N acetylcysteine in the treatment of alcohol use disorder: a randomized, double-blind, placebo-controlled trial.

N-acetyl cysteine (NAC) is a potent antioxidant that modulates glutamatergic signalling which is thought to play a role in alcohol use disorder (AUD). There have been no clinical trials investigating NAC for AUD. We aimed to conduct a 28 day double-blind, placebo-controlled (PL) randomized trial of NAC in the treatment of AUD (NCT03879759). A total of 42 participants with AUD (56% alcohol-related liver disease) were randomized to receive placebo or NAC 2400 mg/day. Feasibility outcomes included treatment retention and adverse events. Primary clinical outcomes included alcohol consumption (heavy drinking days, standard drinks per drinking day). Secondary clinical outcome measures included craving, liver tests, and psychological outcomes. There were no significant differences in overall retention between treatment groups (χ2(1) = 0.14, P = 0.71: 86% vs 76% for placebo and NAC, respectively). The most commonly reported adverse event in NAC-treated individuals included headache (14%). For standard drinks per drinking day, there was a significant overall effect of time (F = 9.18, P < 0.001), no significant effect of treatment (F = 0.75, P = 0.79), and a significant time x treatment (NAC vs PL) effect (F = 2.73, P < 0.05). For number of heavy drinks per day, there was a significant overall effect of time (F = 3.16, P < 0.05) but no significant effect of treatment or time x treatment (P = 0.17). There were no significant NAC vs PL effects on secondary clinical outcome measures. In the first trial of NAC for the management of AUD, NAC appears to be feasible and safe. Although there was a significant effect of NAC vs placebo on some alcohol measures such as drinks per drinking day, there does appear to be a variable pattern of effect across time suggesting that a larger trial incorporating a longer treatment duration is now required to determine efficacy.

The effects of N-acetyl cysteine on intrinsic functional connectivity and neural alcohol cue reactivity in treatment-seeking individuals with alcohol use disorder: a preliminary study.

N-acetyl cysteine (NAC) is a potential pharmacotherapy for alcohol use disorder (AUD), but it is not known whether it modulates neural activation to alcohol cues or intrinsic functional connectivity. We investigated whether NAC attenuates (i) alcohol cue-elicited activation, and (ii) intrinsic functional connectivity compared to placebo in patients with AUD. In this preliminary study, twenty-three individuals (7 females) with moderate-severe AUD received daily NAC (2400 mg/day, n = 9), or a placebo (n = 14) for at least 2 weeks. Participants completed a pre-treatment functional magnetic resonance imaging session (T0) and a post-treatment session (T1) comprising resting-state and visual alcohol cue reactivity task acquisitions. Activation differences between sessions, treatment, and session-by-treatment interaction were assessed. Resting-state functional connectivity examined using 377 node ROI-to-ROIs evaluated whether NAC reduced intrinsic functional connectivity after treatment. There were no differences in alcohol cue reactivity for brain activation or subjective craving between NAC and placebo during treatment or across sessions, or significant interaction. A significant treatment-by-time interaction, with reduced intrinsic connectivity was observed after treatment (T1) for NAC-treated compared to placebo-treated patients in the posterior cingulate node (9, left hemisphere) of the dorsal attentional network and connections to salience, ventral-attentional, somatosensory, and visual-peripheral networks implicated in AUD. NAC reduced intrinsic functional connectivity in patients with moderate-severe AUD after treatment compared to placebo, but did not attenuate alcohol cue-elicited activation. However, the absence of cue reactivity findings may result from low power, rather than the absence of cue reactivity findings associated with NAC. These results provide preliminary evidence that NAC treatment may modulate intrinsic functional connectivity brain activation in patients with alcohol use disorder, but replication in larger studies are required to determine the strength of this effect and any associations with clinical outcomes. Clinical Trials Registration: ClinicalTrials.gov Identifier: NCT03879759.

Neuroimaging studies of cannabidiol and potential neurobiological mechanisms relevant for alcohol use disorders: a systematic review.

The underlying neurobiological mechanisms of cannabidiol's (CBD) management of alcohol use disorder (AUD) remains elusive.Aim We conducted a systematic review of neuroimaging literature investigating the effects of CBD on the brain in healthy participants. We then theorise the potential neurobiological mechanisms by which CBD may ameliorate various symptoms of AUD.Methods This review was conducted according to the PRISMA guidelines. Terms relating to CBD and neuroimaging were used to search original clinical research published in peer-reviewed journals.Results Of 767 studies identified by our search strategy, 16 studies satisfied our eligibility criteria. The results suggest that CBD modulates γ-Aminobutyric acid and glutamate signaling in the basal ganglia and dorso-medial prefrontal cortex. Furthermore, CBD regulates activity in regions associated with mesocorticolimbic reward pathways; salience, limbic and fronto-striatal networks which are implicated in reward anticipation; emotion regulation; salience processing; and executive functioning.Conclusion CBD appears to modulate neurotransmitter systems and functional connections in brain regions implicated in AUD, suggesting CBD may be used to manage AUD symptomatology.

Sex differences in the interrelations between stress, craving and alcohol consumption across individuals and time during baclofen treatment for alcohol dependence.

AIMS: Recent studies have suggested that females respond more favourably to baclofen treatment for alcohol use disorder. Females are generally more likely to drink to regulate stress reactivity and negative affect. This study thus aimed to evaluate the role of sex on the effect of baclofen on the relationship between daily alcohol consumption, stress and craving. METHODS: A network analysis of fluctuations using vectorized autoregressive modelling was used to explore the relationship between daily surveys of alcohol consumption, stress and craving from daily diary data over 84 days from a randomised controlled trial of baclofen (30 mg or 75 mg per day) versus placebo in 104 participants with alcohol dependence (1, 2). Symptom interrelations across patients and across time were examined including temporal networks (time lagged), contemporaneous and between-subjects networks, and were examined for placebo and baclofen stratified by sex. RESULTS: Overall, between persons, there was a significant relationship between stress and drinking in placebo treated individuals in females (r = -0.70, p < 0.001) but not males (r = 0.32, p = 0.054) that was not observed in baclofen treated individuals. No relationship was observed between stress and drinking in the baclofen group for either sex (p's < 0.45). DISCUSSION: There appears to be some sex-specific differences whereby baclofen abolishes an overall association between stress and drinking in females, but this is not observed in males. Network analyses may assist in elucidating the mechanism of action of alcohol pharmacotherapies such as baclofen and understanding which symptoms and mechanisms are key for effective interventions.

Hypothalamic-pituitary-adrenocortical response in alcohol-dependent patients during baclofen treatment and association with clinical outcome: Preliminary results.

Baclofen has been shown to reduce alcohol consumption in some individuals with alcohol use disorder. This preliminary study aimed to evaluate i) the effect of baclofen versus placebo on hypothalamic-pituitary-adrenocortical activity (HPA axis), as measured by cortisol, and ii) the relationship between clinical outcomes such as alcohol consumption on a randomized controlled trial of baclofen (BAC) versus placebo (PL) (Kirsten C. Morley et al., 2018; K. C. Morley, Leung, Baillie, & Haber, 2013). We hypothesized that baclofen will reduce HPA-axis activity following a mild stressor in patients with alcohol dependence. Plasma cortisol levels were taken from N = 25 alcohol-dependent patients at two time points, approximately 60 (pre-MRI scan: PreCortisol) and 180 min (post MRI scan: PostCortisol) following administration of PL, BAC 10 mg, or BAC 25 mg. Participants were followed up for the remaining 10 weeks as part of the trial for clinical outcome (percentage days abstinent). Mixed models revealed a significant main effect of medication on cortisol levels (F = 3.88, p = 0.037), no significant effect of time (F = 0.04, p = 0.84), and a significant time × medication interaction (F = 3.54, p = 0.049). Linear regression (F = 6.98, p = 0.01, R2 = 0.66) revealed that abstinence at follow-up, weighted by gender, was predicted by blunted cortisol response (ß = -0.48 p = 0.023), in addition to medication (ß = 0.73 p = 0.003). In conclusion, our preliminary data suggest that baclofen moderates HPA-axis activity, as measured by blood cortisol, and that these alterations may play a role in long-term treatment response.