Morelli, M.B.; Cameli, G.; Giangrossi, M.; Zeppa, L.; Luongo, M.; Amantini, C.; Nabissi, M. Synergistic In Vitro Effects of Minor Phytocannabinoids and Melatonin Combinations Against Human Glioblastoma Cells. Int. J. Mol. Sci. 2026, 27, 6774. https://doi.org/10.3390/ijms27156774

Combining melatonin with either CBN or CBG creates a potent synergistic effect that kills glioblastoma cells while largely sparing healthy brain cells—and significantly enhances the effectiveness of standard chemotherapy (results obtained in cell culture models).

Melatonin has demonstrated remarkable anti-cancer properties:

Inhibits GBM cell proliferation
Induces cell cycle arrest
Modulates key oncogenic pathways

Minor cannabinoids like CBN and CBG are increasingly recognized for their therapeutic potential:

CBN (Cannabinol):

Formed through oxidative degradation of THC
Only ~10% of THC's psychoactive potency
Modulates TRP channels (TRPV1–4, TRPA1)
Demonstrates anti-inflammatory, analgesic, and antibacterial properties

CBG (Cannabigerol):

Non-psychoactive
Acts as a weak partial agonist at CB1 and CB2 receptors
Activates TRPV1–4 and TRPA1 channels
Interacts with 5-HT1A and α2-adrenergic receptors

Synergy:

Both melatonin and phytocannabinoids:
Cross the blood-brain barrier
Target different receptor systems (MT1/MT2 for melatonin; CB1/CB2 and TRP channels for cannabinoids)
Have neuroprotective profiles in healthy tissues

The researchers hypothesized that hitting multiple pathways simultaneously could overcome glioblastoma's notorious ability to develop resistance.

When tested alone, melatonin, CBN, and CBG each reduced GBM cell viability—but only at relatively high concentrations. However, when combined at lower doses, the researchers observed significant synergy across three genetically distinct GBM cell lines (U87, T98, and U251).

These combinations showed preferential toxicity toward cancer cells while sparing normal human astrocytes. The Net Selectivity Index (SI) reached values up to 2.05, meaning the combinations were up to twice as toxic to GBM cells as to healthy brain cells.

When the combinations killed cancer cells, they did so through necrotic cell death rather than apoptosis (programmed cell death).

Adding the melatonin-cannabinoid combinations to standard temozolomide (TMZ) chemotherapy significantly outperformed TMZ alone and the two-compound combinations.