Pheophytins as bioenhancers: Improving cannabidiol bioavailability and efficacy in cannabis extracts

Medical cannabis extracts with similar cannabinoid profiles often produce variable therapeutic effects, suggesting that additional constituents may influence their efficacy. In this study, chlorophyll derivatives (CDs), particularly pheophytins, were identified as natural bioenhancers that enhance the bioavailability of lipophilic cannabinoids such as cannabidiol (CBD), owing to their amphiphilic structure. A CBD-rich extract with a high content of CDs (high-chlorophyll extract) exhibited a 1.59-fold increase in aqueous dispersibility of CBD compared to an extract with a similar cannabinoid profile but lower CD content (low-chlorophyll extract) (p < 0.01). Enrichment of the low-chlorophyll extract with either a pheophytin-rich fraction derived from the high-chlorophyll extract or with purified pheophytin significantly improved CBD dispersibility, reaching levels comparable to those of the high-chlorophyll extract (p < 0.01). Transmission electron microscopy supported these findings, revealing organized, spherical nanodispersions in the pheophytin-rich or enriched samples. These enhancements translated into improved pharmacokinetic profiles, with more than a two-fold increase in both the maximum plasma concentration and the area under the concentration-time curve (p < 0.05, where applicable) for CBD in rats following oral administration of pheophytin-rich or enriched extracts. Furthermore, these extracts demonstrated superior anticonvulsant efficacy in a pentylenetetrazol-induced seizure model in mice, reducing seizure incidence and latency while increasing survival rates. These findings highlight the therapeutic significance of pheophytins in whole-plant cannabis extracts and challenge the conventional attribution of pharmacological variability among similar cannabis preparations solely to differences in minor cannabinoid content.