A randomized, placebo-controlled laboratory study of the effects of d-cycloserine on craving in cocaine-dependent individuals

Abstract

Rationale D-cycloserine (DCS), a partial glutamate NMDA receptor agonist, enhances extinction of conditioned fear responding; preliminary data suggests that it may facilitate extinction of drug cue reactivity. Objective This study investigates DCS effects on cocaine cue craving and drug use in cocaine-dependent subjects. Methods Thirty-two subjects were randomly assigned to receive 1) DCS only, 2) DCS before sessions 1 and 3, PBO before session 2 or 3) PBO only 15-min before each of 3 1-hour cocaine cue exposure sessions conducted 1 day apart. Craving ratings were obtained before, during and after sessions. Drug use and cue-induced craving were assessed 1 week after the last cue session. Results Repeated presentation of cocaine cues resulted in decreased craving both within and between sessions. DCS did not facilitate extinction learning and may have enhanced craving. The group that received 3 doses of DCS had significantly higher craving than the PBO group at the baseline ratings taken before sessions 2 and 3, as well as significantly higher cue-induced craving at follow-up. The group that received 2 doses of DCS did not differ from the PBO group. There were no group differences in post-extinction cocaine use. Conclusions The reduction of cocaine cue reactivity in the PBO group suggests that the study procedures were sufficient to produce extinction. Under these conditions, DCS did not facilitate extinction and may have enhanced craving. Further studies of glutamatergic agents and extinction in cocaine dependence should include consideration of procedural variables that could have a major impact on study outcomes.

The effects of varied extinction procedures on contingent cue-induced reinstatement in Sprague-Dawley rats

“…Pharmacological treatment has been shown to enhance the utility of exposure therapy for patients with generalized anxiety disorder (51); however, little efficacy has been shown in addicted populations (52). In fact, some studies demonstrate increased cue-induced craving in patients treated with D-cycloserine, an NMDA receptor agonist (53, 54). Notably, the majority of these experiments used exposure that did not involve performance of the instrumental response to reduce craving.…”

Fear Memory

“…This represents an important promise in the treatment of this disorder, which is so prevalent and difficult to handle. Cocaine craving is enhanced in cocaine seekers by D-cycloserine (507). There are similarities between craving behavior for different drugs, but the relation between the effects of D-cycloserine and those of pexacerfont, if any, is not even hinted at; the relation of both to fear learning is not known, although of course there is a strong component of anxiety and even fear in drug-deprived addicts (583,584).…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Cue reactivity encompasses objective measures of sympathetic arousal and/or subjective reports of craving, induced by paraphernalia or pictures associated with the abused drug. These small proof-ofconcept trials have shown decreased cue reactivity for nicotine (Santa Ana et al, 2009), no effect compared with placebo for nicotine (Kamboj et al, 2012;Yoon et al, 2013) and alcohol (Kamboj et al, 2011;Watson et al, 2011), or increased cue reactivity for cocaine (Price et al, 2009(Price et al, , 2013 and alcohol (Hofmann et al, 2012). One study that investigated clinically meaningful outcomes of D-cycloserine for augmenting cueexposure therapy found negative results for nicotine use (Yoon et al, 2013).…”