Chronic itch – known clinically as chronic pruritus – is characterized as an unrelenting and sometimes even debilitating sensation to itch, and often lowers the quality of life for those who suffer with it.
Treating the condition has been difficult because there are few Food and Drug Administration-approved therapies. Now, a recent case study by Johns Hopkins Medicine researchers provides evidence that a promising option for patients with chronic itch may already be available: medical marijuana (cannabis).
“Chronic itch can be an especially difficult condition to treat, with off-label therapeutics often utilized,” says Shawn Kwatra, M.D., assistant professor of dermatology at the Johns Hopkins University School of Medicine.
“With the increased utilization of medical marijuana and our knowledge of the role of the endocannabinoid system [a complex cell-signaling system that regulates a variety of functions in the body] in chronic itch, we decided to try medical marijuana with a patient who failed several therapies and had few options left.”
Kwatra and his colleagues examined an African American woman in her 60s with a 10-year history of chronic itch. The patient initially arrived at the Johns Hopkins Itch Center with complaints of extreme pruritus on her arms, legs and stomach. Upon a skin examination, numerous hyperpigmented, raised skin lesions were revealed.
Several treatments were offered to the patient – including several systemic therapies, centrally acting nasal sprays, steroid creams and phototherapy – but they all failed.
Kwatra says that using medical marijuana – either by smoking or in liquid form – provided the woman with nearly instantaneous improvement.
“We had the patient rate her symptoms using a numerical rating scale, where 10 is the worst itch and zero is no itch at all,” Kwatra says. “She started at 10 but dropped to 4 within 10 minutes after initial administration of the medical marijuana. With continued use of the cannabis, the patient’s itch disappeared altogether.”
The researchers believe that one of the active ingredients in medical marijuana, tetrahydrocannabinol – commonly known by its abbreviation THC – attaches itself to brain receptors that influence the nervous system. When this occurs, inflammation and nervous system activity decrease, which also could lead to a reduction in skin sensations such as itchiness.
Kwatra says that although conclusive studies have yet to be done to validate medical marijuana as an effective measure for the relief of previously unmanageable itch, he believes it warrants further clinical trials.
“Controlled studies are needed to determine dosing, efficacy and safety for medical marijuana in the treatment of various human itch subtypes, and once those are performed, we will better understand which patients are most likely to benefit from this therapy,” he says.
The Endocannabinoid System in Skin
The ECS is an evolutionarily conserved network of molecular signaling that plays a role in bodily homeostasis.1–3 The ECS is made up of multiple components: (a) signaling molecules called endocannabinoids, (b) specific receptors, and (c) enzymes that synthesize and breakdown endocannabinoids and transporters of endocannabi- noids.
The most well-researched functions of the ECS are related to modulation of the central nervous system (CNS) and immune function in the body. Recent research has indicated the critical role of the ECS in maintaining skin homeostasis and barrier function, and its dysregulation has been implicated in various skin disorders like atopic dermatitis, itch, acne, hair growth/loss, and hyper/hypopigmentation.4–7
Endocannabinoids
The existence of an endogenous ECS ligand was first reported by Devane et al in 1988 when they showed that N-arachidonoylethanolamine glycerol (AEA/Anandamide) binds to the cannabinoid brain receptor in a murine model.8,9 Since then, detection of numerous endocannabinoids has also been reported in the human body including the peripheral organs like skin.10 Amongst all endocannabinoids present in skin, ananda- mide (N-arachidonoyl ethanolamide, AEA) and 2-arachidonoyl glycerol (2-AG) are the most widely studied.11,12
Anandamide and 2-AG were detected and quantified in the femtomolar range in both keratinocytes and fibroblast cells by Gegotek et al.13 The biosynthesis pathways and cellular uptake of these two lipid mediators are described in multiple review articles.2,14,15 Other less know endocan- nabinoids detected in skin by Kendall et al are N-palmitoyl ethanolamide (PEA), N-alpha-linolenoyl ethanolamide (ALEA) N-linoleoyl ethanolamide (LEA), N-oleoyl ethano- lamide (OEA), N-stearoyl ethanolamide (SEA), N-eicosapentaenoyl ethanolamide (EPEA), and, N-docosahexaenoyl ethanolamide (DHEA).
Receptors
Cannabinoid (CB) 1 receptors are generally present in abun- dance in the central nervous system (brain and spinal cord) and CB2 receptors are present in the peripheral nervous system (nerves in extremities), the digestive system, and immune system. Research indicates that both CB1 and CB2 receptors are also found in epidermal keratinocytes, cuta- neous nerve fibers, dermal cells, melanocytes, eccrine sweat glands and hair follicles.13,16,17,19–21,22 While cannabi- noid receptors remain the primary targets for endocannabinoids, they have also been shown to bind to Transient Receptor Potential (TRP) receptors present in various types of skin cells (Figure 1) and are involved in different functions like formation and maintenance of the skin barrier, cell growth, cell differentiation, immunological and inflamma- tory processes.23
In addition, endocannabinoids also interact with peroxi- some proliferator-activated receptors (PPAR) via direct (endocannabinoid) or indirect (secondary metabolite of endo- cannabinoids) signaling pathways. PPAR (α and γ) activation partially mediates major biological functions of endocanna- binoids like neuroprotection, antiinflammation, and analgesic actions. The ECS and some other non-cannabinoid (indirect) targets influencing the ECS in different cellular compartments of the skin are also shown in Figure 1. A simplistic mechan- ism of action of endocannabinoids like AEA and 2-AG on and peripheral nervous systems is shown in Figure 2, which also shows the modulation of the ECS by phytocannabinoids (PCBs) by direct activation of CB1 (like THC). Indirect mechanisms of the ECS (not shown in the figure) include inhibition of enzymatic breakdown of endocannabinoids (ECBs) and/or receptor modulation.
Enzymes and Transporters
The synthesis of endocannabinoid AEA is mediated by Phospholipase D while diacylglycerol lipase (DAGL) reg- ulates the synthesis of 2-AG.24,25 The degradation of AEA and 2-AG primarily is regulated by two enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively.2 The biological signaling of endo- cannabinoids via interaction with their receptors is inhibited by a two-step mechanism.
The endocannabinoids are first removed from the intracellular space by a membrane trans- porter known as anandamide membrane transporter (AMT) and then, after reuptake, the endocannabinoids entering the cells are metabolized by enzymes like FAAH and MAGL.26
Potential of Cannabidiol for Skin Health and Dermatological Conditions
Because the ECS plays an important regulatory function in the skin, it is plausible that treatment with topical cannabi- noids could be efficacious for certain disorders or skin health in general. However, most of the clinical evidence to date has focused on the effects of CBD and other canna- binoids when consumed, inhaled, or injected.
There is lim- ited research investigating the therapeutic potential for topical applications. Yet, there is evidence to suggest apply- ing cannabinoids, and specifically CBD, topically may be a viable route of administration for certain conditions. Although CBD has a reasonable molecular weight (314.46 Da), its high log P value (lipid/water partitioning) of ~6.3, poses unique challenges to its transdermal delivery.31 However, this challenge may be overcome if appropriate carrier systems are used, as seen with CBD being absorbed transcutaneously in preclinical models.
In 2003, Lodzki et al reported successful transdermal delivery of CBD in a murine model by using ethosomal carriers.32 Similarly, Hammel et al investigated the efficacy of topically applied CBD (1–10%) in a gel format, specifically for reduction of inflammation-associated symptoms in a monoarthritic rat model, and found that it was well-absorbed, as the plasma concentration showed a linear relationship with the dose applied.33 In vitro diffusion studies using human tissue have demonstrated CBD’s permeation potential.34 However, at present no clinical trials investigating the topi- cal absorptive capability in humans have been identified. Further work is warranted to better understand the appro- priate doses and delivery methods for therapeutic CBD skin applications.
Skin Protection | Barrier Function
Skin serves as a protective barrier against environmental insults which can lead to the generation of reactive oxygen species (ROS).35,36 Oxidative stress induces cell damage and can result in chronic inflammation if left unchecked. It is also implicated in skin disorders and skin aging.36 Keratinocytes are the main cell type in the epidermis and are particularly sensitive to environmental stressors.37
The harmful accumulation of ROS is countered in healthy skin by activation of numerous defense mechan- isms. Many of these systems are controlled by the master regulator of cellular antioxidant defense system, NRF2 (nuclear factor erythroid 2-like 2) and PPAR-γ.38 The stress-induced enzyme Hemeoxygenase1 (HMOX1) is one of the key NRF2 target genes and exhibits antioxidant and anti-inflammatory properties.39 In in vitro studies, CBD has demonstrated the ability to induce expression of HMOX1 and other NRF2-regulated genes.40,41 One study done in Normal Human Epidermal Keratinocytes (NHEK), reported that CBD induced the expression of several NRF2 target genes, with HMOX1 being the most upregulated by CBD.42
In the same study, increased levels of HMOX1 and expression of proliferation and wound repair keratins 16 and 17 were observed in mice epidermis after topical application of CBD. In another in vitro study using human keratinocytes, researchers showed that CBD was able to penetrate the cells and balance the oxidative stress response resulting from UVB irradiation and hydro- gen peroxide. They also demonstrated that CBD had a protective effect against the peroxide-induced reduction of polyunsaturated fatty acids in the cell membrane, help- ing to protect membrane integrity.43
There is evidence to suggest CBD can activate PPAR-γ, as well. Treating 2D and 3D fibroblast cells with CBD resulted in activation of PPAR-γ with a corresponding decrease in levels of NF- kB.44 Since HMOX1 and PPAR-γ play strong cytoprotec- tive roles with anti-inflammatory, antioxidant, and anti- apoptotic properties, treatments regulating their expression could be beneficial for skin conditions characterized by inflammation and keratin disorders, such as eczema or atopic dermatitis.
Eczema or Atopic Dermatitis
Atopic Dermatitis (AD) is a chronic inflammatory skin disorder associated with multifactorial causes like envir- onmental triggers, damaged skin barrier function, micro- biome imbalance, genetic predisposition, and an altered immune response.57 Phytocannabinoids have been shown to modulate inflammatory responses by regulating more than one underlying mechanism. Adelmidrol, a PEA deri- vative, has been shown to be effective in treating mild AD in a pediatric population.58 Though the efficacy of CBD is yet to be clinically validated, in a recent study by Petrosino et al, CBD was shown to exhibit anti- inflammatory properties in an experimental, allergic con- tact dermatitis model.59
The influence of microbiome imbalance, especially due to colonization and biofilm formation of Staphylococcus aureus (S. aureus), has also emerged as an influencing factor which can contribute towards the severity of dermatitis.60,61 The preliminary data indicating the antimicrobial and antibiofilm activity of hemp come from the essential oil (steam distillate) fraction of hemp which is composed mainly of terpenoids such as myrcene, α- pinene, β-caryophyllene and other terpenes, but no signifi- cant levels of CBD.28,62 Zengin et al evaluated the anti- microbial and antibiofilm efficacy of hemp essential oil (EO) against a reference strain (S. aureus American Type Culture Collection (ATCC) 29,213) and three clinical strains (S. aureus 101 TV, S. aureus 104, and S. aureus 105).
The effective Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC), and the Minimum Biofilm Eradication Concentration (MBEC) hemp EO values against all S. aureus strain types were reported as 8, 16 and 24 mg/mL, respectively, which indicated the hemp EO may disrupt and eradicate a mature biofilm of S. aureus. Thus, the antimicrobial and antibiofilm activities of hemp EO against S. aureus suggest its therapeutic potential to prevent skin disorders like atopic dermatitis.63
Itch (Pruritis)
When it becomes chronic, itch or pruritis can severely affect one’s quality of life. The pathogenesis of pruritis is well researched and is described comprehensively in var- ious recent review articles.64–66 Though most of the ECS research indicates that the itch response is primarily modu- lated through CB1 receptors in the CNS,67–69 some reports argue the involvement of peripheral CB1 receptors could also be a potent contributor to itch.70,71
The available data thus far for the involvement of peripheral CB2 receptors are conflicting and more research is needed to conclusively determine its role in pruritis.72,73 It has also been shown that all ionotropic cannabinoid responsive receptors (e.g., TRPV1−4, TRPA1 and TRPM8) play a vital role in the complex cutaneous communication between keratinocytes, immune (Mast) cells and the sensory nerves which leads to an itch sensation.74–78 Thus, inhibiting the activity of such ionotropic channels by selective PCBs may be helpful in alleviating pruritis.
FAAH and MAGL inhibitors, which can increase the levels of endocannabinoids and modulate cannabinoid and non-cannabinoid receptor responses, were found to demonstrate anti-pruritic effects on murine models when administered via intraperitoneal and intrathecal routes.79–81 Though cannabinoids like THC and PEA have been shown to reduce itching in murine models,82 the human clinical data for testing the antipruritic potential of PEA have resulted in conflicting results.83,84 T
o add to the dilemma, a study by Spradley et al indicated that peripheral endocannabinoids have opposite effects on itching behavior in spinally versus trigeminally innervated skin of mice, and therapeutic treatment of itch might be more relevant for treating the lower body than itch arising from trigeminal innervated skin of the face or scalp.85
Since CBD is a FAAH inhibitor, a CB2 inverse agonist86 (antagonist of CB2 agonists) and TRPV1 agonist, it could potentially play a role in modulating itch response, but the scientific evidence remains scarce for this application todate.
reference link :ttp://doi.org/10.2147/CCID.S286411
More information: Youkyung S. Roh et al. Treatment of Chronic Pruritus With Medical Marijuana, JAMA Dermatology (2021). DOI: 10.1001/jamadermatol.2021.1194
