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Cannabis in Dermatology

Vivien Kibitz, Roman Šedivý

Department of Psychology, SUNY Empire State College

CUST 3996: Cannabis: History, Health and Legalization

Simon Weissenberger, Ph.D.

May 14, 2022

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Cannabinoids in Dermatology

There is a growing trend in the use of cannabinoids to treat a wide range of skin

conditions since there is a large body of evidence on the anti-inflammatory, anti-aging, anti

malignancy and antipruritic properties of cannabinoids. The healing properties of

cannabinoids represent promising avenues for the treatment of inflammatory and autoimmune

skin conditions that may be resistant to conventional therapy. The aim of this paper is to

review the potential utilization of cannabinoids in dermatology, especially in conditions

including psoriasis, acne, pruritus and skin cancer.

Cannabinoids

Cannabinoids are naturally occurring compounds that can be found in the Cannabis

sativa plant. There are three types of cannabinoids based on their origins: Endocannabinoids,

phytocannabinoids and synthetic cannabinoids. Endocannabinoids are produced

endogenously by the body and they serve as intercellular lipid messengers (Chilakapati &

Farris, 2014). The most clinically relevant endocannabinoids are anandamide (AEA) and

2-arachidonoylglycerol (2-AG). Phytocannabinoids are plant-derived and they are found in

cannabis plants, particularly in the stalks, leaves, flowers, resin and seeds of the plant.

Phytocannabinoids consist of over 100 compounds, but the most notable ones are

Tetrahydrocannabinol (THC) and cannabidiol (CBD) (Eagleston et al., 2018). Synthetic

cannabinoids are manufactured artificially to mimic the effects of natural cannabinoids and

they are pure agonists with psychoactive effects (Pertwee, 1997). The first synthetic

cannabinoids that were produced in the 20th century are nabilone and dronabinol and both of

them are approved by the Food and Drug Administration. Nabilone is approved for the

treatment of chemotherapy-induced nausea and vomiting and dronabinol is approved for the

treatment of acquired immunodeficiency syndrome‒induced anorexia and for

chemotherapy-induced nausea and vomiting as well (Sivesind et al., 2022).

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Structure of the Skin

The outermost layer of the skin is the epidermis, consisting of specialized cells called

keratinocytes, langerhans cells, melanocyte cells and squamous cells and it acts as a compact

sheet that is responsible for waterproof protection and barrier against microbes, UV

irradiation, heat and cold, allergens and chemicals. Keratinocytes create and store keratin,

which is responsible for strengthening the skin. Langerhans cells prevent infection and

protect the immune system (Bíró et al., 2009). Melanocyte cells produce melanin which

determines the skin tone. Lastly, squamous cells are able to mutate and they can cause basal

cell carcinoma of the skin. Endocannabinoids have been found to be effective in reducing

inflammation in the epidermis (Eagleston et al., 2018).The middle layer of the skin is dermis,

which contains connective tissue, sweat glands and hair follicles and it plays a role in

immune defense of the skin. The dermis produces two important proteins: collagen and

elastin, which impact the shape, elasticity, structure and firmness of the skin (Bíró et al.,

2009). The bottom layer is made of connective tissue, subcutaneous fat, blood vessels and

nerve cells and the tissue in hypodermis produces adipocytes that store fat used for insulation,

energy and cushioning. Each layer of the skin is supplied by a dense network of nerve fibers.

Sensory nerve endings are stimulated by most types of stimuli and the stimulation results in

tactile sensations such as pressure, pain, vibration, itch, heat or cold (Bíró et al., 2009).

The Skin and the Endocannabinoid System

The endocannabinoid system (ECS) is the most widely distributed receptor system in

the body that needs to adjust to constant change within the body and external environment

and it regulates our biology through homeostasis (Pertwee, 1997). The endocannabinoid

system consists of endocannabinoids, receptors and enzymes that synthesize and breakdown

cannabinoids. The ECS has many functions, with modulation of the central nervous system

and immune function being the most well-researched ones. The main physiological functions
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of the cutaneous ECS have been found to be control and regulation of proliferation,

differentiation and survival and immune competence and/or tolerance of skin cells (Bíró et

al., 2009). The ECS plays a crucial role in maintaining skin homeostasis and barrier function

and the imbalance of the endocannabinoid system might facilitate the development of several

skin conditions such as acne, dermatitis, seborrhea, hyperpigmentation and hypopigmentation

(Bíró et al., 2009; Tóth et al., 2019).

The main receptors of the endocannabinoid system are the CB1 and CB2 receptors.

CB1 and CB2 receptors have endogenous ligands on the skin, suggesting the existence of the

skin's very own ECS. Cannabinoids have both an agonist and antagonist effect on the ECS,

which results in inhibition or activation of keratinocyte proliferation, sebum production, hair

production and inflammation. The CB1 receptors are mainly expressed in the central nervous

system and the brain and the CB2 receptors are primarily found in peripheral organs,

non-neuronal tissues, immune cells and the digestive system (Baswan et al., 2020). CB1 and

CB2 receptors are present in epidermal keratinocytes, dermal cells, melanocytes, hair

follicles, sweat glands and cutaneous nerve fibers. These receptors can be bound by

endogenous or exogenous cannabinoids. The engagement of CB1 and CB2 receptors

modifies the functions of epidermal cells through important processes such as proliferation,

differentiation and apoptosis (Eagleston et al., 2018).

Besides CB1 and CB2 receptors, there are also other receptors - GPR18 and GPR55.

GPR18 is expressed in the spleen, testis, peripheral blood leukocytes and lymph nodes and it

is activated by N-arachidonoyl glycine and the activation leads to apoptosis of inflammatory

leukocytes, resulting in dampening of local inflammation. GPR55 is expressed in the central

nervous system and it is activated by phytocannabinoids delta-THC and endocannabinoids

(Sheriff et al., 2019). Activation of the cannabinoid receptors regulates normal function of the

skin and its barrier function.

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Cannabis for Skin Conditions

Cannabinoids have anti-inflammatory, immunosuppressive, anti-pruritic and

anti-microbial properties and they have been found to be useful in management and treatment

of many dermatological diseases. Cannabinoids are most commonly administered either

orally, topically or by inhalation (Gupta & Talukder). Topical cannabinoids are the most

researched ones in relation to skin conditions. The topical application of cannabinoids for

dermatological conditions may be advantageous due to their ability to act locally at the

disease site. Topical cannabinoids can be purchased in the form of creams, patches, and gels

containing plant-derived, endogenous, or synthetic cannabinoids that are designed for

therapeutic purposes (Hashim et al., 2017). Topical cannabinoids also have fewer respiratory

side effects and they can avoid the first-pass metabolism (Gupta & Talukder, 2021). However,

cannabinoids are hydrophobic in nature and this may hinder percutaneous absorption which

could reduce the final therapeutic effect. Oral administration can be in the form of edible

cannabinoids, which are foods and beverages infused with cannabis. The oral route is not as

advantageous as the topical route because the potency and bioavailability of oral

cannabinoids is quite unpredictable with a delayed onset, which may cause the user to

consume more than needed, eventually leading to intoxication. Lastly, inhaling cannabis by

either smoking or vaping, is associated with respiratory symptoms such as coughing,

wheezing, bronchitis or pulmonary function reduction. Vaping has less respiratory side

effects because the vapor contains less carbon monoxide and toxic substances than the smoke

(Gupta & Talukder, 2021).

Acne and seborrhea are the most common dermatological conditions and they are

characterized by highly elevated sebum (lipid) production. CBD has been found to be

effective in the treatment of acne because the application of CBD to cultured human

sebocytes showed an anti-inflammatory, anti-proliferative and sebostatic effect (Baswan et

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al., 2020). Research shows that manipulation of CB2 might exaggerate and inhibit

inflammatory responses in contact dermatitis. Cannabidiol has also been found to play a role

in immune pathways that are involved in atopic dermatitis. Cannabidiol is capable of

inhibiting migration, proliferation and cell maturation responses. Studies found that applying

a cream that contains palmitoylethanolamide (PEA) and anandamide twice daily for three

weeks reduces the severity of pruritus since anandamide has antipruritic properties and

creams containing lipids and endogenous cannabinoids have been found to be effective in the

treatment of uremic pruritus - namely, a lamellar matrix cream that contains both PEA and

AEA called MimyX (Baswan et al., 2020; Gupta & Talukder, 2021). Creams containing PEA

and synthetic cannabinoids have been found to be effective in treatment of itch that is a

symptom of atopic dermatitis, lichen simplex, nodular prurigo and uraemia (Eagleston et al.,

2018). Cannabinoids may also help with inhibition of keratinocyte proliferation in psoriasis

and they may exert inhibitory effects on antigen processing and therefore prevent the release

of inflammatory cytokines that play an important role in pathogenesis of psoriasis (Eagleston

et al., 2018; Sheriff et al., 2019; Baswan et al., 2020). Cannabinoids may be used in the

management of melanoma and non-melanoma skin cancer thanks to their anti-tumorigenic

properties mediated by both the CB1 and CB2 receptors. The role of CB2 receptors in

mediating anti-malignancy properties is likely greater than that of CB1. Activation of these

receptors results in interferences with endothelial cell migration, induction of apoptosis,

inhibition of growth and impaired vascularization in tumorigenic epidermal cells without

impact the normal healthy epidermal cells (Eagleston et al., 2018).

Conclusion

The endocannabinoid system is important for maintaining skin homeostasis and any

imbalances in the endocannabinoid system facilitate the development of dermatological

conditions. Cannabinoids are becoming an increasingly popular natural alternative treatment

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option for a wide range of skin conditions such as psoriasis, acne, seborrhea, skin cancer,

pruritus or itch. Cannabinoids used for treatment of dermatological conditions are most often

administered topically, in the form of gels, creams or patches and they can be either

phytocannabinoids, endocannabinoids or synthetic cannabinoids.

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