Excessive alcohol use is one of the top behavioral causes of global disease burden. A major factor contributing to this burden is the alcohol relapse risk during treatment and recovery from alcoholism. Clinical studies suggest that stress is one of the key factors that contributes to these high-relapse rates (Blaine et al, 2016). Changes in hypothalamic pituitary adrenal (HPA) axis responses, altered and blunted amygdala response to fear/threat potentiated startle in heavy drinkers compared with light social drinkers and autonomic imbalance in sympathetic/parasympathetic systems, have been reported with increased alcohol use (Sinha et al, 2011a). Furthermore, acute alcohol intake stimulates the HPA axis and increases cortisol levels (see Blaine et al (2016) for review), but chronic alcohol abuse is associated with blunted stress cortisol responses (Lovallo et al, 2000). In addition, alcohol withdrawal is associated with elevated basal cortisol (Blaine et al, 2016).

In our laboratory, we have used personalized guided stressful and drug/alcohol cue-related imagery to provoke this stress and high-craving dysfunction in early abstinent alcohol-dependent (AD) men and women. We compared a group of 4-week abstinent and recovering treatment engaged AD individuals to healthy controls across three imagery conditions (stress, alcohol cue, and neutral/relaxing) and assessed subjective and neuroendocrine responses at baseline, immediately following imagery exposure and at additional post-imagery time periods. We found significant HPA axis dysregulation, which was marked by higher basal ACTH levels and blunted stress- and cue-induced ACTH and cortisol responses in the AD patients compared with the control group (Sinha et al, 2011b). The AD individuals also displayed higher anxiety, and greater stress- and cue-induced alcohol craving compared with the control group. Importantly, we found that individuals with high provoked alcohol craving but also high cortisol and greater cortisol/ACTH ratios (which is a measure of sensitivity of the adrenal glands to release cortisol in response to the ACTH signal) relapsed more quickly after discharge from inpatient treatment. In fact, high cortisol/ACTH ratios more than doubled the risk of shorter time to future relapse (Sinha et al, 2011b). These findings suggest that both craving and the stress-related HPA axis dysfunction may play a role in high-relapse rates in alcoholism and that targeting this stress pathophysiology pharmacologically could improve alcohol relapse rates.

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