982 of eCB receptors are found in brain structures associated with reward processing, including the ventral tegmental area, the nucleus accumbens, and prefrontal cortex (Ameri 1999; Gardner 2005). Endocannabinoid agonists have rewarding effects, as has been shown in animals (Gardner 2005; Solinas et al. 2007). Also, blocking the eCB system with the antagonist rimonabant has been shown to reduce the rewarding effects of drugs of abuse such as opiates, nicotine, alcohol, and cocaine, indicating that the eCB system is involved in the neurobiological mechanism underlying drug addiction (De Vries and Schoffelmeer 2005; Maldonado et al. 2006). Further, the cannabinoid agonist Δ9-tetrahydrocannabinol (THC) has rewarding properties by increasing dopamine transmission in the nucleus accumbens (Gardner 2005). However, whether these findings can be extrapolated to humans is unclear. The location of eCB receptors in the human brain suggests that the eCB system is also involved in human reward processing (Glass et al. 1997; Terry et al. 2009). An extensive network of brain regions is involved, including limbic structures (notably striatum) and frontal regions (Bjork and Hommer 2007; Knutson et al. 2001a; Knutson and Cooper 2005; O'Doherty 2004). Chronic cannabis use has been shown to blunten the response of the striatum in anticipation of a reward (Van Hell et al. 2010). Similarly, treatment with the eCB antagonist rimonabant in healthy volunteers resulted in reduced striatal brain activity during reward processing (Horder et al. 2010). Chronic use of rimonabant has been demonstrated to reduce overweight and smoking and to cause depression, but the potential involvement of the reward system is unclear (Cahill and Ussher 2007). However, use of rimonabant in healthy subjects is thwarted by the withdrawal of this drug from registration, following an increased risk of depression and suicide in obese patients (Le Foll et al. 2009). This essentially precludes further use of this drug for elucidating the role of eCB in human brain function. An alternative approach, where the eCB system is challenged with THC, can also provide a powerful tool for studying its role in reward processing in humans. THC is the main psychoactive constituent of cannabis and possesses rewarding as well as addictive properties (Pertwee 2008). Human studies have shown both increased dopamine transmission as measured with positron emission tomography (PET; Bossong et al. 2009) and no change in striatal dopamine transmission after THC administration, measured with PET (Stokes et al. 2009) or single photon emission tomography (Barkus et al. 2011). Here, a pharmacological functional magnetic resonance imaging (fMRI) study is presented that examines the involvement of the eCB system in anticipation to a reward as well as reception of the reward. A monetary incentive delay (MID) task is applied (Knutson et al. 2001b), an established reward paradigm which provides a measure of Psychopharmacology (2012) 219:981–990 sensitivity to anticipation of reward as well as sensitivity to notification that the reward has been won (Hommer et al. 2011). Previous studies using this paradigm have indicated that anticipation of a reward activates the ventral striatum, and especially the nucleus accumbens, while the reward itself activates frontal brain areas (Knutson et al. 2001a; Knutson et al. 2001b). It was expected that THC would increase baseline dopamine transmission in the reward system. As a result, it was expected that the fMRI response to a natural reward would be decreased, especially in regions in which eCB receptors are densely distributed, such as the nucleus accumbens and prefrontal cortex. Methods Subjects This study is part of the Pharmacological Imaging of the Cannabinoid System (PhICS) project, a comprehensive research project on the role of the endocannabinoid system in the regulation of cognitive brain function in healthy volunteers and patients with psychiatric disorders. Methods of the entire study are reported in detail in a methodological paper (Van Hell et al. 2011). The study is registered in both the EudraCT database (2007-004247-30) and the Dutch Trial Register (NTR1787). Fourteen healthy male subjects participated in a randomized placebo-controlled cross-over pharmacological MRI study with THC administration. For ethical reasons, subjects needed to be occasional cannabis users (at least four times a year and at most once a week) who never had negative experiences after cannabis use. Subjects were in good health as assessed by medical history, physical examination, electrocardiogram, and routine laboratory tests. In- and exclusion criteria are described in further detail in Van Hell et al. (2011). All volunteers gave written informed consent before entry into the study and were compensated for their participation. The study was approved by the Ethical Committee of the University Medical Centre Utrecht in accordance with the Declaration of Helsinki 2008. Results are reported on eleven out of the fourteen included subjects. Two data sets were incomplete, due to respectively a technical malfunction of the scanner and feelings of anxiety during the second scanning session. One subject was excluded from analysis due to movement artefacts. Subject characteristics are summarized in Table 1. Procedure At a training session, subjects practiced the procedure of drug administration (inhalation), and participants were