The Endocannabinoid System What do we really know about marijuana? Nick named the “Evil Weed” it has been the target of a hysterical, multibillion dollar campaign intended to destroy the plant and eliminate its use. Yet, it endures. Marijuana is emerging from under a cloud of contempt due to the fact that it is at the center of one of the most exciting developments in biological science in recent times. Research on its psychological effects have led directly to the discovery of a new chemical signaling system in the human body which is now recognized as playing a CRUCIAL role in regulating our neurology and physiology. Called the endocannabinoid system, it has given us a whole new understanding of how our vital mental and physical functions work and remain in balance. The endocannabinoid system is made up of the endocannabioids, which are cannabinoids produced naturally by the body, cannabinoid receptors or (CB), and the chemical mechanisms responsible for synthesizing and eliminating both. Cannabinoids are the unique chemical compounds found in marijuana very similar in structure and function to the endocannabinoids naturally produced by the human body. These molecules act as triggering and regulating agents for this physiological communications system in the same way that serotonin1 or dopamine2 work in their own respective systems. Cannabinoids and endocannabinoids are molecules that regulate certain biological activities by turning them on and off or up and down in part by binding to CB receptor sites on specific kinds of cells. Other cannabinoids regulate our health by influencing the biological activity of various systems, receptors and neurotransmitters3 . The endocannabinoid system does not act alone; it is a complex signaling network that influences numerous physiological pathways. So, what activities do cannabinoids help regulate? According to Dr. Raphael Mechoulam, one of the founding fathers of cannabinoid research, “there is barely a biological or physiological system in our bodies in which the endocannabinoids do not participate. It is not an over overstatement to refer to Dr. Raphael Mechoulam as a founding father of cannabinoid research. It was Mechoulam and his partner Dr. Yehiel Gaoni who first identified and synthesized THC, the principal psychoactive component of cannabis, while working at Hebrew University in Jerusalem in 1964. In the early 1960’s Mechoulam targeted cannabis as a field of investigation because it was almost totally neglected. Up to this point, the search for the agent responsible for the psychoactive effects of cannabis had been difficult. THC is just one member of a large family of similarly-constructed compounds, and it was difficult to tease them apart with techniques available to biochemists at the time. It was not until technological advances such as chromotography4 and nuclear magnetic resonance5 enabled Mechoulam and his colleagues to isolate specific cannabinoids and determine how they differed from one another. Mechoulam initiated his research into cannabis with 5kg of smuggled Lebanese hashish provided by a friend at police headquarters. Starting his research using magnetic resonance on the cannabinoid (CBD) which had been chemically isolated from other cannabinoids, but its chemical structure had not yet been defined. Mechoulam and his colleague Yuval Shvo deciphered the molecular configuration of CBD and began to dig deeper, searching for the elusive chemicals that produced the HIGH that marijuana produces. The team tested molecule after molecule on rhesus monkeys until they finally identified a single psychoactive agent. Much to their surprise, only delta-9-THC affected the monkeys. Following this key discovery, interest in the field began to expand. Over the next 15 years, Mechoulam’s group at Hebrew University and many other scientists in the United States, Europe and Japan conducted a great deal of research on cannabinoids. During that time, much was learned about the pharmacology, biochemistry, and medicinal effects of cannabinoids; yet, how they did what they did was still an enigma. Nearly a quarter century after the discovery of THC, Allyn Howlett PH.D., and her graduate student William Devane marked a synthetic cannabinoid with radioactive tritium6 in order to follow its path through a rat brain. In doing so, they were able to identify where the cannabinoid was binding in the brain. These docking sites were the first cannabinoid receptors to be identified. This profound discovery, in 1988, led to the charting of a novel neurotransmitter system and the emergence of an entirely new branch of biological science. These receptor sites were designated CB1 or Cannabinoid receptor number 1. In the wake of Howlett’s discovery, scientists intensified their search for the endogenous cannabinoids that they knew would match the newly discovered CB1 receptor sites. In 1992 Czech chemist Lumir Ondrej Hanus and William Devane working in Mechoulam’s lab at Hebrew University, Identified an endogenous compound that fit the CB1 receptor like a key in a lock. They named this new endocannabinoid Anadamide. Cannabinoid research was gaining respect among a growing number of clinical investigators. In 1993, a research group at Cambridge University’s Medical Research Council led by Sean Munro, PH.D., identified and successfully cloned the second cannabinoid receptor, CB2. Two years later, in 1995, Mechoulam made another historic discovery when he isolated a second endocannabinoid (AG2) from spleen tissue. Other scientists began plotting the distribution or (expression) of the corresponding receptors throughout the body and soon uncovered the surprising extent of the endocannabinoid system’s regulatory functions. It is now increasingly recognized that the discovery of the existence and scale of the endocannabinoid system represents a significant advancement in our understanding of human biology. Scientists now have a strong grasp of how cannabinoid receptors and endocannabinoids function and what they regulate. Cannabinoid receptors belong to a class of biological structures known as G PORTEIN-COUPLED RECEPTORS which relay signals through the cell membrane into the cell in order to influence its activity. Cannabinoids activate specific kinds of these receptors to convert extracellular stimuli into intercellular signals. Endocannabinoids are not the only compounds that act on the endocannabinoid system. Cannabinoids found outside the body, known as exocannabinoids, include the naturally occurring chemicals found in the marijuana plant such as THC and CBD. Scientists are also producing synthetic cannabinoids like WIN-55212-2. Cannabinoids work by bonding to the cannabinoid receptors in the body, which then send signals into cells that alter their activity. The CB1 receptor is most abundantly expressed in the central nervous system, but is also found in many other parts of the body. CB1 receptors are also concentrated in fat cells as well as the stomach, placenta, lungs, uterus and liver. CB2 receptors are also wide spread, existing in the liver, spleen, gastrointestinal tract, heart kidney, bones, endocrine glands7, lymph8, and immune cells, as well as the peripheral nervous system9. It is clear that the CB2 receptors are involved with everything from digestion to bone strength to the perception of pain. The wide distribution of cannabinoid receptors explains why they can have such powerful effects on appetite, blood pressure, cerebral blood flow, digestion, nausea, immune function, memory, mood, movement, neurological health, pain, reproduction, stress response and much, much, more. It seems that everywhere in the body cannabinoid receptors are regulating activity and maintaining health. The sheer ubiquity of the endocannabinoid system and the immense diversity of cannabinoids that exhist both inside and outside the body has convinced many experts of marijuana’s medical potential. One of these experts, Dr. Ethan Russo, said, “Cannabis is the single most versatile herbal remedy on Earth. No other single plant contains as wide a range of medically herbal constituents.” Given the extensive influence of cannabinoids in the body, it should not surprise us that marijuana has numerous beneficial effects. But what are those beneficial effects, and how might they be maximized?
Posted on: Sun, 28 Jul 2013 15:09:21 +0000