A Membrane‐Centric Plasma Lipidomic Signature of Response to Long‐Acting Naltrexone in Alcohol Use DisorderHuang, Liyao; Zhou, Bojie; Ou, Qinling; Yin, Jubo; Tian, Xiwen; Zhou, Xuhui
doi: 10.1111/adb.70165pmid: N/A
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.
Reduced Coupling of Global Brain Activity and Cerebrospinal Fluid Flow in Individuals With Betel Quid DependenceFu, Li Li; Lv, Chao Qi; Liu, Li Ting; Fu, Qing Qing; Huang, Wei Yuan; Guo, Yi Hao; Liu, Tao; Chen, Hui Juan; Chen, Feng
doi: 10.1111/adb.70164pmid: N/A
Millions of people worldwide are affected by betel quid dependence (BQD), a prevalent psychoactive substance‐use disorder. To evaluate cerebral glymphatic dysfunction in BQD, this work used the coupling between global blood‐oxygen‐level‐dependent (gBOLD) and cerebrospinal fluid (CSF) signals collected via resting‐state functional MRI (rs‐fMRI). Sixty‐six participants (29 BQD individuals and 37 healthy controls) underwent rs‐fMRI scanning. Cross‐correlation analysis between cortical BOLD and CSF time series was carried out to compute the gBOLD‐CSF coupling intensity. Group comparisons were performed via independent sample t‐tests, and correlations with clinical features were assessed using exploratory Pearson's analysis. Bonferroni correction was applied to the five correlation analyses (BQDS, duration, daily consumption, HAMA‐14 and HAMD‐24). The corrected significance threshold was set at p < 0.01 (0.05/5). BQD individuals exhibited significantly reduced gBOLD‐CSF coupling (t = −2.42, p = 0.019), and weaker coupling correlated with longer BQD duration (r = 0.4313, uncorrected p = 0.0195). After Bonferroni correction for multiple comparisons, the correlation between duration and gBOLD‐CSF coupling (original p = 0.0195) did not reach the adjusted threshold. Chronic betel quid exposure may impair glymphatic function, reflecting disrupted brain‐CSF interactions. The gBOLD‐CSF coupling metric could be used as a noninvasive imaging biomarker to evaluate neurotoxic effects and glymphatic dysfunction in substance‐use disorders.
Long‐Acting Naltrexone Restores Network Connectivity in Subjects With Comorbid Cannabis and Opioid Use DisorderBrier, Lindsey M.; Langleben, Daniel D.; Wiers, Corinde E.; Shi, Zhenhao
doi: 10.1111/adb.70159pmid: 42144806
Comorbid substance use disorders (SUDs) are common but difficult to study due to the complex, interacting and overlapping mechanisms through which they affect brain networks. Many datasets collected to investigate a specific SUD include participants with comorbid SUDs. Although most studies treat comorbid SUDs as covariates of no interest, these covariates also contain untapped information. This is particularly relevant as cannabis use disorder (CanUD) has become increasingly prevalent and comorbid with other SUDs that have been more thoroughly studied. While pharmacotherapies have been established for multiple SUDs, none have been approved for CanUD, although naltrexone (NTX) has been associated with reduced use. Here, we conducted a retrospective secondary analysis of functional magnetic resonance imaging (fMRI) data from individuals with primary opioid use disorder (OUD‐only, N = 25 pre‐NTX, N = 20 on‐NTX) with comorbid CanUD (N = 10), alcohol use disorder (AUD, N = 6) or cocaine use disorder (CocUD, N = 7). All participants underwent imaging prior to receiving a therapeutic dose of long‐acting intramuscular NTX (Vivitrol), an approved treatment for OUD and AUD but not for CocUD, and again 2 weeks postadministration. At baseline, OUD individuals with comorbid CanUD, AUD or CocUD exhibited distinct functional connectivity (FC) alterations compared to those with OUD‐only. These differences were greater in younger participants and primarily involved the default mode network. Following NTX administration, FC differences between the comorbid CanUD and OUD‐only groups globally diminished. A similar FC response to NTX was observed in the comorbid AUD group, whereas little change in FC was observed in comorbid CocUD. These findings, combined with prior evidence that NTX reduces cannabis use by dampening reward, suggest NTX may hold promise as a treatment for CanUD.
DNA Methylation Regulates CDK5R1 and NRBP1 to Exert Effects on Alcohol Dependence: Insights From Mendelian RandomizationDeng, Fuyuan; Peng, Junsheng; Lai, Siran; Zhang, Guangpeng; Li, Miaomiao; Huang, Yuxin; Yuan, Mi; Yao, Gaolei; Zhang, Peiming; Lu, Liming
doi: 10.1111/adb.70162pmid: N/A
Alcohol dependence currently lacks targeted pharmacotherapies, underscoring the urgent need for novel therapeutic targets. Existing research on disease‐associated DNA methylation changes and their gene regulatory effects remains inconsistent. To resolve this uncertainty, we applied the Mendelian randomization to elucidate causal mechanisms connecting druggable genes, epigenetic regulation and alcohol dependence development. Integrating MR, colocalization and mediation analyses, we leveraged genome‐wide association study (GWAS) (FinnGen), eQTL (eQTLGen) and methylation (GoDMC) data. We assessed causal gene‐alcohol dependence relationships, shared causal variants via colocalization and methylation‐mediated regulatory mechanisms. Our integrative analysis identified 10 drug‐targetable genes showing significant expression alterations in alcohol dependence (FDR < 0.05), with three genes (CDK5R1, CAMKK2 and NRBP1) demonstrating evidence of shared causal variants through colocalization. Epigenetic regulation was particularly evident at two methylation sites (cg07437263 and cg05102552) that indirectly influenced alcohol dependence risk by modulating CDK5R1 (63.92% mediation) and NRBP1 (95.12% mediation) expression. These findings reveal DNA methylation as a critical regulatory mechanism governing neuronal gene expression patterns in alcohol dependence pathogenesis. The strong mediation effects observed for CDK5R1 and NRBP1, coupled with their colocalization evidence, position these genes as promising candidates for both biomarker development and targeted therapeutic interventions in alcohol dependence. This investigation spotlights the regulatory function of DNA methylation on CDK5R1 and NRBP1 in alcohol dependence. It implies that CDK5R1 and NRBP1 could serve as potential clinical biomarkers or therapeutic targets for the early management of alcohol dependence.
rTMS Suppresses Tobacco Craving via Enhanced Prefronto‐Striato‐Thalamic ConnectivityLuo, Xin; Ma, Xuefeng; Li, Shuang; Chen, Hong'an; Yang, Bo; Zheng, Yanbin; Dong, Guang‐Heng
doi: 10.1111/adb.70167pmid: N/A
Studies have used repetitive transcranial magnetic stimulation (rTMS) to stimulate the left dorsolateral prefrontal cortex (DLPFC) in patients with tobacco use disorder (TUD); consequently, decreased craving for smoking was observed. However, the neural mechanism underlying this process remains unclear. Functional MRI data were collected from 59 valid TUD participants (31 rTMS and 28 shams) when they performed a Go/No‐go task before and after a continuous 5‐day treatment (rTMS on the left DLPFC). Three approaches of data analyses were performed: event‐related data analyses to identify the brain regions that are associated with rTMS treatment; functional connectivity (FC) analyses among the left DLPFC (the stimulate region) and other survived brain regions after group comparison; FC between the left DLPFC and all brain regions to find couplings among the brain regions. rTMS decreased the craving for smoking in patients with TUD. Comparing with the sham group, the rTMS group showed enhanced brain responses in the bilateral ACC, bilateral caudate and left thalamus to the No‐go smoking cues. Further, FC analyses among the survived brain regions showed that rTMS enhanced the FC in DLPFC–caudate and caudate–left thalamus pathways. Notably, enhanced FC between the DLPFC and bilateral basal ganglia thalamus was observed. The current study demonstrated the effectiveness of rTMS in the treatment of TUD, which is associated with enhanced brain responses that are responsible for executive control and reward processing; it enhanced top‐down control by reshaping the prefrontal–striatal pathways.