At this current juncture scientific knowledge of ECS signalling has far outstripped the development of ESC-based therapies. The eloquent Dr. Ethan Russo remarks:
Despite its seeming ubiquity, and obvious importance as a homeostatic regulator of human physiology, the ECS topic receives short shrift in contemporary medical education, if mentioned at all. This educational deficit, born perhaps of lingering prejudice towards a plant called cannabis, must surely end soon, as it is contrary and detrimental to potential significant contributions to public health. Barriers aside, this research on plants affecting the ECS portends to lead to important advances in endocannabinoid tone, as well as a better understanding of the complex stance of the ecological roles of phytochemicals and their interactions with our own biochemistry and pathophysiological mechanisms (Russo, 2016).
We still don’t know much about how ESC-related treatments operate in whole living systems. In their article “Endocannabinoid signaling at the periphery: 50 years after THC” published in Trends in Pharmacological Science, Maccarrone and colleagues also recognize the need to fill this gap in the research. They firmly prod, “Clinical trials are therefore urgently required to assess the putative in vivo efficiency of ECS-oriented treatments in e.g. hyperproliferative skin conditions (tumors, psoriasis), as well as in allergic and inflammatory skin diseases (acne vulgaris, atopic dermatitis)” (reviewed in Maccarrone et al., 2015).
We’ll take a look at the case studies and clinical evidence available. A 2018 case study published in Pediatric Dermatology observed three individuals with epidermolysis bullosa who self-initiated use of topical cannabidiol. Epidermolysis bullosa is a rare blistering skin disorder that’s difficult manage due to skin fragility and repeated wound healing which causes itching, pain, limited mobility, and recurrent infections. With cannabidiol use, one patient was able to completely cease their oral opioid analgesics, while all three reported faster wound healing, less blistering, and pain relief (Chelliah et al., 2018).
Trusler et al. reviewed the relationship between the ECS and skin pathology in their 2017 article “The Endocannabinoid System and Its Role in Eczematous Dermatoses,” published in the official journal of the American Contact Dermatitis Society. In healthy conditions, the cutaneous endocannabinoid system responds to xerotic tissue (xero from the Greek, meaning “dry”) by increasing lipid synthesis in the stratum granulosum.
Researchers have noted an association between abnormally low levels of endocannabinoids and dry skin, and theorize that symptoms of asteatotic eczema and xerotic dermatitis are caused, in part, by impaired skin barrier repair. In one 4-week clinical trial a cannabinoid-containing cream was tested topically on xerotic skin. 60 patients with asteatotic eczema (AE) were randomized to receive treatment with an emollient containing palmitoylethanolamide (PEA) and anandamide (AEA), or a standard emollient sans cannabinoids. Subjects who used the PEA/AEA cream demonstrated significant improvement in itching and skin hydration, along with a reduction in erythema, scaling, and dryness.
PEA, an endogenous fatty acid amide, is not strictly classified as an endocannabinoid because it doesn’t bind to CB1 or CB2 receptors, but it does increase anandamide activity via an “entourage effect.” The authors theorize that, as endogenous cannabinoids in the skin augment skin barrier function by increasing epidermal lipid production, a topical cannabinoid application will thus mimic the natural process and stimulate skin repair.
PEA has been similarly helpful in atopic dermatitis. In one study of adults and children researchers found that the cohort using a PEA-containing cream in combination with a class IV topical steroid cream (0.1% clocortolone pivalate) experienced a prolonged time to before their subsequent atopic dermatitis flare as compared to a cohort treated solely with steroid cream.
Another study of 2000 atopic dermatitis patients found that subjects treated with a PEA-containing cream enjoyed a statistically significant improvement in itch and reduced their weekly topical steroid use by 62%. Finally, a pilot study of 20 pediatric patients with mild atopic dermatitis found that subjects who used a product containing a PEA analogue, 2% adelmidrol, experienced a 80% resolution of symptoms, as measured by the Investigator Global Assessment score of the physician. Researchers propose that pruritus relief in response to ECS simulation occurs via the down-regulation of mast cell degranulation, inhibition of inflammatory cytokines, and reduction of proinflammatory cytokine TNF-ɑ during inflammation, or possibly by inducing analgesia (reviewed in Trusler et al., 2017).
Furthermore, PEA has been found to associate with CB2 receptors on mast cells, and is thought to modify the immune reaction to triggers through mast cell stabilization and downregulation of the Th2 cytokine response that correlates with atopic disease. In one experimental model, PEA down-regulated interleukin 4, a cytokine that is overactive in atopic dermatitis (reviewed by Del Rosso, 2007).
A 2015 study published in the Pakistan Journal of Pharmaceutical Sciences found that topical application of a cream made with 3% Cannabis seed extract reduced sebum production and erythema on the cheeks of 11 healthy male volunteers between the ages of 20 and 35. In this experiment volunteers were given two products, one with a base of paraffin oil and “fragrance,” with added 3% Cannabis seed extract, and one with base alone. The subjects were instructed to apply 500 mg of the cannabis cream to the right cheek and the control cream to the left cheek with their fingertips twice a day (mornings, 7:00-9:00; Evenings, 19:00-21:00). Skin assessment was performed every other week for three months. Sebum levels were measured via Sebumeter, while erythema was evaluated by reflectance spectrophotometer. Cannabis extract was found to significantly reduce sebum production and erythema compared to base cream alone. No irritant or allergic reactions were observed during the test period. Antioxidant activity was assessed by measuring the free radical scavenging capability of the extract.
The researchers attribute reduced sebum production to the inhibition of 5-alpha reductase, the enzyme primarily responsible for converting testosterone to dihydrotestosterone (DHT), DHT is known to be a potent stimulator of sebum secretion. The cannabis seed extract was also observed to have significant antioxidant activity. The authors note that the inflammatory activity associated with acute UV exposure and the degenerative processes resulting from chronic UV radiation are predominantly mediated via the overproduction of reactive oxygen species (ROS). The observed reduction in erythema suggests the calming of inflammatory processes, which is thought by the authors to be protective against dermal photo-damage (Ali and Akhtar, 2015).
A 2010 study published in Biochemical Pharmacology found that CB1 receptor antagonist falcarinol, a skin irritant found in carrots, parsley, celery, and Panax ginseng, had an allergy-promoting effect on the skin. Falcarinol was found to exacerbate histamine-induced edema in skin prick tests. The authors report that falcarinol non-selectively binds to both CB receptors, but selectively alkylates the CB1 receptor. Evidence points to an upregulation of pro-inflammatory chemokines at the CB1 receptor level in keratinocytes via the inhibition of anandamide signaling.
In vitro experiments implicate the involvement of specific chemokine mediators notorious for promoting inflammation. C-C Motif Chemokine Ligand-2 (CCL2), also known as Monocyte Chemoattractant Protein-1 (MCP-1), is one of the key regulators of the migration and infiltration of macrophages and monocytes. Interleukin-8 (IL-8) is a chemokine with potent neutrophil activating and chemotactic attributes that fire up in inflammatory conditions, and is known to synergize with histamine. CCL2/MCP-1 and IL-8 have been implicated in contact dermatitis, while IL-8 is the likely recruiter of neutrophils from the circulation in many human inflammatory skin conditions. The peripheral endocannabinoid system operates predominantly through the keratinocytes, which have been shown to express both CB1 and CB2 receptors. The pro-allergic effects CB1 antagonist effects via falcarinol in the keratinocytes indicate the significance of the endocannabinoid system in modulating inflammation of the skin (Leonti, et al., 2010).
The available research is promising, but the field requires more well-controlled randomized clinical trials to establish safety and efficacy for mainstream medical purposes. Let’s leave the world of scientific validation behind us for now, and take a look at the actual plant that set all these discoveries in motion.
End of Part II. Part III: Cannabis: Plant, Industry, and Ideology to be released next Wednesday, August 15th.
Ali, Atif, and Naveed Akhtar. “The Safety and Efficacy of 3% Cannabis Seeds Extract Cream for Reduction of Human Cheek Skin Sebum and Erythema Content.” Pakistan Journal of Pharmaceutical Sciences 28, no. 4 (July 2015): 1389–95.
Chelliah, Malcolm P., Zachary Zinn, Phoung Khuu, and Joyce M. C. Teng. “Self-Initiated Use of Topical Cannabidiol Oil for Epidermolysis Bullosa.” Pediatric Dermatology, May 22, 2018. https://doi.org/10.1111/pde.13545.
Del Rosso, James. “Use of a Palmitoylethanolamide Containing Nonsteroidal Cream for Treating Atopic Dermatitis: Impact on the Duration of Response and Time Between Flares.” Cosmetic Dermatology 20, no. 4 (April 2007).
Leonti, Marco, Laura Casu, Stefan Raduner, Filippo Cottiglia, Costantino Floris, Karl-Heinz Altmann, and Jürg Gertsch. “Falcarinol Is a Covalent Cannabinoid CB1 Receptor Antagonist and Induces pro-Allergic Effects in Skin.” Biochemical Pharmacology 79, no. 12 (June 15, 2010): 1815–26. https://doi.org/10.1016/j.bcp.2010.02.015.
Maccarrone, Mauro, Itai Bab, Tamás Bíró, Guy A. Cabral, Sudhansu K. Dey, Vincenzo Di Marzo, Justin C. Konje, et al. “Endocannabinoid Signaling at the Periphery: 50 Years after THC.” Trends in Pharmacological Sciences 36, no. 5 (May 2015): 277–96. https://doi.org/10.1016/j.tips.2015.02.008.
Russo, Ethan B. “Beyond Cannabis: Plants and the Endocannabinoid System.” Trends in Pharmacological Sciences 37, no. 7 (July 1, 2016): 594–605. https://doi.org/10.1016/j.tips.2016.04.005.
Trusler, Alexandra R., Ashley K. Clark, Raja K. Sivamani, and Vivian Y. Shi. “The Endocannabinoid System and Its Role in Eczematous Dermatoses.” Dermatitis: Contact, Atopic, Occupational, Drug 28, no. 1 (February 2017): 22–32. https://doi.org/10.1097/DER.0000000000000257.