We have previously demonstrated that the endocannabinoid system is dysregulated at synaptic terminals in the cerebral cortex of aged rats, characterized by reduced availability of the neuroprotective endocannabinoid 2-arachidonoylglycerol (2-AG) as a result of im-paired metabolic enzyme activity. This deficit was only partially compensated by canna-binoid receptor (CBR) ligand binding. Given that Δ9-tetrahydrocannabinol (THC) func-tions as a CBR ligand, the present study was designed to determine whether a full-spectrum cannabis extract with high THC content, its THC-free fraction, or pure THC could modulate the age-related dysregulation of 2-AG. Synaptosomes isolated from the cerebral cortex of adult and aged rats were incubated with a full-spectrum extract, a THC-free fraction, or pure THC, together with the corre-sponding radiolabeled substrates to assess 2-AG-metabolizing enzyme activity. Our re-sults demonstrate that the age-related decline in 2-AG bioavailability (a) is exacerbated by either the THC-free fraction or pure THC, primarily due to a significant reduction in 2-AG synthesis, and (b) is partially attenuated through inhibition of 2-AG hydrolysis when the extract contains THC. Consequently, a high-THC full-spectrum extract regulates 2-AG metabolism more effectively than THC alone. These findings support the concept that cannabis phytochemicals act synergistically (the entourage effect) and highlight the therapeutic potential of high-THC extracts for restoring reduced 2-AG levels in the aging brain.