Psychopharmacology (2012) 219:981–990 DOI 10.1007/s00213-011-2428-8 ORIGINAL INVESTIGATION Involvement of the endocannabinoid system in reward processing in the human brain Hendrika H. van Hell & Gerry Jager & Matthijs G. Bossong & Annelies Brouwer & J. Martijn Jansma & Lineke Zuurman & Joop van Gerven & René S. Kahn & Nick F. Ramsey Received: 30 March 2011 / Accepted: 25 July 2011 / Published online: 6 August 2011 # The Author(s) 2011. This article is published with open access at Springerlink.com Abstract Rationale Disturbed reward processing in humans has been associated with a number of disorders, such as depression, addiction, and attention-deficit hyperactivity disorder. The endocannabinoid (eCB) system has been implicated in reward processing in animals, but in humans, the relation between eCB functioning and reward is less clear. Objectives The current study uses functional magnetic resonance imaging (fMRI) to investigate the role of the eCB system in reward processing in humans by examining the effect of the eCB agonist Δ9-tetrahydrocannabinol (THC) on reward-related brain activity. Methods Eleven healthy males participated in a randomized placebo-controlled pharmacological fMRI study with ad- Electronic supplementary material The online version of this article (doi:10.1007/s00213-011-2428-8) contains supplementary material, which is available to authorized users. H. H. van Hell : G. Jager : M. G. Bossong : A. Brouwer : J. M. Jansma : N. F. Ramsey (*) Department of Neurology and Neurosurgery, G.03.124, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands e-mail: N.Ramsey@umcutrecht.nl G. Jager Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands L. Zuurman : J. van Gerven Centre for Human Drug Research, Leiden, The Netherlands R. S. Kahn Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands ministration of THC to challenge the eCB system. We compared anticipatory and feedback-related brain activity after placebo and THC, using a monetary incentive delay task. In this task, subjects are notified before each trial whether a correct response is rewarded (“reward trial”) or not (“neutral trial”). Results Subjects showed faster reaction times during reward trials compared to neutral trials, and this effect was not altered by THC. THC induced a widespread attenuation of the brain response to feedback in reward trials but not in neutral trials. Anticipatory brain activity was not affected. Conclusions These results suggest a role for the eCB system in the appreciation of rewards. The involvement of the eCB system in feedback processing may be relevant for disorders in which appreciation of natural rewards may be affected such as addiction. Keywords Reward . THC . Endocannabinoid system . fMRI . Monetary reward . Addiction Introduction Disturbed reward processing is associated with a number of psychiatric disorders in humans, such as depression (Domschke et al. 2008), addiction (Pacher et al. 2006), and attention-deficit hyperactivity disorder (Strohle et al. 2008). Animal studies have indicated that the endocanna- binoid (eCB) system in the brain plays an important role in reward processing (Solinas et al. 2007). This system consists of eCB receptors and eCB ligands that work on these receptors and has a retrograde synaptic effect on the release of various neurotransmitters, such as GABA, glutamate, and dopamine (Pertwee 2008). High densities