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Ligand binding, cAMP levels and \u03b2arrestin1 recruitment were measured. CBD and CBD\u2010DMH binding was simulated with models of human CB<jats:sub>1<\/jats:sub> or CB<jats:sub>2<\/jats:sub> receptors, based on the recently published crystal structures of agonist\u2010bound (5XRA) or antagonist\u2010bound (5TGZ) human CB<jats:sub>1<\/jats:sub> receptors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>At CB<jats:sub>1<\/jats:sub> receptors, CBD was a negative allosteric modulator (NAM), and CBD\u2010DMH was a mixed agonist\/positive allosteric modulator. CBD and Org27569 shared multiple interacting residues in the antagonist\u2010bound model of CB<jats:sub>1<\/jats:sub> receptors (5TGZ) but shared a binding site with CP55,940 in the agonist\u2010bound model of CB<jats:sub>1<\/jats:sub> receptors (5XRA). The binding site for CBD\u2010DMH in the CB<jats:sub>1<\/jats:sub> receptor models overlapped with CP55,940 and Org27569. At CB<jats:sub>2<\/jats:sub> receptors, CBD was a partial agonist, and CBD\u2010DMH was a positive allosteric modulator of cAMP modulation but a NAM of \u03b2arrestin1 recruitment. CBD, CP55,940 and SR144528 shared a binding site in the CB<jats:sub>2<\/jats:sub> receptor models that was separate from CBD\u2010DMH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>The pharmacological activity of CBD and CBD\u2010DMH in HEK293A cells and their modelled binding sites at CB<jats:sub>1<\/jats:sub> and CB<jats:sub>2<\/jats:sub> receptors may explain their <jats:italic>in vivo<\/jats:italic> effects and illuminates the difficulties associated with the development of allosteric modulators for CB<jats:sub>1<\/jats:sub> and CB<jats:sub>2<\/jats:sub> receptors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linked Articles<\/jats:title><jats:p>This article is part of a themed section on 8<jats:sup>th<\/jats:sup> European Workshop on Cannabinoid Research. To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v176.10\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v176.10\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14440","type":"journal-article","created":{"date-parts":[[2018,7,7]],"date-time":"2018-07-07T09:28:47Z","timestamp":1530955727000},"page":"1455-1469","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":291,"title":["Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol\u2010dimethylheptyl at the type 1 and type 2 cannabinoid receptors"],"prefix":"10.1111","volume":"176","author":[{"given":"Mylyne","family":"Tham","sequence":"first","affiliation":[{"name":"College of Pharmacy and Nutrition University of Saskatchewan  Saskatoon SK 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