Among the many addictions, cocaine addiction is particularly treatment-resistant, with estimated relapse rates greater than 45%. While most abstaining individuals with cocaine use disorders (iCUD) relapse within the first few weeks of abstinence, relapse continues to occur long after acute withdrawal has abated. Re-exposure to cues previously associated with drug use that evoke craving is a major contributing factor in relapse to drug use. Pre-clinical studies using several animal models of drug addiction (including in cocaine, heroin, alcohol, nicotine, and methamphetamine addiction models) have shown that, contrary to common expectations for the reduction of craving and drug-seeking with abstinence, cue-induced drug craving increases progressively (i.e., incubates) in the first several months of abstinence. Primarily using a cross-sectional study design and subjective measures of craving assessed at different periods of abstinence (from 7 days post abstinence onset up to 24 months of abstinence), several human studies have shown similar effects in nicotine, methamphetamine and heroin use disorders. Together, these studies show highest cue-induced craving at 3 to 6 months of abstinence, suggesting that such incubation of craving renders abstaining drug addicted individuals vulnerable to relapse. However, a systematic investigation that uses objective markers and a within- subjects approach to quantify and longitudinally track the trajectory of cue-induced craving and its incubation for relapse monitoring and prediction is lacking. The late positive potential (LPP) component of the electroencephalography has been shown to objectively track motivated attention to salient stimuli including drug-cues, correlating with cue-induced craving and predicting relapse in cocaine and nicotine addicted individuals. Using LPP, our preliminary data suggests that cue-induced craving increases at 6-months and then decreases at 12-months follow-up compared to a treatment-seeking baseline in initially abstinent iCUD. Thus, we aim to use LPPs to assess cue-induced craving at carefully selected abstinence durations [at 7, 14, 30 days (assessed cross-sectionally) and at 3, 6, 9, and 12 months (assessed longitudinally)] to objectively measure the dynamics of craving incubation in human cocaine addiction. The hypothesized inverted-U shaped trajectory will be elucidated via changes in LPP amplitude, and will be supplemented by measures of simulated drug-seeking and self-reported craving.
Our second aim i s to use the longitudinal dynamics of craving incubation to monitor and prospectively predict relapse. Results could aid in developing time-sensitive personalized interventions to reduce risk of relapse in treatment-seeking individuals with substance use disorders.

Public Health Relevance

This research represents the first systematic attempt to study the psychophysiological correlates of cue- induced craving incubation in humans, a phenomenon observed in animals whereby the propensity for drug relapse escalates (rather than diminishes) upon exposure to drug-related cues during abstinence. This work can therefore help elucidate the biobehavioral regulation mechanisms underlying the high rates of relapse even after the acute withdrawal symptoms have abated and even after prolonged abstinence periods in drug addicted individuals.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Grant, Steven J
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Icahn School of Medicine at Mount Sinai
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New York
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