Marijuana is a complex plant. It contains a diverse set of chemical molecules called cannabinoids. These constituents attach themselves to special receptors in the human body, which make up the endocannabinoid system. Experts frequently describe this process with a “key and lock” metaphor:
Your body has specific binding sites, or “locks,” on many of its cell types, and your body produces various endocannabinoids, or “keys,” which bind to those cannabinoid receptors to activate and “unlock” them.
Back in 1992, scientists discovered, for the first time, an endogenous substance that binds itself to cannabinoid receptors. Known as anandamide, this substance originates from the word “Ananda,” which is Sanskrit for bliss, and “amide,” which relates to its chemical structure. Then, in 1995, researchers found a second endocannabinoid, 2-arachidonoylglycerol, or simply 2-AG.
Anandamide and 2-AG are the most studied endocannabinoids today. We now know about hundreds of cannabinoids, but these resemble the body’s own endocannabinoids and, in what scientists call the “entourage effect,” complement their functions. Some endocannabinoids not only bind to cannabinoid receptors, but also to vanilloid and other receptors, and possibly the CB3 receptor, as well.
Besides the discovery of endocannabinoids, researchers have identified cannabinoids in cannabis plants too. Called phytocannabinoids, they mimic the effects of some endocannabinoids, or they counteract them. The plant’s resin glands, called trichomes, produce terpenes and phytocannabinoids, and they are present in primary fan leaves and flowers during late-stage growth and final maturation.
The quantity of resin a plant produces, and ultimately its cannabinoid content, depends on several factors, including growing conditions, the gender of the plant, and time of harvest. Other factors can affect the chemical stability of phytocannabinoids in plants already harvested, including temperature, moisture, storage, and light. However, regardless of storage methods, cannabinoids degrade over time.
When cannabinoids influence receptors to behave and respond in the same way they would to naturally produced neurotransmitters or hormones, science calls them “agonists.” In contrast, if the cannabinoid stops a receptor from binding to natural compounds, causing an alteration or diminishing of the resultant event, such as appetite, pain, or alertness, it is an “antagonist.”
Scientific evidence is growing. More researchers are studying cannabinoids than ever before, and they are daily improving our understanding of how specific cannabinoids “unlock” specific receptors, or “lock” them in some cases. The cannabis plant contains well over 100 different phytocannabinoids, many of which already have an abundance of proof documenting their medicinal value.
Phytocannabinoids are mostly relatives. Some differ solely by a single chemical part. Tetrahydrocannabinol, or THC, is the most widely talked-about, researched, and known phytocannabinoid because of the high its psychoactive properties give users. Cannabidiol, or CBD, is not far behind, with discoveries about its healing abilities making daily headlines these days.
There are many ways to administer THC, CBD, and other phytocannabinoids in marijuana plants. Consumers can smoke it, vaporize it, ingest it orally, inject it intravenously, absorb it sublingually, deposit it in the rectum, and even stick on a transdermal patch. Most potheads smoke cannabis, but edibles, oils, tinctures, and other infusions and concentrates are growing in popularity.
Understanding the Endocannabinoid System
Every animal on earth has an endocannabinoid system. Known scientifically as the Endogenous Cannabinoid System, or ECS, it regulates a wide array of crucial biological functions. It acts as a biochemical system of control for neuromodulator lipids, or molecules such as waxes, fats, sterols, and fat-soluble vitamins, including vitamins A, D, E, K, and others, and specialized receptors that bind to cannabinoids.
Generally, receptors only accept specific categories of compounds and will be unaffected by other molecules, much the way locks require specific keys to open them. The human body contains specialized receptors throughout, including, but not limited to, the cerebral cortex for emotional behavior and decision-making, the hippocampus for learning and memory, the cerebellum for motor control and coordination, the hypothalamus for body temperature and appetite, the putamen for learning and movement, and the amygdala for emotions.
When specific cannabinoids or combinations of them bind to receptors designed to accept them, it triggers a single or series of events inside the cell. It changes the cell’s gene regulation, activity, and the signals it transmits to other cells. Science calls this process “signal transduction,” and any malfunctioning of this system can result in a severe health crisis.
As a proposed spectrum disorder, clinical endocannabinoid deficiency, or CEDC, may contribute significantly to the development of a range of diseases, including irritable bowel syndrome, migraines, and even fibromyalgia. So far, very little clinical research exists on this disorder, which remains speculative for now. However, we do know that it responds well to cannabinoid treatments.
Understanding Cannabinoid Receptors
The human body contains a myriad of different cannabinoid receptors, but the primary two are either Cannabinoid type I receptors, shortened to CB1-R, and Cannabinoid type II receptors, or CB2-R. There are three types of cannabinoids able to bind to these receptors and “unlock” or activate them. They are:
Endocannabinoids are endogenous fatty acids that the human body produces naturally. They include 2-AG, anandamide, and others scientists are still studying.
Phytocannabinoids are chemical molecules produced by trichomes or resinous glands in plants. In cannabis, it concentrates in the oily resin of leaves and buds.
3. Synthetic Cannabinoids
Synthetic cannabinoids are unnatural. The body does not produce them and neither do plants. Scientists manufacture synthetic cannabinoids artificially, unusually in a laboratory.
Researchers first found CB1 receptors in the brain, but have since found them located throughout the body, including in glands, gonads, connective tissues, and organs. However, there are no CB1 receptors in the medulla oblongata, an area of the brain stem responsible for cardiovascular and respiratory function. CB1 receptors are crucial for movement, spatial orientation, motivation, cognitive performance, and sensory perception, including sound, smell, touch, and taste.
CB1 receptors have various functions, the most important of which is reducing the occurrence of inadequate or overly excessive signaling by neurotransmitters in the brain. By activating CB1 receptors with phytocannabinoids, it is possible to regulate hypo- or hyperactive neurotransmitters back into balance. If THC, for example, binds to CB1-R, it can inhibit pain circuits and thereby treat pain. The same is true of many other symptoms, including nausea, seizures, and muscle spasticity.
CB2 receptors, on the other hand, are involved primarily with the immune system. They are not in the brain, but outside it, such as in the spleen, gut, blood vessels, endocrine glands, bones, reproductive organs, lymph cells, kidneys, heart, and liver. For example, CBD binds well to CB2 receptors, and evidence shows its therapeutic ability in treating inflammatory and neuroinflammatory diseases.
Until very recently, scientists did not believe that CB2 receptors had any effect on nerve bundles or cells, but studies now detail its crucial role in influencing signal processing in the brain. A third receptor exists, one that gets barely any attention. It is the transient receptor potential vanilloid-type I, or TRPV1. The role of TRPV1 is to measure, regulate, and maintain body temperature.
Additionally, TRPV1 is subject to desensitization, and it is responsible for your ability to feel some sensations, including pain and extreme external heat, such as a hot stove. If stimulated continuously, TRPV1 will eventually slow the neuropathic pathway, and perhaps even stop it. For medical agencies, this raises the therapeutic possibility of using it to treat some types of neuropathic pain.
Comparing Old Science with the New
Ever since William Devane and Allyn Howlett discovered the CB1 receptor site in 1988, the scientific community accepts as fact that, unlike THC, CBD does not have any affinity for binding with CB1 receptors. This unfortunate assumption had no scientific basis. The international research community is daily revealing new data indicating that CBD interacts with CB1 receptors in therapeutic, relevant ways.
We now know that CBD binds to a different site on the CB1 receptor, one functionally distinct from the orthosteric-binding site that THC uses. Instead, it binds to an “allosteric” site on the CB1 receptor, and when it attaches, it does not initiate any effect on signaling pathways. Instead, it influences the response of the receptor to THC and other endogenous cannabinoids. Modulating CB1 receptors allosterically alters the receptor’s confirmation, or shape, which can dramatically affect cell signaling efficiency.
However, positive allosteric modulators can actually enhance the signaling of CB1 receptors, which indicates that CBD may be a beneficial treatment for diseases associated with endocannabinoid deficiencies, such as PTSD, fibromyalgia, irritable bowel syndrome, migraines, and anorexia, as well as a helpful therapy for issues linked to endocannabinoid hyperactivity, such as metabolic disorders, obesity, cardiovascular problems and liver disease.
The “Entourage Effect” Explained
Two Israeli scientists, namely Raphael Mechoulam and Shimon Ben-Shabat, introduced the idea of the “entourage effect” back in 1998. According to the theory, phytocannabinoids in marijuana plants work together, using a network of coincidental connections, as part of a much larger organism, affecting the human body in a similar way that its own endocannabinoid system does. In essence, they work better together than when they are on their own.
Because people having been using whole cannabis successfully for millennia, it has become necessary to explain its medicinal superiority over products containing single, isolated compounds of the marijuana plant, or in plain speak, how synthetic cannabinoids could replicate their natural counterparts. Science has already established the benefits of both CBD and THC taken in isolation.
It shows THC with anti-emetic, anti-inflammatory, and analgesic properties, whereas CBD’s properties are more anti-seizure, anti-anxiety, and anti-psychotic. However, mounting evidence suggests that when isolating or creating these cannabinoids in a laboratory, their effects have limited therapeutic uses, which is also the reason for increasing visits to doctors and emergency rooms.
When consumed in sufficiently high concentrations, it is possible to overdose on THC. Despite acute cases of THC overdoses rarely requiring intervention by medics, the side effects of taking too much are extremely unpleasant. Evidence now demonstrates how CBD and THC work together: CBD stops THC from binding to CB1 receptors. Applying the entourage effect by increasing CBD to overdose cases can counteract the effects of THC.
Another example is Marinol, a synthetic cannabinoid. It is a pure, laboratory-created form of THC. When scientists first introduced Marinol in the mid-80s, everyone expected it to have the same effects as the marijuana plant. However, it became very clear very soon that the majority of patients were not responding to it in the same way as when they smoked or ingested naturally grown THC.
Scientists realized soon afterward that the other chemical components of marijuana plants, such as terpenes, CBD, THC, and other phytocannabinoids play significantly larger roles than anyone previously thought. As researchers keep discovering, the maximum potential of cannabis as a therapeutic treatment lies in allowing all compounds to work together and provide whole plant medicine.