The skin is the largest organ in the human body. One of its principal functions is to protect the body against external agents and it is the first defensive barrier of the innate immune system. Other important functions of the skin include controlling body temperature, maintaining the hydro-electrolytic balance and perceiving painful or pleasurable stimuli. Any alteration in the functioning or appearance of the skin can have important consequences for our physical and mental health. Many of the problems present in the skin are limited to it. In some cases, however, the skin can reveal a disorder affecting the entire body.
Development of Pharmaceuticals in Dermatology
Nearly 37% of primary health care patients have some acute or chronic skin disease and it is surprising how few new pharmaceuticals are being developed to treat these conditions – particularly those most commonly treated by dermatologists and non-dermatologists when compared to other diseases and conditions. According to Eaglstein and Corcoran, 2011, one important reason why few pharmaceutical companies are developing drugs for skin diseases is that the economic return on such drugs (especially topical skin products) is relatively small compared to the market for pharmaceuticals for other conditions (e.g. cardiovascular diseases).
Another factor limiting the development of pharmaceuticals based on natural products – including preparations of Cannabis Sativa – is the fact that in most cases it is not possible to establish adequate protection for intellectual property of the drug, an essential inventive to investment in the development of new pharmaceuticals for any application. It is therefore hardly surprising that the great majority of skin diseases, especially inflammatory diseases, are treated with over-the-counter health care products, where the effectiveness, in most cases, is not proven.
Cannabinoids in Dermatology
The topical use of Cannabis Sativa L dates back to ancient China, where cannabis preparations were used externally to treat skin rashes, wounds and hair loss. There is also archaeological evidence suggesting that topical cannabis preparations were used by the ancient Egyptians to treat eye conditions and also in bandages for treating wounds. Cannabis leaves were used in medieval Arab medicine to treat skin diseases such as pityriasis and lichen planus. Most recently, in the early twentieth century, before prohibition, tinctures of cannabis were commonly sold in pharmacies. Among other applications, they were used to treat calluses, irritable bladder, menstrual pains and as an aid for quitting opium addiction.
The skin possesses all the elements of the endocannabinoid system, i.e., endocannabinoid compounds (AEA and 2-AG), metabotropic (CB1R and CB2R) and ionotropic (TRPV-1) receptors of key cannabinoids and the enzymes involved in the synthesis and metabolism of endocannabinoids (e.g. FAAH and MAGL). The various elements in the endocannabinoid system are involved in key mechanisms of skin regulation, such as control of growth of the epidermis and skin annexes, cell survival, immune and inflammatory responses, the transmission of sensory stimuli to the central nervous system (pain, itching) and the synthesis of lipids, among other activities.
Despite this long history of topical use of cannabis and advances in our understanding of the endocannabinoid system of the skin, research into the use of cannabinoids for skin pathologies is one of the youngest fields of research in this area and clinical data on the use of cannabis in dermatological practice remain extremely limited. Nonetheless, there is increasing evidence of the potential of cannabinoids for the treatment of inflammatory skin diseases, including psoriasis and atopic dermatitis and for the treatment of auto-immune diseases such as scleroderma, characterized by inflammation and fibrosis.
Psoriasis is one of the most common chronic inflammatory skin diseases. It is characterized by hyper-proliferation and shedding of keratinocytes, resulting from infiltration of T-cells and neutrophils and activation of dendritic cells and macrophages. Although the pathogenesis of psoriasis is not fully understood, there is solid evidence that deregulation of the immune cells in the skin, in particular, Th1 and Th17 cells, plays a critical role in the development of psoriasis.
Although there is at present only anecdotal evidence on the use of Cannabis Sativa L preparations for topical use in psoriasis, a 2016 study shows the therapeutic possibilities of cannabinoids acting through CB2R and through mechanisms that are independent of classical cannabinoid receptors are very broad, given their role in the regulation of Th1 and Th17 lymphocytes. Another study, done in 2006, indicated that some phytocannabinoids inhibit the proliferation of keratinocytes through non-CB1R and CB2R paths.
Atopic dermatitis (D) is the most frequent chronic inflammatory disease of the skin. Initiation and progression of the disease are induced by interactions of genetic, environmental and immunological factors. The clinical characteristics of AD include dryness of the skin through loss of the epidermal barrier, erythema, exudation, scabs, and lichenification. Moreover, AD is characterized by intense itching which leads to frequent scratching and infection by Staphylococcus. There is no cure for AD and the main goal of treatment is to reduce the symptoms (itching and dermatitis), prevent exacerbations and minimize the risk of skin infection. Standard forms of treatment for managing AD centers on the use of anti-inflammatory topical preparations with corticoids and hydration of the skin, but in serious cases, people may require systemic treatment with powerful immune-suppressants and anti-biotics to prevent infection by staphylococcus-type bacteria.
Numerous para-pharmaceutical preparations are now available based on oil from the cannabis plant, for the treatment of AD. However, despite the misleading advertising often used to market such products, hemp seed oil does not contain cannabinoids or other bioactive phenolic compounds, and its therapeutic effect goes no further than any other preparation containing polyunsaturated fatty acids and favouring skin hydration.
However, to judge form pre-clinical studies, cannabinoids also have a great potential for therapeutic management of AD. In this regard, selective CB1R agonists inhibit the activation of mastocytes and the release of histamine. Moreover, topical application of anandamide analogs has been shown to reduce skin inflammation in animal models of AD. Other authors have suggested that CB1R expression in keratinocytes plays a relevant role in maintaining the epidermal barrier. Finally, in a study done in 2006, it has also been described that the release of histamine from CB2R inhibits the inflammatory skin reaction experienced with AD.
According to another study, the anti-bacterial action of cannabis preparations and phytocannabinoids has been well-known for decades, although only more recently has the anti-bacterial activity of cannabinoids THC, CBD, CBG and their precursors (acid forms) against methicillin-resistant Staphylococcus been demonstrated.
Nearly 100 cannabinoids have been identified in the cannabis plant, together with a large number of bioactive compounds, such as phenolics and terpenes, which also have important antioxidant and anti-inflammatory activities. The cannabinoids and other types of compounds are thought to have interacting synergic effects. This would explain why in some in vitro studies, better results have been obtained with extracts from the plant that with pure, isolated compounds. Although the content of cannabinoids and other types of compounds vary depending on the variety of plant, cannabinoids can be said to have a huge potential for treating AD, given their anti-inflammatory and anti-bacterial properties.
Cannabinoids and Fibrotic Skin Diseases
Systemic scleroderma (or sclerosis) SSc) is a rare auto-immune disease that has three main characteristics: dysfunction of fibroblasts, leading to an increase in the deposition of proteins from the extracellular matrix, vasculopathy of small vessels resulting in tissue hypoxia and immune response with production of pro-inflammatory cytokines and auto-antibodies. SSc is characterized by progressive thickening fibrosis of the skin, secondary to excessive accumulation of collagen, which can be limited to the skin (localized – or limited – cutaneous SSc) or extends to internal bodies (diffuse SSc). SSc begins with microvascular injury and inflammation. This is followed by fibroblast activation, a key event in the development of fibrosis.
Recent evidence shows that genetic and pharmacological manipulation of the endocannabinoid system modulated the fibrotic response. CB1 and CB2 receptors, too, have shown different patterns in experimental models of dermal fibrosis. Blockage of CB1R prevents activation of fibroblasts and has a powerful antifibrotic effect. The role of CB1R as a profibrotic receptor has also been confirmed in mice, in which high levels of endocannabinoids can induce fibrosis through a CB1R-dependent path. On the other hand, activation of CB2R prevents cutaneous fibrosis and the infiltration of tissue leukocytes in models of experimental dermal fibrosis. It has also been demonstrated that dual agonists of CB2R show a powerful anti-inflammatory and anti-fibrotic activity in experimental models of SSc.
While the clinical research remains in the early stages, studies have shown that full extract cannabis topicals show enormous promise for the treatment of inflammatory skin diseases, even more so than some conventional over-the-counter treatments.