Are Cannabinoids the Future of Dermatology?

As more states and countries decriminalize cannabis, interest in the medical properties and benefits of cannabinoids continues to grow in tandem. While current research has so far focused on the role cannabinoids play in pain management, neurologic conditions, and cancers, the use of these compounds in the treatment of skin diseases is emerging as a promising new area for study.

An increasing number of studies are addressing gaps in the understanding and use of these biologic agents. Although their efficacy in specific dermatologic applications requires further research, dermatologists are well positioned to be pioneers in using cannabinoids to understand and treat inflammatory and autoimmune conditions.

THE ENDOCANNABINOID SYSTEM

Research into phytocannabinoids, derivatives from the cannabis plant (Cannabis stavia), in the 1990s led to the discovery of the endocannabinoid system (ECS).^1-3 The ECS is part of the signaling cascade within the central nervous and immune systems3 and has a number of physiologic functions, including the management of pain. Several studies have shown that the ECS system helps the skin maintain homeostasis by mediating inflammation, regulating keratinocyte differentiation and proliferation, and releasing damageinduced keratins, among other processes.3

Endocannabinoids are bioactive lipids released on demand in response to stimuli, such as pain or inflammation. The ECS is composed of 3 parts: ligands that bind to receptors, cannabinoid receptors, and enzymes responsible for controlling the level of ligands. Endogenously produced cannabinoids include anandamide acid (AEA) and arachidonoyl glycerol (2-AG), which are derivatives of arachidonic acid. These activate cannabinoid receptors type 1 (CB₁R) and type 2 (CB₂R), primarily in response to rising intracellular calcium ion levels.

CB₁R is found in the central nervous system on axon terminals, specifically in the basal ganglia, cerebellum, hippocampus, and prefrontal cortex.³ Activation of CB1R is associated with modulating of cognitive, memory, and motor functions, analgesia, as well as the inhibition of excitatory and inhibitory neurotransmission.² CB₂R functions within the immune system in the spleen, tonsils, thymus gland, bones, and skin cells, as well as localized in monocytes, macrophages, B cells, and T cells.^1-3 When activated, CB₂R controls various responses within the innate immune system, such as suppression of pro-inflammatory T cells and cytokines.^2,3 Other receptors within the ECS include peroxisome proliferatoractivated receptors (PPARs), orphan G-protein-coupled receptor GPR55, and vanilloid receptors.

OTHER TYPES OF CANNABINOIDS

In addition to endocannabinoids, there are over 100 phytocannabinoids contained within the cannabis plant. The most commonly studied are tetrahydrocannabinol (THC) and cannabinol (CBD), with more attention on THC due to its psychoactive effects. Both THC and CBD have potential for treating various skin diseases by activating ECS to reduce inflammatory responses within the skin, however, more emphasis has been placed on CBD because it is a nonpsychogenic compound.³ Additionally, research is investigating the optimal ratio of THC to CBD in plant-derived sources to balance the beneficial effects of both compounds while reducing adverse events.

Synthetic cannabinoids are created in labs to enhance the potency of naturally occurring cannabinoids and can be designed to bind to specific receptors within the ECS to target particular responses within the immune system or central nervous system. These include nabilone (Cesamet), ajulemic acid (AJA), HU-210, AB-PINACA, among others.

Endocannabinoids, phytocannabionids, and synthetic cannabinoids are all being pursued for medical purposes and are already utilized in commercial and over-the-counter products available at dispensaries. In dermatology, there is limitless potential for using cannabinoids to treat neoplastic and cancerous growth and inflammatory skin diseases. Efficacy and safety of these categories and methods of delivery—oral, topical, and inhaled treatments—require further study, as well as changes in legislation to allow for research to develop best practices for administering cannabis.

LEGAL RESTRICTIONS

Despite changes in attitudes and perceptions around marijuana, few countries have fully legalized recreational and medical use. Legislation against cannabis in the United States began in 1937 with the Marihuana Act, which limited use to industries. The Controlled Substances Act, passed in 1970, further criminalized cannabis by defining it as a Schedule 1 controlled substance. This made it illegal to use cannabis for recreational and medical purposes, and significantly stymied research.⁴

California was the first state to pass legislation that made medical cannabis use legal in 1996.⁴ Currently, 33 states and the District of Columbia have laws that permit cannabis for medical use, with some states, such as Michigan and Colorado, allowing recreational use. In addition, several countries are decriminalizing cannabis (Israel and Norway) or legalizing recreational and medical uses (Canada and South Africa). While twothirds of the United States has passed legislation allowing for cannabis use, with various requirements and restrictions, it remains illegal at the federal level and is still classified as a Schedule 1 substance.

MEDICAL CANNABINOIDS

Currently, there are only 4 FDA-approved synesthetic and phytocannabinoid medications available in the United States. These are approved for neurologic conditions or adverse effects associated with chemotherapies for cancers:

• Dronabinol (Marinol)
• Nabilone
• Nabiximols (Sativex)
• Cannabidiol (Epidiolex)

In dermatology, preclinical and a few clinical trials are showing the efficacy of cannabinoids for various skin conditions (Table),^3,5 including atopic dermatitis, psoriasis, acne, scleroderma, skin cancers, neutrophil diseases, dermatomyositis, and cutaneous lupus erythematosus (CLE).^3,6-8 Cannabinoids also have potential for the treatment of hidradenitis suppurativa, lichen simplex chronicus, prurigo nodularis, among other inflammatory conditions.

Two studies found evidence suggesting that cannabinoids could be used to target acne. Oláh et al showed that CBD inhibited sebocytes and inflammation in immune cells.⁶ Similarly, Ali et al found that cannabis 3% extract improved acne symptoms among participants.⁷ More trials are needed to examine cannabis’ full potential as a topical acne treatment. In autoimmune diseases, phase 3 trials are investigating the efficacy of synesthetic AJA at treating refractory skinpredominant dermatomyotisis⁸ and cutaneous systemic sclerosis,⁹ with results showing efficacy for both conditions. Preclinical data also demonstrated efficacy of topical 4% AEA, administered with nanoparticles, at reducing symptoms of CLE in mice.¹⁰

These studies and further explorations into the ECS’ role in skin care show the limitless potential for harnessing cannabinoids for the treatment of various skin conditions, including ones with few other therapeutic options.

AREAS FOR CONSIDERATION

Although several forms of cannabinoids are under investigation, many questions regarding best practices for selecting the type or ratio, such as TCH to CBD, administration, and dosage remain unanswered. Patients recommended cannabis by a provider predominately receive the products from dispensaries, limiting the ability of providers and patients to determine which type of cannabis and which ratio of cannabinoids are effective for their condition. In addition, routes of administration for various conditions are still under investigation, with the focus being on oral and topical forms due to negative stigma around inhalable cannabis.

For topical therapies, investigations into the best delivery method are underway. Topical delivery of cannabinoids, in particular, is problematic due to the highly lipophilic nature of the compounds, which have poor penetration outside of fatty environments. One possible solution is using nanoparticles, which slowly delivers cannabinoids into the skin for maximum penetration and benefit to patients. Mouse models of CLE showed the efficacy of using nanoparticles for delivering cannabinoids into the skin and improving symptoms.¹⁰

In addition to drug development, there is a need to educate providers. Survey data of 531 dermatologists and allied health professionals suggests that the majority of providers are open to the exploration of cannabinoids for the treatment of various skin diseases (94%) and were willing to prescribe topical cannabinoids to patients (91%).¹¹ Nearly half of providers (47.5%), particularly those younger than 35 years, reported concerns about the negative perception of prescribing cannabinoids.

One concerning finding from the survey was 64% of responders were not aware that CBD is not psychoactive and 29% did not know THC is psychoactive. Providers recommending cannabis will need some form of education on the benefits, harms, and risks associated with cannabinoids, like other therapies, to ensure that patients are aware of all potential outcomes and can be informed when selecting cannabinoid- based products at dispensaries.¹¹

PRESCRIBING CANNABIS

With the exception of the 4 FDA-approved cannabinoids, cannabis cannot be prescribed. Providers can recommend or refer cannabis to patients based on their state’s requirements. As more state laws change in favor of medical cannabis, providers should be prepared for patients to ask about the potential of these therapies. At the time of the above-mentioned survey in 2018, 55% of dermatologists reported a patient asking about it.¹¹ This number will likely rise over the next few years as cannabis use for medical purposes becomes more legally and culturally acceptable.

Prior to recommending cannabis, providers should be aware of all processes required by their states that must be completed, such as online registration or formal letters, and know their state’s allowable indications. All states that allow the use of medical cannabis (Figure) permit referrals for pain management. Illinois, Michigan, Maine, New Hampshire, and Connecticut have allowable indications for 4 dermatologic conditions: CLE (IL, NH), nail-patella syndrome (IL, MI, ME), neurofibromatosis (IL), and psoriasis (CT).

Similar to other therapies, physicians and patients should discuss risks, benefits, and adverse effects of cannabinoids and cannabis use. When recommending cannabinoids, providers should take steps to avoid blindly handing out referrals to patients and becoming a “marijuana mill.” Organizations including the Canadian Consortium for the Investigation of Cannabinoids (http://www.ccic.net) and the University of Washington’s Alcohol and Drug Abuse Institute (http://adai.uw.edu/mcacp/toolkit.html) offer online toolkits with printable forms to help walk you through steps for recommending cannabis. Other general tips:

Follow a medical cannabis checklist (you can find these in online toolkits such as those mentioned above)

• Use validated quality-of-life measures to record patients’ progress
• Create a signed, written contract with the patient (also in online toolkits)
• Use the following mantra: “start low, go slow, stay low” (use low concentrations to achieve maximum benefit without adverse effects)

LOOKING AHEAD

Paradigm shifts are slow, even in medicine. In 1910, germ theory was considered a controversial topic and remained as such until changes in technology and studies on microorganisms shifted public opinion. Cannabinoids as a medical treatment are facing similar opposition, but research is doing its best to slowly address the gaps caused by social and legal controversies. In the midst of this major paradigm shift, dermatology needs to be at the forefront of current research endeavors on the benefits of cannabinoids for autoimmune and inflammatory conditions, which can then be taught to peers in other fields. It is vital for us to play an active role in bolstering research and improving our understanding of cannabinoids and the ECS, not just be spectators waiting for other fields to discover all the possibilities.

Dr Friedman is a professor of dermatology, residency program director, director of translational research, and director of supportive oncodermatology at George Washington School of Medicine and Health Sciences in Washington, DC.

Disclosures: Dr Friedman was a consultant and/ or worked on the ad board for Loreal, La Roche Posay, Galderma, Aveeno, Valeant, Microcures, Biogen, Pfizer, G&W, Laboratories, Novartis, Sonoma Pharmaceuticals, Intraderm, Encore, Exeltis, Menlo, Lilly, Aclaris, Dermira, Berg, Allergan, Zylo Therapeutics. He was a speaker for Janssen, Regeneron, and AbbVie, as well as received grants from Aclaris and CPN.

References:

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