August 20, 2022 - 7 min read
Skin care is a very active frontier in cannabinoid research right now. That’s because skin disorders collectively are common medical complaints, and because there are still gaps in treatment. Good preparations, like DiolPure, which contains cannabidiol, or ‘CBD’, are popular on the market. CBD is the cannabinoid best understood by researchers at the moment, and has, for this reason, moved freely through regulatory approval and is being deployed for pharmaceutical use. It works as predicted, across an expanding range of skin conditions, and side effects are light. The CBD used in DiolPure is assembled from aromatic terpenes and not from the cannabis plant, which helps assure tolerability and predictability, there being no residual cannabinoids from traditional plant-derived extraction processes.
For the present state of all the cannabinoid research in dermatology, and all the cannabinoids currently under investigation, the following is a synopsis.
Dry skin syndrome
Cannabigerol (CBG) and cannabigerovarin (CBGV), two non‐psychotropic phytocannabinoids, are emerging as potential options for the management of idiopathic dry skin – that is, skin dry for no known pathological condition. This is because these compounds appear to increase the manufacture of skin oil, a natural process spoken of as basal sebaceous lipid synthesis.
There are two neural receptor sites known in the body’s endocannabinoid system, which is part of our onboard cell signaling network (and the reason we are sensitive to cannabinoids). CB2 receptor site antagonists or agonists (surprisingly) may be utilized in the management of skin disorders characterized by any sebaceous gland dysfunctions, such as acne vulgaris, seborrhea or dry skin. Human sebocytes use a paracrine-autocrine, endogenously active, CB2-mediated endocannabinoid signaling system for positively regulating lipid production and cell death.
Cannabichromene (CBC) and cannabidivarin (CBDV) are promising anti-acne agents. CBC suppresses basal sebaceous lipid synthesis, and they both significantly reduce arachidonic acid‐induced ‘acne‐like’ lipogenesis.
CBD also offers potential as an acne treatment because of its combined lipostatic, antiproliferative, and antiinflammatory properties. A great deal is known about how this works. CBD not only inhibits the lipogenic actions of various compounds, like arachidonic acid and linoleic acid and testosterone, it suppresses sebocyte proliferation, by activating transient receptor potential vanilloid-4 (TRPV4) ion channels. Activation of TRPV4 interferes with the prolipogenic ERK1/2 MAPK pathway and results in the downregulation of nuclear receptor interacting protein-1 (NRIP1), which acts on glucose and lipid metabolism.
CBD is above all an anti-inflammatory agent – important in acne, where much of the presenting problem is inflammation. The mechanism of action is at the level of gene expression. At the molecular level, it is an A2a adenosine receptor-dependent upregulation of tribbles homolog 3 (TRIB3) and inhibition of the NF-κB signaling.
For people who desire plant-derived cannabinoid preparation rather than assembled molecules, 3% cannabis seed extract cream has been shown to be an effective, safe and well-tolerated treatment alternative for the management of acne vulgaris, and seborrhea, papules and pustules as well. It works because hemp seed hexane extracts inhibiting P.acnes bacterial activity, by regulating AMPK and AKT/FoxO1 signaling in IGF-1-induced inflammation and lipogenesis of sebocytes, inhibiting 5-lipoxygenase levels and P. acnes-induced MMP-9 activity, and (on in-vitro evidence) promoting biosynthesis of collagen.
Eczema is a form of dermatitis, or skin inflammation. The asteatotic variety is the dry, fissured form that we get in cold and wind, particularly as we age. Regular application of a topical N-palmitoylethanolamine/N-acetylethanolamine emollient shows promise in passive and active skin functions simultaneously. The combined effect of these two endogenous phospholipids on the endocannabinoid system is to improve skin barrier function, increasing skin surface hydration, and reducing itching.
Atopic or contact dermatitis - Eczema
Eczema broadly defined can refer to a hereditary tendency for skin irritability or to one conditioned by exposure to a particular substance. Enormous work has been done on cannabinoid therapy in this area.
It is known that topical application of CB1 agonists down-regulates mast cell activation, and in a dose-dependent way, suppresses cell proliferation and recruitment into the skin. For that reason, levels of blood histamine decrease. It also significantly accelerates the recovery of epidermal permeability barrier function, and shows anti‐inflammatory activity.
CBD demonstrates particular anti-inflammatory properties in allergic contact dermatitis. It elevates the levels of anandamide, an endocannabinoid, and dose-dependently inhibits poly-(I:C)–induced release of MCP-2, IL-6, IL-8, and TNF-α in a manner reversed by CB2 and TRPV1 antagonists 6-iodopravadoline (AM630) and 5′-I-RTX, respectively, with no harmful, or ‘cytotoxic’, effect on cells.
Mimyx, an N-palmitoylethanolamine-containing lamellar matrix cream, repairs and restores skin barrier function and decreases trans-epidermal water loss in atopic dermatitis, and allergic contact dermatitis, and radiation dermatitis. Remission periods afterward are long. It’s a fatty-acid amide, not a cannabinoid, but it binds CB2 receptors and inhibits mast cell activation. It significantly reduces erythema (reddening), pruritus (itching), excoriation (scratching), lichenification (thickening), scaling, and dryness. There are marked improvements, doubtless because of this, in sleep quality. Mimyx helps make it clear what to expect from cannabinoids in therapy.
This is a hereditary skin blistering and scaling. The cannabinoid receptor 1 agonist arachidonyl‐2′‐chloroethylamide (ACEA) (1 μmol L−1, 48 h) can upregulate the expression of keratin 10 protein in human epidermis, and decrease that of keratin 1 in human skin organ culture. This points the way to possible cannabinoid intervention in future therapy.
Psoriasis is a very complex autoimmune disorder. Its pathways are not completely understood yet. One thing that is known, however, is that the observed interaction between the immune and nervous systems through a cholinergic anti-inflammatory pathway mediated partly by activity in the endocannabinoid system suggests cannabinoids as potential addition to the anti-psoriatic toolkit.
It is in up-regulation of keratins K6 and K16 that cannabinoids are a promising treatment option. This has been shown in organ-cultured human skin with the CB1-specific agonist. At the gene and protein levels, ACEA also decreases K6 expression in cultured HaCaT keratinocytes, which show some similarities to psoriatic keratinocytes.
Cannabidiol, cannabinol and cannabigerol in particular inhibit keratinocyte proliferation, a central histological feature of psoriasis. They work better than developmental synthetics so far, too. The selective CB2 receptor agonists JWH015 and BML190, and the non-selective CB agonist HU210, elicit only partial inhibition.
This is a rare, inherited presentation of fragile skin, prone to damage by any but the most superficial touch. Topical use of CBD in this condition has been reported to offer faster wound healing, less blistering, and notable pain reduction.
Pruritis is the medical term for itching. N-palmitoylethanolamine, the non-cannabinoid CB2 receptor agonist, has been shown in creams to reduce the itching reported by patients with atopic dermatitis, lichen simplex, prurigo nodularis, and chronic kidney disease. Cannabinoids, and more specifically the synthetic antagonist WIN 55,212-2, dose-dependently reduce serotonin-induced scratching behavior. The antipruritic effects of cannabinoids are known to be partially mediated by spinal CB1 receptors. There seem to be fundamental differences in endocannabinoid modulation of itch and pain in skin innervated by the trigeminal nerve, lower-body skin, innervated by spinal nerves. This is known because the increase in levels of the endocannabinoids AEA and 2-AG in rostral back skin reduces 5-HT-elicited scratching behavior, whereas the same treatment in skin of the cheek enhances 5-HT-elicited scratching and also AITC-evoked pain-rubbing.
Systemic lupus erythematosus
Systemic lupus erythmatosus (SLE) is an autoimmune disorder that can present as a great number of symptoms. A common focal point is the skin. A new study supports the development of cannabis-based medication for this. There is an alteration of the endocannabinoid system in SLE patients. It is known that 2-arachidonoylglycerol (2-AG) and the 2-AG biosynthetic enzyme DAGL are likely biomarkers of SLE in blood.
Kaposi’s sarcoma is a rare, virus-driven cancer of the skin, and occasionally internal organs. Cannabinoids have a known antiproliferative effect in Kaposi’s sarcoma cell lines. Specifically, the mixed CB1 and CB2 agonist WIN-55,212-2, a synthetic, shows clear antimitogenic effects. It works by inducing activation of caspase-3 and -6, and increasing phosphorylation of the stress kinases p38 and JNK and, in a transient way, phosphorylation of ERK1/2.
CBD is a promising agent for treating Kaposi’s sarcoma. It acts on the common herpesvirus-infected endothelium. There, though it doesn’t act on the virus, it reduces proliferation and induced apoptosis in infected cells. At the molecular level, CBD inhibits the expression of viral G protein–coupled receptor (vGPCR), its agonist, the chemokine growth-regulated protein α (GRO-α), vascular endothelial growth factor receptor 3 (VEGFR-3), and the VEGFR-3 ligand, vascular endothelial growth factor C (VEGF-C).
Skin cancers vary enormously. Generally, though, CB1 and CB2 are of potential use in anti-tumor therapy. In cell cultures, activation of both receptors induces the apoptotic death of tumorigenic epidermal cells, while the viability of nontransformed epidermal cells remains unaffected. Local administration of the mixed CB1 and 2 agonist WIN-55,212-2 or the selective CB2 agonist JWH-133 considerably inhibits growth of malignant tumors in laboratory trials. The upshot is that cannabinoid-treated tumors show an increased number of apoptotic (which is to say dying) cells, there is impairment of tumor vascularization, and a general decrease in expression of proangiogenic factors. There is as well a critical decrease in epidermal growth factor function.
Cannabinoid research has thus far centered on melanoma, the most dangerous of all the skin cancers. It is known without a doubt that cannabinoid administration inhibits melanoma progression and metastatic spreading. Just how is still not completely clear.
It is known that higher than normal protein and mRNA expressions of CB2 are observable in malignant tissue. Melanoma cells are also resistant to dying, even in chemotherapy. Pharmacological modulation of the CB1 receptor in melanoma may suspend this resistance. Indeed, the CB1 antagonist AM251 actually induces massive apoptosis (up to 50%) in human melanoma cell lines. To inhibit tumor growth, the CB1 receptor agonist, Met-F-AEA, as strangely the CB1 receptor inhibitor, AM251, both slow human melanoma cell growth in vitro. It may be that the CB1 receptor especially functions in tumor-promoting signaling. It has been observed that viable cell-count, cell migration, and ability to form colonies are all significantly reduced in cells transduced with CB1 lentiviral shRNAs.
This is a group of diseases typified at the cutaneous level by hardening or tightening of the skin. Cannabinoids and biosimilars have shown encouraging early results in treating the associated inflammation and fibrosis. Lenabasum (JBT-101), an oral selective CB2 agonist, is one. A semi-synthetic cannabinoid, VCE-004.8, a derivative of the CBD quinol, is another. It is a dual agonist of the PPARγ and CB2 receptors. It inhibits TGFβ-induced Col1A2 gene transcription and collagen synthesis. It also reduces dermal thickness and collagen accumulation, and prevents mast cell degranulation and macrophage infiltration into the skin. Finally, EHP-101, an oral formulation of the cannabidiol aminoquinone VCE-004.8, appears able to alleviate bleomycin-induced skin fibrosis.
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