Hypothalamic–pituitary–adrenal axis reactivity to social stress and adolescent cannabis use: the TRAILS study Andrea Prince van Leeuwen 1,2 , Hanneke E. Creemers 1,2 , Kirstin Greaves-Lord 2 , Frank C. Verhulst 2 , Johan Ormel 3 & Anja C. Huizink 1,2,4 Research Institute of Child Development and Education, University of Amsterdam, Amsterdam, the Netherlands, 1 Department of Child and Adolescent Psychiatry, Erasmus University Medical Center Sophia Children’s Hospital, Rotterdam, the Netherlands, 2 Interdisciplinary Center for Psychiatric Epidemiology, Department of Psychiatry, University Medical Center Groningen and University of Groningen, Groningen, the Netherlands 3 and Research Institute for Addiction (IVO), Rotterdam, the Netherlands 4 ABSTRACT Aims To investigate the relationship of life-time and repeated cannabis use with hypothalamic–pituitary–adrenal (HPA) axis reactivity to social stress in a general population sample of adolescents. Design Adolescents who reported life-time or repeated cannabis use, life-time or repeated tobacco use and never use of either cannabis or tobacco were compared with respect to their HPA axis reactivity during the Groningen Social StressTask (GSST), which was based on the Trier Social Stress Task. Setting A large prospective population study of Dutch adolescents [the TRacking Ado- lescents’ Individual Lives Survey (TRAILS) study]. Participants A total of 591 adolescents (51% male) who partici- pated in the GSST, which was an additional measurement during the third assessment wave. Measurements HPA axis stress-reactivity was indexed by four cortisol samples collected before, during and after the GSST. Furthermore, all adolescents in our study completed self-reported questionnaires on life-time and repeated cannabis and tobacco use. Models were adjusted for sex, recent alcohol use, experimental session risk status, socio-economic status, mood and time of the experimental session. Findings Life-time cannabis users had significantly lower stress-reactivity levels when compared to abstainers [odds ratio (OR) = 0.68, confidence interval (CI) = 0.55–0.85, P < 0.01] and life-time tobacco users (OR = 0.79, CI = 0.64–0.98, P < 0.05). In addition, repeated cannabis users also exhibited lower stress- reactivity levels when compared to life-time ever users of either tobacco or cannabis (OR = 0.74, CI = 0.53–0.98, P < 0.05). Conclusions Lower hypothalamic–pituitary–adrenal-axis stress-reactivity in adolescents is related specifi- cally to life-time and repeated cannabis use. Keywords Adolescence, cannabis use, cortisol, HPA axis, stress-reactivity, tobacco use. Correspondence to: Anja Huizink, Research Institute of Child Development and Education, University of Amsterdam, Nieuwe Prinsengracht 130, 1018 VZ Amsterdam, the Netherlands. E-mail: a.c.huizink@uva.nl Submitted 23 October 2010; initial review completed 9 December 2010; final version accepted 18 March 2011 INTRODUCTION Experimenting with cannabis during adolescence has been found to increase the risk of developing a cannabis use disorder later in life [1], later psychosis [2] as well as unemployment and higher school dropout rates [3]. Furthermore, repeated cannabis use during adolescence further increases the likelihood of persistent use in adult- hood [4]. Given that cannabis use during adolescence is associated with myriad consequences, detecting adoles- cents at risk for cannabis use is imperative. In their attempts to pinpoint adolescents who have a higher likelihood to initiate and repeatedly use cannabis, researchers have recently started to focus on hypothalamic–pituitary–adrenal (HPA) axis reactivity [5–7].The HPA axis is part of the human neuroendocrine system that regulates various bodily processes, and is a central component of the body’s neuroendocrine response to stress. Individual differences in HPA axis response to stress can be measured during basal function- ing (i.e. daily rhythm) or during stressful situations, which is a reflection of stress-reactivity of the HPA axis. RESEARCH REPORT doi:10.1111/j.1360-0443.2011.03448.x © 2011 The Authors, Addiction © 2011 Society for the Study of Addiction Addiction, 106, 1484–1492