Leptin hormone replacement to break the cycle of anorexia
The clinical studies below used off-label metreleptin and show what leptin replacement does in patients. Zula's drug is a long-acting leptin built on this biology.
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Understanding Anorexia Nervosa
Understanding Anorexia Nervosa
Anorexia nervosa (AN) is a complex disorder with both psychiatric and metabolic components. Recent genome-wide association studies have characterized AN as a metabo-psychiatric disorder, demonstrating significant genetic correlations between metabolic and psychiatric pathways.
The disease affects approximately 1% of women, typically emerging during adolescence, and has a mortality rate of 5-10%, making it the deadliest mental health disorder. Despite its severity, there are currently no FDA-approved medications specifically for treating anorexia nervosa.
The Leptin Connection
The Leptin Connection
What is Leptin?
What is Leptin?
Leptin is a hormone produced by fat cells (adipose tissue) that signals energy status to the brain. It plays a crucial role in regulating hunger, metabolism, and various physiological processes.
Leptin Deficiency in Anorexia Nervosa
Leptin Deficiency in Anorexia Nervosa
Patients with anorexia nervosa develop hypoleptinemia (leptin deficiency) due to reduced fat mass. This low leptin level triggers a cascade of metabolic and behavioral adaptations that can perpetuate the disorder:
• Hyperactivity and food preoccupation
• Anxiety and depression
• Cognitive rigidity
• Reduced gastric motility
Metreleptin: A Targeted Approach
Metreleptin: A Targeted Approach
Metreleptin is a recombinant form of human leptin that can directly address the neuropsychiatric effects of severe leptin deficiency occurring in anorexia nervosa.
How It Works
How It Works
Short-term metreleptin administration normalizes leptin signaling, potentially breaking the self-perpetuating cycle of:
Starvation → Low leptin → Psychiatric food avoidance → Further lowering leptin
This creates a therapeutic window that may enhance the effectiveness of behavioral interventions and improve outcomes for patients.
Clinical Evidence
Clinical Evidence
Studies conducted by our collaborators at University of Duisburg-Essen and University of Zurich have demonstrated remarkable results in treating anorexia nervosa patients with metreleptin:
Open-label studies (n>30) showed rapid therapeutic effects
Depression scores improved within days of treatment initiation
Significant reduction in food preoccupation and anxiety
Enhanced cognitive flexibility
Improved motivation for recovery
No serious adverse events reported in the AN population
Case studies also showed normalization of gastric motility and metabolic parameters, further supporting metreleptin's potential as a breakthrough treatment.
Key Publications
Key Publications
Clinical experience with metreleptin in anorexia nervosa
Clinical experience with metreleptin in anorexia nervosa
Milos G, Antel J, Kaufmann LK, Barth N, Koller A, Tan S, Wiesing U, Hinney A, Libuda L, Wabitsch M, von Känel R, Hebebrand J. Short-term metreleptin treatment of patients with anorexia nervosa: rapid on-set of beneficial cognitive, emotional, and behavioral effects. Translational Psychiatry. 2020;10:303. doi:10.1038/s41398-020-00977-1 · Open access
The first published case series. Three seriously ill female patients with hyperactivity treated off-label for up to 14 days. Drive for activity, repetitive thoughts of food, inner restlessness, and weight phobia decreased in two patients; depression improved rapidly in all three. No serious adverse events. The authors call placebo-controlled trials mandatory.
Antel J, Tan S, Grabler M, Ludwig C, Lohkemper D, Brandenburg T, Barth N, Hinney A, Libuda L, Remy M, Milos G, Hebebrand J. Rapid amelioration of anorexia nervosa in a male adolescent during metreleptin treatment including recovery from hypogonadotropic hypogonadism. European Child and Adolescent Psychiatry. 2022;31(10):1573-1579. doi:10.1007/s00787-021-01778-7 · Open access
A 15.9-year-old male with severe anorexia nervosa, treated for 24 days. Substantial improvement in mood, eating disorder cognitions, and hyperactivity within two days. Sub-physiological testosterone and free T3 normalized during dosing. Weight did not increase substantially during the dosing period, which separates the psychiatric effect from weight gain.
Gradl-Dietsch G, Milos G, Wabitsch M, Bell R, Tschöpe F, Antel J, Hebebrand J. Rapid emergence of appetite and hunger resulting in weight gain and improvement of eating disorder symptomatology during and after short-term off-label metreleptin treatment of a patient with anorexia nervosa. Obesity Facts. 2023;16(1):99-107. doi:10.1159/000527386 · Open access
A 15-year-old female treated for nine days. Self-reported increases in appetite and hunger, rapid weight gain, and substantial improvement in eating disorder cognitions and depression. The authors explicitly contrast this with the widespread view of leptin as an anorexigenic hormone.
Hebebrand J, Antel J, Peters T, et al. Case report: clinical improvements observed in first off-label metreleptin treatment of a patient with atypical anorexia nervosa. European Child and Adolescent Psychiatry. 2024;33:2267-2272. doi:10.1007/s00787-023-02315-4
First reported off-label use in atypical anorexia nervosa, where patients meet the psychological criteria without being underweight by BMI.
Case report: rapid improvements of anorexia nervosa and probable myalgic encephalomyelitis/chronic fatigue syndrome upon metreleptin treatment during two dosing episodes. Frontiers in Psychiatry. 2023;14:1267495. doi:10.3389/fpsyt.2023.1267495 · Open access
Case report: metreleptin rapidly improved anorexia nervosa related and comorbid psychopathology in a patient with high endogenous leptin levels adjusted for body mass index. European Child and Adolescent Psychiatry. 2025. doi:10.1007/s00787-025-02809-3
A 17-year-old female with anorexia nervosa plus major depressive disorder, OCD, PTSD, and non-suicidal self-injury, treated across two dosing periods of 15 and seven days. Improvements occurred despite endogenous leptin up to the 99th centile adjusted for sex, Tanner stage, and BMI. Extends the hypothesis beyond absolute hypoleptinemia.
Leptin replacement in other hypoleptinemic states
Leptin replacement in other hypoleptinemic states
Vieira DB, Antel J, Peters T, Miehle K, Stumvoll M, Hebebrand J, Schlögl H. Suggestive evidence for an antidepressant effect of metreleptin treatment in patients with lipodystrophy. Obesity Facts. 2022;15(5):685-693. doi:10.1159/000526357 · Open access
Ten patients with partial lipodystrophy and low serum leptin. Significant improvement in depression score under metreleptin, visible within one week. Important because these patients are not underweight, which separates the mood effect from nutritional status.
Hebebrand J, Zorn S, Antel J, von Schnurbein J, Wabitsch M, Gradl-Dietsch G. First account of psychological changes perceived by a female with congenital leptin deficiency upon treatment with metreleptin. Obesity Facts. 2022;15(5):730-735. doi:10.1159/000526169 · Open access
von Schnurbein J, Remy M, Brandt S, Manzoor J, Kohlsdorf K, Mahmood S, et al. Positive effect of leptin substitution on mood and behaviour in patients with congenital leptin deficiency. Pediatric Obesity. 2023. doi:10.1111/ijpo.13057
Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with hypothalamic amenorrhea. New England Journal of Medicine. 2004;351:987-997.
Controlled trial of recombinant leptin in another hypoleptinemic state, establishing restoration of reproductive and neuroendocrine function.
The hypoleptinemia hypothesis
The hypoleptinemia hypothesis
Himmerich H, Hebebrand J, et al. WFSBP Consensus Statement on Candidate Biomarkers for Anorexia Nervosa. World Journal of Biological Psychiatry. 2026. doi:10.1080/15622975.2026.2626934 · Open access
International consensus statement with more than 50 co-authors. Frames anorexia nervosa as a metabo-psychiatric disease, names leptin a leading candidate biomarker, and describes a diagnostic threshold below 2 ng/mL in acute disease against above 4 ng/mL in constitutional thinness.
Hebebrand J, Milos G, Seitz J, Matthews A. Recombinant human leptin for the treatment of anorexia nervosa. The Lancet. 2024. Correspondence. doi:10.1016/S0140-6736(24)01869-5
Responds to Himmerich et al., Lancet 2024;403:2671-2675. Cites the published off-label case data and calls explicitly for pharmaceutical industry support for formal clinical trials. Discloses the University of Duisburg-Essen patent applications.
Hebebrand J, Plieger M, Milos G, Peters T, Hinney A, Antel J. Does hypoleptinemia trigger entrapment in anorexia nervosa? Etiological and clinical considerations. European Eating Disorders Review. 2024;32(3):557-574. doi:10.1002/erv.3071 · Open access
The fullest statement of the weight-loss-induced entrapment construct.
Hebebrand J, Hinney A, Antel J. Could leptin substitution therapy potentially terminate entrapment in anorexia nervosa? Nature Reviews Endocrinology. 2023;19:435-436. doi:10.1038/s41574-023-00863-y
Hebebrand J, Hildebrandt T, Schlögl H, Seitz J, Denecke S, Vieira D, et al. The role of hypoleptinemia in the psychological and behavioral adaptation to starvation: implications for anorexia nervosa. Neuroscience and Biobehavioral Reviews. 2022;141:104807. doi:10.1016/j.neubiorev.2022.104807
Hebebrand J, et al. Clinical trials required to assess potential benefits and side effects of treatment of patients with anorexia nervosa with recombinant human leptin. Frontiers in Psychology. 2019;10:769. doi:10.3389/fpsyg.2019.00769 · Open access
Hebebrand J, Seitz J, Föcker M, et al. Premorbid body weight predicts weight loss in both anorexia nervosa and atypical anorexia nervosa: further support for a single underlying disorder. International Journal of Eating Disorders. 2024;57(4):967-982. doi:10.1002/eat.24189
Hebebrand J, Seitz J, Matthews A. Considering sufficient weight loss as a prerequisite for development of anorexia nervosa and atypical anorexia nervosa. International Journal of Eating Disorders. 2025;58(1):162-167. doi:10.1002/eat.24313
Peters T, Antel J, Naaresh R, Laabs BH, Föcker M, Albers N, Bühlmeier J, Hinney A, Libuda L, Hebebrand J. Suggestive evidence for causal effect of leptin levels on risk for anorexia nervosa: results of a Mendelian randomization study. Frontiers in Genetics. 2021;12:733606. doi:10.3389/fgene.2021.733606 · Open access
Genetic evidence bearing on the direction of causality between leptin levels and anorexia nervosa risk.
Neuroimaging correlates of hypoleptinemia
Neuroimaging correlates of hypoleptinemia
Wronski ML, et al. Dynamic amygdala nuclei alterations in relation to weight status in anorexia nervosa are mediated by leptin. Journal of the American Academy of Child and Adolescent Psychiatry. 2024;63(6):624-639. doi:10.1016/j.jaac.2023.08.015
Wronski ML, et al. Structural alterations of thalamic nuclei and their associations with leptin levels in patients with anorexia nervosa. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2025;136:111248. doi:10.1016/j.pnpbp.2025.111248
Disease burden and epidemiology
Disease burden and epidemiology
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Publishing; 2013.
Arcelus J, Mitchell AJ, Wales J, Nielsen S. Mortality rates in patients with anorexia nervosa and other eating disorders: a meta-analysis of 36 studies. Archives of General Psychiatry. 2011;68(7):724-731. doi:10.1001/archgenpsychiatry.2011.74
Streatfeild J, Hickson J, Austin SB, et al. Social and economic cost of eating disorders in the United States: evidence to inform policy action. International Journal of Eating Disorders. 2021;54(5):851-868.
Peer-reviewed publication of the Deloitte Access Economics analysis prepared for the Strategic Training Initiative for the Prevention of Eating Disorders and the Academy for Eating Disorders.
Petkova H, Simic M, Nicholls D, et al. Incidence of anorexia nervosa in young people in the UK and Ireland: a national surveillance study. BMJ Open. 2019;9(10):e027339.
91% of incident cases in ages 8 to 17 were young women. Incidence 25.66 per 100,000 for young women against 2.28 per 100,000 for young men.
Currin L, Schmidt U, Treasure J, Jick H. Time trends in eating disorder incidence. British Journal of Psychiatry. 2005;186:132-135.
UK primary care, 1994 to 2000. Female incidence 8.6 per 100,000 against male 0.7.
Hudson JI, Hiripi E, Pope HG, Kessler RC. The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biological Psychiatry. 2007;61(3):348-358.
Udo T, Grilo CM. Prevalence and correlates of DSM-5 defined eating disorders in a nationally representative sample of U.S. adults. Biological Psychiatry. 2018;84(5):345-354. doi:10.1016/j.biopsych.2018.03.014
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