Imaging stress- and cue-induced drug and alcohol craving: association with relapse and clinical implications RAJITA SINHA & C.-S. R. LI Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA Abstract Stress- and drug-related cues are major factors contributing to high rates of relapse in addictive disorders. Brain imaging studies have begun to identify neural correlates of stress and drug cue-induced craving states. Findings indicate considerable overlap in neural circuits involved in processing stress and drug cues with activity in the corticostriatal limbic circuitry underlying both affective and reward processing. More recent efforts have begun to identify the relationships between neural activity during stress and drug cue exposure and drug relapse outcomes. Findings suggest medial prefrontal, anterior and posterior cingulate, striatal and posterior insula regions to be associated with relapse outcomes. Altered function in these brain regions is associated with stress-induced and drug cue-induced craving states and an increased susceptibility to relapse. Such alterations can serve as markers to identify relapse propensity and a more severe course of addiction. Efficacy of pharmacological and behavioral treatments that specifically target stress and cue-induced craving and arousal responses may also be assessed via alterations in these brain correlates. [Sinha R, Li C-SR. Imaging stress- and cue-induced drug and alcohol craving: association with relapse and clinical implications. Drug Alcohol Rev 2007;26:25 – 31] Key words: alcohol, drug abuse, drug cues, emotional stress, neuroimaging, relapse outcome. Introduction A hallmark feature of drug and alcohol dependence or ‘addiction’ is the intense desire for the drug, together with an impaired ability to control urges to take the drug, despite related adverse consequences (DSM-IVR) [1]. Craving and the impaired ability to control urges has been associated with disruption in brain pathways associated with motivation, emotion, reward and inhibitory control, functions that are specifically affected by chronic drug and alcohol abuse [2]. Such alterations may increase sensitivity to environmental contexts that provoke increased craving and susceptibility to relapse in addicted individuals. It is well known that in addition to the drug itself, specific environmental contexts, such as stress and drug-related stimuli or ‘cues’, evoke drug craving, with addicted individuals demonstrating marked difficulties in controlling such urges [3]. This paper reviews functional brain imaging (fMRI) studies investigating neural correlates of stress and drug cue- related craving and relapse outcomes, and discusses the clinical implications of these findings. Imaging stress experiences and stress-induced drug craving states Stress is a key factor in substance use and in relapse [4,5]. However, the neural processes underlying this association in humans remain unclear (see [6,7] for a review of rodent studies). In particular, there are few neuroimaging studies that directly examine stress processing and the association with drug craving in addicted individuals. In a series of studies, we examined the effects of ‘emotional’ stress on drug craving and relapse in substance abusing individuals. Stress or ‘distress’ com- monly occurs in situations that are challenging or threatening, and the associated responses influence adaptive processes that require self-regulation or ‘cop- ing’ to regain control and attain desired goals [8,9]. As difficulties in managing stressful life events and regula- tion of the stress state are common in a variety of psychiatric illnesses, including addiction, identifying neural circuits associated with stress is of importance to clinical neuroscience. Received 15 May 2006; accepted for publication 22 July 2006. Rajita Sinha, PhD, Professor of Psychiatry, Director, Research Program on Stress, Addiction and Psychopathology, and C.-S. R. Li, MD, PhD, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA. Correspondence to Rajita Sinha, Depart- ment of Psychiatry, Yale University School of Medicine, 34 Park Street, Room S110, New Haven, CT 06519, USA. Tel: þ1 203 974 7608. Fax: þ1 203 974 7076. E-mail: rajita.sinha@yale.edu Drug and Alcohol Review (January 2007), 26, 25 – 31 ISSN 0959-5236 print/ISSN 1465-3362 online/07/010025–07 ª Australasian Professional Society on Alcohol and Other Drugs DOI: 10.1080/09595230601036960