Expanding the therapeutic dose range of cannabinoid-based therapy

Cannabidiol (CBD) is a non-intoxicating phytocannabinoid with numerous purported therapeutic benefits for a range of medical indications. While human clinical trials have been inconsistent in their demonstration of these benefits, pre-clinical rodent studies that implement a more comprehensive dose-response assessment have often revealed a narrow dose efficacy range that is often symptom-dependent. This narrow dose-efficacy range presents a challenge for implementing CBD-based treatment strategies because a) it is difficult to identify and maintain an efficacious dose, and b) treating multiple symptoms simultaneously with the same dose may be impossible depending on the symptom’s dose-response characteristics. Identifying pharmacological strategies for expanding this dose-efficacy range is critical for improving the therapeutic utility of CBD.

CBD has a complex pharmacodynamic profile with potential disease-relevant targets across a spectrum of enzymes, transporters, ion channels, and receptors. Many of these targets have different EC50 or IC50s, enabling CBD to affect an increasing number of targets with escalating dose leading to an onset of therapeutic benefit or a counteraction. However, this pharmacodynamic profile may be an opportunity for pharmacological optimization.

The “Entourage Effect Hypothesis” states that multiple cannabis-derived compounds enhance the effect of a phytocannabinoid in isolate. If so, then systematic addition of less-abundant phytocannabinoids or other plant-derived chemicals, such as the volatile organic compounds, colloquially referred to as “terpenes”, may enhance the therapeutic range and benefits of CBD alone by extending its dose-efficacy range.

Despite a few recent demonstrations that whole-plant oils are therapeutically superior than CBD isolate, there is little empirically-based guidance for the creation of CBD-based compounds that confer superior therapeutic outcomes. These superior outcomes may stem from a wider dose-response range, or the ability to control multiple symptoms using the same dose. For example, control of epileptic seizures that normally requires a high dose of CBD while simultaneously controlling symptoms associated with comorbid autism spectrum disorder that respond to substantially lower doses of CBD and where benefits are lost at higher doses.

Through this Research Topic, we seek to address key challenges associated with CBD dosing by promoting research into strategies that improve its dose-efficacy relationship and provide symptom management across different conditions with disparate and narrow dose-response ranges. The research published here will direct the development of CBD-based medicines and inform dosing guidelines that are critical for its overall therapeutic utility.

To achieve the aims of this special issue, we particularly welcome submission of original research, review, and perspective articles on the following topics:

- CBD dose-efficacy relationships

- Phytocannabinoid compositions or integration of cannabis-expressing volatile organic compounds

- CBD administration or delivery methods

- Pre-clinical and clinical use of CBD and CBD-based medicines with an emphasis on dose, composition, and symptom management