Introduction
Use of cannabinoids (cannabidiol [CBD], delta-9-tetrahydrocannabinol [THC], and others) has increased since recent changes in state and federal cannabis laws. Dermatologic consequences of increased environmental, occupational, and personal use exposure to cannabis and its derivatives, both intentional and secondhand, have also been reported. This chapter focuses on dermatologic conditions associated with cannabis and cannabinoid use. Some of the proposed mechanisms of action are considered. A sampling of potential disease states that may or may not be influenced by these products is reviewed, and issues of safety and efficacy are discussed.
The use of cannabis for skin conditions is in its infancy. The clinical relevance of in vitro or animal models is unsure in the absence of clinical human studies of sufficient quality, size, and duration to accurately inform the physician.
Cannabis industries are not routinely forced to follow Food and Drug Administration (FDA) quality and safety standards; problems of purity and effectiveness exist. Although early in 2019 the FDA announced a desire to address the problems related to loosely controlled, state-sanctioned cannabis products, few federal enforcement actions have been taken to date.
Although dermatologic uses may be found for certain cannabis compounds and from a better understanding of the endocannabinoid system, adequate evidence-based, medical indication is currently lacking. Conflicts due to funding or sponsorship may exist. Currently, there is not sufficient evidence to warrant or support responsible clinical recommendation of cannabis products for dermatologic uses.
Cannabis as an Allergen
Cannabis allergy may result when there is sensitization to plant-derived allergens through a variety of ways including personal consumption, secondhand smoke, and vape exposure or while handling plant material or product. Symptoms manifest as urticaria, periorbital angioedema, rhinoconjunctivitis, pruritus, and/or severe anaphylaxis.
After decriminalization, legalization, and commercialization of cannabis in several states in the United States and in Canada, allergic hypersensitivity to cannabis allergens has greater recognition as a public health concern [1, 2]. Exposure through increased individual and industrial production, occupational sensitization, consumption of both ingested and smoked products, and passive exposure via airborne cannabis smoke and indirect cutaneous transmission have all been described. Decuyper et al. reported on a 5-year-old boy and two other patients, who suffered from cannabis-related allergies in which sensitization was believed to have occurred through mere passive, secondhand exposure to airborne cannabis allergen and/or skin contact [3].
Environmental exposure is also reported. Cannabis pollen grains are able to float for long distances and thus are widely distributed. In northern Pakistan, where the plant is native and grows easily, 22% of patients in Islamabad showed sensitization by a positive skin test reaction of greater than 2 mm to Cannabis sativa pollen; however, the relationship between the skin prick tests and the individual’s clinical presentation was not investigated by the clinicians. In and around Omaha, Nebraska, where feral cannabis, usually with low THC content, grows widely around former hemp fields, individuals with allergic rhinoconjunctivitis and/or asthma symptoms had a positive scratch test to hemp 61% of the time [4]. Silvers and Bernard [2] surveyed an allergy practice’s exposure to cannabis in Colorado and found that 12% of people who never smoked cannabis had symptoms from secondhand smoke. Of those who had ever smoked, 26% experienced symptoms, while 50% of those who actively smoked reported symptoms that were described as “respiratory, ocular, and skin.” Rabinovitch et al. stated that, with legalization and commercialization, these trends are concerning and suggest cannabis use and exposure could become an increasing public health hazard [5].
Cannabis allergy was first described by Liskow et al., who reported an “anaphylactoid” response to cannabis in a young woman after she inhaled cannabis for the first time. Skin prick testing and passive transfer studies at the time suggested but did not prove a response to THC [6].
Consumption of hemp seed was described by Stadtmauer as leading to an episode of anaphylaxis in a patient who previously smoked cannabis regularly [7]. Smoking cannabis after the event did not elicit an allergic response in the patient. The authors speculate hemp seed may be allergenic when ingested. A series of five pediatric and adult patients suffering anaphylaxis after consuming hemp seed has been described by Bortolin et al. [8]. A Canadian study by Alkhammash et al. described a series of 15 patients who presented with an allergic reaction to hemp seed, cannabis, or both. Eleven individuals experienced an allergic reaction when they first encountered hemp seed; seven of the patients were anaphylactic at presentation. The authors surmise past experience with cannabis allergen may have sensitized these individuals. The results point to a possible clinical cross-reactivity in sensitivity to hemp seed allergy and cannabis. They also suggest anaphylaxis may be a presenting sign or symptom of hemp allergy [9].
In December 2018, the FDA approved as generally recognized as safe (GRAS) the use of hulled hemp seed, hemp seed, and hemp seed protein powder for human consumption, products reportedly with no intrinsic THC (https://www.fda.gov/food/cfsan-constituent-updates/fda-responds-three-gras-notices-hemp-seed-derived-ingredients-use-human-food).
Occupational exposure is increasingly recognized worldwide. Contact urticaria, a hypersensitivity reaction, has resulted from cannabis allergen exposure in a forensic laboratory workplace, as described by Majmudar et al. in their 2006 case report [10]. Another report, published in 2008, involved a technician sensitized by exposure to cannabis while working in a law enforcement laboratory. It was noted three other individuals in the laboratory also showed symptoms resembling this patient’s contact urticaria [11].
Exposed workers in a hemp factory in Croatia had a 64.2% prevalence of positive skin reactions to extracts of hemp organic dust. Fifty-six percent of these workers were noted to have had nasal symptoms, and 22% had asthma associated with their workplace, both values greater than the nonexposed controls. Impaired respiratory function was documented in exposed individuals but not linked to their increased antibody marker levels (IgE) or positive skin testing [12].
The mechanism of the cannabis allergic response in humans and the characterization of the allergens are not yet completely understood. Much research is still needed for the development of meaningful diagnostic testing and recommendations for treatment [4]. Gamboa et al. suggested sensitization to cannabis might be caused by an allergenic lipid transfer protein (LTP) labeled Can s 3 [13]. LTP is an important allergen in plant and food allergies. Ebo noted LTP allergens can induce symptoms by ingestion, inhalation, or even contact and that they are highly stable and cross-react with a number of pollens and foods, especially fruits [14].
Armentia et al. [15] noted that, among their study group of 340 individuals addicted to drugs and with histories of atopy/asthma, tomato and tobacco sensitization appeared to be significant risk factors for cannabis sensitization. The authors noted cannabis consumption may be associated with measurable allergic response. Using cannabis-specific IgE determination, they describe a sensitivity of 88.1% and a specificity of 96% for cannabis sensitization. The authors claim prick tests using cannabis extracts and specific IgE determination using biotinylated cannabis extracts were efficient in detecting sensitization to cannabis and positivity was related to clinical profiles (anaphylaxis, asthma, angioedema) severe enough to require emergency medical attention.
Ebo [14] and others described that, in 21 northern European patients with plant food allergies, those who also tested positive for cannabis allergy using skin testing and basophil activation testing also had more severe reactions than patients without cannabis allergy. Unusual food allergies for this northern European cohort were also seen, such as allergies to banana, tomato, citrus, and others. The authors speculate this is possibly because nonspecific ns-LTPs are stable, ubiquitous allergenic proteins and cross-react with these foods. Sensitization toward ns-LTP from cannabis may explain these unusual allergies, as well as the more severe plant food allergies encountered. One patient with cannabis allergy was not sensitized toward ns-LTP; therefore, more work is required to fully describe all the pathogenic allergens at play in cannabis allergy.
Min and Min’s study [1] of 2671 individuals including 316 current cannabis users describes how cannabis-using patients were found to be more likely than nonusers to be sensitized to allergens unrelated to cannabis, such as molds (Alternaria alternata), dust mites (Dermatophagoides farinae and Dermatophagoides pteronyssinus), plants (ragweed, rye grass, Bermuda grass, oak, birch, and peanut), and cat dander. Higher blood lead and cadmium levels were also found in cannabis-using individuals. Some of these findings may be spurious or possibly due to the known problem of contamination of cannabis with molds, bacteria, and heavy metals [16]. Cross-sectional and observational design also limits the study. Regardless, the authors conclude that cannabis exposure through use or cultivation may be associated with an increased risk of allergen-specific sensitization to cannabis and/or other allergens.
Avoidance of cannabis is the recommended treatment of choice for this allergy.
To date, there is no universally approved and standardized test for cannabis sensitivity, but cannabis as a possible allergen should be kept in the clinician’s differential diagnosis. More clinical studies will be needed to accurately evaluate the presence and severity of the risk cannabis allergy poses to users and/or the public.
Cannabinoids in the Treatment of Allergic Contact Dermatitis
The possible immunosuppressive effects of cannabinoids have been explored as a way to improve the symptoms of allergic contact dermatitis in animal models [17]. Evidence from several studies suggests that the endocannabinoid system may regulate allergic dermatitis by altering the animal’s chemokine system.
Topical and subcutaneous THC has been shown to decrease inflammation in animal models of allergic contact dermatitis [18, 19]. Further investigations revealed the action of THC was independent of cannabinoid receptor 1 (CB1) and/or cannabinoid receptor 2 (CB2) [17]. (The cannabinoid receptors are also referred to as CR1 and CR2) [20]. Subsequent in vitro studies by this group suggested the anti-inflammatory mechanism involves decreased interferon-γ dependent chemokines of the T lymphocytes. Similarly, THC-treated keratinocytes from an allergic contact dermatitis mouse model showed, in the setting of THC treatment, those chemokines associated with increased inflammation were less prominent regardless of the presence of CB1 or CB2. The mechanism of action of THC in these models is unclear, but Katchan et al. [21] suggest it may involve either direct action or action through CB1 and/or CB2 or through receptors other than CB1 and CB2, such as peroxisome proliferator-activated receptors (PPARs) or the G-protein-coupled receptor (GPR55) or another messaging pathway.
In addition to THC and analogues, del Rio et al. have assessed the role CBD may play in decreasing inflammation [22]. An in vitro model of allergic contact dermatitis using human cells appeared to show the addition of CBD decreased chemokines (monocyte chemotactic protein 2, interleukin-6 and interleukin-8, and tumor necrosis factor alpha) made by human keratinocytes. Another in vitro study also appeared to show that, in this model, arachidonylethanolamide/anandamide (AEA, the endocannabinoid analogue to THC) and related [14] compounds increased in CBD-treated human keratinocytes [23]. Although, currently, the roles of CB1, CB2, and related receptors do not appear clear, the authors believe this is the first demonstration of the anti-inflammatory properties of CBD in an experimental human model of allergic contact dermatitis.
Cannabis and Acne
Acne vulgaris is the most prevalent human skin disorder, afflicting around 50 million Americans. The condition is multifactorial, and pathogenesis is related to hormonal influences (both systemic and locally produced and mediated by the pilosebaceous gland), sebum production, infectious agents, inflammation, altered hyperkeratinization, and associated cytokine production [24]. IL-6, tumor necrosis factor-α, IL-12, IL-8, and IL-1β have been shown to underlie this multifactorial and seemingly ubiquitous disease [25].
Cannabinoid receptors have been found to be present in human sebaceous glands, pilosebaceous units, and adnexal structures and on sensory nerve fibers in the human skin [26]. These receptors may be involved in lipid production and apoptosis, reportedly mediated by CB2-coupled signaling involving the MAPK (mitogen-activated protein kinase) pathway [27]. In vitro studies have demonstrated, in addition to other mechanisms, CBD modulates a complex signaling network involving tetrahydrocannabivarin-4 (TRPV4) ion channels, adenosine A2a receptors, and multiple downstream elements, thereby exerting sebostatic and anti-inflammatory effects in a human cellular/organ culture model of acne vulgaris [28, 29]. Olah et al. concluded from another in vitro study [30] that THCV4 and CBD had lipostatic actions and suppressed proliferative fibrocytes; however, the cannabinoids cannabigerol (CBG), cannabichromene (CBC), and cannabidivarin (CBDV) increased sebaceous lipid synthesis. All cannabinoids studied exhibited what the authors described as remarkable anti-inflammatory changes, including decreased inflammatory cytokines.
In another in vitro study, authors Solee Jin and Mi-Young Lee described hemp seed hexane extracts displaying antimicrobial, anti-inflammatory, and anti-lipogenic-promoting properties on P. acnes-induced inflammation in HaCaT cells and IGF-1-stimulated lipogenesis in sebocyte tissue culture [31].
By late 2019, there were no published trials with large numbers of human subjects on CBD for the clinical management of acne [32]. One human trial, a single-blind study of 3% cannabis seed extract cream versus vehicle, was evaluated in 11 normal men followed for safety and efficacy. The authors reported significant reduction in sebum and erythema after 12 weeks of follow-up to the well-tolerated cream [33]. Notwithstanding this clinical study on topical hemp seed cream, it is known that hemp seed extract has a 3:1 omega-6 to omega-3 ratio [34]. Given that omega-6 is a known pro-inflammatory agent [35], it is unknown if or under which circumstances ingesting hemp seed extract may exacerbate outbreaks of acne.
With more than 400 components within the cannabis plant, the real-world use of the product differs from that of a purified drug in the laboratory or clinical setting. Similarly, real-world results differ significantly from in vitro models and human studies. In the clinical setting, dermatologists have noticed that some of their most difficult to control acne cases have involved patients who use cannabis. This is supported by a French survey [36] that found regular use of cannabis was highly associated with acne, with an odds ratio of 2.88 (95% CI: 1.55–5.37) in more than 10,000 subjects. In addition, Dréno et al. [37] stated they could not find more published studies on the topic, but their experience supports the impression there is a relationship between cannabis use and acne outbreaks.
The current lack of clarity as to whether cannabis prevents or exacerbates acne in patients is likely influenced by several factors. Financial incentives in the cannabis industry conceivably play a role in study selection, methods, and outcomes. There is no standard cannabis isolate; therefore, differences in active ingredients make it difficult to gather consistent data. Well-documented effects from the use of cannabis products, like increased appetite or mood change, could make a patient more acne prone or otherwise create an environment conducive to a flare.
Regardless of the above considerations, there are currently enough conflicting data from both studies and clinical experience to preclude formation of solid conclusions about the effects of cannabinoids on acne.
Cannabinoids and Autoimmune Disorders
Lupus Erythematosus, Dermatomyositis, and Systemic Sclerosis
The endocannabinoid system may be an important actor within the human immune response. Because of this possible role, the immune-moderating effects of endocannabinoids and cannabinoids more generally have increasingly been objects of investigation, with resources appropriated to possible use of cannabinoids to treat autoimmune diseases and/or to shed light on the mechanisms of disease.
Autoimmune-mediated dermatological diseases afflict a minority of patients but are of considerable importance to the dermatologist’s practice due to their significant morbidity and mortality. Cannabinoids generally display immunosuppressive properties as they impact the human immune response. Specifically, cannabinoids cause apoptosis in inflammatory cells such as T cells, macrophages, and others; they orchestrate and moderate the production of numerous cytokines; and they reduce an array of pro-inflammatory leukocytes [21]. One of the receptors through which the cannabinoids act is CB2, which is widely represented on inflammatory cells, especially lymphocytes, macrophages, mast cells, natural killer cells, peripheral mononuclear cells, and microglia, and it may be through this receptor that the immune response is modified or decreased [38]. On the other hand, in addition to the apparent anti-inflammatory actions, there are also some indications that point to cannabinoids increasing the propensity for development or exacerbation of an inflammatory response. These include evidence of cannabinoids associated with amplifying B-cell proliferation [39]. Notwithstanding these findings, in vitro and animal studies have begun to evaluate the possible use of cannabinoids as an immunosuppressive for the treatment of autoimmune disease.
Lupus Erythematosus
Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease that involves the skin, with classic features such as “butterfly” malar rash. SLE is characterized by autoantibodies and a dysregulated immune response. Increased endocannabinoids have recently been demonstrated in the serum of lupus patients. Navarini et al. [40] found increased plasma levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) in patients with SLE when compared to controls. Their laboratory analysis of patient sera also suggests the presence of an altered 2-AG metabolism. Other endocannabinoids such as N-arachidonoylethanolamine (AEA) and N-palmitoylethanolamine (PEA) were unaltered in the SLE patients. The authors believe the findings suggest a deranged endocannabinoid system in SLE patients, which may prove pathogenetically significant. They note these studies are preliminary, and more studies are needed to confirm or refute the conclusions and to explore possible clinical implications.
Dermatomyositis
Dermatomyositis (DM) is an autoimmune disease with prominent cutaneous features, including Gottron’s papules and facial violaceous poikiloderma. In patients with DM, it has been shown that inflammatory cytokines are elevated in their skin lesions but not their sera; these cytokines include increased interferons alpha and beta (INF-a, INF-b) and tumor necrosis factor-a (TNF-a) [41]. Peripheral blood mononuclear cells (PWBC) from patients with DM have been studied with an in vitro assay using synthetic cannabinoid ajulemic acid, which has very low affinity for CB1 (generally found in the central nervous system) but high affinity for CB2 (found on immune cells) [42]. CB2 agonists have been shown to play a role in suppressing inflammation. Compared to healthy controls, the ajulemic acid-treated DM cells showed a decrease in IFN-a and IFN-b and TNF-a, consistent with possibly serving an anti-inflammatory role in ameliorating this disease process [43]. More investigation and phase II clinical trials are required to ascertain the clinical significance of this finding.
Systemic Sclerosis
Systemic sclerosis is an autoimmune connective tissue disease of unclear etiology characterized by increased fibroblast activity/dysfunction, increased extracellular matrix deposition, microvascular endothelial cell damage, and autoimmunity associated with immune dysregulation. Women are affected almost 15 times more frequently than men. The condition nearly always impacts the skin but is also seen in multiple internal organs such as the gastrointestinal tract or lungs. Fibroblasts undergo myofibroblast differentiation, show decreased apoptosis, and release increased extracellular matrix [44].
The endocannabinoid system acts through receptors and receptor pathways to impact a wide range of biologic effects, including inflammation, cell turnover, and apoptosis. Some of these involve binding the two protein G-coupled specific receptors: CB1 and CB2 [45]. The transient receptor potential of vanilloid type 1 (TRPV1) channels, the peroxisome proliferator-activating receptors (PPARs) [46], and the adenosine A2A receptors have also been shown to be involved in (endo)cannabinoid action [47]. Because the inflammatory cell infiltrate, macrophages, mast cells, lymphocytes, and associated cytokines are believed to be involved in the development of systemic sclerosis and are linked to the fibroblasts’ growth and increased production of extracellular material, a number of studies have begun to try to elucidate the modulating role that the endocannabinoid system may play in this disease progression.
Inactivation of CB1 has been associated with decreased fibrosis in murine models and in vitro [48]. The same study indicated A2A receptor activation in a tissue culture model stimulated an increased deposition of collagen, apparently mediated through the cannabinoid system, a coupling already described in the central nervous system. On the other hand, CB2 stimulation by agonist led to decreased fibrosis and leukocyte infiltration in an animal model [49].
Further studies showed the activated fibroblasts in systemic sclerosis had decreased apoptotic cells, and this was reversed with cannabinoid exposure. A non-CB1, non-CB2 messaging path (the PPARs) was demonstrated to work alone to decrease inflammation and fibrosis when activated by a THC-like analogue [50].
The immunosuppressive, anti-inflammatory, and pro-apoptotic properties of cannabinoids, coupled with the presence of cannabinoid responsiveness in fibroblasts, make cannabinoids logical candidates for further study. Human trials have been initiated to further explore the role cannabinoids may be able to play in ameliorating the clinical course of the disease. At the time of publication, however, these promising and provocative findings remain preliminary.
Cannabis and Infection
There is some evidence smoking or ingesting cannabis may result in increased susceptibility to cutaneous viral infection. Cannabis use has been associated with a report of increased herpes simplex virus outbreak [51]. An in vitro study by Zhang et al. [52] also demonstrated increased viral load in Kaposi’s sarcoma-associated herpesvirus (KSHV) in the presence of THC, as well as increased Kaposi’s sarcoma cell proliferation. The authors suggest THC may enhance KSHV infection and replication and foster KSHV-mediated endothelial transformation. They also postulate cannabis use may put patients at increased risk for development and progression of Kaposi’s sarcoma. Lastly, there are studies indicating use of cannabis is associated with a decreased immune response to live virus immunization, such as being used in smallpox vaccination [53]. In animal studies, cannabis resin and THC each worsened and prolonged symptoms of viral infection in mice in conjunction with an observed decrease in specific antibody production [54]. At this time, these findings are preliminary, and further study is needed to confirm or refute their clinical significance.
Cannabis and Arteritis
Within the differential diagnosis of arterial ulcers, particularly involving lower extremities, cannabis arteritis may be a consideration, a fact that may conceivably be overlooked in the United States. A recent French study found cannabis use was associated with thromboangiitis obliterans in patients under 50, accounting for 40% of afflicted patients in one study [55]. Timlin et al. [56] stated they believe that over 50 cases they reviewed were an underestimation of the actual prevalence of this condition. With the potential for increased use of cannabis, it is possible this entity could become more common.
Cannabis use has been linked to cardiovascular disease, including myocardial infarction and stroke [57, 58]. The etiology of this phenomenon may be multifactorial but involves, in addition to a dose-dependent increase in heart rate of 20–100% [59, 60], arrhythmias, vasoconstriction (vasospasm), and vasculopathy such as arteritis. While the etiology of the vasculopathy is unclear, the following elements appear to participate: direct vasoconstrictor/vasospasm effect of THC and the effect of possible arsenic, which has been associated with thromboangiitis obliterans and has been found in cannabis and homemade cigarettes [61]. It is also possible THC may act directly on platelets and activate the clotting cascade [62].
The clinical hallmark of cannabis arteritis is a painful necrotic lesion on a distal extremity accompanied by reduced to absent palpable pedal pulses, particularly in young males using cannabis. Symptoms characteristically improve upon cessation of cannabis use but recur with resumption. A negative workup is found for hypercoagulable factors such as proteins C and S, antithrombin III, factor II mutation, resistance to activated C protein, anticardiolipid, and/or cryoglobulins, with no stigmata of emboli or pseudoxanthoma elasticum (PXE) [63]. Studies show narrowing of the involved vessels, but the calcific atherosclerosis typically seen in tobacco smokers is not present in these young patients. The disease generally resolves completely with aspirin and cessation of cannabis use. However, a painful and unrelenting course is observed in reported cases if cannabis use is continued, even involving amputation in 40% of patients in at least one series [63]. More clinical studies will be required to understand the practical clinical significance and actual prevalence or rarity of cannabis arteritis.
Cannabis and Neoplasia
Cannabis and Melanoma and Nonmelanoma Skin Cancer
In the laboratory, endocannabinoids, cannabinoids, and their receptors (CB1/CB2, TRPV1, and others) are linked to the development, growth, spread, regulation, and control of skin cancer, but the exact roles remain unclear. CB1/CB2 ligands are present on normal skin and to a greater degree on malignant tumors that develop in the skin. The development of skin tumors is also associated with an altered endocannabinoid system. Therefore, numerous studies have been aimed at untangling the role of cannabinoids and the various receptors as regulators of cutaneous malignancy, yielding compelling but conflicting results.
While animal and in vitro studies have disclosed information that appears to point toward the possible future use of cannabis derivatives or laboratory-created cannabinoids in the treatment of dermatologic neoplasia, a review of currently available treatments by Li and Kamp [64] found, at this time, for both melanoma and nonmelanoma skin cancers, adequate clinical studies proving efficacy are either insufficient or nonexistent or show negative evidence. The authors found a dearth of clinical trials that would support medical claims when evaluated using the Oxford Centre for Evidence-Based Medicine grading system, making it impossible for them to recommend cannabis as a treatment for skin cancer. Studies adequately exploring toxicity or contraindications that the skin cancer patient may encounter when using cannabis are not generally available. Furthermore, some clinicians have reported harm to patients self-treating their skin cancer with cannabis-derived products purchased over the counter or sourced on the Internet. In fact, use of cannabis during immunotherapy with nivolumab appeared to decrease tumor response rates in a recent preliminary study [65] in patients with advanced malignancies. Response rate decreased from 37% to 15% for nonmelanoma skin cancer and from 40% to 10% for melanoma skin cancer; while overall survival was not affected, the findings prompt caution and further study. In other cases, patients have delayed treatment or surgery in favor of cannabis products that were advertised as remedies for cancer.
Melanoma
Blazquez et al. [66] described how, in human melanoma and melanoma cell lines expressing CB1 and CB2, in vitro THC reduces melanoma cell growth in proportion to the number of CB receptors. Armstrong et al. [67] suggested THC-related melanoma cell death in tissue culture is mediated through apoptosis, and they report this effect is increased when the cells are also exposed to CBD in addition to THC.
Conversely, other studies have found evidence suggesting activation of the endocannabinoid system via CB1 may promote melanoma growth. These studies by Carpi et al. [68] found silencing/reduction of CB1 receptors on human melanoma cells arrested the cells in G1/S phase and decreased expression of P-Akt and p-ERK, both of which work to decrease the number of viable melanoma cells. These findings suggest a possible role of intact CB1 in promoting human melanoma cell growth in vitro. While Glodde et al. [69] found that THC treatment of transplanted melanoma cell tumors in an in vivo mouse model significantly decreased the size of the tumors, the treatment did not impact melanoma cell growth in vitro, nor did the authors find any relationship to the presence of CB1/CB2 receptors. They suggest the effect is mediated through changes to the pro-inflammatory microenvironment.
Sailler et al. [70] studied the altered local endocannabinoid microenvironment in an in vivo mouse melanoma model and were able to translate their observations to humans by assessing cancer-associated changes in circulating endocannabinoids in 298 patients with several types and stages of cancer. In the mouse model, they found plasma 2-arachidonoylglycerol (2-AG) levels were increased in mice with tumors. In the human cancer patients, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) levels rose as the number of metastases increased. While the findings are not yet clear enough to qualify as a measurable marker for cancer prognosis, the statistically significant changes to the endocannabinoid system in the setting of cancer suggest the system may play a role in the regulation of cancer progression.
Arachidonylethanolamide/anandamide (AEA, the endocannabinoid analogue to THC) may act differently at different concentrations: In vitro studies at high doses showed AEA is associated with apoptosis of melanoma cells via TRPV1-dependent pathway. At low levels however, AEA stimulates melanogenesis in a CB1-dependent fashion [71].
Nonmelanoma Skin Cancer
In vitro studies demonstrated that activation of cannabinoid receptors results in cell death through apoptosis of malignant epidermal cells but not benign cells. Casanova et al. [72] also described significant tumor growth inhibition of malignant tumors when treated with a mixed CB1/CB2 agonist. In addition to increased apoptosis, the treated tumors demonstrated reduced tumor vascularization in the setting of decreased expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF), placental growth factor, and angiopoietin 2. However, Zheng et al. [73] have shown how CB1 and CB2 appear to be required for the development of UV-induced inflammation and resulting skin cancer in a mouse model of UV solar irradiation and cutaneous tumors. Mice without CB1/CB2 receptors were resistant to the development of inflammation and tumors.
Synthetic cannabinoid ligands (both street drugs and selected cannabinoids JWH-018, JWH-122 and JWH-210) appear to have significant anti-inflammatory and antitumor characteristics in one reported mouse cancer model [74].
Nonmelanoma skin cancer overexpresses cyclooxygenase 2 (COX-2). AEA-programmed cell death occurs after AEA is metabolized by COX-2 to a prostaglandin (15d-PGJ2-EA) required for AEA-programmed cell death. Impeding AEA metabolism with FAAH inhibitor renders AEA more cytotoxic to the tumor cells. Since noncancerous cells have low COX-2, this AEA-mediated cell death is elegantly selective for malignant cells. The apoptotic pathway also appears to be independent of cannabinoid receptors (CB1/CB2 or TRPV1) [75].
Clearly the relationship between neoplasia and cannabinoids is complex. In laboratory studies and murine models, cannabinoids and manipulation of the endocannabinoid system have shown mixed results as candidates for fighting neoplasia. Currently, none of the mechanisms involved are completely understood, and conflicting results are noted. More studies, including controlled clinical human trials, are needed before cannabinoids should be considered for skin cancer treatment.
Cannabis: Product Reliability and Safety
Drug Delivery and Unreliable Product
The clinical response to cannabis-derived dermatological products relies on good manufacturing practices that assure the quality, purity, identity, and strength of drug products. Products applied as creams, ointments, sprays, gels, transdermal patches, lip balms, oils, moisturizers, and others offer a variety of options for drug delivery. The transdermal, nasal, and oral mucosal products including sprays, chewing gum, patches, and sublingual tablets have been shown to increase patient tolerance of cannabinoids while also avoiding first-pass hepatic metabolism [76].
As with any drug product, adverse events associated with cannabinoid formulations may result from the active ingredients, the inactive ingredients, and the vehicle or delivery system. Yet at the crux of the topic of cannabinoid use in dermatology is the question of safety, reliability, and reproducibility of the final manufactured product achieved by obtaining quality raw materials, ensuring dependable manufacturing operating systems, investigating deviations from quality standards, maintaining reliable testing laboratories and records, and incorporating safe practices for packaging, labeling, and storage of the consumer product [77]. Moreover, if the cannabis plant material from which the drug product is derived contains other compounds, the resulting adulterated product may lead to additional untoward events. The raw plant materials are well known for a propensity for fungal and heavy metal contamination [16]. Since in some areas in the United States the cannabis industry is currently less responsive to regulation, concerns over microbial, mycotoxin, heavy metal, and pesticide contamination persist [78].
The discussion is further complicated by differing individual state standards for purity testing. In California, 18% of cannabis product was found to not meet accuracy standards for product labeling, meaning the product sold had greater than 10% more or less THC or CBD than the label indicated [77, 78]. In another example, Oregon was able to test only 3% of products on sale and 33% of growers for safety and reliability for the state’s cannabis program [79]. Cannabis testing laboratory fraud has been shown to contribute to unreliable consumer product in several states [80]. Therefore, healthcare practitioners need to be aware not only of concentration and content concerns about active ingredients, they also need to be concerned about potential contamination from a wide variety of pathogens and about false or deceptive labeling practices.
Between 2014 and mid-2019, the FDA issued 21 warning letters for cannabis misbranded and adulterated product due to inaccurate label claims for THC, CBD, or hemp. Several examples of similar CBD product issues were presented in oral testimony during the FDA’s May 31, 2019, Public Hearing for Scientific Data and Information on Cannabis and Cannabis-Derived Compounds [81].
To assess how reliable the labels are for CBD products, specifically those claiming to contain pure CBD, Bonn-Miller et al. [82] purchased 84 products sold online from 31 companies. This independent and blinded analysis for cannabinoid content and concentration for CBD found 42.85% of the products were under-labeled by more than 10%, 26.19% were over-labeled by more than 10%, and 30.95% were labeled within 10%, which they considered could be called accurate. In addition, assessment for adulteration with THC found 21.43% of the tested product had up to 6.43 mg/ml of THC, a concentration sufficient to induce intoxication or impairment especially in children with lower body mass indexes. Last, many of the products contained other cannabinoids: 15.48% contained cannabidiolic acid and 2.38% contained cannabigerol.
With a heightened public interest in CBD, some cosmetic manufacturers are exploring marketing strategies to navigate the less stringent cosmetic regulations of the FDA as they introduce new CBD or cannabinoid-containing cosmetic products [83]. Because transdermal absorption of these cannabinoids can occur, a consumer may unwittingly experience psychoactive effects, decreased intellectual and motor performance, and/or a positive drug screen. At this time, it is unclear if limits or outright restrictions will be imposed by the FDA on the cannabinoid content of topical cosmetics.
Unintended Consequences of Increased Cannabis Use in Dermatology
This review of the dermatologic literature suggests a possible emphasis on investigation of cannabinoids as future medications for dermatologic conditions. In comparison, the public’s cannabis exposure as a possible etiology of dermatologic disease has generally been given less investigational attention and resources. Yet, as the likelihood of cannabis-related allergens becomes greater and more individuals are passively, occupationally, environmentally, or intentionally exposed and sensitized, the dermatologist can reasonably expect to see increased cannabis allergy or urticarial cases in clinical practice. It is possible this may also be true for other cannabis-related dermatologic disorders including acne and cannabis arteritis, as previously discussed [36, 55, 56, 63]. More studies will be needed to ascertain the practical clinical prevalence of these and other entities.
Absorption of cannabinoids from dermatological use may also be a cause of impaired or dysregulated immune responses. Infection has resulted from moldy or contaminated cannabis plant material [84, 85]. Studies will need to determine not only how cannabinoids may be used to suppress an overactive immune system but also what ramifications possible immunosuppression by cannabinoids will have on the innate and acquired immune system’s ability to fight infections and mount appropriate host response, particularly in previously immunocompromised individuals such as transplant patients. Assessment of actual clinical relevance and prevalence will also be needed.
Cannabinoids are absorbed through the skin making them potentially available for systemic effects. Anecdotal reports from Colorado and elsewhere include cases where THC skin patches are used to wean users from the smoking and vaping of cannabis and to control withdrawal symptoms such as rebound anxiety attacks (personal communication). Reports of transdermal systemic absorption underline the need for human studies to document possible toxicities and side effects of topical cannabis products in order to protect public health and accurately inform patients and providers alike.
Of concern in the context of potential treatment for acne, dermatitis, and other skin conditions are reports of adults and children experiencing psychoactive effects such as somnolence and disorientation during or after application of CBD oils and creams (personal communication). This could be due to the action of CBD itself or from adulteration of the product with higher than the 0.3% THC levels allowed for legalized products. In addition to somnolence and sedation, the known adverse effects of orally administered CBD include hepatotoxicity, increased suicidal behavior and ideation, increased incidence of infection, vomiting, and diarrhea [86]. It is not well studied if systemic absorption of topical cannabis products could also lead to addiction.
Lastly, it appears largely unmeasured if, or to what extent, patients are forgoing lifesaving treatment because of false medical promises. For example, a patient may arrive at the clinic after having delayed treatment of a skin cancer because it has been “treated” with cannabis oil, which Internet sources claimed would “cure cancer.” Clinical studies have not yet assessed the morbidity or mortality resulting from this delay of treatment due to false medical promises of topical dermatologic cannabis products.
In summary, adverse dermatological effects have been reported from cannabis exposure. More research is needed to accurately measure and describe the characteristics and clinical significance of these untoward events. While the potential for the discovery and development of effective dermatological treatments using cannabis-derived products is clear, thoughtful and comprehensive research is required before medical recommendations should be advanced.