Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb

Δ⁹-tetrahydrocannabinol binds cannabinoid (CB₁ and CB₂) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Δ⁹-tetrahydrocannabinol, which are mediated by activation of brain CB₁ receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Δ⁹-tetrahydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Δ⁹-tetrahydrocannabivarin, a novel CB₁ antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.

Introduction

The plant Cannabis sativa produces over 421 chemical compounds, including about 80 terpeno-phenol compounds named phytocannabinoids that have not been detected in any other plant 1, 2, 3, 4. For obvious reasons, most attention has been paid to Δ⁹-tetrahydrocannabinol (Δ⁹-THC), which is the most psychotropic component and binds specific G-protein-coupled receptors named cannabinoid (CB₁ and CB₂) receptors 5, 6. The discovery of a specific cell membrane receptor for Δ⁹-THC was followed by isolation and identification of endogenous (animal) ligands termed endocannabinoids. The two main endocannabinoids are anandamide (which is metabolized mostly by fatty acid amide hydrolase (FAAH)) and 2-arachidonoylglycerol (which is mostly degraded by monoglyceride lipase (MAGL)) 5, 6. Cannabinoid receptors, endogenous ligands that activate them, and the mechanisms for endocannabinoid biosynthesis and inactivation constitute the “endocannabinoid system”. With its ability to modulate several physiological and pathophysiological processes (e.g. neurotransmitter release in the central and peripheral nervous system, pain perception, and cardiovascular, gastrointestinal and liver functions), the endocannabinoid system represents a potential target for pharmacotherapy [6]. Strategies to improve the efficacy and/or the risk–benefit ratio of drugs that manipulate the endocannabinoid system include the targeting of cannabinoid receptors located outside the blood–brain barrier with selective cannabinoid ligands or compounds that prevent endocannabinoid degradation (e.g. inhibitors of FAAH or MAGL) 5, 6.

In addition to pharmacological modulation of the endocannabinoid system, a different approach to minimize the well-known psychotropic side effects of Cannabis is the use of phytocannabinoids with very weak or no psychotropic effects. These include cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), Δ⁹-tetrahydrocannabivarin (Δ⁹-THCV), cannabidivarin (CBDV) as well as cannabinoid acids such as Δ⁹-tetrahydrocannabinolic acid (Δ⁹-THCA) and cannabidiolic acid (CBDA) (Box 1). These compounds exert multiple actions through mechanisms which are only partially related to modulation of the endocannabinoid system 1, 2. The most promising of this class of safe compounds is CBD. CBD exerts several positive pharmacological effects that make it a highly attractive therapeutic entity in inflammation, diabetes, cancer and affective or neurodegenerative diseases 1, 2, 7, 8. More recently, Δ⁹-THCV has been shown to express the pharmacological profile of a CB₁ antagonist [9], with potential use in obesity treatment [2].

Here, we focus on recent developments in the preclinical pharmacology of non-psychotropic phytocannabinoids. We highlight the novel biochemical/pharmacological advances, mechanisms of action, and possible therapeutic uses of these plant-derived compounds.