The negative and positive enantiomers of 7-hydroxy-6 -tetrahydrocannabinol-dimethylheptyl (designated HU-210 and HU-211 respectively) differentially affect undifferentiated and differentiating cultured pheochromocytoma cells (PC-12 cells). In general, cell viability and cell proliferation were suppressed to a much greater extent with HU-210 than with HU-211 in differentiating cells. The effects of these synthetic cannabinoids on the cytoskeleton of PC-12 cells were examined by epifluorescence and confocal microscopy. In both undifferentiated and differentiating PC-12 cells, HU-211 has little effect on the cytoarchitecture whereas HU-210 disrupts the distribution of microtubules and microfilaments. Vacuoles (2-4 m) were evident in the cytoplasm of HU-210-treated cells but not in the cytoplasm of HU-211-treated cells or in vehicle controls. Tubulin and actin mRNA levels were reduced to 5 and 40%, respectively (relative to untreated controls) in 10 ๏ญ HU-210-treated cells whereas the same concentration of HU-211 reduced tubulin and actin mRNA levels to 90 and 95%, respectively. A comparison of the effects of the paired enantiomers and 1 -THC on the cellular parameters studied reveals that in differentiating cells the action of 1 -THC is intermediate between that of HU-210 and HU-211. This study demonstrates that compared to HU-210 and 1 -THC the positive enantiomer HU-211 has little cellular activity.