Analgesic and toxicological evaluation of cannabidiol-rich Moroccan <i>Cannabis sativa</i> L. (Khardala variety) extract: Evidence from an <i>in vivo</i> and <i>in silico</i> study

The legalization of cannabis for industrial and medicinal purposes has significantly expanded worldwide. This study delves into the analgesic potential toxicity study of chloroformic extract from the Moroccan <i>Cannabis sativa</i> L. (<i>C. sativa</i>) cultivar, Khardala (KH extract). Our findings reveal that the lethal dose of KH extract is ≥5,000 mg/kg, with mice given 2,000 mg/kg exhibiting neurotoxic symptoms, including piloerection, aggressiveness, and fear, along with marked hepato-renal toxicity indicated by elevated levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, and creatinine in both male and female subjects. Importantly, no toxicity was observed at 250 mg/kg and 500 mg/kg doses. Remarkably, at a dose of 500 mg/kg, the KH extract demonstrated a potent analgesic effect superior to cannabidiol (CBD), suggesting a synergistic interaction among the extract's bioactive compounds, such as CBD, cannabidivarin (CBDV), Delta 9 tetrahydrocannabinol (THC), cannabigerol (CBG), Delta 9 tetrahydrocannabivarin (THCV), and β-caryophyllene. <i>In silico</i> analysis supports these findings, showing the strong binding potential of THC, THCV, CBG, and CBDV to delta opioid receptors, with <i>G</i>-scores >-5.0 kcal/mol, highlighting the promising analgesic efficacy of this cannabis cultivar extract. This study underscores the therapeutic potential of the KH cultivar, positioning it as a promising candidate for pain management therapies.