ARCHIVAL REPORT Acute Effects of Heroin on Negative Emotional Processing: Relation of Amygdala Activity and Stress-Related Responses André Schmidt, Stefan Borgwardt, Hana Gerber, Gerhard A. Wiesbeck, Otto Schmid, Anita Riecher-Rössler, Renata Smieskova, Undine E. Lang, and Marc Walter Background: Negative emotional states and abnormal stress reactivity are central components in drug addiction. The brain stress system in the amygdala is thought to play a key role in the maintenance of drug dependence through negative reinforcement. Although acute heroin administration was found to reduce anxiety, craving, and stress hormone release, whether these effects are reflected in amygdala activity has not yet been investigated. Methods: With a randomized, crossover, double-blind design, saline and heroin were administered to 22 heroin-dependent patients, whereas 17 healthy control subjects were included for the placebo administration only. We used functional magnetic resonance imaging to investigate blood oxygen level–dependent responses during fearful faces processing. Stress reactivity was measured by adrenocorticotropic hormone levels and by cortisol concentrations in serum and saliva 60 min after substance administration. Anxiety and craving levels were assessed with self-report ratings. Results: Heroin administration acutely reduced the left amygdala response to fearful faces relative to the saline injection. Patients receiving saline showed a significantly higher left amygdala response to fearful faces than healthy control subjects, whose activity did not differ from patients receiving heroin. The left amygdala activity correlated significantly with scores on state-anxiety and levels of adrenocorticotropic hormone, serum cortisol, and saliva cortisol among all patients and control subjects. Conclusions: Our results show a direct relation between the acute heroin effects on stress-related emotions, stress reactivity, and left amygdala response to negative facial expressions. These findings provide new insights into the mechanisms underlying negative reinforcement in heroin addiction and the effects of regular heroin substitution. Key Words: Acute heroin administration, amygdala, anxiety, fearful face processing, fMRI, stress hormones A cute withdrawal in drug addiction is accompanied by negative affects characterized by dysphoria, irritability, anxiety, as well as abnormal stress reactivity that drives drug seeking through negative reinforcement mechanisms (1). Activation of brain stress systems is hypothesized to be a key element of the negative emotional state produced by depend- ence (2,3), and previous models of negative reinforcement emphasize the pivotal role of negative affect in motivating sustained drug use (4). It has been shown that abstinent heroin-dependent individuals reveal elevated stress reactivity, which could be related to heightened craving and symptoms of withdrawal (5). Indeed, hypothalamic-pituitary-adrenal (HPA) axis activation has been reported during opioid withdrawal syn- dromes (6), whereas opioid agonists are associated with a reduction in stress hormone secretion (7). Our group previously found suppressed cortisol concentrations (5) and reduced craving scores after acute methadone administration in heroin-dependent patients (6). Moreover, we recently demonstrated a normalized HPA axis response measured by adrenocorticotropic hormone (ACTH) and cortisol concentrations as well as a decrease in negative emotions such as anxiety and craving compared with healthy control subjects (HC) when heroin-dependent patients received their regular dose of heroin (8,9). This dampening effect of negative emotions highlights the emotional regulation effect of acute heroin administration and helps to understand how drug taking is maintained through negative reinforcement. However, the neural correlates of these effects have not yet been investigated. Emotional processing including the recognition of the feelings of other people from their facial expression is fundamental to social interaction and behavior (10). Abstinent heroin abusers especially demonstrate an exaggerated number perception of negative expressions and an understated number perception of positive expressions when compared with neutral schematic expressions (11). When compared with HC, abstinent heroin abusers exhibit a significantly heightened number perception of negative expressions (12), suggesting a negative emotional face processing bias in heroin-dependent subjects during states of withdrawal and craving. Emotional faces, especially negative expressions increase neuronal activity relative to neutral faces in specific brain areas, including the left amygdala (13,14), whereas its volume is positively correlated with that of social networks (15). Studies have consistently reported a direct relation between left amygdala response to fearful faces and state-anxiety [for a review see Calder et al. (16)]. Accordingly, the negative emotional processing bias in depressed individuals is characterized by left amygdala hyperactivity in response to fearful faces (17). Further- more, all components of the corticotropin releasing factor system are expressed in the amygdala (18) and compulsive drug use From the Department of Psychiatry (Universitäre Psychiatrische Kliniken) (AS, SB, AR-R, RS, UEL, MW), University of Basel; Medical Image Analysis Centre (AS, SB, RS); Division of Substance Use Disorders (HG, GAW, OS, MW), University Hospital Basel, Basel, Switzerland; and the Department of Psychosis Studies (SB), Institute of Psychiatry, King’s College London, London, United Kingdom. Address correspondence to André Schmidt, Ph.D., University of Basel, University Hospital of Psychiatry Basel, Department of Psychiatry, Petersgraben 4, Basel 4031, Switzerland; E-mail: andre.schmidt@ unibas.ch. Received Jul 19, 2013; revised Oct 10, 2013; accepted Oct 27, 2013. 0006-3223/$36.00 BIOL PSYCHIATRY 2013;]:]]]–]]] http://dx.doi.org/10.1016/j.biopsych.2013.10.019 & 2013 Society of Biological Psychiatry