Baseline gut microbiome and metabolites are correlated with alcohol consumption in a zonisamide clinical trial of heavy drinking alcoholic civilians.

Development and severity of alcohol use disorder (AUD) has been linked to variations in gut microbiota and their associated metabolites in both animal and human studies. However, the involvement of the gut microbiome in alcohol consumption of individuals with AUD undergoing treatment remains unclear. To address this, stool samples (n=48) were collected at screening (baseline) and trial completion from a single site of a multi-site double-blind, placebo-controlled trial of Zonisamide in individuals with AUD. Alcohol consumption, gamma-glutamyl transferase (GGT), and phosphatidylethanol (PEth)levels were measured both at baseline and endpoint of 16-week trial period. Fecal microbiome was analyzed via 16S rRNA sequencing and metabolome via untargeted LC-MS. Both sex (p = 0.003) and psychotropic medication usage (p = 0.025) are associated with baseline microbiome composition. The relative abundance of 12 genera at baseline was correlated with percent drinking reduction, baseline and endpoint alcohol consumption, and changes in GGT and PeTH over the course of treatment (p.adj < 0.05). Overall microbiome community structure at baseline differed between high and low responders (67-100% and 0-33% drinking reduction, respectively; p = 0.03). A positive relationship between baseline fecal GABA levels and percent drinking reduction (R=0.43, p < 0.05) was identified by microbiome function prediction and confirmed by ELISA and metabolomics. Predicted microbiome function and metabolomics analysis have found that tryptophan metabolic pathways are over-represented in low responders. These findings highlight importance of baseline microbiome and metabolites in alcohol consumption in AUD patients undergoing zonisamide treatment.

Analysis of Drugs in Saliva of US Military Veterans Treated for Substance Use Disorders Using Supported Liquid Extraction and Surface-Enhanced Raman Spectral Analysis.

According to the Center for Disease Control, there were more than 107,000 US drug overdose deaths in 2021, over 80,000 of which due to opioids. One of the more vulnerable populations is US military veterans. Nearly 250,000 military veterans suffer from substance-related disorders (SRD). For those seeking treatment, buprenorphine is prescribed to help treat opioid use disorder (OUD). Urinalysis is currently used to monitor buprenorphine adherence as well as to detect illicit drug use during treatment. Sometimes sample tampering occurs if patients seek to generate a false positive buprenorphine urine test or mask illicit drugs, both of which can compromise treatment. To address this problem, we have been developing a point-of-care (POC) analyzer that can rapidly measure both medications used for treatment and illicit drugs in patient saliva, ideally in the physi-cian's office. The two-step analyzer employs (1) supported liquid extraction (SLE) to isolate the drugs from the saliva and (2) surface-enhanced Raman spectroscopy (SERS) to detect the drugs. A prototype SLE-SERS-POC analyzer was used to quantify buprenorphine at ng/mL concentrations and identify illicit drugs in less than 1 mL of saliva collected from 20 SRD veterans in less than 20 min. It correctly detected buprenorphine in 19 of 20 samples (18 true positives, 1 true negative and 1 false negative). It also identified 10 other drugs in patient samples: acetaminophen, amphetamine, cannabidiol, cocaethylene, codeine, ibuprofen, methamphetamine, methadone, nicotine, and norbuprenorphine. The prototype analyzer shows evidence of accuracy in measuring treatment medications and relapse to drug use. Further study and development of the system is warranted.

Clinical Effectiveness of Intravenous Racemic Ketamine Infusions in a Large Community Sample of Patients With Treatment-Resistant Depression, Suicidal Ideation, and Generalized Anxiety Symptoms: A Retrospective Chart Review.

Introduction: Few studies have been published to date exploring the effectiveness of ketamine for treatment-resistant depression (TRD) in large clinical samples. We report on the clinical outcomes of a large cohort treated with ketamine as part of clinical practice.Methods: Deidentified electronic chart data were obtained from a multisite private ketamine infusion clinic for 424 patients with TRD seen from November 9, 2017, to May 4, 2021. Ketamine infusions were administered at a starting dose of 0.5 mg/kg/40 minutes for 6 infusions within 21 days. Maintenance infusions were offered based on clinical response. Changes in outcome measures (scores on the Patient Health Questionnaire-9 [PHQ-9] and Generalized Anxiety Disorder-7 [GAD-7]) within subjects were analyzed using longitudinal multilevel modeling with Kaplan-Meier estimates. Logistic regression was used to analyze for a priori theorized potential moderators of response.Results: Significant improvements from baseline were observed over time on the main outcomes (all P < .001). Based on PHQ-9 self-report data, within 6 weeks of infusion initiation, a 50% response rate and 20% remission rate for depressive symptoms were observed. Response and remission rates were 72% and 38%, respectively, after 10 infusions, and there was a 50% reduction in self-harm/suicidal ideation (SI) symptom scores within 6 weeks. Half of patients with SI at baseline no longer had it after 6 infusions. A 30% reduction in anxiety symptoms (per the GAD-7) was observed.Conclusions: Ketamine was effective at reducing symptoms of SI, depression, and anxiety. The high rates of response and remission were similar to those for interventional treatments in community samples of TRD. Comparative efficacy trials with other interventions and randomized controlled trials of racemic ketamine infusion as the primary treatment for SI are needed.

A serotonergic biobehavioral signature differentiates cocaine use disorder participants administered mirtazapine.

Cocaine use disorder (CUD) patients display heterogenous symptoms and unforeseeable responses to available treatment approaches, highlighting the need to identify objective, accessible biobehavioral signatures to predict clinical trial success in this population. In the present experiments, we employed a task-based behavioral and pharmacogenetic-fMRI approach to address this gap. Craving, an intense desire to take cocaine, can be evoked by exposure to cocaine-associated stimuli which can trigger relapse during attempted recovery. Attentional bias towards cocaine-associated words is linked to enhanced effective connectivity (EC) from the anterior cingulate cortex (ACC) to hippocampus in CUD participants, an observation which was replicated in a new cohort of participants in the present studies. Serotonin regulates attentional bias to cocaine and the serotonergic antagonist mirtazapine decreased activated EC associated with attentional bias, with greater effectiveness in those CUD participants carrying the wild-type 5-HT2CR gene relative to a 5-HT2CR single nucleotide polymorphism (rs6318). These data suggest that the wild-type 5-HT2CR is necessary for the efficacy of mirtazapine to decrease activated EC in CUD participants and that mirtazapine may serve as an abstinence enhancer to mitigate brain substrates of craving in response to cocaine-associated stimuli in participants with this pharmacogenetic descriptor. These results are distinctive in outlining a richer "fingerprint" of the complex neurocircuitry, behavior and pharmacogenetics profile of CUD participants which may provide insight into success of future medications development projects.

Altered effective connectivity of the reward network during an incentive-processing task in adults with alcohol use disorder.

BACKGROUND: Abnormalities of reward sensitivity and impulsivity are known to be correlated with each other and alcohol use disorder (AUD) risk, but the underlying aberrant neural circuitry involved is not clearly defined. We sought to extend the current knowledge of AUD pathophysiology by studying incentive processing in persons with AUD using functional neuroimaging data. METHODS: We utilized functional MRI data from the Human Connectome Project Database obtained during performance of a number-guessing incentive-processing task with win, loss, and neutral feedback conditions in 78 participants with either DSM-IV alcohol abuse or dependence (combined as the AUD group) and 78 age- and sex-matched control (CON) participants. Within a network consisting of anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), insula, ventral striatum, and dorsal striatum (DS) in the right hemisphere, we performed dynamic causal modeling analysis to test group-level differences (AUD vs. CON) in effective directional connectivity (EC) as modulated by "win" and "loss" conditions. We used linear regression analyses to characterize the relations between each EC outcome and measures of cumulative alcohol exposure and impulsivity. RESULTS: During wins, AUD participants had lower ECs from ACC to the other four nodes, greater ECs from insula to the other four nodes, greater ECs from DLPFC to the other four nodes, and greater DS to DS self-connection EC than CON participants. In the total sample, EC from the insula to the DLPFC (insula â†’ DLPFC) during wins was positively correlated with both impulsivity (as measured by the delay-discounting task) and cumulative alcohol exposure. The DS to DS self-connection EC during wins was positively correlated with impulsivity. Many of the altered ECs from the ACC and insula to other nodes were correlated with cumulative alcohol exposure. CONCLUSIONS: Individuals with AUD have disrupted EC in both instrumentally driven and automatized corticostriatal reward circuits during non-alcohol reward feedback. These results point to disrupted corticostriatal EC in both "top-down" and "bottom-up" pathways among individuals with AUD.

Temporal dynamics of the relationship between change in depressive symptoms and cannabis use in adolescents receiving psychosocial treatment for cannabis use disorder.

AIMS: Cannabis use disorder (CUD) and depression frequently co-occur in youth. How depressive symptoms change over the course of CUD treatment and how they impact substance use treatment outcomes is unknown. In the current study, we examine the temporal relationships between cannabis use and depression in adolescents receiving evidence-based treatments for CUD as part of a multisite clinical trial. DESIGN: Six hundred adolescents (age 12-18) with a CUD were randomly assigned to substance use treatment from one of five evidence-based psychosocial interventions. We assessed self-reported cannabis use frequency and depressive symptoms at baseline (BL) and again at 3-, 6-, 9, and 12-months. A bivariate latent change model assessed bidirectional effects of baseline levels and time-lagged changes in depressive symptoms and cannabis use on depression and cannabis use outcomes. FINDINGS: Depressive symptoms (72%) and major depressive disorder (MDD) (18%) were common at BL. Both depression and cannabis use decreased over time and change in cannabis use was significantly associated with change in depressive symptoms (b = 1.22, p = .003). Time-lag analyses showed that within-subject change in depression (from one time point to the next) was predicted by previous depression (b = -0.71, p < .001) but not cannabis use (p = .068), and change (decrease) in cannabis use was predicted by previous (greater) depressive symptoms (b = -1.47, p < .001) but not cannabis use (p = .158), respectively. CONCLUSION: These findings indicate an enduring relationship between decreasing cannabis use and decreasing depression among adolescents lasting for 9-months after receiving psychosocial interventions for CUD. The presence of depressive symptoms did not appear to interfere with substance use treatment or attenuate improvements in cannabis use frequency. A decrease in cannabis use was not contingent upon a reduction in depressive symptoms. These findings are limited by the possibility of regression to the mean for both cannabis use and depressive symptoms, and the lack of a nonintervention control group.

Practice facilitation to promote evidence-based screening and management of unhealthy alcohol use in primary care: a practice-level randomized controlled trial.

BACKGROUND: Unhealthy alcohol use is the third leading cause of preventable death in the United States. Evidence demonstrates that screening for unhealthy alcohol use and providing persons engaged in risky drinking with brief behavioral and counseling interventions improves health outcomes, collectively termed screening and brief interventions. Medication assisted therapy (MAT) is another effective method for treatment of moderate or severe alcohol use disorder. Yet, primary care clinicians are not regularly screening for or treating unhealthy alcohol use. METHODS AND ANALYSIS: We are initiating a clinic-level randomized controlled trial aimed to evaluate how primary care clinicians can impact unhealthy alcohol use through screening, counseling, and MAT. One hundred and 25 primary care practices in the Virginia Ambulatory Care Outcomes Research Network (ACORN) will be engaged; each will receive practice facilitation to promote screening, counseling, and MAT either at the beginning of the trial or at a 6-month control period start date. For each practice, the intervention includes provision of a practice facilitator, learning collaboratives with three practice champions, and clinic-wide information sessions. Clinics will be enrolled for 6-12 months. After completion of the intervention, we will conduct a mixed methods analysis to identify changes in screening rates, increase in provision of brief counseling and interventions as well as MAT, and the reduction of alcohol intake for patients after practices receive practice facilitation. DISCUSSION: This study offers a systematic process for dissemination and implementation of the evidence-based practice of screening, counseling, and treatment for unhealthy alcohol use. Practices will be asked to implement a process for screening, counseling, and treatment based on their practice characteristics, patient population, and workflow. We propose practice facilitation as a robust and feasible intervention to assist in making changes within the practice. We believe that the process can be replicated and used in a broad range of clinical settings; we anticipate this will be supported by our evaluation of this approach. TRIAL REGISTRATION: ClinicalTrials.gov, ClinicalTrials.gov Identifier: NCT04248023, Registered 5 February 2020.

Zonisamide as an Adjunctive Treatment to Cognitive Processing Therapy for Veterans With Posttraumatic Stress Disorder and Comorbid Alcohol Use Disorder: A Pilot Study.

BACKGROUND AND OBJECTIVES: There are high rates of comorbid alcohol use disorder (AUD) among those who have posttraumatic stress disorder (PTSD). Ideally, treatment for comorbidity should address both disorders simultaneously. Zonisamide, an anticonvulsant, may be effective in decreasing alcohol use and may attenuate symptoms of PTSD. Treatment strategies can include medication in combination with a proven evidence-based psychotherapy designed to treat PTSD, such as cognitive processing therapy (CPT). METHODS: This 12-week pilot study was designed to test feasibility, acceptability, and preliminary efficacy of zonisamide (400 mg) as an adjunct to CPT for veterans with PTSD and comorbid AUD. Veterans (n = 24) with PTSD and current alcohol dependence were randomized in a 3:1 ratio to receive zonisamide or placebo in a double-blind fashion. All subjects received CPT enhanced to include sessions addressing drinking behavior. RESULTS: Subjects overall reported a significant decrease in drinking outcomes, craving, and symptoms of PTSD. Zonisamide was well-tolerated and easily administered with CPT, which was also well-tolerated. Exploratory analysis of comparison of groups suggests there was no advantage of zonisamide vs placebo in drinking or PTSD outcomes. There was a numeric but nonsignificant higher rate of abstinence with zonisamide (50%) vs placebo (33%). CONCLUSION AND SCIENTIFIC SIGNIFICANCE: The interpretation of the results is limited by the pilot nature of this study. The combination of psychosocial treatment with medication management mimics real-world treatment. In order to isolate the individual contributions of medication vs psychotherapy a much larger study would need to be conducted. (Am J Addict 2020;29:515-524).

Systematic review and meta-analysis of the moderating effect of rs1799971 in OPRM1, the mu-opioid receptor gene, on response to naltrexone treatment of alcohol use disorder.

BACKGROUND AND AIMS: There is wide inter-individual variability in response to the treatment of alcohol use disorder (AUD) with the opioid receptor antagonist naltrexone. To identify patients who may be most responsive to naltrexone treatment, studies have examined the moderating effect of rs1799971, a single nucleotide polymorphism (SNP) that encodes a non-synonymous substitution (Asn40Asp) in the mu-opioid receptor gene, OPRM1. The aims of this study were to: (1) conduct a systematic review of randomized clinical trials (RCTs); (2) assess the bias of the available studies and gauge publication bias; and (3) meta-analyze the interaction effect of the Asn40Asp SNP on the response to naltrexone treatment. METHODS: We searched for placebo-controlled RCTs that examined the effect of Asn40Asp on the response to naltrexone treatment of heavy drinking or AUD. We tested the hypothesis that the minor (Asp40) allele was associated with a greater reduction in five alcohol consumption measures (relapse to heavy drinking, abstinence, percentage of heavy drinking days, percentage of days abstinent and drinks per day) in naltrexone-treated participants by meta-analyzing the interaction effects using a random effects model. RESULTS: Seven RCTs met the study criteria. Overall, risk of bias was low and we observed no evidence of publication bias. Of the five alcohol consumption outcomes considered, there was a nominally significant moderating effect of the Asn40Asp SNP only on drinks per day (d = -0.18, P = 0.02). However, the effect was not significant when multiple comparisons were taken into account. CONCLUSIONS: From the evidence to date, it remains unclear whether rs1799971, the OPRM1 Asn40Asp single nucleotide polymorphism, predicts naltrexone treatment response in individuals with alcohol use disorder or heavy drinking.

Cingulo-hippocampal effective connectivity positively correlates with drug-cue attentional bias in opioid use disorder.

Individuals with opioid use disorder (OUD) often relapse when exposed to opioid-related cues. Previous functional magnetic resonance imaging (fMRI) studies have identified neuronal corticolimbic changes related to drug cue reactivity in OUD. However, the corresponding manner in which brain regions interact is still unclear. Effective (directional) connectivity was analyzed using dynamic causal modeling of fMRI data acquired from 27 OUD participants (13 with OUD and 14 with OUD and cocaine use disorder [OUD+CUD]), while performing an opioid-word Stroop task. Participants were shown opioid and neutral words presented in different colors and were instructed to indicate word color but ignore word meaning. The effects of opioid words relative to neutral words on effective connectivity and on behavioral reaction time were defined as modulatory change and attentional bias, respectively. For all the 27 participants, left anterior cingulate cortex (ACC) to right hippocampus effective connectivity exhibited the largest modulatory change, which was positively correlated with attentional bias. The findings for the ACC to hippocampus EC were consistent across OUD and CUD found in a previous study.

Targeting neuroinflammation with minocycline in heavy drinkers.

RATIONALE: Alcohol has both acute and chronic effects on neuroimmune signaling, including triggering pro-inflammatory cytokine release by microglia. Minocycline, a second-generation tetracycline antibiotic, inhibits microglial activation and reduces neuroinflammation in preclinical studies. In mice, minocycline also reduces ethanol intake, attenuates ethanol-induced conditioned place preference, and inhibits ethanol-induced microglial activation and pro-inflammatory cytokine release. OBJECTIVE: Here, for the first time, we tested the effects of minocycline on subjective response to ethanol and acute ethanol-induced inflammation in humans. METHODS: Forty-eight heavy drinkers participated in a double-blind, placebo-controlled trial in which they were randomized to receive placebo, 100 mg, or 200 mg of minocycline for 10 days. Each subject then underwent two experimental sessions in which they were given a fixed dose of intravenous ethanol using a "clamp" procedure (100 mg%) or placebo (normal saline) on days 8 and 10 of treatment. RESULTS: Minocycline was well tolerated, but there was no effect of either dose of minocycline on subjective response to ethanol or ethanol-induced craving; minocycline effects on cognitive function seem to interact with age. Minocycline treatment did not alter serum cytokine levels at baseline or during ethanol-exposure, although certain baseline cytokine levels predict sedative response to ethanol. CONCLUSION: These findings indicate that a short-term treatment with minocycline may not alter ethanol-related inflammation or subjective response to ethanol in humans. Further research is needed to identify pharmacological agents with robust effects on ethanol-induced inflammation to determine whether neuroimmune modulation represents a viable treatment strategy for alcohol use disorder.

Topiramate Pharmacotherapy for Alcohol Use Disorder and Other Addictions: A Narrative Review.

: Topiramate is a non-benzodiazepine anticonvulsant medication with multi-faceted pharmacologic action. It has emerged as an efficacious pharmacotherapeutic option for the treatment of addiction, especially alcohol use disorder (AUD). We present a broad narrative review of the putative mechanism of action and clinical utility of topiramate with regard to AUD and other substance use disorders. Collective evidence suggests topiramate is an effective treatment option in AUD, with notable efficacy in reducing harmful drinking patterns in AUD. Though not currently approved by the United States Food and Drug Administration for the indication of AUD, topiramate should be considered as a pharmacological treatment option with high utility among AUD patients. Early pharmacogenetic studies raise the intriguing possibility of identifying patients likely to respond to topiramate using genetic testing, and initial studies show that topiramate may also be useful in treating cocaine use disorder, smoking cessation and behavioral addictions. However, further research is needed in all these areas.

Topiramate Treatment of Alcohol Use Disorder in Clinical Practice.

: Topiramate is an anticonvulsant medication with increasingly strong evidence, supporting its use for treating alcohol use disorder (AUD) based on clinical trials. These clinical cases summarize the initiation and titration of topiramate in AUD treatment. The core issues of patient selection, consideration of comorbid psychiatric and medical conditions, side-effect profile, safety and effectiveness are reviewed. Addiction physicians should take a leading role in using topiramate to treat AUDs, working with patients to balance the benefits of topiramate with the risk.

Impulsivity interacts with momentary PTSD symptom worsening to predict alcohol use in male veterans.

BACKGROUND: Posttraumatic stress disorder (PTSD) is prevalent among veterans who served post-9/11, and co-occurs with problem alcohol and substance use. Studies using ecological momentary assessment have examined the temporal association between time-varying PTSD symptoms and alcohol use. Results suggest individual differences in these associations. OBJECTIVES: We tested hypotheses that alcohol use measured by momentary assessment would be explained by acute increases in PTSD symptoms, and the PTSD-alcohol association would be moderated by trait impulsivity. METHODS: A sample of 28 male post-9/11-era veterans who reported past-month PTSD symptoms and risky alcohol use were enrolled. On a quasi-random schedule, participants completed three electronic assessments daily for 28 days measuring past 2-h PTSD symptoms, alcohol, and substance use. At baseline, trait impulsivity was measured by the Barratt Impulsiveness Scale. Past-month PTSD symptoms and alcohol use were measured. Using three-level hierarchical models, number of drinks recorded by momentary assessment was modeled as a function of change in PTSD symptoms since last assessment, controlling for lag-1 alcohol and substance use and other covariates. A cross-level interaction tested moderation of the within-time PTSD-alcohol association by impulsivity. RESULTS: A total of 1,522 assessments were completed. A positive within-time association between PTSD symptom change and number of drinks was demonstrated. The association was significantly moderated by impulsivity. CONCLUSION: Results provide preliminary support for a unique temporal relationship between acute PTSD symptom change and alcohol use among veterans with trait impulsiveness. If replicated in a clinical sample, results may have implications for a targeted momentary intervention.

The conundrum of opioid tapering in long-term opioid therapy for chronic pain: A commentary.

BACKGROUND: In response to the opioid epidemic and new guidelines, many patients on high-dose long term opioid therapy (LTOT) for chronic pain are getting tapered off opioids. As a result, a unique clinical challenge is emerging: while many on LTOT have poor pain control, functional decline, psychiatric instability, aberrancies and misuse, these issues may often worsen with opioid tapering. Currently, a clear explanation and practical guidance on how to manage this perplexing clinical scenario is lacking. METHODS: We offer a commentary with our perspective on possible mechanisms involved in this clinical phenomena and offer practical management guidance, supported by available evidence. RESULTS: It is not well recognized that allostatic opponent process involved in development of opioid dependence can cause worsening pain, functional status, sleep and psychiatric symptoms over time, and significant fluctuation of pain and other affective symptoms due to their bidirectional dynamic interaction with opioid dependence ('affective dynamism'). These elements of complex persistent dependence (CPD), the grey area between simple dependence and addiction, can lead to escalating and labile opioid need, often generating aberrant behaviors. Opioid tapering, a seemingly logical intervention in this situation, may lead to worsening of pain, function and psychiatric symptoms due to development of protracted abstinence syndrome. We offer practicing clinicians management principles and practical guidance focused on management of CPD in addition to chronic pain in these difficult clinical scenarios. CONCLUSION: Awareness of the science of the neuroplasticity effects of repeated use of opioids is necessary to better manage these patients with complex challenges.

GRIK1 and GABRA2 Variants Have Distinct Effects on the Dose-Related Subjective Response to Intravenous Alcohol in Healthy Social Drinkers.

BACKGROUND: The heritable risk for alcohol use disorder (AUD) is expressed partly through alterations in subjective alcohol response. In this study, we investigated the effects of 2 AUD-risk-associated single nucleotide polymorphisms, GABRA2 rs279858 and GRIK1 rs2832407, on the subjective response to alcohol administered intravenously to healthy social drinkers in a laboratory setting. METHODS: In total, 93 self-identified European American social drinkers underwent 3 blinded laboratory sessions in which they received intravenous infusions of ethanol at 3 target blood alcohol levels (0.00 mg%, 40 mg%, and 100 mg%) using a "clamp" procedure. The self-reported Biphasic Alcohol Effects Scale (BAES) stimulation and sedation subscales were the primary outcome measures. We examined the effects of these 2 genetic variants on subjective response to alcohol. RESULTS: For the BAES stimulation subscale scores, adjusting for age, baseline scores, and time effects, individuals with 2 copies of the GABRA2 rs279858 C "risk" allele for AUD exhibited the greatest stimulant responses to high-dose alcohol compared to the other risk allele counts (dose-by-allele count interaction effect, p = 0.001, post hoc contrast for C-allele, p = 0.012). For the BAES sedation subscale scores, adjusting for the same covariates, we detected a dose-by-allele count interaction effect (p = 0.0044) such that subjects with 2 copies of the GRIK1 C "risk" allele reported the greatest sedative response to the higher alcohol dose. CONCLUSIONS: This study suggests that gene variants contributing to the risk for AUD may alter features of the alcohol dose-response relationship in specific ways. GABRA2 rs279858*C enhances stimulant responses to higher levels of alcohol, while the GRIK1 rs2832407*C-allele increases sedative responses. In summary, GRIK1 and GABRA2 variants have distinct effects on the dose-related subjective response to intravenous alcohol in humans.

Rapid Identification of Buprenorphine in Patient Saliva.

Buprenorphine is becoming the medication of choice to help patients withdraw from opioid addiction. However, treatment is compromised by the inability of physicians to assess patient usage during scheduled examinations. Here we describe the development of a point-of-care (POC) analyzer that can rapidly measure both illicit and treatment drugs in patient saliva, ideally in the physician's office, and with a degree of accuracy similar to chromatography. The analyzer employs a relatively simple supported liquid extraction to isolate the drugs from the saliva and surface-enhanced Raman spectroscopy (SERS) to detect the drugs. The SERS-based POC analyzer was used to identify buprenorphine and opioids in saliva samples by matching library spectra to samples collected from 7 veterans. The total analysis time, including sample preparation, was ~25 minutes. Buprenorphine concentration was estimated between 0 and 3 µg/mL. While no other prescription opioids were detected in any samples, heroin was identified in one sample; Δ-9 tetrahydrocannabinol (THC) was detected in 3 samples; and acetaminophen, caffeine, and nicotine were detected in several samples, none of which interfered with the measurements. The analysis was in very good agreement with urinalysis, correctly identifying the presence or absence of buprenorphine and THC in 13 of 14 measurements.

The burden of alcohol use disorders in US military veterans: results from the National Health and Resilience in Veterans Study.

AIMS: To analyze data from a large, contemporary, nationally representative sample of US veterans to evaluate: (1) the prevalence of life-time alcohol use disorder (AUD) and past-year AUD; (2) common psychiatric comorbidities associated with life-time AUD; and (3) correlates of life-time and past-year probable AUD. DESIGN: Data were analyzed from the National Health and Resilience in Veterans Study (NHRVS), a web-based survey of a random probability sample of a contemporary, nationally representative sample of US military veterans. SETTING: United States. PARTICIPANTS: Nationally representative sample of 3157 US veterans aged 21 years and older. MEASUREMENTS: Life-time alcohol abuse and dependence were assessed according to DSM-IV diagnostic criteria using the Mini International Neuropsychiatric Interview, and combined into a single variable: AUD. Past-year probable AUD was assessed using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C). Correlates of AUD, including psychiatric comorbidities, suicidality and demographic characteristics, were also assessed. FINDINGS: The prevalence of life-time AUD and past-year probable AUD was 42.2% [95% confidence interval (CI) = 40.5-43.9%)] and 14.8% (95% CI = 13.6-16.0%), respectively. Compared with veterans without AUD, those with life-time AUD had substantially elevated rates of life-time and current mood and anxiety disorders [odds ratios (ORs) = 2.6-4.1], drug use disorder (OR = 10.7), life-time suicide attempt (OR = 4.1) and current suicidal ideation (OR = 2.1). Younger age, male sex, lower education, lower annual household income and greater number of life-time traumatic events were associated independently with life-time AUD. Younger age, male sex, unpartnered marital status and a life-time diagnosis of major depressive disorder were associated independently with past-year probable AUD. CONCLUSIONS: More than 40% of US military veterans have a life-time history of alcohol use disorder. Veterans with a life-time history of alcohol use disorder have substantial comorbid psychiatric burden, including elevated rates of suicidal ideation and attempts. Certain socio-demographic (e.g. younger age, male sex, lower education) and clinical (e.g. trauma burden, history of depression) characteristics are associated with increased risk of AUD.

Anticonvulsants for the treatment of alcohol withdrawal syndrome and alcohol use disorders.

Alcoholic patients suffer from harmful allostatic neuroplastic changes in the brain causing an acute withdrawal syndrome upon cessation of drinking followed by a protracted abstinence syndrome and an increased risk of relapse to heavy drinking. Benzodiazepines have long been the treatment of choice for detoxifying patients and managing alcohol withdrawal syndrome (AWS). Non-benzodiazepine anticonvulsants (NBACs) are increasingly being used both for alcohol withdrawal management and for ongoing outpatient treatment of alcohol dependence, with the goal of either abstinence or harm reduction. This expert narrative review summarizes the scientific basis and clinical evidence supporting the use of NBACs in treating AWS and for reducing harmful drinking patterns. There is less evidence in support of NBAC therapy for AWS, with few placebo-controlled trials. Carbamazepine and gabapentin appear to be the most promising adjunctive treatments for AWS, and they may be useful as monotherapy in select cases, especially in outpatient settings and for the treatment of mild-to-moderate low-risk patients with the AWS. The body of evidence supporting the use of the NBACs for reducing harmful drinking in the outpatient setting is stronger. Topiramate appears to have a robust effect on reducing harmful drinking in alcoholics. Gabapentin is a potentially efficacious treatment for reducing the risk of relapse to harmful drinking patterns in outpatient management of alcoholism. Gabapentin's ease of use, rapid titration, good tolerability, and efficacy in both the withdrawal and chronic phases of treatment make it particularly appealing. In summary, several NBACs appear to be beneficial in treating AWS and alcohol use disorders.

Pharmacogenetics of naltrexone and disulfiram in alcohol dependent, dually diagnosed veterans.

BACKGROUND: Disulfiram and naltrexone were evaluated in treatment of individuals with co-occurring alcohol dependence and other Axis I disorders (e.g., Major Depression). We explored pharmacogenetic interactions in genotyped subjects. METHODS: Alcohol dependent (AD) subjects received naltrexone alone, placebo alone, disulfiram with placebo or disulfiram with naltrexone. They were genotyped for OPRM1 rs1799971 (Asn40Asp), and DBH rs1611115 (C-1021T). N = 107 male European-American subjects were included. RESULTS: There were no significant interactions with OPRM1. DBH interacted with naltrexone on the primary outcome of abstinence from heavy drinking (χ(2) (1) = 5.23, p = .02). "T" allele carriers on naltrexone had more abstinence compared to "CC" subjects on naltrexone (FET, p = .01). "T" allele carriers on naltrexone had the highest overall rates of abstinence from heavy drinking (>90%). Also, DBH genotype interacted with disulfram (F(1,17) = 7.52, p = .01) on drinks per drinking day with less drinking for subjects with the "CC" genotype than for T allele carriers on disulfiram. CONCLUSIONS: DBH*rs1611115*T associated with better response to naltrexone, while for those on disulfiram that drank, "CC" subjects drank less than T carriers. For rs1799971*G, we did not replicate findings from previous studies showing a more favorable response to NTX, possibly due to the small available sample. SCIENTIFIC SIGNIFICANCE: Genotyping rs1611115 may be useful in understanding inter-individual differences in AD treatment response. FUTURE DIRECTIONS: Further study of rs1611115 pharmacogenetics is warranted.