The ingestion of unripe ackee fruit (Blighia sapida) is responsible for lethal epidemic encephalopathy in West Africa and the Caribbean. The treatment of ackee poisoning remains empirical and lethality was 100% in a recent epidemic in Burkina Faso. Because ackee poisoning has certain biochemical similarities to ifosfamide encephalopathy, we evaluated the efficacy of methylene blue (MB) and glucose (G), alone and in combination (MB+G) in mice, as a treatment for ackee poisoning. MB administration showed some efficacy towards early mortality (P=0.07) but not to late mortality. No deaths were observed when 8 mg/kg MB was administrated within 1h of the ackee poisoning. The treatment was ineffective if given 6h or later after poisoning. Survival in G and G+MB groups was higher than in MB group (75% and 25% respectively) (P=0.008, R=2.0, 1.14<RR<3.52). Neither hepatitis nor the development of hepatic cirrhosis was observed in animals from any groups. Glucose was more effective than MB and elicited the same survival as MB in conditions of early treatment. MB must be given in multiple doses and the first administration should be performed early, at least within 3 h of poisoning, which may decrease the practical value of MB in the field. In conclusion, considering the high lethality of the ackee apple intoxication, the total absence of any existing treatment and the safety of glucose administration, we recommend at this stage to use early sugar or glucose administration in the field, in addition to a specific population-based prevention programme.