<bold>Importance</bold> Associations among general intelligence (IQ), educational attainment (EA), and alcohol use disorder (AUD) are not well understood. <bold>Objective</bold> To examine the relationship between IQ, EA, and AUD risk. <bold>Design, Setting, and Participants</bold> The association between IQ and AUD risk was examined in a Swedish national conscription cohort. Potential causality was explored using mendelian randomization (MR) analyses, and the association of polygenic scores (PGS) for cognitive performance with AUD diagnosis was assessed. Participant data were obtained from cross-linked Swedish national registers, genome-wide association study (GWAS) summary statistics, and the US Yale-Penn cohort. <bold>Exposures</bold> IQ and genetic variants associated with cognitive performance. <bold>Main Outcomes and Measures</bold> Hazard ratios (HRs; time-to-event analyses) or odds ratios (ORs) for AUD. <bold>Results</bold> Included in this study was a national cohort of 645 488 males, born between 1950 and 1962, from the Swedish Military Conscription Register, of whom 573 855 individuals were included in this analysis. All individuals were aged 18 years at IQ assessment with no substance use disorder diagnosis at conscription, and mean (SD) follow-up time (SD) was 60.5 (7.9) years. Summary statistics from GWAS of cognitive performance (n = 257 481) and AUD (total = 753 248; cases = 113 325) in individuals of European-like genetic ancestry (EUR), with FinnGen AUD GWAS as a replication sample (total = 500 348; cases = 20 597), were used for MR analyses. PGS analyses were conducted using the data of EUR individuals from the Yale-Penn cohort (n = 5424). IQ at age 18 years was inversely associated with AUD risk in Swedish males (adjusted HR, 1.43; 95% CI, 1.40-1.47; P < .001), adjusting for parental substance use disorder, probands' psychiatric disorders, socioeconomic factors, and birth year strata. MR analyses suggested a causal relationship between lower cognitive performance and AUD risk (beta [SE], 0.11 [0.02]; P = 2.6 x 10(-12)). The mediating role of EA differed between national contexts. Higher cognitive performance PGS were associated with reduced odds of AUD in Yale-Penn participants (OR, 0.83; 95% CI, 0.78-0.89). <bold>Conclusions and Relevance</bold> IQ and cognitive performance have a significant but context-dependent association with AUD risk, highlighting the need for a better understanding of the interplay among genetic factors, cognitive traits, and sociocultural influences on AUD susceptibility.

Alcohol use disorder (AUD) is a major global health issue, with current treatments often limited in efficacy and patient acceptance. The gamma-aminobutyric acid (GABA) system, particularly GABAB receptors (GABABR), is crucial in the pathophysiology of AUD. This review aimed to evaluate the potential of transcranial magnetic stimulation (TMS) as a tool for identifying neurophysiological biomarkers of GABABR engagement in AUD. Two independent systematic literature reviews were conducted using MEDLINE, PsychINFO, and EMBASE databases to evaluate: (1) the neurophysiological effects of GABABR pharmacological manipulation, and (2) the neurophysiological alterations linked to alcohol consumption and addiction. Studies included human subjects and assessed cortical excitability using TMS-EMG or TMS-EEG. Data on study design, sample characteristics, TMS protocols, and neurophysiological outcomes were extracted and analyzed. The final analysis included 13 studies evaluating the effects of GABABR agonism (mainly baclofen administration) and 16 studies on acute and chronic alcohol consumption. The GABABR agonism studies were primarily randomized, placebo-controlled experimental medicine studies in healthy controls. Results showed that GABABR agonism enhanced long-interval intracortical inhibition (LICI) and increased post-TMS N100 amplitude, indicating the sensitivity of these parameters to GABABR manipulation. The alcohol consumption studies were mostly case-control or within-subject designs, with fewer randomized controlled trials. Acute and chronic alcohol consumption was found to alter LICI, N100 amplitude, and the cortical silent period (CSP). However, no alcohol-induced changes were observed in short-interval intracortical inhibition (SICI), which depends on GABAAR activation. Despite limitations, this review indicates GABABR functioning to be measurable and different in AUD compared to healthy controls. Overall, the reviewed literature supports the hypothesis that GABABR is involved in the neurotransmission imbalances induced by both acute and chronic alcohol intake, with potential regional differences that warrant further investigation. Standardized protocols and larger studies are needed to validate these findings and their clinical relevance.

A coherent sense of self is crucial for social functioning and mental health. The N-methyl-D-aspartate antagonist ketamine induces short-term dissociative experiences and has therefore been used to model an altered state of self-perception. This randomized double-blind placebo-controlled cross-over study investigated the mechanisms for ketamine's effects on the bodily sense of self in the context of affective touch. Thirty healthy participants (15 females/15 males, age 19-39) received intravenous ketamine or placebo while performing self-touch and receiving touch by someone else during functional MRI - a previously established neural measure of tactile self-other-differentiation. Afterwards, tactile detection thresholds during self- and other-touch were assessed, as well as dissociative states, interoceptive awareness, and social touch attitudes. Compared to placebo, ketamine administration elicited dissociation and reduced neural activity associated with self-other-differentiation in the right temporoparietal cortex, which was most pronounced during other-touch. This reduction correlated with ketamine-induced reductions in interoceptive awareness. The temporoparietal cortex showed higher connectivity to somatosensory cortex and insula during other- compared to self-touch. This difference was augmented by ketamine, and correlated with dissociation strength for somatosensory cortex. These results demonstrate that disrupting the self-experience through ketamine administration affects neural activity associated with self-other-differentiation in a region involved in touch perception and social cognition, especially with regard to social touch by someone else. This process may be driven by ketamine-induced effects on top-down signaling, rendering the processing of predictable self-generated and unpredictable other-generated touch more similar. These findings provide further evidence for the intricate relationship of the bodily self with the tactile sense.

Importance In the last 25 years, functional magnetic resonance imaging drug cue reactivity (FDCR) studies have characterized some core aspects in the neurobiology of drug addiction. However, no FDCR-derived biomarkers have been approved for treatment development or clinical adoption. Traversing this translational gap requires a systematic assessment of the FDCR literature evidence, its heterogeneity, and an evaluation of possible clinical uses of FDCR-derived biomarkers. Objective To summarize the state of the field of FDCR, assess their potential for biomarker development, and outline a clear process for biomarker qualification to guide future research and validation efforts. Evidence Review The PubMed and Medline databases were searched for every original FDCR investigation published from database inception until December 2022. Collected data covered study design, participant characteristics, FDCR task design, and whether each study provided evidence that might potentially help develop susceptibility, diagnostic, response, prognostic, predictive, or severity biomarkers for 1 or more addictive disorders. Findings There were 415 FDCR studies published between 1998 and 2022. Most focused on nicotine (122 [29.6%]), alcohol (120 [29.2%]), or cocaine (46 [11.1%]), and most used visual cues (354 [85.3%]). Together, these studies recruited 19 311 participants, including 13 812 individuals with past or current substance use disorders. Most studies could potentially support biomarker development, including diagnostic (143 [32.7%]), treatment response (141 [32.3%]), severity (84 [19.2%]), prognostic (30 [6.9%]), predictive (25 [5.7%]), monitoring (12 [2.7%]), and susceptibility (2 [0.5%]) biomarkers. A total of 155 interventional studies used FDCR, mostly to investigate pharmacological (67 [43.2%]) or cognitive/behavioral (51 [32.9%]) interventions; 141 studies used FDCR as a response measure, of which 125 (88.7%) reported significant interventional FDCR alterations; and 25 studies used FDCR as an intervention outcome predictor, with 24 (96%) finding significant associations between FDCR markers and treatment outcomes. Conclusions and Relevance Based on this systematic review and the proposed biomarker development framework, there is a pathway for the development and regulatory qualification of FDCR-based biomarkers of addiction and recovery. Further validation could support the use of FDCR-derived measures, potentially accelerating treatment development and improving diagnostic, prognostic, and predictive clinical judgments.

The Nociceptin/Orphanin FQ (N/OFQ) peptide and its receptor NOP are highly expressed within several regions of the mesolimbic system, including the ventral tegmental area (VTA). Evidence indicates that the N/OFQ-NOP receptor system is involved in reward processing and historically it has been proposed that activation of NOP receptors attenuates the motivation for substances of abuse. However, recent findings demonstrated that drug self -administration and relapse to drug -seeking are also attenuated after administration of NOP receptor antagonists. Here, to shed light on the mechanisms through which NOP receptor blockers modulate these processes, we utilized ex vivo patch -clamp recordings to investigate the effect of the selective NOP receptor antagonist LY2817412 on VTA dopaminergic (DA) function in male rats. Results showed that, similar to the endogenous NOP receptor agonist N/OFQ, LY2817412 reduced the spontaneous basal firing discharge of VTA DA neurons. Consistently, we found that NOP receptors are expressed both in VTA DA and GABA cells and that LY2817412 slice perfusion increased GABA release onto VTA DA cells. Finally, in the attempt to dissect the role of postsynaptic and presynaptic NOP receptors, we tested the effect of N/OFQ and LY2817412 in the presence of GABA receptors blockers. Results showed that the effect of LY2817412 was abolished following pretreatment with GABABR, but not GABAAR, blockers. Conversely, inhibition of DA neuronal activity by N/OFQ was unaffected by blockade of GABA receptors. Altogether, these results suggest that both NOP receptor agonists and antagonists can decrease VTA DA neuronal activity, but through distinct mechanisms of action. The effect of NOP receptor antagonists occurs through a GABABR-mediated mechanism while NOP receptor agonists seem to act via a direct effect on VTA DA neurons.

Aim: Alcohol use disorder (AUD) is the most prevalent form of addiction, with a great burden on society and limited treatment options. A recent clinical trial reported significant clinical benefits of deep transcranial magnetic stimulations (Deep TMS) targeting midline frontocortical areas. However, the underlying biological substrate remained elusive. Here, we report the effect of Deep TMS on the microstructure of white matter.Methods: A total of 37 (14 females) AUD treatment-seeking patients were randomized to sham or active Deep TMS. Twenty (six females) age-matched healthy controls were included. White matter integrity was evaluated by fractional anisotropy (FA). Secondary measures included brain functional connectivity and self-reports of craving and drinking units in the 3 months of follow-up period.Results: White matter integrity was compromised in patients with AUD relative to healthy controls, as reflected by the widespread reduction in FA. This alteration progressed during early abstinence (3 weeks) in the absence of Deep TMS. However, stimulation of midline frontocortical areas arrested the progression of FA changes in association with decreased craving and relapse scores. Reconstruction of axonal tracts from white-matter regions showing preserved FA values identified cortical regions in the posterior cingulate and dorsomedial prefrontal cortices where functional connectivity was persistently modulated. These effects were absent in the sham-stimulated group.Conclusions: By integrating brain structure and function to characterize the alcohol-dependent brain, this study provides mechanistic insights into the TMS effect, pointing to myelin plasticity as a possible mediator.

Alcohol use despite negative consequences is a core phenomenon of alcohol addiction. We recently used alcohol self-administration that is resistant to footshock punishment as a model of this behavior, and found that activity of PKC delta + GABAergic neurons in the central amygdala (CeA) is a determinant of individual susceptibility for punishment resistance. In the present study, we examined whether activation of GABA(B) receptors in CeA can attenuate the activity of PKC delta + neurons in this region, and whether this will result in suppression of punishment- resistant alcohol self-administration in the minority of rats that show this behavior. Systemic administration of the clinically approved GABA(B) agonist baclofen (1 and 3 mg/kg) dose- dependently reduced punishment-resistant alcohol self-administration. Bilateral microinjections of baclofen into CeA (64 ng in 0.3 mu l/side) reduced the activity of PKC delta + neurons, as measured by Fos expression. This manipulation also selectively suppressed punished alcohol self-administration in punishment-resistant rats. Expression analysis indicated that virtually all CeA PKC delta + neurons express the GABA(B) receptor. Using in vitro electrophysiology, we found that baclofen induced hyperpolarization of CeA neurons, reducing their firing rate in response to depolarizing current injections. Together, our findings provide a potential mechanism that contributes to the clinical efficacy of baclofen in alcohol addiction. Therapeutic use of baclofen itself is limited by problems of tolerance and need for dose escalation. Our findings support a mechanistic rationale for developing novel, improved alcohol addiction medications that target GABA(B) receptors, and that lack these limitations, such as e.g., GABA(B) positive allosteric modulators (PAM:s).

Alcohol is one of the major risk factors for negative health outcomes worldwide. It accounts for more than 60 alcohol-related diseases, ranging from addiction, through liver cirrhosis, to cancer. Collectively, these conditions account for mortality and morbidity that make alcohol use one of the leading preventable causes of disability adjusted life-years (DALYs) lost globally. In this book, an international faculty covers all aspects of alcohol-related disorders, ranging from addiction/alcohol use disorders (AUD) to alcohol-related diseases of other organs such as liver, heart or cancer. A special focus is to reach out to primary care physicians who are in the front line of this major health problem. The book also provides an update for addiction specialists, as well as specialists in internal medicine, gastroenterology and hepatology. The book is divided into sections that include epidemiology, alcohol use disorders and addiction, alcohol-related liver disease, alcoholic hepatitis, primary care and interdisciplinary approaches and other alcohol-related diseases. Besides current diagnostic measures and treatment strategies, the book deals with the many underlying molecular and genetic mechanisms of alcohol toxicity. Novel insights include prospective data on all-cause mortality and the emerging major role of alcohol-mediated hemolysis and enhanced red blood cell turnover. The book also aims at guiding policy makers to handle the topic of alcohol in our society more responsibly. 

Objectives: Childhood maltreatment (CM), widely held as a risk factor for substance use disorders (SUDs), is commonly assessed using the Childhood Trauma Questionnaire (CTQ). Retrospective self-reports are, however, potentially subject to bias. We used a unique patient sample with prospectively documented CM to examine the performance of the CTQ and how this is affected by the presence of SUD.

Methods: Analysis was based on a total of 104 individuals. Subjects with prospectively recorded CM were identified from a specialized childhood trauma unit in Linköping, Sweden (n = 55; 31 with SUD, 61% females; 24 without SUD, 71% females). Clinical controls had SUD but no CM (n = 25, 48% females). Healthy controls had neither SUD nor CM (n = 24, 54% females). We analyzed the agreement between retrospective CTQ scores and prospectively documented CM by κ analysis and assessed the performance of the CTQ to identify CM exposure using receiver operating characteristic (ROC) analysis.

Results: Agreement between prospectively and retrospectively recorded CM exposure was poor for sexual abuse (36.6%, Cohen κ = 0.32, P = 0.008) and physical abuse (67.3%, κ = 0.35, P = 0.007). Overall CTQ performance was fair (ROC: area under the ROC curve = 0.78, optimal cutoff = 36.5, sensitivity = 0.65, specificity = 0.75). However, performance was excellent in the absence of SUD (area under the ROC curve = 0.93, cutoff = 32.0, sensitivity = 0.88, specificity = 0.88), but poor in participants with lifetime SUD (area under the ROC curve = 0.62, cutoff = 42.0, sensitivity = 0.60, specificity = 0.36).

Conclusions: These data support the CTQ as a tool to assess CM exposure but suggest that it may be less useful in patients with SUD.