Immune Responses Regulated by Cannabidiol
James M. Nichols and Barbara L.F. Kaplan
Cannabis and Cannabinoid Research, 2019, Volume X, Number X
Doi : 10.1089/can.2018.0073
Introduction : Cannabidiol (CBD) as Epidiolex (GW Pharmaceuticals) was recently approved by the U.S. Food and Drug Administration (FDA) to treat rare forms of epilepsy in patients 2 years of age and older. Together with the increased societal acceptance of recreational cannabis and CBD oil for putative medical use in many states, the exposure to CBD is increasing, even though all of its biological effects are not understood. Once such example is the ability of CBD to be anti-inflammatory and immune suppressive, so the purpose of this review is to summarize effects and mechanisms of CBD in the immune system. It includes a consideration of reports identifying receptors through which CBD acts, since the ‘‘CBD receptor,’’ if a single one exists, has not been definitively identified for the myriad immune system effects. The review then provides a summary of in vivo and in vitro effects in the immune system, in autoimmune models, with a focus on experimental autoimmune encephalomyelitis, and ends with identification of knowledge gaps.
Conclusion : Overall, the data overwhelmingly support the notion that CBD is immune suppressive and that the mechanisms involve direct suppression of activation of various immune cell types, induction of apoptosis, and promotion of regulatory cells, which, in turn, control other immune cell targets.
Keywords : cannabidiol; immune response; inflammation
Cannabidiol History and Therapeutic Uses
Cannabidiol (CBD) is a plant-derived cannabinoid that has structural similarity to the primary psychotropic congener in cannabis, D9-tetrahydrocannabinol (THC). While CBD was initially isolated in the 1940s, its structure was not elucidated until the 1960s.1,2 Unlike THC, CBD is bicyclic, comprised a terpene and an aromatic ring, and is a pentyl side chain.1 It exists as two enantiomers, and it is ()CBD3 that is one of the major constituents found in Cannabis sp., and will be the focus of this review. For
many years, THC and CBD were designated as psychoactive and nonpsychoactive, respectively, owing to the fact that THC produces the euphoric high associated with cannabis use, while CBD does not. However, since we know that CBD produces biological effects in the central nervous system (CNS), perhaps it is better defined as psychoactive, but not psychotropic, since it is active in the CNS without producing the euphoric high.
Perhaps itwas the association of the euphoric high with THC that provided the initial focus on THC as opposed to CBD for potential medical use, since THC was originally identified as the active component of the plant.4 However, in recent years, researchers have begun to explore CBD more as a therapeutic addition or alternative to THC. In the United States, oral THC (dronabinol, Marinol) was first approved in 1985 by the Food and Drug Administration (FDA) to treat nausea and vomiting associated with chemotherapy. In 1992, dronabinol was also approved to treat cachexia in AIDS patients.5 The next major advancement in cannabinoid pharmaceuticals was not until the mid-2000s when Sativex (nabiximols), a combination of THC and CBD as an oromucosal spray, was approved in Canada and the EU for neuropathic pain in multiple sclerosis (MS) and intractable cancer pain.6 There are several reasons why combining THC and CBD in a single therapeutic could have value.6 First, additional therapeutic benefit might be gained from hitting multiple targets; for example, if THC alleviates
pain and CBD alleviates anxiety,7–16 the combination therapy could be quite effective for chronic pain sufferers.
Second, for disease states in which both THC and CBD are efficacious, a combination might allow for lower doses of THC, thereby potentially decreasing the psychotropic effects of THC. Third, there are some studies suggesting pharmacokinetic interactions between CBD and THC in which CBD treatment increases THC levels, 17–20 thereby allowing longer duration of effects of THC. Sativex has been evaluated in several clinical trials for spasticity associated with MS, neuropathic pain, and other conditions.21–37
The latest approved cannabinoid pharmaceutical in the United States is CBD as Epidiolex. It was approved by the U.S. FDA in 2018 for epilepsy in children, in particular, for Dravet Syndrome and Lennox-Gastaut Syndrome.38–42 CBD is also being investigated for its effectiveness in other diseases, including Tuberous Sclerosis, a genetic condition that causes growth of benign tumors all over the body,43,44 schizophrenia,45 and refractory epileptic encephalopathy.46 In addition to the federally approved uses ofCBDas Epidolex, CBD, usually as CBD oil, is widely used for putative medical benefit in several states, and is certainly used in states in which cannabis has been decriminalized, or legalized,
for recreational use.47 There are reports that CBD and other cannabinoids are beneficial for sleep, anxiety, pain, post-traumatic stress disorder, schizophrenia, neurodegenerative disorders, and immune-mediated diseases.48 Often these conditions are self-diagnosed and self-treated, so there can be issues with dosing, other drug interactions, and characterization of CBD safety and efficacy.
Overall, it is clear that exposures to CBD are increasing. 47,49–51 It is also clear that CBD possesses therapeutic benefit, and in some cases, the beneficial effects of CBD are for diseases for which other available treatments have not been efficacious.52 Together, these observations demonstrate the critical need to continue research on CBD, and therefore the goal of this review is to provide a summary of the effects and mechanisms by which CBD alters immune function. The review will include an evaluation of the role for various receptors through which CBD acts in the immune system. There will also be a description of CBD effects in animal and human immune responses, a characterization of mechanisms by which CBD mediates immune effects, and identification of knowledge gaps regarding CBD’s actions in the immune system.