From bud to breakthrough

The therapeutic potential and current landscape of cannabinoids in dermatology

Adam Friedman, MD, with John Jesitus

Presented at Montreal Dermatological Society, February 11, 2021, Montreal, Canada

Topical cannabinoids including cannabidiol (CBD) show promise for targeting many inflammatory dermatologic conditions. Although a few such products have begun the path toward FDA approval, much work remains with regard to optimizing formulas, vehicles, and regimens, and overcoming lingering cannabis-associated stigma. There is tremendous potential for CBD if the amount and delivery are optimized.

Targeting inflammation

CBD is one of approximately 120 cannabinoids found in cannabis, and many skin-cell types express cannabinoid receptor 2 (CB2R). Presently, CBD’s primary and best-understood role is as an anti-inflammatory agent.¹

What’s unique about manipulation of the endocannabinoid system (ECS) is that the impact can be multifaceted; for example, resolving, not just inhibiting, inflammation.²

Ligand binding to CB2R and other G-protein coupled receptors (eg, GPR18) creates an anti-inflammatory effect beyond that of blocking a single pathway, signal, or receptor, said Dr. Friedman. CBD binding can block immune cells from infiltrating the skin as well as inhibit their ability to secrete inflammation-perpetuating cytokines. Ligand binding moreover switches certain immune cells such as macrophages from a pro-inflammatory (M1) to an inflammation-resolving subtype (M2).³

CBD also can bind to many other receptors outside the ECS. While we generally don’t think about CBD as an agent that can affect sensation, like tetrahydrocannabinol (THC), CBD can influence pain and itch through its impact on various other receptors and channels like serotonin and opioid receptors and transient receptor potential channels. So CBD has a lot of potential to treat, manage, and maybe even prevent many inflammatory skin diseases.

Supporting data for cannabinoids in acne, atopic dermatitis, and psoriasis are mostly preclinical.^4-6 Such research helps scientists understand how CBD works in these indications. But it all comes down to meaningful development—coming up with the formulation that can get the CBD where it needs to be.

Being highly lipophilic, CBD has challenges permeating through the skin and must be incorporated into a lipid-rich vehicle. What delivery vehicle for cannabinoid makes a huge difference in terms of whether it gets through. The challenge includes not only delivering the CBD, but also determining how much is needed and how frequently. Many more questions than answers exist at this point.

Answering these questions will take time. The 2018 Farm Bill passed by the US Senate legalized CBD containing less than 0.3% THC obtained from hemp. Because cannabinoids previously were a Schedule 1 controlled substance in the US, drug developers have only recently begun CBD development efforts.

This whole field is fledgling because it was very difficult to study these plant-based derivatives. Consumers have now embraced—without evidence of efficacy—multitudinous cannabinoid-containing over-the-counter (OTC) products birthed by the Farm Bill. As a result, convincing the pharmaceutical industry to invest in CBD products is tough.

Why spend $20 million for an FDA pipeline when you can sell something OTC and people will buy it?

A handful of ongoing or recently published clinical trials target inflammatory skin conditions with topical CBD. BTX 1503 gel (Botanix) has recently completed phase 2 in acne and is in phase 1 for rosacea.⁷ In AD, a CBD gel achieved significant reductions inPatient-OrientedEczema Measure (POEM) and other scores.⁸ Canno Cream (Greenway Therapeutix) is also under development for AD (see sidebar). In psoriasis, a topical ointment containing 3% CBD (One World Cannabis) has completed phase 1 testing (NCT02976779). Additionally, early-stage research is exploring potential indications including wound healing and cutaneous lupus erythematosus.

Mellowing out stigma

Meanwhile, some patients and dermatologists remain hesitant to embrace CBD. When queried in 2017, 10% of dermatologists reported being asked by at least 10 patients yearly about medical cannabis.⁹ That figure is probably much higher today. The same survey showed that 64% of dermatologists did not know if CBD has psychoactive effects.

There still is to some degree a stigma. Some patients say other physicians have chastised them for mentioning cannabinoids. There is concern even though the regulatory landscape has changed dramatically.

More than 2/3 of the states allow medical cannabis, and 14, plus the District of Columbia, permit medical and recreational use. A few states allow dermatologic indications including psoriasis (Connecticut and New Mexico), lupus (Hawaii, Illinois, and New Hampshire), and genetic syndromes (Illinois, Maine, and Michigan) as the basis for medical-marijuana use.

Most states don’t have a true dermatologic indication. However, every state with medical marijuana considers chronic pain a legitimate indication. Accordingly, I typically list pain as the qualifying diagnosis when recommending medical cannabis, which I commonly do for local patients with hidradenitis suppurativa, AD, or chronic itch.

Around 30% of patients reject cannabinoids, but most patients are very amenable, especially if I talk to them about why I’m recommending it. That’s why education is so important in the dermatology community. We know there’s an interest among consumers and patients.

Dermatologists interested in educating themselves should consult State Department of Health websites, Health Canada, and online toolkits from organizations such as the University of Washington’s Alcohol and Drug Abuse Institute. Dermatologists also may consider the nation’s first medical-cannabis graduate certification programs, offered through Thomas Jefferson University.

Additionally, professional societies should create multidisciplinary task forces to help address the dearth of CBD-related medical literature and CME. We’re so early in our understanding of CBD—what’s the best way to the deliver it that has an impact on a particular disease? We need clinical-trial programs. We need dose-escalation phase 2 studies.

The future for cannabinoid-based drugs, as well as OTC products, is bright. We just need to prove what works best and how to best use it.

References

1. Marks DH, Friedman A. The therapeutic potential of cannabinoids in dermatology. Skin Therapy Lett. 2018;23(6):1-5.

2. Friedman AJ. From bud to breakthrough: the therapeutic potential and current landscape of cannabinoids in dermatology. Montreal Dermatological Society; February 11, 2021; Montréal.

3. Serhan CN, Chiang N, Dalli J. The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution. Semin Immunol. 2015;27(3):200-215.

4. Oláh A, Tóth BI, Borbíró I, et al. Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. J Clin Invest. 2014;124(9):3713-3724.

5. Kim HJ, Kim B, Park BM, et al. Topical cannabinoid receptor 1 agonist attenuates the cutaneous inflammatory responses in oxazolone-induced atopic dermatitis model. Int J Dermatol. 2015;54(10):e401-e408.

6. Friedman AJ, Momeni K, Kogan M. Topical cannabinoids for the management of psoriasis vulgaris: report of a case and review of the literature. J Drugs Dermatol. 2020;19(8):795. doi:10.36849/JDD.2020.5229.

7. Botanix Pharmaceuticals. Product pipeline. https://botanixpharma.com/pipeline/. Accessed February 11, 2021.

8. Maghfour J, Rietcheck HR, Rundle CW, et al. An observational study of the application of a topical cannabinoid gel on sensitive dry skin. J Drugs Dermatol. 2020;19(12):1204-1208.

9. Robinson E, Murphy E, Friedman A. Knowledge, attitudes, and perceptions of cannabinoids in the dermatology community. J Drugs Dermatol. 2018;17(12):1273-1278.

Disclosures

Dr. Friedman is a consultant and/or advisory board member for Corbus Pharmaceuticals Holdings, Greenway Therapeutix, Hoth Therapeutics, TruPotency, and Zylo Therapeutics.