Enhancing anandamide signalling through FAAH inhibition: Clinical evidence, safety concerns, and precision strategies for psychiatric treatment

Anandamide is an endocannabinoid that helps regulate synaptic transmission, stress responses, mood, anxiety, trauma-related symptoms, and psychosis. This review evaluates fatty acid amide hydrolase (FAAH) inhibitors, which slow anandamide breakdown and aim to enhance endocannabinoid signalling without the broader psychotropic effects and regulatory problems associated with cannabis. Clinical studies show strong target engagement, including substantial increases in plasma and cerebrospinal fluid anandamide, but limited therapeutic efficacy. Only PF-04457845, now JZP150, and JNJ-42165279 reached Phase II trials. Both produced modest or inconsistent benefits in cannabis use disorder, while trials in PTSD, depression, anxiety, and other conditions generally failed to show significant improvement. Most compounds were well tolerated, but the fatal BIA 10-2474 trial underscores the risks of off-target lipid-enzyme inhibition and inadequate safety evaluation. Future development should emphasize selective compounds, rigorous monitoring, biomarker-guided patient selection, FAAH genotype, baseline endocannabinoid levels, neuroimaging, and clinical symptom profiles.