Modulation of the Incretin Axis (GLP-1/GIP) in Behavioral Compulsions: A New Neuropsychopharmacology Frontier

Modulation of the Incretin Axis (GLP-1/GIP) in Behavioral Compulsions: A New Neuropsychopharmacology Frontier | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report Modulation of the Incretin Axis (GLP-1/GIP) in Behavioral Compulsions: A New Neuropsychopharmacology Frontier Luís Jesuíno de Oliveira Andrade, Luís Matos de Oliveira, Gabriela Correia Matos de Oliveira, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9238201/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Behavioral compulsions unrelated to substance use, including compulsive buying disorder and compulsive sexual behavior disorder, share core neurobiological mechanisms with addictions, particularly mesolimbic dopaminergic dysregulation and impaired prefrontal inhibitory control. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert central effects on reward circuitry, and tirzepatide, a dual GLP-1/GIP receptor agonist, may enhance these effects through combined dopaminergic modulation and synaptic plasticity mechanisms involving intracellular signaling pathways. Objective To review the role of the GLP-1/GIP axis, with emphasis on tirzepatide, in modulating non-alimentary behavioral compulsions, integrating neurobiological and clinical evidence, and to present two illustrative case reports. Methods Narrative review of PubMed/MEDLINE-indexed literature, including preclinical, clinical, and real-world evidence through 2026. Two original cases are presented: one involving compulsive buying and one compulsive sexual behavior, both treated with tirzepatide without changes in psychopharmacological or psychotherapeutic management. Results GLP-1RAs modulate mesolimbic circuits, reducing reward salience and behavioral urgency. Preclinical studies show decreased reward-seeking and relapse. Human data demonstrate electrophysiological modulation of the nucleus accumbens following tirzepatide exposure. Clinically, a obese female patient reported reduced compulsive buying after four weeks, while a male patient undergoing psychoanalytic therapy exhibited decreased intrusive sexual thoughts and improved impulse control. However, potential risks include compulsive symptom substitution, reduced hedonic tone, and behavioral instability with nonstandard dosing. Conclusions Tirzepatide may represent a novel transdiagnostic approach to behavioral compulsions, though controlled studies are needed to confirm efficacy and safety. Endocrinology & Metabolism Tirzepatide behavioral compulsions GLP-1 receptor agonists dopaminergic reward system Figures Figure 1 INTRODUCTION Behavioral compulsions, including binge eating disorder, compulsive buying disorder (CBD), and compulsive sexual behavior disorder (CSBD), constitute a heterogeneous cluster of conditions characterized by loss of control over impulses and persistence of maladaptive behaviors despite significant adverse consequences. These conditions share important neurobiological mechanisms with substance use disorders (SUDs), particularly dysfunction of mesolimbic dopaminergic reward circuits involving the nucleus accumbens (NAc) and the prefrontal cortex (PFC). 1 In recent years, growing interest has emerged regarding the role of the incretin axis, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), in modulating these circuits. Initially developed for the management of type 2 diabetes mellitus and obesity, GLP-1RAs have demonstrated central effects that transcend metabolic control, including modulation of food intake, satiety signaling, and, more broadly, responsiveness to rewarding stimuli. 2 Preclinical evidence indicates that these agents act directly on key nodes of the reward system, attenuating dopamine release associated with reinforcing stimuli and reducing compulsive seeking behavior. 3 More recently, dual-acting compounds such as tirzepatide, a GLP-1R/glucose-dependent insulinotropic polypeptide receptor (GIPR) co-agonist, have been proposed as potentially enhanced modulators of these systems, with more robust effects on feeding behavior and possibly on other forms of compulsive consumption. 4 This conceptual framework gave rise to the hypothesis that such agents could function as "transdiagnostic consumption modulators," with therapeutic impact extending beyond food intake to encompass compulsive buying, substance use, and hypersexual behavior. 5 Despite a growing body of mechanistic evidence and indirect clinical data, the application of these agents to behavioral compulsions remains predominantly off-label . 6 Fundamental questions remain unresolved, including heterogeneity of treatment response, the risk of paradoxical effects on impulse control, and the absence of standardized clinical protocols. Against this backdrop, it is essential to synthesize available neurobiological, pharmacological, and clinical evidence to elucidate the potential of the GLP-1/GIP axis as a therapeutic target in behavioral compulsions, while delineating its limitations and future perspectives. The present study aims to conduct a narrative review of the literature, focusing on studies related to the GLP-1 axis, tirzepatide, and addictive behavior, supplemented by two clinically relevant original case reports. NEUROBIOLOGICAL FOUNDATION: BEHAVIORAL COMPULSIONS AND THE GLP-1 AXIS Non-substance behavioral compulsions, including CSBD and CBD, share a neurobiological architecture strikingly similar to that of classical chemical dependencies. Dysregulation of dopaminergic transmission in the NAc, implicated in addiction and affective disorders, underscores the addictive nature of CSBD and supports its classification as a behavioral addiction. 7 Consistent with this, neuroimaging studies demonstrate that individuals with compulsive sexual behavior exhibit heightened activation of the ventral striatum, anterior cingulate cortex, and amygdala in response to sexual stimuli, a pattern that closely mirrors findings in substance use disorders. 8 The shared substrate of these conditions involves three central mechanisms. First, mesolimbic dopaminergic hyperactivity: during the binge/intoxication stage of the addiction cycle, dopaminergic firing in the basal ganglia increases in response to reward-associated stimuli, a phenomenon termed incentive salience. Second, prefrontal inhibitory control dysfunction: during the preoccupation/anticipation stage, executive control systems in the PFC are compromised, manifesting as reduced impulse control, executive planning deficits, and impaired emotion regulation. Third, sensitization to reward cues: the transition to compulsive behavior involves neuroplasticity initiated by alterations in the mesolimbic dopaminergic system and culminating in a cascade of neuroadaptations across the PFC, cingulate cortex, and extended amygdala. 9 In this context, GLP-1RAs emerge as direct modulators of these circuits. Central activation of GLP-1 receptors in mesolimbic and mesocortical circuits, encompassing the ventral tegmental area (VTA), the NAc, and the PFC, modulates dopaminergic, glutamatergic, and GABAergic signaling, thereby attenuating reward salience. 10 At the cellular level, GLP-1 receptors are predominantly expressed on GABAergic neurons; their activation engages mesencephalic inhibitory circuits, consequently reducing cocaine-seeking behavior. 11 Tirzepatide, the dual GLP-1R/GIPR agonist, exhibits a potentially broader profile of action on these circuits. In rodent models, tirzepatide effectively attenuated the rewarding properties of alcohol (as assessed by locomotor sensitization, conditioned place preference, and accumbal dopamine release) and dose-dependently reduced voluntary alcohol consumption while preventing relapse-like behavior. 12 From a molecular standpoint, by combining GLP-1R and GIPR agonism, tirzepatide may reinforce neural circuits involved in executive control and decision-making via mTOR pathway signaling, potentially counterbalancing the dysregulated reward circuitry observed in addiction (Figure 1). 10 Observational human data corroborate this mechanistic model. Emerging evidence suggests that tirzepatide and semaglutide may represent the first effective "anti-consumption" agents, with potential applications encompassing the reduction of food craving, alcohol use, nicotine dependence, recreational drug use, and even compulsive buying behaviors. 13 These findings are consistent with a systematic review demonstrating that GLP-1RAs normalize insulin resistance and may modulate dopaminergic signaling, thereby reducing anhedonia, with potential applications in disorders of motivational and reward processing. 3 Overall, the convergence between the neurobiological mechanisms underlying behavioral compulsions and the molecular targets of GLP-1Ras, particularly within the NAc-VTA-PFC axis, establishes a robust mechanistic rationale for investigating these agents in the treatment of behavioral addictions for which pharmacotherapy remains largely unavailable. EVIDENCE IN NON-ALIMENTARY BEHAVIORAL COMPULSIONS Compulsive Buying Disorder Compulsive buying disorder is classified as an impulse control disorder with features overlapping behavioral addictions, including loss of control, intrusive preoccupation, and behavioral persistence notwithstanding significant financial and relational consequences. Case Report We report a clinical case directly illustrating the impact of tirzepatide on this condition. A 30-year-old female patient with no prior formal psychiatric diagnosis presented for obesity management (baseline BMI: 35.2 kg/m²). During comprehensive history-taking, she disclosed a recurrent pattern of compulsive buying, characterized by frequent intrusive urges to purchase unnecessary items, weekly episodes of excessive spending followed by regret, and progressive financial impairment. She denied substance use but reported that episodes were consistently associated with states of anxiety and boredom. Tirzepatide was initiated under a standard progressive titration protocol. After approximately four weeks of treatment (2.5 mg/week), in addition to the expected reduction in appetite and initial weight loss (~6% of body weight), the patient spontaneously reported a marked reduction in buying impulses. She described decreased frequency of consumption-related intrusive thoughts, improved capacity to defer purchasing decisions, and a reduction in impulsive spending episodes. The patient was not engaged in structured psychotherapy during this period, and no additional psychopharmacological agents were introduced, suggesting a plausible temporal association with tirzepatide initiation. This isolated finding acquires conceptual significance when contextualized within broader reviews. Emerging data suggest that tirzepatide and semaglutide may represent the first effective "anti-consumption" agents, with the potential to reduce binge eating, alcohol consumption, nicotine dependence, recreational drug use, and compulsive buying behaviors, by acting on the brain reward pathway that mediates addictive processes. 14 The "anti-consumption effect" is not merely speculative: a mixed-methods social media analysis encompassing more than 43,000 comments from social platforms between 2019 and 2025 demonstrated that GLP-1Ras, including semaglutide and tirzepatide, were associated with positive effects on non-substance-related behaviors, including compulsive buying, although findings exhibited some inconsistency and warrant cautious interpretation. 15 Sexual Behavior and Compulsive Sexual Behavior Disorder The relationship between GLP-1RAs and sexual behavior is more complex and bidirectional, rendering the evidence simultaneously richer and more ambiguous. The point of departure is the neurobiological overlap between the reward circuits regulating compulsive eating behavior and those sustaining sexual arousal and the pursuit of erotic stimuli. GLP-1RAs are considered capable of acting on multiple pathways, including the brain reward system, appetite signaling circuits, and sexual hormonal regulation through metabolic adaptations. 16 Case Report A 39-year-old male patient in regular psychoanalytic follow-up presented for clinical evaluation for obesity management. During the course of treatment, he presented with compulsive sexual behavior disorder, characterized by persistent intrusive thoughts, frequent seeking of sexual stimuli, and difficulty controlling impulses, with demonstrable impact on his professional routine and interpersonal relationships. The patient demonstrated good insight, associating symptom intensification with anxiety and psychological distress, which were being addressed in analysis. Tirzepatide was initiated under a standard progressive titration regimen. In the context of subsequent analytic sessions, the patient began reporting a progressive reduction in the intensity of compulsive sexual impulses, describing decreased frequency of intrusive thoughts and reduced urgency to act on them. He also reported improved capacity for symbolization and psychic elaboration of affects previously discharged through behavior. No additional psychopharmacological agents were introduced during the period, and the psychoanalytic treatment was maintained without structural modifications, suggesting a plausible temporal association between tirzepatide initiation and behavioral modulation. Pharmacological evidence suggests that the dopaminergic modulation exerted by these agents may reduce the salience of sexual reward stimuli. A cross-sectional analysis of the FDA Adverse Event Reporting System (FAERS) database from 2003 to 2024 identified cases of male sexual dysfunction associated with GLP-1RAs (including tirzepatide, semaglutide, and other agents) encompassing orgasmic dysfunction, erectile dysfunction, and reduced libido. 17 These pharmacovigilance reports, though limited in number, confirm that GLP-1RAs exert measurable effects on sexual functioning. 18 Most relevant to the compulsive behavior context, social media analysis documented heterogeneous patterns: while some users reported reduced libido, others reported increased sexual interest, suggesting that effects on sexual behavior may be contingent on individual baseline characteristics, including the presence or absence of preexisting compulsive patterns. 17 In specific case reports, tirzepatide, owing to its lower-affinity GLP-1R agonism relative to semaglutide, demonstrated a differentiated profile with respect to sexual function, suggesting that the degree of GLP-1 receptor activation directly influences the magnitude of effects on sexual behavior. 14 This pharmacological distinction carries clinical relevance: for patients with compulsive sexual behavior disorder, subtler modulation of dopaminergic circuitry may confer therapeutic advantage without global suppression of sexual function. 19 In summary, available evidence, although still limited to case reports, pharmacovigilance analyses, and real-world data from social media, converges to support a transdiagnostic "anti-consumption" effect of GLP-1RAs that extends beyond alimentary behavior to encompass broader behavioral compulsions, including compulsive buying and sexual impulses. The need for controlled clinical trials remains the most pressing gap in this field. GLP-1 RECEPTOR AGONISTS: A RELEVANT PHARMACODYNAMIC MODEL FOR BEHAVIORAL COMPULSIONS GLP-1 receptor agonists represent a singular pharmacological advance among incretin-based agents, not only for their metabolic profile but also for their potential for sustained behavioral modulation. Tirzepatide is an imbalanced dual agonist, with affinity equivalent to native GIP at the GIPR, but approximately fivefold lower affinity than native GLP-1 at the GLP-1R, a profile that may be critical for maximizing dual efficacy without the gastrointestinal tolerability limitations associated with intense GLP-1R activation. This differential agonism has direct implications for reward circuitry. 20 The GIP pathway confers upon tirzepatide a distinct central mechanism of action not offered by selective GLP-1RAs. While GLP-1 acts directly on dopaminergic neurons of the VTA and on glutamatergic tone within the NAc, GIP promotes PI3K/AKT/mTOR-mediated synaptic plasticity, which may strengthen top-down executive control over the reward circuit. 21 Tirzepatide thus offers a dual lever on compulsive circuits: acute modulation of dopaminergic signaling via GLP-1R, and medium-term synaptic remodeling via GIPR. 10 From a pharmacokinetic standpoint, this dual central action is supported by a favorable temporal profile. The elimination half-life of tirzepatide is approximately five days, enabling sustained plasma exposure with a single weekly subcutaneous injection. 22 This prolonged residence time is clinically relevant for compulsive disorders, as it permits continuous modulation of reward circuitry without the trough plasma concentrations that characterize shorter half-life agents. The most direct human evidence for this central effect was provided by a case study published in Nature Medicine: following a short-term course of tirzepatide, direct electrophysiological changes were identified in the human NAc, specifically, alterations in delta-theta frequency band power, associated with modulation of food-related compulsive behavior. 23 This finding, the first of its kind in humans, confirms that tirzepatide acts on the mesolimbic substrate central to compulsive behavior, and not merely on peripheral pathways. Taken together, the dual GLP-1R/GIPR agonism, the five-day half-life, and the demonstrated capacity to modulate the NAc in vivo constitute a pharmacodynamic model that mechanistically supports the use of tirzepatide in behavioral compulsions, with the additional advantage of enabling gradual titration and non-linear dose adjustments in accordance with individual behavioral response. OFF-LABEL USE WITH VARIABLE DOSES AND INTERVALS: RATIONALE, LIMITATIONS, AND PSYCHOPATHOLOGICAL INTEGRATION Theoretical Rationale and Emerging Use Model Although not formalized in any clinical protocol, the emerging practice of individualized tirzepatide dosing in behavioral compulsions, doses ranging from 2.5 to 10 mg, intervals of 7 to 14 days, or episodic use during "compulsion crises", finds indirect support in three converging neurobiological premises. The first premise concerns the episodic nature of behavioral compulsions. Sexual compulsions and compulsive buying do not follow a uniform continuous pattern: they are fluctuating, trigger-dependent phenomena, highly sensitive to emotional context. Rigid weekly pharmacological regimens may fail to capture this dynamic optimally, whereas impulse-intensity-guided dose adjustments could theoretically optimize the relationship between pharmacological exposure and clinical response. The second premise concerns the dose-dependent nature of the reward salience effect: GLP-1RAs reduce substance consumption and the motivation to seek it, and preclinical evidence suggests these effects depend on the magnitude and consistency of drug exposure, theoretically providing space for posological modulation. 14 The third premise is the hypothetical "pulsatile anti-craving" model: higher doses suppress acute impulses; progressive dose reduction would allow controlled re-emergence of the circuit; and episodic re-introduction would contain relapse phases. This remains, however, a hypothesis entirely lacking experimental validation. 10,24 Limitations and Risks The complete absence of specific clinical evidence constitutes the most critical limitation. No clinical trial has evaluated tirzepatide for CSBD; no study has examined variable dosing regimens in behavioral compulsions; and on-demand use remains entirely empirical. This gap is not trivial, as the risks associated with irregular use are substantial. The first risk is compulsion substitution, the phenomenon of "dopaminergic transfer." GLP-1RA modulation of multiple reward domains requires nuanced interpretation: alcohol use disorders and other substance use conditions may benefit from effects on dopaminergic and opioid pathways, but the same mechanism may worsen anhedonia in individuals with pre-existing depressive vulnerability. In practical terms, suppression of one compulsion may be accompanied by the re-emergence of another, from food to shopping, or from sex to compulsive consumption, without resolution of the underlying dopaminergic dysfunction. 25 The second risk is global hedonic drive suppression. The neuroendocrine mechanisms of GLP-1Ras, including modulation of VTA dopaminergic neurons and attenuation of reward salience, provide a plausible explanation not only for therapeutic effects, but also for adverse outcomes including emotional blunting, dysphoria, and anxiety. 7 Clinically, this may translate into reduced physiological libido, adverse effects on interpersonal relationships, and generalized anhedonia, particularly at high doses or with prolonged use. 26 The third risk arises from the pharmacokinetic oscillation inherent to irregular use: few studies address tolerance, compensatory neuroadaptations, or rebound effects following GLP-1RA discontinuation, rendering intermittent regimens potentially destabilizing to inhibitory control. 24 Psychopathological Integration From a psychopathological standpoint, tirzepatide may modulate three dimensions of compulsion: behavioral urgency (via dopaminergic mechanisms), the intensity of perceived reward, and motivational attention to the compulsive stimulus. There is a consistent biological basis for effects on affective and compulsive behaviors through GLP-1 signaling in the hippocampus, amygdala, and NAc, structures central to the compulsive cycle. 5 However, tirzepatide does not operate on underlying psychic conflicts, OCD-like compulsive structures, or the psychodynamic determinants that frequently sustain behavioral compulsions. The combination of pharmacological interventions with psychotherapeutic approaches produces superior outcomes in the treatment of behavioral disorders, and this principle applies equally to the use of GLP-1RAs. 9 CONCLUSION GLP-1/GIP co-agonism, as exemplified by tirzepatide, represents a genuinely promising therapeutic frontier in non-alimentary behavioral compulsions, with direct initial evidence for compulsive buying disorder and indirect evidence for compulsive sexual behavior disorder. The two original case reports presented herein reinforce the concept of a transdiagnostic "anti-consumption" effect. Nevertheless, use with variable doses or extended intervals remains entirely experimental and lacks validation in controlled clinical trials; it should be undertaken exclusively under rigorous clinical monitoring and in conjunction with structured psychotherapeutic approaches. Prospective randomized controlled trials are urgently needed to establish efficacy, safety, and optimal dosing protocols for these indications. Declarations All patients provided verbal informed consent for the use of their clinical data and case details for research and publication purposes, in accordance with applicable ethical guidelines. Conflict of interests: None declared. References Volkow ND, Morales M. The Brain on Drugs: From Reward to Addiction. Cell. 2015;162(4):712-25. Klausen MK, Thomsen M, Wortwein G, Fink-Jensen A. The role of glucagon-like peptide 1 (GLP-1) in addictive disorders. Br J Pharmacol. 2022;179(4):625-641. Badulescu S, Tabassum A, Le GH, Wong S, Phan L, Gill H, et al. Glucagon-like peptide 1 agonist and effects on reward behaviour: A systematic review. Physiol Behav. 2024;283:114622. Scheen AJ. Add-on value of tirzepatide versus semaglutide. Lancet Diabetes Endocrinol. 2022;10(6):377-378. O'Keefe JH, Franco WG, O'Keefe EL. Anti-consumption agents: Tirzepatide and semaglutide for treating obesity-related diseases and addictions, and improving life expectancy. Prog Cardiovasc Dis. 2025;89:102-112. Guerdjikova AI, Walter LL, McElroy SL. Improvement of Compulsive Shopping on Tirzepatide: A Case Report. J Clin Psychopharmacol. 2026 Feb 9. Puszcz A, Górski J, Pierudzka W. Neurobiological Pathways Linking Compulsive Sexual Behavior Disorder and Psychiatric Comorbidities: A Narrative Review. Cureus. 2025;17(9):e91966. Kraus SW, Voon V, Potenza MN. Neurobiology of Compulsive Sexual Behavior: Emerging Science. Neuropsychopharmacology. 2016;41(1):385-6. Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. 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Arillotta D, Floresta G, Papanti Pelletier GD, Guirguis A, Corkery JM, Martinotti G, Schifano F. Exploring the Potential Impact of GLP-1 Receptor Agonists on Substance Use, Compulsive Behavior, and Libido: Insights from Social Media Using a Mixed-Methods Approach. Brain Sci. 2024;14(6):617. Sehgal NKR, Tronieri JS, Ungar L, Guntuku SG. Self‑reported side effects of semaglutide and tirzepatide in online communities: a large‑scale cross‑sectional analysis of Reddit posts (May 2019–June 2025). arXiv preprint arXiv:2603.12341, 2026. Morris DB. The neurobiology of the obscene: Henry Miller and Tourette syndrome. Lit Med. 1993 Fall;12(2):194-214. Hayes MR, Schmidt HD. GLP-1 influences food and drug reward. Curr Opin Behav Sci. 2016 Jun;9:66-70. Pourabhari Langroudi A, Chen AL, Basran S, Sommer ER, Stinson J, Cheng YS, et al. Male sexual dysfunction associated with GLP-1 receptor agonists: a cross-sectional analysis of FAERS data. Int J Impot Res. 2025;37(8):661-667. Visvabharathy V, MacPhedran S, Shupp K, King B. Anorgasmia following initiation of GLP-1 agonist. Sex Med. 2025;13(3):qfaf047. Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020;5(17):e140532. Alhadeff AL, Rupprecht LE, Hayes MR. GLP-1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control for food intake. Endocrinology. 2012;153(2):647-58. Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010 Jan;35(1):217-38. Erratum in: Neuropsychopharmacology. 2010 Mar;35(4):1051. Choi W, Nho YH, Qiu L, Chang A, Campos G, Seilheimer RL, et al. Brain activity associated with breakthrough food preoccupation in an individual on tirzepatide. Nat Med. 2025 Dec;31(12):4038-4043. Marquez-Meneses JD, Olaya-Bonilla SA, Barrera-Carreño S, Tibaduiza-Arévalo LC, Forero-Cárdenas S, Carrillo-Vaca L, et al. GLP-1 Analogues in the Neurobiology of Addiction: Translational Insights and Therapeutic Perspectives. Int J Mol Sci. 2025;26(11):5338. Pierret ACS, Mizuno Y, Saunders P, Lim E, De Giorgi R, Howes OD, et al. Glucagon-Like Peptide 1 Receptor Agonists and Mental Health: A Systematic Review and Meta-Analysis. JAMA Psychiatry. 2025;82(7):643-653. Sa B, Maristany A, Subramaniam A, Guillen R, Buonocore B, Smith A, et al. Psychiatric effects of GLP-1 receptor agonists: A systematic review of emerging evidence. Diabetes Obes Metab. 2026;28(1):50-59. Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9238201","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":612913621,"identity":"7500c12e-cacc-48bf-9481-3be12ab34e5d","order_by":0,"name":"Luís Jesuíno de Oliveira Andrade","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIiWNgGAWjYBACPgbGBgYGHiCLGYg/MDAkwGQScOhgYEPWwjiDOC1IgJmHKC0Syc0fGGRs7A2O8x58bNtml8fP3sD44WMOQ555Ay4tiW0SDDxpiRsO8yUb57YlF0v2HGCWnLmNoVjmAG4tQL8cTjA4zGMmndvGnLjhRgIbM+82hsQZOB2WCHQYz397sBbLtnqitDQAHXaAcQNIC2PbYSK08DwE+SU5ceZhHmPDnnPHE2f2HGwG+kWiWAKHFn729McfGHvs7PnOnzF88KOsOrGfvfngh4/bbPJwaQEB5r89UBYjOJpAkcuATwMI/IAx/hBQOApGwSgYBSMSAAAthFHtBhERUQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-7714-0330","institution":"Department of Health, Santa Cruz State University, Ilhéus, Bahia, Brazil.","correspondingAuthor":true,"prefix":"","firstName":"Luís","middleName":"Jesuíno de Oliveira","lastName":"Andrade","suffix":""},{"id":612913622,"identity":"1fc44e5c-b828-4287-b6b9-46b3272b4ce4","order_by":1,"name":"Luís Matos de Oliveira","email":"","orcid":"https://orcid.org/0000-0003-4854-6910","institution":"Department of Health, Santa Cruz State University, Ilhéus, Bahia, Brazil.","correspondingAuthor":false,"prefix":"","firstName":"Luís","middleName":"Matos","lastName":"de Oliveira","suffix":""},{"id":612913623,"identity":"d9369f76-1bfc-4445-9c5e-80eea63c0f84","order_by":2,"name":"Gabriela Correia Matos de Oliveira","email":"","orcid":"https://orcid.org/0000-0002-3447-3143","institution":"UNAERP - Electro Bonini Hospital and Cidinha Bonini Maternity Hospital - Ribeirão Preto, São Paulo.","correspondingAuthor":false,"prefix":"","firstName":"Gabriela","middleName":"Correia Matos","lastName":"de Oliveira","suffix":""},{"id":612913624,"identity":"fe4bb5df-5764-4a13-b055-950d34ab7e71","order_by":3,"name":"Ricardo Almeida Sinay Neves","email":"","orcid":"https://orcid.org/0009-0000-4827-1342","institution":"Psychotherapy Clinic, Salvador, Bahia, Brazil.","correspondingAuthor":false,"prefix":"","firstName":"Ricardo","middleName":"Almeida Sinay","lastName":"Neves","suffix":""}],"badges":[],"createdAt":"2026-03-26 22:02:00","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9238201/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9238201/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105907465,"identity":"ebbb8811-cd2d-400b-92da-e262d8e8d943","added_by":"auto","created_at":"2026-04-01 10:31:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1456302,"visible":true,"origin":"","legend":"\u003cp\u003eNeurobiological convergences: The GLP-1 axis as a modulator of behavioral compulsions within the mesocorticolimbic circuit.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9238201/v1/8b3d65d2f61cd35ab1f1ff29.png"},{"id":105909876,"identity":"9adbd08a-ffb5-4fca-93ae-a1ed7c2396a2","added_by":"auto","created_at":"2026-04-01 10:45:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1962988,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9238201/v1/880d993a-db21-4c31-a1c5-099ea08afb00.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eModulation of the Incretin Axis (GLP-1/GIP) in Behavioral Compulsions: A New Neuropsychopharmacology Frontier\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eBehavioral compulsions, including binge eating disorder, compulsive buying disorder (CBD), and compulsive sexual behavior disorder (CSBD), constitute a heterogeneous cluster of conditions characterized by loss of control over impulses and persistence of maladaptive behaviors despite significant adverse consequences. These conditions share important neurobiological mechanisms with substance use disorders (SUDs), particularly dysfunction of mesolimbic dopaminergic reward circuits involving the nucleus accumbens (NAc) and the prefrontal cortex (PFC).\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn recent years, growing interest has emerged regarding the role of the incretin axis, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), in modulating these circuits. Initially developed for the management of type 2 diabetes mellitus and obesity, GLP-1RAs have demonstrated central effects that transcend metabolic control, including modulation of food intake, satiety signaling, and, more broadly, responsiveness to rewarding stimuli.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Preclinical evidence indicates that these agents act directly on key nodes of the reward system, attenuating dopamine release associated with reinforcing stimuli and reducing compulsive seeking behavior.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMore recently, dual-acting compounds such as tirzepatide, a GLP-1R/glucose-dependent insulinotropic polypeptide receptor (GIPR) co-agonist, have been proposed as potentially enhanced modulators of these systems, with more robust effects on feeding behavior and possibly on other forms of compulsive consumption.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e This conceptual framework gave rise to the hypothesis that such agents could function as \"transdiagnostic consumption modulators,\" with therapeutic impact extending beyond food intake to encompass compulsive buying, substance use, and hypersexual behavior.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDespite a growing body of mechanistic evidence and indirect clinical data, the application of these agents to behavioral compulsions remains predominantly \u003cem\u003eoff-label\u003c/em\u003e.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Fundamental questions remain unresolved, including heterogeneity of treatment response, the risk of paradoxical effects on impulse control, and the absence of standardized clinical protocols.\u003c/p\u003e \u003cp\u003eAgainst this backdrop, it is essential to synthesize available neurobiological, pharmacological, and clinical evidence to elucidate the potential of the GLP-1/GIP axis as a therapeutic target in behavioral compulsions, while delineating its limitations and future perspectives. The present study aims to conduct a narrative review of the literature, focusing on studies related to the GLP-1 axis, tirzepatide, and addictive behavior, supplemented by two clinically relevant original case reports.\u003c/p\u003e"},{"header":"NEUROBIOLOGICAL FOUNDATION: BEHAVIORAL COMPULSIONS AND THE GLP-1 AXIS","content":"\u003cp\u003eNon-substance behavioral compulsions, including CSBD and CBD, share a neurobiological architecture strikingly similar to that of classical chemical dependencies. Dysregulation of dopaminergic transmission in the NAc, implicated in addiction and affective disorders, underscores the addictive nature of CSBD and supports its classification as a behavioral addiction.\u003csup\u003e7\u003c/sup\u003e Consistent with this, neuroimaging studies demonstrate that individuals with compulsive sexual behavior exhibit heightened activation of the ventral striatum, anterior cingulate cortex, and amygdala in response to sexual stimuli, a pattern that closely mirrors findings in substance use disorders.\u003csup\u003e8\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe shared substrate of these conditions involves three central mechanisms. First, mesolimbic dopaminergic hyperactivity: during the binge/intoxication stage of the addiction cycle, dopaminergic firing in the basal ganglia increases in response to reward-associated stimuli, a phenomenon termed incentive salience. Second, prefrontal inhibitory control dysfunction: during the preoccupation/anticipation stage, executive control systems in the PFC are compromised, manifesting as reduced impulse control, executive planning deficits, and impaired emotion regulation. Third, sensitization to reward cues: the transition to compulsive behavior involves neuroplasticity initiated by alterations in the mesolimbic dopaminergic system and culminating in a cascade of neuroadaptations across the PFC, cingulate cortex, and extended amygdala.\u003csup\u003e9\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIn this context, GLP-1RAs emerge as direct modulators of these circuits. Central activation of GLP-1 receptors in mesolimbic and mesocortical circuits, encompassing the ventral tegmental area (VTA), the NAc, and the PFC, modulates dopaminergic, glutamatergic, and GABAergic signaling, thereby attenuating reward salience.\u003csup\u003e10\u003c/sup\u003e At the cellular level, GLP-1 receptors are predominantly expressed on GABAergic neurons; their activation engages mesencephalic inhibitory circuits, consequently reducing cocaine-seeking behavior.\u003csup\u003e11\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eTirzepatide, the dual GLP-1R/GIPR agonist, exhibits a potentially broader profile of action on these circuits. In rodent models, tirzepatide effectively attenuated the rewarding properties of alcohol \u0026nbsp;(as assessed by locomotor sensitization, conditioned place preference, and accumbal dopamine release) and dose-dependently reduced voluntary alcohol consumption while preventing relapse-like behavior.\u003csup\u003e12\u003c/sup\u003e From a molecular standpoint, by combining GLP-1R and GIPR agonism, tirzepatide may reinforce neural circuits involved in executive control and decision-making via mTOR pathway signaling, potentially counterbalancing the dysregulated reward circuitry observed in addiction (Figure 1).\u003csup\u003e10\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eObservational human data corroborate this mechanistic model. Emerging evidence suggests that tirzepatide and semaglutide may represent the first effective \u0026quot;anti-consumption\u0026quot; agents, with potential applications encompassing the reduction of food craving, alcohol use, nicotine dependence, recreational drug use, and even compulsive buying behaviors.\u003csup\u003e13\u003c/sup\u003e These findings are consistent with a systematic review demonstrating that GLP-1RAs normalize insulin resistance and may modulate dopaminergic signaling, thereby reducing anhedonia, with potential applications in disorders of motivational and reward processing.\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eOverall, the convergence between the neurobiological mechanisms underlying behavioral compulsions and the molecular targets of GLP-1Ras, particularly within the NAc-VTA-PFC axis, establishes a robust mechanistic rationale for investigating these agents in the treatment of behavioral addictions for which pharmacotherapy remains largely unavailable.\u003c/p\u003e"},{"header":"EVIDENCE IN NON-ALIMENTARY BEHAVIORAL COMPULSIONS","content":"\u003cp\u003e\u003cstrong\u003eCompulsive Buying Disorder\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCompulsive buying disorder is classified as an impulse control disorder with features overlapping behavioral addictions, including loss of control, intrusive preoccupation, and behavioral persistence notwithstanding significant financial and relational consequences.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Report\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eWe report a clinical case directly illustrating the impact of tirzepatide on this condition. A 30-year-old female patient with no prior formal psychiatric diagnosis presented for obesity management (baseline BMI: 35.2 kg/m\u0026sup2;). During comprehensive history-taking, she disclosed a recurrent pattern of compulsive buying, characterized by frequent intrusive urges to purchase unnecessary items, weekly episodes of excessive spending followed by regret, and progressive financial impairment. She denied substance use but reported that episodes were consistently associated with states of anxiety and boredom. Tirzepatide was initiated under a standard progressive titration protocol. After approximately four weeks of treatment (2.5 mg/week), in addition to the expected reduction in appetite and initial weight loss (~6% of body weight), the patient spontaneously reported a marked reduction in buying impulses. She described decreased frequency of consumption-related intrusive thoughts, improved capacity to defer purchasing decisions, and a reduction in impulsive spending episodes. The patient was not engaged in structured psychotherapy during this period, and no additional psychopharmacological agents were introduced, suggesting a plausible temporal association with tirzepatide initiation.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis isolated finding acquires conceptual significance when contextualized within broader reviews. Emerging data suggest that tirzepatide and semaglutide may represent the first effective \u0026quot;anti-consumption\u0026quot; agents, with the potential to reduce binge eating, alcohol consumption, nicotine dependence, recreational drug use, and compulsive buying behaviors, by acting on the brain reward pathway that mediates addictive processes.\u003csup\u003e14\u003c/sup\u003e The \u0026quot;anti-consumption effect\u0026quot; is not merely speculative: a mixed-methods social media analysis encompassing more than 43,000 comments from social platforms between 2019 and 2025 demonstrated that GLP-1Ras, including semaglutide and tirzepatide, were associated with positive effects on non-substance-related behaviors, including compulsive buying, although findings exhibited some inconsistency and warrant cautious interpretation.\u003csup\u003e15\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSexual Behavior and Compulsive Sexual Behavior Disorder\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe relationship between GLP-1RAs and sexual behavior is more complex and bidirectional, rendering the evidence simultaneously richer and more ambiguous. The point of departure is the neurobiological overlap between the reward circuits regulating compulsive eating behavior and those sustaining sexual arousal and the pursuit of erotic stimuli. GLP-1RAs are considered capable of acting on multiple pathways, including the brain reward system, appetite signaling circuits, and sexual hormonal regulation through metabolic adaptations.\u003csup\u003e16\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Report\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eA 39-year-old male patient in regular psychoanalytic follow-up presented for clinical evaluation for obesity management. During the course of treatment, he presented with compulsive sexual behavior disorder, characterized by persistent intrusive thoughts, frequent seeking of sexual stimuli, and difficulty controlling impulses, with demonstrable impact on his professional routine and interpersonal relationships. The patient demonstrated good insight, associating symptom intensification with anxiety and psychological distress, which were being addressed in analysis. Tirzepatide was initiated under a standard progressive titration regimen. In the context of subsequent analytic sessions, the patient began reporting a progressive reduction in the intensity of compulsive sexual impulses, describing decreased frequency of intrusive thoughts and reduced urgency to act on them. He also reported improved capacity for symbolization and psychic elaboration of affects previously discharged through behavior. No additional psychopharmacological agents were introduced during the period, and the psychoanalytic treatment was maintained without structural modifications, suggesting a plausible temporal association between tirzepatide initiation and behavioral modulation.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePharmacological evidence suggests that the dopaminergic modulation exerted by these agents may reduce the salience of sexual reward stimuli. A cross-sectional analysis of the FDA Adverse Event Reporting System (FAERS) database from 2003 to 2024 identified cases of male sexual dysfunction associated with GLP-1RAs (including tirzepatide, semaglutide, and other agents) encompassing orgasmic dysfunction, erectile dysfunction, and reduced libido.\u003csup\u003e17\u003c/sup\u003e These pharmacovigilance reports, though limited in number, confirm that GLP-1RAs exert measurable effects on sexual functioning.\u003csup\u003e18\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eMost relevant to the compulsive behavior context, social media analysis documented heterogeneous patterns: while some users reported reduced libido, others reported increased sexual interest, suggesting that effects on sexual behavior may be contingent on individual baseline characteristics, including the presence or absence of preexisting compulsive patterns.\u003csup\u003e17\u003c/sup\u003e In specific case reports, tirzepatide, owing to its lower-affinity GLP-1R agonism relative to semaglutide, demonstrated a differentiated profile with respect to sexual function, suggesting that the degree of GLP-1 receptor activation directly influences the magnitude of effects on sexual behavior.\u003csup\u003e14\u003c/sup\u003e This pharmacological distinction carries clinical relevance: for patients with compulsive sexual behavior disorder, subtler modulation of dopaminergic circuitry may confer therapeutic advantage without global suppression of sexual function.\u003csup\u003e19\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIn summary, available evidence, although still limited to case reports, pharmacovigilance analyses, and real-world data from social media, converges to support a transdiagnostic \u0026quot;anti-consumption\u0026quot; effect of GLP-1RAs that extends beyond alimentary behavior to encompass broader behavioral compulsions, including compulsive buying and sexual impulses. The need for controlled clinical trials remains the most pressing gap in this field.\u003c/p\u003e"},{"header":"GLP-1 RECEPTOR AGONISTS: A RELEVANT PHARMACODYNAMIC MODEL FOR BEHAVIORAL COMPULSIONS","content":"\u003cp\u003eGLP-1 receptor agonists represent a singular pharmacological advance among incretin-based agents, not only for their metabolic profile but also for their potential for sustained behavioral modulation. Tirzepatide is an imbalanced dual agonist, with affinity equivalent to native GIP at the GIPR, but approximately fivefold lower affinity than native GLP-1 at the GLP-1R, a profile that may be critical for maximizing dual efficacy without the gastrointestinal tolerability limitations associated with intense GLP-1R activation. This differential agonism has direct implications for reward circuitry.\u003csup\u003e20\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe GIP pathway confers upon tirzepatide a distinct central mechanism of action not offered by selective GLP-1RAs. While GLP-1 acts directly on dopaminergic neurons of the VTA and on glutamatergic tone within the NAc, GIP promotes PI3K/AKT/mTOR-mediated synaptic plasticity, which may strengthen top-down executive control over the reward circuit.\u003csup\u003e21\u003c/sup\u003e Tirzepatide thus offers a dual lever on compulsive circuits: acute modulation of dopaminergic signaling via GLP-1R, and medium-term synaptic remodeling via GIPR.\u003csup\u003e10\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eFrom a pharmacokinetic standpoint, this dual central action is supported by a favorable temporal profile. The elimination half-life of tirzepatide is approximately five days, enabling sustained plasma exposure with a single weekly subcutaneous injection.\u003csup\u003e22\u003c/sup\u003e This prolonged residence time is clinically relevant for compulsive disorders, as it permits continuous modulation of reward circuitry without the trough plasma concentrations that characterize shorter half-life agents. The most direct human evidence for this central effect was provided by a case study published in Nature Medicine: following a short-term course of tirzepatide, direct electrophysiological changes were identified in the human NAc, specifically, alterations in delta-theta frequency band power, associated with modulation of food-related compulsive behavior.\u003csup\u003e23\u003c/sup\u003e This finding, the first of its kind in humans, confirms that tirzepatide acts on the mesolimbic substrate central to compulsive behavior, and not merely on peripheral pathways.\u003c/p\u003e\n\u003cp\u003eTaken together, the dual GLP-1R/GIPR agonism, the five-day half-life, and the demonstrated capacity to modulate the NAc in vivo constitute a pharmacodynamic model that mechanistically supports the use of tirzepatide in behavioral compulsions, with the additional advantage of enabling gradual titration and non-linear dose adjustments in accordance with individual behavioral response.\u003c/p\u003e"},{"header":"OFF-LABEL USE WITH VARIABLE DOSES AND INTERVALS: RATIONALE, LIMITATIONS, AND PSYCHOPATHOLOGICAL INTEGRATION","content":"\u003cp\u003e\u003cstrong\u003eTheoretical Rationale and Emerging Use Model\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlthough not formalized in any clinical protocol, the emerging practice of individualized tirzepatide dosing in behavioral compulsions, doses ranging from 2.5 to 10 mg, intervals of 7 to 14 days, or episodic use during \u0026quot;compulsion crises\u0026quot;, finds indirect support in three converging neurobiological premises.\u003c/p\u003e\n\u003cp\u003eThe first premise concerns the episodic nature of behavioral compulsions. Sexual compulsions and compulsive buying do not follow a uniform continuous pattern: they are fluctuating, trigger-dependent phenomena, highly sensitive to emotional context. Rigid weekly pharmacological regimens may fail to capture this dynamic optimally, whereas impulse-intensity-guided dose adjustments could theoretically optimize the relationship between pharmacological exposure and clinical response. The second premise concerns the dose-dependent nature of the reward salience effect: GLP-1RAs reduce substance consumption and the motivation to seek it, and preclinical evidence suggests these effects depend on the magnitude and consistency of drug exposure, theoretically providing space for posological modulation.\u003csup\u003e14\u003c/sup\u003e The third premise is the hypothetical \u0026quot;pulsatile anti-craving\u0026quot; model: higher doses suppress acute impulses; progressive dose reduction would allow controlled re-emergence of the circuit; and episodic re-introduction would contain relapse phases. This remains, however, a hypothesis entirely lacking experimental validation.\u003csup\u003e10,24\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations and Risks\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe complete absence of specific clinical evidence constitutes the most critical limitation. No clinical trial has evaluated tirzepatide for CSBD; no study has examined variable dosing regimens in behavioral compulsions; and on-demand use remains entirely empirical. This gap is not trivial, as the risks associated with irregular use are substantial.\u003c/p\u003e\n\u003cp\u003eThe first risk is compulsion substitution, the phenomenon of \u0026quot;dopaminergic transfer.\u0026quot; GLP-1RA modulation of multiple reward domains requires nuanced interpretation: alcohol use disorders and other substance use conditions may benefit from effects on dopaminergic and opioid pathways, but the same mechanism may worsen anhedonia in individuals with pre-existing depressive vulnerability. In practical terms, suppression of one compulsion may be accompanied by the re-emergence of another, from food to shopping, or from sex to compulsive consumption, without resolution of the underlying dopaminergic dysfunction.\u003csup\u003e25\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe second risk is global hedonic drive suppression. The neuroendocrine mechanisms of GLP-1Ras, including modulation of VTA dopaminergic neurons and attenuation of reward salience, provide a plausible explanation not only for therapeutic effects, but also for adverse outcomes including emotional blunting, dysphoria, and anxiety.\u003csup\u003e7\u003c/sup\u003e Clinically, this may translate into reduced physiological libido, adverse effects on interpersonal relationships, and generalized anhedonia, particularly at high doses or with prolonged use.\u003csup\u003e26\u003c/sup\u003e The third risk arises from the pharmacokinetic oscillation inherent to irregular use: few studies address tolerance, compensatory neuroadaptations, or rebound effects following GLP-1RA discontinuation, rendering intermittent regimens potentially destabilizing to inhibitory control.\u003csup\u003e24\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePsychopathological Integration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFrom a psychopathological standpoint, tirzepatide may modulate three dimensions of compulsion: behavioral urgency (via dopaminergic mechanisms), the intensity of perceived reward, and motivational attention to the compulsive stimulus. There is a consistent biological basis for effects on affective and compulsive behaviors through GLP-1 signaling in the hippocampus, amygdala, and NAc, structures central to the compulsive cycle.\u003csup\u003e5\u003c/sup\u003e However, tirzepatide does not operate on underlying psychic conflicts, OCD-like compulsive structures, or the psychodynamic determinants that frequently sustain behavioral compulsions. The combination of pharmacological interventions with psychotherapeutic approaches produces superior outcomes in the treatment of behavioral disorders, and this principle applies equally to the use of GLP-1RAs.\u003csup\u003e9\u003c/sup\u003e\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eGLP-1/GIP co-agonism, as exemplified by tirzepatide, represents a genuinely promising therapeutic frontier in non-alimentary behavioral compulsions, with direct initial evidence for compulsive buying disorder and indirect evidence for compulsive sexual behavior disorder. The two original case reports presented herein reinforce the concept of a transdiagnostic \"anti-consumption\" effect. Nevertheless, use with variable doses or extended intervals remains entirely experimental and lacks validation in controlled clinical trials; it should be undertaken exclusively under rigorous clinical monitoring and in conjunction with structured psychotherapeutic approaches. Prospective randomized controlled trials are urgently needed to establish efficacy, safety, and optimal dosing protocols for these indications.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cspan\u003eAll patients provided verbal informed consent for the use of their clinical data and case details for research and publication purposes, in accordance with applicable ethical guidelines.\u003c/span\u003e\u003c/p\u003e\u003cp\u003e \u003ch2\u003eConflict of interests:\u003c/h2\u003e \u003cp\u003eNone declared.\u003c/p\u003e \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eVolkow ND, Morales M. The Brain on Drugs: From Reward to Addiction. Cell. 2015;162(4):712-25.\u003c/li\u003e\n \u003cli\u003eKlausen MK, Thomsen M, Wortwein G, Fink-Jensen A. The role of glucagon-like peptide 1 (GLP-1) in addictive disorders. Br J Pharmacol. 2022;179(4):625-641.\u003c/li\u003e\n \u003cli\u003eBadulescu S, Tabassum A, Le GH, Wong S, Phan L, Gill H, et al. Glucagon-like peptide 1 agonist and effects on reward behaviour: A systematic review. Physiol Behav. 2024;283:114622.\u003c/li\u003e\n \u003cli\u003eScheen AJ. Add-on value of tirzepatide versus semaglutide. Lancet Diabetes Endocrinol. 2022;10(6):377-378.\u003c/li\u003e\n \u003cli\u003eO\u0026apos;Keefe JH, Franco WG, O\u0026apos;Keefe EL. Anti-consumption agents: Tirzepatide and semaglutide for treating obesity-related diseases and addictions, and improving life expectancy. Prog Cardiovasc Dis. 2025;89:102-112.\u003c/li\u003e\n \u003cli\u003eGuerdjikova AI, Walter LL, McElroy SL. Improvement of Compulsive Shopping on Tirzepatide: A Case Report. J Clin Psychopharmacol. 2026 Feb 9.\u003c/li\u003e\n \u003cli\u003ePuszcz A, G\u0026oacute;rski J, Pierudzka W. Neurobiological Pathways Linking Compulsive Sexual Behavior Disorder and Psychiatric Comorbidities: A Narrative Review. Cureus. 2025;17(9):e91966.\u003c/li\u003e\n \u003cli\u003eKraus SW, Voon V, Potenza MN. Neurobiology of Compulsive Sexual Behavior: Emerging Science. Neuropsychopharmacology. 2016;41(1):385-6.\u003c/li\u003e\n \u003cli\u003eKoob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016;3(8):760-773.\u003c/li\u003e\n \u003cli\u003eAmorim Moreira Alves G, Teranishi M, Teixeira de Castro Gon\u0026ccedil;alves Ortega AC, James F, Perera Molligoda Arachchige AS. Mechanisms of GLP-1 in Modulating Craving and Addiction: Neurobiological and Translational Insights. Med Sci (Basel). 2025;13(3):136.\u003c/li\u003e\n \u003cli\u003eMerkel R, Hernandez NS, Weir V, Zhang Y, Caffrey A, Rich MT, et al. An endogenous GLP-1 circuit engages VTA GABA neurons to regulate mesolimbic dopamine neurons and attenuate cocaine seeking. Sci Adv. 2025;11(9):eadr5051.\u003c/li\u003e\n \u003cli\u003eEdvardsson CE, Adermark L, Gottlieb S, Alfreji S, Emous TA, Gouda Y, et al. Tirzepatide reduces alcohol drinking and relapse-like behaviours in rodents. EBioMedicine. 2026;124:106119.\u003c/li\u003e\n \u003cli\u003eBruns Vi N, Tressler EH, Vendruscolo LF, Leggio L, Farokhnia M. IUPHAR review - Glucagon-like peptide-1 (GLP-1) and substance use disorders: An emerging pharmacotherapeutic target. Pharmacol Res. 2024 Sep;207:107312.\u003c/li\u003e\n \u003cli\u003eArillotta D, Floresta G, Papanti Pelletier GD, Guirguis A, Corkery JM, Martinotti G, Schifano F. Exploring the Potential Impact of GLP-1 Receptor Agonists on Substance Use, Compulsive Behavior, and Libido: Insights from Social Media Using a Mixed-Methods Approach. Brain Sci. 2024;14(6):617.\u003c/li\u003e\n \u003cli\u003eSehgal NKR, Tronieri JS, Ungar L, Guntuku SG. Self‑reported side effects of semaglutide and tirzepatide in online communities: a large‑scale cross‑sectional analysis of Reddit posts (May 2019\u0026ndash;June 2025). arXiv preprint arXiv:2603.12341, 2026.\u003c/li\u003e\n \u003cli\u003eMorris DB. The neurobiology of the obscene: Henry Miller and Tourette syndrome. Lit Med. 1993 Fall;12(2):194-214.\u003c/li\u003e\n \u003cli\u003eHayes MR, Schmidt HD. GLP-1 influences food and drug reward. Curr Opin Behav Sci. 2016 Jun;9:66-70.\u003c/li\u003e\n \u003cli\u003ePourabhari Langroudi A, Chen AL, Basran S, Sommer ER, Stinson J, Cheng YS, et al. Male sexual dysfunction associated with GLP-1 receptor agonists: a cross-sectional analysis of FAERS data. Int J Impot Res. 2025;37(8):661-667.\u003c/li\u003e\n \u003cli\u003eVisvabharathy V, MacPhedran S, Shupp K, King B. Anorgasmia following initiation of GLP-1 agonist. Sex Med. 2025;13(3):qfaf047.\u003c/li\u003e\n \u003cli\u003eWillard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020;5(17):e140532.\u003c/li\u003e\n \u003cli\u003eAlhadeff AL, Rupprecht LE, Hayes MR. GLP-1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control for food intake. Endocrinology. 2012;153(2):647-58.\u003c/li\u003e\n \u003cli\u003eKoob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010 Jan;35(1):217-38. Erratum in: Neuropsychopharmacology. 2010 Mar;35(4):1051.\u003c/li\u003e\n \u003cli\u003eChoi W, Nho YH, Qiu L, Chang A, Campos G, Seilheimer RL, et al. Brain activity associated with breakthrough food preoccupation in an individual on tirzepatide. Nat Med. 2025 Dec;31(12):4038-4043.\u003c/li\u003e\n \u003cli\u003eMarquez-Meneses JD, Olaya-Bonilla SA, Barrera-Carre\u0026ntilde;o S, Tibaduiza-Ar\u0026eacute;valo LC, Forero-C\u0026aacute;rdenas S, Carrillo-Vaca L, et al. GLP-1 Analogues in the Neurobiology of Addiction: Translational Insights and Therapeutic Perspectives. Int J Mol Sci. 2025;26(11):5338.\u003c/li\u003e\n \u003cli\u003ePierret ACS, Mizuno Y, Saunders P, Lim E, De Giorgi R, Howes OD, et al. Glucagon-Like Peptide 1 Receptor Agonists and Mental Health: A Systematic Review and Meta-Analysis. JAMA Psychiatry. 2025;82(7):643-653.\u003c/li\u003e\n \u003cli\u003eSa B, Maristany A, Subramaniam A, Guillen R, Buonocore B, Smith A, et al. Psychiatric effects of GLP-1 receptor agonists: A systematic review of emerging evidence. Diabetes Obes Metab. 2026;28(1):50-59. \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Tirzepatide, behavioral compulsions, GLP-1 receptor agonists, dopaminergic reward system","lastPublishedDoi":"10.21203/rs.3.rs-9238201/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9238201/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eBehavioral compulsions unrelated to substance use, including compulsive buying disorder and compulsive sexual behavior disorder, share core neurobiological mechanisms with addictions, particularly mesolimbic dopaminergic dysregulation and impaired prefrontal inhibitory control. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert central effects on reward circuitry, and tirzepatide, a dual GLP-1/GIP receptor agonist, may enhance these effects through combined dopaminergic modulation and synaptic plasticity mechanisms involving intracellular signaling pathways.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo review the role of the GLP-1/GIP axis, with emphasis on tirzepatide, in modulating non-alimentary behavioral compulsions, integrating neurobiological and clinical evidence, and to present two illustrative case reports.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eNarrative review of PubMed/MEDLINE-indexed literature, including preclinical, clinical, and real-world evidence through 2026. Two original cases are presented: one involving compulsive buying and one compulsive sexual behavior, both treated with tirzepatide without changes in psychopharmacological or psychotherapeutic management.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eGLP-1RAs modulate mesolimbic circuits, reducing reward salience and behavioral urgency. Preclinical studies show decreased reward-seeking and relapse. Human data demonstrate electrophysiological modulation of the nucleus accumbens following tirzepatide exposure. Clinically, a obese female patient reported reduced compulsive buying after four weeks, while a male patient undergoing psychoanalytic therapy exhibited decreased intrusive sexual thoughts and improved impulse control. However, potential risks include compulsive symptom substitution, reduced hedonic tone, and behavioral instability with nonstandard dosing.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eTirzepatide may represent a novel transdiagnostic approach to behavioral compulsions, though controlled studies are needed to confirm efficacy and safety.\u003c/p\u003e","manuscriptTitle":"Modulation of the Incretin Axis (GLP-1/GIP) in Behavioral Compulsions: A New Neuropsychopharmacology Frontier","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-01 10:11:08","doi":"10.21203/rs.3.rs-9238201/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ab6e42e9-7d0a-4b1a-b6b5-00f76d505028","owner":[],"postedDate":"April 1st, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":65220020,"name":"Endocrinology \u0026 Metabolism"}],"tags":[],"updatedAt":"2026-04-01T10:11:08+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-01 10:11:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9238201","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9238201","identity":"rs-9238201","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}