Ay, there’s the rub! Functional Challenges and Opportunities for Hemp Cannabidiol (CBD) External Analgesic Rubs

February 17, 2021 | Jim Lane

By Ronald Newman, PhD, Lee Enterprises Consulting

Special to The Digest

Summary

The 2020 declared US market for consumer products made from hemp-derived phytocannabinoid extracts is expected to be close to $1billion, with the most significant consumption occurring in the State of California (projected from 2019 data by Statista, Inc). Growth in 2020 was relatively flat compared to 2019 owing to the downturn in the economy and the growing gap between anticipated performance and actual results (1). The overall trend is illustrated in Figure 1. Further, there has been a greater shift towards e-commerce compared to the previous year. The largest segment of the hemp CBD market is currently in dietary supplements, followed by topical application products, and then food & beverage additives.

In this article, we will focus on the reported benefits of topically applied hemp phytocannabinoids extracts including non-cannabinoid co-extracts, and opportunities for functional improvements.

Figure 1. Hemp CBD US Market Growth. Chart Courtesy of NEXT Consulting Group and the New Business Journal.

Hemp Phytocannabinoids and Coextracts

Most companies in California market external analgesic rubs with extracts from hemp in which the Tetrahydrocannabinol (THC) concentration is less than 0.3%. This is exempted by the California Bureau of Cannabis Control from licensing and all associated fees. Currently, the types of extracts used predominantly in these applications are Full Spectrum extract containing a small quantity of THC (less than 0.3%), and Broad Spectrum extract with THC removed. The use of Full Spectrum extract requires a higher degree of analytical tracking because of the possibility of THC exceeding 0.3% in various lots.

The predominant cannabinoid in these hemp extracts are stereoisomers of CBD. Small concentrations of other cannabinoids are also present. Total cannabinoids account for more than 75% of the extract. Aromatic terpenes and terpenoids are also found in these extracts. Typical examples are d-limonene, beta-myrcene and beta caryophyllene. Finally, flavonoids and steroids make up minor classes of molecules present.

Making Claims of Analgesia in Topical Rubs

Topical rub formulations and claims are regulated by the Food & Drug Administration (FDA). If a label states that the use of the product will relieve pain, then it is classified as a drug, and must be registered as such. Further, the active ingredients must either be listed on an existing FDA Monograph or be approved under a New Drug Application (NDA). For example, menthol and camphor are terpenoids listed in “External Analgesic Drug Products for Over-the-Counter [OTC][Non-Prescription] Human Use; Tentative Final Monograph” (2). These can be claimed, within specified concentrations, as actives in an OTC topical analgesic rub. However, CBD is not in the Monograph, nor are there any Randomized Clinical Trials, as required under an NDA, demonstrating external analgesic properties. Companies labeling such claims on their products, or violating interstate commerce regulations have been receiving warning letters from the FDA (3). The Federal Trade Commission (FTC) has also been citing companies for making misleading claims (4).

Pharmacological Activity of Hemp Cannabinoids and Coextracts in Topical Application Products

The focus of our discussion is on CBD-containing external rubs that are not making claims of analgesia and are intended as cosmetics. According to the FDA, it’s the intended use of a product that determines whether it’s a cosmetic, drug, food or medical device. The intended use might be stated explicitly, or merely implied by the labeling or other information (5). Most producers of CBD-containing rubs attempt to stay within regulatory guidelines by not making false or implied claims of analgesia, even though known analgesics such as menthol and camphor are being added in some cases. Such rubs are cosmetics that may be supplied as lotions, roll-ons, balms/salves, and the like. This does not include transdermal products, which deliver drugs through the skin for access to other sites within the physiology. There is evidence that CBD is active in pain management when delivered transdermally (6). The reference entitled “Topical Agents for the Management of Musculoskeletal Pain”, has more detailed definitions of topical and transdermal agents (7).

While there is currently no data on the analgesic effects from Hemp CBD in topical applications products with no intended transdermal delivery, there are other documented benefits. CBD has been shown to reduce the oxidative stress on skin cells resulting from UV absorption (8). There is also evidence that CBD stimulates the production of melanin in the skin (9). This suggests that CBD would act beneficially in skin protectant/barrier products and possibly as a functional adjunct in sunscreen formulations. There is work demonstrating that CBD inhibits the production of sebum from skin cells and therefore may be useful for skin conditions where excessive sebum secretion may be exacerbating, such as acne (10).

CBD is largely oil-soluble and is prone to oxidative degradation in solution. CBD hydoxyquinone (HQ) has been cited as a significant oxidation product (11); and there is no data on topical analgesic effects for CBD HQ either.

Other hemp cannabinoid extract components that have been identified as having topical analgesic effects are THC, cannabigerol (CBG), cannabichromene (CBC), and beta-caryophyllene (a sesquiterpene) (12,13,14)*. However, these are present in small concentrations in Full Spectrum CBD, and therefore CBD would have to be removed in order to enhance the benefits of the remaining terpenoid and flavonoid components. This separation is currently being practiced as CBD is being removed to obtain a higher purity CBD.

While Hemp-extracted CBD exists predominantly as one particular stereoisomer (Figure 2), it is not known by the author whether the other stereoisomers made by other means would have differentiated pharmacological effects.

Figure 2. (-) – Cannabidiol enantiomer IUPAC name:

2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol (Courtesy of PubChem)

Safety of CBD Topical Application Products.

A 2018 critical report review of CBD by the World Health Organization suggests that CBD generally has low toxicity (15). In the paper “Potential risks from use of topically applied CBD-containing cosmetic products” (16), where multiple formulation tests were conducted, the principal results were as follows:

“It has also been shown that the formulation and composition of dermally applied CBD products can greatly impact the ability of the CBD to enter systemic circulation.”
“From the safety and tolerability information presented in this report on dermally applied CBD, there appears to be few acute toxicity findings.”

The FDA is currently working to assess the toxicity of products containing CBD (17).

Outlook for Hemp CBD Topical Application Products

The market for Hemp CBD products is expected to be flat until late 2022 following economic recovery in the post Covid-19 era (Figure 1). The topical application product segment is then expected to diversify. In analgesic rubs, while the presence of CBD has a strong marketing pull and is “fashionable” it is not cost competitive with non-cannabinoid dermal analgesics and not proven to be effective. Even the use of non-cannabinoid Hemp extracts, such as terpenoids and flavonoids, is not as cost effective as reconstructing their chemical profiles from other lower cost botanical sources. CBD made by fermentation of sugars using modified microbes is now available and expected to lower the cost compared to the Hemp extraction route. The stereoisomer composition of fermentation CBD is expected to be similar to hemp CBD. Other cannabinoids such as cannabigerol (CBG), cannabinol (CBN) and cannabichromene (CBC) are already available as products of fermentation. There are also patents claiming formulations for topical pain relief with a mix of cannabinoids including THC, CBD. CBG and CBN (18).

While Cannabis extracts like THC and non-cannabinoid co-extracts have known topical analgesic effects, formulated products containing THC still require a license and associated fees in States in which they are permitted. Licenses are limited, and take some effort to obtain, making hemp CBD topical products more prevalent in commerce than cannabis THC topical products.

The research article “Therapeutic Potential of Cannabidiol (CBD) for Skin Health and Disorders” (19) is a very good review of possible benefits for CBD in skin care. While analgesia may not be one of them, other applications where it would be useful, have been cited. With respect to new pharmaceutical applications, such as topical treatments for acne, psoriasis and eczema, and transdermal delivery for pain management, cost-benefit analyses would be required to assess their relative merits vis-a-vis current treatments. While there has been a lot of work on the synergistic effects of cannabinoids and the terpenoids, in reference (20) for example, there do not appear to be many that address synergistic analgesic effects when applied topically. Given that CBD is the most abundant hemp cannabinoid, and that it readily oxidized to CBD HQ and its dimer, it would be worthwhile exploring the therapeutic benefits of these materials. More than 150 phytocannabinoids have been identified to date, with ongoing research to identify their benefits.

*Identified as endocannabinoid CB2 receptor agonists. CB2 receptors are present in epidermal keratinocytes.

About the Author

Ronald Newman is a member of Lee Enterprises Consulting, the world’s premier bioeconomy consulting group, with more than 150 consultants and experts worldwide who collaborate on interdisciplinary projects, including those requiring the technologies discussed in this article. He is an expert in formulation chemistry and consumer product development. He creates custom formulations in his laboratory at Newman Anouvair LLC. The opinions expressed herein are those the author, and do not necessarily express the views of Lee Enterprises Consulting.

Bibliography

(1) Boyaji, S, MD, “CBD for chronic pain: The science doesn’t match the marketing”, Harvard Health Publishing, September 23, 2020.

(2) DEPARTMENT-OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 348

[Docket No. 78N-0301]

External Analgesic Drug Products for

Over-the-Counter Human Use;

Tentative Final Monograph

(3) “FDA warns 15 companies for illegally selling various products containing cannabidiol as agency details safety concerns”, FDA News Release, November 25, 2019;

(4) Grabenhofer, R “U.S. Federal Trade Commission Lays Down the Law on Deceptive CBD Claims”, Cosmetics & Toiletries, December 18, 2020.

(5) Greenberg, E., “Cosmetics Claims: Stay In Your Lane”. Healthcare Packaging, May 14, 2019.

(6) Bruni, N. et al., “Cannabinoid Delivery Systems for Pain and Inflammation Treatment”, Molecules 23 (10), October 2018.

(7) Stanos, S., “Topical Agents for the Management of Musculoskeletal Pain”, Journal of Pain & Symptom Management, Volume 33, Issue 3, p342-355, March 01, 2007.

(8) Jastrzab, A, at al., “Cannabidiol Regulates the Expression of Keratinocyte Proteins Involved in the Inflammation Process through Transcriptional Regulation”, Cells, v.8(8); August 2019.

(9) Toth, K.F, at al., “Cannabinoid Signaling in the Skin: Therapeutic Potential of the “C(ut)annabinoid” System”, Molecules, 24 (5), March 2019.

(10) Olah, A. et al., “Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes”, Journal of Clinical Investigation, 124(9):3713-24, September 2014.

(11) Sannikova, N., “The Effect of Storage Conditions on Cannabinoid Stability”, Ascension Sciences Inc., White Paper, June 2020.

(12) Scheau, C. et al, “Cannabinoids in the Pathophysiology of Skin Inflammation”, Molecules, 25 (3), February 2020.

(13) Koyama, S. et al, “Beta-caryophyllene enhances wound healing through multiple routes”, PLOS One, 14 (12), December 2019.

(14) Udoh, M. et al., “Cannabichromene is a cannabinoid CB2 receptor agonist”, British Journal of Pharmacology, 176 (23), December 2019.

(15) “CANNABIDIOL (CBD) Critical Review Report”, World Health Organization, Expert Committee on Drug Dependence, Geneva, 4-7 June 2018.

(16) “Potential risks from use of topically applied CBD-containing cosmetic products”, Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment, UK, TOX/2020/23.

(17) “What You Need to Know (And What We’re Working to Find Out) About Products Containing Cannabis or Cannabis-derived Compounds, Including CBD”, US FDA Website.

(18) Wallace, W.H., “Method of relieving analgesia and reducing inflammation using a cannabinoid delivery topical liniment”, US Patent No. 6,949,582, September 2005.

(19) Baswan, S.M. at al, “Therapeutic Potential of Cannabidiol (CBD) for Skin Health and Disorders”, Clinical, Cosmetic and Investigational Dermatology. 2020;13:927-942.

(20) Russo, E.B., “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects”, British Journal of Pharmacology, 163 (7), August 2011.