Several studies have shown that the major psychoactive component in marihuana, (-)-(trans)-delta 9-tetrahydrocannabinol (THC), increases the level of unesterified arachidonic acid (AA) in non-neural cells in culture. Little is known, however, about the effects of THC on AA metabolism in the mammalian brain. In the present study, slices from guinea pig brain cortex were prelabeled with [14C]AA, and the effects of THC and other cannabinoids on the disposition of esterified and unesterified [14C]AA were measured. Incubation of prelabeled cortical slices with THC rapidly increased free [14C]AA levels in a dose-dependent and saturable manner. A maximal increase of over 4-fold was elicited by 32 microM THC, with the half-maximal response occurring at 8.0 microM. Comparison of the potencies of several other cannabinoids revealed that the inactive stereoisomer of THC [(+)-THC] was equipotent with the naturally occurring isomer in increasing unesterified [14C]AA levels. The relative rank-order of potencies in the cannabinoid series we examined were (-)-THC = (+)-THC greater than cannabinol greater than delta 8-THC greater than cannabidiol. We also measured cannabinoid-induced changes in the disposition of esterified [14C]AA in the neutral lipids and phospholipids of brain cortex slices. After incubation with 8 microM THC for 1 hr, the radioactivity in triacylglycerols was reduced by over one third. The loss of esterified [14C] AA from triacylglycerols accounted for less than 20% of the THC-induced rise in free [14C]AA; the remainder was accounted for by losses in the radioactivity contained in the phospholipid fraction, particularly from phosphatidylinositol. The loss in radioactivity from phosphatidylinositol alone accounted for over one half of the THC-induced rise in unesterified [14C]AA. The results of the present study indicate that in brain, as in extra-neural cells in culture, cannabinoids increase unesterified AA levels; however, the relative potencies of the cannabinoids we examined in increasing AA levels do not correlate well with their in vivo psychoactive potencies.