Given the high tolerability, positive safety profile, and low risk of drug interactions of topical products derived from Cannabis spp, the administration of them for chronic pain may represent an underutilized form of therapy. This article reviews the limited animal and human studies investigating cutaneous applications of cannabinoids and cannabis-derived products, with a focus on cannabidiol (CBD) and its potential mechanisms of action. Animal models show topical penetration of cannabinoids into underlying tissues, as well as dose-dependent anti-inflammatory and pain-relieving effects. While randomized, controlled trials are needed to substantiate anecdotal claims of efficacy in humans, evidence exists to warrant clinical exploration of these products by healthcare professionals.
Interest in the therapeutic use of CBD, a phytocannabinoid found in Cannabis spp (ie, marijuana or hemp), has reached a fever pitch as CBD products, mostly derived from hemp, appear nearly everywhere, from online retailers to grocery stores and gas stations. In the United States (US), marijuana-derived CBD products are available only in licensed dispensaries in states with medical and/or adult-recreational cannabis (ie, marijuana) regulations.1 In Canada, however, CBD products are available only through licensed producers, regardless of whether they are derived from hemp or marijuana.2
The widespread availability of CBD products sold and marketed as dietary supplements in the United States is confounding given that the US Food and Drug Administration (FDA) has explicitly stated that as an active pharmaceutical ingredient in an FDA-approved drug (ie, Epidiolex®, Greenwich Biosciences Inc.), CBD is precluded from being added to food and beverages or included in dietary supplements.3 Nonetheless, consumer demand for CBD is high and growing, including demand for topical products, which are not foods, beverages, or dietary supplements and, thus, may not violate FDA regulations, assuming no drug claims are made in marketing materials.4
In humans, relief of painful joints and sore muscles is one of the most commonly reported uses of topical cannabis products. Cross-sectional studies of CBD product users indicate that consumers are predominantly using these products to treat chronic pain conditions, including arthritis and joint pain.1 Clinical trials investigating hemp-derived CBD products, while limited, have reported reductions in opioid use; lower pain and disability scores; and improvements in sleep quality, sleep quantity, and quality of life.5,6
Management of Chronic Pain
Chronic pain is consistently one of the most common reasons adults seek medical care in the United States.7 It is associated with restrictions in mobility and daily activities;8,9 loss of work productivity;10 dependence on opioids;10 comorbidities such as anxiety, depression, and sleep disorders;8 and reduced quality of life.8,9 Chronic pain is responsible for an estimated $560 billion in direct medical costs, lost productivity, and disability programs each year.10
Clinical trials investigating hemp-derived CBD products, while limited, have reported reductions in opioid use; lower pain and disability scores; and improvements in sleep quality, sleep quantity, and quality of life.
Current treatments for chronic pain are inadequate. Opioid analgesics present a wide array of serious and nonserious risks, including adverse effects, opioid use disorders, and overdose mortality. Clinical evidence does not support the safety and efficacy of long-term opioid use, and such use has led to an epidemic of opioid dependence and mortality.11 Nonopioid analgesics pose risks of their own, along with cumulative toxicity in target organs and potential drug interactions. Risks are also attributable to the route of administration, as most of these medications are taken orally, which increases the risk of adverse effects.
Topical agents for treating chronic pain represent a small percentage of the total global market for prescription and over-the-counter (OTC) analgesics ($8.9 billion in 2019 out of an estimated $71.4 billion).12,13 This route of administration avoids potential gastrointestinal adverse effects, as well as first-pass metabolism. Given the lower risk of adverse effects, drug interactions, and toxicity as compared to oral treatments, and the high reported tolerability,9,14 topical treatments for chronic pain may represent an underutilized therapy.
Cannabinoids and Pain
In general, phytocannabinoids mediate their effects by binding to specific G-protein coupled receptors (ie, cannabinoid receptor 1 [CB1] and cannabinoid receptor 2 [CB2]). CB1 receptors are principally found on neurons and glial cells in the central and peripheral nervous systems, while CB2 receptors are principally found on immune cells and tissues.15,16 CBD has been described as a “promiscuous ligand” due to its interactions with a broad range of other molecular targets, including noncannabinoid receptors (eg, transient receptor potential vanilloid type 1 [TRPV1],17 G protein-coupled receptor 55 [GPR55],18,19 adenosine receptor subtype A1A,20 5-hydroxytryptamine receptor subtype 1A [5-HT1A], and others).21
The mechanisms underlying CBD-induced analgesia are not well understood. Potential pain-relieving mechanisms may include actions at CB1 and CB2 receptors.22-24 CBD has also been shown to inhibit the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL),25,26 which has been associated with increased endocannabinoid levels, analgesia, and opioid-sparing effects in preclinical models of pain.27 Interestingly, a 2019 case report of a woman, aged 66 years, with a microdeletion of a pseudogene that codes for FAAH reported no requirement for postoperative analgesia following a normally painful orthopedic hand surgery (trapeziectomy) along with a lifelong history of painless injuries.28
CBD has also been shown to act as a TRPV1 agonist of potency equivalent to the exogenous ligand capsaicin,29-31 although not all studies concur.32 TRPV1 is thought to modulate inflammation, temperature, and pain perception and is a known antinociception target.17 Activation of TRPV1, including by phytocannabinoids, has been shown to inhibit hyperalgesia in an animal model of acute pain.17,33
Broadly speaking, cannabinoids are powerful modulators of inflammatory mediators.34-36 For example, inhibition of tumor necrosis factor-alpha (TNF-α) and other inflammatory mediators by CBD has been demonstrated in a rodent model of acute pain37 and in another of rheumatoid arthritis.38 Enhancement of adenosine signaling by CBD through inhibition of adenosine uptake has been associated with decreased inflammation in other preclinical models.20,39
The Entourage Effect
Cannabis spp have been called “the plant of the thousand and one molecules” because of the phytochemical diversity of the constituents (eg, cannabinoids, terpenoids, fatty acids).40 Growing research has focused on identifying synergistic interactions of major and minor constituents in extracts, a phenomenon popularized as the entourage effect.41
Compared to highly purified plant extracts, which may be composed of more than 95% CBD, less-refined extracts (ie, “full spectrum” or “broad spectrum”) contain a multitude of biologically active compounds, in addition to CBD. This potentially introduces the possibility of interactions among these constituents (ie, entourage effects), including dermal delivery enhancement mediated by terpenes and terpenoids.42
Cutaneous Application of Cannabinoids
Oral methods of administering CBD products are most common. Enteric bioavailability of CBD is low, however, due to the hydrophobic nature of CBD and first-pass metabolism.1,43 Topical or transdermal administration is also popular.1 While evidence of topical phytocannabinoid absorption is limited, experimental models of human skin have measured skin permeation rates of delta-9-tetrahydrocannabinol (delta-9-THC or THC; CBD is a structural isomer of THC).44 Animal studies with plasma data also show transdermal penetration of cannabinoids into the bloodstream of different animal species.45,46 In one study, topical CB1 and CB2 agonists reduced pain behaviors when applied peripherally in a rodent model of muscular pain.22 In another, transdermal CBD reduced inflammation and pain-related behaviors in a rat model of arthritis; the researchers also observed reductions in joint swelling, limb posture scores (as a rating of spontaneous pain), immune cell infiltration, and thickening of the synovial membrane in a dose-dependent manner.22
Different cannabinoids have higher barriers to penetration than others. In animal models, for example, CBD crosses the skin barrier much more easily, by a factor of 10, than delta-8-tetrahydrocannabinol.47 CBD is also more easily absorbed through the skin than cannabinol (CBN). Carriers such as ethanol may enhance topical penetration across the skin.47 Topical effects appear to be concentration-dependent, meaning that in animal models, a more concentrated product yielded better experimental results than those with lower cannabinoid content.24,48,49
Clinical trials using topical cannabinoid-containing products are scant but desperately needed. In one small case report, topical cannabis was associated with pain relief and reduced opioid use in 3 patients with pyoderma gangrenosum.50 In another small human study, topical therapy with a cannabinoid receptor agonist for facial postherpetic neuralgia was effective and well-tolerated.51
Randomized, controlled trials are needed to substantiate anecdotal claims of the efficacy of topical CBD products for pain. Future research should focus on placebo-controlled clinical studies that compare full-spectrum cannabis extracts to isolated constituents, such as CBD, and to placebo. These studies should specifically evaluate pharmacokinetics and clinically relevant safety, tolerability, and efficacy endpoints.
Given the widespread use of over-the-counter CBD products, the position of the FDA on topical products specifically, and the relative safety of this route of administration, investments in clinical research in this domain are important. While the experimental evidence base is not yet adequate for drawing strong conclusions about efficacy, there is enough evidence to warrant a clinical exploration of these products by healthcare professionals.
Conflicts of Interest Statement
Jake F. Felice, ND, LMP is a consultant and founder of Cannabis Matrix Consulting LLC, and former National Hemp Educator at Manitoba Harvest Fresh Hemp Foods. J.C. is the Medical Director at the Center for Medical Cannabis Education, a for-profit clinical, research and consulting entity.
- Corroon J, Phillips JA. A cross-sectional study of cannabidiol users. Cannabis Cannabinoid Res. 2018;3(1):152-16
- Health Canada. Health products containing cannabis or for use with cannabis: guidance for the Cannabis Act, the Food and Drugs Act, and related regulations. Government of Canada website. https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/guidance-cannabis-act-food-and-drugs-act-related-regulations/document.html#a34. Accessed June 9, 2021.
- FDA regulation of cannabis and cannabis-derived products, including cannabidiol (CBD). U.S. Food and Drug Administration website. https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd. Accessed June 9, 2021.
- Corroon J, MacKay D, Dolphin W. Labeling of cannabidiol products: a public health perspective. Cannabis Cannabinoid Res.2020;5(4):274-278.
- Capano A, Weaver R, Burkman E. Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: a prospective cohort study. Postgrad Med. 2020;132(1):56-61.
- Lopez HL, Cesareo KR, Raub B, et al. Effects of hemp extract on markers of wellness, stress resilience, recovery and clinical biomarkers of safety in overweight, but otherwise healthy subjects. J Diet Suppl. 2020;17(5):561-586
- Schappert SM, Burt CW. Ambulatory care visits to physician offices, hospital outpatient departments, and emergency departments: United States, 2001-02. Vital Health Stat 13. 2006(159):1-66.
- Gureje O, Von Korff M, Simon GE, et al. Persistent pain and well-being: a World Health Organization Study in primary care. JAMA. 1998;280(2):147-151.
- Smith BH, Elliott AM, Chambers WA, et al. The impact of chronic pain in the community. Fam Pract. 2001;18(3):292-29
- Institute of Medicine Committee on Advancing Pain Research Care and Education. The National Academies Collection: Reports funded by National Institutes of Health. In: Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Press (US) National Academy of Sciences; 2011.
- Understanding the epidemic. Centers for Disease Control and Prevention website. https://www.cdc.gov/drugoverdose/epidemic/index.html. Accessed June 9. 2021.
- Bhardwaj V, Sumant O. Topical pain relief market. Allied Market Research website. https://www.alliedmarketresearch.com/topical-pain-relief-market. Accessed June 9, 2021.
- Pain Management Drugs Market Size | Analysis & Forecast 2027. @Allied_MR. https://www.alliedmarketresearch.com/pain-management-therapeutics-market. Published 2021. Accessed June 27, 2021.
- Peppin JF, Albrecht PJ, Argoff C, et al. Skin matters: a review of topical treatments for chronic pain. Part two: treatments and applications. Pain Ther. 2015;4(1):33-50.
- Galiegue S, Mary S, Marchand J, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995;232(1):54-61.
- Tuduri E, Imbernon M, Hernandez-Bautista RJ, et al. GPR55: a new promising target for metabolism? J Mol Endocrinol. 2017;58(3):R191-R202.
- Costa B, Giagnoni G, Franke C, et al. Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. Br J Pharmacol. 2004;143(2):247-250.
- Pertwee RG. GPR55: a new member of the cannabinoid receptor clan? Br J Pharmacol. 2007;152(7):984-986.
- Pertwee RG, Howlett AC, Abood ME, et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB(1) and CB(2). Pharmacol Rev. 2010;62(4):588-631.
- Carrier EJ, Auchampach JA, Hillard CJ. Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci United S A. 2006;103(20):7895-7900.
- Russo EB, Burnett A, Hall B, et al. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005;30(8):1037-1043.
- Sanchez Robles EM, Bagues Arias A, Martin Fontelles MI. Cannabinoids and muscular pain. Effectiveness of the local administration in rat. Eur J Pain. 2012;16(8):1116-1127.
- Zhu CZ, Mikusa JP, Fan Y, et al. Peripheral and central sites of action for the non-selective cannabinoid agonist WIN 55,212-2 in a rat model of post-operative pain. Br J Pharmacol. 2009;157(4):645-655.
- Dogrul A, Gul H, Akar A, et al. Topical cannabinoid antinociception: synergy with spinal sites. Pain. 2003;105(1-2):11-16.
- Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2:e94.
- Di Marzo V, Piscitelli F. The endocannabinoid system and its modulation by phytocannabinoids. Neurotherapeutics. 2015;12(4):692-698.
- Wilkerson JL, Ghosh S, Mustafa M, et al. The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice. Neuropharmacology. 2017;114:156-167.
- Habib AM, Okorokov AL, Hill MN, et al. Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity. Br J Anaesth. 2019;123(2):e249-253.
- Bisogno T, Hanus L, De Petrocellis L, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134(4):845-852.
- De Petrocellis L, Ligresti A, Moriello AS, et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2011;163(7):1479-1494.
- Starkus J, Jansen C, Shimoda LMN, et al. Diverse TRPV1 responses to cannabinoids. Channels (Austin). 2019;13(1):172-191.
- Heblinski Marika, Santiago Marina, Fletcher Charlotte, et al. Terpenoids commonly found in Cannabis sativa do not modulate the actions of phytocannabinoids or endocannabinoids on TRPA1 and TRPV1 channels. Cannabis Cannabinoid Res. 2020;5(4):305-317.
- Akopian AN, Ruparel NB, Jeske NA, et al. Role of ionotropic cannabinoid receptors in peripheral antinociception and antihyperalgesia. Trends Pharmacol Sci. 2009;30(2):79-84.
- Klein TW, Newton C, Larsen K, et al. The cannabinoid system and immune modulation. J Leukoc Biol. 2003;74(4):486-496.
- Klein TW, Lane B, Newton CA, et al. The cannabinoid system and cytokine network. Proc Soc Exp Biol Med. 2000;225(1):1-8.
- Klein TW. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol. 2005;5(5):400-411.
- Gallily R, Yekhtin Z, Hanus L. Overcoming the bell-shaped dose-response of cannabidiol by using Cannabis extract enriched in cannabidiol. Pharmacol Pharm. 2015;6:75-85.
- Malfait AM, Gallily R, Sumariwalla PF, et al. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci U S America. 2000;97(17):9561-9566.
- Olah A, Toth BI, Borbiro I, et al. Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. J Clin Invest. 2014;124(9):3713-3724.
- Andre CM, Hausman JF, Guerriero G. Cannabis sativa: the plant of the thousand and one molecules. Front Plant Sci. 2016; 7:19.
- Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344-1364.
- I Nikolic, E Mitsou, I Pantelic, et al. Microstructure and biopharmaceutical performances of curcumin-loaded low-energy nanoemulsions containing eucalyptol and pinene: Terpenes' role overcome penetration enhancement effect? Eur J Pharmaceutical Sci. 2020;142:105135.
- Mechoulam R, Hanus L. Cannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspects. Chem Phys Lipids. 2002;121(1-2):35-
- Challapalli PV, Stinchcomb AL. In vitro experiment optimization for measuring tetrahydrocannabinol skin permeation. Int J Pharm. 2002;241(2):329-339.
- Lodzki M, Godin B, Rakou L, et al. Cannabidiol-transdermal delivery and anti-inflammatory effect in a murine model. J Control Release.2003;93(3):377-387.
- Paudel KS, Milewski M, Swadley CL, et al. Challenges and opportunities in dermal/transdermal delivery. Ther Deliv. 2010;1(1):109-131.
- Stinchcomb AL, Valiveti S, Hammell DC, et al. Human skin permeation of Delta8-tetrahydrocannabinol, cannabidiol and cannabinol. J Pharm Pharmacol. 2004;56(3):291-297.
- Hammell DC, Zhang LP, Ma F, et al. Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis. Eur J Pain. 2016;20(6):936-9
- Liput DJ, Hammell DC, Stinchcomb AL, et al. Transdermal delivery of cannabidiol attenuates binge alcohol-induced neurodegeneration in a rodent model of an alcohol use disorder. Pharmacol Biochem Behav. 2013;111:120-127.
- Maida V, Corban J. Topical medical cannabis: a new treatment for wound pain-three cases of pyoderma gangrenosum. J Pain Sympt Manage. 2017;54(5):732-736.
- Phan NQ, Siepmann D, Gralow I, et al. Adjuvant topical therapy with a cannabinoid receptor agonist in facial postherpetic neuralgia. J Dtsch Dermatol Ges. 2010;8(2):88-91.