An Orally Active Cannabis Extract with High Content in Cannabidiol attenuates Chemically-induced Intestinal Inflammation and Hypermotility in the Mouse

Abstract

Anecdotal and scientific evidence suggests that Cannabis use may be beneficial in inflammatory bowel disease (IBD) patients. Here, we have investigated the effect of a standardized Cannabis sativa extract with high content of cannabidiol (CBD), here named CBD BDS for "CBD botanical drug substance," on mucosal inflammation and hypermotility in mouse models of intestinal inflammation. Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Motility was evaluated in the experimental model of intestinal hypermotility induced by irritant croton oil. CBD BDS or pure CBD were given - either intraperitoneally or by oral gavage - after the inflammatory insult (curative protocol). The amounts of CBD in the colon, brain, and liver after the oral treatments were measured by high-performance liquid chromatography coupled to ion trap-time of flight mass spectrometry. CBD BDS, both when given intraperitoneally and by oral gavage, decreased the extent of the damage (as revealed by the decrease in the colon weight/length ratio and myeloperoxidase activity) in the DNBS model of colitis. It also reduced intestinal hypermotility (at doses lower than those required to affect transit in healthy mice) in the croton oil model of intestinal hypermotility. Under the same experimental conditions, pure CBD did not ameliorate colitis while it normalized croton oil-induced hypermotility when given intraperitoneally (in a dose-related fashion) or orally (only at one dose). In conclusion, CBD BDS, given after the inflammatory insult, attenuates injury and motility in intestinal models of inflammation. These findings sustain the rationale of combining CBD with other minor Cannabis constituents and support the clinical development of CBD BDS for IBD treatment.

Keywords: Cannabis sativa; cannabidiol; cannabinoids; colitis; inflammatory bowel disease; intestinal motility.

FIGURE 1

Effect of CBD BDS (5–30 mg/kg, intraperitoneally) on body weight (A) and colon weight/colon length ratio(B) and effect of CBD BDS (10–60 mg/kg, oral gavage) on body weight (C) and colon weight/colon length ratio(D) in DNBS induced colitis in mice (DNBS, 150 mg/kg, intracolonically). CBD BDS was given once a day for three consecutive days starting from 1 day after DNBS administration. Mice were euthanized 3 days after DNBS. Mice were weighted before DNBS (or vehicle) administration and immediately before the sacrifice. Bars are mean ± SEM of 8–12 mice for each experimental group. ^#p < 0.001 vs. control and ^∗p < 0.05 vs. DNBS alone.

FIGURE 2

Effect of pure CBD (5–30 mg/kg, intraperitoneally) on body weight (A) and colon weight/colon length ratio(B) and effect of pure CBD (10–60 mg/kg, by oral gavage) on body weight (C) and colon weight/colon length ratio(D) in DNBS induced colitis in mice (DNBS, 150 mg/kg, intracolonically). Pure CBD was given once a day for three consecutive days starting from 1 day after DNBS administration. Mice were euthanized 3 days after DNBS. Mice were weighted before DNBS (or vehicle) administration and immediately before the sacrifice. Bars are mean ± SEM of 8–12 mice for each experimental group. ^#p < 0.001 vs. control.

FIGURE 3

Inhibitory effect of CBD BDS 30 mg/kg, intraperitoneally (A) and CBD BDS 60 mg/kg, by oral gavage (B) on myeloperoxidase (MPO) activity in DNBS induced colitis in mice (DNBS, 150 mg/kg, intracolonically). MPO activity was measured on colonic tissues 3 days after vehicle or DNBS administration. CBD BDS was given once a day for three consecutive days starting from 1 day after DNBS administration. Mice were euthanized 3 days after DNBS. Bars are mean ± SEM of 4–5 mice for each experimental group. ^#p < 0.001 vs. control and ^∗p < 0.05 ^∗∗p < 0.01 vs. DNBS alone.

FIGURE 4

Effect of CBD BDS (1–10 mg/kg, intraperitoneally) on intestinal transit in healthy mice (A) and croton oil-treated mice (B). Bars represent the mean ± SEM of 8–10 animals for each experimental group. ° and ^#p < 0.05, ^∘∘p < 0.01, and ^∘∘∘p < 0.001 vs. control and ^∗p < 0.05 and ^∗∗∗p < 0.001 vs. croton oil alone. Insert: Difference between the curves representing the inhibitory effect of CBD BDS on intestinal transit in healthy mice and mice with hypermotility (mice treated with croton oil). Results are expressed as mean ± SEM of 8–10 mice for each experimental group. ^∗∗∗p < 0.001 vs. healthy mice.

FIGURE 5

Effect of CBD BDS (10–60 mg/kg, by oral gavage) on intestinal transit in healthy mice (A) and croton oil-treated mice (B). Bars represent the mean ± SEM of 8–10 animals for each experimental group. ° and ^#p < 0.05, ^∘∘p < 0.01 and ^∘∘∘p < 0.001 vs. control and ^∗∗p < 0.01 and ^∗∗∗p < 0.001 vs. croton oil alone. Insert: Difference between the curves representing the inhibitory effect of CBD BDS on intestinal transit in healthy mice and mice with hypermotility (mice treated with croton oil). Results are expressed as mean ± SEM of 8–10 mice for each experimental group. ^∗∗∗p < 0.001 vs. healthy mice.

FIGURE 6

Effect of intraperitoneal administration of pure CBD (1–10 mg/kg) on intestinal transit in healthy mice (A) and croton oil-treated mice (B), and oral gavage administration of pure CBD (5–60 mg/kg) on intestinal transit in healthy mice (C) and croton oil-treated mice (D). Bars represent the mean ± SEM of 8–10 animals for each experimental group. ^#p < 0.05–0.01 vs. control; ^∗p < 0.05 and ^∗∗p < 0.01 vs. croton oil alone.

FIGURE 7

CBD levels in colon (A), brain (B), and liver (C) of DNBS-treated mice after oral administration of either CBD BDS or CBD. Data are means ± SEM of N = 5–6 mice.