5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) for alcohol use disorder: An open-label, phase 2, proof-of-concept, clinical trial.

Alcohol Use and Anxiety: Diagnostic and Management Issues

ContextAccording to the World Health Organization, alcohol is a major global public health problem, leading to a significant increase in illness and death. To treat alcohol use disorders, new therapeutic tools are being promoted, among which virtual reality (VR) shows promise. Previous research has demonstrated the efficacy of VR in reducing alcohol cravings in patients, but there is a lack of data on its effectiveness in maintaining abstinence or reducing consumption in recently abstinent individuals.The E-Reva study aims to compare the efficacy of a treatment strategy combining virtual reality cue exposure therapy (VR-CET) and cognitive behavioral therapy (CBT) with conventional CBT in reducing alcohol consumption and craving in patients with alcohol use disorder (AUD). In addition to this primary objective, the study will compare the effects of VR-CET combined with CBT on anxiety, depression, rumination, and feelings of self-efficacy versus conventional CBT.MethodsThis prospective randomized controlled trial will be conducted over 8 months in four addiction departments in France. It includes two parallel groups: i) the VR-CET + CBT group, and ii) the CBT-only group, which serves as a control group.Participants will be recruited by the investigating doctor in the addiction centers. The sample will consist of 156 patients diagnosed with AUD and abstinent for at least 15 days.Both treatment groups will participate in four group CBT sessions followed by four individual sessions: i) the VR-CET group will be exposed to virtual environments associated with alcohol-related stimuli, ii) the CBT-only group will receive traditional CBT sessions. After completion of the 8 sessions, patients will be followed up for 6 months. The primary outcome is the cumulative number of standard drinks consumed at 8 months, assessed using the TLFB method.DiscussionDespite the promise of VR-CET to reduce the desire to drink, the effect on alcohol consumption remains uncertain in the existing literature. Our protocol aims to address the limitations of previous research by increasing sample size, targeting consumption reduction, and incorporating neutral environments. E-Reva aims to enrich the literature on the use of VR in the treatment of AUD and open new perspectives for future interventions.Trial registrationClinicalTrials.gov ID NCT06104176, Registered 2023/11/13 (https://clinicaltrials.gov/study/NCT06104176?id=NCT06104176&rank=1).N° IDRCB: 2022-A02797-36.Protocol version 1.0, 12/05/2023.

The American Psychiatric Association Practice Guideline for the Pharmacological Treatment of Patients With Alcohol Use Disorder.

Alcohol Use Disorders (AUD) are widespread and have serious consequences, but are among the most undertreated mental disorders. Internet interventions have been found effective in treating AUD, but we know little about long-term outcomes, two years or more after treatment. This study explored 12- and 24-month outcomes in alcohol consumption following initial 6-month improvements after a therapist-guided high-intensity internet intervention and an unguided low-intensity internet intervention among individuals with alcohol use disorder. Between-group comparisons were analyzed, as well as within-group comparisons with (1) pre-treatment measurements (2) post-treatment measurements. Participants consisted of a general population sample of internet help-seekers in Sweden. A total of 143 adults (47% men) with a score of 14 (women)/16 (men) or more on the Alcohol Use Disorders Identification Test, alcohol consumption of 11 (women)/14 (men) or more standard drinks the preceding week and ≥ 2 DSM-5 alcohol use disorder (AUD) criteria based on a diagnostic interview were included. The high- and low-intensity internet interventions (n = 72 and n = 71 respectively) consisted of modules based on relapse prevention and cognitive-behavioral therapy. The primary outcome was self-reported alcohol consumption in the preceding week measured as (1) number of standard drinks and (2) number of heavy drinking days. Attrition from self-reported questionnaires was 36% at the 12-month follow-up and 53% at the 24-month follow-up. No significant between-group differences occurred in outcomes at either long-term follow-up. Regarding within-group differences, compared to pre-treatment, alcohol consumption was lower in both high- and low-intensity interventions at both long-term follow-ups [within-group standard drinks effect sizes varied between g = 0.38–1.04 and heavy drinking days effect sizes varied between g = 0.65–0.94]. Compared to post-treatment, within-group alcohol consumption in the high intensity intervention increased at both follow-ups; for the low-intensity intervention, within-group consumption decreased at 12-month follow-up, but did not differ compared to post-treatment at 24 months. Both high- and low-intensity internet interventions for AUD were thus associated with overall reductions in alcohol consumption at long term follow-ups, with no significant differences between the two. However, conclusions are hampered by differential and non-differential attrition.

Toward Personalized Medicine in the Pharmacotherapy of Alcohol Use Disorder: Targeting Patient Genes and Patient Goals

Cognitive behavioral therapy (CBT) is an evidence-based treatment for alcohol use disorder (AUD). Exposure to high-risk situations in virtual reality (VR) has been suggested to have a potential therapeutical benefit, but no previous study has combined VR and CBT for AUD. We aimed to investigate the feasibility of using VR-simulated high-risk environments in CBT-based treatment of AUD. We randomized ten treatment-seeking AUD-diagnosed individuals to three sessions of conventional CBT or VR-assisted CBT performed at two outpatient clinics in Denmark. In each session, patients randomized to VR-CBT were exposed to VR-simulations from a restaurant to induce authentic thoughts, emotions, physiological reactions, and craving for CBT purposes. The primary outcome measure was feasibility: Drop-out rate, psychological reactions, and simulator sickness. Secondary outcomes were assessment of preliminary short-term changes in alcohol consumption and craving from baseline to one-week and one-month follow-up. In addition, the study was conducted for training in operationalization of VR equipment, treatment manuals, and research questionnaires. The majority of patients completed all study visits (90%). VR induced authentic high-risk related thoughts, emotions, and physiological reactions that were considered relevant for CBT by patients and therapists. Four of five patients randomized to VR-CBT experienced cravings during VR simulations, and most of these patients (3/5) experienced mild simulator sickness during VR exposure. The preliminary data showed that patients receiving VR-CBT had more reduction in alcohol consumption than patients receiving conventional CBT at one week- (median 94% vs. 72%) and one-month follow-up (median 98% vs. 55%). Similar results were found regarding changes in cravings. We demonstrated VR-CBT to be a feasible intervention for patients with AUD which supports continued investigations in a larger randomized clinical trial evaluating the efficacy of VR-CBT. https://www.clinicaltrials.gov/study/NCT04990765?cond=addiction%20CRAVR&rank=2, identifier NCT05042180.

Alcohol is among the leading contributors to the global burden of morbidity and mortality. Alcohol Use Disorders (AUD) account for the majority of this burden. Numerous interventions have demonstrated effectiveness in the treatment of AUD, but treatment response is modest and relapse rates remain high. No one treatment approach has demonstrated unequivocal superiority, prompting calls for individualised intervention strategies. Insufficient understanding of the mechanisms involved in AUD maintenance and treatment response impair the design and implementation of such approaches. The aim of this thesis was to progress understanding of potential treatment targets within personalised treatments for AUD. Alcohol craving, alcohol outcome expectancies, and rash impulsivity comprise the focus of this thesis, as each has been implicated in AUD maintenance and treatment response. A series of studies examining clinical applications of alcohol craving, outcome expectancies, and rash impulsivity within personalised AUD interventions were conducted.Study 1 (Chapter Two) examined the clinical utility of alcohol craving, focusing on issues of measurement. Highlighting the absence of a theoretically and psychometrically robust measure of craving which is also brief enough to be routinely administered within busy clinical settings, the study aimed to develop a new measure. Using data from 747 treatment seeking AUD patients the 22-item Alcohol Craving Experience Questionnaire (ACE) was reduced to 5-items while preserving its key theoretical elements, psychometric integrity, and clinical implications. The shortened ‘Mini ACE’ (MACE) is ideal for use with AUD populations in time-limited settings, such as weekly assessment in treatment contexts. An extended review of common issues in craving measurement is provided in the following chapter (Chapter Three). The chapter is intended to assist researchers and treatment providers in the selection, effective application, interpretation of the scales comprising the Alcohol Craving Experience Questionnaire.Study 2 (Chapter Four) highlights an absence of research on targeting alcohol outcome expectancies within Cognitive Behavioural Therapy (CBT) for AUD. Alcohol expectancies of 175 patients who completed a 12-week CBT program for AUD were assessed pre-and post-treatment. Several positive expectancies were predictive of drinking behaviour during treatment, and most reduced toward community norms post-treatment. However, positive expectancy change was not related to drinking behaviour during treatment, challenging cognitive theory emphasising the importance of this process. Increase in negative expectations of alcohols effect on mood was associated with fewer drinking days, supporting emphasis on modification of negative alcohol expectations within treatment. Further implications of both positive and negative alcohol outcome expectancies regarding AUD treatment are discussed.Study 3 (Chapter Five) is a large clinical randomised controlled trial (RCT; n = 379) examining the effectiveness of personalising AUD treatment based on individual differences in a) alcohol craving, b) alcohol outcome expectancies, and c) rash impulsivity. Patients were randomly assigned to Treatment as Usual (TAU, 8 sessions of standard CBT for AUD) or Targeted Treatment (TT). TT manualised content for 4 of 8-sessions sessions to address the risk-factor most elevated for each patient based on measures standardised by AUD norms (either Craving, Expectancy or Impulsivity). No significant differences in treatment outcome were observed between overall TT and standard, CBT (TAU) conditions. Craving and impulsivity, though not positive outcome expectancies, were found to reduce more for patients within their respective target modules. Only reduction in craving was associated with reduced drinking, supporting an indirect effect for personalised interventions targeting craving. The effectiveness of targeting rash impulsivity and outcome expectancies within personalised AUD could not be confirmed. Alcohol craving stands out as useful construct for consideration within future research of personalised interventions.Study 4 (Chapter Six) examined the association between alcohol craving and rash impulsivity in the prediction of treatment response. Craving and rash impulsivity were positively associated among 470 AUD patients. Both were found to predict lapse-risk during treatment, though impulsivity was mediated by craving. Patients with higher craving pre-treatment, were found to have more persistent craving as treatment progressed, which increased risk of lapse. These findings have clinical implications for the assessment and treatment of AUD, as well as theoretical implications for cognitive models of craving and impulsivity. The mediating role of craving is further considered in the context of the RCT findings (Chapter Three, Study 4).These four studies progress understanding of key mechanisms implicated within AUD maintenance and treatment response. Support was found for the utility of alcohol craving, outcome expectancies, and rash impulsivity as prognostic markers for AUD treatment. The novel contributions of this thesis pertain to understanding their utility as treatment targets. The processes which determine treatment response are complex, requiring equally sophisticated procedures to effectively adapt treatment to individuals. The findings of this program of research can inform the progression of such approaches.

Topiramate (TPM), a GABA/glutamate modulator, has shown positive results for treating alcohol use disorder (AUD), but causes significant cognitive adverse effects. TPM causes cognitive side effects by reducing glutathione levels in the frontal lobe. N-acetyl cysteine (NAC) increases level of intracellular glutathione. We hypothesized that combining NAC with TPM may mitigate the possible cognitive side effects of TPM, as well as working synergistically in reducing alcohol consumption more efficaciously than using TPM alone. A 12-week, double-blind randomized trial assessing the effects of combining NAC (1200mg/day) with TPM (200mg/day) vs TPM alone (i) cognitive side effects caused by TPM, (ii) percentage of heavy drinking days (PHDD) and percentage of days abstinent (PDA) using weekly calendar, and (iii) craving outcomes using the obsessive-compulsive drinking scale. Seventeen participants were randomized into the study (nine received TPM + NAC and eight matching TPM + Placebo). Cognitive adverse events were not significantly different between the treatment arms (P = 0.581). There was no difference in PHDD (P = 0.536) and in PDA over the entire study period (P = 0.892). However, both treatment groups at study end, compared with the baseline, significantly reduced their PHDD and increased their PDA. As for cravings: TPM + NAC group has shown higher level in automaticity of drinking (P = 0.029) and interference due to drinking (P = 0.014) subscales compared with the TPM + Placebo group. No difference was observed between groups in terms of Drinking Obsessions and Alcohol Consumption subscales. This pilot study indicates that combining NAC with TPM is overall safe, but the addition of NAC has no significant benefit over placebo in the incidence of TPM-related cognitive impairment, and alcohol drinking. Furthermore, craving outcomes may become worse with the addition of NAC.

Alcohol use disorder treatment delivered outside hepatology clinic.

Cognitive behavioral therapy (CBT) is an evidence-based treatment for alcohol use disorders (AUDs), yet is rarely implemented with high fidelity in clinical practice. Computer-based delivery of CBT offers the potential to address dissemination challenges, but to date there have been no evaluations of a web-based CBT program for alcohol use within a clinical sample. This study randomized treatment-seeking individuals with a current AUD to 1 of 3 treatments at a community outpatient facility: (i) standard treatment as usual (TAU); (ii) TAU plus on-site access to a computerized CBT targeting alcohol use (TAU+CBT4CBT); or (iii) CBT4CBT plus brief weekly clinical monitoring (CBT4CBT+monitoring). Participant alcohol use was assessed weekly during an 8-week treatment period, as well as 1, 3, and 6months after treatment. Sixty-eight individuals (65% male; 54% African American) were randomized (TAU=22; TAU+CBT4CBT=22; CBT4CBT+monitoring=24). There were significantly higher rates of treatment completion among participants assigned to 1 of the CBT4CBT conditions compared to TAU (Wald=6.86, p<0.01). Significant reductions in alcohol use were found across all conditions within treatment, with participants assigned to TAU+CBT4CBT demonstrating greater increases in percentage of days abstinent (PDA) compared to TAU, t(536.4)=2.68, p<0.01, d=0.71, 95% CI (0.60, 3.91), for the full sample. Preliminary findings suggest the estimated costs of all self-reported AUD-related services utilized by participants were considerably lower for those assigned to CBT4CBT conditions compared to TAU, both within treatment and during follow-up. This trial demonstrated the safety, feasibility, and preliminary efficacy of web-based CBT4CBT targeting alcohol use. CBT4CBT was superior to TAU at increasing PDA when delivered as an add-on, and it was not significantly different from TAU or TAU+CBT4CBT when delivered with clinical monitoring only.

Alcohol is a major risk factor for mortality and morbidity worldwide (Agabio et al., 2017). Women are affected by specific alcohol-related consequences, including a dose-dependent increased risk of breast cancer from relatively low levels of alcohol consumption, of which many women remain unaware (Agabio et al., 2022), and risk of foetal alcohol syndrome, in their offspring, if alcohol is consumed during pregnancy (Minozzi et al., 2024). Alcohol use disorder (AUD) is a severe and frequent mental disorder with devasting consequences (Agabio et al., 2017). In US, approximately one out of 4 women suffer for this disorder during their lifetime (MacKillop et al. 2022). Although effective treatments are available (Agabio et al., 2024), AUD is undertreated, with stigma being one of the main reasons for not seeking medical treatment (MacKillop et al. 2022) Women usually experience more severe barriers to AUD treatment than men, with pregnant women experiencing more severe barriers than non-pregnant women (Agabio et al., 2017). Another reason of the scarce use of medical treatment is constituted by the widespread belief that available medications are not effective, or rather, are not effective for all people with AUD. Although sex and gender differences have been described in the response to medications, AUD medications have been studied almost exclusively in men (Agabio et al., 2016). In addition, the number of women with AUD is increasing and services for treatment of AUD should (a) consider women’s specific needs, and (b) realize effective policies to reduce latency prior to accessing medical treatment for both men and women with AUD (Agabio et al., 2021). Nevertheless, recent studies show that only a small number of services have adopted a gender medicine approach in AUD treatment (Vignoli et al., 2024).ReferencesAgabio et al. Efficacy of Medications Approved for the Treatment of Alcohol Dependence and Alcohol Withdrawal Syndrome in Female Patients: A Descriptive Review. Eur Addict Res. 2016.Agabio et al. Sex Differences in Alcohol Use Disorder. Curr Med Chem. 2017.Agabio et al. Gender Differences among Sardinians with Alcohol Use Disorder. J Clin Med. 2021.Agabio et al. Alcohol Consumption Is a Modifiable Risk Factor for Breast Cancer: Are Women Aware of This Relationship? Alcohol Alcohol. 2022.Agabio et al. Efficacy of medications for the treatment of alcohol use disorder (AUD): A systematic review and meta-analysis considering baseline AUD severity. Pharmacol Res. 2024.MacKillop et al. Hazardous drinking and alcohol use disorders. Nat Rev Dis Primers. 2022.Minozzi et al. Psychosocial and medication interventions to stop or reduce alcohol consumption during pregnancy. Cochrane Database Syst Rev. 2024.Vignoli et al. Needs of female outpatients with alcohol use disorder: data from an Italian study. Alcohol Alcohol. 2024.Disclosure of InterestNone Declared

EASL Clinical Practice Guidelines: Management of alcohol-related liver disease

Pharmacotherapy of Alcohol Use Disorders in the Veterans Health Administration

Meta-analysis of randomized studies using lysergic acid diethylamide (LSD) for alcohol use disorder (AUD) showed large, significant effects for LSD efficacy compared to control conditions. Clinical studies suggest potential anti-addiction effects of LSD and mechanistically-related classic psychedelics for alcohol and other substance use disorders. To supplement clinical studies, reports of psychedelic use in naturalistic settings can provide further data regarding potential effects of psychedelics on alcohol use. An anonymous online survey of individuals with prior AUD reporting cessation or reduction in alcohol use following psychedelic use in non-clinical settings. 343 respondents, mostly White (89%), males (78%), in the USA (60%) completed the survey. Participants reported seven years of problematic alcohol use on average before the psychedelic experience to which they attributed reduced alcohol consumption, with 72% meeting retrospective criteria for severe AUD. Most reported taking a moderate or high dose of LSD (38%) or psilocybin (36%), followed by significant reduction in alcohol consumption. After the psychedelic experience 83% no longer met AUD criteria. Participants rated their psychedelic experience as highly meaningful and insightful, with 28% endorsing psychedelic-associated changes in life priorities or values as facilitating reduced alcohol misuse. Greater psychedelic dose, insight, mystical-type effects, and personal meaning of experiences were associated with a greater reduction in alcohol consumption, controlling for prior alcohol consumption and related distress. Although results cannot demonstrate causality, they suggest that naturalistic psychedelic use may lead to cessation or reduction in problematic alcohol use, supporting further investigation of psychedelic-assisted treatment for AUD.

Pre-clinical studies suggest that the simultaneous blockade of the α1b and 5HT2A receptors may be effective in reducing alcohol consumption. This study aimed to assess the efficacy and safety of prazosin (α1b blocker) and cyproheptadine (5HT2A blocker) combination in decreasing total alcohol consumption (TAC) in alcohol use disorder (AUD). This was a double-blind, parallel group, placebo-controlled, Phase 2, randomized clinical trial conducted in 32 addiction treatment centres in France. A total of 108 men and 46 women with severe AUD took part. Participants were randomly assigned to one of the following 3-month treatments: (1) low-dose group (LDG) receiving 8mg cyproheptadine and 5mg prazosin extended-release (ER) formulation daily; (2) high-dose group (HDG) receiving 12 mg cyproheptadine and 10mg prazosin ER daily; and (3) placebo group (PG) receiving placebo of cyproheptadine and prazosin ER. A total of 154 patients were randomized: 54 in the PG, 54 in the LDG and 46 in the HDG. The primary outcome was TAC change from baseline to month 3. A significant main treatment effect in the change in TAC was found in the intent-to-treat population (P = 0.039). The HDG and LDG showed a benefit in the change in TAC from baseline to month 3 compared with PG: -23.6g/day, P = 0.016, Cohen's d = -0.44; -18.4g/day, P = 0.048 (Bonferroni correction P < 0.025), Cohen's d = -0.36. In a subgroup of very high-risk drinking-level participants (> 100 g/day of pure alcohol for men and > 60 g/day for women), the difference between the HDG and the PG in the primary outcome was -29.8g/day (P = 0.031, Cohen's d = -0.51). The high and low doses were well-tolerated with a similar safety profile. A randomized controlled trial of treatment of severe alcohol use disorder with a cyproheptadine-prazosin combination for 3months reduced drinking by more than 23 g per day compared with placebo. A higher dose combination was associated with a larger magnitude of drinking reduction than a lower dose combination while showing similar safety profile.