IMPORTANCE Craving, which is a strong desire for drugs, is a new DSM-5 diagnostic criterion for substance use disorders (SUDs), which are the most prevalent, costly, and deadly forms of psychopathology. Despite decades of research, the roles of drug cues and craving in drug use and relapse remain controversial. OBJECTIVE To assess whether 4 types of drug cue and craving indicators, including cue exposure, physiological cue reactivity, cue-induced craving, and self-reported craving (without cue exposure), are prospectively associated with drug use and relapse. DATA SOURCES Google Scholar was searched for published studies from inception through December 31, 2018. In addition, backward and forward searches were performed on included articles to identify additional articles. STUDY SELECTION Included studies reported a prospective statistic that linked cue and craving indicators at time 1 to drug use or relapse at time 2, in humans. DATA EXTRACTION AND SYNTHESIS The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed. Study characteristics and statistics were extracted and/or coded by 1 of the 2 authors and then checked by the other. Statistical analyses were performed from May to July 2021. MAIN OUTCOMES AND MEASURES Random-effects models were used to calculate prospective odds ratios (ORs) representing the association between cue and craving indicators and subsequent drug use/relapse. RESULTS A total of 18 205 records were identified, and 237 studies were included. Across 656 statistics, representing 51 788 human participants (21 216 with confirmed SUDs), a significant prospective association of all cue and craving indicators with drug use/relapse was found (OR, 2.05; 95% CI, 1.94-2.15), such that a 1-unit increase in cue and craving indicators was associated with more than double the odds of future drug use or relapse. A Rosenthal fail-safe analysis revealed that 180 092 null studies would need to be published to nullify this finding. Trim-and-fill analysis brought the adjusted effect size to an OR of 1.31 (95% CI, 1.25-1.38). Moderator analyses showed that some of the strongest associations were found for cue-induced craving, real cues or images, drug use outcome, same-day time lag, studies using ecological momentary assessment, and male participants. CONCLUSIONS AND RELEVANCE Findings from this systematic review and meta-analysis suggest that drug cue and craving indicators play significant roles in drug use and relapse outcomes and are an important mechanism underlying SUDs. Clinically, these results support incorporating craving assessment across stages of treatment, as early as primary care.
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