D-Cycloserine Effects on Extinction of Conditioned Responses to Drug-Related Cues

D-cycloserine (DCS) is an N-methyl-D-aspartate (NMDA) receptor partial agonist that facilitates extinction of conditioned fear in animals and cue exposure therapy (CET) for fear and anxiety disorders in people. Recent preclinical and clinical studies have examined the effect of DCS on extinction of conditioned responses elicited by cues paired with administration of or withdrawal from drugs of abuse, including physiological responses, craving, withdrawal, and drug-seeking behavior. DCS facilitates extinction and blunts postextinction recovery of these responses in animal models, including place conditioning and drug self-administration, but DCS effects on CET in substance users/abusers are less robust. Some of the null effects in the clinical literature might be attributable to issues related to sample size, data characteristics, DCS administration, and participant characteristics, among others. In this review we describe the preclinical and clinical literatures on DCS modulation of extinction of addiction-related conditioned responses, consider possible limitations of the clinical studies that have been published to date, and propose ways of designing future clinical studies so as to maximize the probability of detecting a DCS effect. We also discuss concerns with regard to potential harmful effects of DCS-coupled CET in addicts and describe how these concerns might be mitigated. We conclude that it is as yet unclear whether DCS-coupled CET might be a useful approach in the treatment of addiction.