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Importantly, a growing body of evidence suggests that regular cannabis users develop tolerance to the impairing, as well as the rewarding, effects of the drug. However, the neuroadaptations that may underlie cannabis tolerance remain unclear. Therefore, this double\u2010blind, randomized, placebo\u2010controlled, cross\u2010over study assessed the acute influence of cannabis on the brain and behavioral outcomes in two distinct cannabis user groups. Twelve occasional and 12 chronic cannabis users received acute doses of cannabis (300\u2010\u03bcg\/kg delta\u20109\u2010tetrahydrocannabinol) and placebo and underwent ultrahigh field functional magnetic resonance imaging and magnetic resonance spectroscopy. In occasional users, cannabis induced significant neurometabolic alterations in reward circuitry, namely, decrements in functional connectivity and increments in striatal glutamate concentrations, which were associated with increases in subjective high and decreases in performance on a sustained attention task. Such changes were absent in chronic users. The finding that cannabis altered circuitry and distorted behavior in occasional, but not chronic users, suggests reduced responsiveness of the reward circuitry to cannabis intoxication in chronic users. Taken together, the results suggest a pharmacodynamic mechanism for the development of tolerance to cannabis impairment, of which is important to understand in the context of the long\u2010term therapeutic use of cannabis\u2010based medications, as well as in the context of public health and safety of cannabis use when performing day\u2010to\u2010day operations.<\/jats:p>","DOI":"10.1111\/adb.12870","type":"journal-article","created":{"date-parts":[[2019,12,22]],"date-time":"2019-12-22T17:48:22Z","timestamp":1577036902000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Reduced responsiveness of the reward system is associated with tolerance to cannabis impairment in chronic users"],"prefix":"10.1111","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7115-0389","authenticated-orcid":false,"given":"Natasha L.","family":"Mason","sequence":"first","affiliation":[{"name":"Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience Maastricht University  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eef L.","family":"Theunissen","sequence":"additional","affiliation":[{"name":"Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience Maastricht University  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia R.P.W.","family":"Hutten","sequence":"additional","affiliation":[{"name":"Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience Maastricht University  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desmond H.Y.","family":"Tse","sequence":"additional","affiliation":[{"name":"Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience Maastricht University  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan W.","family":"Toennes","sequence":"additional","affiliation":[{"name":"Institute of Legal Medicine University of Frankfurt  Frankfurt\/Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacobus F.A.","family":"Jansen","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine Maastricht University Medical Center+ (MUMC+)  Maastricht The Netherlands"},{"name":"School for Mental Health and Neuroscience Maastricht University Medical Center  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Stiers","sequence":"additional","affiliation":[{"name":"Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience Maastricht University  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes G.","family":"Ramaekers","sequence":"additional","affiliation":[{"name":"Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience Maastricht University  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,12,22]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"UN. 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