Centrally administered growth hormone secretagogue receptor antagonist DLys decreases alcohol intake and preference in male mice.

Alcohol use disorder (AUD) is a highly prevalent public health problem. The ghrelin system has been identified as a potential target for therapeutic intervention for AUD. Previous work showed that systemic administration of the growth hormone secretagogue receptor (GHSR) antagonist DLys reduced alcohol intake and preference in male mice. Yet, it is unclear whether central or peripheral GHSRs mediated these effects. We hypothesized that alcohol consumption is driven by central GHSRs and addressed this hypothesis by testing the effects of central administration of DLys. Male C57BL/6J mice consumed alcohol in a two-bottle choice procedure (10% ethanol versus water). DLys (2 nmol) was administered intracerebroventricularly for 7 days to examine alcohol intake and preference. DLys decreased alcohol intake and preference but had no effect on food intake. The effects on alcohol intake and preference persisted after several administrations, indicating lack of tolerance to DLys' effects. These results suggest that central administration of DLys is sufficient to reduce alcohol drinking and that DLys remains effective after several administrations when given intracerebroventricularly. Moreover, this work suggests that the effects of intracerebroventricularly administered DLys are specific to alcohol and do not generalize to other calorie-driven behaviors.

The crosstalk between fibroblast growth factor 21 (FGF21) system and substance use.

Existing literature indicates that communication between the central nervous system and the peripheral nervous system is disrupted by substance use disorders (SUDs), including alcohol use disorder (AUD). Fibroblast growth factor 21 (FGF21), a liver-brain axis hormone governing energy homeostasis, has been shown to modulate alcohol intake/preference and other substances. To further elucidate the relationship between FGF21, alcohol use, and other substance use, we conducted a scoping review to explore the association between FGF21 and SUDs. Increases in FGF21 reduce alcohol consumption while suppressing FGF21 increases alcohol consumption, demonstrating an inverse relationship. Alcohol elevates FGF21 levels primarily via the liver, subsequently promoting neuronal signals to curb alcohol intake. FGF21 activation engages molecular pathways that defend against alcohol-induced fat accumulation, oxidative stress, and inflammation. Considering the bidirectional association between FGF21 and alcohol, further studies on the FGF21 system as a potential pharmacotherapy for AUD and alcohol-associated liver disease are warranted.

IUPHAR review - Glucagon-like peptide-1 (GLP-1) and substance use disorders: An emerging pharmacotherapeutic target.

Addiction is a chronic relapsing disease with high morbidity and mortality. Treatments for addiction include pharmacological and psychosocial interventions; however, currently available medications are limited in number and efficacy. The glucagon-like-peptide-1 (GLP-1) system is emerging as a potential novel pharmacotherapeutic target for alcohol and other substance use disorders (ASUDs). In this review, we summarize and discuss the wealth of available evidence from testing GLP-1 receptor (GLP-1R) agonist medications in preclinical models and humans with ASUDs, possible mechanisms underlying the impact of GLP-1R agonists on alcohol/substance use, gaps in knowledge, and future directions. Most of the research with GLP-1R agonists has been conducted in relation to alcohol use; psychostimulants, opioids, and nicotine have also been investigated. Preclinical evidence suggests that GLP-1R agonists reduce alcohol/substance use and other related outcomes. The main proposed mechanisms are related to reward processing, stress, and cognitive function, as well as broader mechanisms related to satiety, changes in gastric motility, and glucose homeostasis. More in-depth mechanistic studies are warranted. Clinical studies have been limited and their findings have been less conclusive; however, most support the safety and potential efficacy of GLP-1R agonists in ASUD treatment. Identifying preferred compounds, as well as possible subgroups who are most responsive to GLP-1R agonists are some of the key research questions to translate the promising preclinical data into clinical settings. Several clinical trials are underway to test GLP-1R agonists in people with ASUDs.

Novel medications for problematic alcohol use.

Alcohol-related harm, a major cause of disease burden globally, affects people along a spectrum of use. When a harmful pattern of drinking is present in the absence of significant behavioral pathology, low-intensity brief interventions that provide information about health consequences of continued use provide large health benefits. At the other end of the spectrum, profound behavioral pathology, including continued use despite knowledge of potentially fatal consequences, warrants a medical diagnosis, and treatment is strongly indicated. Available behavioral and pharmacological treatments are supported by scientific evidence but are vastly underutilized. Discovery of additional medications, with a favorable balance of efficacy versus safety and tolerability can improve clinical uptake of treatment, allow personalized treatment, and improve outcomes. Here, we delineate the clinical conditions when pharmacotherapy should be considered in relation to the main diagnostic systems in use and discuss clinical endpoints that represent meaningful clinical benefits. We then review specific developments in three categories of targets that show promise for expanding the treatment toolkit. GPCRs remain the largest category of successful drug targets across contemporary medicine, and several GPCR targets are currently pursued for alcohol-related indications. Endocrine systems are another established category, and several promising targets have emerged for alcohol indications. Finally, immune modulators have revolutionized treatment of multiple medical conditions, and they may also hold potential to produce benefits in patients with alcohol problems.

Gut microbial diversity and functional characterization in people with alcohol use disorder: A case-control study.

Individuals with Alcohol Use Disorder (AUD) typically have comorbid chronic health conditions, including anxiety and depression disorders, increased sleep disruption, and poor nutrition status, along with gut microbial dysbiosis. To better understand the effects of gut dysbiosis previously shown in individuals with AUD, gut microbiome and metabolome were investigated between three cohorts. Two groups of individuals with AUD included treatment-seeking newly abstinent for at least six weeks (AB: N = 10) and non-treatment-seeking currently drinking (CD: N = 9) individuals. The third group was age, gender, and BMI-matched healthy controls (HC: N = 12). Deep phenotyping during two weeks of outpatient National Institutes of Health Clinical Center visits was performed, including clinical, psychological, medical, metabolic, dietary, and experimental assessments. Alpha and beta diversity and differential microbial taxa and metabolite abundance of the gut microbiome were examined across the three groups. Metabolites derived from the lipid super-pathway were identified to be more abundant in the AB group compared to CD and HC groups. The AB individuals appeared to be most clinically different from CD and HC individuals with respect to their gut microbiome and metabolome. These findings highlight the potential long-term effects of chronic alcohol use in individuals with AUD, even during short-term abstinence.

Integrated and collaborative care across the spectrum of alcohol-associated liver disease and alcohol use disorder.

The public health impact of alcohol-associated liver disease (ALD), a serious consequence of problematic alcohol use, and alcohol use disorder (AUD) is growing, with ALD becoming a major cause of alcohol-associated death overall and the leading indication for liver transplantation in the United States. Comprehensive care for ALD often requires treatment of AUD. Although there is a growing body of evidence showing that AUD treatment is associated with reductions in liver-related morbidity and mortality, only a minority of patients with ALD and AUD receive this care. Integrated and collaborative models that streamline both ALD and AUD care for patients with ALD and AUD are promising approaches to bridge this treatment gap and rely on multidisciplinary and interprofessional teams and partnerships. Here, we review the role of AUD care in ALD treatment, the effects of AUD treatment on liver-related outcomes, the impact of comorbid conditions such as other substance use disorders, obesity, and metabolic syndrome, and the current landscape of integrated and collaborative care for ALD and AUD in various treatment settings. We further review knowledge gaps and unmet needs that remain, including the role of precision medicine, the application of harm reduction approaches, the impact of health disparities, and the need for additional AUD treatment options, as well as further efforts to support implementation and dissemination.

Designing clinical trials to address alcohol use and alcohol-associated liver disease: an expert panel Consensus Statement.

Most patients with alcohol-associated liver disease (ALD) engage in heavy drinking defined as 4 or more drinks per day (56 g) or 8 (112 g) or more drinks per week for women and 5 or more drinks per day (70 g) or 15 (210 g) or more drinks per week for men. Although abstinence from alcohol after diagnosis of ALD improves life expectancy and reduces the risk of decompensation of liver disease, few studies have evaluated whether treatment of alcohol use disorders will reduce progression of liver disease and improve liver-related outcomes. In November 2021, the National Institute of Alcohol Abuse and Alcoholism commissioned a task force that included hepatologists, addiction medicine specialists, statisticians, clinical trialists and members of regulatory agencies to develop recommendations for the design and conduct of clinical trials to evaluate the effect of alcohol use, particularly treatment to reduce or eliminate alcohol use in patients with ALD. The task force conducted extensive reviews of relevant literature on alcohol use disorders and ALD. Findings were presented at one in-person meeting and discussed over the next 16 months to develop the final recommendations. As few clinical trials directly address this topic, the 28 recommendations approved by all members of the task force represent a consensus of expert opinions.

Parosmia Is Positively Associated With Problematic Drinking, as Is Phantosmia With Depressive Symptoms.

OBJECTIVES: Alcohol use disorder (AUD) is a global health problem with significant negative consequences, including preventable deaths. Although olfactory dysfunction is associated with chronic alcohol drinking, the relationship among specific types of olfactory deficits, depressive symptoms, and problematic drinking remains to be explored. Here, we examined the prevalence of olfactory distortion (parosmia) and hallucination (phantosmia) and assessed their associations with problematic drinking and depressive symptoms. METHODS: In April-June 2022, 250 participants across the spectrum of AUD were recruited for assessment in the National Institute on Alcohol Abuse and Alcoholism COVID-19 Pandemic Impact on Alcohol study. Surveys covered self-reported olfactory function, depressive symptoms, and problematic drinking, with key measures assessed, including the Alcohol Use Disorders Identification Test and the Patient Health Questionnaire. Predictors in the analysis included parosmia and phantosmia, with covariates comprising age, sex, socioeconomic status, race, ethnicity, COVID-19 infection status, and smoking status. RESULTS: Among 250 individuals, 5.2% experienced parosmia and 4.4% reported phantosmia. Parosmia was associated with higher Alcohol Use Disorders Identification Test scores (ß = 7.14; 95% confidence interval = 3.31, 10.96; P < 0.001), whereas phantosmia was linked to higher Patient Health Questionnaire scores (ß = 3.32; 95% confidence interval = 0.22, 6.42; P = 0.03). These associations persisted in both the full sample and the subset of participants without COVID-19. CONCLUSIONS: Our study highlights strong existing links among olfactory deficits, problem drinking, and depressive symptoms, underscoring the need to assess smell impairments in clinical settings. Future research should explore these connections further to develop new treatments for individuals with AUD and depression.

Alcohol use disorder and body mass index show genetic pleiotropy and shared neural associations.

Background: The prevalence of co-occurring heavy alcohol consumption and obesity is increasing in the United States. Despite neurobiological overlap in the regulation of alcohol consumption and eating behavior, alcohol- and body mass index (BMI)-related phenotypes show no or minimal genetic correlation. We hypothesized that the lack of genetic correlation is due to mixed effect directions of variants shared by AUD and BMI. Methods: We applied MiXeR, to investigate shared genetic architecture between AUD and BMI in individuals of European ancestry. We used conjunctional false discovery rate (conjFDR) analysis to detect loci associated with both phenotypes and their directional effect, Functional Mapping and Annotation (FUMA) to identify lead single nucleotide polymorphisms (SNPs), Genotype-Tissue Expression (GTEx) samples to examine gene expression enrichment across tissue types, and BrainXcan to evaluate the shared associations of AUD and BMI with brain image-derived phenotypes. Results: MiXeR analysis indicated polygenic overlap of 80.9% between AUD and BMI, despite a genetic correlation (r g ) of -.03. ConjFDR analysis yielded 56 lead SNPs with the same effect direction and 76 with the opposite direction. Of the 132 shared lead SNPs, 53 were novel for both AUD and BMI. GTEx analyses identified significant overexpression in the frontal cortex (BA9), hypothalamus, cortex, anterior cingulate cortex (BA24), hippocampus, and amygdala. Amygdala and caudate nucleus gray matter volumes were significantly associated with both AUD and BMI in BrainXcan analyses. Conclusions: More than half of variants significantly associated with AUD and BMI had opposite directions of effect for the traits, supporting our hypothesis that this is the basis for their lack of genetic correlation. Follow-up analyses identified brain regions implicated in executive functioning, reward, homeostasis, and food intake regulation. Together, these findings clarify the extensive polygenic overlap between AUD and BMI and elucidate several overlapping neurobiological mechanisms.

Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet.

The stomach-derived hormone ghrelin regulates essential physiological functions. The ghrelin receptor (GHSR) has ligand-independent actions; therefore, GHSR gene deletion may be a reasonable approach to investigate the role of this system in feeding behaviors and diet-induced obesity (DIO). Here, we investigate the effects of a long-term (12-month) high-fat (HFD) versus regular diet on obesity-related measures in global GHSR-KO and wild-type (WT) Wistar male and female rats. Our main findings are that the GHSR gene deletion protects against DIO and decreases food intake during HFD in male but not in female rats. GHSR gene deletion increases thermogenesis and brain glucose uptake in male rats and modifies the effects of HFD on brain glucose metabolism in a sex-specific manner, as assessed with small animal positron emission tomography. We use RNA-sequencing to show that GHSR-KO rats have upregulated expression of genes responsible for fat oxidation in brown adipose tissue. Central administration of a novel GHSR inverse agonist, PF-5190457, attenuates ghrelin-induced food intake, but only in male, not in female mice. HFD-induced binge-like eating is reduced by inverse agonism in both sexes. Our results support GHSR as a promising target for new pharmacotherapies for obesity.

Role of ghrelin hormone in the development of alcohol-associated liver disease.

Fatty liver is the earliest response of the liver to excessive alcohol consumption. Previously we identified that chronic alcohol administration increases levels of stomach-derived hormone, ghrelin, which by reducing circulating insulin levels, ultimately contributes to the development of alcohol-associated liver disease (ALD). In addition, ghrelin directly promotes fat accumulation in hepatocytes by enhancing de novo lipogenesis. Other than promoting ALD, ghrelin is known to increase alcohol craving and intake. In this study, we used a ghrelin receptor (GHSR) knockout (KO) rat model to characterize the specific contribution of ghrelin in the development of ALD with emphasis on energy homeostasis. Male Wistar wild type (WT) and GHSR-KO rats were pair-fed the Lieber-DeCarli control or ethanol diet for 6 weeks. At the end of the feeding period, glucose tolerance test was conducted, and tissue samples were collected. We observed reduced alcohol intake by GHSR-KOs compared to a previous study where WT rats were fed ethanol diet ad libitum. Further, when the WTs were pair-fed to GHSR-KOs, the KO rats exhibited resistance to develop ALD through improving insulin secretion/sensitivity to reduce adipose lipolysis and hepatic fatty acid uptake/synthesis and increase fatty acid oxidation. Furthermore, proteomic data revealed that ethanol-fed KO exhibit less alcohol-induced mitochondrial dysfunction and oxidative stress than WT rats. Proteomic data also confirmed that the ethanol-fed KOs are insulin sensitive and are resistant to hepatic steatosis development compared to WT rats. Together, these data confirm that inhibiting ghrelin action prevent alcohol-induced liver and adipose dysfunction independent of reducing alcohol intake.

Amylin in Alcohol Addiction: A Potential New Treatment Target or an Adjuvant to Other Treatments?

Amylin is a neuroendocrine hormone with a potential role in addictive disorders, including alcohol use disorder (AUD). In addition to reducing appetitive behavior, amylin has been shown to affect alcohol-related behaviors in rodents. Delineating the biobehavioral correlates of amylin in relation to alcohol seeking and consumption has the potential of identifying new treatment targets for AUD, yet additional translational and human research is needed.

Ghrelin decreases sensitivity to negative feedback and increases prediction-error related caudate activity in humans, a randomized controlled trial.

The stomach-derived hormone ghrelin plays not only a role in feeding, starvation, and survival, but it has been suggested to also be involved in the stress response, in neuropsychiatric conditions, and in alcohol and drug use disorders. Mechanisms related to reward processing might mediate ghrelin's broader effects on complex behaviors, as indicated by animal studies and mostly correlative human studies. Here, using a within-subject double-blind placebo-controlled design with intravenous ghrelin infusion in healthy volunteers (n = 30), we tested whether ghrelin alters sensitivity to reward and punishment in a reward learning task. Parameters were derived from a computational model of participants' task behavior. The reversal learning task with monetary rewards was performed during functional brain imaging to investigate ghrelin effects on brain signals related to reward prediction errors. Compared to placebo, ghrelin decreased punishment sensitivity (t = -2.448, p = 0.021), while reward sensitivity was unaltered (t = 0.8, p = 0.43). We furthermore found increased prediction-error related activity in the dorsal striatum during ghrelin administration (region of interest analysis: t-values ≥ 4.21, p-values ≤ 0.044). Our results support a role for ghrelin in reward processing that extends beyond food-related rewards. Reduced sensitivity to negative outcomes and increased processing of prediction errors may be beneficial for food foraging when hungry but could also relate to increased risk taking and impulsivity in the broader context of addictive behaviors.

Reduced drug use as an alternative valid outcome in individuals with stimulant use disorders: Findings from 13 multisite randomized clinical trials.

BACKGROUND AND AIMS: Total abstinence has historically been the goal of treatment for substance use disorders; however, there is a growing recognition of the health benefits associated with reduced use as a harm reduction measure in stimulant use disorders treatment. We aimed to assess the validity of reduced stimulant use as an outcome measure in randomized controlled trials (RCTs) of pharmacological interventions for stimulant use disorder. DESIGN: We conducted a secondary analysis of a pooled dataset of 13 RCTs. SETTING AND PARTICIPANTS: Participants were individuals seeking treatment for cocaine or methamphetamine use disorders (N = 2062) in a wide range of treatment facilities in the United States. MEASUREMENTS: We validated reduced stimulant use against a set of clinical indicators drawn from harmonized measurements, including severity of problems caused by drug use, comorbid depression, global severity of substance use and improvement, severity of drug-seeking behavior, craving and high-risk behaviors, all assessed at the end of the trial, as well as follow-up urine toxicology. A series of mixed effect regression models was conducted to validate reduction in frequency of use against no reduction in use and abstinence. FINDINGS: More participants reduced frequency of primary drug use than achieved abstinence (18.0% vs. 14.2%, respectively). Reduced use was significantly associated with decreases in craving for the primary drug [60.1%, 95% confidence interval (CI) = 54.3%-64.7%], drug seeking behaviors (41.0%, 95% CI = 36.6%-45.7%), depression severity (39.9%, 95% CI = 30.9%-48.3%), as well as multiple measures of global improvement in psychosocial functioning and severity of drug-related problems, albeit less strongly so than abstinence. Moreover, reduced use was associated with sustained clinical benefit at follow-up, as confirmed by negative urine tests (adjusted odds ratio compared with those with no reduction in use: 0.50, 95% CI = 0.35-0.71). CONCLUSION: Reduced frequency of stimulant use appears to be associated with meaningful improvement in various clinical indicators of recovery. Assessment of reduced use, in addition to abstinence, could broaden the scope of outcomes measured in randomized controlled trials of stimulant use disorders and facilitate the development of more diverse treatment approaches.

Lifetime use of alcohol and cannabis among U.S. adolescents across age: Exploring differential patterns by sex and race/ethnicity using the 2019 NSDUH data.

Background: Early use of alcohol and cannabis is associated with health and social problems. It is unclear how lifetime use changes for each additional year of age during adolescence, and whether this change varies by sex and race/ethnicity. This study characterized lifetime rates of alcohol and cannabis use by age among 12- to 17-year-old American youth and explored differential patterns by sex and race/ethnicity. Methods: Data were obtained from the 2019 National Survey on Drug Use and Health. Analyses were restricted to 12-17-year-olds who were non-Hispanic White, non-Hispanic Black, or Hispanic/Latino (n = 11,830). We estimated the increase in lifetime use of alcohol and cannabis by age for the full sample and stratified by sex and race/ethnicity. Slopes of the regression lines were compared to assess differential patterns across groups. Results: In these cross-sectional analyses, reported lifetime use increased substantially from age 12 to 17 for alcohol (6.4 % to 53.2 %) and cannabis (1.3 % to 35.9 %). The increase in lifetime alcohol use was slightly, but not significantly, steeper among girls than boys (F1,8 = 3.40, p = 0.09). White and Latino youth showed similar rates of increase in lifetime alcohol use, which was significantly flatter among Black youth (F2,12=21.26, p<0.0001). Latino youth had a slightly, but not significantly, steeper increase in lifetime cannabis use than White and Black youth (F2,12=3.17, p = 0.07). Conclusions: Reports of lifetime alcohol and cannabis use substantially increase from age 12 to 17 and the rates are different according to sex and race/ethnicity, highlighting the need for early and tailored substance use prevention in adolescents.