Study: Combining CBD and CBG Cuts Effective CBD Seizure Dose in Half in Standard Epilepsy Model

New research published in Basic & Clinical Pharmacology & Toxicology by scientists at the University of Toronto found that the non-psychoactive cannabinoids cannabidiol (CBD) and cannabigerol (CBG) both suppress seizures on their own and, when combined, significantly reduce the amount of CBD needed to achieve seizure protection. Using the well-established maximal electroshock seizure (MES) model in mice—a standard screening tool for antiseizure drugs—researchers generated full dose–response and dose-toxicity curves for CBD alone, CBG alone, and a 1:1 combination of the two. The goal was to determine whether CBG could enhance CBD’s antiseizure effects without introducing the psychotoxic issues associated with tetrahydrocannabinol (THC), which has previously been shown to potentiate CBD but is unsuitable for clinical use due to its psychoactive effects.

Both cannabinoids demonstrated clear antiseizure activity when administered individually. The effective dose required to protect 50% of animals from seizures (ED50) was 133 mg/kg for CBD and 149 mg/kg for CBG—remarkably similar values. Toxicity did not appear until much higher doses, with CBD showing a TD50 (toxic dose for 50% of animals) of 560 mg/kg and CBG a TD50 of 544 mg/kg.

The key finding came when the two cannabinoids were combined. In a 1:1 ratio, the ED50 for CBD dropped from 133 mg/kg to just 60 mg/kg—a reduction of more than 50%. In other words, much lower doses of CBD were required to achieve the same level of seizure protection when CBG was present.

At the same time, toxicity thresholds also shifted. The TD50 for CBD in the combination fell to 320 mg/kg, about 40% lower than CBD alone. Despite this, the overall therapeutic index—the balance between effective and toxic doses—actually improved when the two were combined, suggesting a more favorable efficacy-to-toxicity profile.

Isobologram analysis indicated that the interaction between CBD and CBG was likely additive rather than synergistic. This means the two compounds appear to work through similar mechanisms that compound each other’s effects, rather than producing a supra-additive effect seen in some CBD-THC studies. Researchers point to shared actions on voltage-gated sodium channels, TRPV1 receptors, and PPARγ pathways as plausible explanations for the overlapping antiseizure activity.

Importantly, when sub-effective doses of each drug were given together, seizure protection increased dramatically without observable toxicity at those levels. Doses of CBD and CBG that produced little protection individually became highly effective in combination.

The study also highlights a critical gap in cannabinoid research: this is the first time detailed dose–response and toxicity data have been published for CBG in a seizure model, and the first to examine its interaction with CBD in this context.

While the work was conducted in mice, the findings have meaningful clinical implications. CBD is already approved for certain severe forms of epilepsy, but its effectiveness is often limited by the high doses required and associated side effects such as sedation and liver enzyme elevation. A strategy that cuts the required CBD dose in half could improve tolerability for patients.

Researchers caution that additional studies are needed, particularly in other seizure models and with pharmacokinetic measurements, to determine how these findings translate to humans. However, the data suggest that CBG could serve as a practical, non-psychoactive adjunct to CBD therapy, potentially improving outcomes for patients whose seizures are not fully controlled with CBD alone.