In recent years it has become evident that the endocannabinoid system plays an important role in both, healthy and diseased skin. This doesn’t come as a surprise, considering the long history of cannabis usage dating back to ancient times. In most cases, the usage has been related to the antibacterial activity of cannabis, whose flower heads were mixed up with honey and applied on wounds. Cannabis was also mixed with fats and used for the treatment of skin excrescences (probably tumors in the modern medical language), bruises, and pain.
Lost in translation
The topical uses of cannabis with the most controversy are thought to be those related to the Holy Oil of the Bible, whose composition contains a plant referred to as kaneh bosem. As it has been suggested, kaneh bosem refers to Cannabis and not to sweet flag (Acorus calamus L.) or lemongrass (Cymbopogon citratus D.C. Stapf), as reported in the modern translations of the Bible. According to the anthropologist Sula Benet, this error first occurred in the oldest Greek translation of the Hebrew Bible, Septuagint, in the third century B.C., where the terms ‘kaneh, kaneh bosm’ were incorrectly translated as “calamus”, a fragrant marsh plant, and afterward repeated in many translations to follow. The Holy Oil had both a ritual and medical use and is also mentioned in the New Testament as a healing balm.
The discovery of c[ut]annabinoids
The first modern medical study on C. sativa dates from 1832, but the knowledge on the bioactive constituents of the plant and the existence of the endocannabinoid system (ECS) is more recent and can be traced back to the seminal characterization of the psychoactive principle of the plant (Δ9 -tetrahydrocannabinol, Δ9 -THC), reported in 1964. Later, the main G protein-coupled membrane cannabinoid receptors, designated cannabinoid type 1 receptor (CB1) and cannabinoid type 2 receptor (CB2) were cloned and identified.
The endocannabinoid system (ECS) is a widespread neuromodulatory system that plays an important role in the central nervous system (CNS) development, synaptic plasticity, and the response to endogenous and environmental insults. The ECS is comprised of cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes responsible for the synthesis and degradation of the endocannabinoids. The most abundant cannabinoid receptor is CB1. However, CB2 cannabinoid receptors, transient receptor potential (TRP) channels, and peroxisome proliferator-activated receptors (PPAR’s) are also proved to be engaged by some cannabinoids.
CB1 was initially described in the central nervous system (CNS), and the expression of CB2 was originally believed to be limited to immune cells. However, further research has shown that the ECS is also present in peripheral tissues. This confirmed that both cannabinoid receptors as well as the two main endocannabinoids (anandamide – N-arachidonoylethanolamine, AEA and 2-arachidonoylglycerol – 2-AG) and the enzymes responsible for their metabolism are present in the skin. A great review of the endocannabinoid system of the skin published in Biochemical Pharmacology in 2018 explains all the key findings in this field.
Keeping the balance
As it has been established by the research, the main physiological function of the cutaneous ECS is to control the proper and well-balanced proliferation, differentiation, and survival, as well as immune competence and tolerance of skin cells. In the case of the disruption of this balance, multiple pathological conditions and diseases can be developed. Those include acne, seborrhea, allergic dermatitis, itch and pain, psoriasis , hair growth disorders, systemic sclerosis and cancer.
The normal skin and its appendages are rich in CB1 and CB2 receptors, both identified in keratinocytes, hair follicles, sebaceous glands, melanocytes, fibroblasts, nerve fibers, and adipocytes. The abundance of cutaneous structures yielding cannabinoid receptors hints to the multiple signaling and regulating functions played by these substances. Benign and malignant skin tumors also express functional CB1 and CB2 receptors, an observation that led to the pursuit of anti-tumoral applications of cannabinoids. Among the non-CB1, non-CB2 receptors targeted by cannabinoids, TRP channels play the most prominent role, as they respond to natural and synthetic cannabinoids that may trigger apoptosis or the release of chemokines and other signaling molecules. The distribution of TRPs in keratinocytes, hair follicles, mast cells, melanocytes, sebocytes, nerve fibers, and other skin structures facilitates the cannabinoids’ supplementary effects in inflammation and immune response modulation.
Fine-tuning and safety issues
Targeted manipulation of the ECS is seen to be beneficial in a multitude of human skin diseases, and cannabinoid products have obvious potential to treat a variety of skin conditions. However, it is still necessary to conduct more high-quality controlled human trials in order to establish this fine targeting model for different cannabinoids with different skin conditions.
One small trial has been conducted on patients with postherpetic neuralgia, a frequent adverse event in herpes zoster patients. A cream containing the cannabinoid receptor agonist N-palmitoylethanolamine was administred to eight patients. As a result, five patients experienced a reduction in pain by 87,8%, with no adverse effects.
This fine-tuning gains even more importance when we have in mind the complexity of the ECS, especially CB2s regulation of immune responses. As research has shown, CB2 is capable of suppressing immune responses, which provides it with great potential as anti-inflammatory therapeutics. On the other hand, in certain models, CB2 was shown to induce or aggravate inflammatory responses, and finding the correct dosage would be critical for the safe and efficient targeting of CB2 for the treatment of human diseases.
Similar controversy can be found in hair growth, where certain synthetic cannabinoids have shown to produce hair loss and graying while administrating other CB1 antagonists promoted hair growth, along with having an anti-obesity effect.
Also, the use of phytocannabinoids might draw potential safety issues related to its impurities with psychoactivity or legal concerns in some countries.
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