CBD attenuates MC activation, inflammation, neuroinflammation, and oxidative stress in sickle mice. Female HbSS-BERK sickle mice were treated daily for 9 days with vehicle (5% DMSO, 5% Tween 20, in sterile phosphate-buffered saline) or pure CBD (from Cayman) intraperitoneally at 20 mg/kg per day except when indicated for 50 mg/kg per day. After 9 days of treatment, mice were humanely euthanized, and plasma and punch biopsies of dorsal skin were collected for analysis. (A) MC activation in the skin biopsies: (i) the number of total MCs per field and percent of degranulating MCs; (ii) toluidine blue–stained sections of skin showing intact and degranulating MCs. Key features observed in representative images of dorsal skin from female sickle mice (ii) include degranulating MCs (black arrows), MC granules (red arrows), intact MCs (yellow arrow), and (iii) tryptase released from the skin after 24-hour incubation. (B) Cytokines released from the skin biopsies of CBD-treated mice in culture medium are expressed as percent of vehicle-treated mice for (i) 20 mg/kg per day CBD (green bars) and (ii) 50 mg/kg per day CBD (red bars). (C) SAP expression in the plasma of vehicle and CBD-treated mice. (D) Substance P, marker of neuroinflammation in the skin releasate after 24-hour incubation. (E) MDA, a measure of lipid peroxidation and oxidative stress in the skin releasate after 24-hour incubation. Data are expressed as mean ± SEM. Data analyzed with Mann-Whitney U test. ∗P ≤ .05, ∗∗P < .01. n = 5 to 10 per condition. Age ∼3.5 months. GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-γ, interferon gamma; MCP-1, monocyte chemoattractant protein 1.