Boosting the brain's natural cannabinoids to treat psychiatric disorders

Endocannabinoids (eCBs) are lipid-derived neuromodulators that regulate numerous neurophysiological processes by modulating synaptic transmission. Synthesised on demand in response to increased postsynaptic intracellular calcium or activation of postsynaptic G-protein coupled receptors, eCBs are rapidly degraded, resulting in transient, tightly regulated signalling. Dysregulation in the endocannabinoid system (ECS), including altered peripheral and central eCB concentrations and/or cannabinoid-1 receptor (CB1R) expression, has been observed across psychiatric syndromes, including major depressive disorder, psychotic disorders, and post-traumatic stress disorder (PTSD). These associations have prompted growing interest in pharmacological strategies targeting the ECS. Though medical cannabis is increasingly prescribed for psychiatric symptoms, its clinical use remains controversial due to limited high-quality evidence, psychotropic side effects, and regulatory constraints. An alternative is to enhance the signalling of a principal eCB, anandamide (AEA), potentially offering more physiologically constrained CB1R engagement, by inhibiting fatty acid amide hydrolase (FAAH), the main enzyme degrading AEA and its congener, N-acylethanolamines (NAE), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This review consolidates recent clinical evidence for FAAH inhibitors, examining their influence on AEA, safety and efficacy in ameliorating symptoms across a range of psychiatric conditions, including depression, anxiety, PTSD, and cannabis use disorder (CUD). Presently, only two compounds, PF-04457845 (JZP150) and JNJ-42165279, have progressed to Phase II trials, demonstrating modest clinical benefit in CUD, with no efficacy in PTSD or osteoarthritis pain. Herein, we discuss emerging insights, safety considerations, broader mechanistic implications, and future directions for FAAH-targeted therapeutics, advocating for a precision medicine approach to realise their potential in the treatment of psychiatric disorders.