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The relatively recent discovery of the endogenous cannabinoid system and the quickly evolving, yet still convoluted, legal status of cannabis in the United States has spurred excitement over expanded research opportunities. Despite its checkered legal history, marijuana – derived from Cannabis sativa and Cannabis indica – has long been used for medical purposes and is one of the most widely used drugs throughout the world.1 Modern medicine has deployed this dynamic plant to treat chronic pain, glaucoma, and nausea, and continues to investigate its application in a broad array of conditions: anorexia, spasticity, atherosclerosis, autoimmune disorders, inflammatory bowel disease, multiple sclerosis, spasticity, tumorigenesis, and multiple cutaneous disorders, including acne, eczematous disorders, lichen simplex, melanoma and nonmelanoma skin cancer, melasma, prurigo, pruritus, psoriasis, scleroderma and systemic sclerosis, and seborrheic dermatitis.1-4 This .
Acne
Oláh et al. have demonstrated that the nonpsychotropic phytocannabinoid ((-)-cannabidiol [CBD]) imparts anti-acne benefits by diminishing sebaceous lipid synthesis, decreasing proliferation, and easing inflammation in human SZ95 sebocytes.5 In additional investigations of nonpsychotropic phytocannabinoids and their effects on human sebocyte function, they reported in 2016 that the phytocannabinoids (-)-cannabigerol [CBG] and (-)-cannabigerovarin (CBGV) appear to exhibit promise in treating xerotic and seborrheic skin, and ((-)-cannabichromene [CBC], (-)-cannabidivarin [CBDV], and (-)-delta9-tetrahydrocannabivarin [THCV], in particular, display notable potential as anti-acne ingredients. The investigators added that these compounds, due to their substantial anti-inflammatory effects, warrant consideration for use in treating skin inflammation.5 Previously, Ali and Akhtar conducted a single-blinded, 12-week comparative study in healthy male volunteers to evaluate the effects of twice-daily application of 3% cannabis seed extract cream on human cheek skin. The researchers found the base with 3% cannabis seed extract to be safe and effective, with skin sebum and erythema content on the treated side reduced significantly compared with the side treated only with the control base. They concluded that this well-tolerated formulation could be indicated for the treatment of acne and seborrhea to enhance facial appearance.6
Psoriasis
The endocannabinoid system itself is thought to play a potentially important role in the treatment of psoriasis, as interactions between the immune and nervous systems via cholinergic anti-inflammatory pathways are considered to be key in psoriasis etiology and the endocannabinoid system interacts with both systems through the cannabinoid (CB) receptors CB1 and CB2.7 Compared with normal human skin, psoriatic skin is characterized by fewer CB receptors.8
In 2007, Wilkinson and Williamson used a keratinocyte proliferation assay to study the phytocannabinoids delta9-tetrahydrocannabinol (THC), CBD, CBG, and cannabinol (CNB) to assess their capacity to halt the growth of a hyper-proliferating human keratinocyte cell line with an eye toward potential use in treating psoriasis. CB1 and CB2 receptors were confirmed present by Western blot and RT-PCR analyses. All cannabinoids investigated concentration-dependently hindered keratinocyte proliferation, as the authors concluded that these compounds show potential for use in psoriasis treatment.9
In 2013, Ramot et al. found that treating human skin culture with the CB1-specific agonist arachidonoyl-chloro-ethanolamide reduced the expression of keratins K6 and K16 in vitro and in situ, which may have implications for psoriasis treatment as K6 and K16 are upregulated in that disorder.10 The same team has also recently shown that the CB1 agonist arachidonyl-2’-chloroethylamide upregulated K10 protein expression in human epidermis and reduced K1 in human skin culture thus suggesting its potential as a treatment for epidermolytic ichthyosis.11
Notably, the synthetic cannabinoid JWH-133, known for its potent antiangiogenic and anti-inflammatory properties, has been shown in vivo and in vitro to suppress various inflammatory cytokines and angiogenic growth factors involved in psoriasis pathogenesis, including hypoxia inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor (VEGF), matrix metalloproteinases, basic fibroblast growth factor (bFGF), angiopoietin-2, interleukin-8 (IL-8), IL-17, and IL-2. While more research is necessary to determine the safety and efficacy of this product, it appears promising as an anti-psoriatic agent.12
Pruritus
Stimulation of the CB1 receptor has been demonstrated to inhibit histamine-induced pruritus.8
In 2005, Szepietowski et al. conducted a preliminary study to ascertain the efficacy and tolerance of a cream with structured physiological lipids and endogenous cannabinoids in managing pruritus in 21 patients on maintenance dialysis. For 3 weeks, the patients with uremic pruritus applied the test cream twice daily, with eight patients experiencing full eradication of pruritus at the end of this period. Further, xerosis was completely eliminated in 17 patients after the study, and significantly decreased during the 3-week period. The investigators suggested that while more research was needed, the well-tolerated product is thought to have been enhanced by the addition of endocannabinoids.13
A year later, Ständer et al. assessed the effects of the use of the topical cannabinoid agonist N-palmitoyl ethanolamine (PEA), which stimulates the endocannabinoid arachidonoyl ethanolamide (AEA) to activate CB1, in an open application study with 22 patients with prurigo, lichen simplex, and pruritus. Antipruritic benefits were seen in 14 patients, with an average decrease in itch of 86.4%. The treatment was reported to be well tolerated, as no patients complained of adverse effects such as contact dermatitis or a burning sensation.14
Eczematic dermatoses
Atopic dermatitis
In a small pilot study on pediatric atopic dermatitis in 2007, Pulvirenti et al. evaluated the safety and efficacy of the twice-daily application of a topical emulsion containing a synthetic aliamide (adelmidrol 2%), comparable to its parent substance PEA, in the treatment of 11 males and 9 females with atopic dermatitis (AD), whose mean age was 8 years. Among the 20 pediatric patients, 16 experienced complete resolution of symptoms after 4 weeks of treatment and had no relapses at the 8-week follow-up assessment. No improvement was noted in the six patches of AD in six patients with several untreated lesions that served as controls.15 Also in 2007, Del Rosso reported on a trial in which a PEA-containing nonsteroidal cream significantly lowered the mean time between flares in pediatric and adult AD patients.16
One year later, Eberlein et al. evaluated an emollient containing PEA in AD patients, finding that itch severity and sleep loss were improved by an average of 60%, with 38% of participants stopping oral antihistamines, 33.6% discontinuing topical steroid regimens, and 20% ending their use of topical immunomodulators as the study concluded.4,17
In 2018, Río et al. suggested that targeted manipulation of the endocannabinoid system at various AD stages might rein in the inflammatory and immune responses and ensuing alterations in keratinocytes, thus helping to preserve epidermal barrier function.18 As Trusler et al. noted, though, no control groups were used in the latter two studies, so it is unknown what effect the application of the vehicle alone would have had on the pruritus in these patients.19
Allergic contact dermatitis
In 2007, Karsak et al. demonstrated that mice lacking CB1/2 receptors exhibited aggravated contact hypersensitivity, whereas mice with higher levels of AEA evinced lower cutaneous allergic responses.20
Recently, Petrosino et al. provided the first evidence that the nonpsychotropic cannabinoid cannabidiol conferred anti-inflammatory activity in an experimental in vitro model of allergic contact dermatitis.21
Dermatomyositis
Robinson et al. have found that treating blood samples of patients with dermatomyositis with the nonpsychoactive cannabinoid ajulemic acid appears to limit the production of pathogenic cytokines. They suggest that oral administration of this cannabinoid merits consideration for dermatomyositis.22
Skin cancer
In 2015, Glodde et al. used a mouse model to investigate the role of cannabinoids in skin cancer pathogenesis. They considered THC, which binds to CB1 and CB2, and the endogenous cannabinoid system. The researchers found that in a CB receptor-dependent fashion THC significantly hindered the tumor growth of HCmel12 melanomas in vivo, verifying the merit of exogenous cannabinoids in melanoma treatment. They did not identify a role of the endogenous cannabinoid system in skin cancer pathogenesis.23
Additional studies suggest that endocannabinoids, phytocannabinoids, and synthetic cannabinoids diminish skin cancer growth (melanoma and nonmelanoma) in vitro and in vivo through CB receptor-dependent and -independent pathways, though in vivo human studies have not yet been conducted.8,24
Epidermolysis bullosa
In a promising observational study in 2018, Chelliah et al. reported on three cases of self-initiated topical cannabidiol use in patients with epidermolysis bullosa. Each patient experienced more rapid wound healing, less blistering, and reduced pain as a result of cannabidiol treatment, and one was able to discontinue oral opioids. The authors were encouraged by such findings, but cautioned that randomized, double-blind clinical trials are needed to establish cannabidiol as an effective therapy.25
This seems particularly important given the climate of expanding legalization of medical and recreational cannabis use, as well as the increasing use of topical cannabinoids among dermatology patients.26 Nevertheless, it is important to be cognizant of one’s own state laws as topical cannabinoids may be restricted; these products are marketed for pain and pruritus on the Internet but are unavailable by prescription unless the physician has a special license.4
Attitudes about cannabinoid use in dermatology
In an intriguing study last year about the knowledge, cognizance, and perceptions of cannabinoids among dermatologists, Robinson et al. created a 20-question online survey that netted a response rate of 21% (n = 531). In terms of awareness, 29% of respondents did not know that THC is psychoactive and a significant majority (64%) did not know that CBD is not psychoactive. Nevertheless, the majority thought that cannabinoids should be legal for medical treatment (86%), and even more (94%) support researching dermatologic applications of cannabinoids. More responders (86%) would prescribe a Food and Drug Administration–approved cannabinoid-containing topical formulation than an oral product (71%). In also noting that 55% revealed at least one conversation about cannabinoids initiated by a patient in the previous year, while 48% expressed concern about a possible stigma associated with suggesting cannabinoid treatments to patients, Robinson et al. call for further education about the benefits and risks of cutaneous cannabinoids for dermatologists.27
Conclusion
It is important that we educate ourselves as to the effects of orally administered and topical products containing cannabis so that we are prepared for questions from patients. Data on psoriasis, pruritus, eczema, and acne warrant optimism and much additional research. Now that the FDA is allowing research sites to enroll for a special license to investigate schedule I drugs, we stand to learn much more about the various effects on the health benefits of cannabis. Despite the longstanding traditional use of C. sativa and C. indica, we are in the early stages of research on the impact of phytocannabinoids and synthetic cannabinoids on human health and the role that the endocannabinoid system plays. The extant findings provide reasons to consider the endocannabinoid system as a target for therapeutic intervention for various cutaneous disorders as research continues.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. She has no relevant disclosures related to this column. Write to her at dermnews@mdedge.com.
References
1. Russo EB. Chem Biodivers. 2007 Aug;4(8):1614-48.
2. Goldenberg M et al. Drug Alcohol Depend. 2017 May 1;174:80-90.
3. Mounessa JS et al. J Am Acad Dermatol. 2017 Jul;77(1):188-90.
4. Shalaby M et al. Pract Dermatol. 2018;68-70.
5. Oláh A et al. Exp Dermatol. 2016 Sep;25(9):701-7.
6. Ali A et al. Pak J Pharm Sci. 2015 Jul;28(4):1389-95.
7. Derakhshan N et al. Curr Clin Pharmacol. 2016;11(2):146-7.
8. Singh D et al. Clin Dermatol. 2018 May-Jun;36(3):399-419.
9. Wilkinson JD et al. J Dermatol Sci. 2007 Feb;45(2):87-92.
10. Ramot Y et al. PeerJ. 2013 Feb 19;1:e40.
11. Ramot Y et al. Br J Dermatol. 2018 Jun;178(6):1469.
12. Norooznezhad AH et al. Med Hypotheses. 2017 Feb;99:15-18.
13. Szepietowski JC et al. Acta Dermatovenerol Croat. 2005;13(2):97-103.
14. Ständer S et al. Hautarzt. 2006 Sep;57(9):801-7.
15. Pulvirenti N et al. Acta Dermatovenerol Croat. 2007;15(2):80-3.
16. Del Rosso JQ. Cosmetic Dermatol. 2007 Apr; 20(4):208-211.
17. Eberlein B et al. J Eur Acad Dermatol Venereol. 2008 Jan;22(1):73-82.
18. Del Río CD et al. Biochem Pharmacol. 2018 Nov;157:122-133.
19. Trusler AR et al. Dermatitis. 2017 Jan/Feb;28(1):22-32.
20. Karsak M et al. Science. 2007 Jun 8;316(5830):1494-7.
21. Petrosino S et al. J Pharmacol Exp Ther. 2018 Jun;365(3):652-63.
22. Robinson ES et al. J Invest Dermatol. 2017 Nov;137(11):2445-7.
23. Glodde N et al. Life Sci. 2015 Oct 1;138:35-40.
24. Soliman E. et al. J Dermatol Clin Res. 2016;4(2):1069-76.
25. Chelliah MP et al. Pediatr Dermatol. 2018 Jul;35(4):e224-e227.
26. Hashim PW et al. Cutis. 2017 Jul;100(1):50-52.
27. Robinson E et al. J Drugs Dermatol. 2018 Dec 1;17(12):1273-8.
The relatively recent discovery of the endogenous cannabinoid system and the quickly evolving, yet still convoluted, legal status of cannabis in the United States has spurred excitement over expanded research opportunities. Despite its checkered legal history, marijuana – derived from Cannabis sativa and Cannabis indica – has long been used for medical purposes and is one of the most widely used drugs throughout the world.1 Modern medicine has deployed this dynamic plant to treat chronic pain, glaucoma, and nausea, and continues to investigate its application in a broad array of conditions: anorexia, spasticity, atherosclerosis, autoimmune disorders, inflammatory bowel disease, multiple sclerosis, spasticity, tumorigenesis, and multiple cutaneous disorders, including acne, eczematous disorders, lichen simplex, melanoma and nonmelanoma skin cancer, melasma, prurigo, pruritus, psoriasis, scleroderma and systemic sclerosis, and seborrheic dermatitis.1-4 This .
Acne
Oláh et al. have demonstrated that the nonpsychotropic phytocannabinoid ((-)-cannabidiol [CBD]) imparts anti-acne benefits by diminishing sebaceous lipid synthesis, decreasing proliferation, and easing inflammation in human SZ95 sebocytes.5 In additional investigations of nonpsychotropic phytocannabinoids and their effects on human sebocyte function, they reported in 2016 that the phytocannabinoids (-)-cannabigerol [CBG] and (-)-cannabigerovarin (CBGV) appear to exhibit promise in treating xerotic and seborrheic skin, and ((-)-cannabichromene [CBC], (-)-cannabidivarin [CBDV], and (-)-delta9-tetrahydrocannabivarin [THCV], in particular, display notable potential as anti-acne ingredients. The investigators added that these compounds, due to their substantial anti-inflammatory effects, warrant consideration for use in treating skin inflammation.5 Previously, Ali and Akhtar conducted a single-blinded, 12-week comparative study in healthy male volunteers to evaluate the effects of twice-daily application of 3% cannabis seed extract cream on human cheek skin. The researchers found the base with 3% cannabis seed extract to be safe and effective, with skin sebum and erythema content on the treated side reduced significantly compared with the side treated only with the control base. They concluded that this well-tolerated formulation could be indicated for the treatment of acne and seborrhea to enhance facial appearance.6
Psoriasis
The endocannabinoid system itself is thought to play a potentially important role in the treatment of psoriasis, as interactions between the immune and nervous systems via cholinergic anti-inflammatory pathways are considered to be key in psoriasis etiology and the endocannabinoid system interacts with both systems through the cannabinoid (CB) receptors CB1 and CB2.7 Compared with normal human skin, psoriatic skin is characterized by fewer CB receptors.8
In 2007, Wilkinson and Williamson used a keratinocyte proliferation assay to study the phytocannabinoids delta9-tetrahydrocannabinol (THC), CBD, CBG, and cannabinol (CNB) to assess their capacity to halt the growth of a hyper-proliferating human keratinocyte cell line with an eye toward potential use in treating psoriasis. CB1 and CB2 receptors were confirmed present by Western blot and RT-PCR analyses. All cannabinoids investigated concentration-dependently hindered keratinocyte proliferation, as the authors concluded that these compounds show potential for use in psoriasis treatment.9
In 2013, Ramot et al. found that treating human skin culture with the CB1-specific agonist arachidonoyl-chloro-ethanolamide reduced the expression of keratins K6 and K16 in vitro and in situ, which may have implications for psoriasis treatment as K6 and K16 are upregulated in that disorder.10 The same team has also recently shown that the CB1 agonist arachidonyl-2’-chloroethylamide upregulated K10 protein expression in human epidermis and reduced K1 in human skin culture thus suggesting its potential as a treatment for epidermolytic ichthyosis.11
Notably, the synthetic cannabinoid JWH-133, known for its potent antiangiogenic and anti-inflammatory properties, has been shown in vivo and in vitro to suppress various inflammatory cytokines and angiogenic growth factors involved in psoriasis pathogenesis, including hypoxia inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor (VEGF), matrix metalloproteinases, basic fibroblast growth factor (bFGF), angiopoietin-2, interleukin-8 (IL-8), IL-17, and IL-2. While more research is necessary to determine the safety and efficacy of this product, it appears promising as an anti-psoriatic agent.12
Pruritus
Stimulation of the CB1 receptor has been demonstrated to inhibit histamine-induced pruritus.8
In 2005, Szepietowski et al. conducted a preliminary study to ascertain the efficacy and tolerance of a cream with structured physiological lipids and endogenous cannabinoids in managing pruritus in 21 patients on maintenance dialysis. For 3 weeks, the patients with uremic pruritus applied the test cream twice daily, with eight patients experiencing full eradication of pruritus at the end of this period. Further, xerosis was completely eliminated in 17 patients after the study, and significantly decreased during the 3-week period. The investigators suggested that while more research was needed, the well-tolerated product is thought to have been enhanced by the addition of endocannabinoids.13
A year later, Ständer et al. assessed the effects of the use of the topical cannabinoid agonist N-palmitoyl ethanolamine (PEA), which stimulates the endocannabinoid arachidonoyl ethanolamide (AEA) to activate CB1, in an open application study with 22 patients with prurigo, lichen simplex, and pruritus. Antipruritic benefits were seen in 14 patients, with an average decrease in itch of 86.4%. The treatment was reported to be well tolerated, as no patients complained of adverse effects such as contact dermatitis or a burning sensation.14
Eczematic dermatoses
Atopic dermatitis
In a small pilot study on pediatric atopic dermatitis in 2007, Pulvirenti et al. evaluated the safety and efficacy of the twice-daily application of a topical emulsion containing a synthetic aliamide (adelmidrol 2%), comparable to its parent substance PEA, in the treatment of 11 males and 9 females with atopic dermatitis (AD), whose mean age was 8 years. Among the 20 pediatric patients, 16 experienced complete resolution of symptoms after 4 weeks of treatment and had no relapses at the 8-week follow-up assessment. No improvement was noted in the six patches of AD in six patients with several untreated lesions that served as controls.15 Also in 2007, Del Rosso reported on a trial in which a PEA-containing nonsteroidal cream significantly lowered the mean time between flares in pediatric and adult AD patients.16
One year later, Eberlein et al. evaluated an emollient containing PEA in AD patients, finding that itch severity and sleep loss were improved by an average of 60%, with 38% of participants stopping oral antihistamines, 33.6% discontinuing topical steroid regimens, and 20% ending their use of topical immunomodulators as the study concluded.4,17
In 2018, Río et al. suggested that targeted manipulation of the endocannabinoid system at various AD stages might rein in the inflammatory and immune responses and ensuing alterations in keratinocytes, thus helping to preserve epidermal barrier function.18 As Trusler et al. noted, though, no control groups were used in the latter two studies, so it is unknown what effect the application of the vehicle alone would have had on the pruritus in these patients.19
Allergic contact dermatitis
In 2007, Karsak et al. demonstrated that mice lacking CB1/2 receptors exhibited aggravated contact hypersensitivity, whereas mice with higher levels of AEA evinced lower cutaneous allergic responses.20
Recently, Petrosino et al. provided the first evidence that the nonpsychotropic cannabinoid cannabidiol conferred anti-inflammatory activity in an experimental in vitro model of allergic contact dermatitis.21
Dermatomyositis
Robinson et al. have found that treating blood samples of patients with dermatomyositis with the nonpsychoactive cannabinoid ajulemic acid appears to limit the production of pathogenic cytokines. They suggest that oral administration of this cannabinoid merits consideration for dermatomyositis.22
Skin cancer
In 2015, Glodde et al. used a mouse model to investigate the role of cannabinoids in skin cancer pathogenesis. They considered THC, which binds to CB1 and CB2, and the endogenous cannabinoid system. The researchers found that in a CB receptor-dependent fashion THC significantly hindered the tumor growth of HCmel12 melanomas in vivo, verifying the merit of exogenous cannabinoids in melanoma treatment. They did not identify a role of the endogenous cannabinoid system in skin cancer pathogenesis.23
Additional studies suggest that endocannabinoids, phytocannabinoids, and synthetic cannabinoids diminish skin cancer growth (melanoma and nonmelanoma) in vitro and in vivo through CB receptor-dependent and -independent pathways, though in vivo human studies have not yet been conducted.8,24
Epidermolysis bullosa
In a promising observational study in 2018, Chelliah et al. reported on three cases of self-initiated topical cannabidiol use in patients with epidermolysis bullosa. Each patient experienced more rapid wound healing, less blistering, and reduced pain as a result of cannabidiol treatment, and one was able to discontinue oral opioids. The authors were encouraged by such findings, but cautioned that randomized, double-blind clinical trials are needed to establish cannabidiol as an effective therapy.25
This seems particularly important given the climate of expanding legalization of medical and recreational cannabis use, as well as the increasing use of topical cannabinoids among dermatology patients.26 Nevertheless, it is important to be cognizant of one’s own state laws as topical cannabinoids may be restricted; these products are marketed for pain and pruritus on the Internet but are unavailable by prescription unless the physician has a special license.4
Attitudes about cannabinoid use in dermatology
In an intriguing study last year about the knowledge, cognizance, and perceptions of cannabinoids among dermatologists, Robinson et al. created a 20-question online survey that netted a response rate of 21% (n = 531). In terms of awareness, 29% of respondents did not know that THC is psychoactive and a significant majority (64%) did not know that CBD is not psychoactive. Nevertheless, the majority thought that cannabinoids should be legal for medical treatment (86%), and even more (94%) support researching dermatologic applications of cannabinoids. More responders (86%) would prescribe a Food and Drug Administration–approved cannabinoid-containing topical formulation than an oral product (71%). In also noting that 55% revealed at least one conversation about cannabinoids initiated by a patient in the previous year, while 48% expressed concern about a possible stigma associated with suggesting cannabinoid treatments to patients, Robinson et al. call for further education about the benefits and risks of cutaneous cannabinoids for dermatologists.27
Conclusion
It is important that we educate ourselves as to the effects of orally administered and topical products containing cannabis so that we are prepared for questions from patients. Data on psoriasis, pruritus, eczema, and acne warrant optimism and much additional research. Now that the FDA is allowing research sites to enroll for a special license to investigate schedule I drugs, we stand to learn much more about the various effects on the health benefits of cannabis. Despite the longstanding traditional use of C. sativa and C. indica, we are in the early stages of research on the impact of phytocannabinoids and synthetic cannabinoids on human health and the role that the endocannabinoid system plays. The extant findings provide reasons to consider the endocannabinoid system as a target for therapeutic intervention for various cutaneous disorders as research continues.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. She has no relevant disclosures related to this column. Write to her at dermnews@mdedge.com.
References
1. Russo EB. Chem Biodivers. 2007 Aug;4(8):1614-48.
2. Goldenberg M et al. Drug Alcohol Depend. 2017 May 1;174:80-90.
3. Mounessa JS et al. J Am Acad Dermatol. 2017 Jul;77(1):188-90.
4. Shalaby M et al. Pract Dermatol. 2018;68-70.
5. Oláh A et al. Exp Dermatol. 2016 Sep;25(9):701-7.
6. Ali A et al. Pak J Pharm Sci. 2015 Jul;28(4):1389-95.
7. Derakhshan N et al. Curr Clin Pharmacol. 2016;11(2):146-7.
8. Singh D et al. Clin Dermatol. 2018 May-Jun;36(3):399-419.
9. Wilkinson JD et al. J Dermatol Sci. 2007 Feb;45(2):87-92.
10. Ramot Y et al. PeerJ. 2013 Feb 19;1:e40.
11. Ramot Y et al. Br J Dermatol. 2018 Jun;178(6):1469.
12. Norooznezhad AH et al. Med Hypotheses. 2017 Feb;99:15-18.
13. Szepietowski JC et al. Acta Dermatovenerol Croat. 2005;13(2):97-103.
14. Ständer S et al. Hautarzt. 2006 Sep;57(9):801-7.
15. Pulvirenti N et al. Acta Dermatovenerol Croat. 2007;15(2):80-3.
16. Del Rosso JQ. Cosmetic Dermatol. 2007 Apr; 20(4):208-211.
17. Eberlein B et al. J Eur Acad Dermatol Venereol. 2008 Jan;22(1):73-82.
18. Del Río CD et al. Biochem Pharmacol. 2018 Nov;157:122-133.
19. Trusler AR et al. Dermatitis. 2017 Jan/Feb;28(1):22-32.
20. Karsak M et al. Science. 2007 Jun 8;316(5830):1494-7.
21. Petrosino S et al. J Pharmacol Exp Ther. 2018 Jun;365(3):652-63.
22. Robinson ES et al. J Invest Dermatol. 2017 Nov;137(11):2445-7.
23. Glodde N et al. Life Sci. 2015 Oct 1;138:35-40.
24. Soliman E. et al. J Dermatol Clin Res. 2016;4(2):1069-76.
25. Chelliah MP et al. Pediatr Dermatol. 2018 Jul;35(4):e224-e227.
26. Hashim PW et al. Cutis. 2017 Jul;100(1):50-52.
27. Robinson E et al. J Drugs Dermatol. 2018 Dec 1;17(12):1273-8.
The relatively recent discovery of the endogenous cannabinoid system and the quickly evolving, yet still convoluted, legal status of cannabis in the United States has spurred excitement over expanded research opportunities. Despite its checkered legal history, marijuana – derived from Cannabis sativa and Cannabis indica – has long been used for medical purposes and is one of the most widely used drugs throughout the world.1 Modern medicine has deployed this dynamic plant to treat chronic pain, glaucoma, and nausea, and continues to investigate its application in a broad array of conditions: anorexia, spasticity, atherosclerosis, autoimmune disorders, inflammatory bowel disease, multiple sclerosis, spasticity, tumorigenesis, and multiple cutaneous disorders, including acne, eczematous disorders, lichen simplex, melanoma and nonmelanoma skin cancer, melasma, prurigo, pruritus, psoriasis, scleroderma and systemic sclerosis, and seborrheic dermatitis.1-4 This .
Acne
Oláh et al. have demonstrated that the nonpsychotropic phytocannabinoid ((-)-cannabidiol [CBD]) imparts anti-acne benefits by diminishing sebaceous lipid synthesis, decreasing proliferation, and easing inflammation in human SZ95 sebocytes.5 In additional investigations of nonpsychotropic phytocannabinoids and their effects on human sebocyte function, they reported in 2016 that the phytocannabinoids (-)-cannabigerol [CBG] and (-)-cannabigerovarin (CBGV) appear to exhibit promise in treating xerotic and seborrheic skin, and ((-)-cannabichromene [CBC], (-)-cannabidivarin [CBDV], and (-)-delta9-tetrahydrocannabivarin [THCV], in particular, display notable potential as anti-acne ingredients. The investigators added that these compounds, due to their substantial anti-inflammatory effects, warrant consideration for use in treating skin inflammation.5 Previously, Ali and Akhtar conducted a single-blinded, 12-week comparative study in healthy male volunteers to evaluate the effects of twice-daily application of 3% cannabis seed extract cream on human cheek skin. The researchers found the base with 3% cannabis seed extract to be safe and effective, with skin sebum and erythema content on the treated side reduced significantly compared with the side treated only with the control base. They concluded that this well-tolerated formulation could be indicated for the treatment of acne and seborrhea to enhance facial appearance.6
Psoriasis
The endocannabinoid system itself is thought to play a potentially important role in the treatment of psoriasis, as interactions between the immune and nervous systems via cholinergic anti-inflammatory pathways are considered to be key in psoriasis etiology and the endocannabinoid system interacts with both systems through the cannabinoid (CB) receptors CB1 and CB2.7 Compared with normal human skin, psoriatic skin is characterized by fewer CB receptors.8
In 2007, Wilkinson and Williamson used a keratinocyte proliferation assay to study the phytocannabinoids delta9-tetrahydrocannabinol (THC), CBD, CBG, and cannabinol (CNB) to assess their capacity to halt the growth of a hyper-proliferating human keratinocyte cell line with an eye toward potential use in treating psoriasis. CB1 and CB2 receptors were confirmed present by Western blot and RT-PCR analyses. All cannabinoids investigated concentration-dependently hindered keratinocyte proliferation, as the authors concluded that these compounds show potential for use in psoriasis treatment.9
In 2013, Ramot et al. found that treating human skin culture with the CB1-specific agonist arachidonoyl-chloro-ethanolamide reduced the expression of keratins K6 and K16 in vitro and in situ, which may have implications for psoriasis treatment as K6 and K16 are upregulated in that disorder.10 The same team has also recently shown that the CB1 agonist arachidonyl-2’-chloroethylamide upregulated K10 protein expression in human epidermis and reduced K1 in human skin culture thus suggesting its potential as a treatment for epidermolytic ichthyosis.11
Notably, the synthetic cannabinoid JWH-133, known for its potent antiangiogenic and anti-inflammatory properties, has been shown in vivo and in vitro to suppress various inflammatory cytokines and angiogenic growth factors involved in psoriasis pathogenesis, including hypoxia inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor (VEGF), matrix metalloproteinases, basic fibroblast growth factor (bFGF), angiopoietin-2, interleukin-8 (IL-8), IL-17, and IL-2. While more research is necessary to determine the safety and efficacy of this product, it appears promising as an anti-psoriatic agent.12
Pruritus
Stimulation of the CB1 receptor has been demonstrated to inhibit histamine-induced pruritus.8
In 2005, Szepietowski et al. conducted a preliminary study to ascertain the efficacy and tolerance of a cream with structured physiological lipids and endogenous cannabinoids in managing pruritus in 21 patients on maintenance dialysis. For 3 weeks, the patients with uremic pruritus applied the test cream twice daily, with eight patients experiencing full eradication of pruritus at the end of this period. Further, xerosis was completely eliminated in 17 patients after the study, and significantly decreased during the 3-week period. The investigators suggested that while more research was needed, the well-tolerated product is thought to have been enhanced by the addition of endocannabinoids.13
A year later, Ständer et al. assessed the effects of the use of the topical cannabinoid agonist N-palmitoyl ethanolamine (PEA), which stimulates the endocannabinoid arachidonoyl ethanolamide (AEA) to activate CB1, in an open application study with 22 patients with prurigo, lichen simplex, and pruritus. Antipruritic benefits were seen in 14 patients, with an average decrease in itch of 86.4%. The treatment was reported to be well tolerated, as no patients complained of adverse effects such as contact dermatitis or a burning sensation.14
Eczematic dermatoses
Atopic dermatitis
In a small pilot study on pediatric atopic dermatitis in 2007, Pulvirenti et al. evaluated the safety and efficacy of the twice-daily application of a topical emulsion containing a synthetic aliamide (adelmidrol 2%), comparable to its parent substance PEA, in the treatment of 11 males and 9 females with atopic dermatitis (AD), whose mean age was 8 years. Among the 20 pediatric patients, 16 experienced complete resolution of symptoms after 4 weeks of treatment and had no relapses at the 8-week follow-up assessment. No improvement was noted in the six patches of AD in six patients with several untreated lesions that served as controls.15 Also in 2007, Del Rosso reported on a trial in which a PEA-containing nonsteroidal cream significantly lowered the mean time between flares in pediatric and adult AD patients.16
One year later, Eberlein et al. evaluated an emollient containing PEA in AD patients, finding that itch severity and sleep loss were improved by an average of 60%, with 38% of participants stopping oral antihistamines, 33.6% discontinuing topical steroid regimens, and 20% ending their use of topical immunomodulators as the study concluded.4,17
In 2018, Río et al. suggested that targeted manipulation of the endocannabinoid system at various AD stages might rein in the inflammatory and immune responses and ensuing alterations in keratinocytes, thus helping to preserve epidermal barrier function.18 As Trusler et al. noted, though, no control groups were used in the latter two studies, so it is unknown what effect the application of the vehicle alone would have had on the pruritus in these patients.19
Allergic contact dermatitis
In 2007, Karsak et al. demonstrated that mice lacking CB1/2 receptors exhibited aggravated contact hypersensitivity, whereas mice with higher levels of AEA evinced lower cutaneous allergic responses.20
Recently, Petrosino et al. provided the first evidence that the nonpsychotropic cannabinoid cannabidiol conferred anti-inflammatory activity in an experimental in vitro model of allergic contact dermatitis.21
Dermatomyositis
Robinson et al. have found that treating blood samples of patients with dermatomyositis with the nonpsychoactive cannabinoid ajulemic acid appears to limit the production of pathogenic cytokines. They suggest that oral administration of this cannabinoid merits consideration for dermatomyositis.22
Skin cancer
In 2015, Glodde et al. used a mouse model to investigate the role of cannabinoids in skin cancer pathogenesis. They considered THC, which binds to CB1 and CB2, and the endogenous cannabinoid system. The researchers found that in a CB receptor-dependent fashion THC significantly hindered the tumor growth of HCmel12 melanomas in vivo, verifying the merit of exogenous cannabinoids in melanoma treatment. They did not identify a role of the endogenous cannabinoid system in skin cancer pathogenesis.23
Additional studies suggest that endocannabinoids, phytocannabinoids, and synthetic cannabinoids diminish skin cancer growth (melanoma and nonmelanoma) in vitro and in vivo through CB receptor-dependent and -independent pathways, though in vivo human studies have not yet been conducted.8,24
Epidermolysis bullosa
In a promising observational study in 2018, Chelliah et al. reported on three cases of self-initiated topical cannabidiol use in patients with epidermolysis bullosa. Each patient experienced more rapid wound healing, less blistering, and reduced pain as a result of cannabidiol treatment, and one was able to discontinue oral opioids. The authors were encouraged by such findings, but cautioned that randomized, double-blind clinical trials are needed to establish cannabidiol as an effective therapy.25
This seems particularly important given the climate of expanding legalization of medical and recreational cannabis use, as well as the increasing use of topical cannabinoids among dermatology patients.26 Nevertheless, it is important to be cognizant of one’s own state laws as topical cannabinoids may be restricted; these products are marketed for pain and pruritus on the Internet but are unavailable by prescription unless the physician has a special license.4
Attitudes about cannabinoid use in dermatology
In an intriguing study last year about the knowledge, cognizance, and perceptions of cannabinoids among dermatologists, Robinson et al. created a 20-question online survey that netted a response rate of 21% (n = 531). In terms of awareness, 29% of respondents did not know that THC is psychoactive and a significant majority (64%) did not know that CBD is not psychoactive. Nevertheless, the majority thought that cannabinoids should be legal for medical treatment (86%), and even more (94%) support researching dermatologic applications of cannabinoids. More responders (86%) would prescribe a Food and Drug Administration–approved cannabinoid-containing topical formulation than an oral product (71%). In also noting that 55% revealed at least one conversation about cannabinoids initiated by a patient in the previous year, while 48% expressed concern about a possible stigma associated with suggesting cannabinoid treatments to patients, Robinson et al. call for further education about the benefits and risks of cutaneous cannabinoids for dermatologists.27
Conclusion
It is important that we educate ourselves as to the effects of orally administered and topical products containing cannabis so that we are prepared for questions from patients. Data on psoriasis, pruritus, eczema, and acne warrant optimism and much additional research. Now that the FDA is allowing research sites to enroll for a special license to investigate schedule I drugs, we stand to learn much more about the various effects on the health benefits of cannabis. Despite the longstanding traditional use of C. sativa and C. indica, we are in the early stages of research on the impact of phytocannabinoids and synthetic cannabinoids on human health and the role that the endocannabinoid system plays. The extant findings provide reasons to consider the endocannabinoid system as a target for therapeutic intervention for various cutaneous disorders as research continues.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. She has no relevant disclosures related to this column. Write to her at dermnews@mdedge.com.
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