By Ed Bruder
In full disclosure, I am a Trustee for the Town of Lyons, a patient advocate member of the Department of Revenue’s (DoR) Medical Marijuana Working Group, I am a patient myself, a caregiver, and a current business license holder. At this time I have NO financial interest in any medical marijuana business. I write this as an individual member of these various communities. I don’t speak for the Board of Trustees (BoT), and I don’t speak for anyone else but myself.
This week I want to provide the reader with some detailed information about cannabis research in the United States, and how cannabinoids work in the animal/human body.It is worth pointing out that with the exception of a few State of California sponsored research projects, ALL the cannabinoid research that has occurred in the U.S. for the past 60 years has been following the U.S. Government’s mandated model of demonstrating why cannabinoids are addictive and cause dependance.
In order to do research in the United States, any cannabis that will be used in the study must be sourced from one government agency. “In 1968, the National Institute of Mental Health (NIMH) began funding a Drug Supply Program to provide researchers with compounds necessary to conduct biomedical research. Initially, the program focused on THC and other naturally occurring cannabinoids, and then gradually expanded to a wide range of compounds. ... Cannabis was among the first substances to be made available through the Drug Supply Program for use by scientists conducting both nonhuman research and human research under a variety of investigational new drug protocols. It was grown through a contract with the University of Mississippi. With its establishment in 1974, the National Institute on Drug Abuse (NIDA) became the successor to NIMH as the administrator of the cannabis contract and the sole U.S. source for legal cannabis.”
According to a report released by Americans for Safe Access, titled; “The Obstruction of Medical Cannabis Research in the U.S.: “As a result of its monopoly on the supply of cannabis that can be legally used in federally-approved research, The National Institute on Drug Abuse (NIDA), a subdivision of the National Institutes of Health (NIH), oversees all cannabis research in the U.S. and funds the vast majority of approved studies involving cannabis. While a nominal number of studies in the U.S. are aimed at investigating the medical efficacy of cannabis, mainly funded by the State of California’s Center for Medicinal Cannabis Research (CMCR), NIDA focuses exclusively on the supposed harmful effects of the plant. One consequence of this focus can be found in NIDA’s policy of underwriting the cannabis supplied for “drug abuse” research that it funds, whereas researchers studying medical efficacy are required to pay for research-grade cannabis at a price set by NIDA.
“At the time this report was issued [April 2009], only 14 cannabis studies were under way, 13 of which were NIDA-funded drug abuse studies. ....
“Even after the FDA approves medical cannabis research studies, those studies are still subject to additional approval that is not required for any other Schedule I substance. Multiple researchers in the U.S. have been granted approval by the FDA to study medical cannabis, but have been significantly delayed or prevented from conducting their research at all as a result of NIDA’s refusal to sell the cannabis.”
The major themes in U.S. Research have been; “Do cannabinoids act like other drugs of abuse?” “Do cannabinoids elevate dopamine levels?” “Does cannabinoid use support the suggested ‘gateway theory’?” “What is the abuse liability of cannabis?” “Do cannabinoid receptors influence other drugs of abuse?”
It has been estimated that hundreds of thousands of animal’s lives have been sacrificed,researching these issues. After a substantial number of well controlled studies have been conducted on how cannabinoids act, or don’t act, like other addictive drugs, the evidence has been presented. In repeated preclinical research (think animal testing) it has been definitively proven that cannabinoids do not fit well in the accepted paradigm distinguishing other drugs of abuse. This is not to say that people genetically predisposed, and those experiencing the environmental triggers associated with addiction, cannot develop harmful momentum with cannabis. This issue will be discussed more in next week’s article.
Luckily, the United States was not the only country doing research on cannabinoids. Up until the late 1980s, and before the work of Dr. Raphael Mechoulam was published, it was hypothesized that cannabinoids produced their physiological and behavioral effects through nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors. In 1990 the cannabinoid receptor, the “lock” or “binding site” into which cannabinoids fit, thus activating the specific biochemical events, was discovered. These receptors are common in animals, and have been found in mammals, birds, fish, reptiles, and even the common sea sponge. There are at least two known types of cannabinoid receptors, termed CB1 and CB2, with mounting evidence of more.
In 1992 Dr. William Devane and Dr. Raphael Mechoulam identified a natural brain molecule that binds to the cannabinoid receptor. They called it anandamide, from the Sanskrit word for “eternal bliss.” While anandamide mimics the action of THC, interestingly, on paper it doesn’t look anything like THC until it is folded over on itself in a 3 dimensional space. This discovery proved that mammals organically produce a chemical in their bodies that mimics THC. The endocannabinoid 2-AG has been found in bovine and human breast milk.
CB1 cannabinoid receptors are the most densely populated of all receptor genes in the human brain. We are specifically wired to sense and regulate function through endocannabinoids.
CB1 receptors are found primarily in the brain, specifically in the basal ganglia (A sub-cortical network that is important to sensory motor integration and the voluntary control of movement.
There is research that suggests that the basal ganglia is also critically involved in the learning of behavioral habits. In some people, this part of the brain may have been improperly wired. This can be expressed through the formation of unwanted habits and behaviors, like Tourette Syndrome, obsessive compulsive disorder, and even drug addiction. CB1 receptors are found in the limbic system, including the hippocampus. (The hippocampus is related to learning, memory and sensory processing) They are also found in the cerebellum and in both male and female reproductive systems.
What is tremendously important to understand, is where CB1 receptors are not found. CB1 receptors are essentially absent in the medulla oblongata, (The part of the brain stem that is responsible for respiratory and cardiovascular functions.) Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs and alcohol. CB1 receptors appear to be responsible for the euphoric and anti-spasmodic or anti-convulsive effects of cannabis.
CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen and liver. While generally found only in the peripheral nervous system, a report does indicate that CB2 is expressed by a subpopulation of microglia in the human cerebellum. CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.
Phytocannabinoids, (Refereed to as natural cannabinoids, herbal cannabinoids, or classical cannabinoids) are only known to occur naturally in relatively significant quantity in the cannabis plant, and are concentrated in a viscous resin that is produced in glandular structures known as trichomes. In addition to cannabinoids, the resin is rich in terpenes, which are largely responsible for the odor of the cannabis plant. At least 85 cannabinoids have been isolated so far from the cannabis plant.
Endocannabinoids function in an opposite manner, compared to how most classic neurotransmitters work. Classic neurotransmitters work by completing circuits across the synapses, thereby hitting the target cell, and then either activate or inhibit it. They are bundled up in little vesicles and released at the ends of neurons.
Endocannabinoids are understood to be retrograde messengers. In order to regulate function they travel in reverse across the synapse. CB1 receptors are located pre-synaptically; this allows for them to provide many different functions.
Endocannabinoids serve as intercellular lipid messengers, signaling molecules that are released from one cell and activate the cannabinoid receptors present on other nearby cells, and when the cells receive a lot of sensory input, the endocannabinoids are released in response to the stimulation. If this is an excitatory connection, the endocannabinoids released from the cell diminish the excitation and regulate how strongly that cell is fired.
Activation of cannabinoid receptors temporarily reduce the amount of conventional neurotransmitter released. It is through these endocannabinoids that the neurons can fine tune their synaptic inputs. In other words, endocannabinoids act on neurotransmitters like a dimmer switch acts when attached to a light bulb. This mechanism of decreased activity is like an on-demand protection circuit (meaning endocannabinoids are believed to be synthesized “on-demand” rather than made and stored for later use as is the case for classic neurotransmitters).
For example: with epilepsy, and MS, there is a rampant over excitation of neurotransmitters, the brain releases endocannabinoids to essentially turn down the excitation. This is why cannabis use has been indicated as a reliable treatment for MS.
Endocannabinoids play a pivotal role in the bodies own “natural reward system”, like what is often experienced during endurance running. And not just the runners “high,” but the overall sense of well being that is associated with endurance activities that makes them a good adjunct therapy for mental health treatments. Endocannabinoids have been found to regulate our perception and the contextualizing of experiences that are rewarding to humans.
Returning to the fact that the areas of the brain that regulate life sustaining function are pretty much free of cannabinoid receptors, it is easy to understand why cannabis hasn’t killed anyone, like all Schedule II drugs have.
Here are some interesting excerpts from the US Department of Justice, Drug Enforcement Administration, “In the Matter of Marijuana Rescheduling Petition” (Docket #86-22), September 6, 1988, p. 56-57.
“The most obvious concern when dealing with drug safety is the possibility of lethal effects. Can the drug cause death? Nearly all medicines have toxic, potentially lethal effects. But marijuana is not such a substance. There is no record in the extensive medical literature describing a proven, documented cannabis-induced fatality. This is a remarkable statement.”
“First, the record on marijuana encompasses 5,000 years of human experience. Second, marijuana is now used daily by enormous numbers of people throughout the world. Estimates suggest that from twenty million to fifty million Americans routinely, albeit illegally, smoke marijuana without the benefit of direct medical supervision. Yet, despite this long history of use and the extraordinarily high numbers of social smokers, there are simply no credible medical reports to suggest that consuming marijuana has caused a single death.”
“...By contrast aspirin, a commonly used, over-the-counter medicine, causes hundreds of deaths each year.”
“Drugs used in medicine are routinely given what is called an LD-50. The LD-50 rating indicates at what dosage fifty percent of test animals receiving a drug will die as a result of drug induced toxicity. A number of researchers have attempted to determine marijuana’s LD-50 rating in test animals without success. Simply stated, researchers have been unable to give animals enough marijuana to induce death.”
“At present it is estimated that marijuana’s LD-50 is around 1:20,000 or 1:40,000. In layman terms this means that in order to induce death a marijuana smoker would have to consume 20,000 to 40,000 times as much marijuana as is contained in one marijuana cigarette. NIDA-supplied marijuana cigarettes weigh approximately .9 grams. A a smoker would theoretically have to consume nearly 1,500 pounds of marijuana within about fifteen minutes to induce a lethal response. In practical terms, marijuana cannot induce a lethal response as a result of drug-related toxicity.”
Additional references: Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse, “Provision of Marijuana and Other Compounds For Scientific Research - Recommendations of The National Institute on Drug Abuse National Advisory Council”
Gregory Gerdeman, PhD (2010) “The endocannabinoid roots of medical marijuana: liberating cannabis from the drug abuse paradigm”
Begg M, Pacher P, Bátkai S, Osei-Hyiaman D, Offertáler L, Mo FM, Liu J, Kunos G (2005). “Evidence for novel cannabinoid receptors”. Pharmacol. Ther. 106 (2): 133–45. doi:10.1016/j.pharmthera.2004.11.005. PMID 15866316.
Núñez E, Benito C, Pazos MR, et al. (2004). “Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study”. Synapse 53 (4): 208–13. doi:10.1002/syn.20050. PMID 15266552