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Rationale: Treatments based on exposure/response prevention (Exp/RP) produce only modest benefits in substance dependence disorders. However, a new strategy, which has shown promise in animal models of addiction involves combining Exp/RP with extinction-enhancing pharmacological treatments. A prototype of the latter is D-cycloserine (DCS), a partial agonist at the glycine site of the NMDA receptor. Methods: In a laboratory-based randomised, double-blind, placebo-controlled trial with non-treatment-seeking heavy smokers (n = 32), we examined the efficacy of Exp/RP combined with DCS (125 mg). Two sessions of Exp/RP were carried out during which cue reactivity was monitored. Effects on attentional bias and/or subjective craving and smoking behaviour were also evaluated after at least 48 h and 2 weeks following session 2 of Exp/RP. Results: Within- and between-session reductions in cue reactivity were observed in both treatment groups, although the DCS group did not show an enhanced reduction by the end of session 2. However, a subtle effect of DCS on the emotionality subscale of the Tobacco Craving Questionnaire was observed, with a trend towards a sustained reduction in this aspect of craving at 2-week follow-up. Conclusion: Our findings suggest that two sessions of Exp/RP combined with DCS does not enhance the reduction in episodic cue reactivity in non-treatment seeking smokers. A trend towards a greater sustained reduction in the emotionality scale of the TCQ in the DCS group suggests that further detailed study of the effects of combined Exp/RP-DCS on different aspects of craving is warranted, especially in smokers with a current intention to quit.

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