Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB1 (cannabinoid receptor type 1) receptors after chronic exposure to cannabis. However, whether downregulation occurs in humans who chronically smoke cannabis is unknown. Here we show, using positron emission tomography imaging, reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in human subjects who chronically smoke cannabis. Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After ∼4 weeks of continuously monitored abstinence from cannabis on a secure research unit, CB1 receptor density returned to normal levels. This is the first direct demonstration of cortical cannabinoid CB1 receptor downregulation as a neuroadaptation that may promote cannabis dependence in human brain.
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We thank Kimberly Jenko, Kacey Anderson, and David Clark for measurements of radioligand in plasma; Maria D Ferraris Araneta, Yulin Chu, Denise Rallis-Frutos, Gerald Hodges, William C Kreisl, Christina Hines and Barbara Scepura as well as Kathleen Demuth and the NIDA and BPRU nursing staff for subject recruitment and care; the NIH PET Department for imaging; and PMOD Technologies for providing its image analysis and modeling software. This research was supported by the Intramural Programs of the NIMH (project no. Z01-MH-002852-04) and the NIDA (project no. Z01-DA000413-13). Jussi Hirvonen was supported by personal grants from The Academy of Finland; The Finnish Cultural Foundation; The Finnish Foundation for Alcohol Studies; The Finnish Medical Foundation; The Instrumentarium Foundation; The Jalmari and Rauha Ahokas Foundation; The Paulo Foundation; The Research Foundation of Orion Corporation; and The Yrjö Jahnsson Foundation.
The authors declare no conflict of interest.
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Hirvonen, J., Goodwin, R., Li, CT. et al. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol Psychiatry 17, 642–649 (2012). https://doi.org/10.1038/mp.2011.82
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