We performed a cross-sectional study of 35 women (13 women with active anorexia nervosa, 9 with weight-recovered anorexia nervosa, and 13 healthy controls). Anorexia nervosa was diagnosed according to DSM-IV-TR criteria. Serum oxytocin and cortisol and plasma leptin levels were measured fasting and 30, 60, and 120 minutes after a standardized mixed meal. The area under the curve (AUC) and, for oxytocin, postprandial nadir and peak levels were determined. Anxiety and depressive symptoms were assessed using the Spielberger State-Trait Anxiety Inventory (STAI) and Beck Depression Inventory II (BDI-II). The study was conducted from January 2009 to March 2011., Results: In women with anorexia nervosa, oxytocin AUC and postprandial nadir and peak levels were positively associated with STAI trait and STAI premeal and postmeal state scores. Oxytocin AUC and nadir levels were positively associated with BDI-II scores. After controlling for cortisol AUC, all of the relationships remained significant. After controlling for leptin AUC, most of the relationships remained significant. Oxytocin secretion explained up to 51% of the variance in STAI trait and 24% of the variance in BDI-II scores., Conclusions: Abnormal postprandial oxytocin secretion in women with anorexia nervosa is associated with increased symptoms of anxiety and depression. This link may represent an adaptive response of oxytocin secretion to food-related symptoms of anxiety and depression., (© Copyright 2013 Physicians Postgraduate Press, Inc.)

Context: Animal data suggest that oxytocin is a satiety hormone. We have demonstrated that anorexia nervosa (anorexia), a disorder characterized by food restriction, low weight, and hypoleptinemia, is associated with decreased nocturnal oxytocin secretion. We have also reported functional magnetic resonance imaging (fMRI) hypoactivation in anorexia in brain regions involved in food motivation. The relationships between oxytocin, food-motivation neurocircuitry, and disordered eating psychopathology have not been investigated in humans., Objective: The objective of the study was to determine whether the oxytocin response to feeding in anorexia differs from healthy women and to establish the relationship between oxytocin secretion and disordered eating psychopathology and food-motivation neurocircuitry., Design: This was a cross-sectional study., Setting: The study was conducted at a clinical research center., Participants: Participants included 35 women: 13 anorexia (AN), nine weight-recovered anorexia (ANWR), and 13 healthy controls (HC)., Measures: Peripheral oxytocin and leptin levels were measured fasting and 30, 60, and 120 min after a standardized mixed meal. The Eating Disorder Examination-Questionnaire was used to assess disordered eating psychopathology. fMRI was performed during visual processing of food and nonfood stimuli to measure brain activation before and after the meal., Results: Mean oxytocin levels were higher in AN than HC at 60 and 120 min and lower in ANWR than HC at 0, 30, and 120 min and AN at all time points. Mean oxytocin area under the curve (AUC) was highest in AN, intermediate in HC, and lowest in ANWR. Mean leptin levels at all time points and AUC were lower in AN than HC and ANWR. Oxytocin AUC was associated with leptin AUC in ANWR and HC but not in AN. Oxytocin AUC was associated with the severity of disordered eating psychopathology in AN and ANWR, independent of leptin secretion, and was associated with between-group variance in fMRI activation in food motivation brain regions, including the hypothalamus, amygdala, hippocampus, orbitofrontal cortex, and insula., Conclusions: Oxytocin may be involved in the pathophysiology of anorexia.