Study Finds CBN and CBG With Melatonin Enhance Chemotherapy Against Glioblastoma Cells

A new study found that the marijuana compounds cannabinol (CBN) and cannabigerol (CBG), when combined with melatonin, produced synergistic effects against human glioblastoma cells and significantly enhanced the effectiveness of a commonly used chemotherapy drug.

The study, published in the International Journal of Molecular Sciences by researchers primarily from the University of Camerino in Italy, examined CBN and CBG in combination with melatonin against three genetically distinct human glioblastoma cell lines: U87, T98 and U251. Researchers also tested the treatments on normal human astrocytes to evaluate their selectivity toward cancer cells.

Both CBN-melatonin and CBG-melatonin combinations produced synergistic reductions in glioblastoma cell viability, with the strongest effects generally occurring at intermediate to higher concentrations. The effects occurred in both p53 wild-type and p53-mutated or deficient cells, which researchers said is particularly noteworthy because p53 mutations can contribute to resistance to conventional chemotherapy.

When tested on healthy astrocytes, the treatments generally showed greater toxicity toward glioblastoma cells than healthy cells, although the degree of selectivity varied substantially between combinations and cell lines. Selectivity index values ranged from 1.0, indicating no preferential toxicity, to just over 2.0, indicating roughly twice the effect against cancer cells.

Researchers also investigated how the combinations killed the cancer cells. Rather than triggering apoptosis, the treatments caused a necrotic form of cell death associated with severe double-strand DNA damage. The combinations produced an early increase in reactive oxygen species, disrupted mitochondrial membrane potential and mitochondrial mass, and in certain cell lines caused substantial lipid peroxidation. CBN-based combinations generally produced more pronounced biochemical effects than those containing CBG.

The researchers then combined the cannabinoid-melatonin treatments with temozolomide (TMZ), a chemotherapy drug used in standard glioblastoma treatment. TMZ alone produced a moderate reduction in cell viability, but adding either cannabinoid-melatonin regimen significantly increased the inhibitory effect. The three-drug combination of TMZ, melatonin and CBN produced lower cell viability than either TMZ alone or melatonin and CBN without chemotherapy across all three glioblastoma cell lines. Similar enhanced effects were observed with the TMZ-melatonin-CBG combination.

The findings remain preclinical. Researchers noted that the experiments were conducted entirely in cell cultures and therefore cannot reproduce the complex environment of a tumor in the human brain. They also cited drug delivery as a significant challenge, including the poor aqueous solubility and rapid metabolism of CBN and CBG and the short plasma half-life of melatonin. Animal studies will be needed to evaluate brain penetration, pharmacokinetics, safety and effectiveness before clinical trials can be considered.

Researchers said the findings provide a strong preclinical foundation for further investigation of minor cannabinoids and melatonin as a way to complement conventional glioblastoma treatment, particularly by potentially increasing the effectiveness of temozolomide.