This unjustly demonized plant is about to change the scope of medicine and disease management as we know it.
Historical Maligning of Marijuana
Although legalizing recreational marijuana is a polarizing political issue, the ceremonial and medicinal use of this botanical agent dates back thousands of years (1). Paleobotanical, anthropological, and ethnographic records date the first human interactions with marijuana to 11,000 years ago, in the Holocene era, when human groups in the Eurasian continent used the seeds and stalks as sources of food and fiber, and the resin-laden female flowers within spiritual contexts (2, 3, 4). According to Wei and colleagues (2017), the medicinal actions, as well as the heightened euphoria, modified time perception, intensified sensation, and sense of tranquility produced by consuming the flowers or inhaling their smoke was “intimately woven into religious ritual” (p. 1). Marijuana was likewise used to cement social bonding during weddings, funerals, supernatural rites, and festivals, from cultures ranging to the Scythians inhabiting the Eurasian steppe to the Hindus of the Himalayan mountains (5).
Nonetheless, the plant has been embroiled in a miasma of mythology and its reputation tarnished by its affiliation with counterculture, a segment of the population to which policymakers have harbored historical animus. According to Schafer (1972), “Many see the drug as fostering a counterculture which conflicts with basic moral precepts as well as with the operating functions of our society….Marihuana becomes more than a drug; it becomes a symbol of the rejection of cherished values” (p. 9).
Despite its extensive medical use in the United States into the twentieth century, marijuana became entangled with negative cultural connotations and hyperbolic rhetoric after Nixon passed the Controlled Substances Act, which exiled the plant to Schedule One status alongside heroin, mescaline, psilocybin, and LSD, with the implication that marijuana was devoid of medicinal properties, fraught with high abuse potential, and would be inaccessible for clinical research trials (7, 8). The Shafer Commission, appointed to perform a non-partisan, independent appraisal of marijuana, made a formal recommendation that its Schedule One status be repealed, but this was rejected by President Nixon, and future appeals in the matter by independent agencies, advocacy groups, and political leaders have likewise been denied (9).
Prior to the mid-twentieth century, marijuana use was, “…mainly confined to underprivileged socioeconomic groups in our cities and to certain insulated social groups, such as jazz musicians and artists,” such that marijuana became conflated with cohorts marginalized by society (6, p.7). However, in the mid-1960s, marijuana use began to encompass mainstream sectors, and became emblematic of a broader social movement, a symbolic rite of protest, challenge to authority, and political demonstration for those involved in anti-war and civil rights efforts (6). Marijuana was adopted as both an “agent of group solidarity” and an instrument of political activism, and became equated with intergenerational and cultural divide as well as “disaffection with traditional society,” “political radicalism,” and “defiance of the established order” (6, p.10).
Due to its demonization by the Nixon administration during their infamous war on drugs, marijuana was relegated to the realm of street crime, and became ensnared with legal penalties, affixed with false stereotypes, and had its side effects sensationalized. False propaganda surrounding its use lingered after the federal prohibition of marijuana in 1937, such that marijuana instilled fear in the public (6). The erroneous narrative surrounding its side effects included aggressive behavior, juvenile delinquency, crime, addiction, insanity, and lethality (6, p. 9). In fact, the independent research panel appointed by Nixon described, “Although based much more on fantasy than on proven fact, the marihuana ‘evils’ took root in the public mind, and now continue to color the public reaction to the marihuana phenomenon” (6, p. 9).
The Schafer Report, submitted to Nixon to repeal its Class One status, chronicles how the association between marijuana and the undermining of the prevailing social hierarchy led to the plant’s fall from grace, as “Such mass deviance was a problem and the scope of the problem was augmented by frequent publicity” (6, p. 8). Thus, when interpreted against the backdrop of institutional defiance, sociopolitical turbulence, campus unrest, communal living, and abdication of traditional moral values, the historical origins of the vitriol against marijuana use by more conservative segments of the population can be contextualized.
The Endocannabinoid System Rekindles Scientific Interest
The early 1990s, however, heralded the discovery of the mammalian endocannabinoid system, comprised of two heterotrimeric G-protein coupled cannabinoid receptors, CB1 and CB2, along with their endogenous lipid-derived ligands, the most important of which were arachidonylethanolamide (anandamide) and 2-arachidonyl glycerol (2-AG) (10). This lipid-signaling regulatory system was based on endocannabinoids derived from arachidonic acid metabolites, which are generated on demand in response to escalating levels of intracellular calcium from phospholipids residing in the lipid bilayer of cell membranes (11).
The revolutionary insight that humans have an endocannabinoid system, which controls executive function, mood, social behavior, and pain, is conserved from invertebrates to high mammals, and can be activated by cannabinoids in marijuana, renewed interest in its medicinal applications (5, 52). Advances in this field of study engendered a platform for the examination of the therapeutic effects of cannabinoids (11).
Marijuana primarily refers to the species Cannabis sativa, Cannabis indica, and Cannabis ruderalis, whereas Cannabis species lacking psychoactive cannabinoids are classified as hemp, which has been used historically for industrial production of ropes and textiles (7, 6, 8). Approximately one hundred pharmacologically active cannabinoids have been isolated; however, the bulk of scientific research has revolved around two, ∆9-tetrahydrocannabinol (THC), to which the ‘high’ is attributed, and cannabidiol (CBD), which does not produce this psychoactive effect and may in fact counteract it (12).
It was discovered that CB1 cannabinoid receptors are heterogeneously expressed in the central and peripheral nervous systems, and are particularly enriched in areas of the brain such as the cerebellum, cerebral cortex, caudate-putamen, hippocampus, substantia nigra pars reticulata, entopeduncular nucleus, and globus pallidus (10). CB1 receptors are particularly concentrated in regions of the brain that modulate nociception, motor function, and higher executive functions such as memory and cognition (13).
On the other hand, CB2 cannabinoid receptors are primarily localized in non-neuronal tissues, especially immune cells, where they mediate immunosuppressive effects and inhibit pain transmission (13, 10). However, both CB1 and CB2 receptors have been found on immune cells, supporting the notion that cannabinoids contribute to immunoregulation (11). Whereas CBD lacks significant agonist activity at CB1 receptors, which explains its non-psychotropic effects, Δ9-tetrahydrocannabinol (THC), the psychoactive component of marijuana, exhibits comparable activity at both the CB1 and CB2 receptors (10).
Although the endocannabinoid system regulates the autonomic nervous system, microcirculation, and immunity in the periphery, “Studies to date indicate that the main pharmacological function of the endocannabinoid system is in neuromodulation: controlling motor functions, cognition, emotional responses, homeostasis and motivation” (11, p. 2).
Anti-Inflammatory Effects of Cannabinoids
Cannabinoids have been demonstrated to have immunomodulatory effects, and are now being re-conceived as novel anti-inflammatory drugs (11). Although cannabinoids are pleiotropic, functioning through multiple mechanisms, recent studies have elucidated that cannabinoids induce apoptosis, or programmed cell death, in immune cell populations, a process involving molecular and morphological changes required for physiological equilibrium and immunosuppression (14).
In vitro studies have elucidated that THC provokes apoptosis in macrophages and T cells by activating caspases and the apoptosis regulator Bcl-2 (15). Likewise, ex vivo studies have shown that THC is capable of inducing apoptosis in T cell, B cell, and macrophage lineages (51). Importantly, THC has been shown to precipitate apoptosis in dendritic cells, the foremost professional antigen presenting cells that modulate maturation of naive T lymphocytes into effector T cells such as Th1, Th2, or Th17 cells, which can elicit the immune imbalances implicated in autoimmunity (11). CBD also leads to apoptosis of CD4+ and CD8+ T cells by promoting reactive oxygen species (ROS) production and up-regulating activity of caspases, which are integral to the execution phases of apoptosis (16).
On the other hand, “Cannabinoids can protect from apoptosis in nontransformed cells of the CNS, which can play a protective role in autoimmune conditions such as multiple sclerosis” (11, p. 3). Specifically, cannabinoids enhance signaling through the PI3K/AKT pathway, which regulates the cell cycle and promotes brain growth and differentiation (11, 2009). Cannabinoids also inhibit apoptosis of oligodendrocytes, a subset of neuroglial cells injured in multiple sclerosis, which are responsible for producing the myelin sheath, or the fatty insulation of nerves that allows for conduction of electrochemical signals (17, 11).
In addition, although results are highly variable depending on cell population and cannabinoid concentration, cannabinoids have been demonstrated to reduce synthesis of inflammatory intercellular messenger molecules known as cytokines and chemokines, which contribute to the pathogenesis of autoimmune disease. THC, for instance, has been observed to suppress the expression of pro-inflammatory interleukins (ILs) IL-1α, IL-1β, and IL-6, as well as tumor necrosis factor alpha (TNF-α) in cultured rat microglial cells exposed to lipolysaccharide (LPS), the outer cell wall component of Gram-negative bacteria that is implicated in autoimmune and cardiometabolic disorders (18). In similar fashion, synthetic cannabinoids WIN55,212-2 and HU210 reduce synthesis of pro-inflammatory TNF-α and IL-12 while increasing levels of anti-inflammatory IL-10 in a rodent model of LPS challenge (19).
In other studies, CBD blocks the LPS-induced increase in TNF-α in mouse models (20). Moreover, synthetic cannabinoids such as AjA, CP55,940 and WIN55,212-2 have been shown to reduce secretion of IL-6, an inflammatory cytokine that contributes to tissue injury (11). Thus, researchers suggest that these cannabinoid compounds “may have a value for treatment of joint inflammation in patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and osteoarthritis” (11, p. 4).
Importantly, some studies have shown that cannabinoids up-regulate activity of FOXP3+ regulatory T cells (Tregs), a subset of immune cells depleted in autoimmunity which promote peripheral immune tolerance, and restore equilibrium between the Th1, Th2, and Th17 arms of the immune system (11). For instance, in response to low-level stimulation of T cells, CBD up-regulates IL-2 production, which is essential for induction of Treg activity along with TGF-β1 (21). Dhital and colleagues (2017) illustrated that CBD increases populations of Tregs, which results in immunosuppression via robust inhibition of T cell proliferation, effectively protracting the production of lymphocyte populations underlying autoimmune etiology (21).
Lastly, CBD has been shown to inhibit nuclear factor kappa beta (NFκB), a pathway that can be over-active in autoimmune disease (22). NFκB is a master transcription factor that controls hundreds of genes for innate immunity and leads to the expression of downstream pro-inflammatory products (22).
Therapeutic Application to Autoimmune Disease
Cannabinoids are effective in combating many of the hallmark symptoms that accompany autoimmune disease, such as mood disturbance. For example, a double-blind human study revealed that CBD modulates neural activity in the limbic and paralimbic systems to significantly reduce subjective anxiety (23). Likewise, CBD may improve motivation and reduce clinical depression and anhedonia (53). Case series and a meta-analysis of eighteen studies have highlighted a role for cannabis in improvement of chronic pain and sleep as well (24, 25). In addition, cannabinoids may improve an array of organ- and tissue-specific autoimmune disorders.
Potent anti-arthritic properties of cannabinoids have been demonstrated such that their use may be indicated for rheumatoid arthritis (RA), an autoimmune disorder where immune complexes are deposited in the joints, leading to progressive joint pain, stiffness, and deformity. In particular, CBD has been shown to prevent disease progression and protect joints against severe damage in rodent collagen-induced arthritis (20). Ex vivo studies of animal models of rheumatoid arthritis have demonstrated attenuation of immunoproliferative responses in draining lymph nodes with CBD, as well as a reduction in interferon gamma (IFN-γ) production, and diminished release of TNF by knee synovial cells (20). Mitogen-stimulated and antigen-specific clonal expansion of lymphocyte populations was also suppressed by CBD in vivo (20).
In addition, synthetic cannabinoids such as AjA have been shown to reduce secretion of IL-6, and to protect against osteoclastogenesis, or the creation of cells associated with bone resorption (26, 27). AjA also suppresses production of an inflammatory cytokine, IL-1β, in peripheral blood monocytes (PBMs) and synovial fluid monocytes (SFMs) extracted from patients with RA (28).
Type 1 Diabetes
Another autoimmune condition where cannabinoids hold therapeutic promise is type 1 diabetes mellitus (TIDM), or insulin-dependent diabetes, where autoimmune processes result in loss of insulin-producing pancreatic β cells. In rodent models of T1D induced by streptozotocin, it was found that THC mitigated the severity of the immune response, transiently prevented hyperglycemia and loss of pancreatic insulin, and decreased expression of pro-inflammatory elements including CD3+ T cells, IL-12, IFN-γ and TNF-α (50).
Inflammatory Bowel Disease
Further, data support that cannabinoids confer protection in two forms of inflammatory bowel disease (IBD), Crohn’s and ulcerative colitis. Crohn’s disease is an autoimmune disorder that generally involves the ileum and colon and can be accompanied by intestinal fistulas, granulomas, and strictures, while ulcerative colitis is an autoimmune disease characterized by inflammation in the colonic mucosa and submucosa (29, 30). According to Nagarkatti et al. (2009), “Cannabinoids have been shown to regulate the tissue response to excessive inflammation in the colon, mediated by both dampening smooth-muscular irritation caused by inflammation and suppressing proinflammatory cytokines, thus controlling the cellular pathways leading to inflammatory responses” (p. 7).
CB1 receptors, for instance, are expressed in the colon and ileum and are increased upon inflammation as a protective mechanism (31). Genetic ablation of CB1 receptors enhances sensitivity to inflammatory stimuli in mice (11). In oral dextran sodium sulfate (DSS)-induced rodent models of colitis, pharmacological antagonists, which block stimulation of CB1 receptors, exacerbated colitis, whereas pharmacological activation of cannabinoid receptors with the agonist HU210 ameliorated colitis (11). Likewise, oil of mustard (OM)-induced colitis and sequelae including inflammatory and histological damage, diarrhea, and colonic weight gain were reduced by CB1- and CB2- selective agonists, ACEA and JWH-133, respectively (32). In addition, mice with genetic deletion of fatty acid amide hydrolase (FAAH), the enzyme that degrades anandamide, have significant protection against 2,4-dinitrobenzene sulfonic acid (DNBS)-induced Crohn’s due to longer half-life of this endogenous cannabinoid, likely leading to increased cannabinoid receptor stimulation (33).
Ocular Manifestations of Autoimmune Disease
In an in vivo model of experimental autoimmune uveoretinitis (EAU), which is an animal model of human autoimmune ocular disorders, JWH-133, a CB2-selective agonist, elicited an immunosuppressive effect (34, 35). This cannabinoid agonist appeared to work through down-regulation of antigen presentation and T cell proliferation and favorable alterations in cytokine profiles (35, 36). For instance, JWH-133 improved levels of IL-10, which prevents EAU development, and decreased levels of IL-12p40, a cytokine pivotal to EAU pathogenesis (36).
Cannabinoids are likewise useful in arresting two primary steps in the pathogenesis of psoriasis, an autoimmune skin disease characterized by plaques and lesions. A synthetic cannabinoid JWH-133 is able to suppress angiogenic growth factors and inflammatory cytokines including hypoxia inducible factor-1α (HIF-1α), angiopoitin-2, vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), basic fibroblast growth factor (bFGF), cellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), IL-8,IL-17, and IL-2, all of which are etiological factors in psoriasis development (37).
Finally, cannabinoids exert neuroprotective and immunosuppressive effects in multiple sclerosis (MS), a neurological autoimmune disorder wherein nerve fibers and axons are progressively demyelinated (11). At least eight clinical studies have illuminated the benefits of cannabis, THC, and the cannabinoid receptor agonist Nabilone for improving pain, spasticity, tremor, ataxia, and bladder control in MS (38, 39). A survey of 112 MS patients similarly showed that using cannabis improved these symptoms, as well as depression, in 90% of individuals (11).
At a molecular level, activation of the CB1 receptor suppresses myelin-specific T cells which infiltrate the brain and spinal cord and are responsible for myelin sheath destruction (40). CB2 cannabinoid agonists such as WIN55,212-2 inhibit experimental autoimmune encephalomyelitis (EAE), an animal model of MS, by mediating apoptosis of the encephalitogenic cells that induce brain inflammation (41). The same cannabinoid agonist works through the nuclear receptor nuclear receptor PPAR-γ to reduce endothelial and vascular cell adhesion molecules expression, which effectively inhibits migration of pathogenic CD4+ T cells into the central nervous system (CNS) (42).
Cannabinoids such as AEA also reduce antigen presentation by microglial cells, the macrophages of the CNS, which drive myelin sheath elimination via production of glutamate, nitric oxide, and inflammatory interleukins (11). AEA further functions via CB2 receptors to suppress production of pro-inflammatory cytokines such as IL-12 and IL-23, which promote Th1 proliferation and maintain destructive Th17 cell populations, respectively (43). The vital immunomodulatory role played by the endocannabinoid system in preventing or mitigating MS is underscored by a study where CB2 knockout mice had exacerbated EAE and robust infiltration of myeloid progenitor cells into neuroinflamed tissue (44). Aberrant trafficking of myeloid progenitors, which can be prevented by cannabinoids, replenishes microglia populations, the cell subset which contributes to myelin sheath damage (44). Lastly, because astrocytes harbor CB1 and CB2 receptors, cannabinoids contribute to immunosuppression of these brain cells, which are responsible for augmenting the inflammatory response in MS via nitric oxide, chemokine, and cytokine production (11).
The Future of Medical Marijuana
Grassroots lobbying efforts, activism, and ballot initiatives have mobilized to repeal draconian laws, reclassify marijuana, and decriminalize its use, resulting in unprecedented medical and recreational access to marijuana in approximately half of the states in the United States (8).
However, in many states, markets are saturated with products unregulated with regard to potency and quality, lacking standardization of their active constituents. Due to cross-breeding, hybridization, and variable cultivation methods, marijuana tends to contain high levels of THC relative to CBD, and unpredictable levels of other cannabinoids (8).
There are several methods of delivery, each of which vary in their onset of action, time to peak effects, and duration of effect (8). Smoking, which “releases the cannabinoid substances into a volatile mixture that is introduced into the lungs via smoke and absorbed though the alveolar membrane and into the pulmonary circulation,” enables compounds to readily translocate across the blood-brain barrier and exert systemic central and peripheral effects (8, p. 241). Although it produces rapid effects and simplifies titration of dose, smoking exposes the user to tar, microbial contaminants, heavy metals, pesticides, and other toxicants, as well as increases the risk of myocardial infarction secondary to coronary artery spasm in susceptible individuals (8). Further, long-term sequelae of marijuana smoking likely include chronic cough, wheezing, increased sputum production, respiratory tract inflammation, and obstruction of air flow (45, 46).
With vaporization, on the other hand, marijuana leaves are heated just below combustion point, liberating the cannabinoids into vapor and eliciting fast acting effects without the concomitant production of airway-damaging smoke (47). In contrast, edibles, which incorporate marijuana into food products such as baked goods, teas, oils, and lozenges, are convenient to administer but are accompanied by a delay between when the product is ingested and when peak drug effects occur, due to first-pass metabolism in the liver before absorption into the nervous system and systemic circulation (12, 48). Tinctures and sprays of plant extract negate this problem due to their absorption through the oral mucosal membranes, which bypasses the liver, generating relatively rapid peak-effects (8).
For those who live in states where medical marijuana is prohibited, or for individuals wanting to avoid psychotropic effects of marijuana, isolated hemp-derived CBD extracts may be a viable option. As summarized by Kogan and Mechoulam (2007), “The therapeutic value of cannabinoids is too high to be put aside…In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable” (49, p. 413).
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