Effects of cue-exposure-treatment and single-dose nalmefene on neural cue-reactivity in alcohol-dependen patients and harmful drinkers

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Vollstädt-Klein S1, Mann K1, Kiefer F1
1Central Institute of Mental Health, Medical Faculty Mannheim / Heidelberg University, Department of Addictive Behavior and Addiction Medicine, Mannheim, Germany

Mesocorticolimbic reactivity to substance-associated cues has been shown to be associated with relapse (1). Neural cue-reactivity is not equally pronounced in addicted individuals (2, 3), which is highly relevant for individualized treatment.
In three studies we assessed cue-reactivity (CR) in alcohol-dependence and heavy drinking. We examined the reduction of mesolimbic cue-reactivity (CR) by cue-exposure-based extinction treatment (CET) [with and without support of the partial NMDA-receptor agonist D-cycloserine (DCS] and by the opioid system modulator nalmefene.
Neural cue-reactivity was assessed using functional Magnetic Resonance Imaging (fMRI) with pictorial cues at 3T. Alcohol-dependent patients were examined in two studies (N=30, N=32) before treatment and three weeks after treatment onset (standard treatment, CET or combined CET/DCS treatment). Non-treatment-seeking heavy drinkers were examined as part of an ongoing study on single-dose effects of nalmefene.
Alcohol-dependent patients showed different levels of neural cue-reactivity before treatment. After treatment, patients receiving CET demonstrated lower cue-reactivity in the ventral striatum compared to the standard treatment group (4). Following treatment with CET plus DCS, cue-induced brain activation in the ventral and dorsal striatum was decreased compared to treatment with CET plus placebo (5). The results on the effects of single-dose nalmefene will be presented after deblinding of the ongoing study.
Differential neural cue-reactivity in subgroups of patients might be associated with different motivation for alcohol-intake with implications for individualized treatment. Hedonic responses to alcohol cues, which were shown to be predictive of relapse, could be decreased by CET and by combined CET/DCS treatment. Patients with these appetitive responses might also benefit from nalmefene treatment.


1. Mann K., Vollstadt-Klein S., Reinhard I., Lemenager T., Fauth-Buhler M., Hermann D. et al. Predicting naltrexone response in alcohol-dependent patients: the contribution of functional magnetic resonance imaging, Alcohol Clin Exp Res 2014: 38: 2754-2762.
2. Vollstädt-Klein S., Kobiella A., Buhler M., Graf C., Fehr C., Mann K. et al. Severity of dependence modulates smokers’ neuronal cue reactivity and cigarette craving elicited by tobacco advertisement, Addict Biol 2011: 16: 166-175.
3. Vollstädt-Klein S., Wichert S., Rabinstein J., Buhler M., Klein O., Ende G. et al. Initial, habitual and compulsive alcohol use is characterized by a shift of cue processing from ventral to dorsal striatum, Addiction 2010: 105: 1741-1749.
4. Vollstädt-Klein S., Loeber S., Kirsch M., Bach P., Richter A., Buhler M. et al. Effects of Cue-Exposure Treatment on Neural Cue Reactivity in Alcohol Dependence: A Randomized Trial, Biol Psychiatry 2011: 69: 1060-1066.
5. Kiefer F., Kirsch M., Bach P., Hoffmann S., Reinhard I., Jorde A. et al. Effects of D-cycloserine on extinction of mesolimbic cue-reactivity in alcoholism: A randomized placebo-controlled trial, Psychopharmacology (Berl) 2015: 232: 2353-2362.