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Abstract

Over 400 million people worldwide meet the criteria for an alcohol use disorder, which is associated with health impairments, increased mortality and negative so-cial consequences. A key symptom is alcohol craving, which can be triggered by exposure to alcohol stimuli or stressors. Alcohol craving, cue-reactivity and negative affect are considered risk factors for alcohol relapse. Although naltrexone and acamprosate are approved to reduce alcohol craving, their clinical efficacy is lim-ited, despite the urgent need for effective treatments. Therefore, novel effective and well-tolerated treatment approaches are warranted to close the existing treatment gap. Cannabidiol and Oxytocin are considered promising candidates to comple-ment existing treatment approaches due to their potential effects on central mecha-nisms of alcohol use disorder. Preclinical and preliminary clinical studies indicate positive effects of Cannabidiol on substance use and craving, relapse, impulsivity and alcohol-related damage to the liver and brain. Oxytocin has been shown to have positive effects on alcohol craving, alcohol withdrawal symptoms, stress regu-lation and the reduction of negative affect. However, previous studies involved in most cases small, often exclusively male samples. Therefore, the aim of this disser-tation was to investigate the effects of Cannabidiol on the reduction of alcohol cue-reactivity in the nucleus accumbens and alcohol craving as well as the effects of Oxytocin on the reduction of amygdala activation during emotion processing and alcohol craving. In the first randomized double-blind placebo-controlled study, 28 male and female individuals with alcohol use disorder received either 800mg Can-nabidiol or a placebo capsules. Afterwards a combined stress- and alcohol-exposure as well as an examination of neuronal alcohol cue- reactivity using func-tional magnetic resonance imaging and repeated measurements of subjective al-cohol craving were conducted. In the second randomized double-blind placebo-controlled crossover study, 24 male and female individuals with alcohol use disor-der each received 24 IU oxytocin intranasally and a placebo once. This was fol-lowed by alcohol exposure with the preferred alcoholic beverage and an examina-tion of the neuronal activation of the amygdala during emotion processing using functional magnetic resonance imaging and repeated measurements of subjective alcohol craving. Cannabidiol reduced bilateral activation of the nucleus accumbens as well as alcohol craving while being presented with alcohol stimuli during func-tional magnetic resonance imaging. Compared to placebo, a smaller increase in alcohol craving after the combined stress and alcohol exposure was observed. Cannabidiol blood plasma-levels were significantly higher after Cannabidiol admin-istration and correlated negatively with the cue-reactivity of the nucleus accumbens, indicating a dose-dependent effect of cannabidiol. Oxytocin attenuated the activa-tion of the right amygdala during the processing of negative emotional stimuli, which correlated with situational alcohol craving after the alcohol exposure. However, no direct effect of Oxytocin on alcohol craving was observed. Both substances were well tolerated, can be administered non-invasively and have a low abuse potential. While Cannabidiol effectively reduces cue-reactivity and craving, Oxytocin does not appear to be effective as pharmacological treatment for alcohol craving. Oxytocin, on the other hand, could be effective as an intervention for negative affective states when alcohol craving occurs as a result, which in turn may be associated with an increased risk of relapse. Oxytocin and Cannabidiol target distinct neurobiological mechanisms underlying alcohol use disorder, suggesting either a context-specific application based on the risk factors (cue-reactivity or negative affect) or a combina-tion with existing pharmacotherapies, for example as an as-needed medication in the case of alcohol exposure or acute negative affective states, when currently ap-proved medications are insufficient. Since neither Oxytocin nor Cannabidiol are cur-rently approved for the treatment of alcohol use disorder and both empirical studies only investigated acute effects in individuals with mild to moderate alcohol use dis-order, larger randomized placebo-controlled trials including males and females with more severe alcohol use disorder and multiple applications are needed to replicate the results and evaluate the clinical relevance over a longer period of time.