The Polypharmacological Effects of Cannabidiol

Abstract

Cannabidiol (CBD) is a major phytocannabinoid present in Cannabis sativa (Linneo, 1753). This naturally occurring secondary metabolite does not induce intoxication or exhibit the characteristic profile of drugs of abuse from cannabis like Δ9-tetrahydrocannabinol (∆9-THC) does. In contrast to ∆9-THC, our knowledge of the neuro-molecular mechanisms of CBD is limited, and its pharmacology, which appears to be complex, has not yet been fully elucidated. The study of the pharmacological effects of CBD has grown exponentially in recent years, making it necessary to generate frequently updated reports on this important metabolite. In this article, a rationalized integration of the mechanisms of action of CBD on molecular targets and pharmacological implications in animal models and human diseases, such as epilepsy, pain, neuropsychiatric disorders, Alzheimer’s disease, and inflammatory diseases, are presented. We identify around 56 different molecular targets for CBD, including enzymes and ion channels/metabotropic receptors involved in neurologic conditions. Herein, we compiled the knowledge found in the scientific literature on the multiple mechanisms of actions of CBD. The in vitro and in vivo findings are essential for fully understanding the polypharmacological nature of this natural product.

Direct Inhibition of BK Channels by Cannabidiol, One of the Principal Therapeutic Cannabinoids Derived from Cannabis sativa

“…Most of these mechanisms involve the inhibition of different voltage-operated operated ion channels. 3,12 The blockage of voltage-gated sodium (Na V ) channels, responsible for the depolarization phase of the action potential, is the most common mechanism of action for anticonvulsant drugs. 9 Notably, CBD has been shown to inhibit all the Na V isoforms expressed in the central nervous system (Na 4 Similarly, Ttype calcium channels, which are involved in various neuronal processes like low-threshold calcium spiking, neuronal pacemaker activity, and modulation of basal calcium levels in neurons and presynaptic terminals, are also inhibited by antiepileptic drugs and CBD at sub-micromolar concentrations.…”

“…The low concentration range at which CBD inhibits BK channels suggests a potential synergistic effect with other previously described anticonvulsant mechanisms, ultimately reducing neuronal excitability. Most of these mechanisms involve the inhibition of different voltage-operated operated ion channels. , The blockage of voltage-gated sodium (Na V ) channels, responsible for the depolarization phase of the action potential, is the most common mechanism of action for anticonvulsant drugs . Notably, CBD has been shown to inhibit all the Na V isoforms expressed in the central nervous system (Na V 1.1, Na V 1.2, Na V 1.3, and Na V 1.6) .…”

“…Diverging from tetrahydrocannabinol, CBD exhibits a low affinity for endocannabinoid receptors, but it is associated with many other potential biological targets. In particular, CBD directly binds and modulates ion channels with substantial structural differences such as the pentameric ligand-gated ionotropic receptors and tetrameric voltage-operated channels (recently reviewed by Castillo-Arellano et al) Within the latter, electrophysiological studies have shown that CBD exhibits inhibitory effects on certain voltage-dependent ion channels (e.g., Na V , T-type Ca V , and K V 2.1) at low-micromolar or submicromolar IC 50 values, while others (e.g., HCN1 and TRP) are activated at similar concentrations. − Nevertheless, the full spectrum of ion channels modulated by CBD remains unknown, including actions that could potentially explain its therapeutic effects.…”

CBD enhances the cognitive score of adolescent rats prenatally exposed to THC and fine-tunes relevant effectors of hippocampal plasticity

“…Actually, multiple other receptors, channels, and systems can be involved as putative targets for CBD buffering activity in our experimental conditions, such as, but not only, adenosine-, GABA-A, and serotonin receptors (Sylantyev et al, 2013;Aso et al, 2019;De Gregorio et al, 2019). Indeed, we do not aim at reviewing CBD pharmacological properties (for a complete review see Castillo-Arellano et al, 2023), although the investigation of the causal interpretation of the current results is in progress. This research adds significant behavioral and molecular evidence to the increasing reports of pTHC-induced detrimental effects on cognitive functions, and stresses the importance of a collective endeavor to curb gestational cannabis use (Groff et al, 2023).…”

Morphine-induced side effects can be differentially modulated by cannabidiol in male and female rats

“…Cannabidiol (CBD), the second most prevalent compound present in the Cannabis plant, has shown to produce a wide range of therapeutic effects such as antiinflammatory, antioxidant [24], anxiolytic and antidepressant [25,26] and efficacy in substance use disorder [27]. CBD does not show to interact as a direct agonist or antagonist on cannabinoid receptors, but rather as an allosteric modulator in cannabinoid and opioid receptors [28]. In addition, CBD does not show reinforcing effects by itself, and can also reduce the rewarding characteristic of drugs of abuse, such as cocaine and opioids, by mechanisms involving 5-HT1A and TRPV1 receptors, for instance [29][30][31].…”