Abstract Introduction: Cannabis is extensively abused in Egypt; approximately 800 million dollars are paid annually for management. Cannabis neurophysiologic disturbances represent an annoying health issue, thus, efficient safer treatments are needed. The neurosteroid pregnenolone has been recently observed as a potent inhibitor of cannabis on its receptors. Objectives: To capture cannabis leaves induced brain pathological changes, to assess the myelin basic protein as prognostic biomarker and the potential therapeutic use of pregnenolone against these changes. Materials and Methods: This study was carried out on 160 adult albino rats divided equally into: Group I (negative control), group II (pregnenolone group) gavaged pregnenolone orally, group III (cannabis leaves extract) rats gavaged orally once daily 1/10 of the LD50 of cannabis leaves extract (172.9 mg/kg) and group IV (cannabis leaves extract+pregnenolone) gavaged orally same as before. This study was carried for 12 weeks. Results: There was a significant increase in values of serum myelin basic protein in group (III) compared to group (I); upon supplementation of pregnenolone to intoxicated rats, significant improvement of its values was noticed. Microscopic and immunohistochemistry brain tissues examination of cannabis leaves extract group revealed shrunken cell with dense nuclei and vacuolated cytoplasm & negative immunoreactivity of myelin basic protein antibodies in comparison to control group. Pregnenolone administration to intoxicated rats induced cells improvement and increased the immunoreactivity. Conclusion: cannabis leaves induced brain toxicity in rats with administration of prgnenolone protects brain tissues.