The Endocannabinoid System

Cannabis has been at the center of one of the most exciting—and underreported—developments in modern science. Research on marijuana’s effects led directly to the discovery of a hitherto unknown biochemical communication system in the human body, the Endocannabinoid System, which plays a crucial role in regulating our physiology, mood, and everyday experience.

The discovery of receptors in the brain that respond pharmacologically to cannabis—and the subsequent identification of endogenous cannabinoid compounds in our own bodies that bind to these receptors—has significantly advanced our understanding of human biology, health, and disease.

It is an established scientific fact that cannabinoids and other components of cannabis can modulate many physiological systems in the human brain and body. Cannabinoids are chemical compounds that trigger cannabinoid (and other) receptors. More than 100 cannabinoids have been identified in the marijuana plant. Of these marijuana molecules, tetrahydrocannabinol (THC) and cannabidiol (CBD) have been studied most extensively. In addition to cannabinoids produced by the plant, there are endogenous cannabinoids (such as anandamide and 2AG) that occur naturally in the mammalian brain and body, as well as synthetic cannabinoids created by pharmaceutical researchers.

Extensive preclinical research—much of it sponsored by the U.S. government—indicates that CBD has potent anti-tumoral, antioxidant, anti-spasmodic, anti-psychotic, anti-convulsive, and neuroprotective properties. CBD directly activates serotonin receptors, causing an anti-anxiety effect, as well.

“Cannabidiol offers hope of a non-toxic therapy that could treat aggressive forms of cancer without any of the painful side effects of chemotherapy,” says McAllister.

In recent years, scientists associated with the International Cannabinoid Research Society (ICRS) have elucidated a number of molecular pathways through which CBD exerts a therapeutic impact. For example, a preclinical study by Dr. Sean McAllister and his colleagues at the California Pacific Medical Center in San Francisco report on how CBD destroys breast cancer cells by down-regulating a gene called ID-1, which is implicated in several types of aggressive cancer. Silencing the ID-1 gene is, thus, is a potential strategy for cancer treatment.

CBD and THC Synergy

According to McAllister’s lab, the best results were obtained when CBD was administered along with THC. Several studies underscore the therapeutic advantages for combining CBD and THC—particularly for treating peripheral neuropathy, a painful condition associated with cancer, multiple sclerosis (MS), diabetes, arthritis, and other neurodegenerative ailments. Clinical research conducted by with GW Pharmaceuticals, a British company, has also shown that CBD is most effective as an analgesic when administered in combination with whole plant THC.

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.

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.

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.

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.

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