Cannabinoids have been of recent research interest due to their antioxidant properties, particularly their potential to prevent oxidative stress, which is linked to various diseases and health conditions. This study explores the primary, secondary, and tertiary antioxidant activity of cannabidiol (CBD), the second most abundant cannabinoid in cannabis sativa. The M06-2X or the M06 functional is used combined with the SMD solvation method and the 6-31++G(d,p) basis set. Water and pentyl ethanoate are the solvents considered at physiological pH to simulate hydrophilic and hydrophobic environments.

The primary activity study focuses on the quenching of methoxy and peroxyl radicals by CBD via hydrogen-atom transfer (HAT) reaction, considering all the possible reaction sites of CBD in both water and pentyl ethanoate. Radical-adduct formation and single-electron transfer (SET) reactions are also considered. The rate constants of the exergonic reactions are calculated.

The secondary activity study explores the aqueous CBD complex formation with Cu2+ and Fe3+ and their subsequent reduction by reaction with the superoxide radical anion or ascorbate. Various coordination numbers and high- and low-spin options are explored. If the SET rate constant for the reduction of these complexes is significantly smaller than that of the reduction of the free metal ions in solution, the subsequent formation of hydroxy radicals during the Fenton reaction of the Haber-Weiss cycle could be inhibited, significantly reducing their damaging effects.

The tertiary activity study focuses on the CBD repair of a damaged leucine as a lateral chain in a protein environment, simulated by N-formyl leucinamide, by HAT reaction. Only the hydroxy hydrogens of CBD, and the repair of the β and δ sites of leucine are considered, as the repair of these sites have produced the highest rate constants in previous studies by our group.