Best Summary _ ECS _ Cannabinoid _ Information____________________________________________________________________________________________________________

THE ENDOCANNABINOID SYSTEM - ECS -

The Endocannabindoid System (ECS) is an ancient body system that is found in all animals with vertebrate, including humans. The function of the ECS is to maintain homeostasis throughout the animal’s body utilizing neuro-metabolic signaling and the CB1 and CB2 receptors. Within a cell, cannabinoids control basic metabolic processes such as glucose metabolism. Cannabinoids regulate intercellular communication, especially in the immune and nervous systems. In general, cannabinoids modulate and coordinate tissues, organ and body systems (including the cardiovascular, digestive, endocrine, excretory, immune, musculo- skeletal, nervous, reproductive, and respiratory systems). The effects of cannabinoids on consciousness are not well understood, but are well known. These effects also have therapeutic possibilities.

In September of 2005, Sanofi Aventis, the world’s 3rd largest pharmaceutical company, placed an advertisement in the Journal of the American Medical Association (JAMA) 09/21/05 issue and plainly stated the biological basis for how marijuana affects so many systems within the body.

The endocannabinoid system “impacts metabolic functions” and “consists of signaling molecules and their receptors, including the cannabinoid receptors (CB1 and CB2). The CB1 receptors “may impact lipid levels and insulin sensitivity.” They are “located centrally in the brain and peripherally in liver, muscle and adipose tissue.

Adipose tissue is defined as “a metabolically active endocrine organ -more than just a storage facility for fat, it has metabolic effects.” ECS over-activity in adipose tissue is associated with decreases in the hormone adiponectiun, which may be linked to dylipidemia, insulin resistance, and intra-abdominal adiposity.” CB1 receptors are “at the

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center of a cascade of events with potential impact on cardiometabolic risk.” And they “May assist in regulating physiologic processes, e.g., lipid and glucose metabolism.”

The Endocannabinoid system (ECS) is involved in regulating many physiological processes: Nervous Cardiovascular Immune Reproductive Sleeping Eating Memory function Relaxation

What are Cannabinoids?Phytocannabinoids — Cannabinoids produced by the plant.

Phytocannabinoids are complex chemical compounds that are secreted by the cannabis plant through its flowers that mimic naturally occurring compounds produced by our bodies, called endocannabinoids (Anandamide and 2-AG).

Endocannabinoids — Cannabinoids produced by the body.

AEA (Anandamide)—An endogenous cannabinoid neurotransmitter found in organs in humans and most animals with an abundant amount located in the brain. While delta-9-tetrahydrocannabinol (THC) was first synthesized by Mechoulam in 1967, it was not until 1990 that the cannabinoid receptor was localized in the brain and cloned. Since then, discoveries in the field have proceeded at an ever-increasing pace.

Cannabinoid Receptor SitesWhen cannabis is consumed, the cannabinoids bind to receptor sites throughout our brain and body (CB-1 and CB-2 respectively), with a wide variety of effects possible depending on the cannabinoid profile present in a given strain.

CB1 Receptor—Primarily found in the brain.CB2 Receptor—Primarily found in the immune system.

How Do Cannabinoids Work in the Human Body?

THE FUNCTION OF THE ECS

The “simplest” description of the effects of marijuana in humans is that it modulates the regulation of homeostasis. Homeostasis is keeping the various systems in the body in relative balance. The balance between inhibition and excitation, bone formation and resorption, inflammatory/anti-inflammatory signaling, fat storage and release, blood sugar, blood pressure, hormone levels; all these systems are held in balance by the endocannabinoid system (ECS).

Though the ECSinvolved in maintaining nearly every biological process in all humans, this system wasn’t discovered until the late 1980’s. The human body contains not only contains receptors for cannabinoids, but an

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entire endocannabinoid system that processes cannabinoids. This system allows the body to benefit from the cannabinoids found in cannabis, some of which aren’t found anywhere else in nature.

Research revealed that the human body contains not only receptors for cannabinoids, but an entire endocannabinoid system (ECS) that processes cannabinoids. This system allows the body to benefit from the cannabinoids found in cannabis, some of which aren’t found anywhere else in nature. The endocannabinoid system regulates many of the functions of the human body: appetite, food intake, motor behavior, reproduction, and much more. That’s why the plant has such a wide therapeutic potential, and every day more are discovered.

CannabinoidsPhytocannabinoids — Cannabinoids produced by the plant.Phytocannabinoids are complex chemical compounds that are secreted by the cannabis plant through its flowers that mimic naturally occurring compounds produced by our bodies, called endocannabinoids, such as Anandamide and 2-AG.

At least 85 different phytocannabinoids have been isolated from the cannabis plant. For years THC has been described as the primary compound in cannabis due to its famous psychoactive effects, but recent research has identified many other important cannabinoids, each linked with specific medicinal effects. During prohibition (the last 80 years), cannabis has been primarily bred to increase THC content to increase the altering effect of the plant, as demanded by the black market. Now that things are changing, other cannabinoids are reaching the medical spotlight and strains are being bred to increase their presence.

Common testing methods provide profiling for the three most prevalent cannabinoids – THC, CBD and CBN, but there are many others to be aware of, including the acid forms of each cannabinoid. There is still much to be studied about this plant and its many components, but with restrictions on scientific research of cannabis slowly relaxing, more information continues to come to light.

Here is an overview of the four (4) major cannabinoids that are supported by a solid body of research at this time:

1 THC: Tetrahydrocannabinol

Effects: Responsible for the ‘’high’’ effect (psychotropic, euphoric), it amplifies all sensory functions such as sight, hearing, color sensitivity, and promotes a greater sense of well-being. THC produces strong feelings of euphoria. It sharpens the mind (cerebral) and promotes creativity. THC displays a wide range of properties, which can be expressed differently when accompanied by various other cannabinoids and terpenes.Side effects vary from one person to another and include: dry mouth, dry eyes, disorientation, short-term memory malfunctions, increased heart-rate, anxiety, and paranoia. Most of these are a result of over-medication and are avoidable with low doses.

Medical Applications: Neuroprotective – protects against nerve damage Anxiolytic – reduces the symptoms of anxiety Antispasmodic – relieves spasms and convulsions Antiemetic – reduces vomiting and nausea Analgesic – reduces pain Appetite Stimulant – encourages eating and appetite Antioxidant – fights free radicals in the bloodstream Neuropathic analgesic – reduces pain from nerve damage Bronchi-dilator -acts similarly to an inhaler to assist asthmatics with breathing

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Anti-proliferative anticancer – reduces spread of certain cancers Anti-inflammatory – reduces inflammation Neurogenesis – promotes growth of new nerve tissue

 2 CBD: Cannabidiol

Effects: CBD has medical effects but does not make people feel “stoned” and actually counters some of the effects of THC. After decades in which only high-THC Cannabis was available, CBD-rich strains are now being grown by and for medical users. The reduced psychoactivity of CBD-rich Cannabis may make it an appealing treatment option for patients seeking anti-inflammatory, anti-pain, anti-anxiety and/or anti-spasm effects without euphoria or lethargy.

Medical Applications: Rheumatoid arthritis Diabetes Alcoholism PTSD Epilepsy AIDS Anti-cancer/tumor Arthritis Depression Crohn’s Disease Eating Disorders Glaucoma Epilepsy/Seizure Disorders Migraines Multiple Sclerosis

 3 CBN: Cannabinol

Effects: Mildly psychoactive, sedative, analgesic. CBN is, just like aspirin, a non-narcotic type analgesic, but 3 times as strong. CBN is a breakdown product of THC. During storage (aging) CBN will slowly increase as THC deteriorates. CBN is effective at relieving tension headaches.

Medical Applications: Antispasmodic – relieves spasms and convulsions Analgesic – reduces pain Anti-inflammatory – reduces inflammation Antioxidant – fights free radicals in the bloodstream

 

4 CBG: Cannabigerol **

CBG is perhaps the most under-studied of all cannabinoids, but holds promise of perhaps the most therapeutic properties.

** Cannabigerol (CBG) is the “stem cell” for many chemicals in marijuana, including THC and CBD. Scientists first discovered cannabigerol, or CBG, in 1964 as a constituent of hashish. In 1975, researchers found out that CBGA (the acid form of CBG) is the first cannabinoid formed in the plant, essentially the first expression of cannabis’ unique class of constituents. From there, CBGA gets transformed into THCA, CBDA or CBCA by the action of enzymes. CBGA is the precursor for all the cannabinoids we know and love.

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CBG also has a number of medicinal properties of its own. Cannabigerol (CBG) is non-psychoactive but still affects the overall effects of Cannabis. Many users find that strains with high CBG have less negative side effects of THC. CBG has been shown to promote apoptosis in cancer cells and inhibit tumor growth in mice.

Medical Applications: Antioxidant – fights free radicals in the bloodstream Anti-inflammatory – reduces inflammation Anti-emetic (vomiting) and anti-nausea Antibacterial Eases Inflammatory Bowel Disease Slows the proliferation of tumor cells Pain relief Eases effects of Psoriasis

Major Usefulness of the Major CannabinoidsCannabinoid Therapeutic Effect

THC (9 Tetrahydrocannabinol)

Anti cancer Anti nauseant Analgesic Appetite stimulant Antispasmodic Muscle relaxant Anti microbial Neuroprotective Helps with the symptoms of Crohn’s disease (anti-spasmodic, anti

inflammatory) Anti inflammatory Antioxidant

CBD (Cannabidiol)

Protects against cancer Reduces nausea Pain reliever Sleep aid Relieves spasms Decreases seizures Reduces anxiety Muscle relaxant Antibacterial Protects nervous system Anti diabetic Improves circulation Relieves psoriasis Relieve Crohn’s Disease Anti inflammatory Bone stimulant Relieves rheumatoid arthritis Antioxidant

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CBC (Cannabichromene)

Anti cancer Anti bacterial Anti fungal Anti inflammatory Stimulates bone

CBG (Cannabigerol) Anti cancer Anti inflammatory Stimulates bone

CBN (Cannabichromene)

Pain reliever Sleep aid Antispasmodic Anti inflammatory Antioxidant

THCV (Tetrahydrocannabivarin)

Appetite suppressant Anti seizure Stimulates bone

The information in this chart was sent via email from Dr. David Bearman.

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October 15, 2005

Cannabinoids Arrive in Realm of Established Fact

Just as the marketing of Prozac by Eli Lilly familiarized the public with “clinical depression” and “selective serotonin reuptake inhibitors” (SSRIs), so

The marketing of Rimonabant as a weight-loss drug by Sanofi Aventis will educate millions about the endocannabinoid system (ECS). This was foreseen by Philip Denney, MD, who forwards, as part of the mounting evidence that he was right, a full-spread advertisement placed by Sanofi Aventis in the Sept. 21, 2005 issue of JAMA, the Journal of the American Medical Association. Denney and others remain skeptical about the longterm safety profile of a synthetic “cannabinoid-antagonist” drug that works by blocking the natural receptor system.

The JAMA ad touts: “A NEWLY DISCOVERED PHYSIOLOGICAL SYSTEM… The Endocannabinoid System (ECS).”

It succinctly explains the role the ECS appears to play in “metabolic syndrome,” the condition for which Sanofi Aventis hopes to get FDA approval to market Rimonabant. Footnotes direct interested physicians to papers from reputable sources. The significance of this carefully documented ad in such a prestigious journal is huge. It seems like only yesterday that the Drug

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Czar was ridiculing Tod Mikuriya as a practitioner of “Cheech and Chong medicine.” Now, plainly stated in JAMA by the world’s third-largest pharmaceutical company, is the biological basis for how marijuana affects so many systems within the body.

The left-hand page depicts an endocannabinoid floating like a stylized dolphin over a cell membrane from which cannabinoid receptors protrude like plugs in a distributor cap. Accompanying text asserts, “CB1-receptor activation triggers a cascade of intracellular events that impact cardiometabolic risk.” Metabolic syndrome is defined on the right-hand page as a cluster of risk factors: decreased “good” cholesterol; elevated blood pressure, trigycerides and glucose levels; and a widening waistline. Adipose tissue is defined as “a metabolically active endocrine organ -more than just a storage facility for fat, it has metabolic effects.”

The endocannabinoid system “impacts metabolic functions” and “consists of signaling molecules and their receptors, including the cannabinoid receptors (CB1 and CB2). The CB1 receptors “may impact lipid levels and insulin sensitivity.” They are “located centrally in the brain and peripherally in liver, muscle and adipose tissue. ECS over-activity in adipose tissue is associated with decreases in the hormone adiponectiun, which may be linked to dylipidemia, insulin resistance, and intra-abdominal adiposity.” CB1 receptors are “at the center of a cascade of events with potential impact on cardiometabolic risk.” And they “May assist in regulating physiologic processes, e.g., lipid and glucose metabolism.”

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OverviewHumans and animals alike naturally synthesize endocannabinoids, chemical compounds that activate the same receptors as delta-9-tetrahydrocannabinol (THC), the active component of marijuana (Cannabis sativa). Marijuana, as smoked in cigarettes, has many names both formal—cannabis, cannabis, hashish, hemp, sinsemilla—and informal—pot, dope, grass, weed, Mary Jane, bud, hash, bhang, kef, ganja, locoweed, reefer, doob, spliff, toke, roach.Marijuana is famous for its significant psychoactive effects. Its ability to provide relief to chronic pain sufferers, to induce an increase in appetite, to alleviate nausea, and to ease anxiety are only some of the common uses for hemp. The interest in cannabis has risen in the United States since its medical and recreational use is now (2015) legal in 20 states.Medical use of marijuana is allowed in the following 20 states (2015):

Washington Oregon California Nevada Arizona New Mexico Montana Colorado Illinois Alaska Hawaii Michigan Maine Massachusetts Rhode Island Connecticut

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New Jersey Delaware Maryland Washington, DC

Recreational use of marijuana is allowed in the following two states (2015): Colorado Washington

AbbreviationsAbbreviations used in the discussion of cannabinoids and in this article are as follows:

THC: Δ9-Tetrahydrocannabinol AEA: Anandamide 2-AG: 2-Arachidonoylglycerol AA: Arachidonic acid EC: Endocannabinoids ECS: Endocannabinoid system CB1-R: Cannabinoid binding receptor-1 (predominantly in brain) CB2-R: Cannabinoid-binding receptor-2 (predominantly in immune system) PE: Phosphatidylethanolamine NAT: N -acyltransferase NAPE: N -acyl-phosphatidylethanolamine NAPE-PLD: NAPE-specific phospholipase D MGL: Monoacylglycerol lipase FAAH: Fatty acid amide hydrolase

Further investigationEndocannabinoids are crucial to bioregulation. Their main role is in cell-signaling, and, because they are hydrophobic, their main actions are limited to paracrine (cell-to-cell) or autocrine (same cell), rather than systemic, effects. Unique characteristics of the ECS are as follows:

Lipid structure, making it lipophilic Hydrophobic with limited mobility in an aqueous environment Local cell-signaling (paracrine or autocrine) Retrograde transmission in the brain; travels backward from postsynaptic to presynaptic cells Formed from the internal lipid constituents of cellular membrane Synthesized “on demand” and not stored Very short half-life Degradation by FAAH may regulate ECS bioactivity Two G-protein–coupled receptors in the brain (CB1-R) and immune system (CB2-R)

With scientific evidence suggesting their role in inflammation, insulin sensitivity, and fat and energy metabolism, inhibition of endocannabinoids may be a tool in reducing the prevalence of metabolic syndrome and augmenting the benefits of physical exercise.[1, 2] Furthermore, modulation of the endocannabinoid system may be a cure for more chronic neurologic and immune conditions. Many questions are left unanswered about this relatively newly discovered regulatory system. Further investigation into this exciting field promises to shed insights into the mechanisms of health and disease and provide new therapeutic options. History of endocannabinoid researchWhen Mechoulam and colleagues isolated THC in 1964, they made it possible to further understand the complex nature of the endocannabinoid system.[3] Other important events in endocannabinoid research are as follows:

2000-650 BCE: Cannabis (azaluu or gurgurru) mentioned in Assyrian pharmacopoeia at the library of Assurbanipal

1964: THC isolation and structure elucidation 1988: Cannabinoid-binding sites in rat brains identified

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1991: Human CB1-R receptor successfully cloned 1992: Endogenous CB1-R ligand (EC), anandamide (based on Sanskrit for “supreme joy”),

discovered in the brain 1993: CB2-R receptor found in the immune system successfully cloned 1995: Second EC, 2-AG discovered and more abundant in the brain than AEA

In the 21st century, new discoveries of other endocannabinoids, their site distributions, and roles are deepening our understanding of the endocannabinoid system.

Chemical Structure

Although the first EC to be identified was AEA, 2-AG is the most abundant in the brain.[4] Several other ECs have been identified, but their function and role in ECS physiology remains to be determined. Five of the best-known ECs are in the figure below. Note that all of them share the same 19-C backbone structure but differ in the R-group constituents.

The five best-known endocannabinoids showing the common 19-C backbone structure and specific R-group constituents.

Endocannabinoid System Roles

Multiple human and animal studies support that endocannabinoids play a key role in memory, mood, brain reward systems, drug addiction, and metabolic processes, such as lipolysis, glucose metabolism, and energy balance.[5]

Several competing pathways for AEA biosynthesis have been described. The best-described pathway is shown in the figure below. AEA biosynthesis is initiated following a postsynaptic neuronal depolarization and an influx of calcium. The calcium then activates N- acylphosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) and diacylglycerol (DAG) lipase, each of which forms AEA and 2-AG, respectively.[4, 6] The anterograde neurotransmitter transmission and retrograde EC modulation form the closed signaling loop depicted in the figure below.

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This figure depicts the neuromodulatory signaling loop between anterograde neurotransmitter release and the retrograde inhibition by postsynaptic anandamide (AEA). More specifically, it shows the biosynthesis of AEA and activation of the cannabinoid binding receptor-1 (CB1-R) receptor pathway (2-arachidonoylglycerol [2-AG] pathway is similar but not shown here). The initiation of AEA biosynthesis differs from 2-AG. Important to note is that these two processes are mutually exclusively so that AEA and AG cannot be co-synthesized. The endocannabinoid system (ECS) steps shown are as follows: (1) the initiation of AEA biosynthesis starts with activation of N-acyltransferase (NAT), which transfers an acyl group to the membrane phospholipid, phosphatidylethanolamine (PE), forming N-acyl-phosphatidylethanolamine (NAPE); (2) a NAPE-specific phospholipase D (NAPE-PLD) next cleaves NAPE to produce AEA; (3) once synthesized, AEA is susceptible to degradation by fatty acid amide hydrolase (FAAH), possibly an important point of regulation; (4) the AEA that escapes FAAH degradation can diffuse across the synaptic cleft to activate the presynaptic G-coupled membrane bound CB1-R receptor; (5) this activation results in inhibition of anterograde neurotransmitter release. It is obvious that one of the purposes of this ECS is to enable postsynaptic neuron control over neurotransmitter action.

Owing to their lipophilic nature, the endocannabinoids act locally and are not synthesized until needed. Central nervous system messengers that act in a retrograde fashion, the endocannabinoids, are agonists to CB1-R and CB2-R.[7, 8]

Endocannabinoid receptors (CB1-R and CB2-R)

CB1-R and CB2-R are membrane-bound G-protein receptors that activate cyclic-AMP like other classic G-protein receptors. A non–CB1-R/non–CB2-R has been theorized based on indirect data but has yet to be characterized.

CB1-R and CB2-R are G-protein receptors. CB1-R receptors are abundant in the brain, specifically the mesocorticolimbic system, the spinal cord, and the peripheral neurons. CB1-R receptors are particularly concentrated on both gamma-aminobutyric acid (GABA)–releasing neurons (inhibitory neurons) and glutaminergic-releasing neurons (excitatory). Hence, activation of CB1-R leads to retrograde suppression of neurotransmitter release, which may be excitatory or inhibitory depending on the location in the brain.[7, 9]

Interestingly, CB1R gene polymorphisms have been described but their functional effects are not well-characterized. Some are associated with anxiety and depression.[10]

CB2-R receptors are located peripherally, with a high density on immune-modulating cells, including microglia in the brain. It is believed the CB2-R may have a protective effect on autoimmunity and inflammation.[1, 10] CB2-

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R may have some relationship to depression based on animal studies and the finding of a high-incidence of CB2-R polymorphisms in a depressed Japanese population.[10]

Table. Comparison of EC Receptors CB1-R AND CB2-R Characteristics (Open Table in a new window)

CB1-R CB2-R Principal Endogenous LigandsAEA and 2-AG 2-AG (AEA partial agonist)Major Tissue LocationsBrain and peripheral nervous system Immune system

Other Tissue LocationsPituitary, thyroid, and adrenal glands; male and female reproductive system; liver, adipocytes, lungs, kidney

Spleen, tonsils, thymus gland, gastrointestinal tract, osteocytes

Cellular Location Presynaptic glutamate and GABA neurons Monocytes, macrophages, microglia, B-cells, and T-cells

Gene/Chromosome CNR1/6q14 CNR2/1p36

General Action Inhibits release of glutamate and GABA Modulates cytokine release and immune response

Physiologic ActionsGastrointestinal SystemDecreases gut motility Reduces bowel inflammationPeripheral Nervous System Analgesic Effects Nociceptive interneurons in the dorsal horn of the spinal cordAnti-inflammatory action mast cells in

spinal cord

Reproductive System

Male – Leydig cells

Female – Ovary, ducts, uterus, placenta, embryo implantation

Placenta, embryo, T-cell cytokine release

Promotes fibrosis, increases steatosis Inhibits fibrosis, decreases steatosisCardiovascular SystemHypotension, bradycardia Atherosclerotic plaque inflammationDrug-Seeking BehaviorStimulates Reduces

 

CB1-R CB2-R physiologic and pathophysiologic roles in the body

Chronic stress

Although stress responses can be life-saving in the face of a threat, chronic stress often has negative health effects. The ECS is the central mediator of the stress response. The ECS regulates the release of stress-induced neurotransmitters including the systemic release of norepinephrine and cortisol. The ECS plays a role in the stress alterations of mood, cognition, and activation of the hypothalamic-pituitary-adrenal axis. The ECS may also mediate some of the dysmetabolic effects glucocorticoids on lipid metabolism, leading to hepatic steatosis and potentially contributing to the metabolic syndrome.[11] Therefore, the ECS is an important control point and therapeutic target to reduce the deleterious effects of chronic stress.[12]

Obesity

CB1-R is important for energy balance in the body. With fasting or starvation, anandamide and 2-AG levels increase in the limbic forebrain and, to a less significant extent, in the hypothalamus. CB1-R activation

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increases food intake and effects energy metabolism through coordination of the mesolimbic reward system and the hypothalamus’ appetite control pathway.[9, 13] This receptor also promotes food intake by increasing odor detection via stronger odor processing in the olfactory bulb.[14]

Some obese people may have excess CB1-R activation. Obese and overweight individuals may have a mutation in FAAH, the enzyme that degrades AEA. This can lead to increased levels of AEA (15-fold increase in FAAH “knock-out” mice) and stimulation of the hypothalamic appetite control center.[13]

It is uncertain if there is a regulatory feedback loop between the ECS and obesity. Wild-type mice that develop diet-induced obesity have a hyperactive ECS, with an increase in receptor availability and an increase in circulating ECs. In presatiated mice, an intrahypothalamic injection of AEA induced substantial hyperphagia. Inactivation of CB1-R receptors decreases plasma insulin and leptin levels, ultimately leading to more efficient energy metabolism.[15, 16]

Nervous system

The ECS obviously plays a significant role in the normal functioning of the brain, spinal cord, and peripheral nervous system. Therefore, the ECS can either cause or become altered by diseases of the neurologic system. For example, hyperactivity of the ECS reduces dopaminergic tone in the basal ganglia, contributing to the pathophysiology of Parkinson disease.[17] Other diseases with potentially significant ECS interactions include multiple sclerosis, seizure disorders, Alzheimer disease, Huntington disease, amyotrophic lateral sclerosis, and psychiatric diseases such as schizophrenia.[18, 19]

Pain

Pain is already a well established and important therapeutic target for ECs. CB1-R agonists act on nociceptive interneurons in the dorsal horn of the spinal cord to alleviate pain. In addition, CB2-R–selective agonists have proven to be helpful in reducing inflammation and undoing established inflammation hypersensitivity involved in peripheral pain and skin disorders.[20, 1]

Heart and blood vessels

CB1-R activation aids in vasodilation and cardiac contractility, regulating blood pressure and improving left-sided heart function. CB2-R has been implicated in the inflammation in atherosclerotic plaques. In this regard, CB2-R activation is a therapeutic strategy for reducing atherosclerotic plaque inflammation and reducing vulnerability to rupture and thrombosis.[21]

Cancer

Both marijuana and ECs are anti-inflammatory, antiproliferative, anti-invasive, antimetastatic, and proapoptotic in most cancers, in vitro and in vivo, in animals. In some cancers, ECs are proproliferative and antiapoptotic, but in the majority they show cell cycle arrest, autophagy, apoptosis, and tumor inhibition. At present, cannabinoid cancer therapy is limited to nausea and pain, but future studies are needed to determine its full chemotherapeutic potential.[20, 22, 23]

Gastrointestinalsystem

Activation of CB-1 receptors and, to a lesser extent, CB2-R receptors, by AEA also reduces gastrointestinal motility and secretions. CB1-R receptor activation inhibits proinflammatory responses in the colon.[24, 25]

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Liver

CB1-R receptors aid in modulating hepatic lipogenesis. Activation in the liver leads to fatty acid synthesis, causing hepatic steatosis and diet-induced obesity. In addition, the CB1-R promotes hepatic fibrosis and contributes to the hemodynamic abnormalities in cirrhosis. By reducing inflammatory cell infiltration and lipid peroxidation, CB2-R receptor activation is protective against hepatic ischemia-reperfusion injury. Targeting the hepatic ECS may have therapeutic potential in a variety of liver diseases.[26]

Reproductive system

The ECS has a role in reproduction. The CB1-R is found in the male (Leydig cells) and the female (ovary, ducts, uterus). Furthermore, normal folliculogenesis and spermatogenesis may require the ECS. The CB1-R is also present in the placenta and is necessary for embryo implantation.[22] The use of cannabis is associated with implantation failure, spontaneous miscarriage, fetal growth restriction, and premature birth in humans. Future research efforts will be needed to unravel the full complexity of the ECS involvement in the process of reproduction.

Skeletal system

In addition to immunomodulatory pathways, CB2-R receptors are involved in maintaining proper bone mass.[27]

CB2-R receptors are abundant in osteocytes, osteoclasts, and osteoblasts. CB2-R agonists enhance endocortical osteoblast reproduction and activation, while inhibiting osteoclastogenesis.

Endocannabinoid degradation

Endocannabinoids have a short life span. AEA and 2-AG are quickly degraded through transport protein reuptake and hydrolyzation by either FAAH or MAG lipase, respectively.[28] Degradation may be an important regulatory control point, since inactivation of FAAH results in 15-fold elevated AEA levels in genetic FAAH knock-out mouse brains. Furthermore, these enzymes, FAAH and MGL, have become therapeutic targets for pharmacologic interventions of the ECS. FAAH inhibition has shown the advantages of a lack of abuse potential or physical dependence compared with MGL.[6, 10, 25] See the figure below.

The principal catabolic pathways for both AEA and 2-AG by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), respectively, both producing arachadonic acid.

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Other less important enzymatic pathways exist, demonstrating redundancy in EC degradation. Interestingly, the catabolite AA is a precursor for the cyclooxygenase (COX)–2 enzyme, leading to a number of bioactive eicosanoids (eg, prostaglandins, prostacyclin, thromboxane, leukotrienes). The significance of the EC–COX-2 eicosanoid pathway is under investigation.[29]

Conclusion

In summary, the ECS is a unique and ubiquitous cell-signaling system that is just beginning to be understood. The biochemistry of EC synthesis, metabolism, and bioactivity has been difficult to study in the past. Newer techniques such as genetically modified animals, pharmacologic probes, and molecular biology promise to reveal some of these mysteries in the future. The greater promise is that with this understanding, the ECS will yield an important therapeutic target for future pharmacologic therapy.

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Comprehensive Cannabis Course Topic I: The Endocannabinoid System and Phytocannabinoids

The Endocannabinoid System (ECS):

 

In order to fully appreciate the rationale for the clinical use of medical cannabis, it is essential that one has knowledge of the endocannabinoid system, an endogenous regulating system found in all vertebrates (1, 2).  It is also important to understand the clinical sequelae that might develop as a result of endocannabinoid system dysfunction.

 

It has been proposed that a properly functioning endogenous cannabinoid system is essential for good health and that certain disease types may be the result of deficiencies within this system (3). "Modulating the activity of the endocannabinoid system … hold[s] therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson's and Huntington's disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome and osteoporosis, to name just a few" (4).  In this introductory section, we will discuss the endocannabinoid system, Clinical Endocannabinoid Deficiency Syndrome and phytocannabinoids.

 

For more information, please review The Medical Use of Marijuana Course Table of Contents.

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Editors' Note:  Medical marijuana has become an important area of study in healthcare. Doctors and healthcare professionals must understand the medical, legal, social and political issues to best respond to their patients' questions and attend to their needs.  This content area is not intended to encourage or dissuade the use of medical marijuana, but has been created to provide a balanced portrayal of the research in this area.

Questions and Answers

What is the endocannabinoid system?

The endocannabinoid system (ECS) is an internal homeostatic regulatory system that influences multiple physiological processes, including the modulation of pain, seizure threshold, appetite, digestion, mood and other processes. The ECS may also play a role in regulation of the immune system, tumor surveillance, fertility, bone physiology, the hypothalamic-pituitary-adrenal axis and intraocular pressure (3).

This homeostatic system was only discovered within the last three decades and was referred to as the endocannabinoid system because it is an endogenous system whose components interact with or resemble a compound derived from the cannabis plant called delta-9-tetrahydrocannabinol or THC.

What is cannabis?  What are phytocannabinoids?

Cannabis is a genus of flowering plants that includes multiple subspecies.  One species is Cannabis sativa. Scientists have identified over 400 chemical compounds produced by the cannabis plant. Well over 80 of these compounds are unique to the cannabis plant, and they are called cannabinoids (or phytocannabinoids).  Examples of phytocannabinoids include delta-9-tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiol (CBD), cannabichromene (CBC), and cannabigerol (CBG).

THC and the analogues of THC that are derived from the cannabis plant and interact with endocannabinoid receptors or otherwise affect the endocannabinoid system are called phytocannabinoids. Phytocannabinoids have pharmacological activity due to their receptor-based effects on the endocannabinoid system. Additional pharmacological effects, such as anti-inflammatory mechanisms, may be non-receptor mediated.

What are the components of the endocannabinoid system?

The endocannabinoid system is comprised of three main components: endocannabinoids, receptors and regulatory enzymes.

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Endocannabinoids (also called endogenous cannabinoids)—These compounds are endogenous agonists of the receptors to which delta-9-tetrahydrocannabinol (THC) also binds. (This statement is key to understanding the significance of exogenous cannabis products.)

Two of the most well-studied endocannabinoids are derivatives of arachidonic acid:o N-arachidonoylethanolamine (also called anandamide or AEA)o 2-arachidonoylglycerol (2-AG)

Receptors – There are two well-known cannabinoid receptors: cannabinoid receptor-1 (CB1) and cannabinoid receptor-2 (CB2). In addition to the CB1 and CB2 receptors, some endocannabinoids and some phytocannabinoids bind to other receptors. For example, anandamide and cannabidiol (a compound derived from the cannabis plant) are partial agonists of the TRPV1 receptor (Transient receptor potential vanilloid type-1) (5). Also, evidence indicates that GPR55 is an endocannabinoid receptor and this receptor has been referred to as CB3. All four receptors are G-protein coupled receptors (GPCRs).

Regulatory enzymes – Some endogenous regulatory enzymes synthesize endocannabinoids, while others catabolize endocannabinoids. For example, fatty acid amidohydrolase (FAAH) is an enzyme that breaks down the endocannabinoid anandamide.

Describe the two most well-studied endocannabinoids.

Anandamide (AEA), an essential fatty acid neurotransmitter, was first isolated in 1992. It is a partial agonist of CB1 receptors; its affinity and efficacy at CB2 receptors are low (6). It is a partial agonist at TRPV1 receptors (5).

The existence of 2-AG in mammals was first described in 1994. It was later isolated from the canine gut in 1995 by Dr. Raphael Mechoulam and his colleagues. 2-AG is a fully efficacious agonist of both CB1 and CB2 receptors.

Both of these endocannabinoids are synthesized on demand, meaning that there is no evidence for their storage inside vesicles. When these endocannabinoids are produced, they travel in a retrograde fashion across a synapse to inhibit neurotransmitter release.

Describe cannabinoid receptor-1 (CB1).

The CB1 receptor is a G protein receptor that serves as a target for both endocannabinoids and phytocannabinoids (plant derived cannabinoids). It was only in 1990 that researchers mapped the locations of the CB1 receptors and determined that the CB1 receptor is very highly expressed throughout the brain. In humans, the CB1 receptor is 10 times more prevalent in the central nervous system as compared to the μ-opioid receptor (7). In the brain, CB1 receptors are located on presynaptic terminals and, when signaled, these receptors modulate neurotransmitter release (8). These receptors are the primary psychoactive cannabinoid receptors, and mediate numerous physiological processes, including cardiovascular function, energy homeostasis and reproduction, as well. The activation of CB1 receptors also effects cognition and memory, reward

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sensation and emotional behavior, sensory perception, motor control, pain modulation and other functions (8).

CB1 receptors are also found in non-neural tissue, including adipose, liver, pancreas, skeletal muscle and immune cells (9).

Describe cannabinoid receptor-2 (CB2).

Similar to CB1, CB2 is a G protein receptor that serves as a target for both endocannabinoids and phytocannabinoids (plant derived cannabinoids). These cannabinoid receptors are primarily immunomodulatory and anti-inflammatory (10). They are expressed on the cell membranes of B cells, T cells and macrophages. When signaled, CB2 receptors are generally inhibitory to immune cell activation, and proinflammatory cytokine production is inhibited. Expression of CB2 receptors is inducible and the number of receptors is increased by inflammation (11).  As found in studies conducted in mice, reduced CB2 receptor signaling results in increased severity of inflammation in multiple organs, including the brain (12) and the liver (13).

Additional information: Describe the enzymes that synthesize and catabolize the endocannabinoids.

The enzymes that modulate the levels of endocannabinoids are considered to be part of the endocannabinoid system.

The pathways controlling the production of anandamide (AEA) are not well understood. However, it is believed that anandamide is formed from membrane phospholipid precursors through the activation of phospholipase C followed by the activation of diacylglycerol lipase – alpha (14).

Anandamide is hydrolyzed by the enzyme fatty acid amide hydrolase (FAAH) into two breakdown products: arachidonic acid and ethanolamine. In preclinical mouse models, it has been found that inhibition of FAAH raises brain anandamide concentrations and reduces anxiety-like behaviors (15).

2-arachidonoylglycerol (2-AG) is synthesized from diacylglycerol through the actions of diacylglycerol lipase (16) and is hydrolyzed primarily by monoacylglycerol lipase (MAGL) into breakdown products arachidonic acid and glycerol, and to a lesser extent by members of the alpha beta hydrolase family (ABHD6, ABHD12) (17).

What other chemicals interact with the endocannabinoid signaling system?

The endocannabinoid signaling system interacts with phytocannabinoids (plant derived cannabinoids), synthetic cannabinoids, indirect agonists and antagonists.

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Have selective antagonists for both CB1 and CB2 receptors been developed?

Yes.  The most well studied CB1 receptor antagonists are rimonabant and AM251. Rimonabant was marketed in Europe for the treatment of obesity. It was withdrawn from the market because it produced significant adverse effects in some individuals, including depression and suicidal ideation (18). Several selective CB2 receptor antagonists have been developed for research purposes (SR144528 and AM630), but their clinical relevance needs to be studied.

Editors, Author, References

Editors:

Editor-in-Chief:

Meredith Fisher-Corn, MD

Founding Editor-in-Chief:

Stephen B. Corn, MD

Author(s):

Ethan Russo, MD

Sunil Aggarwal, MD

Cecilia J. Hillard, PhD

References:

1.  Rodriguez de Fonseca, F., del Arco, I, Bermudez-Silva, F. J., Bilbao, A. et al. The endocannabinoid system: physiology and pharmacology. Alcohol Alcohol, 2005; 40: 2-14.

2.  McPartland J. Phylogenomic and chemotaxonomic analysis of the endocannabinoid system. Brain Res Rev, 2003; 45: 18-29

3.  Russo E. Clinical endocannabinoid deficiency (CECD): Can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinology Letters 2003; 25: 31-39.H

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4.  Pacher et al. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacological Reviews 2006; 58: 389-462.

5.  Di Marzo V and De Petrocellis L. Endocannabinoids as regulators of transient receptor potential (TRP) channels: A further opportunity to develop new endocannabinoid-based therapeutic drugs. Curr Med Chem, 2010; 17(14): 1430-49.

6. Hillard CJ, Manna S, Greenberg MJ, DiCamelli R, Ross RA, Stevenson LA, Murphy V, Pertwee RG, and Campbell WB. Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). J Pharmacol Exp Ther, 1999; 289(3): 1427-33.

7. Burns HD, Van Laere K, Sanabria-Boho´ rquez S, et al. [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. Proc Natl Acad Sci USA. 2007;104:9800–9805.

8. Mackie K. Cannabinoid receptors: where they are and what they do. J Neuroendocrinol, 2008; 20 Suppl 1: 10-4.

9. Freund TF, Katona I, and Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev, 2003; 83(3): 1017-66.

10.  Pacher P, Kunos G. Modulating the endocannabinoid system in human health and disease--successes and failures. The FEBS journal 2013; 280:1918-43.

11.  Maresz K, Carrier EJ, Ponomarev ED, Hillard CJ, and Dittel BN. Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli. J Neurochem, 2005; 95(2): 437-45.

12.  Maresz K, Pryce G, Ponomarev ED, Marsicano G, Croxford JL, Shriver LP, Ledent C, Cheng X, Carrier EJ, Mann MK, Giovannoni G, Pertwee RG, Yamamura T, Buckley NE, Hillard CJ, Lutz B, Baker D, and Dittel BN. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat Med, 2007; 13(4): 492-7.

13.  Guillot A, Hamdaoui N, Bizy A, Zoltani K, Souktani R, Zafrani ES, Mallat A, Lotersztajn S, and Lafdil F. Cannabinoid receptor 2 counteracts interleukin-17-induced immune and fibrogenic responses in mouse liver. Hepatology, 2014; 59(1): 296-306.

14.  Russo EB, Hohmann AG.  Role of cannabinoids in pain management IN: Comprehensive Treatment of Chronic Pain by Medical, Interventional and Integrative Approaches, (Deer TR, et al, eds).  American Academy of Pain Medicine, Chapter 18, 2013:181-197

15.  Patel S and Hillard CJ. Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J Pharmacol Exp Ther, 2006; 318(1): 304-11.

16.  Hillard CJ. Biochemistry and pharmacology of the endocannabinoids arachidonoylethanolamide and 2-arachidonoylglycerol. Prostaglandins Other Lipid Mediat, 2000; 61(1-2): 3-18.

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17. Savinainen J, Saario SM, Laitinen JT. The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signaling through cannabinoid receptors. Acta Physiol (Oxf), 2012; 204(2): 267-76.

18. Christensen R, Kristensen PK, Bartels EM, Bliddal H, and Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet, 2007; 370(9600): 1706-13.

 

Suggested Reading

For a comprehensive review of the endocannabinoid system and its potential therapeutic effects , the reader is referred to:

Pacher et al. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacological Reviews 2006; 58: 389-462.

 

Related Articles

1. Ben-Shabat S, Fride E, Sheskin T, et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. European Journal of Pharmacology 1998;353:23-31.

2. Mechoulam R, Ben-Shabat S. From gan-zi-gun-nu to anandamide and 2-arachidonoylglycerol: The ongoing story of cannabis. Nat Prod Rep 1999;16:131-43.

3. Mackie K. Cannabinoid receptors: where they are and what they do. J Neuroendocrinol 2008; 20 Suppl 1: 10-4.

4. Freund TF, Katona I, and Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev, 2003; 83(3): 1017-66.

5. Bisogno T, Hanus L, De Petrocellis L, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 2001;134:845-52.

6. Pacher P, Kunos G. Modulating the endocannabinoid system in human health and disease--successes and failures. The FEBS journal 2013;280:1918-43.

7. Pacher P, Mechoulam R. Is lipid signaling through cannabinoid 2 receptors part of a protective system? Prog Lipid Res 2011.

8. Ben-Shabat, S., Fride, E., Sheskin, T., Tamiri, T. and others. (1998). An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur. J.Pharmacol. 353: 23-31.

9. Rodriguez de Fonseca, F., del Arco, I, Bermudez-Silva, F. J., Bilbao, A. and others. (2005). The endocannabinoid system: physiology and pharmacology. Alcohol Alcohol. 40: 2-14.

10. Pertwee, R. G. (2008). The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br.J.Pharmacol.

11. Howlett, A. C., Barth, F., Bonner, T. I., Cabral, G. and others. (2002). International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol.Rev. 54: 161-202.153: 199-215.

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12. Bisogno, T. (2008). Endogenous cannabinoids: structure and metabolism. J.Neuroendocrinol. 20 Suppl 1: 1-9.

13. Miller, L. K. and Devi, L. A. (2011). The highs and lows of cannabinoid receptor expression in disease: mechanisms and their therapeutic implications. Pharmacol.Rev. 63: 461-470.

14. Di Marzo, V, Bifulco, M., and De Petrocellis, L. (2004). The endocannabinoid system and its therapeutic exploitation. Nat.Rev.Drug Discov. 3: 771-784.

15. Elsohly, M. A. and Slade, D. (2005). Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci. 78: 539-548.

16. Huestis, M. A. (2007). Human cannabinoid pharmacokinetics. Chem.Biodivers. 4: 1770-1804.17. Ashton, C. H. (2001). Pharmacology and effects of cannabis: a brief review. Br.J.Psychiatry. 178:

101-106.18. Russo, E. B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid

entourage effects. Br. J. Pharmacol. 163: 1344-1364.

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