Ketone Supplementation Dampens Subjective and Objective Responses to Alcohol: Evidence From a Preclinical Rat Study and a Randomized, Cross-Over Trial in Healthy Volunteers.

BACKGROUND: Previous preclinical and human studies have shown that a high-fat ketogenic diet and ketone supplements (KS) are efficacious in reducing alcohol craving, alcohol consumption, and signs of alcohol withdrawal. However, the effects of KS on alcohol sensitivity are unknown. METHODS: In this single-blind, cross-over study, 10 healthy participants (3 females) were administered a single, oral dose of a KS (25 g of ketones from D-ß-hydroxybutyric acid and R-1,3-butanediol) or placebo 30 minutes before an oral alcohol dose (0.25 g/kg for women; 0.31 g/kg for men). Assessments of breath alcohol concentration and blood alcohol levels (BAL) and responses on the Drug Effect Questionnaire were repeatedly obtained over 180 minutes after alcohol consumption. In a parallel preclinical study, 8 Wistar rats (4 females) received an oral gavage of KS (0.42 g ketones/kg), water, or the sweetener allulose (0.58 g/kg) followed 15 minutes later by an oral alcohol dose (0.8 g/kg). BAL was monitored for 240 minutes after alcohol exposure. RESULTS: In humans, the intake of KS before alcohol significantly blunted breath alcohol concentration and BAL, reduced ratings of alcohol liking and wanting more, and increased disliking for alcohol. In rats, KS reduced BAL more than either allulose or water. CONCLUSION: KS altered physiological and subjective responses to alcohol in both humans and rats, and the effects were likely not mediated by the sweetener allulose present in the KS drink. Therefore, KS could potentially reduce the intoxicating effects of alcohol.

Association of topiramate prescribed for any indication with reduced alcohol consumption in electronic health record data.

BACKGROUND AND AIMS: Topiramate is a medication that is widely prescribed to treat a variety of conditions, including alcohol use disorder (AUD). We used electronic health record (EHR) data to measure topiramate's effects on drinking in individuals differentiated by a history of AUD. DESIGN: Parallel-groups comparison of patients prescribed topiramate and a propensity score-matched comparison group. SETTING: A large US integrated health-care system. PARTICIPANTS: Patients with Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores prior to and after a minimum of 180 days of topiramate prescription for any indication and a propensity score-matched group. The sample included 5918 patients with an electronic health record diagnosis of alcohol use disorder at any time (AUD-hx-pos) (1738 topiramate-exposed and 4180 controls) and 23 614 patients with no EHR diagnosis of AUD (AUD-hx-neg) (6324 topiramate-exposed and 17 290 controls). MEASUREMENTS: Regression analyses compared difference-in-difference (DiD) estimates, separately by AUD history. DiD estimates represent exposure-group (i.e. topiramate versus control) differences on the pre-post difference in AUDIT-C score. Effects of baseline AUDIT-C score and daily topiramate dosage were also tested. FINDINGS: AUD-hx-neg patients who received topiramate had a greater reduction in AUDIT-C score (-0.11) than matched controls (-0.04). This yielded a DiD score of -0.07 [95% confidence interval (CI) = -0.11,-0.03; P = 0.002], with the greatest effect among AUD-hx-neg patients with a baseline AUDIT-C score of 4+ (DiD = -0.35, 95% CI = -0.49, -0.21; P < 0.0001) and those prescribed > 150 mg/day of the medication (DiD = -0.15, 95%CI = -0.23, -0.07; P < 0.001). DISCUSSION: Among individuals with no history of alcohol use disorder, topiramate appears to be associated with reduced drinking. This small effect is most evident among patients with higher baseline drinking levels and at a higher average daily topiramate dosage.

Nutritional Ketosis as a Potential Treatment for Alcohol Use Disorder.

Alcohol use disorder (AUD) is a chronic, relapsing brain disorder, characterized by compulsive alcohol seeking and disrupted brain function. In individuals with AUD, abstinence from alcohol often precipitates withdrawal symptoms than can be life threatening. Here, we review evidence for nutritional ketosis as a potential means to reduce withdrawal and alcohol craving. We also review the underlying mechanisms of action of ketosis. Several findings suggest that during alcohol intoxication there is a shift from glucose to acetate metabolism that is enhanced in individuals with AUD. During withdrawal, there is a decline in acetate levels that can result in an energy deficit and could contribute to neurotoxicity. A ketogenic diet or ingestion of a ketone ester elevates ketone bodies (acetoacetate, ß-hydroxybutyrate and acetone) in plasma and brain, resulting in nutritional ketosis. These effects have been shown to reduce alcohol withdrawal symptoms, alcohol craving, and alcohol consumption in both preclinical and clinical studies. Thus, nutritional ketosis may represent a unique treatment option for AUD: namely, a nutritional intervention that could be used alone or to augment the effects of medications.

Genetic underpinnings of risky behaviour relate to altered neuroanatomy.

Previous research points to the heritability of risk-taking behaviour. However, evidence on how genetic dispositions are translated into risky behaviour is scarce. Here, we report a genetically informed neuroimaging study of real-world risky behaviour across the domains of drinking, smoking, driving and sexual behaviour in a European sample from the UK Biobank (N = 12,675). We find negative associations between risky behaviour and grey-matter volume in distinct brain regions, including amygdala, ventral striatum, hypothalamus and dorsolateral prefrontal cortex (dlPFC). These effects are replicated in an independent sample recruited from the same population (N = 13,004). Polygenic risk scores for risky behaviour, derived from a genome-wide association study in an independent sample (N = 297,025), are inversely associated with grey-matter volume in dlPFC, putamen and hypothalamus. This relation mediates roughly 2.2% of the association between genes and behaviour. Our results highlight distinct heritable neuroanatomical features as manifestations of the genetic propensity for risk taking.

Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium.

To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = -5.39, p = 7.2 × 10-8). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10-8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10-6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10-8) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10-7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10-5; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10-5). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10-5; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.

Opioid Misuse as a Predictor of Alcohol Treatment Outcomes in the COMBINE Study: Mediation by Medication Adherence.

BACKGROUND: Alcohol is often consumed with opioids and alcohol misuse interferes with treatment for opioid use disorder (OUD). Drug misuse is associated with worse alcohol use disorder (AUD) treatment outcomes, yet no studies have investigated the role of opioid misuse in AUD treatment outcomes. METHODS: We conducted secondary analyses of the medication conditions of the COMBINE study (n = 1,226), a randomized clinical trial of medications (acamprosate and/or naltrexone) and behavioral interventions (medication management and/or behavioral intervention) for alcohol dependence. We examined associations between baseline opioid misuse and the use of cannabis and other drugs with time to first drinking day, time to first heavy drinking day, and the frequency and intensity of drinking during treatment and 1 year following treatment, based on latent profile analysis. Opioid misuse was defined as use of illicit or prescription opioids without a prescription or not as directed in the previous 6 months, in the absence of OUD. Self-reported cannabis and other drug use were also examined. Seventy individuals (5.7%) met the opioid misuse definition and 542 (44.2%) reported use of cannabis or other drugs without opioid misuse. We also examined medication adherence as a potential mediator. RESULTS: Baseline opioid misuse significantly predicted the time to first heavy drinking day (OR = 1.38 [95% CI: 1.13, 1.64], p = 0.001) and a higher probability of being in a heavier and more frequent drinking profile at the end of treatment (OR = 2.90 [95% CI: 1.43, 5.90], p = 0.003), and at 1 year following treatment (OR = 2.66 [95% CI: 1.26, 5.59], p = 0.01). Cannabis and other drug use also predicted outcomes. Medication adherence partially mediated the association between opioid misuse, cannabis use, other drug use, and treatment outcomes. CONCLUSIONS: Opioid misuse and other drug use were associated with poorer AUD treatment outcomes, which was partially mediated by medication adherence. Clinicians and researchers should assess opioid misuse and other drug use in patients undergoing AUD treatment.

Alcohol and opioid dependence medications: prescription trends, overall and by physician specialty.

Over the past decade, advances in addiction neurobiology have led to the approval of new medications to treat alcohol and opioid dependence. This study examined data from the IMS National Prescription Audit (NPA) Plus database of retail pharmacy transactions to evaluate trends in U.S. retail sales and prescriptions of FDA-approved medications to treat substance use disorders. Data reveal that prescriptions for alcoholism medications grew from 393,000 in 2003 ($30 million in sales) to an estimated 720,000 ($78 million in sales) in 2007. The growth was largely driven by the introduction of acamprosate in 2005, which soon became the market leader ($35 million in sales). Prescriptions for the two buprenorphine formulations increased from 48,000 prescriptions ($5 million in sales) in the year of their introduction (2003) to 1.9 million prescriptions ($327 million in sales) in 2007. While acamprosate and buprenorphine grew rapidly after market entry, overall substance abuse retail medication sales remain small relative to the size of the population that could benefit from treatment and relative to sales for other medications, such as antidepressants. The extent to which substance dependence medications will be adopted by physicians and patients, and marketed by industry, remains uncertain.

Opioid-, cannabis- and alcohol-dependent women show more rapid progression to substance abuse treatment.

UNLABELLED: Alcohol-dependent women progress faster from onset of alcohol drinking to entry into treatment, experiencing an earlier onset (i.e., "telescoping") of alcohol-related complications. This phenomenon also appears to be evident in drug-dependent women, though the data available to support telescoping in drug dependence is less abundant. OBJECTIVE: To evaluate gender effects on progression to treatment entry and on the frequency, severity and related complications of DSM-III-R drug and alcohol dependence among 271 substance-dependent patients (mean age: 32.6 years; 156 women). METHOD: Multivariate and univariate ANCOVA was used to compare age at onset of regular use of cocaine, opioids, cannabis and alcohol and time elapsed between initiation of regular use of each substance and entry into an index or current substance abuse treatment. Scores on the Addiction Severity Index (ASI) were also examined. RESULTS: There was no gender difference among patients in the age at onset of regular use of any substance. Women experienced fewer years of regular use of opioids and cannabis, and fewer years of regular alcohol drinking before entering treatment. Although the severity of drug and alcohol dependence did not differ by gender, women reported more severe psychiatric, medical and employment complications. CONCLUSIONS: These findings support the notion of an accelerated progression to treatment entry among opioid-, cannabis- and alcohol-dependent women, and suggest that there exists a gender-based vulnerability to the adverse consequences of these disorders.

Effects of nicotine deprivation on urges to drink and smoke in alcoholic smokers.

AIM: This study examined the effect of nicotine deprivation on alcohol and smoking urges in a sample of alcohol-dependent smokers in early recovery. DESIGN: Using a within-subjects design, participants underwent two cue-reactivity laboratory sessions in which they rated their urges for alcohol and cigarettes during the following three trials: baseline, neutral cue and mood induction combined with alcohol beverage cue exposure. One session was completed after 34 hours of nicotine deprivation and another in a non-deprived state. PARTICIPANTS: Forty alcohol-dependent heavy smokers recruited from a substance abuse day treatment program. MEASUREMENTS: Self-reported urge to drink, urge to smoke and salivation. FINDINGS: Results showed that during the non-deprived session, alcohol cue presentations were associated with significant increases in urges to drink and urges to smoke. Acute nicotine deprivation led to increased smoking urges, but was not associated with increased urges to drink alcohol. CONCLUSIONS: Findings suggest that the acute effects of smoking cessation are unlikely to increase risk of relapse to alcohol in alcoholic patients who are undergoing treatment.