Background/Objectives: Acute pancreatitis (AP) lacks disease-modifying pharmacotherapy. Neuroimmune, serotonergic, and redox-regulated pathways may modulate inflammatory amplification and acinar injury, although pharmacovigilance data link some psychotropic drug classes to AP risk. This review synthesized controlled rodent studies evaluating neuromodulatory interventions with serotonergic, stress-axis, or ferroptosis-linked targets in experimental AP. Methods: PubMed, Scopus, eLIBRARY.ru, and Elicit were searched in January 2026, supplemented by Google Scholar audit and citation chasing. Eligible studies were controlled in vivo rodent experiments using validated AP models with quantitative outcomes. Intervention timing was classified a priori as a primary analytic variable. Risk of bias was assessed with SYRCLE. A prespecified audit showed that no subset met the criteria for quantitative pooling because of heterogeneity in model class, compounds, timing, outcome definitions, units, and sampling timepoints. Mechanism-stratified qualitative synthesis was therefore performed. The protocol was registered on OSF (doi: 10.17605/OSF.IO/CZXDJ). Results: Nine studies (1992–2023) yielded 410 outcome rows across three mechanistic strands. Serotonergic modulation (5-HT2/5-HT2A-focused; six studies) reduced serum amylase/lipase (−37% to −65% vs. disease controls) and histological injury, with receptor-selectivity data supporting 5-HT2A-mediated mechanisms. Stress-axis modulation with thiadiazine L-17 reduced 7-day mortality in two severe models (from 50–70% to 30%). Olanzapine attenuated ferroptosis-linked injury via off-target antioxidant activity independent of serotonergic receptors. All interventions were prophylactic, peri-induction, or very early post-induction; no delayed therapeutic-window studies were identified. Most SYRCLE domains were unclear, particularly allocation concealment and blinding-related procedures. Conclusions: Neuromodulatory pathways modulate experimental AP in rodents, but evidentiary strength differs across mechanistic strands. Inference is constrained by absent therapeutic-window testing, heterogeneous endpoints, and reporting deficits. The findings support mechanism-level target prioritization rather than clinical repurposing.
Rantsev et al. (Thu,) studied this question.