The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities

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“The endocannabinoid system (ECS) and the skin. Recent studies have intriguingly suggested the existence of a functional ECS in the skin and implicated it in various biological processes. It seems that the main physiological function of the cutaneous ECS is to constitutively control the proper and well-balanced proliferation, differentiation and survival, as well as immune competence and/or tolerance, of skin cells. The disruption of this delicate balance might facilitate the development of multiple pathological conditions and diseases of the skin (e.g. acne, seborrhea, allergic dermatitis, itch and pain, psoriasis, hair growth disorders, systemic sclerosis and cancer).

Perspectives in the ECS-targeted management of skin diseases

… preclinical data encourage one to systematically explore whether ECS-modulating drugs can be exploited in the management of common skin disorders…

 … we review preliminary data and discuss the possible applications of ECS-targeted therapies…ECS-targeted approaches in skin diseases. Modulations of the fine-tuned tone of the cutaneous endocannabinoid system (ECS) could have therapeutic values in the management of a large variety of human skin diseases…

Conclusions and future directions in experimental and clinical research

… it is envisaged (this is also strongly supported by pilot studies) that the targeted manipulation of the ECS might be beneficial in a multitude of human skin diseases. However, to predict the real therapeutic potential and translate the exciting preclinical observations discussed earlier into clinical practice, numerous important questions should carefully be addressed. Nevertheless, targeting the cutaneous ECS for therapeutic gain remains an intriguing and provocative possibility warranting future studies.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757311/

The Cannabinoid Receptors are Required for UV-Induced Inflammation and Skin Cancer Development

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“Solar ultraviolet (UV) irradiation is an important carcinogen that leads to the development of skin cancer, which is the most common human cancer. However, the receptors that mediate UV-induced skin carcinogenesis have not yet been unequivocally identified. Here we showed that UV irradiation directly activates the cannabinoid receptors 1 and 2 (CB1/2)…

These data provide direct evidence indicating that the CB1/2 receptors play a key role in UV-induced inflammation and skin cancer development…

Manipulation of the cannabinoid receptors has been useful in the management of pain, treatment of osteoporosis, inflammation, and cancer…”

.Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2390870/

 

A Population-based Case-Control Study of Marijuana Use and Head and Neck Squamous Cell Carcinoma

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“Marijuana (Cannabis sativa) contains more than 60 unique compounds known as cannabinoids. Cannabinoids, constituents of marijuana smoke, have been recognized to have potential antitumor properties. However, the epidemiological evidence addressing the relationship between marijuana use and the induction of head and neck cancer (HNSCC) is inconsistent and conflicting. An early epidemiological study reported that marijuana use was associated with an elevated risk for head and neck cancer.  However, more recent studies have failed to confirm the association of marijuana use with an increased head and neck cancer risk.

 In fact, many of these studies reported non-significant protective estimates of effect, consistent with a possible anticarcinogenic action of cannabinoids.

A recent epidemiologic review raised the need for additional, well conducted, large studies to clarify the nature of the association of marijuana use with the risk of cancer, especially head and neck cancer. In order to further elucidate the association between marijuana use and head neck cancer risk, we assessed marijuana use in detail in a population-based case-control study.

After adjusting for potential confounders (including smoking and alcohol drinking), 10 to 20 years of marijuana use was associated with a significantly reduced risk of HNSCC.

Our study suggests that moderate marijuana use is associated with reduced risk of HNSCC.”

[Expression of cannabinoid receptor 2 in squamous cell carcinoma].

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“The expression of CB2 protein and mRNA levels were detected in normal human skin and squamous cell carcinoma… Both the normal skin and squamous cell carcinoma expressed CB2, which was localized mainly in the basal cell layer and prickle cell layer in human skin with low expressions in the subcutaneous tissue.

 

CONCLUSION:

Squamous cell carcinoma over-expresses CB2 at both the protein and mRNA levels. High expression of CB2 in squamous cell carcinoma suggests an important role of CB2 in the tumorigenesis and development of squamous cell carcinoma.”

http://www.ncbi.nlm.nih.gov/pubmed/20335147

Dronabinol for supportive therapy in patients with malignant melanoma and liver metastases.

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“Loss of appetite and nausea can reduce the quality of life of patients with malignant melanoma and liver metastases. Often established antiemetic drugs fail to bring relief. Tetrahydrocannabinol (THC, Marinol), which is the active agent of Indian hemp, has been used successfully in this situation for other malignant tumors.

PATIENTS AND METHODS:

We treated 7 patients with hematogenous metastatic melanoma and liver metastases suffering from extensive loss of appetite and nausea supportively with dronabinol (Marinol. All of these patients had previously received standard antiemetic therapy without adequate relief. Dronabinol is a synthetic Delta-tetrahydrocannabinol. The drug was administered in capsule form. We evaluated the palliative effects of dronabinol with a special patient evaluation form, which was filled out at the beginning of the therapy and again after 4 weeks.

RESULTS:

The majority of patients described a significant increase in appetite and decrease in nausea. These effects remained for some weeks, but then decreased as metastases progressed and the general condition worsened. All of the patients experienced slight to moderate dizziness, but it was not sufficiently troubling to cause interruption or termination of therapy.

CONCLUSION:

Loss of appetite and nausea due to liver metastases of malignant melanoma can be treated in individual cases supportively with Dronabinol.”

http://www.ncbi.nlm.nih.gov/pubmed/16408219

Peripheral Cannabinoids Attenuate Carcinoma Induced Nociception in Mice

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“Cancer pain remains poorly understood and there are no effective therapies…

 We tested whether a local CBr2 agonist produces antinociception. Our findings suggest that a peripheral CBr2 agonist could provide relief for cancer patients. Cannabinoids also potentiate the analgesic effects of morphine and prevent tolerance.

These desirable effects of cannabinoids show promise for management of cancer pain and may lead to improved analgesic therapy.

These findings support the suggestion that cannabinoids are capable of producing antinociception in carcinoma-induced pain.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2771220/

Cannabidiol bioavailability after nasal and transdermal application: effect of permeation enhancers.

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“The nonpsychoactive cannabinoid, cannabidiol (CBD), has great potential for the treatment of chronic and ‘breakthrough’ pain that may occur in certain conditions like cancer. To fulfill this goal, suitable noninvasive drug delivery systems need to be developed for CBD. Chronic pain relief can be best achieved through the transdermal route, whereas ‘breakthrough’ pain can be best alleviated with intranasal (IN) delivery. Combining IN and transdermal delivery for CBD may serve to provide patient needs-driven treatment in the form of a nonaddictive nonopioid therapy.

CONCLUSION:

The results of this study indicated that CBD could be successfully delivered through the IN and transdermal routes.”

http://www.ncbi.nlm.nih.gov/pubmed/20545522

Inhibition of basal and ultraviolet B-induced melanogenesis by cannabinoid CB(1) receptors: a keratinocyte-dependent effect.

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“Ultraviolet radiation is the major environmental insult to the skin and stimulates the synthesis of melanin in melanocytes, which then distribute it to the neighboring keratinocytes where it confers photo-protection. Skin color results from the paracrine interaction between these two cell types. Recent studies suggest that endocannabinoids are potential mediators in the skin. Here, we investigated whether cannabinoid drugs play a role in melanogenesis and if ultraviolet radiation modifies the cutaneous endocannabinoid system.

We provide evidence that human melanoma cells (SK-mel-1) express CB(1) receptors… 

Furthermore, ultraviolet-B radiation increased endocannabinoids levels only in keratinocytes, whereas CB(1) cannabinoid receptor expression was up-regulated only in melanoma cells.

Our results collectively suggest that ultraviolet radiation activates paracrine CB(1)-mediated endocannabinoid signaling to negatively regulate melanin synthesis.

The endocannabinoid system in the skin may be a possible target for future therapies in pigmentary disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/21298280

The association of N-palmitoylethanolamine with the FAAH inhibitor URB597 impairs melanoma growth through a supra-additive action.

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“The incidence of melanoma is considerably increasing worldwide. Frequent failing of classical treatments led to development of novel therapeutic strategies aiming at managing advanced forms of this skin cancer. Additionally, the implication of the endocannabinoid system in malignancy is actively investigated…

CONCLUSIONS:

This study suggests the interest of targeting the endocannabinoid system in the management of skin cancer and underlines the advantage of associating endocannabinoids with enzymatic hydrolysis inhibitors.

This may contribute to the improvement of long-term palliation or cure of melanoma.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364151/