In this study, we provide proof of concept for this hypothesis by showing that (i) elevated SM leads to reduced CB1 expression and altered localization in neurons, (ii) there is a pathological downregulation of the eCB system in neurons of ASM‐KO mice and of an infantile ASMD patient, and (iii) inhibitors of the eCB hydrolytic enzyme FAAH exhibit safety and efficacy to treat brain and peripheral pathology in ASM‐KO mice. The gene discussed is SMPD1; the disease is anterior segment dysgenesis.