Maddox_2025_Neurotherapeutics__e00814

Substance use disorder (SUD) remains a critical public health issue characterized by high rates of relapse and limited effective pharmacotherapies, particularly for non-opioid substances. A key challenge in addressing SUD lies in the persistent neuroadaptations within the brain's reward circuitry. The endocannabinoid (eCB) system plays a crucial role in modulating reward and reinforcement processes and is disrupted by chronic drug exposure. Recent work highlights the therapeutic potential of indirectly modulating cannabinoid 1 (CB1) receptor signaling by targeting eCB-metabolizing enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), to restore homeostatic eCB tone. We review and synthesize findings from both genetic and pharmacological studies, highlighting the contributions of FAAH and MAGL across major classes of abused substances and considering their potential as therapeutic targets for SUD treatment.