Cannabinoids may elevate therapy for connective tissues diseases to a higher level
Nov. 2, 2017
Medical “reefer madness” is taking hold in the United States with approximately 10% of cannabis users utilizing it for diverse medical conditions, including dermatologic disorders such as pruritus and atopic dermatitis. To date, at least 28 states allow for the use of medical cannabis. (1)
Cannabinoids are diverse chemical compounds that can bind to receptors of the endocannabinoid system. Typed of cannabinoids include: endocannabinoids, when produced by our own body, phytocannabinoids, present naturally in the plant Cannabis sativa, or synthetic cannabinoids. (2) Two specific G-coupled protein receptors known as cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2), and their endogenous ligands (anadamide, 2 acylglycerol), have been identified. CB1 receptors are predominantly located in the central nervous system, mediating the well-known psychoactive effects. CB2 receptors are mostly distributed peripherally, modulating immunological and inflammatory processes. (3)
Optimally, medical use of cannabinoids is non-psychoactive (feel free to argue that point). Are they of value in immunologically-mediated collagen vascular disease?
Ajulemic acid (AjA, 1’1’-dimethylheptyl-THC-11-oic acid) has exhibited potent anti-inflammatory and analgesic effects in several animal models. Parker et al demonstrated that the addition of AjA to human monocyte derived macrophages in vitro reduced steady state levels of IL-6 mRNA and the subsequent secretion of IL-6 from stimulated cells. The authors speculated that AjA could prove to be a safe, effective anti-inflammatory agent, because IL-6 is an important cytokine in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus. (4)
Garcia-Gonzalez et al demonstrated, by protein expression experiments, that both CB1 and CB2 receptors were overexpressed in diffuse systemic sclerosis (DSS) skin fibroblasts compared to healthy control fibroblasts. The incubation of DSS fibroblasts with a synthetic cannabinoid receptor agonist (WIN55, 212- 2) decreased their expression in a dose-dependent manner, together with a parallel reduction in collagen production and pro- fibrotic cytokines, including transforming growth factor-beta (TGF-beta), connective tissue growth factor and interleukin-6 (IL-6). Interestingly, this inhibitory effect was not abrogated by selective cannabinoid receptor antagonism, suggesting that it was not mediated by classical CB1 nor CB2 receptors, but possibly via other receptors, such as PPAR (peroxisome proliferator-activated receptor-gamma). Based on these studies, the authors conducted in vivo experiments in mice with bleomycin-induced dermal fibrosis (a reliable experimental model for scleroderma). The oral administration of AjA prevented the development of skin fibrosis, reducing skin thickness almost to control levels. (3)
AjA has a 65-fold higher affinity for CB2 than CB1, enabling it to be anti-inflammatory without significant psychoactive effects. Robinson et al isolated peripheral blood mononuclear cells from the blood of 18 patients with dermatomyositis, treating them with AjA. They demonstrated that moderate and high AjA concentrations significantly suppressed tumor necrosis factor (TNF)-alpha secretion, whereas all AjA doses significantly reduced interferon (IFN)-alpha and INF-beta production. Because these are key inflammatory cytokines in the pathogenesis of dermatomyositis, the authors suggest that orally administered AjA may be a valuable treatment for these patients.
Much remains to be learned regarding the potential use of cannabinoids for patients with collagen vascular diseases. Perhaps oral administration of AjA will prove to be a valuable additional therapeutic option (especially if administered with brownies!). (5)
1. Mounessa JS, et al. The role of cannabinoids in dermatology. J Am Acad Dermatol 2017; 77: 188-90.
2. Katchan V, et al. Cannabinoids and autoimmune diseases: A systematic review. Autoimmun Rev 2016; 15: 513-28.
3. Garcia-Gonzalez E, et al. Can cannabinoids modulate fibrotic progression in systemic sclerosis? Isr Med Assoc 2016; 18: 156-8.
4. Parker J, et al. Suppression of human macrophage interleukin-6 by a nonpsychoactive cannabinoid acid. Rheumatol Int 2008; 28: 631-5.
5. Robinson ES, et al. Cannabinoid reduces inflammatory cytokines, tumor necrosis factor-alpha, and type I interferons in dermatomyositis in vitro. J Invest Dermatol 2017; 137: 2445-7.
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