{"doi":"10.20944/preprints202510.1849.v1","title":"GLP-1 Agonists Can Be Heaven or Hell Dependent Upon Dopaminergic Genetic/Epigenetic Antecedents","abstract":"Background: GLP‑1 receptor agonists (GLP‑1RAs) are effective for type 2 diabetes and obesity and engage central stress and reward pathways (HPA axis; mesolimbic dopamine). Psychiatric signals have been reported in some settings. Objective :To narratively synthesize evidence on neuropsychiatric effects of GLP‑1RAs—mood, anxiety, suicidality, reward processing, substance use, and migraine—and to consider genetic/epigenetic moderators (e.g., hypodopaminergia/reward deficiency syndrome).Evidence: Mechanistic and imaging studies demonstrate GLP‑1 engagement of HPA and reward circuitry; animal work suggests acute anxiogenic responses with mixed chronic effects. Pharmacovigilance datasets (FAERS/EudraVigilance) show signals for headache, dizziness, sensory changes, and less consistently for depression/anxiety/suicidality; such data are hypothesis‑generating and not causal. Clinical trials and meta‑analyses report heterogeneous outcomes, including small antidepressant effects in some T2DM cohorts. Conclusions: Neuropsychiatric outcomes with GLP‑1RAs appear context‑dependent. Individuals with hypodopaminergic biology may be vulnerable to reward blunting/anxiety, whereas others may experience mood benefits. A pragmatic approach is screen–stratify–monitor, with slow titration and prompt adjustment if psychiatric signals emerge. Prospective, genotype‑informed studies are needed to identify who benefits or is harmed and why.","journal":"Preprints.org","year":2025,"id":579154,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9584,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1470144,"name":"Shaurya Mahajan","orcid":"0009-0005-3984-2891","position":1,"is_corresponding":false},{"id":1245128,"name":"Alireza Sharafshah","orcid":"0000-0001-8048-9587","position":2,"is_corresponding":false},{"id":1148958,"name":"Keerthy Sunder","orcid":null,"position":3,"is_corresponding":false},{"id":1245127,"name":"Kai‐Uwe Lewandrowski","orcid":"0000-0001-7842-2914","position":4,"is_corresponding":false},{"id":1475372,"name":"Kavya Mohankumar","orcid":null,"position":5,"is_corresponding":false},{"id":1489392,"name":"Morgan P. Lorio","orcid":"0000-0003-1623-2095","position":6,"is_corresponding":false},{"id":1489393,"name":"Álvaro Dowling","orcid":"0000-0001-9963-4131","position":7,"is_corresponding":false},{"id":1489806,"name":"Rafaela Dowling","orcid":null,"position":8,"is_corresponding":false},{"id":1489394,"name":"João Paulo Machado Bergamaschi","orcid":"0000-0002-6992-9876","position":9,"is_corresponding":false},{"id":1148600,"name":"Milan Makale","orcid":"0000-0001-5414-0517","position":10,"is_corresponding":false},{"id":430661,"name":"Panayotis K. Thanos","orcid":"0000-0002-5663-3478","position":11,"is_corresponding":false},{"id":1424608,"name":"Alexander P. L. Lewandrowski","orcid":null,"position":12,"is_corresponding":false},{"id":533277,"name":"Abdalla Bowirrat","orcid":"0000-0001-8185-0688","position":13,"is_corresponding":false},{"id":931840,"name":"Debmalya Barh","orcid":"0000-0002-2557-7768","position":14,"is_corresponding":false},{"id":1245129,"name":"Sergio L. Schmidt","orcid":"0000-0001-7654-5507","position":15,"is_corresponding":false},{"id":1439172,"name":"Rossano Kepler Alvim Fiorelli","orcid":"0000-0001-5236-0903","position":16,"is_corresponding":false},{"id":903542,"name":"Catherine A. Dennen","orcid":null,"position":17,"is_corresponding":false},{"id":683912,"name":"Igor Elman","orcid":"0000-0002-1345-2677","position":18,"is_corresponding":false},{"id":109350,"name":"David Baron","orcid":"0000-0001-7670-2613","position":19,"is_corresponding":false},{"id":1148601,"name":"Nicole Jafari","orcid":"0000-0001-7762-9673","position":20,"is_corresponding":false},{"id":1148602,"name":"Foojan Zeine","orcid":"0009-0006-7709-5580","position":21,"is_corresponding":false},{"id":1304105,"name":"Brian Fuehrlein","orcid":"0000-0002-3202-8089","position":22,"is_corresponding":false},{"id":533278,"name":"Edward J. Modestino","orcid":"0000-0001-7611-5144","position":23,"is_corresponding":false},{"id":711890,"name":"Paul R. Carney","orcid":"0000-0001-6248-1493","position":24,"is_corresponding":false},{"id":327018,"name":"Rene Cortese","orcid":"0000-0001-9262-7828","position":25,"is_corresponding":false},{"id":460951,"name":"Kenneth Blum","orcid":"0000-0001-6727-803X","position":26,"is_corresponding":false},{"id":1489805,"name":"Yatharth Mahajan","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:58:30.282164Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}