Introduction to the Endocannabinoid System
Dustin Sulak, DO
Maine Integrative Healthcare
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?
In my integrative medicine clinic in central Maine, we treat over a thousand patients with a huge diversity of diseases and symptoms. In one day I might see cancer, Crohn’s disease, epilepsy, chronic pain, multiple sclerosis, insomnia, Tourette’s syndromeand 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 writing, a PubMed search for scientific journal articles published in the last 20 years containing the word “cannabis” revealed 7,704 results. Add the word “cannabinoid,” and the results increase to 15,899 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.
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 marijuana 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 marijuana can signal the body to make more endocannabinoids and build more cannabinoid receptors. This is why many first-time marijuana 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 marijuana 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 marijuana 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 marijuana is safe and works well when smoked, many patients prefer to use a vaporizer or cannabis tincture. Scientific inquiry and patient testimonials both indicate that herbal marijuana 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 marijuana 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 marijuana, 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 physician associations (American Medical Association and American College of Physicians) calling for more research, the Obama administration promising not to arrest patients protected under state medical cannabis laws, 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.
Endocannabinoids are natural compounds within the human body that are essentially identical to medicinal compounds found in cannabis. The endocannabinoid system regulates many aspects of health with receptors located throughout the body including the brain and nervous system. All mammals are known to have cannabinoid receptors, presumably because mammals have evolved along with cannabis throughout history. Interestingly, even fish have receptors for cannabis compounds. One modern researcher, Dr. Gregory T. Carter of the University of Washington, explains some of the current understandings of the cannabis-like compounds crucial to human life:
“It now appears that the cannabinoid system evolved with our species and is intricately involved in normal human physiology, specifically in the control of movement, pain, memory, and appetite, among others. The detection of widespread cannabinoid receptors in the brain and peripheral tissues suggests that the cannabinoid system represents a previously unrecognized ubiquitous network in the nervous system. Dense receptor concentrations have been found in the cerebellum, basal ganglia and hippocampus, accounting for the effects on motor tone, coordination and mood state. Low concentrations are found in the brainstem, accounting for remarkable low toxicity.”
“Two endogenous lipids, anandamide (AEA) and 2-aracidonylglycerol (2-AG) have been identified as cannabinoids, although they are likely to be more. The physiological roles of these endocananbinoids have been only partially clarified but available evidence suggests they function as diffusible and short-lived intercellular messengers that modulate synaptic transmission.”
“Both endogenous and exogenous cannabinoids appear to have neuroprotective and antioxidant effects. Recent studies have demonstrated the neuroprotective effects of synthetic, non-psychotropic cannabinoids, which appear to protect neurons from chemically-induced excitotoxicity. Direct measurement of oxidative stress reveals that cannabinoids prevent cell death by antioxidation. The antioxidative property of cannabinoids is confirmed by their ability to antagonize oxidative stress and consequent cell death induced by the powerful oxidant, retinoid anhydroretinol. Cannabinoids also modulate cell survival and the growth of B-lymphocytes and fibroblasts.”
“The most recent therapeutic role for cannabinoids in the central nervous system evolved from the discover that cannabinoids selectively induce apoptosis in glioma cells in vitro and that THC and other cannabinoids lead to a spectacular regression of malignany gliomas in immune-compromised rats in vivo. The mechanism underlying this is not yet clear but it appears to involved both CB1 and CB2 activation.”
— Carter, Weydt, “Cannabis: Old medicine with new promise for neurological disorders.” Department of Rehabilitation and Department of Neurology, University of Washington School of Medicine, Seattle, WA 98531, email@example.com
Further elaboration is provided by one of the world’s most advanced HIV/cannabis researchers, Dr. Donald Abrams of San Francisco General Hospital and UCSF:
“The central nervous system responses to cannabis are mediated primarily by way of the CB1 receptor which is concentrated in the basal ganglion in the cerebellum, parts of the brain involve in coordination and movement, etc., and again activation of this receptor produces a lot of changes, including increasing production of prostaglandin’s which are the substances which cause inflammation. The CB2 receptor, interestingly, the second cannabinoid receprot, is not found in the brain at all, but is predominantly located in the immune issues, the macrophages which are circulating blood cells that go into tissues and fight infections, and also the spleen.”
—DonaldAbrams, Lindesmith Lecture, May 17, 1999
The recent discoveries of endocannabinoid reserach present one of the most promising avenues of modern medicine. The studies cited below explore some of the facets of the endocannabinoid system as it is known today:
“Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy.” Rice AS, Farquhar-Smith WP, Nagy I. Department of Anaesthetics, Pain Research Group, Imperal College of Science, Technology and Medicine, CHelsea and Westminster Hospital Campus, London, UK, email: firstname.lastname@example.org PMID: 12052040 (PubMed)
“Cannabinoid receptors and pain.” Pertwee RG, Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Scotland, UK email: email@example.com PMID: 11164622 (Pubmed)
“Cannabinoid receptor ligands: clinical and neuropharmeacological considerations relevant to future drug discovery and development.” Pertwee RG, Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Scotland, UK email: firstname.lastname@example.org PMID: 11060760 (Pubmed)
“Therapeutic potential of the endocannabinoid system in the brain.” RMOA, JA, et al, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain. email@example.com PMID: 16026307 (PubMed)
“Pharmacological and therapeutic secrets of plant and brain (Endo)cannabinoids” Hanus LO, epartment of Medical Chemistry and Natural Products, School of Pharmacy, Faculty of Medicine, Hebrew University, Ein Keram Campus, Jeruselem, Israel 2008 WIley Periodicals, Inc. PMID: 18777572 (PubMed)