The Diminished Availability of 2-AG in Aged Synaptic Terminals Is Ameliorated by a Full-Spectrum Cannabis Extract with a High THC Content

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.