Cannabinoids: Potential Role in Inflammatory and Neoplastic Skin Diseases

Rose Milando; Adam Friedman


Am J Clin Dermatol. 2019;20(2):167-180. 

In This Article

The Endocannabinoid System

The study of the endocannabinoid system began in the late 1980s and early 1990s with the discovery of the cannabinoid receptor CB1r, which was activated by THC, an isolated derivative of marijuana. Subsequently, the endogenously produced ligand, arachidonylethanolamide (anandamide [AEA]), was also found to activate CB1r, and thus began the study of the endocannabinoid system.[2] Since the 1990s, knowledge about the endocannabinoid system and its various components has grown extensively.

The endocannabinoid system comprises three elements: (1) cannabinoid receptors, (2) ligands that bind to those receptors, and (3) enzymes that modulate the levels of those ligands.

Cannabinoid Receptors

Classical Cannabinoid Receptors. Not long after the discovery of the first cannabinoid receptor, CB1r, a second cannabinoid receptor, CB2r, was identified.[9,10] While these two G-protein-coupled receptors have 44% of their amino acid identity in common and have some similar binding affinities, they are distinct receptors.[2] For example, while both CB1r and CB2r are similarly activated by AEA, some cannabinoid compounds bind selectively to one cannabinoid receptor; for instance, the aminoalkylindole AM1241 binds CB2r selectively.[11]

CB1r is found most abundantly in the central nervous system (CNS), particularly in the basal ganglia, cerebellum, hippocampus, and prefrontal cortex, and stimulation of these receptors causes psychoactivity.[12,13] The effects of CB1 stimulation in the CNS is mediated through inhibition of gamma-aminobutyric acid (GABA) or glutamate release; reduction of GABA causes increased dopamine release in the ventral tegmental area and results in a euphoric response, whereas reduction of glutamate, the major excitatory neurotransmitter in the brain, confers protection against excitotoxicity, a major pathology in neurological disorders such as epilepsy.[14,15] CB1r is also found to a much lesser extent in peripheral tissues such as fat, pancreas, uterus, testes, ovaries, and prostate, although their role in regulating the function of these tissues is less widely known.[16–18] In human skin, CB1r is found in differentiated keratinocytes, hair follicle cells, sebaceous glands, immune cells, and sensory neurons (Figure 1).[19] Activation of CB1r in these cells reduces pain and itch sensation, regulates keratinocyte differentiation and proliferation, decreases hair follicle growth, and modulates the release of damage-induced keratins and inflammatory mediators to control the homeostasis of the skin environment.[8,19]

Figure 1.

The endocannabinoid system in the skin. Activation of the endocannabinoid system in cell types such as keratinocytes, melanocytes, immune cells, and sebocytes modulates everything from pain sensation to cell proliferation and inflammatory response in the skin. CB1r, CB2r cannabinoid receptors, Th2 T-helper 2 cell, TRPV transient receptor potential vanilloid 1, PPAR peroxisome proliferator-activated receptors

CB2r is expressed in a number of immune cells such as monocytes, macrophages, and B and T cells, as well as in peripheral tissues such as the spleen, tonsils, thymus gland, bone, and skin.[7] To a smaller extent, CB2r is also found in the CNS, localized predominately in microglia—the macrophages of the CNS.[20] By analyzing levels of proand anti-inflammatory cytokines in the presence of CB2r antagonists, CB2r activation has been linked to a shift from a pro-inflammatory T-helper cell (Th)-1 response to an antiinflammatory Th2 response.[20] CB2 receptors in human skin are expressed in keratinocytes, immune cells, sebaceous glands, and sensory neurons, and their activation promotes sebum production, modulates pain sensation, suppresses keratinocyte differentiation and proliferation, and inhibits inflammatory response in the skin (Figure 1).[8,19]

Non-Classical Cannabinoid Receptors. To learn about the specific effects of CB1r and CB2r activation, researchers developed compounds capable of antagonizing these receptors. In doing so, researchers noted that certain cannabinoids, such as AEA, were able to regulate inflammation, even in the presence of CB1r and CB2r antagonism.[21] It thus became clear that the endocannabinoid system might also include non-classical cannabinoid receptors. These included the nuclear hormone family peroxisome proliferator-activated receptors (PPARs), particularly PPARα and PPARγ, as well as the orphan G-protein-coupled receptor GPR55 and transient receptor potential channels such as transient receptor potential vanilloid 1 (TRPV1).[19,22] Increased understanding of these alternative receptors helps to explain the varied and sometimes contradictory effects of the endocannabinoid system.

PPARs are nuclear receptor proteins that are present in many tissues throughout the body, but in the skin, regulate inflammatory responses, lipid metabolism, cell growth, apoptosis, and differentiation (Figure 1).[23] Certain endocannabinoids, such as AEA, synthetic cannabinoids such as ajulemic acid (AJA), and endocannabinoid-like compounds, such as palmitoylethanolamide (PEA), act as agonists of PPAR α and PPARγ.[24] In inflammatory skin conditions such as psoriasis and atopic dermatitis (AD) and allergic contact dermatitis (ACD), both PPARα and PPARγ are expressed to a lower extent in keratinocytes than in normal skin, suggesting that activation of these receptors has some therapeutic benefit.[25] Additionally, because PPARs have been shown to regulate apoptosis, terminal differentiation of keratinocytes, and proliferation of melanocytes, they may also be a target for skin malignancies such as squamous cell carcinoma and melanoma.[26]

GPR55 is an "orphan" G-protein-coupled receptor that is structurally and functionally similar to CB1r and CB2r.[27,28] GPR55 is expressed in the brain, vascular endothelium, vascular smooth muscle, and the immune system.[29] In the skin, GPR55 has been found on keratinocytes and melanocytes and is activated by a number of cannabinoids such as AEA and 2-arachidonoyl glycerol (2-AG) to regulate skin homeostasis (Figure 1). For example, AEA stimulation of GPR55 significantly reduces cell viability in A375 melanoma cells via a lipid-raft mediated mechanism,[30] and GPR55 stimulation by the endocannabinoids AEA and 2-AG can decrease pain hypersensitivity.[31] Additionally, PEA activation of GPR55 was shown to reduce nerve growth factor (NGF) release from mast cells.[32] NGF plays a role in neurogenic inflammation and stimulates keratinocyte proliferation in psoriasis, thus pointing at a potential use for PEA-induced GPR55 activation in psoriasis treatment.[33]

The vanilloid receptors are classically activated by capsaicin (found in hot peppers) and heat and are integral in the detection of painful stimuli. However, in the late 1990s, scientists discovered that AEA was able to activate transient receptor potential vanilloid 1 (TRPV1).[34] In the skin, TRPV1 is expressed in sensory neurons, dermal mast cells, dendritic cells, sebocytes, keratinocytes, and hair follicle cells (Figure 1).[35–38] Activation of TRPV1 by cannabinoids causes cutaneous pain and itch sensations as well as neurogenic inflammation.[19] Studies have also shown that TRPV1 is an important mediator of epidermal barrier function in dermatitis, neurogenic inflammation in rosacea, and ultraviolet B (UVB)-induced skin thickening.[39–41] Stimulation of TRPV1 by cannabinoids can cause opposing effects to CB1r or CB2r stimulation, even within the same dermal or epidermal environment. In fact, much evidence exists of crosstalk between the two receptor types in the skin; some studies show that, at low concentrations, cannabinoids such as AEA suppress TRPV1 effects via activation of CB1r, but at higher concentrations they directly activate TRPV1 independent of CB1r or CB2r.[42] However, another study showed that tonic CB1r activation maintains TRPV1 in an activatable state in skin nerves.[43] Therefore, although more study is needed to clarify these complexities, it is clear that cannabinoids can modulate TRVP1 activation through both CB-independent and -dependent mechanisms.

Cannabinoid Ligands

Cannabinoids are diverse hydrophobic compounds that are generally divided into three broad categories: (1) endogenously made cannabinoids (endocannabinoids), (2) cannabinoids present in the plant Cannabis sativa (phytocannabinoids), and (3) cannabinoids made in the laboratory (synthetic cannabinoids) (see Figure 2).

Figure 2.

Structures of frequently referenced cannabinoids

Endocannabinoids. Endocannabinoids are cannabinoids produced endogenously from the cleavage of membrane fatty acids, primarily arachidonic acid in a calcium-dependent manner.[44,45] They are generated as needed by neurons and immune cells to activate receptors on the same or nearby cells. The production of endocannabinoids is triggered by neurotransmitters (for neurons) and inflammation (for immune cells).[46] The most heavily researched among the endocannabinoids are AEA and 2-AG.

2-AG is a full agonist of CB2r, whereas AEA activates both CB1r and CB2r and vanilloid receptors.[46–49] AEA is hydrolyzed by fatty acid amide hydrolase (FAAH) into ethanolamide and arachidonic acid, which is oxidized by lipoxygenase enzymes to form products that are TRPV1 agonists.[50] Inhibition of FAAH exerts a cutaneous antiinflammatory effect by maintaining AEA activity.[51] Endocannabinoids and the enzymes that synthesize and degrade them are produced in the epidermis, sebaceous glands, and hair follicles and regulate everything from sensation, nociception, cell growth, and survival to cellular immunity.[8]

Finally, certain compounds, such as palmitoylethanolamide (PEA), are not technically endocannabinoids as they do not bind CB receptors but play a role in the endocannabinoid system because of their ability to assist endocannabinoid binding and reducing endocannabinoid turnover by inhibiting FAAH.[52,53]

Phytocannabinoids. The Cannabis sativa plant contains more than 120 compounds called phytocannabinoids.[54] The most studied phytocannabinoid is THC, which elicits the psychotropic effects associated with marijuana by binding to CB1r. THC has been shown to induce an anti-inflammatory response via activation of both classical and non-classical cannabinoid receptors, such as PPARγ.[24,54] However, because of its psychoactive properties via CB1r, THC is not an ideal therapeutic agent.

CBD is one of the major non-psychogenic compounds in the Cannabis sativa plant. It has been found to be a GPR55 receptor antagonist, CB1r antagonist, CB2r inverse agonist, and weak TRPV1 agonist.[30] Inverse agonists are agents that act at the same binding sites as agonists but exhibit an opposite effect by stabilizing receptors in an inactive state.[55] Cannabidiol's action at these receptors regulates skin physiology by being anti-inflammatory, lipostatic, antiproliferative, and capable of modulating keratinocyte differentiation.[56,57]

Synthetic Cannabinoids. Synthetic cannabinoids can be purposefully designed to have specific binding affinities to desired receptors in the endocannabinoid system. For example, some synthetic cannabinoids such as AJA were developed to preferentially bind CB2r over CB1r so as to avoid the central psychogenic effects of CB1r stimulation. AJA has 12 times higher affinity for CB2r over CB1r, thus avoiding psychoactive effects at therapeutic doses.[58,59]

Selective receptor antagonists were created to enable the effects of a broad range of cannabinoids to be studied. CB1r antagonists and inverse agonists have the potential for therapeutic value, since they inhibit the psychoactive properties associated with stimulation of CB1r.[5] However, pharmacological CB1r antagonism has been shown to predispose patients to depressive episodes, so there are limitations to its utility.[60]