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Changing Medicine together
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~ The Endocannabiniod System ~
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~ How they found & verified the bodies Cannabiniod Receptors
& the different types ~
& the different types ~
A study using weakly radioactive THC-like synthetic drugs investigated where the human cannabinoid receptors were located. When people were given this radioactive drug and their brains were scanned, CB1 receptors were found all over the brain. The results showed that cannabinoid receptor binding sites in the human brain are localized mainly in: the forebrain areas associated with higher cognitive functions; the forebrain, midbrain and hindbrain areas associated with the control of movement; and in hindbrain areas associated with the control of motor and sensory functions of the autonomic nervous system. This is consistent with the fact that cannabis has many different effects on mental function.
General Overview
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Cannabis a Miracle Plant/Medicine
The endocannabinoid system (ECS) is a group of endogenous cannabinoid receptors located in the mammalian brain and throughout the central and peripheral nervous systems, consisting of neuromodulatory lipids and their receptors
Cannabis has been at the center of one of the most exciting—and underreported—developments in modern science. Research on marijuana’s effects led directly to the discovery of a hitherto unknown biochemical communication system in the human body, the Endocannabinoid System, which plays a crucial role in regulating our physiology, mood, and everyday experience.
The discovery of receptors in the brain that respond pharmacologically to cannabis—and the subsequent identification of endogenous cannabinoid compounds in our own bodies that bind to these receptors—has significantly advanced our understanding of human biology, health, and disease.
It is an established scientific fact that cannabinoids and other components of cannabis can modulate many physiological systems in the human brain and body. Cannabinoids are chemical compounds that trigger cannabinoid (and other) receptors. More than 100 cannabinoids have been identified in the marijuana plant. Of these marijuana molecules, tetrahydrocannabinol (THC) and cannabidiol (CBD) have been studied most extensively. In addition to cannabinoids produced by the plant, there are endogenous cannabinoids (such as anandamide and 2AG) that occur naturally in the mammalian brain and body, as well as synthetic cannabinoids created by pharmaceutical researchers.
Extensive preclinical research—much of it sponsored by the U.S. government—indicates that CBD has potent anti-tumoral, antioxidant, anti-spasmodic, anti-psychotic, anti-convulsive, and neuroprotective properties. CBD directly activates serotonin receptors, causing an anti-anxiety effect, as well.
“Cannabidiol offers hope of a non-toxic therapy that could treat aggressive forms of cancer without any of the painful side effects of chemotherapy,” says McAllister.In recent years, scientists associated with the International Cannabinoid Research Society (ICRS) have elucidated a number of molecular pathways through which CBD exerts a therapeutic impact. For example, a preclinical study by Dr. Sean McAllister and his colleagues at the California Pacific Medical Center in San Francisco report on how CBD destroys breast cancer cells by down-regulating a gene called ID-1, which is implicated in several types of aggressive cancer. Silencing the ID-1 gene is, thus, is a potential strategy for cancer treatment.
“Cannabidiol offers hope of a non-toxic therapy that could treat aggressive forms of cancer without any of the painful side effects of chemotherapy,” says McAllister.
Cannabis’ tumor-fighting propertiesThe images above are from an experiment by McAllister testing how CBD can stop the invasion of cancer cells in human cell lines. Compare the untreated breast cancer cells on the left to the breast cancer cells destroyed by CBD on the right. Photo credit: The California Pacific Medical Center
CBD and THC SynergyAccording to McAllister’s lab, the best results were obtained when CBD was administered along with THC. Several studies underscore the therapeutic advantages for combining CBD and THC—particularly for treating peripheral neuropathy, a painful condition associated with cancer, multiple sclerosis (MS), diabetes, arthritis, and other neurodegenerative ailments. Clinical research conducted by with GW Pharmaceuticals, a British company, has also shown that CBD is most effective as an analgesic when administered in combination with whole plant THC.
The discovery of receptors in the brain that respond pharmacologically to cannabis—and the subsequent identification of endogenous cannabinoid compounds in our own bodies that bind to these receptors—has significantly advanced our understanding of human biology, health, and disease.
It is an established scientific fact that cannabinoids and other components of cannabis can modulate many physiological systems in the human brain and body. Cannabinoids are chemical compounds that trigger cannabinoid (and other) receptors. More than 100 cannabinoids have been identified in the marijuana plant. Of these marijuana molecules, tetrahydrocannabinol (THC) and cannabidiol (CBD) have been studied most extensively. In addition to cannabinoids produced by the plant, there are endogenous cannabinoids (such as anandamide and 2AG) that occur naturally in the mammalian brain and body, as well as synthetic cannabinoids created by pharmaceutical researchers.
Extensive preclinical research—much of it sponsored by the U.S. government—indicates that CBD has potent anti-tumoral, antioxidant, anti-spasmodic, anti-psychotic, anti-convulsive, and neuroprotective properties. CBD directly activates serotonin receptors, causing an anti-anxiety effect, as well.
“Cannabidiol offers hope of a non-toxic therapy that could treat aggressive forms of cancer without any of the painful side effects of chemotherapy,” says McAllister.In recent years, scientists associated with the International Cannabinoid Research Society (ICRS) have elucidated a number of molecular pathways through which CBD exerts a therapeutic impact. For example, a preclinical study by Dr. Sean McAllister and his colleagues at the California Pacific Medical Center in San Francisco report on how CBD destroys breast cancer cells by down-regulating a gene called ID-1, which is implicated in several types of aggressive cancer. Silencing the ID-1 gene is, thus, is a potential strategy for cancer treatment.
“Cannabidiol offers hope of a non-toxic therapy that could treat aggressive forms of cancer without any of the painful side effects of chemotherapy,” says McAllister.
Cannabis’ tumor-fighting propertiesThe images above are from an experiment by McAllister testing how CBD can stop the invasion of cancer cells in human cell lines. Compare the untreated breast cancer cells on the left to the breast cancer cells destroyed by CBD on the right. Photo credit: The California Pacific Medical Center
CBD and THC SynergyAccording to McAllister’s lab, the best results were obtained when CBD was administered along with THC. Several studies underscore the therapeutic advantages for combining CBD and THC—particularly for treating peripheral neuropathy, a painful condition associated with cancer, multiple sclerosis (MS), diabetes, arthritis, and other neurodegenerative ailments. Clinical research conducted by with GW Pharmaceuticals, a British company, has also shown that CBD is most effective as an analgesic when administered in combination with whole plant THC.
The Endocannabinoid System
A description of the lipid signaling system essential to health, healing, and homeostasis, long excluded from the medical school curriculum
A description of the lipid signaling system essential to health, healing, and homeostasis, long excluded from the medical school curriculum
Introduction
You may be wondering why, as a clinician, you’ve never learned about the endocannabinoid system (ECS) during any of your training. The discovery of this system is relatively new, but it’s been around for 20 years, and a huge body of evidence and peer-reviewed research has been published on various aspects of the endocannabinoid system. There are two different cannabinoid receptors, the CB1 and the CB2, which are very similar in structure. They follow the classic pattern of the G protein-coupled receptor with seven passes through the cell membrane. Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system, which is involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory.[1]
Cannabinoid receptors are of a class of cell membrane receptors in the G protein-coupled receptor superfamily.[2][3][4] As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains.[5] Cannabinoid receptors are activated by three major groups of ligands: endocannabinoids, produced by the mammillary body; plant cannabinoids (such as cannabidiol, produced by the cannabis plant); and synthetic cannabinoids (such as HU-210). All of the endocannabinoids and plant cannabinoids are lipophilic, such as fat soluble compounds.
You may be wondering why, as a clinician, you’ve never learned about the endocannabinoid system (ECS) during any of your training. The discovery of this system is relatively new, but it’s been around for 20 years, and a huge body of evidence and peer-reviewed research has been published on various aspects of the endocannabinoid system. There are two different cannabinoid receptors, the CB1 and the CB2, which are very similar in structure. They follow the classic pattern of the G protein-coupled receptor with seven passes through the cell membrane. Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system, which is involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory.[1]
Cannabinoid receptors are of a class of cell membrane receptors in the G protein-coupled receptor superfamily.[2][3][4] As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains.[5] Cannabinoid receptors are activated by three major groups of ligands: endocannabinoids, produced by the mammillary body; plant cannabinoids (such as cannabidiol, produced by the cannabis plant); and synthetic cannabinoids (such as HU-210). All of the endocannabinoids and plant cannabinoids are lipophilic, such as fat soluble compounds.
There are currently two known subtypes of cannabinoid receptors, termed CB1 and CB2.[6][7] The CB1 receptor is expressed mainly in the brain (central nervous system or "CNS"), but also in the lungs, liver and kidneys. The CB2 receptor is expressed mainly in the immune system and in hematopoietic cells.[8] Mounting evidence suggests that there are novel cannabinoid receptors[9] that is, non-CB1 and non-CB2, which are expressed in endothelial cells and in the CNS. In 2007, the binding of several cannabinoids to the G protein-coupled receptor GPR55 in the brain was described.[10]
The protein sequences of CB1 and CB2 receptors are about 44% similar.[11][12] When only the transmembrane regions of the receptors are considered, amino acid similarity between the two receptor subtypes is approximately 68%.[5] In addition, minor variations in each receptor have been identified. Cannabinoids bind reversibly and stereo-selectively to the cannabinoid receptors. Subtype selective cannabinoids have been developed which theoretically may have advantages for treatment of certain diseases such as obesity.[13]
CB1 receptors are located primarily in the nervous system, but also found in reproductive tissues, connective tissues, adipose tissues, and other glands and organs. The CB2 receptors are found primarily in cells of the immune system, but during situations of injury or inflammation, the CB2 receptors can also be created and up-regulated in other tissues where they’re not normally found. The cannabinoid system is extremely old. Phylogenetic studies suggest the cannabinoid receptors evolved some 600 million years ago. Insects don’t have any cannabinoid receptors. Very primitive animals like sea squirts and nematodes have a cannabinoid receptor that’s almost identical to the human CB1 receptor. This high level of evolutionary conservation suggests that this receptor and receptor system is very important for the function of life. G protein receptors G protein-coupled receptors can open or close the ion channels and they can inhibit or stimulate the formation of adenylate cyclase, which will have other downstream effects in the cell. “Agonist trafficking” means that the function of the cannabinoid receptor depends on which agonist actually activates that receptor, which adds another layer of com
The protein sequences of CB1 and CB2 receptors are about 44% similar.[11][12] When only the transmembrane regions of the receptors are considered, amino acid similarity between the two receptor subtypes is approximately 68%.[5] In addition, minor variations in each receptor have been identified. Cannabinoids bind reversibly and stereo-selectively to the cannabinoid receptors. Subtype selective cannabinoids have been developed which theoretically may have advantages for treatment of certain diseases such as obesity.[13]
CB1 receptors are located primarily in the nervous system, but also found in reproductive tissues, connective tissues, adipose tissues, and other glands and organs. The CB2 receptors are found primarily in cells of the immune system, but during situations of injury or inflammation, the CB2 receptors can also be created and up-regulated in other tissues where they’re not normally found. The cannabinoid system is extremely old. Phylogenetic studies suggest the cannabinoid receptors evolved some 600 million years ago. Insects don’t have any cannabinoid receptors. Very primitive animals like sea squirts and nematodes have a cannabinoid receptor that’s almost identical to the human CB1 receptor. This high level of evolutionary conservation suggests that this receptor and receptor system is very important for the function of life. G protein receptors G protein-coupled receptors can open or close the ion channels and they can inhibit or stimulate the formation of adenylate cyclase, which will have other downstream effects in the cell. “Agonist trafficking” means that the function of the cannabinoid receptor depends on which agonist actually activates that receptor, which adds another layer of com
plexity to the ECS. This is analogous to an assortment of keys opening the same lock. But depending on which key is used, the door will open into different rooms. CB1 receptors are distributed throughout the central nervous system, with highest densities shown in red. CB2 receptors are found throughout the periphery, with especially high density in the liver.
CB 1 Receptors
Cannabinoid receptor type 1 (CB1) receptors are thought to be one of the most widely expressed Gαi protein-coupled receptors in the brain. This is due to endocannabinoid-mediated depolarization-induced suppression of inhibition, a very common form of retrograde signaling, in which the depolarization of a single neuron induces a reduction in GABA-mediated neurotransmission. Endocannabinoids released from the depolarized post-synaptic neuron bind to CB1 receptors in the pre-synaptic neuron and cause a reduction in GABA release due to limited presynaptic calcium ions entry.[medical citation needed]
They are also found in other parts of the body. For instance, in the liver, activation of the CB1 receptor is known to increase de novo lipogenesis.[15]
A 2004 study suggested that the endocannabinoids and their cannabinoid receptors play a major role during pre- and postnatal development.[16][17] In another recent study a group of researchers combined stochastic optical reconstruction microscopy (STORM) and patch clamp in order to see CB1 distribution on a nano scale with incredible resolution.[18][19]
They are also found in other parts of the body. For instance, in the liver, activation of the CB1 receptor is known to increase de novo lipogenesis.[15]
A 2004 study suggested that the endocannabinoids and their cannabinoid receptors play a major role during pre- and postnatal development.[16][17] In another recent study a group of researchers combined stochastic optical reconstruction microscopy (STORM) and patch clamp in order to see CB1 distribution on a nano scale with incredible resolution.[18][19]
CB 2 Receptors
CB2 receptors are mainly expressed on T cells of the immune system, on macrophages and B cells, and in hematopoietic cells. They also have a function in keratinocytes. They are also expressed on peripheral nerve terminals. These receptors play a role in antinociception, or the relief of pain. In the brain, they are mainly expressed by microglial cells, where their role remains unclear. While the most likely cellular targets and executors of the CB2 receptor-mediated effects of endocannabinoids or synthetic agonists are the immune and immune-derived cells (e.g. leukocytes, various populations of T and B lymphocytes, monocytes/macrophages, dendritic cells, mast cells, microglia in the brain, Kupffer cells in the liver, astrocytes, etc.), the number of other potential cellular targets is expanding, now including endothelial and smooth muscle cells, fibroblasts of various origins, cardiomyocytes, and certain neuronal elements of the peripheral or central nervous systems.[8]
Other Cannabinoids Receptors
Endogenous Cannabinoids and Their Targets
The endogenous (endo-) cannabinoids are molecules our bodies make to interact with the cannabinoid receptors. The two most well-known are anandamide and 2-arachidonoyl glycerol (2-AG). Anandamide is named after the Sanskrit word ananda, which means bliss. The endocannabinoids are arachidonic acid derivatives synthesized on demand from precursors in the cell membrane.
Endogenous Cannabinoids and Their Targets
The endogenous (endo-) cannabinoids are molecules our bodies make to interact with the cannabinoid receptors. The two most well-known are anandamide and 2-arachidonoyl glycerol (2-AG). Anandamide is named after the Sanskrit word ananda, which means bliss. The endocannabinoids are arachidonic acid derivatives synthesized on demand from precursors in the cell membrane.
- They act as “retrograde messengers.”
- Elsewhere in the body these endocannabinoids function as autocrine (within cells) and paracrine (cell-to-cell) mediators. When the endocannabinoids have finished their signaling role, they’re degraded by enzyme hydrolysis; FAAH (fatty acid amide hydrolase) degrades anandamide and MAGL(monoaglycerol lipase) degrades 2-AG. Several other endogenous cannabinoids, less well understood than anandamide and 2-AG, play a significant role in the function of the endocannabinoid system. The endocannabinoids also have other targets in the body besides the CB1 and CB2 receptors.
- For example, G-protein receptor 55 (or GPR55) some are categorized as the CB3 receptor, is a post-synaptic membrane receptor involved in hyperalgesia and endocannabinoid production. Stimulating this receptor likely signals the cell to cease the production of endocannabinoids.
- The Vanilloid TRPV1 receptor (also know as the capsaicin receptor) is another target of endocannabinoids. It has implications in pain, inflammation, respiratory, and cardiovascular disorders.
- Peroxisome proliferator-activated receptors (or PPARs) are nuclear membrane receptors located inside the cell that are also targets of endocannabinoids. They regulate the translation of genes that are involved in metabolism, energy homeostasis, cell differentiation, and inflammation. PPAR agonists tend to have anti-inflammatory, cardioprotective, and neuro-protective properties.
- N-arachidonoyl glycine (NAGly) receptor GPR18 is the molecular identity of the abnormal cannabidiol receptor and additionally suggests that NAGly, the endogenous lipid metabolite of anandamide (also known as arachidonoylethanolamide or AEA), initiates directed microglial migration in the CNS through activation of GPR18.[22]
- Furthermore, endocannabinoids can control voltagegated ion channels and ligand-gated ion channels.
- GPR119 has been suggested as a fifth possible cannabinoid receptor.[26]
Signaling
Cannabinoid receptors are activated by cannabinoids, generated naturally inside the body (endocannabinoids) or introduced into the body as cannabis or a related synthetic compound.[11]
After the receptor is engaged, multiple intracellular signal transduction pathways are activated. At first, it was thought that cannabinoid receptors mainly inhibited the enzyme adenylate cyclase (and thereby the production of the second messenger molecule cyclic AMP), and positively influenced inwardly rectifying potassium channels (=Kir or IRK).[27] However, a much more complex picture has appeared in different cell types, implicating other potassium ion channels, calcium channels, protein kinase A and C, Raf-1, ERK, JNK, p38, c-fos, c-jun and many more.[27]
Separation between the therapeutically undesirable psychotropic effects, and the clinically desirable ones, however, has not been reported with agonists that bind to cannabinoid receptors. THC, as well as the two major endogenous compounds identified so far that bind to the cannabinoid receptors --anandamide and 2-arachidonylglycerol (2-AG)— produce most of their effects by binding to both the CB1 and CB2 cannabinoid receptors. While the effects mediated by CB1, mostly in the central nervous system, have been thoroughly investigated, those mediated by CB2 are not equally well defined.
After the receptor is engaged, multiple intracellular signal transduction pathways are activated. At first, it was thought that cannabinoid receptors mainly inhibited the enzyme adenylate cyclase (and thereby the production of the second messenger molecule cyclic AMP), and positively influenced inwardly rectifying potassium channels (=Kir or IRK).[27] However, a much more complex picture has appeared in different cell types, implicating other potassium ion channels, calcium channels, protein kinase A and C, Raf-1, ERK, JNK, p38, c-fos, c-jun and many more.[27]
Separation between the therapeutically undesirable psychotropic effects, and the clinically desirable ones, however, has not been reported with agonists that bind to cannabinoid receptors. THC, as well as the two major endogenous compounds identified so far that bind to the cannabinoid receptors --anandamide and 2-arachidonylglycerol (2-AG)— produce most of their effects by binding to both the CB1 and CB2 cannabinoid receptors. While the effects mediated by CB1, mostly in the central nervous system, have been thoroughly investigated, those mediated by CB2 are not equally well defined.
Cannabinoid function in the nervous system
Why you can't have a lethal overdose!
The CB1 receptor is the most common G-protein receptor found in the human brain. The highest densities of CB1 are found in the hippocampus, the cerebral cortex, the cerebellum, the amygdala nucleus, and the basal ganglia —areas of the brain involved with short-term memory, cognition, mood and emotion, motor function, and nociception. Ironically, Cannabinoid receptors are virtually absent in brainstem cardiorespiratory centers. This is why that there is no lethal overdose of cannabinoids.
Why you can't have a lethal overdose!
The CB1 receptor is the most common G-protein receptor found in the human brain. The highest densities of CB1 are found in the hippocampus, the cerebral cortex, the cerebellum, the amygdala nucleus, and the basal ganglia —areas of the brain involved with short-term memory, cognition, mood and emotion, motor function, and nociception. Ironically, Cannabinoid receptors are virtually absent in brainstem cardiorespiratory centers. This is why that there is no lethal overdose of cannabinoids.
Upon nerve depolarization, these neurotransmitters are released, and they move across the synapse to stimulate a receptor on the post-synaptic cell. Cannabinoids follow the opposite path. They’re produced on the cell membrane of the post-synaptic cell and travel retrograde across the synapse to interact with the CB1 receptor on the pre-synaptic nerve terminal.
Looking at the function of retrograde signaling in a little more depth,
beginning with depolarization-induced suppression of excitation. In the illustrations at right we see an excitatory glutamatergic nerve releasing its glutamate neurotransmitter into the synapse. This occurs after an action potential arrives at the accent terminal and opens voltage-gated calcium channels. The glutamate diffuses across the synapse to interact with receptors in the post-synaptic cell. Cannabinoids are produced in the post synaptic membrane and act on the presynaptic cell to halt this excitatory process. The same model applies to inhibitory GABAnergic neurons. In the study one can see 2-AG diffusing retrosynaptically to a presynaptic CB1 receptor, closing calcium channels and preventing the release of GABA into the synapse. This is called depolarization-induced suppression of inhibition.
Looking at the function of retrograde signaling in a little more depth,
beginning with depolarization-induced suppression of excitation. In the illustrations at right we see an excitatory glutamatergic nerve releasing its glutamate neurotransmitter into the synapse. This occurs after an action potential arrives at the accent terminal and opens voltage-gated calcium channels. The glutamate diffuses across the synapse to interact with receptors in the post-synaptic cell. Cannabinoids are produced in the post synaptic membrane and act on the presynaptic cell to halt this excitatory process. The same model applies to inhibitory GABAnergic neurons. In the study one can see 2-AG diffusing retrosynaptically to a presynaptic CB1 receptor, closing calcium channels and preventing the release of GABA into the synapse. This is called depolarization-induced suppression of inhibition.
Neuroplasticity - Nervous System
The function of the endocannabinoid system in the nervous system is more than just homeostatic prevention of too much excitation or too much inhibition. There is a significant protective and repair function, and the endocannabinoid system is heavily involved in neuroplasticity.
Neuroplasticity involves the sprouting and pruning of synapses, changes in dendritic spine density, and changes in neurotransmitter pathways. It gives rise to all types of adaptive learning, including recovering from a stroke, the conscious act of gaining a new skill, and the unconscious acquisition of a new emotional response. It is also involved in pathological processes such as central sensitization to pain. There are multiple mechanisms by which cannabinoids modulate neural plasticity, including neurogenesis (the formation of new neurons), aiding in long-term potentiation and long-term depression. Research in humans has shown that the administration of exogenous cannabinoids can cause neuroplastic changes. One study that looked at volunteers who were heavy cannabis users found neuroplastic changes in the nucleus accumbens and amygdala. These are two areas of the brain that are involved in the enjoyment of activities such as eating and sex, and also involved in addiction. Other studies have shown that cannabinoids can enhance a process called fear extinction. Fear extinction is a neuroplastic event that’s essential for preventing and recovering from post-traumatic stress. Anandamide and 2-AG are also endogenous neuroprotective agents, produced by the nervous system in response to both chemical and mechanical trauma. Other phytocannabinoids and synthetic cannabinoids have been shown to decrease glutamate excitotoxicity in a situation of a seizure or a stroke. When neurons become injured or ill, they tend to release their contents. Excitatory neurons release levels of glutamate that become toxic to the surrounding cells, and we see a domino effect of excitotoxicity. Cannabinoids have been shown to halt that process. The United States Department of Health and Human Services actually owns a patent on the use of cannabinoids as anti-oxidants and neuroprotectants. The authors of this patent discuss the potential benefit of using cannabinoids in neurodegenerative conditions such as multiple sclerosis, Alzheimer’s, Parkinson’s, Huntington’s, and more. Cannabinoids also affect autonomic tone. In the sympathetic nervous system, CB1 receptor stimulation will inhibit noroepinephrine release. It will dampen sympathetically mediated pain and modulate the hypothalamic- pituitary-adrenal axis and the hypothalamic locus coerulius-norepinephrine axis.
The function of the endocannabinoid system in the nervous system is more than just homeostatic prevention of too much excitation or too much inhibition. There is a significant protective and repair function, and the endocannabinoid system is heavily involved in neuroplasticity.
Neuroplasticity involves the sprouting and pruning of synapses, changes in dendritic spine density, and changes in neurotransmitter pathways. It gives rise to all types of adaptive learning, including recovering from a stroke, the conscious act of gaining a new skill, and the unconscious acquisition of a new emotional response. It is also involved in pathological processes such as central sensitization to pain. There are multiple mechanisms by which cannabinoids modulate neural plasticity, including neurogenesis (the formation of new neurons), aiding in long-term potentiation and long-term depression. Research in humans has shown that the administration of exogenous cannabinoids can cause neuroplastic changes. One study that looked at volunteers who were heavy cannabis users found neuroplastic changes in the nucleus accumbens and amygdala. These are two areas of the brain that are involved in the enjoyment of activities such as eating and sex, and also involved in addiction. Other studies have shown that cannabinoids can enhance a process called fear extinction. Fear extinction is a neuroplastic event that’s essential for preventing and recovering from post-traumatic stress. Anandamide and 2-AG are also endogenous neuroprotective agents, produced by the nervous system in response to both chemical and mechanical trauma. Other phytocannabinoids and synthetic cannabinoids have been shown to decrease glutamate excitotoxicity in a situation of a seizure or a stroke. When neurons become injured or ill, they tend to release their contents. Excitatory neurons release levels of glutamate that become toxic to the surrounding cells, and we see a domino effect of excitotoxicity. Cannabinoids have been shown to halt that process. The United States Department of Health and Human Services actually owns a patent on the use of cannabinoids as anti-oxidants and neuroprotectants. The authors of this patent discuss the potential benefit of using cannabinoids in neurodegenerative conditions such as multiple sclerosis, Alzheimer’s, Parkinson’s, Huntington’s, and more. Cannabinoids also affect autonomic tone. In the sympathetic nervous system, CB1 receptor stimulation will inhibit noroepinephrine release. It will dampen sympathetically mediated pain and modulate the hypothalamic- pituitary-adrenal axis and the hypothalamic locus coerulius-norepinephrine axis.
Depending on the situation, stimulation of the CB1 receptors could increase or decrease heart rate and contractility.
Heart - Nervous System & EC System
Cannabioid receptors also have peripheral activities that affect autonomic tone: For example, myocardial CB1 receptors, when activated, cause vagally mediated biphasic effects in heart rate and cardiac contractility. Depending on the situation, stimulation of the CB1 receptors could increase or decrease heart rate and contractility. In vascular tissues CB1 activation causes vasodilation, which leads to an anti-hypertensive effect that has been demonstrated in humans. Some rodent studies suggest that cannabinoid receptor activation has a protective role in myocardial ischemia.
The Parasympathetic Nervous System
The parasympathetic nervous system also has CB1 receptors, which will reduce parasympathetic activity when stimulated. And this is likely providing the anti-emetic effect of cannabinoids.
Cannabioid receptors also have peripheral activities that affect autonomic tone: For example, myocardial CB1 receptors, when activated, cause vagally mediated biphasic effects in heart rate and cardiac contractility. Depending on the situation, stimulation of the CB1 receptors could increase or decrease heart rate and contractility. In vascular tissues CB1 activation causes vasodilation, which leads to an anti-hypertensive effect that has been demonstrated in humans. Some rodent studies suggest that cannabinoid receptor activation has a protective role in myocardial ischemia.
The Parasympathetic Nervous System
The parasympathetic nervous system also has CB1 receptors, which will reduce parasympathetic activity when stimulated. And this is likely providing the anti-emetic effect of cannabinoids.
Pain signaling - Nervous System
The endocannabinoid system is heavily involved in pain signaling. Pre-clinical models have shown that endocannabinoid activation causes antinociceptive effects in the three major types of pain: acute pain, persistent inflammatory pain, and neuropathic pain. The antinociceptive effects of cannabinoids involve many mechanisms in different parts of the body, including the central nervous system’s periaqueductal gray, ventroposterior lateral nucleus of the thalamus, and rostral ventromedial medulla), as well as the spinal cord, the peripheral nervous system, and the peripheral tissues. One mechanism by which cannabinoids are able to decrease nociception and decrease the perception of pain involves the descending pain inhibitory pathway depicted below. This pathway has components in the mid-brain, the medulla, and the spinal cord that decrease the nociceptive signals that make it to pain areas in the brain. In the dorsal horn of the spinal cord there are inhibitory interneurons that release GABA and actually suppress this descending pain inhibitory pathway. Cannabinoids will suppress these GABA-releasing interneurons, thus enabling the descending pain pathway to do its work in decreasing the amount of pain experienced. Cannabinoids also decrease pain associated with injury via the homeostasis of activators and sensitizers. When we experience an injury, activators and sensitizers cause peripheral sensitization including hyperalgesia and eventually allodynia. These activators and sensitizers come from a variety of sources including the damaged tissue itself, the leukocytes, leukocyte-activated platelets, the neighboring autonomic nerves, and the nociceptive nerves themselves. All can release activators and sensitizers, leading to peripheral sensitization, which elicits a homeostatic response by the endocannabinoid system. As peripheral sensitization begins after an injury, the function of the endocannabinoid system provides the first line of defense against pain. CB1 receptors will decrease the release of activators and sensitizers around the site of the tissue injury. CB1 receptors on the nociceptor will also open potassium channels and cause the nociceptor to hyperpolarize, making it less likely to fire. At the same time, CB2 receptor signaling decreases the release of activators and sensitizers from the neighboring immune cells. As noted, CB2 receptors are found not only in immune cells but also in other tissues, especially during situations of injury. CB2 receptors have been found, for example, in painful neuromas. And CB2 agonists produce anti-nociceptive effects in pre-clinical models of inflammatory and nociceptive pain.
The endocannabinoid system is heavily involved in pain signaling. Pre-clinical models have shown that endocannabinoid activation causes antinociceptive effects in the three major types of pain: acute pain, persistent inflammatory pain, and neuropathic pain. The antinociceptive effects of cannabinoids involve many mechanisms in different parts of the body, including the central nervous system’s periaqueductal gray, ventroposterior lateral nucleus of the thalamus, and rostral ventromedial medulla), as well as the spinal cord, the peripheral nervous system, and the peripheral tissues. One mechanism by which cannabinoids are able to decrease nociception and decrease the perception of pain involves the descending pain inhibitory pathway depicted below. This pathway has components in the mid-brain, the medulla, and the spinal cord that decrease the nociceptive signals that make it to pain areas in the brain. In the dorsal horn of the spinal cord there are inhibitory interneurons that release GABA and actually suppress this descending pain inhibitory pathway. Cannabinoids will suppress these GABA-releasing interneurons, thus enabling the descending pain pathway to do its work in decreasing the amount of pain experienced. Cannabinoids also decrease pain associated with injury via the homeostasis of activators and sensitizers. When we experience an injury, activators and sensitizers cause peripheral sensitization including hyperalgesia and eventually allodynia. These activators and sensitizers come from a variety of sources including the damaged tissue itself, the leukocytes, leukocyte-activated platelets, the neighboring autonomic nerves, and the nociceptive nerves themselves. All can release activators and sensitizers, leading to peripheral sensitization, which elicits a homeostatic response by the endocannabinoid system. As peripheral sensitization begins after an injury, the function of the endocannabinoid system provides the first line of defense against pain. CB1 receptors will decrease the release of activators and sensitizers around the site of the tissue injury. CB1 receptors on the nociceptor will also open potassium channels and cause the nociceptor to hyperpolarize, making it less likely to fire. At the same time, CB2 receptor signaling decreases the release of activators and sensitizers from the neighboring immune cells. As noted, CB2 receptors are found not only in immune cells but also in other tissues, especially during situations of injury. CB2 receptors have been found, for example, in painful neuromas. And CB2 agonists produce anti-nociceptive effects in pre-clinical models of inflammatory and nociceptive pain.
Cannabinoid-opioid interaction
Opioids and cannabinoids share several pharmacologic effects including antinociception. In animal studies, the crosstalk between these two signaling pathways has shown promise for combination pain therapy and novel treatments for opioid addiction and abuse. The spinal administration of various cannabinoids with morphine produces a greater-than-additive anti-nociceptive effect in mice. The “tail-flick test” enables researchers to assess pain levels. The rodent is positioned with its tail on a hot plate and the heat is gradually increased until the animal feels the pain and flicks its tail. Various doses of morphine can be given to rodents to plot the dose response curve of antinociception in the tail flick test. When very low doses of THC —doses that are marginally active in a tail-flick test— are added to morphine, the dose response curve of morphine shifts to the left by four-to-12-fold. The same is true in the opposite experiment. When low doses of morphine are added to the THC trial, we see the dose response curve shifting to the left again. This points to an analgesic synergy beyond just the additive effects of morphine plus THC.
Opioids and cannabinoids share several pharmacologic effects including antinociception. In animal studies, the crosstalk between these two signaling pathways has shown promise for combination pain therapy and novel treatments for opioid addiction and abuse. The spinal administration of various cannabinoids with morphine produces a greater-than-additive anti-nociceptive effect in mice. The “tail-flick test” enables researchers to assess pain levels. The rodent is positioned with its tail on a hot plate and the heat is gradually increased until the animal feels the pain and flicks its tail. Various doses of morphine can be given to rodents to plot the dose response curve of antinociception in the tail flick test. When very low doses of THC —doses that are marginally active in a tail-flick test— are added to morphine, the dose response curve of morphine shifts to the left by four-to-12-fold. The same is true in the opposite experiment. When low doses of morphine are added to the THC trial, we see the dose response curve shifting to the left again. This points to an analgesic synergy beyond just the additive effects of morphine plus THC.
Adding cannabinoids to opioids will potentiate analgesia but will not increase the risk of cardio-respiratory suppression or fatal overdose.
THC has also been shown to trigger the release of endogenous opioids, which stimulate both the delta and kappa opioid receptors. Combination treatment with cannabinoids and opioids is surprisingly safe. The cannabinoid and opioid receptors are both found in areas of the brain and spinal cord that control pain signaling. But because the cannabinoid receptors have such low densities in the brainstem’s cardio-respiratory center, adding cannabinoids to opioids will potentiate the analgesia but will not increase the risk of cardiorespiratory suppression or fatal overdose. Therefore, combination therapy actually increases the therapeutic index of opioids. We all know that, clinically, treating chronic pain with opioids is a major problem due to tolerance building and the need for dose escalation. Cannabinoids, when co-administered with opioids, can prevent tolerance building to the opioids. Opioid receptor proteins are upregulated in the spinal cord of animals treated with both cannabinoids and opioids. Mice treated with low doses of THC and morphine in combination showed avoidance of tolerance to the opioids while retaining their anti-nociceptive effects. CB1 and MU opioid receptors are also co-localized in the areas of the brain that are important for morphine abstinence, such as the nucleus accumbens.
Cannabinoids & Bone Growth
Endocannabinoids and connective tissue In bone, both osteoblasts and osteoclast produce anandamide and 2-AG, and both express the CB2 receptor. Stimulation of this receptor leads to decreased osteoclast activity and increased osteoblast activity, thus increasing bone formation. There are CB1 receptors on the sympathetic nerve terminals close to the osteoblasts. These nerves release norepinephrine, which restrains bone formation. Retrograde CB1 signaling will inhibit the release of the norepinephrine and alleviate this tonic sympathetic restraint, thus allowing bone to form. Cells in other connective tissues —fibroblasts, myofibroblasts, chondrocytes, and synoviocytes— express both CB1 and CB2 receptors, and the enzymes used to metabolize endocannabinoids. CB1 receptors have been found to be upregulated after exposure to inflammatory cytokines and equiaxial stretching of fibroblasts in models of stress. Cannabinoids also modulate fascia remodeling via fibroblast focal adhesions. Cannabinoids have been shown to prevent cartilage destruction by inhibiting chondrocyte expression of cytokines and metalloproteinase enzymes. Cannabinoids have also been shown to decrease connective tissue inflammation. Animal models of atherosclerosis demonstrate that CB2 receptor activation on macrophages within atherosclerotic plaques can decrease atherosclerosis
Immune System
ECBs in the immune system. In contrast to the drug war propaganda that cannabinoids are immunosuppressive, researchers have found that cannabinoids modulate the immune system, just as they modulate other bodily systems. The Immune system has a majority of CB 2 receptors on which it seems to utilize, although that's not to say that it does not utilize the CB 1 receptors as there about a 80/20 ratio. Cannabinoids have been shown to decrease Th1 cytokine levels, increase the levels of Th2 cytokines, and increase certain subsets of B, T, and NK (natural killer) cells. Phytocannabinoids also have other immune-mediating mechanisms that are separate from cannabinoid receptors. For example, THCa, the acidic form of THC, can inhibit the release of tumor necrosis factor-alpha from macrophages. finding are also showing the Immune System will send CB receptors or (signals for the cells to produce receptors) to areas of need, injury, inflammation or the need for homeostasis.
Neoplasm - Cellular
As clinicians, when we think of cannabinoids and cancer, we tend to think of the management of cancer symptoms and the side effects of chemotherapy. Many clinicians are surprised to discover that cannabinoids also have direct oncologic effects.
As clinicians, when we think of cannabinoids and cancer, we tend to think of the management of cancer symptoms and the side effects of chemotherapy. Many clinicians are surprised to discover that cannabinoids also have direct oncologic effects.
The animals treated with cannabinoids tend to have much slower growing tumors than the animals treated with a control vehicle.
Cannabinoids have been shown to inhibit tumor growth in multiple cell lines. This is a hot area of research. Numerous human cancer cells lines have been xenografted to immunosuppressed rodents and treated with cannabinoids. The animals treated with cannabinoids tend to have much slower growing tumors than the animals treated with a control vehicle. Cannabinoids affect neoplasm via multiple mechanisms of action, including cytostatis, apoptotis, antiangiogenesis, and antimetastesis. Cannabinoids are selective anti-tumor compounds that can kill cancer cells without injuring healthy cells at the same dosage. This makes cannabinoids much less toxic than traditional chemotherapy agents. Cannabinoids in embryology Cannabinoids are also heavily involved in embryology and cell growth and differentiation. CB1 receptors have been detected in mouse embryos as early as the second day of gestation. Blastocyst implantation into the endometrium, which is thought of as the first suckling function, requires suitable levels of anandamide. The proliferation and differentiation of neural stem cells are shaped by extracellular cues provided by endocannabinoids. Adult neurogenesis is regulated by many of these same embryonic endocannabinoid mechanisms.
Digestive
Endocannabinoids in the Gastrointestinal System
In the digestive system, CB2 receptors are found in the lamina propria, the plasma cells, activated macrophages, and in the myenteric and submucosal plexus ganglia in the human ilium. CB2 receptor signaling likely involves the inhibition of inflammation, visceral pain, and intestinal motility in the inflamed gut.
In the digestive system, CB2 receptors are found in the lamina propria, the plasma cells, activated macrophages, and in the myenteric and submucosal plexus ganglia in the human ilium. CB2 receptor signaling likely involves the inhibition of inflammation, visceral pain, and intestinal motility in the inflamed gut.
Liver
The Endocannabinoid System In The Liver
The liver expresses both CB1 and CB2 receptors at low levels. The CB1 receptors are mostly found in endothelial cells and hepatocytes, and the CB2 receptors are mostly found in Kupffer cells. Anandamide and 2-AG are present at substantial levels in the liver, along with the enzymes needed to break down Anandamide & 2-AG the endocannabinoids. Liver injury is associated with an increased endocannabinoid tone in several pathologic settings. During injury or inflammation, CB1 receptors are induced in hepatocytes, hepatic myofibroblasts, and endothelial cells. CB2 receptors are induced in Kupffer cells as well as the hepatic myofibroblasts. Levels of 2-AG also increase in hepatic stellate cells and hepatocytes during liver injury. The Kupffer cells are involved in our response to early liver injury via the production of tumor necrosis factoralpha. This signals the stellate cells to synthesize collagen and cause fibrosis. Fibrosis will eventually lead to cirrhosis or loss of liver function.
As we can expect from a signaling system that has homeostatic properties, the cannabinoid system can both increase and decrease liver fibrosis via different mechanisms of CB1 and CB2. It’s been shown that stimulation of the CB1 receptor can enhance fibrogenesis, while stimulation of the CB2 receptor counteracts the progression of fibrosis. It’s important to note that effective antifibrotic treatments are not available in humans yet. And numerous efforts are being directed at the development of liver-specific antifibrotic therapies to treat liver disease and prevent cirrhosis. CB1 and CB2 receptors have opposite effects on liver fibrosis, there are three typical liver insults: a high fat diet, alcohol, and a virus such as hepatitis C. Early liver injury leads to steatosis, which is enhanced by CB1 receptor activation on hepatocytes and on adipocytes, but inhibited by CB2 receptor activation on the Kupffer cells. Prolonged steatosis will lead to liver inflammation and steatohepatitis. Again, this process is enhanced by CB1 signaling on the hepatocytes and this time inhibited by CB2 signaling on the myofibroblasts. Both CB1 signaling and CB2 signaling can promote liver regeneration at this step. Prolonged inflammation, however, will lead to fibrogenesis, as mentioned previously. This process is enhanced by CB1 signaling in myofibroblasts and inhibited by CB2 signaling in the same cells. The endocannabinoid system also helps control both hunger and feeding. Human breast milk contains endocannabinoids, and newborn mice that are given a CB1 receptor antagonist stop suckling and die, Indicating the CB 1 receptor is required for the initial development of the tongue muscles for suckling. The endocannabinoid system modulates cellular metabolism via many other hormones include ghrelin, leptin, orexin, and adiponectin. In obesity, adipocytes produce excessive levels of endocannabinoids which can drive CB1 receptors into a feed-forward dysfunction, contributing to metabolic syndrome. Interestingly, long-term heavy recreational cannabis use is inversely associated with both obesity and Type 2 diabetes. It has been suggested that blocking CB1 receptor activation could reduce hunger and be a treatment for obesity. A drug that blockes CB1 receptors, Rimonanbant, was approved in Europe, but was later withdrawn from the market because it was found to cause severe psychiatric side effects such as suicide. The endocannabinoid system is incredibly complex and simply blocking a CB receptor is unlikely to offer health benefits without significant side effects in other systems, and goes to suggest it was in the signalling to the EC system, . Which leads to the need for more clinical studies on Phytocannabiniods regulation role on hyperactive systems.
The liver expresses both CB1 and CB2 receptors at low levels. The CB1 receptors are mostly found in endothelial cells and hepatocytes, and the CB2 receptors are mostly found in Kupffer cells. Anandamide and 2-AG are present at substantial levels in the liver, along with the enzymes needed to break down Anandamide & 2-AG the endocannabinoids. Liver injury is associated with an increased endocannabinoid tone in several pathologic settings. During injury or inflammation, CB1 receptors are induced in hepatocytes, hepatic myofibroblasts, and endothelial cells. CB2 receptors are induced in Kupffer cells as well as the hepatic myofibroblasts. Levels of 2-AG also increase in hepatic stellate cells and hepatocytes during liver injury. The Kupffer cells are involved in our response to early liver injury via the production of tumor necrosis factoralpha. This signals the stellate cells to synthesize collagen and cause fibrosis. Fibrosis will eventually lead to cirrhosis or loss of liver function.
As we can expect from a signaling system that has homeostatic properties, the cannabinoid system can both increase and decrease liver fibrosis via different mechanisms of CB1 and CB2. It’s been shown that stimulation of the CB1 receptor can enhance fibrogenesis, while stimulation of the CB2 receptor counteracts the progression of fibrosis. It’s important to note that effective antifibrotic treatments are not available in humans yet. And numerous efforts are being directed at the development of liver-specific antifibrotic therapies to treat liver disease and prevent cirrhosis. CB1 and CB2 receptors have opposite effects on liver fibrosis, there are three typical liver insults: a high fat diet, alcohol, and a virus such as hepatitis C. Early liver injury leads to steatosis, which is enhanced by CB1 receptor activation on hepatocytes and on adipocytes, but inhibited by CB2 receptor activation on the Kupffer cells. Prolonged steatosis will lead to liver inflammation and steatohepatitis. Again, this process is enhanced by CB1 signaling on the hepatocytes and this time inhibited by CB2 signaling on the myofibroblasts. Both CB1 signaling and CB2 signaling can promote liver regeneration at this step. Prolonged inflammation, however, will lead to fibrogenesis, as mentioned previously. This process is enhanced by CB1 signaling in myofibroblasts and inhibited by CB2 signaling in the same cells. The endocannabinoid system also helps control both hunger and feeding. Human breast milk contains endocannabinoids, and newborn mice that are given a CB1 receptor antagonist stop suckling and die, Indicating the CB 1 receptor is required for the initial development of the tongue muscles for suckling. The endocannabinoid system modulates cellular metabolism via many other hormones include ghrelin, leptin, orexin, and adiponectin. In obesity, adipocytes produce excessive levels of endocannabinoids which can drive CB1 receptors into a feed-forward dysfunction, contributing to metabolic syndrome. Interestingly, long-term heavy recreational cannabis use is inversely associated with both obesity and Type 2 diabetes. It has been suggested that blocking CB1 receptor activation could reduce hunger and be a treatment for obesity. A drug that blockes CB1 receptors, Rimonanbant, was approved in Europe, but was later withdrawn from the market because it was found to cause severe psychiatric side effects such as suicide. The endocannabinoid system is incredibly complex and simply blocking a CB receptor is unlikely to offer health benefits without significant side effects in other systems, and goes to suggest it was in the signalling to the EC system, . Which leads to the need for more clinical studies on Phytocannabiniods regulation role on hyperactive systems.
Genes & Nervous system
Deficiency Syndroms/Potential Disregulations
migraine, M.S., Huntington’s, and Parkinson’s, I.B.S, anorexia, motion sickness, fibromyalgia, menstrual symptoms, etc!
Although cannabinoid deficiency syndromes have not yet been clearly defined in humans, there is some pre-clinical evidence and some human evidence that dysregulation of the endocannabinoid system is associated with several conditions. Endocannabinoid deficiencies have been implicated in schizophrenia, migraine, multiple sclerosis, Huntington’s, and Parkinson’s, irritable bowel syndrome, anorexia, motion sickness, fibromyalgia, menstrual symptoms, and other conditions that involve hyperalgesia and abnormal sensitization to pain. Several polymorphisms [differing forms] have been identified in the genes that code for the cannabinoid receptors. And some of these polymorphisms have been associated with clinical outcomes, such as a tendency towards happiness or depression, and the likelihood of developing a post-traumatic stress disorder. Therefore if your coding ( gene transcription is off, Phytocannabiniods supplemented (which are mimics to the cannabinoids proper form & Cannabiniods/Phytocannabiniods have gene transcription modulation properties, potentially aiding in the correction of the improper coding
migraine, M.S., Huntington’s, and Parkinson’s, I.B.S, anorexia, motion sickness, fibromyalgia, menstrual symptoms, etc!
Although cannabinoid deficiency syndromes have not yet been clearly defined in humans, there is some pre-clinical evidence and some human evidence that dysregulation of the endocannabinoid system is associated with several conditions. Endocannabinoid deficiencies have been implicated in schizophrenia, migraine, multiple sclerosis, Huntington’s, and Parkinson’s, irritable bowel syndrome, anorexia, motion sickness, fibromyalgia, menstrual symptoms, and other conditions that involve hyperalgesia and abnormal sensitization to pain. Several polymorphisms [differing forms] have been identified in the genes that code for the cannabinoid receptors. And some of these polymorphisms have been associated with clinical outcomes, such as a tendency towards happiness or depression, and the likelihood of developing a post-traumatic stress disorder. Therefore if your coding ( gene transcription is off, Phytocannabiniods supplemented (which are mimics to the cannabinoids proper form & Cannabiniods/Phytocannabiniods have gene transcription modulation properties, potentially aiding in the correction of the improper coding
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