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(\u2212)\u2010CBD has complex pharmacology but is a relatively weak inhibitor of CB\n                    <jats:sub>1<\/jats:sub>\n                    and CB\n                    <jats:sub>2<\/jats:sub>\n                    receptor signaling. Cannabidiol has two chiral centres and thus four stereoisomers. (+)\u2010\n                    <jats:italic>trans<\/jats:italic>\n                    \u2010CBD ((+)\u2010CBD) has a higher affinity than (\u2212)\u2010CBD at CB\n                    <jats:sub>1<\/jats:sub>\n                    and CB\n                    <jats:sub>2<\/jats:sub>\n                    , but its pharmacodynamic effects at these receptors are incompletely described. We examined the activity of (+)\u2010CBD at human CB\n                    <jats:sub>1<\/jats:sub>\n                    and CB\n                    <jats:sub>2<\/jats:sub>\n                    receptors using a fluorescence\u2010based assay of membrane potential in AtT20 cells stably expressing CB\n                    <jats:sub>1<\/jats:sub>\n                    or CB\n                    <jats:sub>2<\/jats:sub>\n                    receptors. (+)\u2010CBD produced a rapid, concentration\u2010dependent hyperpolarization in CB\n                    <jats:sub>2<\/jats:sub>\n                    \u2010expressing cells (\n                    <jats:italic>p<\/jats:italic>\n                    EC\n                    <jats:sub>50<\/jats:sub>\n                    6.63\u2009\u00b1\u20090.08) with a maximal effect 90% of the response to CP55940. The CB\n                    <jats:sub>2<\/jats:sub>\n                    response was blocked by pertussis toxin pretreatment and competitively inhibited by the CB\n                    <jats:sub>2<\/jats:sub>\n                    antagonist AM630 (Schild slope 1.1\u2009\u00b1\u20090.1). (+)\u2010CBD was a low\u2010efficacy, low\u2010potency CB\n                    <jats:sub>1<\/jats:sub>\n                    agonist and inhibited somatostatin\u2010receptor effects at high concentrations (10\u201330\u2009\u03bcM). (+)\u2010CBD had no effect on the membrane potential of AtT20 wild\u2010type cells.\n                    <jats:italic>In silico<\/jats:italic>\n                    modeling of ligand interactions with CB\n                    <jats:sub>2<\/jats:sub>\n                    indicated that (+)\u2010CBD but not (\u2212)\u2010CBD formed an H\u2010bond with Ser285, a residue crucial for agonist activation of CB\n                    <jats:sub>2<\/jats:sub>\n                    . Our data suggests (+)\u2010CBD acted as a CB\n                    <jats:sub>2<\/jats:sub>\n                    agonist via the orthosteric binding site on the receptor. Synthetic CBD, including (+)\u2010CBD, has previously been administered in clinical trials, presumably without consideration of its potential CB\n                    <jats:sub>2<\/jats:sub>\n                    agonist activity. Given the relative safety of (\u2212)\u2010CBD in people, (+)\u2010CBD may be a useful drug to explore CB\n                    <jats:sub>2<\/jats:sub>\n                    \u2010sensitive disease states.\n                  <\/jats:p>","DOI":"10.1002\/prp2.70325","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T04:24:39Z","timestamp":1789532679000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["(+)\u2010Trans\u2010Cannabidiol Is an Agonist at Human\n                    <scp>\n                      CB\n                      <sub>2<\/sub>\n                    <\/scp>\n                    Receptors"],"prefix":"10.1002","volume":"14","author":[{"given":"Pedro Bans","family":"Burtchaell","sequence":"first","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences Trinity College Dublin, University of Dublin  Dublin Ireland"},{"name":"Macquarie Medical School Macquarie University  North Ryde New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9388-8309","authenticated-orcid":false,"given":"Marina Junqueira","family":"Santiago","sequence":"additional","affiliation":[{"name":"Macquarie Medical School Macquarie University  North Ryde New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences Trinity College Dublin, University of Dublin  Dublin Ireland"},{"name":"Macquarie Medical School Macquarie University  North Ryde New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehdi","family":"Hagdoost","sequence":"additional","affiliation":[{"name":"Nalu Bio  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1108-1192","authenticated-orcid":false,"given":"Evie J. M.","family":"Clay","sequence":"additional","affiliation":[{"name":"School of Natural Sciences Macquarie University  Sydney New South Wales Australia"},{"name":"School of Biological Sciences University of Bristol  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7780-3012","authenticated-orcid":false,"given":"Dani","family":"Mohnot","sequence":"additional","affiliation":[{"name":"Macquarie Medical School Macquarie University  North Ryde New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2538-2001","authenticated-orcid":false,"given":"Mark","family":"Connor","sequence":"additional","affiliation":[{"name":"Macquarie Medical School Macquarie University  North Ryde New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916\u2010022\u201002459\u20101"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M707104200"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.004929"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.73246"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2025.111588"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1711351114"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-005-6978-1"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16674"},{"key":"e_1_2_11_10_1","doi-asserted-by":"crossref","unstructured":"S. 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