The Endocannabinoid System and Skin

The Skin's Endocannabinoid System

The endocannabinoid system is the body’s homeostatic regulatory system—and plays a key role in all physiological processes. The ECS is a mediator of various aspects within the skin. The body’s endogenous cannabinoids are the essential modulators in inflammation and immunity.

Both the CB1 and CB2 receptors are present within the skin and regulate such things as—the immune cells (CB1 & CB2), sebaceous glands (CB2), sensory nerves (CB1), sweat glands (CB1 & CB2), and hair follicles (CB1). The endogenous cannabinoids are extremely important and can suppress inflammatory conditions or support them. Maintaining a healthy endocannabinoid tone is essential for good health since the skin functions as a neuroimmunoendocrine organ.


Cannabinoids as Therapeutics for Non-Melanoma and Melanoma Skin Cancer

The results of these reports suggest that cannabinoid receptor stimulation by chemical carcinogens and UVB light promotes tumor development but that exogenously administered cannabinoid ligands induce tumor cell death.

Whereas the endogenous levels of endocannabinoids (nanomolar range) associated with carcinogen exposure increases tumor growth, the exogenous administration of cannabinoids (micromolar range) decreases tumor growth.

This suggestion is consistent with our previous studies demonstrating that low concentrations of anandamide (< 10 μM) increased NMSC cell proliferation while high concentrations (> 10 μM) caused cell death and apoptosis [35].

Collectively, the data suggest that ECS components are functional in keratinocytes and can be targeted to bring about tumor cell death.

Recent research suggests that the ECS plays a critical role in melanoma development and progression. Cannabinoid receptors CB1 and CB2 are expressed in human melanomas and numerous melanoma cell lines suggesting functional endocannabinoid signaling in this cancer type [19].

In this study, the cytotoxicity of ∆9-THC was further increased in melanoma cells co-treated with cannabidiol (CBD). Furthermore, the anti-tumor effects were replicated in a melanoma xenograft mouse model [46]. Similarly, Glodde’s group reported that ∆9-THC decreased the growth of melanoma in vitro and in vivo and that this effect was not observed in mice lacking CB1 and CB2 receptors, pointing to a CB receptor-dependent mechanism [31]. Interestingly, a different report demonstrated that ∆9-THC preferentially eliminated melanoma compared to non-tumorigenic melanocytes by inhibiting the activity of the pro-survival proteins, Akt and pRb [19]. As such, phytocannabinoids may emerge as a selective and effective class of anti-melanoma agents.

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The Endocannabinoid System in Human Keratinocytes

EVIDENCE THAT ANANDAMIDE INHIBITS EPIDERMAL DIFFERENTIATION THROUGH CB1 RECEPTOR-DEPENDENT INHIBITION OF PROTEIN KINASE C, ACTIVATING PROTEIN-1, AND TRANSGLUTAMINASE

In this investigation we report evidence that human keratinocytes have a functional “endocannabinoid system,” i.e. AEA and the biochemical machinery to bind, synthesize, transport, and hydrolyze it.

We also show that differentiating keratinocytes have decreased levels of endogenous AEA, due to increased degradation of this lipid through AMT and FAAH. In addition, we demonstrate that exogenous AEA inhibits keratinocyte differentiation in vitro, through a CB1-dependent mechanism that involves inactivation of protein kinase C, activating protein-1, and transglutaminase.

Our findings give a biochemical foundation for the effects of AEA on epidermal cells, especially in relation to pain sensation (12), response to UV irradiation (16), cell proliferation (17), and tumor growth (18). In this context, the finding, that human keratinocytes partake in the peripheral endocannabinoid system and that AEA can inhibit epidermal differentiation, opens new perspectives in the understanding of skin development and in the treatment of human skin diseases where cell hyperproliferation takes place.

In conclusion, we report evidence that human keratinocytes have a functional “endocannabinoid system,” which may sustain the peripheral actions of AEA at the skin level.

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Targeting Cutaneous Cannabinoid Signaling in Inflammation - A “High”-way to Heal?

On the footsteps of Karsak et al., we further investigated the immunological role of the eCB-signaling using human epidermal keratinocytes. We found that protein (but, interestingly, not mRNA) expression and activity of the aforementioned eCB-degrading enzyme FAAH was positively regulated by Toll-like receptor (TLR) 2 activation (Oláh et al., 2016a). This quite fascinating result clearly demonstrated how deeply the ECS is involved in the regulation of one of the most fundamental immune processes, i.e. the TLR-activation-induced pro-inflammatory signaling.

Indeed, administration of selective FAAH-inhibitors (and thereby restoration of the homeostatic, anti-inflammatory eCB signaling leading to the activation of CB1 and CB2 receptors) was able to almost completely abrogate the TLR2-mediated pro-inflammatory response (Oláh et al., 2016a).

Based on these data, FAAH appears to be an important “decision maker” in the initiation and maintenance of cutaneous inflammation; thus, increase/restoration of the homeostatic cutaneous eCB tone by topically applied FAAH-inhibitors possesses great potential in alleviating skin inflammation (Fig. 1A).

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

Excitingly, modulating the activity of the ECS has turned out to hold tremendous therapeutic potential for a multitude of diseases and pathological conditions affecting humans [13,15,16], ranging from inflammatory [17], neurodegenerative [18–20], gastrointestinal [21,22], liver [23,24], cardiovascular disorders [25,26] and obesity [27,28], to ischemia/reperfusion injury [29], cancer [30] and pain [31].

The pilosebaceous unit of the human skin, comprising the intimately localized hair follicle (HF) and the sebaceous gland (SG), can be regarded as the ‘brain’ of the skin because it controls a wide-array of the biological functions of this organ (from stem-cell supply through immunomodulation to cytokine production)

Casanova et al. [36] have demonstrated that various human skin tumors (e.g. basal cell carcinoma, squamous cell carcinoma) express both CB1 and CB2.

Local administration of synthetic CB1 and CB2 agonists induced growth inhibition of malignant skin tumors generated by intradermal inoculation of tumorigenic PDV.C57 mouse keratinocytes into nude mice.

The ECS has numerous important immune modulatory effects (e.g. suppression of production of various cytokines, chemokines, arachidonic acid-derived pro-inflammatory metabolites and nitric oxide) during inflammation [17].

Moreover, the skin inflammation was suppressed by locally administered THC [40].

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I appreciate the information, and the way you are approaching this critical mass subject.

I cannot stress this enough. This work must be an overwhelming effort, an avalanche.
Because dark, insane forces are in certain death throes, and won't die easy, as they should,
in rank shame for their work of sin, praise God.

I have been learning about natural remedies, for a variety of reasons.
Last month I spent close to fifty bucks on some fine herbs and spices (generally spices come from roots/herbs from leaves). The results have been amazing, and I am almost ashamed to speak of them, lest I gush....

The matter at hand really burns my ass. It has been the source of many upheavals which have ruined lives and destroyed harmony, besides causing the loss of simple cognitive function with my avocation, music. I am essentially a dullard until I am not. Oh...there it is. Zing.

How come, no matter what effort applied, or amount of study, I never saw that?.

Oh, it's because somehow, somewhere, something gave the bastards the right to regulate herbal nutrition, that's why. Only recently have we been allowed to talk of it. Only recently has the pursuit of happiness not been met with threats of the popo seizing goods, life, and liberty. Only recently have I been able to source harmony for fair equity. Thank God Donald Trump is here to show us the way to giving America back to the American People!

To think that I was worried about the plantain patch, the dandelions, and andrographis paniculata growing in my yard. Thank GOD for Donald J. Trump! Is he going to let these healthful plants be regulated, and taxed, as well? Does this include regulation of watercress. Well we shall certainly find out. Time and money's a wastin'!

And it is coming to an end. Keep up the good work. I am bookmarking every one of these gems of preventive and holistic medicine. Self-care I can believe in. Keep your filthy MRSA hospital hands and phlebotomist proboscises off my clean ass, unless I specifically request your molesting it.

And just think of all the prisoners who will spring from the dungeons as soon as everything is made right! Freedom for the innocent! Justice for the maligned masses at last. I knew Ivana was right about Donald J. Trump the instant I saw her shining angelic face beaming praise of him at the Convention. Get out of his way, you
awful partisan lobbyist-loyal lawmakers, so he can do God's work, lest when he pull the plug to drain the swamp,
you incur God's wrath and gnashing of teeth in unquenchable hellfire.

Godspeed to us all!

THANK GOD FOR DONALD J. TRUMP

# 732

a reply to: TheWhiteKnight

Thank you for your comments, and I agree, there are forces that are trying extremely hard to suppress, hinder, and discredit using nature's medicine. I personally think that is it essential that such kinds of medicines and information about them are made easily available to the people, everyone. Getting back to the basics, like educating people how to easily and affordably cook healthy meals at home and what food stuffs are essential and beneficial in maintaining a healthy mind and body. I am not going to pretend I am one of these people that lives a great healthy lifestyle and consumes only healthy things. I enjoy researching this subject and learning from it. Especially how I am personally change my bad habits into good ones. Ever since I learned that cannabinoids are one of three things that can prevent cell death and could have been of enormous benefit for so many people in the world that suffer from things that could have beem prevented (or at least given a change to prevent) and treat those that suffer from debilitating diseases and disorders—I have personally made it an effort to keep a source of exogenous cannabinoids in my kitchen.

Please share any good information on some of the herbs and spices you enjoy using and cooking with the most.

Here are some invaluable sources to what kind of food sources are of benefit to the endocannabinoid system.

Care and Feeding of the Endocannabinoid System

Beyond Cannabis: Plants and the Endocannabinoid System

Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

The Memorial Sloan Kettering Cancer Center website actually is a great source of information on this very subject. They have an extensive list of herbs, botanicals, fungi, spices, etc., within their Integrative Medicine section, and complete with all their known mechanism of actions, therapeutic benefits, side effects, contraindications, significant clinical research studies associated with them.

It is pretty on point as far as being non-biased, as their Integrative Medicine programs do studies and research with everything from music and acupuncture to meditation and breathing techniques. They actually have 4 studies currently being conducted on acupuncture, which definitely has a lot of therapeutic benefit, as my friend who is a physician has been recently been having acupuncture sessions once/twice a week. She reports that it helps her tremendously.

• Herbs, Botanicals, and Other Products

www.mskcc.org...

• Mind Body Therapy

www.mskcc.org...

• Acupuncture Clinical Trials

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This is very interesting. I used cannabis oil to treat a disease I have that manifest itself in skin lesions. (Hidradenitits suppurativa). I say "used" because my case seems to be linked closly to hormones and since having my baby and nursing, it has been behaving well without intervention. I hadn't been able to explore different ways of using cannabis to get the best results, since it's hard to experiment in some places. However, simply ingesting a small amount each day lead to drastic results that greatly improved my life.

a reply to: M4ngo

bump

Weird then that the US government is spending millions to synthetically produce it. I guess that's the government for you, trying to poison us again. But, I would take my chances with it because of the many non studied benefits.

Its interesting how the other components in natural cannabis come into play also.. Big Pharma wants you focused on a single molecule, so they can create a imitation and sell it... Well it doesnt work, so now they are testing new ways to fake it. By adding more synthetic crap, and telling everyone "molecules are molecules synthetic or natural" which is a load of cancerous crap.

There's no reason Cannabis should be rated by its thc content. Breeding for thc or cbd is not relative to quality or effectiveness of the product in any way but detrimental.

Reworking reworked gmo commerce strains instead of starting over from scratch.. = every producer has lost sight of what Cannabis was. No one in today's world is smoking pot and running companies. The stuff is not motivating and uplifting like it once was.

a reply to: BigBangWasAnEcho

This is a rather interesting topic—a single synthetic or semi synthetic compound vs the entourage from whole plant.

On one hand you have folks, like organic chemists, that create synthetic/semi synthetic compounds and tag them to act as a probe to explore their potential and to discover new things. And while synthetic/semisynthetic cannabinoids can be anywhere to 10s-1000s times more potent than a natural cannabinoid, some of these could be very important and useful in conditions like TBI or osteoporosis, in which natural whole plant Cannabis would never be able to produce the therapeutic benefit.

Take Prof. Raphael Mechoulam for example, organic chemist and one of the original fathers of Cannabis research and endocannabinoid research. He synthesized an entire family of cannabinoid compounds. His research team was first to isolate, elucidate and synthesize THC in pure form, and also isolated and elucidated two endocannabinoids—Anandamide and 2-AG. I would never call this man a sell-out or BP supporter, he is the exact opposite in fact. However, he is involved with companies, only one public that I know of and the others private, and acts as a scientific advisor. He is actually pro-whole plant Cannabis, but realizes the enormous potential for certain synthetic and semi-synthetic cannabinoids, particularly CBD and particularly with osteoporosis and TBI, among other things, that the consumption of whole plant Cannabis simply would never be able to accomplish. He is also the main reason Israel is what it is today. He is a huge advocate for medicinal Cannabis use. I think he and others are very aware of the corruption that is prevalent within 99% of BPs. It just honestly takes a very potent form to, like synthetic/semi-synthetics to be able to utilize the compound beneficially in certain health conditions.

I am in no way disagreeing with you though. Whole plant Cannabis, especially if shifted away from the current drive of selective breeding (high THC, low/virtually no CBD) would be of so much benefit to pretty much everyone. I think specific selective breeding though is essential for medicine and treating certain illnesses and conditions. What works for epilepsy (CBD dominate and/or THC:CBD 1:1 ratios) might not work as well for PTSD or depression and so on. Also, we get into terpenes which are major players in Cannabis' effects and therapeutic qualities. Like b-caryophyllene, which is a phytocannabinoid present in many species of herbs and plants and is actually a full agonist (THC is a partial agonist).

Honestly there is just so much to be discovered still and until the regulatory burden is lifted entirely, many people will never have the medicine they need and researchers will continue to slowly progress in clinical research and be able to conduct solid clinical trials. The last thing I want to see is corrupt BP getting into this space. But I would love to see honest and loving and caring people, like Raphael Mechoulam, contribute to a company that shares the same vision and compassion.

Cannabis is the holy grail and I keep some exogenous cannabinoids around every change I get. There is just so much potential to help so many lives with this there is going to be corrupt individuals and corporations and companies tying to take a profit without caring at all for the patient. It's sad. Fortunately, endocannabinoid researchers around the world mostly know each other and many collaborate and share knowledge. They have no agenda, and feel just as strongly as about preserving this plant in its righteous place without being exploited and misused by BP.

I highly recommend this documentary film on Raphael Mechoulam.

The Scientist—Raphael Mechoulam