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Cannabis as Medicine: How CBD Benefits the Brain and Nervous System (Stillness in the Storm); Biosynthesis and the Human Endocannabinoid System


Cannabis as Medicine: How CBD Benefits the Brain and Nervous System

STILLNESS IN THE STORM  Audrey Lefebvre   March 20th, 2016

Cannabidiol (CBD) is an active cannabinoid found in cannabis which, unlike THC (tetrahydrocannabinol), does not produce a psychoactive effect in the brain. For this reason, CBD has become a primary focus of medicinal cannabis studies.

CBD has been found to have a wide range of benefits, including lowering blood sugar levels, promoting bone growth, and importantly, protecting the human brain and nervous system from degeneration.

How CBD Protects the Nervous System

The nervous system is comprised of two main parts: the peripheral nervous system, which includes the nerves and ganglia on the outside of the brain and spinal cord, and the central nervous system, which includes the brain, cranial nerves, spiral cord, etc. CBD prevents the degeneration of the nervous system in several ways.

The human body has a fatty acid called amide hydroxylase (FAAH), an enzyme which and breaks down the neurotransmitter, anandamide, which is associated with the neural generation of motivation and pleasure, as well as neural development in early stage embryos.

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CBD suppresses the effect of FAAH in the body, creating higher levels of anandamide, which in turn naturally binds to Cannabinoid type 1 receptors (known as CB1), which are concentrated in our central nervous systems.

Additionally, CBD successfully stimulates the release of 2-AG, an endocannabinoid that stimulates both CB1 and Cannabinoid receptor type 2 (known as CB2).

These receptors play a key role in regulating mood, memory, appetite, sleep, and reduction of inflammation within the human body. For this reason, topical treatments of CBD can help reduce brain inflammation associated with autoimmune disorders, and which may lead to damage of the neurons’ fatty covering.

Reducing inflammation in the brain may also be used to treat neuropathic pain, which is caused by damage to the somatosensory nervous system.

A dosage of 20-40 mg of CBD has also been used to successfully treat high eye pressure, a painful condition caused by elevated levels of fluid in the eye. For this reason, CBD may benefit individuals who are affected by Glaucoma due to intraocular hypertension (high eye pressure), thereby preventing optic nerve damage.

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Additional CBD Benefits

CBD has been shown to benefit diabetes patients by naturally lowering the body’s blood sugar level as well as chronic inflammation which increases the development of insulin resistance within the body and type 2 diabetes.

In parallel, CBD may lower blood pressure, indirectly assist in the development of bone tissue, and act as a natural antibacterial. CBD has also been show to protect against cancerous cells and tumors. Consequently, CBD is of high interest and is researched for the future treatment of cancer.

Cannabidiol (CBD): The Cat’s Out of the Bag with This CURE-ALL

CBD Production Challenges and Current Legal Status

Discovered in the 1940s, CBD is a prominent active compound in cannabis. Although CBD’s medicinal benefits have been well studied and documented, nearly 8 decades later this essential ingredient’s full value is still relatively untapped and unrecognized by mainstream medicine.

Despite centuries of use in ancient cultures, there is today a negative connotation around the medical use of cannabis, particularly as the recreational use of cannabis is illegal in many parts of the United States.

Still considered a Schedule I drug with “no medicinal value”, it is a controlled substance that is legal in only a hand-full of States (such as Alaska, Colorado, Oregon, and Washington.) However, it is important to note that CBD provides zero psychoactive properties, does not get you “high”, and is not addictive.

Interestingly, CBD (usually found in oil form) is legal in all 50 states as long as it contains less than 0.3% THC, but it is not readily available as the CBD compound needs to be extracted from a plant that is currently prohibited from commercial growth in the United States.

However, with a wealth of scientific support for the health benefits of cannabis, and a ground-swell of public pressure to legalize the possession and use of this plant, the U.S. Congress may soon exempt CBD from the definition of cannabis, or decriminalize cannabis entirely.

With so many proven health benefits, reconsideration of the legal status of cannabis and further study into the medicinal uses of CBD and how it protects the nervous system, are critical to the future of medicine.


Biosynthesis and the Human Endocannabinoid System: The Science Behind the Medical Potential of Cannabis and WHY BIG PHARMA Lobbies Hard to Keep it SCHEDULE ONE with HEROIN

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Source Visual Capitalist     Reblogged at Zero Hedge
JEFF DESJARDINS

December 7, 2017 at 12:27 pm

Attitudes are changing fast on cannabis, and investors are taking note.

With the birth of legal recreational markets in places like California and a growing appreciation for the medical applications of cannabinoids such as CBD, the floodgates are open for companies to pursue new and groundbreaking opportunities in the sector.

Unlike other fields where medical research has been mainstream for many decades, the work behind cannabis – an incredibly complex plant – is only getting started.

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UNTAPPED POTENTIAL

Today’s infographic comes from InMed Pharmaceuticals and it explains the medical potential behind the 90+ cannabinoids that we have yet to fully understand.

It also details a scientific process known as biosynthesis, which helped revolutionize the production of insulin for diabetics. A process such as this may be a key in unlocking the medical potential of understudied cannabinoids.

The medical benefits of cannabis are many, and scientific research is being conducted to explore the application of the plant in several disease categories, including multiple sclerosis, seizures, glaucoma, cancer, Alzheimer’s, and migraines.

However, this is just the tip of the iceberg. To understand the full potential of the cannabis plant, you need to know what cannabinoids are, and how they work.

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THE HUMAN ENDOCANNABINOID SYSTEM

Like all mammals, the human body is loaded with natural cannabinoid receptors.

These receptors interact with cannabinoids, which occur naturally in the human body, but also in the cannabis plant.

Type of Cannabinoid Description
Endocannabinoids Made in the human body
Plant cannabinoids Found in the cannabis plant
Synthetic cannabinoids Manufactured artificially to mimic natural cannabinoids
Biosynthesized cannabinoids Biofermentation process using E. Coli-based system, which creates cannabinoids identical to those found in nature

Some cannabinoids you may know include THC and CBD – and they have a wide variety of applications. They also make up the majority of cannabinoids (by volume) that can be easily extracted from the plant.

However, there are actually 90+ other cannabinoids that have potential medical benefits as well, and they make up less than 0.1% of total biomass. Because they are so difficult to isolate, they remain understudied in medicinal science.

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A PROBLEM OF VOLUME

With only a tiny portion of the cannabis plant having medicinal value (the cannabinoids), a large degree of biomass must be harvested to extract even small amounts of medicine.

For example, 3 lbs (1.36 kg) of hig-CBD flowers may only yield 50 grams of pharmaceutical-grade compounds.

But this ratio is even more strenuous for the 90+ rare cannabinoids that make up less than 0.1% of the plant. With costs in the millions of dollars-per-gram range, it is extremely cost prohibitive to be researching these cannabinoids in any in-depth capacity.

BIOSYNTHESIS FOR CANNABINOIDS?

The process of biosynthesis could be a clue to maximizing the potential of these understudied cannabinoids.

In fact, this innovation has already helped democratize access to insulin, which originally was an extremely rare and expensive compound. To get just eight ounces of insulin, over 5,000 pig pancreases had to be harvested and processed. With biosynthesis, that is no longer the case.

Biosynthesis is a process that can occur by genetically modifying an organism to produce a pharmaceutically bioactive compounds that it normally would not make. Biosynthesis could thus be used to produce rare cannabinoids that are biologically identical to those produced by the cannabis plant itself.

Here’s how it works:

1) A biosynthetic cluster is inserted into a DNA vector.
2) DNA is inserted into E. Coli bacteria, where it provides instructions to produce cannabinoid compound(s)
3) The process is conducted at a large scale, resulting in materials that can be further processed into purified cannabinoids

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THE POTENTIAL OF BIOSYNTHESIS

The world’s largest cannabis biotech company, GW Pharmaceuticals, has signed a contract with British Sugar to grow 18 hectares of cannabis for its CBD epilepsy drug, Epidiolex™.

Equivalent to approximately 23 football fields of greenhouse space, this represents a considerable amount of resources and investment needed to grow enough crops to treat 40,000 children with the disease.

If biosynthesis can produce similar quantities of cannabinoids from a much smaller space, it would be disruptive to the industry. Further, it may also make getting other understudied cannabinoids more economic – helping to possibly unleash the full medicinal potential of the cannabis plant.

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Introduction to the Endocannabinoid System

Source NORML    Dustin Sulak, DO      Healer.com

As you read this review of the scientific literature regarding the therapeutic effects of cannabis and cannabinoids, one thing will become quickly evident: cannabis has a profound influence on the human body. This one herb and its variety of therapeutic compounds seem to affect every aspect of our bodies and minds. How is this possible?

At our integrative medical clinics in Maine and Massachusetts, my colleagues and I treat over 18,000 patients with a huge diversity of diseases and symptoms. In one day I might see cancerCrohn’s diseaseepilepsychronic painmultiple sclerosis, insomnia, Tourette’s syndrome and eczema, just to name a few. All of these conditions have different causes, different physiologic states, and vastly different symptoms. The patients are old and young. Some are undergoing conventional therapy. Others are on a decidedly alternative path. Yet despite their differences, almost all of my patients would agree on one point: cannabis helps their condition.

As a physician, I am naturally wary of any medicine that purports to cure-all. Panaceas, snake-oil remedies, and expensive fads often come and go, with big claims but little scientific or clinical evidence to support their efficacy. As I explore the therapeutic potential of cannabis, however, I find no lack of evidence. In fact, I find an explosion of scientific research on the therapeutic potential of cannabis, more evidence than one can find on some of the most widely used therapies of conventional medicine.

At the time of this writing (February 2015), a PubMed search for scientific journal articles published in the last 20 years containing the word “cannabis” revealed 8,637 results. Add the word “cannabinoid,” and the results increase to 20,991 articles. That’s an average of more than two scientific publications per day over the last 20 years! These numbers not only illustrate the present scientific interest and financial investment in understanding more about cannabis and its components, but they also emphasize the need for high quality reviews and summaries such as the document you are about to read.

How can one herb help so many different conditions? How can it provide both palliative and curative actions? How can it be so safe while offering such powerful effects? The search to answer these questions has led scientists to the discovery of a previously unknown physiologic system, a central component of the health and healing of every human and almost every animal: the endocannabinoid system.

What Is The Endocannabinoid System?

The endogenous cannabinoid system, named after the plant that led to its discovery, is perhaps the most important physiologic system involved in establishing and maintaining human health. Endocannabinoids and their receptors are found throughout the body: in the brain, organs, connective tissues, glands, and immune cells. In each tissue, the cannabinoid system performs different tasks, but the goal is always the same: homeostasis, the maintenance of a stable internal environment despite fluctuations in the external environment.

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Cannabinoids promote homeostasis at every level of biological life, from the sub-cellular, to the organism, and perhaps to the community and beyond. Here’s one example: autophagy, a process in which a cell sequesters part of its contents to be self-digested and recycled, is mediated by the cannabinoid system. While this process keeps normal cells alive, allowing them to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products, it has a deadly effect on malignant tumor cells, causing them to consume themselves in a programmed cellular suicide. The death of cancer cells, of course, promotes homeostasis and survival at the level of the entire organism.

Endocannabinoids and cannabinoids are also found at the intersection of the body’s various systems, allowing communication and coordination between different cell types. At the site of an injury, for example, cannabinoids can be found decreasing the release of activators and sensitizers from the injured tissue, stabilizing the nerve cell to prevent excessive firing, and calming nearby immune cells to prevent release of pro-inflammatory substances. Three different mechanisms of action on three different cell types for a single purpose: minimize the pain and damage caused by the injury.

The endocannabinoid system, with its complex actions in our immune system, nervous system, and all of the body’s organs, is literally a bridge between body and mind. By understanding this system we begin to see a mechanism that explains how states of consciousness can promote health or disease.

In addition to regulating our internal and cellular homeostasis, cannabinoids influence a person’s relationship with the external environment. Socially, the administration of cannabinoids clearly alters human behavior, often promoting sharing, humor, and creativity. By mediating neurogenesis, neuronal plasticity, and learning, cannabinoids may directly influence a person’s open-mindedness and ability to move beyond limiting patterns of thought and behavior from past situations. Reformatting these old patterns is an essential part of health in our quickly changing environment.

endocannabinoid-system
What Are Cannabinoid Receptors?

Sea squirts, tiny nematodes, and all vertebrate species share the endocannabinoid system as an essential part of life and adaptation to environmental changes. By comparing the genetics of cannabinoid receptors in different species, scientists estimate that the endocannabinoid system evolved in primitive animals over 600 million years ago.

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While it may seem we know a lot about cannabinoids, the estimated twenty thousand scientific articles have just begun to shed light on the subject. Large gaps likely exist in our current understanding, and the complexity of interactions between various cannabinoids, cell types, systems and individual organisms challenges scientists to think about physiology and health in new ways. The following brief overview summarizes what we do know.

Cannabinoid receptors are present throughout the body, embedded in cell membranes, and are believed to be more numerous than any other receptor system. When cannabinoid receptors are stimulated, a variety of physiologic processes ensue. Researchers have identified two cannabinoid receptors: CB1, predominantly present in the nervous system, connective tissues, gonads, glands, and organs; and CB2, predominantly found in the immune system and its associated structures. Many tissues contain both CB1 and CB2 receptors, each linked to a different action. Researchers speculate there may be a third cannabinoid receptor waiting to be discovered.

Endocannabinoids are the substances our bodies naturally make to stimulate these receptors. The two most well understood of these molecules are called anandamide and 2-arachidonoylglycerol (2-AG). They are synthesized on-demand from cell membrane arachidonic acid derivatives, have a local effect and short half-life before being degraded by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).

Phytocannabinoids are plant substances that stimulate cannabinoid receptors. Delta-9-tetrahydrocannabinol, or THC, is the most psychoactive and certainly the most famous of these substances, but other cannabinoids such as cannabidiol (CBD) and cannabinol (CBN) are gaining the interest of researchers due to a variety of healing properties. Most phytocannabinoids have been isolated from cannabis sativa, but other medical herbs, such as echinacea purpura, have been found to contain non-psychoactive cannabinoids as well.

Interestingly, the cannabis plant also uses THC and other cannabinoids to promote its own health and prevent disease. Cannabinoids have antioxidant properties that protect the leaves and flowering structures from ultraviolet radiation – cannabinoids neutralize the harmful free radicals generated by UV rays, protecting the cells. In humans, free radicals cause aging, cancer, and impaired healing. Antioxidants found in plants have long been promoted as natural supplements to prevent free radical harm.

Laboratories can also produce cannabinoids. Synthetic THC, marketed as dronabinol (Marinol), and nabilone (Cesamet), a THC analog, are both FDA approved drugs for the treatment of severe nausea and wasting syndrome. Some clinicians have found them helpful in the off-label treatment of chronic pain, migraine, and other serious conditions. Many other synthetic cannabinoids are used in animal research, and some have potency up to 600 times that of THC.

Cannabis, the Endocannabinoid System, and Good Health

As we continue to sort through the emerging science of cannabis and cannabinoids, one thing remains clear: a functional cannabinoid system is essential for health. From embryonic implantation on the wall of our mother’s uterus, to nursing and growth, to responding to injuries, endocannabinoids help us survive in a quickly changing and increasingly hostile environment. As I realized this, I began to wonder: can an individual enhance his/her cannabinoid system by taking supplemental cannabis? Beyond treating symptoms, beyond even curing disease, can cannabis help us prevent disease and promote health by stimulating an ancient system that is hard-wired into all of us?

I now believe the answer is yes. Research has shown that small doses of cannabinoids from cannabis can signal the body to make more endocannabinoids and build more cannabinoid receptors. This is why many first-time cannabis users don’t feel an effect, but by their second or third time using the herb they have built more cannabinoid receptors and are ready to respond. More receptors increase a person’s sensitivity to cannabinoids; smaller doses have larger effects, and the individual has an enhanced baseline of endocannabinoid activity. I believe that small, regular doses of cannabis might act as a tonic to our most central physiologic healing system.

Many physicians cringe at the thought of recommending a botanical substance, and are outright mortified by the idea of smoking a medicine. Our medical system is more comfortable with single, isolated substances that can be swallowed or injected. Unfortunately, this model significantly limits the therapeutic potential of cannabinoids.

Unlike synthetic derivatives, herbal cannabis may contain over one hundred different cannabinoids, including THC, which all work synergistically to produce better medical effects and less side effects than THC alone. While cannabis is safe and works well when smoked, many patients prefer to avoid respiratory irritation and instead use a vaporizer, cannabis tincture, or topical salve. Scientific inquiry and patient testimonials both indicate that herbal cannabis has superior medical qualities to synthetic cannabinoids.

In 1902 Thomas Edison said, “There were never so many able, active minds at work on the problems of disease as now, and all their discoveries are tending toward the simple truth that you can’t improve on nature.” Cannabinoid research has proven this statement is still valid.

So, is it possible that medical cannabis could be the most useful remedy to treat the widest variety of human diseases and conditions, a component of preventative healthcare, and an adaptive support in our increasingly toxic, carcinogenic environment? Yes. This was well known to the indigenous medical systems of ancient India, China, and Tibet, and as you will find in this report, is becoming increasingly well known by Western science. Of course, we need more human-based research studying the effectiveness of cannabis, but the evidence base is already large and growing constantly, despite the DEA’s best efforts to discourage cannabis-related research.

Does your doctor understand the benefit of medical cannabis? Can he or she advise you in the proper indications, dosage, and route of administration? Likely not. Despite the two largest U.S. physician associations (American Medical Association and American College of Physicians) calling for more research, the U.S. Congress prohibiting federal interference in states’ medical cannabis programs, a 5,000 year history of safe therapeutic use, and a huge amount of published research, most doctors know little or nothing about medical cannabis.

This is changing, in part because the public is demanding it. People want safe, natural and inexpensive treatments that stimulate our bodies’ ability to self-heal and help our population improve its quality of life. Medical cannabis is one such solution. This summary is an excellent tool for spreading the knowledge and helping to educate patients and healthcare providers on the scientific evidence behind the medical use of cannabis and cannabinoids.


The Endocannabinoid System For Dummies (We’ve Made It Easy For You)

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Source HERB.co  Anna Wilcox       July 28, 2016

Have you ever wondered how THC works? Well, it just-so-happens to be a similar shape to a compound our bodies create naturally. Thanks to its shape, THC is able to tap into a network in our bodies called the endocannabinoid system. It’s this ability that gives THC it’s psychoactive effects. But, what is the endocannabinoid system and what does it do? To help you understand, we’ve created a handy guide to the endocannabinoid system for dummies.

What is the endocannabinoid system (ECS)?

The endocannabinoid system (ECS) refers to a collection of cell receptors and corresponding molecules. You can think of cell receptors like little locks on the surface of your cells. The keys to these locks are chemical molecules called agonists. Each time an agonist binds to a cell it relays a message, giving your cell specific direction.

The endocannabinoid system is the name for a series of cell receptors that respond to certain kinds of agonists. Two primary cell receptors make up the ECS, Cannabinoid Receptor 1 (CB1) and Cannabinoid Receptor 2 (CB2). The keys for these receptors are called endocannabinoids. Endocannabinoids are like the body’s natural Endocannabinoids are like the body’s natural THC. In fact, endocannabinoids got their name from cannabis. Plant cannabinoids were discovered first. Endo means within, and cannabinoid referring to a compound that fits into cannabinoid receptors.

There are two main endocannabinoid molecules, named anandamide and 2-Ag. Funny thing, scientists wouldn’t have discovered anandamide without THC. Psychoactive (THC) was first discovered by Israeli scientist Raphael Mechoulam back in the 1960s. His finding quickly spurred a rush to figure out how THC worked, and whether or not our own bodies produced a similar compound.

More than two decades after the search began, anandamide was found. Yet, once they isolated the chemical, they faced another challenge. What should it be called? They turned to Sanskrit. Anandamide comes from the Sanskrit word Ananda, which means bliss. So, basically, anandamide means bliss molecule.

What does the ECS do?

Cannabinoid receptors are found all throughout the body, giving them a wide variety of functions. However, certain receptors are more concentrated in specific regions. CB1 receptors are abundant in the central nervous system. CB2 receptors are more often found on immune cells, in the gastrointestinal tract, and in the peripheral nervous system.The diversity of receptor locations shows just how important endocannabinoids are for day-to-day bodily function. They help regulate the following:

Endocannabinoids are the chemical messengers that tell your body to get these processes moving and when to stop. They help maintain optimal balance in the body, also known as homeostasis. When the ECS is disrupted, any one of these things can fall out of balance. Dysregulation in the ECS is thought to contribute to a wide variety of conditions, including fibromyalgia and irritable bowel syndrome.The ECS theory of disease is termed “Clinical Endocannabinoid Deficiency“.  The idea is simple: when the body does not produce enough endocannabinoids or cannot regulate them properly, you are more susceptible to illnesses that affect one or several of the functions listed above.

Where do endocannabinoids come from?

Endocannabinoid System2 1 The Endocannabinoid System For Dummies (Weve Made It Easy For You)

If your body cannot produce enough endocannabinoids, you might be in for some trouble. But, where do endocannabinoids come from, anyway? This question has another simple answer: diet.Your body creates endocannabinoids with the help of fatty acids. Omega-3 fatty acids are especially important for this. Recent research in animal models has found a connection between diets low in omega-3s and mood changes caused by poor endocannabinoid regulation.Fortunately, hemp seeds are a quality source of omgea-3s. However, fish like salmon and sardines produce a form of omega-3s that is easier for your body to put to use.

Beyond cell receptors

Endocannabinoid System3 1 The Endocannabinoid System For Dummies (Weve Made It Easy For You)

Cannabinoid receptors are often what we associate with the endocannabinoid system. But, the ECS is more complicated than that. Enzymes also have a crucial role to play in the process. In a way, enzymes are kind of like Pacman. They gobble up various compounds, change them, and then spit out the parts. In the ECS, enzymes break down leftover endocannabinoids. Enter non-psychoactive CBD.

Enter non-psychoactive CBD. While THC binds with cannabinoid receptors directly, CBD does not. Instead, it works it’s magic on an enzyme. The enzyme in question is called FAAH, and it is responsible for pulling excess anandamide out of circulation.CBD puts a stop to this. Psychoactive THC works by mimicking the body’s own endocannabinoids. But, CBD increases the amount of endocannabinoids in your system.CBD stops enzyme FAAH from breaking down all of the anandamide, and therefore makes more of it available for use by your cells. This is why CBD is a natural mood-lifter without psychoactive effects.This is just a brief overview of the endocannabinoid system.

Each year, new studies shed light into what this amazing network does inside our bodies. The discovery of the ECS is what makes medical cannabis such a big deal.People often joke about the herb’s ability to heal a wide variety of seemingly unrelated conditions. But, we now understand that these conditions are all regulated in part by the ECS. The medical implications of this finding are endless.


Scientist Reveal What Cannabis Does to Your Bones…

Source Health Times   By Dr. Fateh Malik     October 4, 2017

A study was published by The Journal of Bone and Mineral Research, conducted by researchers from Tel Aviv University and Hebrew University. This study showed that a chemical in marijuana, known as cannabinoid cannabidiol (CBD), strengthens bones and accelerates the healing of fractures, without causing any psychotropic effects.

The researcher Yankel Gabet explained:

 “WE FOUND THAT CBD ALONE MAKES BONES STRONGER DURING HEALING, ENHANCING THE MATURATION OF THE COLLAGENOUS MATRIX, WHICH PROVIDES THE BASIS FOR NEW MINERALIZATION OF BONE TISSUE. AFTER BEING TREATED WITH CBD, THE HEALED BONE WILL BE HARDER TO BREAK IN THE FUTURE.”

The team of experts inflicted mild femoral fractures on rats, and then gave an injection of CBD to some of them, while others received CBD plus tetrahydrocannabinol (THC, the ingredient that causes the marijuana high). They analyzed the healing between them and the rats that had not received any marijuana chemicals. Their conclusion was that rats injected with CBD experienced the same effects, regardless of the addition of THC.

Gabet added:

“WE FOUND CBD ALONE TO BE SUFFICIENTLY EFFECTIVE IN ENHANCING FRACTURE HEALING. OTHER STUDIES HAVE ALSO SHOWN CBD TO BE A SAFE AGENT, WHICH LEADS US TO BELIEVE WE SHOULD CONTINUE THIS LINE OF STUDY IN CLINICAL TRIALS TO ASSESS ITS USEFULNESS IN IMPROVING HUMAN FRACTURE HEALING.”

The same team previously found that the body contains receptors which respond to cannabinoid compounds, and they are not confined to the brain. This study showed that the skeleton has cannabinoid receptors which trigger bone formation and prevent bone loss, and the second study just confirmed this.

Gabet said:

“WE ONLY RESPOND TO CANNABIS BECAUSE WE ARE BUILT WITH INTRINSIC COMPOUNDS AND RECEPTORS THAT CAN ALSO BE ACTIVATED BY COMPOUNDS IN THE CANNABIS PLANT.”

This study is just a part of all research dedicated to the medical benefits of marijuana compounds, and new findings might stimulate researchers to analyze the positive effects of marijuana in the treatment of osteoporosis or other bone diseases.

Gabet added:

“THE CLINICAL POTENTIAL OF CANNABINOID-RELATED COMPOUNDS IS SIMPLY UNDENIABLE AT THIS POINT. WHILE THERE IS STILL A LOT OF WORK TO BE DONE TO DEVELOP APPROPRIATE THERAPIES, IT IS CLEAR THAT IT IS POSSIBLE TO DETACH A CLINICAL THERAPY OBJECTIVE FROM THE PSYCHOACTIVITY OF CANNABIS. CBD, THE PRINCIPAL AGENT IN OUR STUDY, IS PRIMARILY ANTI-INFLAMMATORY AND HAS NO PSYCHOACTIVITY.”

The medical properties of marijuana are numerous, and it is primarily used to boost appetite in the case of AIDS, to lower the side-effects of chemotherapy, and to soothe chronic pain. Numerous studies claim that it can regulate blood sugar, decelerate the HIV progression, and treat multiple sclerosis and Parkinson’s disease.

Researchers have shown that CBD suppresses seizures, inhibits the metastasis of many aggressive cancers, and destroys leukemia cells.

The journal Neuropsychopharmacology published a 2013 study which discovered that CBD is as effective as one antipsychotic drug, which is commonly used in the treatment of schizophrenia and paranoia but causes no side-effects. Other studies have also found that CBD can be used as a safe antipsychotic.

Marijuana is still technically illegal under U.S. federal law, but 17 U.S. states allow the use of CBD for research or for limited medical functions. Plus, the laws of 23 other countries permit the medical use of marijuana.

Marijuana is still classified as having “no currently accepted medical use” by the federal government. What might be a change in this approach is the recent decision of the FDA to approve the use of CBD extracts an experimental treatment for the Dravet syndrome, a rare form of childhood epilepsy.


CBD is a Non-Psychoactive Compound in Marijuana that Shows Promise in Epilepsy and Pain Therapy, So the DEA Wants to Class it with Heroin

Source BOING BOING     December 17, 2017

The World Health Organization’s new report on cannabidiol (CBD) found that the compound (which does not produce any kind of high — and may actually counteract the psychoactive properties of THC) is not addictive, has no potential for abuse, and shows promise in a number of medical trials.

So of course Trump’s Drug Enforcement Agency wants to class it as a Schedule I narcotic, reserved for substances with “a high potential for abuse”; “no currently accepted medical treatment use in the U.S.”; and “a lack of accepted safety for use of the drug or substance under medical supervision.”

CBD is currently in US Phase III clinical trials as an effective treatment for epilepsy, and in earlier trials for other applications.

Apologists for Trump’s prohibition on using the phrases “evidence-based” and “science-based” say that these phrases are used ““as a bullying tactic, in lieu of an actual argument” and argue that the phrase “CDC bases its recommendations on science in consideration with community standards and wishes” isn’t a denial of objective reality, because “Science is (ought to be) value-free, yet CDC and more broadly federal policy should embody values too.”

But the plan to schedule CBD is a crisp, unambiguous example of how policy making in the absence of evidence, because of values that are unsupported by evidence, produces terrible outcomes. People with chronic pain have turned to extremely dangerous substances to treat them, prompting an epidemic that has killed more Americans that the Vietnam war. The evidence for the existence of a non-habituating, safe pain treatment is a major cause for celebration.

But the Trump administration and the Republican party represent a base whose “values” are largely aligned in opposition to the legalization of any part or derivative of marijuana. So the “evidence” of the harm from marijuana is weighed against the faith of the policymakers and their base, and the evidence is discarded in favor of the “values,” to the detriment of individuals who are doomed be denied an effective treatment for debilitating illness, and to society because of the loss of those peoples’ productivity, the pain and suffering of their families, and the foreclosure of CBD to help mitigate the opiod crisis.

Instead, CBD is thought to have a broad range of actions on the endocannabinoid system—a collection of neurotransmitters that bind to receptors in the nervous system to mediate a variety of physiological processes, including mood, appetite, pain, and inflammation. Though researchers are still working out all of CBD’s functions, studies on animals and a small number on humans have found no evidence that it is toxic or addictive. It’s a relatively safe compound that is no more addictive than placebo in studies.

In terms of therapeutic potential, several clinical studies have found that pure CBD is effective at treating some types of epilepsy. In some cases it can completely eliminate seizures. There’s even a pure CBD product (Epidiolex®) currently in phase III trials. And researchers are also looking into using CBD for a range of other medical conditions. Though this work isn’t as far along as the epilepsy research, the ECDD noted that there’s positive preliminary data for treating a range of conditions. These include Alzheimer’s disease, Parkinson’s, anxiety, pain, nausea, inflammatory bowel disease, and rheumatoid arthritis. There’s also evidence to suggest that CBD may be helpful in combating opioid addiction.

With the expanding data and the growing acceptance of marijuana in the States, there has been a crescendo of interest in CBD and other cannabis products. Yet, the DEA has doubled-down on its position that CBD, as a part of marijuana, is a schedule I drug. In December of last year, the DEA made the point clear by creating a new drug code for marijuana extracts, including pure CBD.


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Endocannabinoid System

From Wikipedia, the free encyclopedia

The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the mammalian central nervous system (including the brain) and peripheral nervous system. The endocannabinoid system is involved in regulating a variety of physiological and cognitive processes including fertility,[1] pregnancy,[2] during pre– and postnatal development,[3] appetitepain-sensationmood, and memory, and in mediating the pharmacological effects of cannabis.[4][5] The ECS is also involved in mediating some of the physiological and cognitive effects of voluntary physical exercise in humans and other animals, such as contributing to exercise-induced euphoria as well as modulating locomotor activity and motivational salience for rewards.[6][7][8][9] 

In humans, the plasma concentration of certain endocannabinoids (i.e., anandamide) have been found to rise during physical activity;[6][7] since endocannabinoids can effectively penetrate the blood–brain barrier, it has been suggested that anandamide, along with other euphoriant neurochemicals, contributes to the development of exercise-induced euphoria in humans, a state colloquially referred to as a runner’s high.

Two primary endocannabinoid receptors have been identified: CB1, first cloned in 1990; and CB2, cloned in 1993. CB1 receptors are found predominantly in the brain and nervous system, as well as in peripheral organs and tissues, and are the main molecular target of the endocannabinoid ligand (binding molecule), Anandamide, as well as its mimetic phytocannabinoid, THC. One other main endocannabinoid is 2-Arachidonoylglycerol (2-AG) which is active at both cannabinoid receptors, along with its own mimetic phytocannabinoid, CBD. 2-AG and CBD are involved in the regulation of appetite, immune system functions and pain management.[10][11][12]

Basic overview[edit]

The endocannabinoid system, broadly speaking, includes:

The neuronsneural pathways, and other cells where these molecules, enzymes, and one or both cannabinoid receptor types are all colocalized from the endocannabinoid system.

The endocannabinoid system has been studied using genetic and pharmacological methods. These studies have revealed that cannabinoids act as neuromodulators[14][15][16] for a variety of processes, including motor learning,[17] appetite,[18] and pain sensation,[19] among other cognitive and physical processes. The localization of the CB1 receptor in the endocannabinoid system has a very large degree of overlap with the orexinergic projection system, which mediates many of the same functions, both physical and cognitive.[20] Moreover, CB1 is colocalizedon orexin projection neurons in the lateral hypothalamus and many output structures of the orexin system,[20][21] where the CB1 and orexin receptor 1 (OX1) receptors physically and functionally join together to form the CB1–OX1 receptor heterodimer.[20][22][23]

Expression of receptors[edit]

Cannabinoid binding sites exist throughout the central and peripheral nervous systems. The two most relevant receptors for cannabinoids are the CB1 and CB2 receptors, which are expressed predominantly in the brain and immune system respectively.[24] Density of expression varies based on species and correlates with the efficacy that cannabinoids will have in modulating specific aspects of behavior related to the site of expression. For example, in rodents, the highest concentration of cannabinoid binding sites are in the basal ganglia and cerebellum, regions of the brain involved in the initiation and coordination of movement.[25] In humans, cannabinoid receptors exist in much lower concentration in these regions, which helps explain why cannabinoids possess a greater efficacy in altering rodent motor movements than they do in humans.

A recent analysis of cannabinoid binding in CB1 and CB2 receptor knockout mice found cannabinoid responsiveness even when these receptors were not being expressed, indicating that an additional binding receptor may be present in the brain.[25] Binding has been demonstrated by 2-arachidonoylglycerol (2-AG) on the TRPV1 receptor suggesting that this receptor may be a candidate for the established response.[26]

In addition to CB1 and CB2, certain orphan receptors are known to bind endocannabinoids as well, including GPR18GPR55 (a regulator of neuroimmune function), and GPR119. CB1 has also been noted to form a functional human receptor heterodimer in orexin neurons with OX1, the CB1–OX1 receptor, which mediates feeding behavior and certain physical processes such as cannabinoid-induced pressor responses which are known to occur through signaling in the rostral ventrolateral medulla.[27][28]

Endocannabinoid synthesis, release, and degradation[edit]

During neurotransmission, the pre-synaptic neuron releases neurotransmitters into the synaptic cleft which bind to cognate receptors expressed on the post-synaptic neuron. Based upon the interaction between the transmitter and receptor, neurotransmitters may trigger a variety of effects in the post-synaptic cell, such as excitation, inhibition, or the initiation of second messengercascades. Based on the cell, these effects may result in the on-site synthesis of endogenous cannabinoids anandamide or 2-AG by a process that is not entirely clear, but results from an elevation in intracellular calcium.[24] Expression appears to be exclusive, so that both types of endocannabinoids are not co-synthesized. This exclusion is based on synthesis-specific channel activation: a recent study found that in the bed nucleus of the stria terminalis, calcium entry through voltage-sensitive calcium channels produced an L-type current resulting in 2-AG production, while activation of mGluR1/5 receptors triggered the synthesis of anandamide.[26]

Evidence suggests that the depolarization-induced influx of calcium into the post-synaptic neuron causes the activation of an enzyme called transacylase. This enzyme is suggested to catalyze the first step of endocannabinoid biosynthesis by converting phosphatidylethanolamine, a membrane-resident phospholipid, into N-acyl-phosphatidylethanolamine (NAPE). Experiments have shown that phospholipase D cleaves NAPE to yield anandamide.[29][30] This process is mediated by bile acids.[31] In NAPE-phospholipase D (NAPEPLD)-knockout mice, cleavage of NAPE is reduced in low calcium concentrations, but not abolished, suggesting multiple, distinct pathways are involved in anandamide synthesis.[32] The synthesis of 2-AG is less established and warrants further research.

Once released into the extracellular space by a putative endocannabinoid transporter, messengers are vulnerable to glial cell inactivation. Endocannabinoids are taken up by a transporter on the glial cell and degraded by fatty acid amide hydrolase (FAAH), which cleaves anandamide into arachidonic acid and ethanolamine or monoacylglycerol lipase (MAGL), and 2-AG into arachidonic acid and glycerol.[33] While arachidonic acid is a substrate for leukotriene and prostaglandin synthesis, it is unclear whether this degradative byproduct has unique functions in the central nervous system.[34][35] Emerging data in the field also points to FAAH being expressed in postsynaptic neurons complementary to presynaptic neurons expressing cannabinoid receptors, supporting the conclusion that it is major contributor to the clearance and inactivation of anandamide and 2-AG after endocannabinoid reuptake.[25] A neuropharmacological study demonstrated that an inhibitor of FAAH (URB597) selectively increases anandamide levels in the brain of rodents and primates. Such approaches could lead to the development of new drugs with analgesic, anxiolytic-like and antidepressant-like effects, which are not accompanied by overt signs of abuse liability.[36]

Binding and intracellular effects[edit]

Cannabinoid receptors are G-protein coupled receptors located on the pre-synaptic membrane. While there have been some papers that have linked concurrent stimulation of dopamine and CB1 receptors to an acute rise in cyclic adenosine monophosphate (cAMP) production, it is generally accepted that CB1 activation via cannabinoids causes a decrease in cAMP concentration by inhibition of adenylyl cyclase and a rise in the concentration of mitogen-activated protein kinase (MAP kinase).[13][25] The relative potency of different cannabinoids in inhibition of adenylyl cyclase correlates with their varying efficacy in behavioral assays. This inhibition of cAMP is followed by phosphorylation and subsequent activation of not only a suite of MAP kinases (p38/p42/p44), but also the PI3/PKB and MEK/ERK pathway (Galve-Roperh et al., 2002; Davis et al., 2005; Jones et al., 2005; Graham et al., 2006). Results from rat hippocampal gene chipdata after acute administration of tetrahydrocannabinol (THC) showed an increase in the expression of transcripts encoding myelin basic protein, endoplasmic proteins, cytochrome oxidase, and two cell adhesion molecules: NCAM, and SC1; decreases in expression were seen in both calmodulin and ribosomal RNAs (Kittler et al., 2000). In addition, CB1 activation has been demonstrated to increase the activity of transcription factors like c-Fos and Krox-24 (Graham et al., 2006).

Binding and neuronal excitability[edit]

The molecular mechanisms of CB1-mediated changes to the membrane voltage have also been studied in detail. Cannabinoids reduce calcium influx by blocking the activity of voltage-dependent N-P/Q- and L-type calcium channels.[37][38] In addition to acting on calcium channels, activation of Gi/o and Gs, the two most commonly coupled G-proteins to cannabinoid receptors, has been shown to modulate potassium channel activity. Recent studies have found that CB1 activation specifically facilitates potassium ion flux through GIRKs, a family of potassium channels.[38] Immunohistochemistry experiments demonstrated that CB1 is co-localized with GIRK and Kv1.4 potassium channels, suggesting that these two may interact in physiological contexts.[39]

In the central nervous system, CB1 receptors influence neuronal excitability, reducing the incoming synaptic input.[40] This mechanism, known as presynaptic inhibition, occurs when a postsynaptic neuron releases endocannabinoids in retrograde transmission, which then bind to cannabinoid receptors on the presynaptic terminal. CB1 receptors then reduce the amount of neurotransmitter released, so that subsequent excitation in the presynaptic neuron results in diminished effects on the postsynaptic neuron. It is likely that presynaptic inhibition uses many of the same ion channel mechanisms listed above, although recent evidence has shown that CB1 receptors can also regulate neurotransmitter release by a non-ion channel mechanism, i.e. through Gi/o-mediated inhibition of adenylyl cyclase and protein kinase A.[41] Direct effects of CB1 receptors on membrane excitability have been reported, and strongly impact the firing of cortical neurons.[42] A series of behavioral experiments demonstrated that NMDAR, an ionotropic glutamate receptor, and the metabotropic glutamate receptors (mGluRs) work in concert with CB1 to induce analgesia in mice, although the mechanism underlying this effect is unclear.[citation needed]

Functions of the endocannabinoid system[edit]
Memory[edit]

Mice treated with tetrahydrocannabinol (THC) show suppression of long-term potentiation in the hippocampus, a process that is essential for the formation and storage of long-term memory.[43] These results concur with anecdotal evidence suggesting that smoking Cannabis impairs short-term memory.[44] Consistent with this finding, mice without the CB1 receptor show enhanced memory and long-term potentiation indicating that the endocannabinoid system may play a pivotal role in the extinction of old memories. One study found that the high-dose treatment of rats with the synthetic cannabinoid HU-210 over several weeks resulted in stimulation of neural growth in the rats’ hippocampus region, a part of the limbic system playing a part in the formation of declarative and spatial memories, but did not investigate the effects on short-term or long-term memory.[45] Taken together, these findings suggest that the effects of endocannabinoids on the various brain networks involved in learning and memory may vary.

Role in hippocampal neurogenesis[edit]

In the adult brain, the endocannabinoid system facilitates the neurogenesis of hippocampal granule cells.[45][46] In the subgranular zone of the dentate gyrus, multipotent neural progenitors (NP) give rise to daughter cells that, over the course of several weeks, mature into granule cells whose axons project to and synapse onto dendrites on the CA3 region.[47] NPs in the hippocampus have been shown to possess fatty acid amide hydrolase (FAAH) and express CB1 and utilize 2-AG.[46] Intriguingly, CB1 activation by endogenous or exogenous cannabinoids promote NP proliferation and differentiation; this activation is absent in CB1 knockouts and abolished in the presence of antagonist.[45][46]

Induction of synaptic depression[edit]

The inhibitory effects of cannabinoid receptor stimulation on neurotransmitter release have caused this system to be connected to various forms of depressant plasticity. A recent study conducted with the bed nucleus of the stria terminalis found that the endurance of the depressant effects was mediated by two different signaling pathways based on the type of receptor activated. 2-AG was found to act on presynaptic CB1 receptors to mediate retrograde short-term depression (STD) following activation of L-type calcium currents, while anandamide was synthesized after mGluR5 activation and triggered autocrine signalling onto postsynapic TRPV1 receptors that induced long-term depression (LTD). Similar post-synaptic receptor dependencies were found in the striatum, but here both effects relied on presynaptic CB1 receptors.[26] These findings provide the brain a direct mechanism to selectively inhibit neuronal excitability over variable time scales. By selectively internalizing different receptors, the brain may limit the production of specific endocannabinoids to favor a time scale in accordance with its needs.

Appetite[edit]

Evidence for the role of the endocannabinoid system in food-seeking behavior comes from a variety of cannabinoid studies. Emerging data suggests that THC acts via CB1 receptors in the hypothalamic nuclei to directly increase appetite.[48] It is thought that hypothalamic neurons tonically produce endocannabinoids that work to tightly regulate hunger. The amount of endocannabinoids produced is inversely correlated with the amount of leptin in the blood.[49] For example, mice without leptin not only become massively obese but express abnormally high levels of hypothalamic endocannabinoids as a compensatory mechanism.[18] Similarly, when these mice were treated with an endocannabinoid inverse agonists, such as rimonabant, food intake was reduced.[18] When the CB1 receptor is knocked out in mice, these animals tend to be leaner and less hungry than wild-type mice. A related study examined the effect of THC on the hedonic (pleasure) value of food and found enhanced dopamine release in the nucleus accumbens and increased pleasure-related behavior after administration of a sucrose solution.[50]A related study found that endocannabinoids affect taste perception in taste cells[51] In taste cells, endocannabinoids were shown to selectively enhance the strength of neural signaling for sweet tastes, whereas leptin decreased the strength of this same response. While there is need for more research, these results suggest that cannabinoid activity in the hypothalamus and nucleus accumbens is related to appetitive, food-seeking behavior.[48]

Energy balance and metabolism[edit]

The endocannabinoid system has been shown to have a homeostatic role by controlling several metabolic functions, such as energy storage and nutrient transport. It acts on peripheral tissues such as adipocyteshepatocytes, the gastrointestinal tract, the skeletal muscles and the endocrine pancreas. It has also been implied in modulating insulin sensitivity. Through all of this, the endocannabinoid system may play a role in clinical conditions, such as obesitydiabetes, and atherosclerosis, which may also give it a cardiovascular role.[52]

Stress response[edit]

While the secretion of glucocorticoids in response to stressful stimuli is an adaptive response necessary for an organism to respond appropriately to a stressor, persistent secretion may be harmful. The endocannabinoid system has been implicated in the habituation of the hypothalamic-pituitary-adrenal axis (HPA axis) to repeated exposure to restraint stress. Studies have demonstrated differential synthesis of anandamide and 2-AG during tonic stress. A decrease of anandamide was found along the axis that contributed to basal hypersecretion of corticosterone; in contrast, an increase of 2-AG was found in the amygdala after repeated stress, which was negatively correlated to magnitude of the corticosterone response. All effects were abolished by the CB1 antagonist AM251, supporting the conclusion that these effects were cannabinoid-receptor dependent.[53] These findings show that anandamide and 2-AG divergently regulate the HPA axis response to stress: while habituation of the stress-induced HPA axis via 2-AG prevents excessive secretion of glucocorticoids to non-threatening stimuli, the increase of basal corticosterone secretion resulting from decreased anandamide allows for a facilitated response of the HPA axis to novel stimuli.

Exploration, social behavior, and anxiety[edit]

.[54] These contrasting effects reveal the importance of the endocannabinoid system in regulating anxiety-dependent behavior. Results suggest that glutamatergic cannabinoid receptors are not only responsible for mediating aggression, but produce an anxiolytic-like function by inhibiting excessive arousal: excessive excitation produces anxiety that limited the mice from exploring both animate and inanimate objects. In contrast, GABAergic neurons appear to control an anxiogenic-like function by limiting inhibitory transmitter release. Taken together, these two sets of neurons appear to help regulate the organism’s overall sense of arousal during novel situations.

Immune function[edit]

Evidence suggests that endocannabinoids may function as both neuromodulators and immunomodulators in the immune system. Here, they seem to serve an autoprotective role to ameliorate muscle spasms, inflammation, and other symptoms of multiple sclerosis and skeletal muscle spasms.[13] Functionally, the activation of cannabinoid receptors has been demonstrated to play a role in the activation of GTPases in macrophagesneutrophils, and BM cells. These receptors have also been implicated in the proper migration of B cells into the marginal zone (MZ) and the regulation of healthy IgM levels.[55] Interestingly, some disorders seem to trigger an upregulation of cannabinoid receptors selectively in cells or tissues related to symptom relief and inhibition of disease progression, such as in that rodent neuropathic pain model, where receptors are increased in the spinal cord microglia, dorsal root ganglion, and thalamic neurons.[24]

Multiple sclerosis[edit]

Historical records from ancient China and Greece suggest that preparations of Cannabis indica were commonly prescribed to ameliorate multiple sclerosis-like symptoms such as tremors and muscle pain. Modern research has confirmed these effects in a study on diseased mice, wherein both endogenous and exogenous agonists showed ameliorating effects on tremor and spasticity. It remains to be seen whether pharmaceutical preparations such as dronabinol have the same effects in humans.[56][57] Due to increasing use of medical Cannabis and rising incidence of multiple sclerosis patients who self-medicate with the drug, there has been much interest in exploiting the endocannabinoid system in the cerebellum to provide a legal and effective relief.[44] In mouse models of multiple sclerosis, there is a profound reduction and reorganization of CB1 receptors in the cerebellum.[58] Serial sections of cerebellar tissue subjected to immunohistochemistry revealed that this aberrant expression occurred during the relapse phase but returned to normal during the remitting phase of the disease.[58] Other studies suggest that CB1 agonists promote the survival of oligodendrocytes in vitro in the absence of growth and trophic factors; in addition, these agonist have been shown to promote mRNA expression of myelin lipid protein. (Kittler et al., 2000; Mollna-Holgado et al., 2002). Taken together, these studies point to the exciting possibility that cannabinoid treatment may not only be able to attenuate the symptoms of multiple sclerosis but also improve oligodendrocyte function (reviewed in Pertwee, 2001; Mollna-Holgado et al., 2002). 2-AG stimulates proliferation of a microglialcell line by a CB2 receptor dependent mechanism, and the number of microglial cells is increased in multiple sclerosis.[59]

Female reproduction[edit]

The developing embryo expresses cannabinoid receptors early in development that are responsive to anandamide secreted in the uterus. This signaling is important in regulating the timing of embryonic implantation and uterine receptivity. In mice, it has been shown that anandamide modulates the probability of implantation to the uterine wall. For example, in humans, the likelihood of miscarriage increases if uterine anandamide levels are too high or low.[60] These results suggest that intake of exogenous cannabinoids (e.g. marijuana) can decrease the likelihood for pregnancy for women with high anandamide levels, and alternatively, it can increase the likelihood for pregnancy in women whose anandamide levels were too low.[61][62]

Autonomic nervous system[edit]

Peripheral expression of cannabinoid receptors led researchers to investigate the role of cannabinoids in the autonomic nervous system. Research found that the CB1 receptor is expressed presynaptically by motor neurons that innervate visceral organs. Cannabinoid-mediated inhibition of electric potentials results in a reduction in noradrenaline release from sympathetic nervous system nerves. Other studies have found similar effects in endocannabinoid regulation of intestinal motility, including the innervation of smooth muscles associated with the digestive, urinary, and reproductive systems.[25]

Analgesia[edit]

At the spinal cord, cannabinoids suppress noxious-stimulus-evoked responses of neurons in the dorsal horn, possibly by modulating descending noradrenaline input from the brainstem.[25]As many of these fibers are primarily GABAergic, cannabinoid stimulation in the spinal column results in disinhibition that should increase noradrenaline release and attenuation of noxious-stimuli-processing in the periphery and dorsal root ganglion.

The endocannabinoid most researched in pain is palmitoylethanolamide. Palmitoylethanolamide is a fatty amine related to anandamide, but saturated and although initially it was thought that palmitoylethanolamide would bind to the CB1 and the CB2 receptor, later it was found that the most important receptors are the PPAR-alpha receptor, the TRPV receptor and the GPR55 receptor. Palmitoylethanolamide has been evaluated for its analgesic actions in a great variety of pain indications[63] and found to be safe and effective. Basically these data are proof of concept for endocannabinoids and related fatty amines to be therapeutically useful analgesics; palmitoylethanolamide is available under the brand names Normast and PeaPure as nutraceuticals.

Endocannabinoids are involved in placebo induced analgesia responses.[64]

Thermoregulation[edit]

Anandamide and N-arachidonoyl dopamine (NADA) have been shown to act on temperature-sensing TRPV1 channels, which are involved in thermoregulation.[65] TRPV1 is activated by the exogenous ligand capsaicin, the active component of chili peppers, which is structurally similar to endocannabinoids. NADA activates the TRPV1 channel with an EC50 of approximately of 50 nM.[clarify] The high potency makes it the putative endogenous TRPV1 agonist.[66] Anandamide has also been found to activate TRPV1 on sensory neuron terminals, and subsequently cause vasodilation.[25] TRPV1 may also be activated by methanandamide and arachidonyl-2′-chloroethylamide (ACEA).[13]

Sleep[edit]

Increased endocannabinoid signaling within the central nervous system promotes sleep-inducing effects. Intercerebroventricular administration of anandamide in rats has been shown to decrease wakefulness and increase slow-wave sleep and REM sleep.[67] Administration of anandamide into the basal forebrain of rats has also been shown to increase levels of adenosine, which plays a role in promoting sleep and suppressing arousal.[68] REM sleep deprivation in rats has been demonstrated to increase CB1 receptor expression in the central nervous system.[69] Furthermore, anandamide levels possess a circadian rhythm in the rat, with levels being higher in the light phase of the day, which is when rats are usually asleep or less active, since they are nocturnal.[70]

Physical exercise[edit]

Anandamide is an endogenous cannabinoid neurotransmitter that binds to cannabinoid receptors.[6] It has been shown that aerobic exercise causes an increase in plasma anandamide levels, where the magnitude of this increase is highest at moderate exercise intensity (i.e., exercising at ~70–80% maximum heart rate).[6] Increases in plasma anandamide levels are associated with psychoactive effects because anandamide is able to cross the blood–brain barrier and act within the central nervous system.[6] Thus, because anandamide is a euphoriant and aerobic exercise is associated with euphoric effects, it has been proposed that anandamide partly mediates the short-term mood-lifting effects of exercise (e.g., the euphoria of a runner’s high) via exercise-induced increases in its synthesis.[7][6]

In mice it was demonstrated that certain features of a runner’s high depend on cannabinoid receptors. Pharmacological or genetic disruption of cannabinoid signaling via cannabinoid receptors prevents the analgesic and anxiety-reducing effects of running.[71][non-primary source needed]

Experimental use of CB1 -/- phenotype[edit]

Neuroscientists often utilize transgenic CB1 knockout mice to discern novel roles for the endocannabinoid system. While CB1 knockout mice are healthy and live into adulthood, there are significant differences between CB1 knockout and wild-type mice. When subjected to a high-fat diet, CB1 knockout mice tend to be about sixty percent leaner and slightly less hungry than wildtype.[72] Compared to wildtype, CB1 knockout mice exhibit severe deficits in motor learning, memory retrieval, and increased difficulty in completing the Morris water maze.[17][73][74] There is also evidence indicating that these knockout animals have an increased incidence and severity of stroke and seizure.[75][76]

Endocannabinoids in plants[edit]

The endocannabinoid system is by molecular phylogenetic distribution of apparently ancient lipids in the plant kingdom, indicative of biosynthetic plasticity and potential physiological roles of endocannabinoid-like lipids in plants,[77] and detection of arachidonic acid (AA) indicates chemotaxonomic connections between monophyletic groups with common ancestor dates to around 420 million years ago (silurian; devonian). The phylogenetic distribution of these lipids may be a consequence of interactions/adaptations to the surrounding conditions such as chemicalplant-pollinator interactions, communication and defense mechanisms. The two novel EC-like molecules derived from the eicosatetraenoic acid juniperonic acid, an omega-3 structural isomerof AA, namely juniperoyl ethanolamide and 2-juniperoyl glycerol (1/2-AG) in gymnospermslycophytes and few monilophytes, show AA is an evolutionarily conserved signalling molecule that acts in plants in response to stress similar to that in animal systems.[78]

See also[edit]
References[edit]
  1. Jump up^ Klein, Carolin; Hill, Matthew N.; Chang, Sabrina C.H.; Hillard, Cecilia J.; Gorzalka, Boris B. (2012-6). “Circulating Endocannabinoid Concentrations and Sexual Arousal in Women”The journal of sexual medicine9 (6). doi:10.1111/j.1743-6109.2012.02708.xISSN 1743-6095PMC 3856894Freely accessiblePMID 22462722. Check date values in: |date= (help)
  2. Jump up^ Wang, Haibin; Xie, Huirong; Dey, Sudhansu K. (June 2006). “Endocannabinoid signaling directs periimplantation events”The AAPS Journal8 (2): E425–E432. doi:10.1007/BF02854916ISSN 1550-7416PMC 3231559Freely accessiblePMID 16808046.
  3. Jump up^ Fride, Ester (1 October 2004). “The endocannabinoid-CB1 receptor system in pre- and postnatal life”European Journal of Pharmacology. SPECIAL CELEBRATORY VOLUME 500 Dedicated to Professor David de Wied Honorary and Founding Editor. 500 (1): 289–297. doi:10.1016/j.ejphar.2004.07.033.
  4. Jump up^ Aizpurua-Olaizola, Oier; Elezgarai, Izaskun; Rico-Barrio, Irantzu; Zarandona, Iratxe; Etxebarria, Nestor; Usobiaga, Aresatz (2016). “Targeting the endocannabinoid system: future therapeutic strategies”Drug Discovery Todaydoi:10.1016/j.drudis.2016.08.005PMID 27554802.
  5. Jump up^ Donvito, Giulia; Nass, Sara R.; Wilkerson, Jenny L.; Curry, Zachary A.; Schurman, Lesley D.; Kinsey, Steven G.; Lichtman, Aron H. (31 August 2017). “The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain”Neuropsychopharmacologydoi:10.1038/npp.2017.204ISSN 1740-634X.
  6. Jump up to:a b c d e f g Tantimonaco M, Ceci R, Sabatini S, Catani MV, Rossi A, Gasperi V, Maccarrone M (2014). “Physical activity and the endocannabinoid system: an overview”. Cell. Mol. Life Sci71 (14): 2681–2698. doi:10.1007/s00018-014-1575-6PMID 24526057The traditional view that PA engages the monoaminergic and endorphinergic systems has been challenged by the discovery of the endocannabinoid system (ECS), composed of endogenous lipids, their target receptors, and metabolic enzymes. Indeed, direct and indirect evidence suggests that the ECS might mediate some of the PA-triggered effects throughout the body. … the evidence that PA induces some of the psychotropic effects elicited by the Cannabis sativa active ingredient Δ9-tetrahydrocannabinol (Δ9-THC, Fig. 1), like bliss, euphoria, and peacefulness, strengthened the hypothesis that endocannabinoids (eCBs) might mediate, at least in part, the central and peripheral effects of exercise [14]. … To our knowledge, the first experimental study aimed at investigating the influence of PA on ECS in humans was carried out in 2003 by Sparling and coworkers [63], who showed increased plasma AEA content after 45 min of moderate intensity exercise on a treadmill or cycle ergometer. Since then, other human studies have shown increased blood concentrations of AEA … A dependence of the increase of AEA concentration on exercise intensity has also been documented. Plasma levels of AEA significantly increased upon 30 min of moderate exercise (heart rate of 72 and 83 %), but not at lower and significantly higher exercise intensities, where the age-adjusted maximal heart rate was 44 and 92 %, respectively … Several experimental data support the hypothesis that ECS might, at least in part, explain PA effects on brain functions, because: (1) CB1 is the most abundant GPCR in the brain participating in neuronal plasticity [18]; (2) eCBs are involved in several brain responses that greatly overlap with the positive effects of exercise; (3) eCBs are able to cross the blood–brain barrier [95]; and (4) exercise increases eCBplasma levels [64–67].
  7. Jump up to:a b c d Raichlen DA, Foster AD, Gerdeman GL, Seillier A, Giuffrida A (2012). “Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the ‘runner’s high'”. J. Exp. Biol215 (Pt 8): 1331–1336. doi:10.1242/jeb.063677PMID 22442371Humans report a wide range of neurobiological rewards following moderate and intense aerobic activity, popularly referred to as the ‘runner’s high’, which may function to encourage habitual aerobic exercise. … Thus, a neurobiological reward for endurance exercise may explain why humans and other cursorial mammals habitually engage in aerobic exercise despite the higher associated energy costs and injury risks
  8. Jump up^ Thompson, Z., D. Argueta, T. Garland, Jr., and N. DiPatrizio. 2017. Circulating levels of endocannabinoids respond acutely to voluntary exercise, are altered in mice selectively bred for high voluntary wheel running, and differ between the sexes. Physiology & Behavior 170:141–150.
  9. Jump up^ Kuhn, S. L., D. A. Raichlen, and A. E. Clark. 2016. What moves us? How mobility and movement are at the center of human evolution. Evolutionary Anthropology: Issues, News, and Reviews 25:86–97.
  10. Jump up^ Grotenhermen, Franjo (23 July 2012). “The Therapeutic Potential of Cannabis and Cannabinoids”Dtsch Arztebl Int109 (PMC3442177): 495–501. doi:10.3238/arztebl.2012.0495PMC 3442177Freely accessiblePMID 23008748.
  11. Jump up^ Blázquez, C; Chiarlone, A; Bellocchio, L; Resel, E; Pruunsild, P; García-Rincón, D; Sendtner, M; Timmusk, T; Lutz, B; Galve-Roperh, I; Guzmán, M (20 February 2015). “The CB1 cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway”Cell Death and Differentiation22 (10): 1618–1629. doi:10.1038/cdd.2015.11.
  12. Jump up^ Russo, Ethan B (August 2011). “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects”British Journal of Pharmacology163 (7): 1344–1364. doi:10.1111/j.1476-5381.2011.01238.xPMC 3165946Freely accessiblePMID 21749363.
  13. Jump up to:a b c d Pertwee RG (April 2006). “The pharmacology of cannabinoid receptors and their ligands: an overview”. Int J Obes (Lond)30 (Suppl 1): S13–8. doi:10.1038/sj.ijo.0803272PMID 16570099.
  14. Jump up^ Fortin DA, Levine ES (2007). “Differential effects of endocannabinoids on glutamatergic and GABAergic inputs to layer 5 pyramidal neurons”. Cereb. Cortex17 (1): 163–74. doi:10.1093/cercor/bhj133PMID 16467564.
  15. Jump up^ Good CH (2007). “Endocannabinoid-dependent regulation of feedforward inhibition in cerebellar Purkinje cells”. J. Neurosci27 (1): 1–3. doi:10.1523/JNEUROSCI.4842-06.2007PMID 17205618.
  16. Jump up^ Hashimotodani Y, Ohno-Shosaku T, Kano M (2007). “Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus”. J. Neurosci27 (5): 1211–9. doi:10.1523/JNEUROSCI.4159-06.2007PMID 17267577.
  17. Jump up to:a b Kishimoto Y, Kano M (2006). “Endogenous cannabinoid signaling through the CB1 receptor is essential for cerebellum-dependent discrete motor learning”. J. Neurosci26 (34): 8829–37. doi:10.1523/JNEUROSCI.1236-06.2006PMID 16928872.
  18. Jump up to:a b c Di Marzo V, Goparaju SK, Wang L, Liu J, Bátkai S, Járai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G (April 2001). “Leptin-regulated endocannabinoids are involved in maintaining food intake”. Nature410 (6830): 822–5. doi:10.1038/35071088PMID 11298451.
  19. Jump up^ Cravatt BF, et al. (July 2001). “Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase”Proc. Natl. Acad. Sci. U.S.A98 (16): 9371–6. Bibcode:2001PNAS…98.9371Cdoi:10.1073/pnas.161191698JSTOR 3056353PMC 55427Freely accessiblePMID 11470906.
  20. Jump up to:a b c Flores A, Maldonado R, Berrendero F (2013). “Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far”Front Neurosci7: 256. doi:10.3389/fnins.2013.00256PMC 3868890Freely accessiblePMID 24391536Direct CB1-HcrtR1 interaction was first proposed in 2003 (Hilairet et al., 2003). Indeed, a 100-fold increase in the potency of hypocretin-1 to activate the ERK signaling was observed when CB1 and HcrtR1 were co-expressed … In this study, a higher potency of hypocretin-1 to regulate CB1-HcrtR1 heteromer compared with the HcrtR1-HcrtR1 homomer was reported (Ward et al., 2011b). These data provide unambiguous identification of CB1-HcrtR1 heteromerization, which has a substantial functional impact. … The existence of a cross-talk between the hypocretinergic and endocannabinoid systems is strongly supported by their partially overlapping anatomical distribution and common role in several physiological and pathological processes. However, little is known about the mechanisms underlying this interaction.
    • Figure 1: Schematic of brain CB1 expression and orexinergic neurons expressing OX1 or OX2
    • Figure 2: Synaptic signaling mechanisms in cannabinoid and orexin systems
    • Figure 3: Schematic of brain pathways involved in food intake
  21. Jump up^ Watkins BA, Kim J (2014). “The endocannabinoid system: helps to direct eating behavior and macronutrient metabolism”Front Psychol5: 1506. doi:10.3389/fpsyg.2014.01506PMC 4285050Freely accessiblePMID 25610411CB1 is present in neurons of the enteric nervous system and in sensory terminals of vagal and spinal neurons in the gastrointestinal tract (Massa et al., 2005). Activation of CB1 is shown to modulate nutrient processing, such as gastric secretion, gastric emptying, and intestinal motility. … CB1 is shown to co-localize with the food intake inhibiting neuropeptide, corticotrophin-releasing hormone, in the paraventricular nucleus of the hypothalamus, and with the two orexigenic peptides, melanin-concentrating hormone in the lateral hypothalamus and with pre-pro-orexin in the ventromedial hypothalamus (Inui, 1999; Horvath, 2003). CB1 knockout mice showed higher levels of CRH mRNA, suggesting that hypothalamic EC receptors are involved in energy balance and may be able to mediate food intake (Cota et al., 2003). … The ECS works through many anorexigenic and orexigenic pathways where ghrelin, leptin, adiponectin, endogenous opioids, and corticotropin-releasing hormones are involved (Viveros et al., 2008).
  22. Jump up^ Thompson MD, Xhaard H, Sakurai T, Rainero I, Kukkonen JP (2014). “OX1 and OX2 orexin/hypocretin receptor pharmacogenetics”Front Neurosci8: 57. doi:10.3389/fnins.2014.00057PMC 4018553Freely accessiblePMID 24834023OX1–CB1 dimerization was suggested to strongly potentiate orexin receptor signaling, but a likely explanation for the signal potentiation is, instead, offered by the ability of OX1 receptor signaling to produce 2-arachidonoyl glycerol, a CB1 receptor ligand, and a subsequent co-signaling of the receptors (Haj-Dahmane and Shen, 2005; Turunen et al., 2012; Jäntti et al., 2013). However, this does not preclude dimerization.
  23. Jump up^ Jäntti MH, Mandrika I, Kukkonen JP (2014). “Human orexin/hypocretin receptors form constitutive homo- and heteromeric complexes with each other and with human CB1 cannabinoid receptors”. Biochem. Biophys. Res. Commun445 (2): 486–90. doi:10.1016/j.bbrc.2014.02.026PMID 24530395Orexin receptor subtypes readily formed homo- and hetero(di)mers, as suggested by significant BRET signals. CB1 receptors formed homodimers, and they also heterodimerized with both orexin receptors. … In conclusion, orexin receptors have a significant propensity to make homo- and heterodi-/oligomeric complexes. However, it is unclear whether this affects their signaling. As orexin receptors efficiently signal via endocannabinoid production to CB1 receptors, dimerization could be an effective way of forming signal complexes with optimal cannabinoid concentrations available for cannabinoid receptors.
  24. Jump up to:a b c Pertwee RG (January 2008). “The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin”Br. J. Pharmacol153 (2): 199–215. doi:10.1038/sj.bjp.0707442PMC 2219532Freely accessiblePMID 17828291.
  25. Jump up to:a b c d e f g Elphick MR, Egertová M (March 2001). “The neurobiology and evolution of cannabinoid signalling”Philos. Trans. R. Soc. Lond. B Biol. Sci356 (1407): 381–408. doi:10.1098/rstb.2000.0787PMC 1088434Freely accessiblePMID 11316486.
  26. Jump up to:a b c Puente N, Cui Y, Lassalle O, Lafourcade M, Georges F, Venance L, Grandes P, Manzoni OJ (December 2011). “Polymodal activation of the endocannabinoid system in the extended amygdala”. Nat. Neurosci14 (12): 1542–7. doi:10.1038/nn.2974PMID 22057189.
  27. Jump up^ Ibrahim BM, Abdel-Rahman AA (2014). “Cannabinoid receptor 1 signaling in cardiovascular regulating nuclei in the brainstem: A review”J Adv Res5 (2): 137–45. doi:10.1016/j.jare.2013.03.008PMC 4294710Freely accessiblePMID 25685481.
  28. Jump up^ Ibrahim BM, Abdel-Rahman AA (2015). “A pivotal role for enhanced brainstem Orexin receptor 1 signaling in the central cannabinoid receptor 1-mediated pressor response in conscious rats”Brain Res1622: 51–63. doi:10.1016/j.brainres.2015.06.011PMC 4562882Freely accessiblePMID 26096126Orexin receptor 1 (OX1R) signaling is implicated in cannabinoid receptor 1 (CB1R) modulation of feeding. Further, our studies established the dependence of the central CB1R-mediated pressor response on neuronal nitric oxide synthase (nNOS) and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation in the RVLM. We tested the novel hypothesis that brainstem orexin-A/OX1R signaling plays a pivotal role in the central CB1R-mediated pressor response. Our multiple labeling immunofluorescence findings revealed co-localization of CB1R, OX1R and the peptide orexin-A within the C1 area of the rostral ventrolateral medulla (RVLM). Activation of central CB1R … in conscious rats caused significant increases in BP and orexin-A level in RVLM neuronal tissue. Additional studies established a causal role for orexin-A in the central CB1R-mediated pressor response
  29. Jump up^ Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N (February 2004). “Molecular characterization of a phospholipase D generating anandamide and its congeners”. J. Biol. Chem279 (7): 5298–305. doi:10.1074/jbc.M306642200PMID 14634025.
  30. Jump up^ Liu J, Wang L, Harvey-White J, Osei-Hyiaman D, Razdan R, Gong Q, Chan AC, Zhou Z, Huang BX, Kim HY, Kunos G (September 2006). “A biosynthetic pathway for anandamide”Proc. Natl. Acad. Sci. U.S.A103 (36): 13345–50. Bibcode:2006PNAS..10313345Ldoi:10.1073/pnas.0601832103PMC 1557387Freely accessiblePMID 16938887.
  31. Jump up^ Magotti P, Bauer I, Igarashi M, Babagoli M, Marotta R, Piomelli D, Garau G (2014). “Structure of Human N-Acylphosphatidylethanolamine-Hydrolyzing Phospholipase D: Regulation of Fatty Acid Ethanolamide Biosynthesis by Bile Acids”Structure23 (3): 598–604. doi:10.1016/j.str.2014.12.018PMC 4351732Freely accessiblePMID 25684574.
  32. Jump up^ Leung D, Saghatelian A, Simon GM, Cravatt BF (April 2006). “Inactivation of N-acyl phosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids”Biochemistry45 (15): 4720–6. doi:10.1021/bi060163lPMC 1538545Freely accessiblePMID 16605240.
  33. Jump up^ Pazos MR, Núñez E, Benito C, Tolón RM, Romero J (June 2005). “Functional neuroanatomy of the endocannabinoid system”. Pharmacol. Biochem. Behav81 (2): 239–47. doi:10.1016/j.pbb.2005.01.030PMID 15936805.
  34. Jump up^ Yamaguchi T, Shoyama Y, Watanabe S, Yamamoto T (January 2001). “Behavioral suppression induced by cannabinoids is due to activation of the arachidonic acid cascade in rats”. Brain Res889 (1–2): 149–54. doi:10.1016/S0006-8993(00)03127-9PMID 11166698.
  35. Jump up^ Brock TG (December 2005). “Regulating leukotriene synthesis: the role of nuclear 5-lipoxygenase”. J. Cell. Biochem96 (6): 1203–11. doi:10.1002/jcb.20662PMID 16215982.
  36. Jump up^ Clapper JR, Mangieri RA, Piomelli D (2009). “The endocannabinoid system as a target for the treatment of cannabis dependence”Neuropharmacology56 (Suppl 1): 235–43. doi:10.1016/j.neuropharm.2008.07.018PMC 2647947Freely accessiblePMID 18691603.
  37. Jump up^ Twitchell W, Brown S, Mackie K (1997). “Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons”. J. Neurophysiol78 (1): 43–50. PMID 9242259.
  38. Jump up to:a b Guo J, Ikeda SR (2004). “Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons”. Mol. Pharmacol65 (3): 665–74. doi:10.1124/mol.65.3.665PMID 14978245.
  39. Jump up^ Binzen U, Greffrath W, Hennessy S, Bausen M, Saaler-Reinhardt S, Treede RD (2006). “Co-expression of the voltage-gated potassium channel Kv1.4 with transient receptor potential channels (TRPV1 and TRPV2) and the cannabinoid receptor CB1 in rat dorsal root ganglion neurons”. Neuroscience142 (2): 527–39. doi:10.1016/j.neuroscience.2006.06.020PMID 16889902.
  40. Jump up^ Freund TF, Katona I, Piomelli D (2003). “Role of endogenous cannabinoids in synaptic signaling”. Physiol. Rev83 (3): 1017–66. doi:10.1152/physrev.00004.2003PMID 12843414.
  41. Jump up^ Chevaleyre V, Heifets BD, Kaeser PS, Südhof TC, Purpura DP, Castillo PE (2007). “ENDOCANNABINOID-MEDIATED LONG-TERM PLASTICITY REQUIRES cAMP/PKA SIGNALING AND RIM1α”Neuron54 (5): 801–12. doi:10.1016/j.neuron.2007.05.020PMC 2001295Freely accessiblePMID 17553427.
  42. Jump up^ Bacci A, Huguenard JR, Prince DA (2004). “Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids”. Nature431 (7006): 312–6. Bibcode:2004Natur.431..312Bdoi:10.1038/nature02913PMID 15372034.
  43. Jump up^ Hampson RE, Deadwyler SA (1999). “Cannabinoids, hippocampal function and memory”. Life Sci65 (6–7): 715–23. doi:10.1016/S0024-3205(99)00294-5PMID 10462072.
  44. Jump up to:a b Pertwee RG (2001). “Cannabinoid receptors and pain”. Prog. Neurobiol63 (5): 569–611. doi:10.1016/S0301-0082(00)00031-9PMID 11164622.
  45. Jump up to:a b c Jiang W, Zhang Y, Xiao L, Van Cleemput J, Ji SP, Bai G, Zhang X (2005). “Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects”J. Clin. Invest115 (11): 3104–16. doi:10.1172/JCI25509PMC 1253627Freely accessiblePMID 16224541.
  46. Jump up to:a b c Aguado T, Monory K, Palazuelos J, Stella N, Cravatt B, Lutz B, Marsicano G, Kokaia Z, Guzmán M, Galve-Roperh I (2005). “The endocannabinoid system drives neural progenitor proliferation”. FASEB J19 (12): 1704–6. doi:10.1096/fj.05-3995fjePMID 16037095.
  47. Jump up^ Christie BR, Cameron HA (2006). “Neurogenesis in the adult hippocampus”. Hippocampus16 (3): 199–207. doi:10.1002/hipo.20151PMID 16411231.
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  49. Jump up^ Di Marzo V, Sepe N, De Petrocellis L, Berger A, Crozier G, Fride E, Mechoulam R (December 1998). “Trick or treat from food endocannabinoids?”. Nature396 (6712): 636–7. Bibcode:1998Natur.396..636Ddoi:10.1038/25267PMID 9872309.
  50. Jump up^ De Luca MA, Solinas M, Bimpisidis Z, Goldberg SR, Di Chiara G (July 2012). “Cannabinoid facilitation of behavioral and biochemical hedonic taste responses”Neuropharmacology63 (1): 161–8. doi:10.1016/j.neuropharm.2011.10.018PMC 3705914Freely accessiblePMID 22063718.
  51. Jump up^ Yoshida R, et al. (January 2010). “Endocannabinoids selectively enhance sweet taste”Proc. Natl. Acad. Sci. U.S.A107 (2): 935–9. Bibcode:2010PNAS..107..935Ydoi:10.1073/pnas.0912048107JSTOR 40535875PMC 2818929Freely accessiblePMID 20080779.
  52. Jump up^ Bellocchio L, Cervino C, Pasquali R, Pagotto U (June 2008). “The endocannabinoid system and energy metabolism”. J. Neuroendocrinol20 (6): 850–7. doi:10.1111/j.1365-2826.2008.01728.xPMID 18601709.
  53. Jump up^ Hill MN, McLaughlin RJ, Bingham B, Shrestha L, Lee TT, Gray JM, Hillard CJ, Gorzalka BB, Viau V (May 2010). “Endogenous cannabinoid signaling is essential for stress adaptation”Proc. Natl. Acad. Sci. U.S.A107 (20): 9406–11. Bibcode:2010PNAS..107.9406Hdoi:10.1073/pnas.0914661107PMC 2889099Freely accessiblePMID 20439721.
  54. Jump up^ Häring M, Kaiser N, Monory K, Lutz B (2011). Burgess HA, ed. “Circuit specific functions of cannabinoid CB1 receptor in the balance of investigatory drive and exploration”PLoS ONE6 (11): e26617. Bibcode:2011PLoSO…626617Hdoi:10.1371/journal.pone.0026617PMC 3206034Freely accessiblePMID 22069458.
  55. Jump up^ Basu S, Ray A, Dittel BN (December 2011). “Cannabinoid receptor 2 is critical for the homing and retention of marginal zone B lineage cells and for efficient T-independent immune responses”J. Immunol187 (11): 5720–32. doi:10.4049/jimmunol.1102195PMC 3226756Freely accessiblePMID 22048769.
  56. Jump up^ Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Huffman JW, Layward L (2000). “Cannabinoids control spasticity and tremor in a multiple sclerosis model”. Nature404 (6773): 84–7. doi:10.1038/35003583PMID 10716447.
  57. Jump up^ Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Makriyannis A, Khanolkar A, Layward L, Fezza F, Bisogno T, Di Marzo V (2001). “Endocannabinoids control spasticity in a multiple sclerosis model”. FASEB J15 (2): 300–2. doi:10.1096/fj.00-0399fjePMID 11156943.
  58. Jump up to:a b Cabranes A, Pryce G, Baker D, Fernández-Ruiz J (August 2006). “Changes in CB1 receptors in motor-related brain structures of chronic relapsing experimental allergic encephalomyelitis mice”. Brain Res1107 (1): 199–205. doi:10.1016/j.brainres.2006.06.001PMID 16822488.
  59. Jump up^ Carrier EJ, Kearn CS, Barkmeier AJ, Breese NM, Yang W, Nithipatikom K, Pfister SL, Campbell WB, Hillard CJ (April 2004). “Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism”. Mol. Pharmacol65 (4): 999–1007. doi:10.1124/mol.65.4.999PMID 15044630.
  60. Jump up^ Maccarrone M, Valensise H, Bari M, Lazzarin N, Romanini C, Finazzi-Agrò A (2000). “Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage”. Lancet355 (9212): 1326–9. doi:10.1016/S0140-6736(00)02115-2PMID 10776746.
  61. Jump up^ Das SK, Paria BC, Chakraborty I, Dey SK (1995). “Cannabinoid ligand-receptor signaling in the mouse uterus”Proc. Natl. Acad. Sci. U.S.A92 (10): 4332–6. Bibcode:1995PNAS…92.4332Ddoi:10.1073/pnas.92.10.4332PMC 41938Freely accessiblePMID 7753807.
  62. Jump up^ Paria BC, Das SK, Dey SK (1995). “The preimplantation mouse embryo is a target for cannabinoid ligand-receptor signaling”Proc. Natl. Acad. Sci. U.S.A92 (21): 9460–4. Bibcode:1995PNAS…92.9460Pdoi:10.1073/pnas.92.21.9460PMC 40821Freely accessiblePMID 7568154.
  63. Jump up^ Hesselink JM (2012). “New Targets in Pain, Non-Neuronal Cells, and the Role of Palmitoylethanolamide”. The Open Pain Journal5 (1): 12–23. doi:10.2174/1876386301205010012.
  64. Jump up^ Colloca, Luana (28 August 2013). Placebo and Pain: From Bench to Bedside (1st ed.). Elsevier Science. pp. 11–12. ISBN 9780123979315.
  65. Jump up^ Ross RA (November 2003). “Anandamide and vanilloid TRPV1 receptors”Br. J. Pharmacol140 (5): 790–801. doi:10.1038/sj.bjp.0705467PMC 1574087Freely accessiblePMID 14517174.
  66. Jump up^ Huang SM, Bisogno T, Trevisani M, Al-Hayani A, De Petrocellis L, Fezza F, Tognetto M, Petros TJ, Krey JF, Chu CJ, Miller JD, Davies SN, Geppetti P, Walker JM, Di Marzo V (June 2002). “An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors”Proc. Natl. Acad. Sci. U.S.A99 (12): 8400–5. Bibcode:2002PNAS…99.8400Hdoi:10.1073/pnas.122196999PMC 123079Freely accessiblePMID 12060783.
  67. Jump up^ Murillo-Rodríguez E, Sánchez-Alavez M, Navarro L, Martínez-González D, Drucker-Colín R, Prospéro-García O (November 1998). “Anandamide modulates sleep and memory in rats”. Brain Res812 (1–2): 270–4. doi:10.1016/S0006-8993(98)00969-XPMID 9813364.
  68. Jump up^ Santucci V, Storme JJ, Soubrié P, Le Fur G (1996). “Arousal-enhancing properties of the CB1 cannabinoid receptor antagonist SR 141716A in rats as assessed by electroencephalographic spectral and sleep-waking cycle analysis”. Life Sci58 (6): PL103–10. doi:10.1016/0024-3205(95)02319-4PMID 8569415.
  69. Jump up^ Wang L, Yang T, Qian W, Hou X (January 2011). “The role of endocannabinoids in visceral hyposensitivity induced by rapid eye movement sleep deprivation in rats: regional differences”. Int. J. Mol. Med27 (1): 119–26. doi:10.3892/ijmm.2010.547PMID 21057766.
  70. Jump up^ Murillo-Rodriguez E, Désarnaud F, Prospéro-García O (May 2006). “Diurnal variation of arachidonoylethanolamine, palmitoylethanolamide and oleoylethanolamide in the brain of the rat”. Life Sci79 (1): 30–7. doi:10.1016/j.lfs.2005.12.028PMID 16434061.
  71. Jump up^ Fuss J, Steinle J, Bindila L, Auer MK, Kirchherr H, Lutz B, and Gass P (2015). “A runner’s high depends on cannabinoid receptors in mice”PNAS112 (42): 13105–13108. doi:10.1073/pnas.1514996112PMC 4620874Freely accessiblePMID 26438875Exercise is rewarding, and long-distance runners have described a runner’s high as a sudden pleasant feeling of euphoria, anxiolysis, sedation, and analgesia. A popular belief has been that endogenous endorphins mediate these beneficial effects. However, running exercise increases blood levels of both β-endorphin (an opioid) and anandamide (an endocannabinoid). Using a combination of pharmacologic, molecular genetic, and behavioral studies in mice, we demonstrate that cannabinoid receptors mediate acute anxiolysis and analgesia after running. We show that anxiolysis depends on intact cannabinoid receptor 1 (CB1) receptors on forebrain GABAergic neurons and pain reduction on activation of peripheral CB1 and CB2 receptors. We thus demonstrate that the endocannabinoid system is crucial for two main aspects of a runner’s high. Sedation, in contrast, was not influenced by cannabinoid or opioid receptor blockage, and euphoria cannot be studied in mouse models.
  72. Jump up^ Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrié P (2004). “CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity”. Int. J. Obes. Relat. Metab. Disord28 (4): 640–8. doi:10.1038/sj.ijo.0802583PMID 14770190.
  73. Jump up^ Varvel SA, Lichtman AH (2002). “Evaluation of CB1 receptor knockout mice in the Morris water maze”. J. Pharmacol. Exp. Ther301 (3): 915–24. doi:10.1124/jpet.301.3.915PMID 12023519.
  74. Jump up^ Niyuhire F, Varvel SA, Martin BR, Lichtman AH (2007). “Exposure to marijuana smoke impairs memory retrieval in mice”. J. Pharmacol. Exp. Ther322 (3): 1067–75. doi:10.1124/jpet.107.119594PMID 17586723.
  75. Jump up^ Parmentier R, Ohtsu H, Djebbara-Hannas Z, Valatx JL, Watanabe T, Lin JS (September 2002). “Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knockout mice: evidence for the role of brain histamine in behavioral and sleep-wake control”J. Neurosci22 (17): 7695–711. PMID 12196593.
  76. Jump up^ Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutiérrez SO, van der Stelt M, López-Rodriguez ML, Casanova E, Schütz G, Zieglgänsberger W, Di Marzo V, Behl C, Lutz B (October 2003). “CB1 cannabinoid receptors and on-demand defense against excitotoxicity”. Science302 (5642): 84–8. Bibcode:2003Sci…302…84Mdoi:10.1126/science.1088208PMID 14526074.
  77. Jump up^ Gachet, María Salomé; Schubert, Alexandra; Calarco, Serafina; Boccard, Julien; Gertsch, Jürg (25 January 2017). “Targeted metabolomics shows plasticity in the evolution of signaling lipids and uncovers old and new endocannabinoids in the plant kingdom”Scientific Reports7doi:10.1038/srep41177ISSN 2045-2322PMC 5264637Freely accessiblePMID 28120902.
  78. Jump up^ Wasternack, C.; Hause, B. (2013-6). “Jasmonates: biosynthesis, perception, signal transduction and action in plant stress response, growth and development. An update to the 2007 review in Annals of Botany”Annals of Botany111 (6): 1021–1058. doi:10.1093/aob/mct067ISSN 0305-7364PMC 3662512Freely accessiblePMID 23558912. Check date values in: |date= (help)
Further reading[edit]
External links[edit]

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A thorough explanation of the Endocannabinoid System
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