Antispasmodic and antidiarrheal activity of cannabidiol (CBD): involvement of K⁺ channels in intestinal smooth muscle

• CBD showed antispasmodic effects in rat intestinal tissue. • CBD reduced diarrhea in mice induced by castor oil. • The effects involve K⁺ channels, including ATP-sensitive potassium (K ATP ) channels. Functional gastrointestinal disorders, such as irritable bowel syndrome and colitis, are highly prevalent and often poorly responsive to conventional therapies. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has been reported to modulate intestinal motility. Purpose: To evaluate the antispasmodic and antidiarrheal effects of CBD and investigate the mechanisms underlying its action. Study design: A combined in vitro and in vivo experimental approach was used to assess spasmolytic and antidiarrheal properties. Methods: Antispasmodic activity was evaluated in isolated rat small intestine using carbachol-induced concentration–response curves (CCh-CRCs), with CBD applied at 30–300 ng/mL. CBD solution employed was quantified by HPLC/UV-DAD. Mechanistic studies included calcium-induced CRCs and potassium channel blockade with tetraethylammonium (TEA, 20 mM) or glibenclamide (GLIB, 50 μM). In vivo antidiarrheal activity was tested in a murine model of castor oil-induced diarrhea, with oral CBD at 3, 10, and 30 mg/kg. Results: CBD produced a non-competitive inhibition of CCh-induced contractions (IC₅₀ = 0.154 ± 0.054 μg/mL). Its affinity constant (pKCBD) was 6.97, decreasing to 5.87 and 5.93 in the presence of TEA and GLIB, respectively. CBD did not affect calcium-induced contractions, suggesting a mechanism independent of l -type Ca²⁺ channels . In vivo , at 10 and 30 mg/kg, CBD significantly increased dried feces number and provided 56 % protection, comparable to loperamide, without reducing total defecation. Conclusion: CBD exerts antispasmodic and antidiarrheal effects mediated by potassium channels, with evidence indicating a possible contribution of K ATP channels. These findings support its therapeutic potential in functional gastrointestinal disorders.