ABSTRACT Long‐acting naltrexone is a first‐line pharmacotherapy for alcohol use disorder (AUD), but clinical response is heterogeneous and the underlying biology remains incompletely understood. In a randomised, double‐blind, placebo‐controlled trial of naltrexone implants ( n = 70), the prespecified primary endpoint—percentage of heavy‐drinking days (PHDD) over 24 weeks—favoured naltrexone (median 1.49% vs. 13.39%; p = 0.042). In a prespecified Week‐12 mechanistic lipidomics substudy, untargeted liquid chromatography–mass spectrometry (LC–MS) profiling was performed in a responder‐enriched subset comprising naltrexone responders (RN, n = 18), placebo‐treated participants (PL, n = 10) and age‐ and BMI‐matched healthy male controls (HC, n = 10). We derived membrane‐related indices reflecting two prespecified axes of phospholipid remodelling: headgroup balance (PC/PE) and acyl‐chain composition (arachidonic acid AA and n‐3 polyunsaturated fatty acids within phospholipid pools). RN showed higher PC/PE and coordinated acyl‐chain shifts versus PL, with species‐level changes preferentially moving toward the healthy‐control direction. Exploratory analyses in naltrexone nonresponders (NR, n = 10) revealed partial Lands‐cycle‐related shifts but lacked the broader dual‐axis configuration observed in RN. In RN + PL ( n = 28), higher n‐3 in PE and lower AA in PE at Week 12 were prospectively associated with greater subsequent heavy‐drinking burden. These findings support a dual‐axis membrane remodelling phenotype associated with naltrexone response and prospectively linked to heavy‐drinking burden in AUD, providing a biologically grounded framework for future mechanistic and biomarker studies.
Huang et al. (Fri,) studied this question.