Department of Psychiatry, UCSD

BACKGROUND:Alcoholism is a multifactorial disorder influenced by multiple gene loci, each with small effect. Studies suggest shared genetic influences across DSM-IV alcohol dependence symptoms, but shared effects across DSM-5 alcohol use disorder remains unknown. We aimed to test the assumption of genetic homogeneity across the 11 criteria of DSM-5 alcohol use disorder (AUD). METHODS:Data from 2596 alcohol using individuals of European ancestry from the Study of Addiction: Genetics and Environment were used to examine the genomewide SNP-heritability (h2SNP) and SNP-covariance (rGSNP) between 11 DSM-5 AUD symptoms. Phenotypic relationships between symptoms were examined to confirm an underlying liability of AUD and the SNP-heritability of the observed latent trait and the co-heritabilityamong AUD symptoms was assessed using Genomic-Relatedness-Matrix-Restricted-Maximum-Likelihood. Genetic covariance among symptoms was examined using factor analysis. RESULTS:Phenotypic relationships confirmed a unidimensional underlying liability to AUD. Factor and parallel analyses of the observed genetic variance/covariance provided evidence of genetic homogeneity. Additive genetic effects on DSM-5 AUD symptoms varied from 0.10 to 0.37 and largely overlapped (rG-SNP across symptoms ranged from 0.49 - 0.92). The additive genetic effect on the DSM-5 AUD factor was 0.36, 0.14 for DSM-5 AUD diagnosis, and was 0.22 for DSM-5 AUD severity. CONCLUSIONS:Common genetic variants influence DSM-5 AUD symptoms. Despite evidence for a common AUD factor, the evidence of only partially overlapping genetic effects across AUD symptoms further substantiates the need to simultaneously model common and symptom-specific genetic effects in molecular genetic studies in order to best characterize the genetic liability.

OBJECTIVES:Methamphetamine (MA) dependence contributes to neurotoxicity and neurocognitive deficits. Although combined alcohol and MA misuse is common, how alcohol consumption relates to neurocognitive performance among MA users remains unclear. We hypothesized that alcohol and MA use would synergistically diminish neurocognitive functioning, such that greater reported alcohol consumption would exert larger negative effects on neurocognition among MA-dependent individuals compared to MA-nonusing persons. METHODS:Eighty-seven MA-dependent (MA+) and 114 MA-nonusing (MA-) adults underwent neuropsychological and substance use assessments. Linear and logistic regressions examined the interaction between MA status and lifetime average drinks per drinking day on demographically corrected global neurocognitive T scores and impairment rates, controlling for recent alcohol use, lifetime cannabis use, WRAT reading performance, and lifetime depression. RESULTS:MA+ displayed moderately higher rates of impairment and lower T scores compared to MA-. Lifetime alcohol use significantly interacted with MA status to predict global impairment (ORR = 0.70, p = .003) such that greater lifetime alcohol use increased likelihood of impairment in MA-, but decreased likelihood of impairment in MA+. Greater lifetime alcohol use predicted poorer global T scores among MA- (b = -0.44, p = .030) but not MA+ (b = 0.08, p = .586). CONCLUSIONS:Contrary to expectations, greater lifetime alcohol use related to reduced risk of neurocognitive impairment among MA users. Findings are supported by prior research identifying neurobiological mechanisms by which alcohol may attenuate stimulant-driven vasoconstriction and brain thermotoxicity. Replication and examination of neurophysiologic mechanisms underlying alcohol use in the context of MA dependence are warranted to elucidate whether alcohol confers a degree of neuroprotection.

BACKGROUND:Genomewide association studies (GWAS) have begun to identify loci related to alcohol consumption, but little is known about whether this genetic propensity overlaps with specific indices of problem drinking in ascertained samples. METHODS:In 6,731 European Americans who had been exposed to alcohol, we examined whether polygenic risk scores (PRS) from a GWAS of weekly alcohol consumption in the UK Biobank predicted variance in 6 alcohol-related phenotypes: alcohol use, maximum drinks within 24 hours (MAXD), total score on the Self-Rating of the Effects of Ethanol Questionnaire (SRE-T), DSM-IV alcohol dependence (DSM4AD), DSM-5 alcohol use disorder symptom counts (DSM5AUDSX), and reduction/cessation of problematic drinking. We also examined the extent to which an single nucleotide polymorphism (rs1229984) in ADH1B, which is strongly associated with both alcohol consumption and dependence, contributed to the polygenic association with these phenotypes and whether PRS interacted with sex, age, or family history of alcoholism to predict alcohol-related outcomes. We performed mixed-effect regression analyses, with family membership and recruitment site included as random effects, as well as survival modeling of age of onset of DSM4AD. RESULTS:PRS for alcohol consumption significantly predicted variance in 5 of the 6 outcomes: alcohol use (Δmarginal R2  = 1.39%, Δ area under the curve [AUC] = 0.011), DSM4AD (Δmarginal R2  = 0.56%; ΔAUC = 0.003), DSM5AUDSX (Δmarginal R2  = 0.49%), MAXD (Δmarginal R2  = 0.31%), and SRE-T (Δmarginal R2  = 0.22%). PRS were also associated with onset of DSM4AD (hazard ratio = 1.11, p = 2.08e-5). The inclusion of rs1229984 attenuated the effects of the alcohol consumption PRS, particularly for DSM4AD and DSM5AUDSX, but the PRS continued to exert an independent effect for all 5 alcohol measures (Δmarginal R2 after controlling for ADH1B = 0.14 to 1.22%). Interactions between PRS and sex, age, or family history were nonsignificant. CONCLUSIONS:Genetic propensity for typical alcohol consumption was associated with alcohol use and was also associated with 4 of the additional 5 outcomes, though the variance explained in this sample was modest. Future GWAS that focus on the multifaceted nature of AUD, which goes beyond consumption, might reveal additional information regarding the polygenic underpinnings of problem drinking.

BACKGROUND:Alcohol consumption and problems are increasing among older adults, who are at elevated risk for alcohol-related accidents and medical problems. This paper describes a pilot follow-up of older adults with a history of alcohol dependence that was designed to determine the feasibility of conducting a more extensive investigation. METHODS:The sample consisted of previously assessed subjects in the Collaborative Studies on the Genetics of Alcoholism who: a) were age 50+; b) had lifetime DSM-IV AD; and c) had DNA available. Individuals were located through family contacts, internet searches, and death registries. A brief telephone interview assessed demographics, health, and alcohol involvement. RESULTS:Of the total sample (N = 2174), 36% were contacted, 24% were deceased, and 40% were not yet located. Most (89%) contacted subjects were interviewed, and 99% of them agreed to future evaluation. Thirty percent of interviewed subjects reported abstinence for 10+ years, 56% reported drinking within the past year, and 14% last drank between >1 and 10 years ago. There were no age-related past-year differences in weekly consumption (overall sample mean: 16 drinks), number of drinking weeks (30.8), maximum number of drinks in 24 hours (8.1). or prevalence of weekly risky drinking (19%). Among those who drank within the past five years, the three most common alcohol-related problems were spending excessive time drinking or recovering (49%), drinking more/longer than intended (35%), and driving while intoxicated (35%); and about a third (32%) received some form of treatment. CONCLUSIONS:Over a one-year period, we located 60% of individuals last seen an average of 23 years ago. The majority of contacted individuals were interviewed and willing to be evaluated again. Although the proportion of individuals currently drinking diminished with age, subjects exhibited troublesome levels of alcohol consumption and problems. Our findings suggest the importance and feasibility of a more comprehensive follow-up. This article is protected by copyright. All rights reserved.

BACKGROUND:Selective serotonin reuptake inhibitors are often used in alcohol use disorders. Clinical trials with selective serotonin reuptake inhibitors for alcohol use disorders, however, have yielded mixed results. The goal of this project was to assess whether a single i.v. dose of a selective serotonin reuptake inhibitor reduces craving for alcohol and/or simultaneously increases striatal dopamine concentration in individuals with alcohol dependence. METHODS:Alcohol-dependent (DSM-IV-TR criteria) volunteers and matched controls (n = 10/group) underwent a double-blind, placebo-controlled, within-subjects study. Participants received i.v. citalopram (40 mg) or saline (counter-balanced) followed by a cue-induced craving assessment and [18F]-fallypride positron emission tomography scanning. RESULTS:In the alcohol-dependent individuals, the citalopram (compared with saline) resulted in decreased cue-induced craving for alcohol. For the whole study group, cue-induced alcohol craving was inversely correlated with thalamic (but not striatal) dopamine D2/3 receptor availability. CONCLUSIONS:Acute serotonin reuptake inhibition reduces cue-induced alcohol craving. Furthermore, thalamic dopamine abnormalities and the striatal hyperdopaminergic hypothesis of alcohol use disorder are supported.

KEY POINTS:Exercise elicits circadian phase-shifting effects, but additional information is needed. The phase-response curve describing the magnitude and direction of circadian rhythm phase shifts, depending on the time of the zeigeber (time cue) stimulus, is the most fundamental chronobiological tool for alleviating circadian misalignment and related morbidity. Fifty-one older and 48 young adults followed a circadian rhythms measurement protocol for up to 5.5 days, and performed 1 h of moderate treadmill exercise for 3 consecutive days at one of eight times of the day/night. Temporal changes in the phase of 6-sulphatoxymelatonin (aMT6s) were measured from evening onset, cosine acrophase, morning offset and duration of excretion. Significant phase-response curves were established for aMT6 onset and acrophase with large phase delays from 7:00 pm to 10:00 pm and large phase advances at both 7:00 am and from 1:00 pm to 4:00 pm. Delays or advances would be desired, for example, for adjustment to westward or eastward air travel, respectively. Along with known synergism with bright light, the above PRCs with a second phase advance region (afternoon) could support both practical and clinical applications. ABSTRACT:Although bright light is regarded as the primary circadian zeitgeber, its limitations support exploring alternative zeitgebers. Exercise elicits significant circadian phase-shifting effects, but fundamental information regarding these effects is needed. The primary aim of the present study was to establish phase-response curves (PRCs) documenting the size and direction of phase shifts in relation to the circadian time of exercise. Aerobically fit older (n = 51; 59-75 years) and young adults (n = 48; 18-30 years) followed a 90 min laboratory ultrashort sleep-wake cycle (60 min wake/30 min sleep) for up to 5½ days. At the same clock time on three consecutive days, each participant performed 60 min of moderate treadmill exercise (65-75% of heart rate reserve) at one of eight times of day/night. To describe PRCs, phase shifts were measured for the cosine-fitted acrophase of urinary 6-sulphatoxymelatonin (aMT6s), as well as for the evening rise, morning decline and change in duration of aMT6s excretion. Significant PRCs were found for aMT6s acrophase, onset and duration, with peak phase advances corresponding to clock times of 7:00 am and from 1:00 pm to 4:00 pm, delays from 7:00 pm to 10:00 pm, and minimal shifts around 4:00 pm and 2:00 am. There were no significant age or sex differences. The amplitudes of the aMT6s onset and acrophase PRCs are comparable to expectations for bright light of equal duration. The phase advance to afternoon exercise and the exercise-induced PRC for change in aMT6s duration are novel findings. The results support further research exploring additive phase-shifting effects of bright light and exercise and health benefits.

BACKGROUND AND AIMS:Few studies have explored how polygenic propensity to cannabis use unfolds across development, and no studies have yet examined this question in the context of environmental contributions such as peer cannabis use. Outlining the factors that contribute to progression from cannabis initiation to problem use over time may ultimately provide insights into mechanisms for targeted interventions. We sought to examine the relationships between polygenic liability for cannabis use, cannabis use trajectories from ages 12-30 years and perceived peer cannabis use at ages 12-17 years. DESIGN:Mixed-effect logistic and linear regressions were used to examine associations between polygenic risk scores, cannabis use trajectory membership and perceived peer cannabis use. SETTING:United States. PARTICIPANTS:From the Collaborative Study on the Genetics of Alcoholism (COGA) study, a cohort of 1167 individuals aged 12-26 years at their baseline (i.e. first) interview. MEASUREMENTS:Key measurements included life-time cannabis use (yes/no), frequency of past 12-month cannabis use, maximum life-time frequency of cannabis use, cannabis use disorder (using DSM-5 criteria) and perceived peer cannabis use. Polygenic risk scores (PRS) were created using summary statistics from a large (n = 162 082) genome-wide association study (GWAS) of cannabis use. FINDINGS:Three trajectories reflecting no/low (n = 844), moderate (n = 137) and high (n = 186) use were identified. PRS were significantly associated with trajectory membership [P = 0.002-0.006, maximum conditional R2  = 1.4%, odds ratios (ORs) = 1.40-1.49]. Individuals who reported that most/all of their best friends used cannabis had significantly higher PRS than those who reported that none of their friends were users [OR = 1.35, 95% confidence interval (CI) = 1.04, 1.75, P = 0.023]. Perceived peer use itself explained up to 11.3% of the variance in trajectory class membership (OR = 1.50-4.65). When peer cannabis use and the cannabis use PRS were entered into the model simultaneously, both the PRS and peer use continued to be significantly associated with class membership (P < 0.01). CONCLUSIONS:Genetic propensity to cannabis use derived from heterogeneous samples appears to correlate with longitudinal increases in cannabis use frequency in young adults.

A multistage model of drug addiction in which individuals' motivations for use change as they develop problems is widely accepted; however, the evidence for this model comes mostly from animal work and cross-sectional studies. We used longitudinal data to test whether positive and negative reinforcement associated with alcohol consumption differed as a function of alcohol dependence (AD). Specifically, we tested whether (a) positive reinforcement is more strongly associated with alcohol consumption than is negative reinforcement among individuals without AD, (b) negative reinforcement is more strongly associated with AD than is positive reinforcement, and (c) in the presence of AD, the association between positive reinforcement and alcohol consumption becomes weaker, whereas the association with negative reinforcement becomes stronger. We included assessments between Ages 18 and 30 years from participants who indicated they ever had a drink (N = 2,556; 51.6% female) from the Collaborative Study on the Genetics of Alcoholism Prospective Study. Results from generalized estimating equations indicated that positive, but not negative, reinforcement was associated with alcohol consumption among individuals without AD. Both positive and negative reinforcement were associated with AD, but the association was stronger with negative reinforcement. Results from the multilevel growth model indicated that the association between negative reinforcement and alcohol consumption became stronger with the presence of AD, whereas the association between positive reinforcement and alcohol consumption did not differ as a function of AD. We provide empirical evidence that positive and negative reinforcement are differentially associated with alcohol consumption as a function of AD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Background: A recent meta-analysis affirmed the benefit of medicinal cannabis for chronic neuropathic pain, a disabling and difficult-to-treat condition. As medicinal cannabis use is becoming increasingly prevalent among Americans, an exploration of its economic feasibility is warranted. We present this cost-effectiveness analysis of adjunctive cannabis pharmacotherapy for chronic peripheral neuropathy. Materials and Methods: A published Markov model comparing conventional therapies for painful diabetic neuropathy was modified to include arms for augmenting first-line, second-line (if first-line failed), or third-line (if first- and second-line failed) therapies with smoked cannabis. Microsimulation of 1,000,000 patients compared the cost (2017 U.S. dollars) and effectiveness (quality-adjusted life years [QALYs]) of usual care with and without adjunctive cannabis using a composite of third-party and out-of-pocket costs. Model efficacy inputs for cannabis were adapted from clinical trial data. Adverse event rates were derived from a prospective study of cannabis for chronic noncancer pain and applied to probability inputs for conventional therapies. Cannabis cost was derived from retail market pricing. Parameter uncertainty was addressed with one-way and probabilistic sensitivity analysis. Results: Adding cannabis to first-line therapy was incrementally less effective and costlier than adding cannabis to second-line and third-line therapies. Third-line adjunctive cannabis was subject to extended dominance, that is, the second-line strategy was more effective with a more favorable incremental cost-effectiveness ratio of $48,594 per QALY gained, and therefore, third-line adjunctive cannabis was not as cost-effective. At a modest willingness-to-pay threshold of $100,000/QALY gained, second-line adjunctive cannabis was the strategy most likely to be cost-effective. Conclusion: As recently proposed willingness-to-pay thresholds for the United States health marketplace range from $110,000 to $300,000 per QALY, cannabis appears cost-effective when augmenting second-line treatment for painful neuropathy. Further research is warranted to explore the long-term benefit of smoked cannabis and standardization of its dosing for chronic neuropathic pain.