As more states and countries decriminalize cannabis, interest in the medical properties and benefits of cannabinoids continues to grow in tandem. While current research has so far focused on the role cannabinoids play in pain management, neurologic conditions, and cancers, the use of these compounds in the treatment of skin diseases is emerging as a promising new area for study.
An increasing number of studies are addressing gaps in the understanding and use of these biologic agents. Although their efficacy in specific dermatologic applications requires further research, dermatologists are well positioned to be pioneers in using cannabinoids to understand and treat inflammatory and autoimmune conditions.
The Endocannabinoid System
Research into phytocannabinoids, derivatives from the cannabis plant (Cannabis stavia), in the 1990s led to the discovery of the endocannabinoid system (ECS).1-3 The ECS is part of the signaling cascade within the central nervous and immune systems3 and has a number of physiologic functions, including the management of pain. Several studies have shown that the ECS system helps the skin maintain homeostasis by mediating inflammation, regulating keratinocyte differentiation and proliferation, and releasing damage-induced keratins, among other processes.3
Endocannabinoids are bioactive lipids released on demand in response to stimuli, such as pain or inflammation. The ECS is composed of 3 parts: ligands that bind to receptors, cannabinoid receptors, and enzymes responsible for controlling the level of ligands. Endogenously produced cannabinoids include anandamide acid (AEA) and arachidonoyl glycerol (2-AG), which are derivatives of arachidonic acid. These activate cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), primarily in response to rising intracellular calcium ion levels.
CB1R is found in the central nervous system on axon terminals, specifically in the basal ganglia, cerebellum, hippocampus, and prefrontal cortex.3 Activation of CB1R is associated with modulating of cognitive, memory, and motor functions, analgesia, as well as the inhibition of excitatory and inhibitory neurotransmission.2 CB2R functions within the immune system in the spleen, tonsils, thymus gland, bones, and skin cells, as well as localized in monocytes, macrophages, B cells, and T cells.1-3 When activated, CB2R controls various responses within the innate immune system, such as suppression of pro-inflammatory T cells and cytokines.2,3 Other receptors within the ECS include peroxisome proliferator-activated receptors (PPARs), orphan G-protein-coupled receptor GPR55, and vanilloid receptors.
Other Types of Cannabinoids
In addition to endocannabinoids, there are over 100 phytocannabinoids contained within the cannabis plant. The most commonly studied are tetrahydrocannabinol (THC) and cannabinol (CBD), with more attention on THC due to its psychoactive effects. Both THC and CBD have potential for treating various skin diseases by activating ECS to reduce inflammatory responses within the skin, however, more emphasis has been placed on CBD because it is a nonpsychogenic compound.3 Additionally, research is investigating the optimal ratio of THC to CBD in plant-derived sources to balance the beneficial effects of both compounds while reducing adverse events.
Synthetic cannabinoids are created in labs to enhance the potency of naturally occurring cannabinoids and can be designed to bind to specific receptors within the ECS to target particular responses within the immune system or central nervous system. These include nabilone (Cesamet), ajulemic acid (AJA), HU-210, AB-PINACA, among others.
Endocannabinoids, phytocannabionids, and synthetic cannabinoids are all being pursued for medical purposes and are already utilized in commercial and over-the-counter products available at dispensaries. In dermatology, there is limitless potential for using cannabinoids to treat neoplastic and cancerous growth and inflammatory skin diseases. Efficacy and safety of these categories and methods of delivery—oral, topical, and inhaled treatments—require further study, as well as changes in legislation to allow for research to develop best practices for administering cannabis.
Despite changes in attitudes and perceptions around marijuana, few countries have fully legalized recreational and medical use. Legislation against cannabis in the United States began in 1937 with the Marihuana Act, which limited use to industries. The Controlled Substances Act, passed in 1970, further criminalized cannabis by defining it as a Schedule 1 controlled substance. This made it illegal to use cannabis for recreational and medical purposes, and significantly stymied research.4
California was the first state to pass legislation that made medical cannabis use legal in 1996.4 Currently, 33 states and the District of Columbia have laws that permit cannabis for medical use, with some states, such as Michigan and Colorado, allowing recreational use. In addition, several countries are decriminalizing cannabis (Israel and Norway) or legalizing recreational and medical uses (Canada and South Africa). While two-thirds of the United States has passed legislation allowing for cannabis use, with various requirements and restrictions, it remains illegal at the federal level and is still classified as a Schedule 1 substance.
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