Radiodermatitis is one of the most common adverse effects of radiation therapy. More severe skin manifestations can significantly impact patient quality of life and can even result in interruptions in therapy that can impact long-term outcomes (Lazarev, Adv Radiat Oncol, 2018; Bese, Oncology, 2005). Though preventative and symptomatic therapies exist to combat the symptoms of radiodermatitis, more effective therapies are needed to improve the patient experience.
In recent years, cannabis and its active constituents have gained popularity in the treatment of a wide variety of conditions due to their documented anti-inflammatory, antioxidant, and analgesic properties (Pellati, Biomed Res Int, 2018). The cannabis plant contains a number of active compounds, termed cannabinoids, that include tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabigerol (CBG).
Varian TruBeam Linear Accelerator Used to Deliver Radiotherapy
Cannabinoids exert their diverse effects through a series of receptors and signaling pathways, collectively referred to as the endocannabinoid system (ECS). In the skin, cannabinoid receptors were recently shown to be expressed on keratinocytes, sebaceous glands, immune cells, and sensory nerves, and the ECS is now appreciated for its important role in normal skin homeostasis (Biro, Trends Pharmacol Sci, 2009; Toth, Molecules, 2019).
CBD/CBG as an Adjunct to Standard of Care Treatment
Therapeutic administration of either oral or topical cannabinoids are now being studied for a variety of inflammatory skin conditions, with some initial success demonstrated in clinical trials for atopic dermatitis (Yuan, Clin Interv Aging, 2014), acne vulgaris (Spleman, J Invest Dermatol, 2018; Ali, Pak J Pharm Sci, 2015), and epidermal bullosa (Chelliah, Pediatr Dermatol, 2018).
Topical cannabinoids have yet to be explored in the treatment of radiodermatitis, though the demonstrated benefit in other similar inflammatory and wound-forming conditions suggests they may represent a novel and successful adjunctive therapy.
Of the potential cannabinoids to be used in therapeutic formulations, THC, which is responsible for the psychoactive properties of marijuana, can result in undesirable mood effects. CBD and CBG, on the other hand, are not psychotropic and are therefore more attractive candidates for translation into therapeutic practice.
A growing body of literature indicates that cannabinoids, and CBD in particular, may target key pathways disrupted in the development of radiation-induced skin toxicity. Most notably, CBD was shown to have a profound anti-inflammatory effect in the skin. In one study using stimulated HaCaT keratinocytes, CBD dose-dependently decreased the production of the pro-inflammatory mediators CCL8, IL-6, IL-8, and TNF-α (Petrosino, J Pharmacol Exp Ther, 2018).
Additionally, CBD was shown to inhibit neutrophil migration in vitro (McHugh, Mol Pharmacol, 2008). These effects are highly relevant to the pathophysiology of radiodermatitis, as damaged keratinocytes, among other cells, produce the pro-inflammatory cytokines that ultimately recruit other immune cells to the irradiated site. Importantly, CBD was also shown to have anti-inflammatory effects in a mouse model of dermatitis, demonstrating that these properties can be recapitulated in vivo (Tubaro, Filoterapia, 2010).
Wound Healing and Oxidative Stress
CBD administration may also support wound healing and resolution of oxidative stress. Multiple in vitro studies have demonstrated that cannabinoids can influence the proliferation and differentiation of keratinocytes in a dose- and receptor-dependent manner, with some interactions promoting and others attenuating keratinocyte response (Wilkinson, J Dermatol Sci, 2007; Paradisi, J Biol Chem, 2008). Evidence from in vivo murine studies demonstrates that topical administration of CBD and other synthetic cannabinoids promote keratinocyte proliferation and restoration of barrier function (Kim, Int J Dermatol, 2015; Casares, Redox Biol, 2019).
More specifically, to model the effects of commercially available CBD creams on skin homeostasis, topical formulations of CBD in concentrations similar to those available (0.1-1%) were applied to the skin of adult mice. CBD not only stimulated the proliferation of keratinocytes thereby increasing skin thickness, but also enhanced the production of the anti-oxidant molecule heme oxygenase 1 (HMOX1) as well as the production of keratins 16 and 17, which are important for wound repair (Casares, Redox Biol, 2019).
Pain and Pruritis
Beyond attenuating toxic reactions initiated by radiotherapy, CBD and other cannabinoids may help soothe the pain and pruritis associated with this condition. The pain of desquamation may result from frank tissue destruction as well as inflammation, and cannabinoids have been shown to modulate both pathways. Cannabinoids have a well-documented analgesic effect, acting through CB1 receptors in the central and peripheral nervous system, as well as CB2 and TRPV1 receptors on peripheral nerves and immune cells (Walker, Life Sci, 1999; Baker, Lancet Neurol, 2003).
Topical CBD has been explored in the treatment of chronic cancer-associated pain, and initial success has been demonstrated in a small clinical trial of patients with pyoderma gangrenosum, an inflammatory disorder leading to chronic painful ulcerations (Maida, J Pain Symptom Manage, 2017). Nonetheless, clinical trials are now needed to study the effects of topical cannabinoids in the management of radiodermatitis specifically.
Though most research to date has focused on CBD, other cannabinoids, such as CBG, are also gaining attention in the field. CBG, like CBD, is not psychoactive and was shown to have anti-inflammatory properties both in vitro and in vivo (Borrelli, Biochem Pharmacol, 2013; Ruhaak, Biol Pharm Bull, 2011). Furthermore, combination therapies of multiple cannabinoids are thought to confer a greater therapeutic benefit due to additive or synergistic effects (Scott, Anticancer Res, 2013; Russo, Br J Pharmacol, 2011).