The administration of sertraline plus naltrexone reduces ethanol consumption and motivation in a long-lasting animal model of post-traumatic stress disorder.

This study was aimed to evaluate the effects of sertraline (STR) and/or naltrexone (NTX) on ethanol consumption and motivation in an animal model of post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD). Male C57BL/6J mice were submitted to an intermittent and progressively increasing stressful stimuli simulating PTSD behavioural features. Behavioural alterations were explored by the fear conditioning (FC), novelty suppressed feeding test (NSFT) and acoustic startle response (ASR) paradigms. Afterwards, mice were evaluated in the voluntary ethanol consumption (VC) and the oral ethanol self-administration (OEA) paradigms. The effects of STR (10 mg/kg) and/or NTX (0.7 mg/kg) on ethanol consumption and motivation were analysed in the OEA. Furthermore, relative gene expression analyses of tyrosine hydroxylase (Th), mu-opioid receptor (Oprm1) and 5-hydroxitryptamine transporter (Slc6a4) were performed in the ventral tegmental area (VTA), nucleus accumbens (NAcc) and dorsal raphe nucleus (DR), respectively. PTSD-like mice presented increased fear-related memory, anxiety-like behaviours, and startle response, as well as enhanced ethanol consumption and motivation in the VC and OEA paradigms. Interestingly, STR plus NTX combination significantly reduced ethanol intake and motivation in the OEA. Gene expression analyses revealed reduced Th and Oprm1 whereas Slc6a4 gene expression increased in PTSD-like mice. STR and/or NTX modulated Th and Slc6a4 gene expression changes in PTSD-like mice. Furthermore, NTX increased Oprm1 gene expression revealing a synergistic action when combined with STR. These results provide evidence about the efficacy of the STR plus NTX to attenuate ethanol reinforcement and motivation in an animal model of PTSD and AUD dual pathology.

Combining behavioral harm-reduction treatment and extended-release naltrexone for people experiencing homelessness and alcohol use disorder in the USA: a randomised clinical trial.

BACKGROUND: The rate of alcohol-related mortality in people experiencing homelessness and alcohol use disorder is high and necessitates accessible and effective treatment for alcohol use disorder. However, typical abstinence-based treatments do not optimally engage this population. Recent studies have shown that harm-reduction treatment, which does not require abstinence, but instead aims to incrementally reduce alcohol-related harm and improve health-related quality of life, is acceptable to and effective for this population. The aim of this study was to test the efficacy of combined pharmacological and behavioural harm-reduction treatment for alcohol use disorder (HaRT-A) in people experiencing homelessness and alcohol use disorder. METHODS: This randomised clinical trial was done at three community-based service sites (low-barrier shelters and housing programmes) in Seattle (WA, USA). Eligible participants were adults (aged 21-65 years) who met the DSM-IV-TR criteria for alcohol use disorder and who experienced homelessness in the past year. Participants were randomly assigned (1:1:1:1) by permuted block randomisation, stratified by site, to receive either HaRT-A plus intramuscular injections of 380 mg extended-release naltrexone (XR-NTX; HaRT-A plus XR-NTX group); HaRT-A plus placebo injection (HaRT-A plus placebo group); HaRT-A alone (HaRT-A alone group); or community-based supportive services as usual (services-as-usual control group). Patients assigned to receive HaRT-A attended sessions at baseline (week 0) and in weeks 1, 4, 8, and 12. XR-NTX and placebo injections were administered in weeks 0, 4, and 8. During the study, participants, interventionists, and investigators were masked to group assignment in the two injection arms. All participants were invited to follow-up assessments at weeks 4, 8, 12, 24, and 36. The primary outcomes were self-reported alcohol use quantity (ie, alcohol quantity consumed on peak drinking occasion, as measured with the Alcohol Quantity Use Assessment questionnaire) and frequency (measured with the Addiction Severity Index), alcohol-related harm (measured with the Short Inventory of Problems-2R questionnaire), and physical and mental health-related quality of life (measured with the Short Form-12 survey). Using piecewise growth modelling and an intention-to-treat model, we compared the effects of the three active treatment groups with the services-as-usual control group, and the HaRT-A plus XR-NTX group with the HaRT-A plus placebo group, over the 12-week treatment course and during the 24 weeks following treatment withdrawal. Safety analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT01932801. FINDINGS: Between Oct 14, 2013, and Nov 30, 2017, 417 individuals experiencing homelessness and alcohol use disorder were screened, of whom 308 were eligible and randomly assigned to the HaRT-A plus XR-NTX group (n=74), the HaRT-A plus placebo group (n=78), the HaRT-A alone group (n=79), or the services-as-usual control group (n=77). Compared with the services-as-usual control group, the HaRT-A plus XR-NTX group showed significant improvements from baseline to 12 weeks post-treatment across four of the five primary outcomes: peak alcohol quantity (linear B -0·48 [95% CI -0·79 to -0·18] p=0·010; full model Cohen's d=-0·68), alcohol frequency (linear B -4·42 [-8·09 to -0·76], p=0·047; full model Cohen's d=-0·16), alcohol-related harm (linear B -2·22 [-3·39 to -1·06], p=0·002; full model Cohen's d=-0·56), and physical health-related quality of life (linear B 0·66 [0·23 to 1·10], p=0·012; full model Cohen's d=0·43). Compared with the services-as-usual control group, the HaRT-A plus placebo group showed significant improvements in three of the five primary outcomes: peak alcohol quantity (linear B -0·41 [95% CI -0·67 to -0·15] p=0·010; full model Cohen's d=-0·23), alcohol frequency (linear B -5·95 [-9·72 to -2·19], p=0·009; full model Cohen's d=-0·13), and physical health-related quality of life (linear B 0·53 [0·09 to 0·98], p=0·050; full model Cohen's d=0·35). Compared with the services-as-usual control group, the HaRT-A alone group showed significant improvements in two of the five primary outcomes: alcohol-related harm (linear B -1·58 [95% CI -2·73 to -0·42] p=0·025; full model Cohen's d=-0·40) and physical health-related quality of life (linear B 0·63 [0·18 to 1·07], p=0·020; full model Cohen's d=0·41). After treatment discontinuation at 12 weeks, the active treatment groups plateaued, whereas the services-as-usual group showed improvements. Thus, during the post-treatment period (weeks 12 to 36), the services-as-usual control group showed greater reductions in alcohol-related harm compared with both the HaRT-A plus XR-NTX group (linear B 0·96 [0·24 to 1·67], p=0·028; full model Cohen's d=0·24) and the HaRT-A alone group (linear B 1·02 [0·35 to 1·70], p=0·013; full model Cohen's d=0·26). During the post-treatment period, the services-as-usual control group significantly improved on mental health-related quality of life compared with the HaRT-A alone group (linear B -0·46 [-0·79 to -0·12], p=0·024; full model Cohen's d=-0·28), and on physical health-related quality of life compared with the HaRT-A plus XR-NTX group (linear B -0·42 [-0·67 to -0·17], p=0·006; full model Cohen's d=-0·27), the HaRT-A plus placebo group (linear B -0·42 [-0·69 to -0·15], p=0·009; full model Cohen's d=-0·27), and the HaRT-A alone group (linear B -0·47 [-0·72 to -0·22], p=0·002; full model Cohen's d=-0·31). For all other primary outcomes, there were no significant linear differences between the services-as-usual and active treatment groups. When comparing the HaRT-A plus placebo group with the HaRT-A plus XR-NTX group, there were no significant differences for any of the primary outcomes. Missing data analysis indicated that participants were more likely to drop out in the services-as-usual control group than in the active treatment groups; however, primary outcome findings were found to be robust to attrition. Participants in the HaRT-A plus XR-NTX, HaRT-A plus placebo, and HaRT-A alone groups were not more likely to experience adverse events than those in the services-as-usual control group. INTERPRETATION: Compared with existing services, combined pharmacological and behavioural harm-reduction treatment resulted in decreased alcohol use and alcohol-related harm and improved physical health-related quality of life during the 12-week treatment period for people experiencing homelessness and alcohol use disorder. Although not as consistent, there were also positive findings for behavioural harm-reduction treatment alone. Considering the non-significant differences between participants receiving HaRT-A plus placebo and HaRT-A plus XR-NTX, the combined pharmacological and behavioural treatment effect cannot be attributed to XR-NTX alone. Future studies are needed to further investigate the relative contributions of the pharmacological and behavioural components of harm-reduction treatment for alcohol use disorder, and to ascertain whether a maintenance treatment approach could extend these positive outcome trajectories. FUNDING: National Institute on Alcohol Abuse and Alcoholism.

Effects of 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine on alcohol consumption in Long-Evans rats.

The objectives of this study were to determine alcohol consumption after administration of (R)(-)-2,5-dimethoxy-4-iodoamphetamine (DOI) or naltrexone in Long-Evans rats, and to assess the effectiveness of these treatments based on individual differences in alcohol consumption. Adult male Long-Evans rats (N = 16) were given opportunities to orally self-administer a 20% (v/v) ethanol (EtOH) solution using an intermittent access, two-bottle (vs. tap water) choice procedure in their home cages. EtOH consumption and preference, total fluid consumption and food intake were measured. Last, we assessed the effects of naltrexone (1 mg/kg; subcutaneous) and (R)(-)-DOI (0.1-1 mg/kg; subcutaneous) on EtOH intake and preference using a quartile analysis. Rats showed stable EtOH (20%) intake and preference after 15 EtOH access sessions. Naltrexone produced a transient decrease in EtOH intake, but an inconsistent effect on EtOH preference, whereas DOI dose-dependently reduced EtOH intake and preference for at least 24 h. Subsequent quartile analyses revealed that rats with the highest EtOH intake during the first 60 min of access to EtOH showed greater reductions in EtOH intake and preference after DOI treatment. This is the first report to show that DOI-elicited reductions in EtOH intake and preference in rats depend on baseline EtOH intake, perhaps supporting a 'baseline dependency' hypothesis of effectiveness with phenethylamine psychedelics on EtOH consumption. If so, individuals with greater potential to develop severe AUDs may be particularly responsive to the positive motivational changes produced by treatment with psychedelics that target the 5-HT2 receptor family.

Disulfiram Ethanol Reaction with Alcohol-Based Hand Sanitizer: An Exploratory Study.

AIMS: We conducted a cross-sectional survey to estimate the prevalence and clinical manifestation of disulfiram ethanol reaction (DER) and isopropanol toxicity (IT) in patients with alcohol use disorders, on disulfiram. Alcohol-based hand rub contains either ethanol or isopropanol or both. COVID-19 pandemic has led to wide scale usage of sanitizers. Patients with alcohol use disorders, on disulfiram, might experience disulfiram ethanol like reactions with alcohol-based sanitizers. METHODS: We telephonically contacted 339 patients, prescribed disulfiram between January 2014 and March 2020. The assessment pertained to the last 3 months (i.e. third week of March to third week of June 2020). RESULT: The sample consisted of middle-aged men with a mean 16 years of alcohol dependence. Among the 82 (24%) patients adherent to disulfiram, 42 (12.3%) were using alcohol-based hand rubs. Out of these, a total of eight patients (19%; 95% CI 9-33) had features suggestive of DER; four of whom also had features indicative of IT. Five patients (62.5%) had mild and self-limiting symptoms. Severe systemic reactions were experienced by three (37.5%). Severe reactions were observed with exposure to sanitizers in greater amounts, on moist skin or through inhalation. CONCLUSION: Patients on disulfiram should be advised to use alternate methods of hand hygiene.

Differences in Sociodemographic and Alcohol-Related Clinical Characteristics Between Treatment Seekers and Nontreatment Seekers and Their Role in Predicting Outcomes in the COMBINE Study for Alcohol Use Disorder.

BACKGROUND: One of the challenges in early-stage clinical research aimed at developing novel treatments for alcohol use disorder (AUD) is that the enrolled participants are heavy drinkers, but do not seek treatment for AUD. AIMS: To compare nontreatment seekers with alcohol dependence (AD) from 4 human laboratory studies conducted at Brown University (N = 240; 65.4% male) to treatment seekers with AD from the multisite COMBINE study (N = 1,383; 69.1% male) across sociodemographic and alcohol-related clinical variables and to evaluate whether the variables that significantly differentiate the 2 samples predict the 3 main COMBINE clinical outcomes: time to relapse, percent days abstinent (PDA), and good clinical outcome. METHODS: Sample characteristics were assessed by parametric and nonparametric testing. Three regression models measured the association between the differing variables and the 3 main COMBINE clinical outcomes. RESULTS: The nontreatment seekers, compared to the treatment seekers, were more ethnically diverse, less educated, single, and working part-time or unemployed (p's < 0.05); they met fewer DSM-IV AD criteria and had significantly lower scores on alcohol-related scales (p's < 0.05); they were less likely to have a father with alcohol problems (p < 0.0001) and had a significantly earlier age of onset and longer duration of AD (p's < 0.05); they also had significantly more total drinks, drinks per drinking day, heavy drinking days (HDD), and lower PDA in the 30 days prior to baseline (p's < 0.0001 to <0.05). Having more HDD in the 30 days prior to baseline predicted all of the 3 COMBINE clinical outcomes. All the other characteristics mentioned above that differed significantly between the 2 groups predicted at least 1 of the 3 COMBINE clinical outcomes, except for level of education, age of onset, and duration of AD. CONCLUSIONS: The observed differences between groups should be considered in efforts across participant recruitment at different stages of the development of new treatments for AUD.

Interaction of Ethanol and Oral ANS-6637, a Selective ALDH2 Inhibitor in Males: A Randomized, Double-Blind, Placebo-Controlled, Single-Ascending Dose Cohort Study.

BACKGROUND: ANS-6637, an orally bioavailable selective and reversible aldehyde dehydrogenase-2 (ALDH2) inhibitor, is under development for drug and alcohol use disorders. During the elimination of alcohol, ALDH2 metabolizes acetaldehyde to acetate; inhibiting this enzyme can lead to aversive reactions due to the accumulation of acetaldehyde. Thus, understanding the safety and tolerability of ANS-6637 in combination with alcohol is essential. TRIAL DESIGN AND METHODS: Forty eight healthy males participated in a randomized, double-blind, placebo-controlled, single-ascending dose cohort study of oral ANS-6637. Eligible participants were randomized to ANS-6637 (n = 36) or placebo (n = 12) in a 3:1 fashion in each of 6 dose cohorts (8 per cohort; ANS-6637 dose levels were 25, 50, 100, 200, 400, and 600 mg). Two hours after receiving study drug, participants drank up to 5 standard drinks, 1 every 30 minutes. Safety assessments, pharmacodynamic measures, and pharmacokinetic blood samples were obtained. RESULTS: Flushing was the most common adverse event (AE) associated with ANS-6637 (24 of 36 participants) compared with placebo (3 of 12). Statistically significant, but modest, increases in heart rate (HR) occurred (+10.5 bpm after 2 drinks; +16.9 to + 20.5 bpm after 3rd through 5th drink). No participant met HR or systolic blood pressure criteria for stopping ethanol administration. There were no clinically significant QTc interval prolongations. Individuals receiving ANS-6637 reported lower ratings of liking, alcohol effects, and feeling drunk. CONCLUSIONS: A single oral dose of ANS-6637 with up to 5 standards drinks over 2.5 hours was generally well tolerated in healthy males. The most common pharmacological response was flushing and an increase in HR, which are known effects of acetaldehyde accumulation and consistent with inhibition of ALDH2 with oral ANS-6637 in combination with alcohol. The results of this alcohol interaction study support further testing of ANS-6637 in individuals who consume alcohol heavily.

Impact of Acamprosate on Chronic Tinnitus: A Randomized-Controlled Trial.

OBJECTIVES: Tinnitus is a common and distressing otologic symptom, with various probable pathophysiologic mechanisms, such as an imbalance between excitatory and inhibitory mechanisms. Acamprosate, generally used to treat alcoholism, is a glutaminergic antagonist and GABA agonist suggested for treating tinnitus. Thus, we aimed to evaluate the efficacy and safety of acamprosate in the treatment of tinnitus. METHODS: The current randomized-controlled trial study included 20 subjects with chronic tinnitus. After performing psycho-acoustic, psychometric and electrophysiological evaluations, all studied tinnitus subjects were randomly divided into two groups of acamprosate and placebo. The first group received oral acamprosate (two tablets of 333 mg/d, three times a day), whereas the second group was given placebo treatment (two tablets, three times a day). After the first 30 days, all evaluations were repeated for the studied groups just in the same manner before the study. Subsequently, the final results of each evaluation were compared together with the baseline values. RESULTS: Nine studied subjects randomly received acamprosate, whereas eleven others received a placebo. There was no significant improvement in the psycho-acoustic tests, except a decrease was observed in the pitch match of tinnitus (P = .039). For those subjects who were receiving acamprosate, a significant reduction was observed in tinnitus handicap inventory (P = .006), tinnitus questionnaire scores (P = .007), and the visual analog scores (P = .007) compared to the placebo group. There was a significant reduction in Action Potential latency (P = .048) as well as an increase in the amplitude of distortion product otoacoustic emissions at 4 kHz (P = .048). CONCLUSIONS: The study results indicated a subjective relief of tinnitus as well as some degree of the electrophysiological improvement at the level of the cochlear and the distal portion of the auditory nerve among the subjects who received the acamprosate. CLINICAL TRIAL REGISTRATION CODE: IRCT2013121115751N1.

Evidence-Based Pharmacotherapies for Alcohol Use Disorder: Clinical Pearls.

Pathologic alcohol use affects more than 2 billion people and accounts for nearly 6% of all deaths worldwide. There are three medications approved for the treatment of alcohol use disorder by the US Food and Drug Administration (FDA): disulfiram, naltrexone (oral and long-acting injectable), and acamprosate. Of growing interest is the use of anticonvulsants for the treatment of alcohol use disorder, although currently none are FDA approved for this indication. Baclofen, a γ-aminobutyric acid B receptor agonist used for spasticity and pain, received temporary approval for alcohol use disorder in France. Despite effective pharmacotherapies, less than 9% of patients who undergo any form of alcohol use disorder treatment receive pharmacotherapies. Current evidence does not support the use of pharmacogenetic testing for treatment individualization. The objective of this review is to provide knowledge on practice parameters for evidenced-based pharmacologic treatment approaches in patients with alcohol use disorder.

Bioresponsive nanostructured systems for sustained naltrexone release and treatment of alcohol use disorder: Development and biological evaluation.

In this study, microemulsions capable of transforming into nanostructured hexagonal phase gels in vivo upon uptake of biological fluids for naltrexone prolonged release were investigated as a strategy for management of alcohol use disorder (AUD). Microemulsions were prepared using monoolein, tricaprylin, water and propylene glycol; after preliminary characterization, one formulation was selected, which contained 55% of monoolein-tricaprylin (M-55). This microemulsion displayed size below 200 nm and Newtonian rheological behavior. Liquid crystalline gels formed in vitro upon 8 h of contact with water following a second order kinetics. After 120 h, <50% of naltrexone was released in vitro independently on drug loading (5 or 10%). In vivo, gels formed within 24 h of M-55 subcutaneous administration, and persisted locally for over 30 days providing slow release of the fluorescent marker Alexa fluor compared to a solution. Using the conditioned place preference paradigm, a test used to measure drug's rewarding effects, a single dose of M-55 containing 5% naltrexone reduced the time spent in the ethanol-paired compartment by 1.8-fold compared to saline; this effect was similar to that obtained with daily naltrexone injections, demonstrating the formulation efficacy and its ability to reduce dosing frequency. A more robust effect was observed following administration of M-55 containing 10% of naltrexone, which was compatible with aversion. These results support M-55 as a platform for sustained release of drugs that can be further explored for management of AUD to reduce dosing frequency and aid treatment adherence.

Very Low Frequency of Drug Therapy of Alcohol Dependence in Germany - Analysis of Data of A Statutory Health Insurance.

Acamprosate and naltrexone are medications of proven efficacy in the treatment of alcohol dependence. In order to investigate the prescription of these drugs in outpatient routine treatment in Germany (frequency of prescription, duration, medical specialty of prescribing physician), data of a large statutory health insurance were analyzed. Persons were included who were discharged from inpatient treatment with an alcohol-related disorder among their diagnoses during a one year observation period and with no diagnosed additional substance-related disorder (apart from nicotine- and cannabis-related disorders). Thus 12.958 patients were identified (mainly male, 77.9%; at average 51.4 years [+/-12.7] of age). 44.3% of these patients were treated in a psychiatric hospital, the remaining patients in hospitals of other specialties (e. g. 9.2% in departments of surgery). During an observation period of 6 months after discharge, acamprosate or naltrexone were prescribed at least once to 98 persons (0.76% of 12.958 patients; acamprosate n=80, 0.62%; naltrexone n=18, 0.14%). 16 (0.12%) patients were prescribed acamprosate or naltrexone for more than 3 months. Half of the prescriptions were issued by general practitioners. Possible reasons for this under-prescription are lack of knowledge about the drug treatment of alcohol dependence outside of addiction psychiatry, neglect of biological aspects (including medication) regarding etiology and treatment of substance-related disorders, and stigma of patients with substance-related disorders.

Fomepizole to treat disulfiram-ethanol reaction: a case series.

Introduction: Disulfiram-ethanol reaction (DER) due to acetaldehyde accumulation occurs after drinking ethanol during disulfiram therapy. DER may result in life-threatening toxicity requiring urgent critical care. Fomepizole, an alcohol dehydrogenase inhibitor used to treat toxic alcohol poisoning, has been suggested for treating DER by preventing the metabolism of ethanol to acetaldehyde. However, its effectiveness and safety have been poorly assessed in this setting.Cases: Ten DER patients (median age, 40 years; 7 males/3 females) were included in the study. DER features consisted of consciousness impairment (median Glasgow coma score, 13; need for mechanical ventilation, 30%) with flushing (50%), vomiting (40%), electrocardiogram abnormalities (30%) and circulatory failure requiring norepinephrine (30%). Patients were successfully treated with a single intravenous infusion of fomepizole (median dose, 7.5 mg/kg). The three patients receiving norepinephrine did not improve until fomepizole was administered. The other seven patients improved promptly following fomepizole infusion without requirement for vasopressor support. All patients fully recovered. Local pain at the injection site was the only reported adverse reaction in one patient.Conclusion: Our case series supports the effectiveness and safety of fomepizole in rapidly reversing DER-induced vasodilatation and toxicity.

Adherence Across FDA-Approved Medications for Alcohol Use Disorder in a Veterans Administration Population.

OBJECTIVE: U.S. Food and Drug Administration (FDA)-approved medications exist for the treatment of alcohol use disorders. However, their effectiveness depends on proper adherence to the prescribed regimen. Differences in adherence across medications may have implications for clinical outcomes and may provide helpful information in considering treatment options. This study aims to identify significant differences in adherence if present. METHOD: A retrospective chart review was conducted in the Veterans Integrated Service Networks (VISN)-7 region of Veterans Affairs hospital and community-based outpatient clinics within South Carolina and Georgia. Prescriptions of FDA-approved alcohol use disorder medications from 2010 through 2015 were reviewed. Adherence was determined by the proportion of days the veteran had oral or injectable medication available over a 6-month period as noted by medication fills (reported as 0%-100% medication availability). We compared adherence for specific medications using chi-square, t test, logistic regression for dichotomous outcomes, and linear regression for continuous outcomes. RESULTS: A total of 715 subjects and 807 medication trials were included. Mean adherence (percentage of days that medication was available) was 41.3% for disulfiram, 44.7% for acamprosate, 49.8% for oral naltrexone, and 54.6% for extended-release injectable naltrexone. The mean adherence was significantly different between disulfiram and oral naltrexone (p = .002) as well as disulfiram and extended-release injectable naltrexone (p = .004). Adherence of 80% was achieved in 11.9%, 19.4%, 22.7%, and 24.4% of treatment courses with disulfiram, acamprosate, naltrexone, and extended-release injectable naltrexone, respectively. These differences were significant for disulfiram versus oral naltrexone (p = .004) and disulfiram versus extended-release injectable naltrexone (p = .05). CONCLUSIONS: These results demonstrate that overall adherence to medication-assisted treatment for alcohol use disorder is low across all medications. When directly compared, disulfiram had significantly lower adherence than both oral and extended-release injectable naltrexone.

Disulfiram and Hypotension in a 53-year-old Woman.

We describe a case of disulfiram-ethanol reaction in a patient presenting with altered mental status. The patient was found to be profoundly hypotensive, requiring multiple vasopressor agents. As the symptoms associated with disulfiram reaction are non-specific, it is important to maintain a high level of suspicion for drug reaction when caring for the undifferentiated altered and hypotensive patient.

First study of safety and tolerability of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in patients with alcohol use disorder: preliminary data on the first four participants.

We present the preliminary data in an ongoing open-label safety and tolerability proof of concept study exploring the potential role for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in treating patients with alcohol use disorder. At this stage, seven participants have completed the full 8-week MDMA-assisted psychotherapy course, including two therapy sessions each with MDMA. This paper focuses on the safety and tolerability of the therapeutic course for the first four participants to complete treatment. Longer-term outcomes of drinking behaviour will be presented later when the full project data are published. Results show all four participants have successfully tolerated the treatment. There have been no serious adverse events related to MDMA, no unexpected physiological responses to the MDMA sessions or changes to blood results or electrocardiograms, measured before and after the 8-week course. We conclude that the treatment is well- tolerated and are making plans to expand the project into a randomised placebo-controlled study.

Pharmacogenetics of alcohol use disorder treatments: an update.

Introduction: Alcohol use disorder (AUD) is highly prevalent; costly economically, socially, and interpersonally; and grossly undertreated. The low rate of utilization of medications with demonstrated (albeit modest) efficacy is particularly noteworthy. One approach to increasing the utility and safety of available medications is to use a precision medicine approach, which seeks to identify patients for whom specific medications are likely to be most efficacious and have the fewest adverse effects. Areas Covered: We review the literature on the pharmacogenetics of AUD treatment using both approved and off-label medications. We cover both laboratory studies and clinical trials, highlighting valuable mechanistic insights and underscoring the potential value of precision-based care for AUD. Expert Opinion: Pharmacotherapy can be a useful component of AUD treatment. Currently, the evidence regarding genetic predictors of medication efficacy is very limited. Thus, a precision medicine approach is not yet ready for widespread clinical implementation. Further research is needed to identify candidate genetic variants that moderate the response to both established and novel medications. The growing availability of large-scale, longitudinal datasets that enable the synthesis of genetic and electronic health record data provides important opportunities to develop this area of research.

Dispensing of medication for alcohol use disorder; an examination of large databases in a New Zealand context.

AIM: To report dispensing of disulfiram, naltrexone, antidepressants and quetiapine for New Zealanders diagnosed with alcohol use disorder. METHOD: The Pharmaceutical Collection is the national dispensing database for medications in New Zealand. PRIMHD is the national mental health and addiction service database. Dispensing data was extracted from the Pharmaceutical Collection and merged with diagnostic data from PRIMHD to report pharmacological treatment of alcohol use disorders in New Zealand. RESULTS: In 2014, there were 5,004 individuals diagnosed with an alcohol use disorder by mental health and addiction services. Four hundred and eighty-nine individuals also received a major depressive disorder diagnosis. 2.1% of the group with alcohol use disorder were dispensed disulfiram and 0.7% were dispensed naltrexone. Treatment with antidepressants (12.7%) and quetiapine (5.6%) was more common. In the group with comorbid alcohol use disorder and depression, 2% were dispensed disulfiram, 0.2% were dispensed naltrexone, 27.4% were dispensed antidepressants and 11.2% were dispensed quetiapine. CONCLUSION: Overall rates of dispensing were relatively low. Antidepressants followed by quetiapine were the most common treatments. In contrast, disulfiram and naltrexone were only used for a minority of clients. This suggests inadequate and poorly targeted pharmacological treatments are used for the treatment of alcohol use disorders in New Zealand.