The Endocannabinoid System
Cannabinoids and the endocannabinoid system (ECS) encompass both ancient and complex aspects of our biology. The endocannabinoid system exists in all vertebrate species, and may have begun evolving as early as 600 million years ago based on the fact that species as primitive as nematodes and sea squirts have receptor genes for cannabinoids.  Documentation of human medicinal cannabis use dates back as far as 2800 B.C. in China, with use in ancient India, Israel, Greece, and Rome. 
While many of our ancestors may have been familiar with cannabis and its effects, how the endocannabinoid system and cannabinoids work remained a mystery. While CBD was first isolated in 1940, cannabis’ primary psychoactive compound, THC, wasn’t identified and isolated until 1964 by Dr. Raphael Mechoulam. An endocannabinoid receptor was then identified by Allyn Howlett and William Devane in 1988.
“Relax, eat, sleep, forget and protect.”
-Professor Di Marzo, a leading cannabinoid scientist, summarizing the functions of the endocannabinoid system
Considering its recent discovery, we are still just beginning to explore and understand the ECS. The research that has been done, however, shows us that the ECS is an essential regulator of bodily function in its many facets. There is hardly any physiological process that is not affected by it to some degree, as the endocannabinoid system is the largest receptor system in the human body. 
There are three components to the endocannabinoid system: endocannabinoids, cannabinoid receptors, and enzymes. The interactions of these three components in different areas of the body are responsible for a wide range of biological processes and health outcomes.
Endocannabinoids are the “keys,” or ligands, that fit into the cannabinoid receptor “locks.” Endocannabinoids are endogenous (naturally occurring in the body) whereas phytocannabinoids come from plants and synthetic cannabinoids are man-made. Endocannabinoids, phytocannabinoids, and synthetic cannabinoids serve as “keys” that fit into cannabinoid receptors.
Our bodies produce many endocannabinoids, and two of them have been well-studied: arachidonylethanolamine (anandamide - from the Sanskrit word for “bliss”) and 2-arachidonylglycerol (2-AG). Both are synthesized on demand for homeostatic functions. Many other endocannabinoids exist, and when interacting with anandamide, 2-AG, and each other they provide significant increase in function. It appears that endocannabinoids use the entourage effect, similar to the entourage effect observed with phytocannabinoids, where they work better within the whole ECS rather than as isolated chemicals. 
Receptors are “locks” that sit on the surface of cells, to which corresponding compounds, or ligands, can fit as “keys.” Depending on the fit, a ligand may fully activate a receptor, partially activate a receptor, fit but not activate anything, or deactivate the receptor’s normal activity. The two main cannabinoid receptors are CB1 and CB2. Both are “G protein-coupled receptors”, a class that also includes opioid, dopamine, and serotonin receptors. 
- The most abundant G protein-coupled receptor in the brain, suggesting it plays an important role in brain function, health, and disease;
- Largely present in the basal ganglia, hippocampus, cerebral cortex, cerebellum, and amygdaloid nucleus areas of the brain;
- Unlike opioid receptors, largely absent from the brain stem, accounting for the lack of cannabis-related fatalities;
- Receptors in the brain where THC exerts its effects by modulating short-term memory, pain, emotion, and hunger;
- Abundantly occurring in the spinal cord and peripheral nervous system;
- Occurs in the gastrointestinal tract and modulates propulsion and excretion;
- Regulates endocrine function, fertility and cellular growth;
- Anandamide, 2-AG, and THC all bind to CB1 receptors in a similar way. Anandamide and 2-AG are produced on demand by nerve cells as a response to stimulation. They can also block the release of other neurotransmitters (e.g. glutamate, which is associated with neuropathic inflammation and damage when present in excessive amounts).
- Primarily associated with cells governing the immune system;
- Non-psychoactive receptors on the periphery of the brain;
- Key regulators related to pain and inflammation.
Enzymes are substances that the body produces to create biochemical reactions. Within the endocannabinoid system, there are enzymes that synthesize anandamide and 2-AG as well as enzymes that break down both anandamide and 2-AG. The most active endocannabinoid breakdown enzyme is fatty acid amide hydrolase (FAAH) which breaks down anandamide. Manipulation of FAAH can increase the activity of anandamide, much like selective serotonin reuptake inhibitors (SSRIs) increase serotonin activity to treat depression. 
The Endocannabinoid System in Health
The ECS interacts with many different systems and functions of the body, however its general role is to maintain homeostasis, or balance. A person with a fully functioning ECS would, in theory, have no pain, a healthy appetite with good digestion, and normal mental function. In the absence of serious trauma or disease, the ECS fulfills many functions related to healthy growth and homeostasis:
- Embryonic Development: Cannabinoid receptors are present from the blastocyst period of gestation (5-7 days). Embryonal implantation on the uterine wall requires a temporary and localized reduction in anandamide, development of the fetal nervous system is regulated and protected from trauma by anandamide, and newborn suckling is critically dependent on activation of the CB1 receptors.
- Adult Neurogenesis: Similar to the role the ECS plays in embryonic brain development, the ECS also moderates adult neurogenesis, or the development of new neurons in the brain.  It also plays a part in protecting the brain from trauma, decreasing the inflammatory reaction that damages brain tissue.
- Hunger and Metabolism: The ECS modulates cell metabolism. Of note, blastocyst implantation, which the ECS plays a vital role in, is considered the “first suckling,” as it is an impulse to implant and take in nutrients from the endometrium. 
- Central Nervous System Feedback: The ECS is involved in regulating the release of classical neurotransmitters, the chemical messengers that transport signals across the synapses. The ECS also regulates neural plasticity, which is the brain’s ability to reorganize itself in response to injury, disease, or other changes in the environment. 
- Immune System: Cannabinoids, again functioning to create balance, suppress the production of some immune system cells and increases the secretion of others. In addition, CB2 receptors and endocannabinoids are integral to the functioning of B cell lymphocytes (defender cells) and other killer cells.  Cannabis is considered an “adaptogen” in that it supports the body in adapting to stressors and normalizes functioning.
- Anti-tumor effects: Cannabinoids have been noted to cause antitumor effects by various mechanisms, including the induction of cell death, inhibition of cell growth, and inhibition of tumor metastasis. Cannabinoids also inhibit tumor angiogenesis (the growth of blood and lymphatic systems that support tumors). 
- Bone Mass: Both CB1 and CB2 receptors play a role in bone health, and protect against age-related bone loss as well as bone resorption. 
- Positive Attitude: Maintaining a healthy ECS tone in the brain contributes to “hedonic tone,” or a person’s ability to experience pleasure. 
The Endocannabinoid System in Disease
The ECS plays a significant role in the expression of symptoms of many diseases, for which cannabinoid and endocannabinoid system-based treatments have been shown to be effective. It also appears that there are diseases of the endocannabinoid system itself, where imbalance in the ECS may cause or contribute to disease.
Clinical Endocannabinoid Deficiency (CECD)-Related Diseases
Endocannabinoid deficiency may account for many “mysterious” diseases. Often times these diseases are difficult to diagnose and treat, are co-morbid (more than one occurring in the same patient at the same time), and are characterized by “central sensitization,” where normal sensations are magnified to the point of being perceived as painful. CECD-related conditions include:
- Irritable Bowel Syndrome (IBS)
- Intractable Depression
- Post-Herpetic Neuralgia
- Interstitial Cystitis
- Infertility/Early Miscarriage
- Reflex Sympathetic Dystrophy (burning pain caused by peripheral nerve injury)
- Neuropathic Pain Conditions
- For some CECD-related conditions such as fibromyalgia, migraine, and irritable bowel syndrome, it appears that introducing phytocannabinoids (cannabinoids from the cannabis plant) may help treat the body’s deficiency, or lack of endocannabinoids. 
Cancer arises when malignant cells no longer undergo normal apoptosis (cell death), and continue to divide and grow uncontrollably, invading and damaging surrounding tissue. In many cases the body naturally increases the expression of CB1 and CB2 as a response to cancer. 
Phytocannabinoids work through CB1 and CB2 receptors to combat cancer, but may also work through other non-receptor pathways. Beyond the goal of eliminating the malignancy itself, appropriately formulated and dosed cannabinoid treatment may hold the promise of additional “side benefits” by simultaneously addressing attendant symptoms of cancer including pain, nausea, sleep disturbance, depression and anxiety.  Cannabinoids have been shown to inhibit tumor growth specifically in breast, prostate, and lung carcinomas as well as gliomas, melanomas, hepatocellular carcinomas and lymphomas. 
Inflammation is part of the immune system’s natural response to injury, however when this inflammation response is out of balance it can create unnecessary pain as well as additional damage to the body. Activating both CB1 and CB2 receptors can help alleviate inflammation. Activation of CB2 suppresses pro-inflammatory cytokines (secretions of immune system cells) and increases activity in anti-inflammatory cytokines.  CB1 receptors are found on pro-inflammatory cytokines, but also play a role in regulating the perception of pain that is often associated with inflammation.  As a result, THC, CBD have both been shown to be effective at treating inflammation arising from a variety of conditions including:
- Cartilage and Collagen Breakdown
- Myofascial Pain
- Crohn’s Disease
- Ulcerative Colitis
- Allergic Inflammation
The ECS has also been shown to play a role in the health and repair of connective tissue. Cannabinoids prevent cartilage destruction and collagen breakdown. Studies have shown that the release of endocannabinoids may be upregulated in cases of osteoarthritis as part of the body’s response to the disease. 
The ECS plays a role in a variety of neurological conditions through the modulation and balancing of other receptor and transmitter activities. With the abundance of cannabinoid receptors in the nervous system, it makes sense that endo-and phytocannabinoids have been shown to help in the prevention, treatment, and/or slowing the progression of certain neurological conditions. For example, anandamide and 2-AG prevent the onset of Alzheimer’s Disease by blocking beta-amyloid plaque formation, while also preventing Parkinson’s Disease symptoms by balancing neural activity in the striatum. 
Both THC and CBD are anti-inflammatory and anti-spasmodic, contributing to their efficacy in treating neurological disease. Studies have been done with cannabinoids that show benefit, or potential benefit, for the following diseases:
- Parkinson Disease
- Multiple Sclerosis
- Neuropathic Pain
- Huntington Disease
- Amyotrophic Lateral Sclerosis
- Seizure Disorders/Epilepsy
As we expand our understanding of the endocannabinoid system, we are finding that seemingly unrelated parts and functions of the body may actually be related in unexpected ways. The endocannabinoid system’s employment of the entourage effect, with the activity of components taken together being greater than any one part taken individually, provides a perspective that may be helpful to apply to health and disease. For many patients, integrating cannabis into their treatment represents a shift towards a more holistic understanding of their condition and model of care. Further research will allow us to have a better understanding of this complex system, and how to work with it to expand the efficacy and number of options patients have.
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