An Individuality of Response to Cannabinoids: Challenges in Safety and Efficacy of Cannabis Products

Abstract

Since legalization, cannabis/marijuana has been gaining considerable attention as a functional ingredient in food. ∆-9 tetrahydrocannabinol (THC), cannabidiol (CBD), and other cannabinoids are key bioactive compounds with health benefits. The oral consumption of cannabis transports much less hazardous chemicals than smoking. Nevertheless, the response to cannabis is biphasically dose-dependent (hormesis; a low-dose stimulation and a high-dose inhibition) with wide individuality in responses. Thus, the exact same dose and preparation of cannabis may be beneficial for some but toxic to others. The purpose of this review is to highlight the concept of individual variations in response to cannabinoids, which leads to the challenge of establishing standard safe doses of cannabis products for the general population. The mechanisms of actions, acute and chronic toxicities, and factors affecting responses to cannabis products are updated. Based on the literature review, we found that the response to cannabis products depends on exposure factors (delivery route, duration, frequency, and interactions with food and drugs), individual factors (age, sex), and susceptibility factors (genetic polymorphisms of cannabinoid receptor gene, N-acylethanolamine-hydrolyzing enzymes, THC-metabolizing enzymes, and epigenetic regulations). Owing to the individuality of responses, the safest way to use cannabis-containing food products is to start low, go slow, and stay low.

Keywords: cannabis; functional food; genetic polymorphism; hormesis; individual variation; response; toxicity.

Figure 1

The biphasic-dose-response concept of cannabinoids’ effects on an individual. The blue line represents the theoretical dose-response curve between dose and health effects regarding benefits and toxicity. The vertical dash line indicates the optimum dose to provide health benefits. The range of health-beneficial doses is presented in the hermetic zone. The green and red lines represent the trends in sensitive and tolerant populations, respectively.

Figure 2

Factors influencing acute and chronic cannabis toxicity in an individual. (a) Depending on the species, the amounts of CBD and the psychoactive component THC can vary. (b) The toxicity of cannabis depends on exposure factors (route of exposure, duration, frequency, and method of use), individuality factors (age, sex, and genetic differences), and individual susceptibility factors (genetic polymorphism and epigenetics).