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Kathleen T. Brady, MD, PhD; Aimee L. McRae, PharmD; Megan M. Moran-Santa Maria, PhD; Stacia M. DeSantis, PhD; Annie N. Simpson, MSc; Angela E. Waldrop, PhD; Sudie E. Back, PhD; Mary Jeanne Kreek, MD, PhD

Arch Gen Psychiatry. 2009;66(4):422-430.

Context  Corticotropin-releasing hormone (CRH), through the hypothalamic pituitary adrenal axis and other brain stress systems, is involved in the emotional dysregulation associated with cocaine dependence. Little is known about the response of cocaine-dependent individuals to CRH administration.

Objective  The primary objective was to examine the hypothalamic-pituitary-adrenal axis and the subjective and physiologic response to CRH in cocaine-dependent individuals and controls.

Design  A case-control study.

Setting  Subjects were admitted to a General Clinical Research Center for testing and abstinence was verified with a urine drug screening.

Participants  Participants were male controls (n = 23), female controls (n = 24), cocaine-dependent men (n = 28), and cocaine-dependent women (n = 25). Individuals with dependence on other substances (except caffeine or nicotine) or with major depression, posttraumatic stress disorder, bipolar disorder, or psychotic or eating disorders were excluded.

Intervention  Subjects received 1 µg/kg of CRH intravenously.

Main Outcome Measures  Primary outcomes included plasma corticotropin levels, cortisol levels, and heart rate and subjective measurements.

Results  Cocaine-dependent individuals exhibited higher stress (P < .001) and craving for CRH compared with controls. A positive correlation (r_s = 0.51; P < .001) between stress and craving was found in cocaine-dependent subjects. Intravenous CRH elevated heart rates in all groups; however, cocaine-dependent women demonstrated a significantly higher heart rate at all time points (P = .05). Women had higher cortisol responses to CRH (P = .03). No effect of cocaine status was observed. The corticotropin response to CRH was independent of sex and cocaine dependence. Cortisol and corticotropin were positively correlated in the controls and cocaine-dependent men, but not in cocaine-dependent women (r_s = 0.199; P = .4).

Conclusions  There is an increased subjective and heart rate response to CRH and a relationship between stress and craving in cocaine-dependent individuals. The lack of difference in hypothalamic pituitary adrenal axis response between the cocaine-dependent and control groups suggests that the heart rate and subjective responses in the cocaine group may be mediated by sensitization of nonhypothalamic stress-responsive CRH systems.

Author Affiliations: Psychiatry and Behavioral Neurosciences, Clinical Neurosciences Division, Medical University of South Carolina, Charleston (Drs Brady, McRae, Moran-Santa Maria, DeSantis, Waldrop, and Back and Ms Simpson); The Rockefeller University, New York, New York (Dr Kreek).

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