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From the Townsend Letter
October 2017

Cannabinoid Deficiency and Its Impact on Human Health and Disease, Part 1 and Part 2
by Jonn Desnoes, OMD, MD, PhD and Sandra Kischuk, MSMIS, MCPM
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Discovery and Functions of the Endocannabinoid System
Up until the 1980s, the National Institute of Drug Abuse subsidized cannabis studies with the objective of proving that the drug was toxic. What actually came out of those studies was a new understanding of how the human brain functions on the chemical level. As noted by Martin A. Lee, the breakthroughs which resulted were "among the most exciting developments in brain chemistry of our time (and) spawned a revolution in medical science and a profound understanding of health and healing."31,32 Studying the plant led to the discovery of a previously-unknown, immensely-important physiological system.32

In 1964, Raphael Mechoulam, an Israeli organic chemist and professor of Medicinal Chemistry at the Hebrew University of Jerusalem, Israel, and his colleague, Yechiel Gaoni, identified and synthesized tetrahydrocannabinol (THC). Up until then, scientists had learned a lot about the pharmacology, biochemistry, and clinical effects of cannabis, but no one understood how it worked in the brain at the molecular level. How could one herb "alter consciousness, stimulate appetite, dampen nausea, quell seizures, and relieve pain"? How did marijuana smoke stop an asthma attack instantaneously?32

In 1973, American researchers at Johns Hopkins University found the sites in the human brain, receptors, where opioids fit, each one like a key in a lock. These receptors, "specialized protein molecules embedded in cell membranes,"32 are locations in the brain to which specialized chemicals (neurotransmitters) attach, triggering brain cells to start, stop, and/or regulate functions within the body and the brain.33

A neurotransmitter is a chemical messenger used by the body to transmit a signal from one neuron (nerve cell), across a chemical synapse (gap) to a "target" neuron, muscle cell, or gland cell.34 Conventional neurotransmitters are water-soluble. They are stored in high concentrations in little packets (vesicles) at the tips of neurons. When a neuron fires, an electrical signal travels down its axon to its tips (pre-synaptic terminals), releasing the neurotransmitters. The neurotransmitters jump the gap (the synaptic cleft) to receptors on the next (postsynaptic) neuron.34

Why would the human brain have these sites that were seemingly custom-designed for such strong and often dangerous drugs as morphine and heroin? The answer appeared the following year, when two independent groups of researchers identified endorphins—endogenous (produced naturally in the body) morphine.35,36

Immediately after discovering endogenous endorphins, scientists began the search for similar receptor sites for cannabis. The answer to whether such sites even existed required the development of a potent synthetic cannabinoid, which Allyn Howlett, William Devane, and associates then used to test rats—scientifically proving, in a study at the St. Louis University School of Medicine, that rats' brains had cannabinoid receptors. The following year, at the National Institute of Mental Health, Ross Johnson and Lawrence Melvin, past associates of Howlett and Devane, localized cannabinoid receptors in the brains of humans and other species.32

Interestingly, there are more cannabinoid receptors in the brain than there are of any other class of neurotransmitter receptor. But, where were they located? After Pfizer developed a potent, synthetic THC, researchers radioactively tagged the molecules. This THC bonded to the cannabinoid receptors, providing a detailed map of their locations. Concentrations were found "…in regions responsible for mental and physiological processes: the hippocampus (memory), cerebral cortex (higher cognition), the cerebellum (motor coordination), the basal ganglia (movement), the hypothalamus (appetite), the amygdala (emotions) and elsewhere."32

Klaire LabsThe cannabinoid receptor, which appears in all animals except insects, is a protein made up of a scrunched-up chain of 472 amino acids zigzagging seven times in a transmembrane weave set on a cell's surface.37 "Cannabinoid receptors function as subtle sensing devices, tiny vibrating scanners perpetually primed to pick up biochemical cues that flow through fluids surrounding each cell."32

In contrast to endorphins, endocannabinoids are fat based. Upon stimulation of a cell, the endocannabinoids are quickly synthesized from their precursors located all over the cell membrane and then released.32 The neurotransmitters the body produces are referred to as endogenous ligands. Some of these endogenous ligands partner with the cannabinoid receptors, and some pharmaceutical drugs mimic the endogenous ligands and can be used to boost the body's function in a desired direction.32

At the July 18, 1990, meeting of the National Academy of Science's Institute of Medicine, Lisa Matsuda reported that her team at the National Institute of Mental Health (NIMH) had identified the DNA sequence of a rat's THC-sensitive receptor and "had successfully cloned the marijuana receptor."32 The cloned receptor enabled scientists to design molecules to fit the receptor, building agonist "keys" to turn the receptor on and antagonist "keys" to turn it off.32

This key-lock analogy gets hijacked when we ask, "Why do different strains of cannabis cause different psychoactive responses?" The receptors stay the same. It would seem that, if a key fits, it would unlock the door, period. The answer is in the type of agonist fitting the lock. Each type of agonist will distort the transmembrane in a distinctive way: each specific reshaping of the transmembrane stimulates a cascade of a different set of chemicals. It is as if "an assortment of keys unlocks the same lock, but the door opens into different rooms" depending on the key used.37

Genetically engineered mice lacking the CB1 receptor failed to respond to THC, proving that THC brought about its effects through cannabinoid receptor activation in the brain and central nervous system.32

In a short time, researchers discovered a second cannabinoid receptor and named it CB2. This receptor resided in the brain but was more heavily and widely distributed in the immune and peripheral nervous systems, and "in the gut, spleen, liver, heart, kidneys, bones, blood vessels, lymph cells, endocrine glands and reproductive organs,"32 on leukocytes, where they may modulate cell migration at a higher than normal cannabinoid dose,38 and on the microglia in the brain (which has implications for the treatment of Alzheimer's).38 While the CB1 receptor mediates psychoactivity, CB2 exerts a powerful influence on the body's immune system.32

In 1992, Raphael Mechoulam, in collaboration with NIMH research fellow William Devane and Dr. Lumir Hanus, discovered a naturally-occurring "endocannabinoid" (a cannabinoid produced within the body) that attached to the same mammalian CB1 brain-cell receptors as did THC. They named it "anandamide," using as its basis the Sanskrit word for bliss39 (anandin: blissful, making happy40). In 1995, Mechoulam's group discovered a second major endocannabinoid, 2-arachidonoylglycerol (2-AG). This one formed bonds with both CB1 (THC) and CB2 (CBD) receptors.39

Mechoulam found that the body builds anandamide and 2-AG at the time they are needed, using localized fatty acid precursors. These endocannabinoids then act in unique and characteristic ways, primarily in the area of the body where they were "assembled." However, local action does not mean that anandamide and 2-AG are limited within the body; the precursors are located throughout the body and "are involved in most physiological systems that have been investigated."32,39

As noted above, most CB2 receptors are located on immune cells and tissues. The primary nonpsychotropic cannabinoid, cannabidiol (CBD), appears to be an inverse agonist because it dampens the psychotropic effect of THC. Although it does not appear to directly affect CB1 or CB2 receptors, it may boost anandamide (an endogenous CB2-receptor-friendly cannabinoid) activity. Stimulating CB2 receptors alters the body's inflammatory and immunosuppressive activities.32

For the CB1 receptor, the full agonist is HU-210 (synthetic), partial agonists are delta-9- tetrahydrocannabinol (THC) (found in cannabis) and anandamide (made by the body). The antagonist is rimonabant (a synthetic used for weight control); the inverse agonist cannabidiol (CBD) does not directly interact with CB1 but appears to influence it "from a distance." The exact combination of agonists, antagonists, and inverse agonists in cannabis is unknown.41

Thus, in researching THC metabolism, scientists made the amazing discovery of a molecular signaling system that controlled diverse biological functions. The endocannabinoid system, named for the cannabis plant that brought it to light, is ancient and began its evolutionary journey over 600 million years ago, a time at which the most highly-evolved organisms on earth were sponges.32

Today, endocannabinoids and endocannabinoid receptors are present in every animal lifeform, aquatic or terrestrial, with the exception of insects. The fact that the endocannabinoid system took so long to evolve and the fact that it is uniformly present in so many species (both vertebrate and invertebrate) suggests that the endocannabinoid system in animals is essential to basic physiological functioning.32

Endocannabinoids and their receptors modulate a variety of physiological processes in the brain: movement, nociception (the nervous system's response to harmful or potentially harmful stimuli42), brain reward, learning and memory, feeding, and emesis (vomiting). Peripheral processes impacted include those involved in immune regulation, the cardiovascular system, the reproductive endocrine processes, and energetic metabolism control.43

Three types of cannabinoids can trigger responses in CB1 and CB2 receptors: endogenous-fatty-acid cannabinoids, which are produced in the body; phyto-cannabinoids, which are present in an oil on cannabis plant leaf and bud surfaces; and laboratory-produced synthetic cannabinoids.23 The strength and purity of synthetic cannabinoids facilitated experimentation on a whole new scale. With synthetic cannabinoids, experimenters know the exact chemical composition and precise quantity of the drug they are testing, and they do not have to be concerned with whether the effect is the result of the drug they want to test or of some other cannabinoid or combination of cannabinoids in the cannabis. Phyto-cannabinoids do not exist in isolation in the cannabis plant.

Big Pharma genetically engineered a mouse with no CB receptors, and created an animal model of osteoporosis in both the No-CB-receptor and the normal mice. A synthetic cannabinoid was given to both groups of mice. The cannabinoid relieved the osteoporosis in the normal mice (those with intact CB receptors), but did nothing for the No-CB-receptor mice, proving that "CB receptors are instrumental in regulating bone density."32 Human bone is constantly broken down by cells called osteoclasts44 and rebuilt by cells called osteoblasts.45 A German research team eventually discovered that activating the CB2 receptor "down-regulated" osteoclast precursors; with fewer osteoclasts formed, the osteoblasts gained an advantage and bone was restored.32

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