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The endocannabinoid signaling and control system is a major regulatory system of the body that contributes to homeostasis. It is very complex and is involved in many physiological and pathophysiological processes. Although cannabis has been used as a medicine for many years, this is mainly due to its activity on cannabinoid receptors on nerve cells in the brain and spinal cord. However, cannabinoid receptors CB1 and CB2 are also expressed in the skin, making it suitable for use in dermatology. 

For a long time, the occurrence of the corresponding cannabinoid receptor 1 (CB1) was known only in the central nervous system, but it was later discovered in many other organs such as the spleen, adrenal glands, lungs, heart and pancreas. The second important cannabinoid receptor (CB2) is found mainly in peripheral blood cells and tissues of the immune system such as the spleen. It is expressed in particular by B lymphocytes, natural killer cells and monocytes. What the cannabinoid receptors have in common is that they belong to the group of 7-helix transmembrane proteins, which are coupled to intracellular effector systems via G proteins. The endocannabinoid system also performs many important functions in the skin, where the expression of both receptors has been found [3], opening up promising therapeutic possibilities. 

The cannabinoid group 

Chemically speaking, cannabinoids are C-21 terpene phenols, a characteristic group of substances produced by Cannabis sativa L., from which over 100 compounds have been isolated [4]. The term phytocannabinoids is adopted for compounds synthesized by the plant. 

The best known and most studied cannabinoid is (-)-trans-Δ9-tetrahydrocannabinol (INN: dronabinol), which has a fixed configuration (6aR, 10aR). When referring to Δ9-THC, or even more simply, THC, this stereoenantiomer is implicitly included. Dronabinol is produced from the hemp plant, but it is also produced as a synthetic molecule and is contained in the American product Marinol®. 

Phytocannabinoids 

The cannabis plant has been valued as a medicine for thousands of years for its sedative, antidepressant, analgesic, anticonvulsant, antiemetic, anti-inflammatory and appetite-stimulating effects. With the study of the human endocannabinoid signaling and control system, we are beginning to understand the vast pharmacological potential of the plant and how it can be used specifically. 

In addition to plant extracts, thanks to intensive research over the last two decades, the isolated active ingredients from the plant, primarily its various phytocannabinoids, can also be used for medicine. 

 A long time ago with Δ9-THC, cannabidiol is the only cannabinoid that is already being intensively studied in clinical trials for multiple sclerosis, neuropathic pain, schizophrenia, social phobia, sleep disorders and epilepsy. In addition to its systemic use, cannabidiol also shows positive therapeutic effects as a dermatological agent. It can be used for neuropathic pain after an outbreak of herpes zoster, pruritus, acne, psoriasis and atopic dermatitis. 

Endocannabinoids against skin diseases 

The endocannabinoid system, with its cannabinoid receptors distributed throughout the body, is very complex. In addition to cannabinoids from the cannabis plant, the body's own cannabinoids (endocannabinoids) can also influence the endocannabinoid system. One of these is anandamide, which is very similar to the cannabinoid tetrahydrocannabinol (THC) from the cannabis plant. 

N-palmitoylethanolamine (PEA) also belongs to the endocannabinoid class, but is less well known. However, PEA is now known to have endocannabinoid-like effects and is found in the skin. 

Cannabinoid receptors are also found on the uncoated C-nerve fibers of the skin. Here they are responsible, among other things, for the development and transmission of itching. Various studies have shown that the body's own cannabinoid PEA can alleviate the symptoms of atopic dermatitis. A 2008 study conducted at the Technical University of Munich investigated the effects of PEA in a cream on patients with atopic dermatitis. A total of 2,456 subjects were surveyed. Symptoms such as itching, redness of the skin, scaling and thickening of the eczema improved by approximately 60 percent. In addition, 56 percent of the subjects discontinued the use of cortisone. Other subjects were able to reduce their weekly cortisone intake by an average of 62 percent. 

The endocannabinoid system of the skin is involved in various biological processes. It is known to influence proliferation, differentiation, apoptosis, and cytokine and hormone production in various types of skin cells. Its main function appears to be controlled proliferation and differentiation, as well as immune competence and tolerance. 

In addition to the skin, psoriasis can also manifest in the skin appendages (psoriatic onychopathy) and joints (psoriatic arthritis). 

Cannabidiol exerts its effects in different ways. First, it inhibits keratinocyte proliferation in a concentration-dependent manner, thereby counteracting hyperproliferation. Second, it exerts anti-inflammatory effects through different mechanisms (e.g., by inhibiting the NF-κB signaling pathway). Cell culture studies have shown that peroxisome proliferator-activated receptor gamma (PPAR-γ) is another cannabinoid receptor that may play an important role in psoriasis therapy. PPAR-γ is downregulated in inflammatory skin diseases such as psoriasis and atopic dermatitis. Cannabidiol acts as an agonist and, as has been recently shown for synthetic ligands (antidiabetic agents of the glitazone group), may not only have an antidiabetic effect but also suppress plaque formation by inhibiting hyperproliferation. 

The endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are produced by epidermal cells, hair follicles, and sebaceous glands (green arrows) and, through the receptor subtypes CB1 and CB2, exert significant effects on skin function (red arrows). For example, activation of CB1 and CB2 on keratinocytes suppresses cell proliferation, cell differentiation, and production of inflammatory mediators, as well as inducing apoptosis. Similarly, endocannabinoids inhibit inflammatory processes in immune cells via CB1 and CB2. In the hair follicle, activation of CB1 by anandamide reduces hair growth. This occurs by inhibiting intrafollicular proliferation, stimulating apoptosis, and causing hair follicle regression. Sebaceous glands respond to activation of CB2 with increased lipid production and apoptosis. CB1 receptors on sensory afferent nerves suppress itching and pain. 

Dysfunction of the endocannabinoid system can be the cause of numerous skin diseases (acne, seborrhea, allergic dermatitis, pruritus, psoriasis) as well as tumors. Conversely, targeted modulation of this system, for example with phytocannabinoids such as cannabidiol, offers broad therapeutic approaches. 

The pathogenesis and etiology of psoriasis are complex and not yet fully understood. It is characterized by dysfunction of various immune cells, hyperproliferation of epidermal keratinocytes, accompanied by migration of proinflammatory mediators and their increased expression. The result is increased scaling of the skin with limited, erythematous, sometimes pruritic patches. 

In addition to the skin, psoriasis can also manifest itself in the skin appendages (psoriatic onychopathy) and joints (psoriatic arthritis). 

Cannabidiol exerts its effects in different ways. First, it inhibits keratinocyte proliferation in a concentration-dependent manner, thereby counteracting hyperproliferation. Second, it exerts an anti-inflammatory effect through different mechanisms (e.g. by inhibiting the NF-κB signaling pathway). Cell culture studies have shown that peroxisome proliferator-activated receptor gamma (PPAR-γ) is another cannabinoid receptor that may play an important role in psoriasis therapy. PPAR-γ is downregulated in inflammatory skin diseases such as psoriasis and atopic dermatitis. Cannabidiol acts as an agonist here and, as has recently been shown for synthetic ligands (antidiabetic agents of the glitazone group), may not only have an antidiabetic effect but also suppress plaque formation by inhibiting hyperproliferation. 

Cannabidiol as an active ingredient in the therapy of atopic dermatitis Atopic dermatitis is caused by a disrupted skin barrier. 

The associated symptoms such as dry skin, inflammation, excruciating itching and burning, as well as secondary infections, cause significant suffering to those affected. There is a wealth of evidence, including patent applications, that describes cannabidiol or cannabidiol-rich hemp extracts as potent active ingredients in the treatment of atopic dermatitis. The effect is claimed to be at least comparable to cortisone preparations or calcineurin inhibitors, and so far there have been no noticeable adverse effects. The main benefit of cannabidiol, also in atopic dermatitis, lies in its broad spectrum of effects. In addition to the anti-inflammatory and antibacterial effect (see above), the antipruritic effect is particularly remarkable, which occurs within a few minutes and lasts for 12 to 24 hours. In this way, skin lesions caused by scratching with subsequent lichenification are avoided and the skin barrier is allowed to regenerate. Whether and to what extent cannabidiol treatment may also have adverse effects, for example through a possible reduction in sebum production (see acne therapy), remains to be determined. 

In summary, the discovery and study of the endocannabinoid system and its ligands forms the basis for many new therapeutic possibilities. Cannabidiol is an innovative active ingredient that, in addition to many areas of application, is also promising in dermatology. 

Cannabidiol as an active ingredient in acne therapy Acne vulgaris is one of the most common skin diseases, affecting millions of people worldwide. To date, there are no well-tolerated therapeutic agents that simultaneously address the various pathophysiological triggers (sebum overproduction, increased proliferation of sebaceous glands, inflammatory processes). 

Cannabidiol has the potential to fill this gap. It regulates precisely this triad and has a marked antibacterial effect. The mechanism of action has already been elucidated at the cellular level using human sebocyte cultures and skin cell cultures. Treatment of sebocytes with cannabidiol leads to their suppression by activating the ion channel TRPV4 (transient receptor potential vanilloid-4). 

At the same time, cannabidiol inhibits the effects of substances that increase lipogenesis (arachidonic acid and the combination of linoleic acid with testosterone). The anti-inflammatory effects are explained by inhibition of the NF-κB (nuclear factor kappa-light chain enhancer of activated B cells) signaling pathway and by upregulation of TRIB3 (tribbles homolog 3) via the A2a adenosine receptor. This polyvalent mode of action is novel compared to existing acne therapeutics and opens up new therapeutic perspectives. 

Cannabidiol meets all the important requirements for use as an active ingredient in dermatology. Due to its lipophilicity, it can be easily dissolved in lipophilic media and thus incorporated into a suitable base (lotion, cream, ointment and paste) depending on the indication. 

Due to its oxidative stability, no oxidative protection is required. It is easily absorbed by the skin and no adverse systemic effects are expected, as cannabidiol accumulates in the stratum corneum without penetrating into the deeper layers of the skin. 

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Atopic dermatitis is caused by a damaged skin barrier. The associated symptoms such as dry skin, inflammation, excruciating itching and burning, as well as secondary infections, cause significant suffering for those affected. There is a wealth of evidence, including patent applications, that describes cannabidiol or cannabidiol-rich hemp extracts as potent active ingredients in the treatment of atopic dermatitis. The effect is said to be at least comparable to cortisone preparations or calcineurin inhibitors, and to date, there have been no noticeable adverse effects. The main benefit of cannabidiol in atopic dermatitis is its broad range of effects. 

In addition to the anti-inflammatory and antibacterial effects (see above), the antipruritic effect, which occurs within a few minutes and lasts for 12 to 24 hours, is worth highlighting. This prevents scratch-induced skin lesions with subsequent lichenification, allowing the skin barrier to regenerate. Studies have yet to show whether and to what extent treatment with cannabidiol may also have adverse effects, such as a possible reduction in sebum production (see acne therapy). 

In summary, the discovery and research of the endocannabinoid system and its ligands forms the basis for many new therapeutic options. Cannabidiol is an innovative active ingredient that, in addition to its many applications, also holds promise in dermatology.