Finshaggy
Well-Known Member
I would like to stress the Cannabis Reuptake Inhibitors are not recreational drugs, they should be viewed more like vitamins to be used only in certain situations. PLEASE READ THE BOTTOM OF THIS POST)
Anyone that came here looking for information on Cancer or Tumor medication, I can not help you. I have personally read anecdotal reports that state because of the mode of action of Cannabinoid Reuptake Inhibitors it helps cancer by helping the body produce more natural Cannabinoids, and others that say they with hurt cancer treatment by not allowing as many Cannabinoids to get out of your brain
But I CAN tell you why I am researching this. My 11 year old brother died from brain swelling that came after a heart attack that was caused by allergies. EndoCannabinoids help with many things that NO OTHER MEDICATION is known to do:
Reduce Brain Swelling (NO OTHER MEDICINE CAN DO THIS, and it is the leading cause of death after stroke, and is the reason my brother died)
Reduce the effect of Brain Trauma (and in some cases when administered late, it even REVERSED the effects. This is according to studies in Israel)
And Even in some cases, bring people out of a Coma
Here is a scholarly article proving that it can help protect your brain, not just cure it:
http://www.sciencemag.org/content/302/5642/84.short
If your loved one is in the hospital because of head trauma or brain swelling, this thread could save their life
The information provided about blood brain barrier boosters should help with people who have a weak heart beat
Your brain has natural Cannabinoids that it produces to regulate MANY things, these are called EndoCannabinoids.
Here is a link to the Wiki about EndoCannabinoids function in the brain: http://en.wikipedia.org/wiki/Endocannabinoid_system#Functions_of_the_endocannabinoid_system
I'm not sure if this is proven, but I have heard that there are studies saying that smoking THC and other Cannabinoids makes your brain feel as if it is unnecessary to produce its own Cannabinoids, since you are activating your CB1 receptor on your own.
But there is now a chem out there that is NOT a cannabinoid (I'm not sure what it is) called LY-2183240. What this chem is said to do is this:
Acts both as a potent inhibitor of the reuptake of the endocannabinoid anandamide, and as an inhibitor of fatty acid amide hydrolase (FAAH), the primary enzyme responsible for degrading anandamide. This leads to markedly elevated anandamide levels in the brain, and LY-2183240 has been shown to produce both analgesic and anxiolytic effects in animal models.
So basically,what this does is GETS YOU HIGH ON YOUR OWN CANNABINOIDS. It creates an environment where when a certain Cannabinoid enters the CB1 & CB2 region of the brain, it has to stay there until it DOES SOMETHING. It can't just go back into your blood and get pissed out.
Firstly, it "is a potent inhibitor of the reuptake of the endocannabinoid Anandamine".
Secondly, it stops your body from producing things that EAT Anandamine.
Thirdly, all of these things could slightly effects other Cannabinoids. As your brain is meant for Endocannabinoids, but when you smoke Marijuana, you add to the supply in a way that the brain isn't exactly meant to handle.
Here is what Anandamine is (a natural Cannabinoid that your brain produces: http://en.wikipedia.org/wiki/Anandamide
In 1992, in Raphael Mechoulam's lab, the first such compound was identified as arachidonoyl ethanolamine and named anandamide, a name derived from the Sanskrit word for bliss and -amide. Anandamide is derived from the essential fatty acid arachidonic acid. It has a pharmacology similar to THC, although its chemical structure is different. Anandamide binds to the central (CB1) and, to a lesser extent, peripheral (CB2) cannabinoid receptors, where it acts as a partial agonist. Anandamide is about as potent as THC at the CB1 receptor.[41] Anandamide is found in nearly all tissues in a wide range of animals.[42] Anandamide has also been found in plants, including small amounts in chocolate.
Mangoes have become pretty well known over the past year or so for helping Cannabinoids cross the blood brain barrier, so that more THC goes from your blood to your brain in the first place, and faster.
Mangoes:
https://www.google.com/search?newwi...1.0....0...1c.1.28.hp..11.25.2354.c59K2M7YJvM
Endocannabinoids play an important role in every day things, as well as important things like your ability to get pregnant. So do not take Endo-Cannabinoid reuptake inhibitors as if they are Marijuana replacements. They should be used as a tool for brain building (like a once a month boost maybe) just to tell your brain "Hey, those natural Cannabinoids are good for you" so it keeps making them.
ALSO, VERY IMPORTANT. Cannabinoid Reuptake Inhibitors are UNDERSTUDIED. So I would suggest not eating a variety of foods while on them. Ex: When you use MAOI, which is another form of inhibitor that CAN effect cannabis, but is not specifically selective of cannabinoids, is safe for humans to ingest. But because of the effects it has on your immune system you can get headaches, or even die if you eat or drink: Chocolate, Cheese or Alcohol. Simply because these things are toxic to our system, until our bodies break it down. So BE CAREFUL.
Here are the things EndoCannabinoids regulate, and these are the ONLY situations they could possibly be viewed useful in. THEY ARE NOT RECREATIONAL DRUGS.
http://en.wikipedia.org/wiki/Endocannabinoid_system#Functions_of_the_endocannabinoid_system
Memory[edit]
Mice treated with tetrahydrocannabinol (THC) show suppression of long-term potentiation in the hippocampus, a process that is essential for the formation and storage of long-term memory.[25] These results concur with anecdotal evidence suggesting that smoking Cannabis impairs short-term memory[26] Consistent with this finding, mice without the CB1 receptor show enhanced memory and long-term potentiation indicating that the endocannabinoid system may play a pivotal role in the extinction of old memories. In contrast, a recent study found that the high-dose treatment of rats with the synthetic cannabinoid HU-210 over several weeks resulted in stimulation of neural growth in the rats' hippocampus region, a part of the limbic system playing a part in the formation of declarative and spatial memories.[27] Taken together, these findings suggest that the effects of endocannabinoids on memory are dependent on what type of neurons are being targeted (excitatory vs. inhibitory) and the location of these networks in the brain.
Role in hippocampal neurogenesis[edit]
In the adult brain, the endocannabinoid system facilitates the neurogenesis of hippocampal granule cells.[27][28] In the subgranular zone of the dentate gyrus, multipotent neural progenitors (NP) give rise to daughter cells that, over the course of several weeks, mature into granule cells whose axons project to and synapse onto dendrites on the CA3 region.[29] NPs in the hippocampus have been shown to possess FAAH and express CB1 and utilize 2-AG.[28] Intriguingly, CB1 activation by endogenous or exogenous cannabinoids promote NP proliferation and differentiation; this activation is absent in CB1 knockouts and abolished in the presence of antagonist.[27][28]
Induction of synaptic depression[edit]
The inhibitory effects of cannabinoid receptor stimulation on neurotransmitter release have caused this system to be connected to various forms of depressant plasticity. A recent study conducted with the bed nucleus of the stria terminalis found that the endurance of the depressant effects was mediated by two different signaling pathways based on the type of receptor activated. 2-AG was found to act on presynaptic CB1 receptors to mediate retrograde short-term depression (STD) following activation of L-type calcium currents, while anandamide was synthesized after mGluR5 activation and triggered autocrine signalling onto postsynapic TRPV1 receptors that induced long-term depression (LTD). Similar post-synaptic receptor dependencies were found in the striatum, but here both effects relied on presynaptic CB1 receptors.[11] These findings provide the brain a direct mechanism to selectively inhibit neuronal excitability over variable time scales. By selectively internalizing different receptors, the brain may limit the production of specific endocannabinoids to favor a time scale in accordance with its needs.
Appetite[edit]
Evidence for the role of the endocannabinoid system in food-seeking behavior comes from a variety of cannabinoid studies. Emerging data suggests that THC acts via CB1 receptors in the hypothalamic nuclei to directly increase appetite.[30] It is thought that hypothalamic neurons tonically produce endocannabinoids that work to tightly regulate hunger. The amount of endocannabinoids produced is inversely correlated with the amount of leptin in the blood.[31] For example, mice without leptin not only become massively obese but express abnormally high levels of hypothalamic endocannabinoids as a compensatory mechanism.[7] Similarly, when these mice were treated with an endocannabinoid inverse agonists, such as rimonabant, food intake was reduced.[7] When the CB1 receptor is knocked-out in mice, these animals tend to be leaner and less hungry than wild-type mice. A related study examined the effect of THC on the hedonic value of food and found enhanced dopamine release in the nucleus accumbens and increased pleasure-related behavior after administration of a sucrose solution.[32] A related study found that endocannabinoids affect taste perception in taste cells [33] In taste cells, endocannabinoids were shown to selectively enhance the strength of neural signaling for sweet tastes, whereas leptin decreased the strength of this same response. While there is need for more research, these results suggest that cannabinoid activity in the hypothalamus and nucleus accumbens is related to appetitive, food-seeking behavior.[30]
Energy balance & metabolism[edit]
The endocannabinoid system has been shown to have a homeostatic role by controlling several metabolic functions, such as energy storage and nutrient transport. It acts on peripheral tissues such as adipocytes, hepatocytes, the gastrointestinal tract, the skeletal muscles and the endocrine pancreas. It has also been implied in modulating insulin sensitivity. Through all of this, the endocannabinoid system may play a role in clinical conditions, such as obesity, diabetes, and atherosclerosis, which may also give it a cardiovascular role.[34]
Stress response[edit]
While the secretion of glucocorticoids in response to stressful stimuli is an adaptive response necessary for an organism to respond appropriately to a stressor, persistent secretion may be harmful. The endocannabinoid system has been implicated in the habituation of the hypothalamic-pituitary-adrenal axis (HPA axis) to repeated exposure to restraint stress. Studies have demonstrated differential synthesis of anandamide and 2-AG during tonic stress. A decrease of anandamide was found along the axis that contributed to basal hypersecretion of corticosterone; in contrast, an increase of 2-AG was found in the amygdala after repeated stress, which was negatively correlated to magnitude of the corticosterone response. All effects were abolished by the CB1 antagonist AM251, supporting the conclusion that these effects were cannabinoid-receptor dependent.[35] These findings show that anandamide and 2-AG divergently regulate the HPA axis response to stress: while habituation of the stress-induced HPA axis via 2-AG prevents excessive secretion of glucocorticoids to non-threatening stimuli, the increase of basal corticosterone secretion resulting from decreased anandamide allows for a facilitated response of the HPA axis to novel stimuli.
Exploration, social behavior, and anxiety[edit]
Prolonged, systemic exposure to cannabinoids has often been associated with anti-social effects. To investigate this theory, a cannabinoid receptor-knockout mouse study examined the effect that these receptors play on exploratory behavior. Researchers selectively targeted glutamatergic and GABAergic cortical interneurons and studied results in open field, novel object, and sociability tests. Eliminating glutamaterigic cannabinoid receptors led to decreased object exploration, social interactions, and increased aggressive behavior. In contrast, GABAergic cannabinoid receptor-knockout mice showed increased exploration of objects, socialization, and open field movement.[36] These contrasting effects reveal the importance of the endocannabinoid system in regulating anxiety-dependent behavior. Results suggest that glutamatergic cannabinoid receptors are not only responsible for mediating aggression, but produce an anxiolytic-like function by inhibiting excessive arousal: excessive excitation produces anxiety that limited the mice from exploring both animate and inanimate objects. In contrast, GABAergic neurons appear to control an anxiogenic-like function by limiting inhibitory transmitter release. Taken together, these two sets of neurons appear to help regulate the organism's overall sense of arousal during novel situations.
Immune function[edit]
Evidence suggests that endocannabinoids may function as both neuromodulators and immunomodulators in the immune system. Here, they seem to serve an autoprotective role to ameliorate muscle spasms, inflammation, and other symptoms of multiple sclerosis and skeletal muscle spasms.[1] Functionally, the activation of cannabinoid receptors has been demonstrated to play a role in the activation of GTPases in macrophages, neutrophils, and BM cells. These receptors have also been implicated in the proper migration of B cells into the marginal zone (MZ) and the regulation of healthy IgM levels.[37] Interestingly, some disorders seem to trigger an upregulation of cannabinoid receptors selectively in cells or tissues related to symptom relief and inhibition of disease progression, such as in that rodent neuropathic pain model, where receptors are increased in the spinal cord microglia, dorsal root ganglion, and thalmic neurons.[9]
Multiple sclerosis[edit]
Historical records from ancient China and Greece suggest that preparations of Cannabis Indica were commonly prescribed to ameliorate multiple sclerosis-like symptoms such as tremors and muscle pain. Modern research has confirmed these effects in a study on diseased mice, wherein both endogenous and exogenous agonists showed ameliorating effects on tremor and spasticity. It remains to be seen whether pharmaceutical preparations such as dronabinol have the same effects in humans.[38][39] Due to increasing use of medical Cannabis and rising incidence of multiple sclerosis patients who self-medicate with the drug, there has been much interest in exploiting the endocannabinoid system in the cerebellum to provide a legal and effective relief.[26] In mouse models of multiple sclerosis, there is a profound reduction and reorganization of CB1 receptors in the cerebellum.[40] Serial sections of cerebellar tissue subjected to immunohistochemistry revealed that this aberrant expression occurred during the relapse phase but returned to normal during the remitting phase of the disease.[40] Other studies suggest that CB1 agonists promote the survival of oligodendrocytes in vitro in the absence of growth and trophic factors; in addition, these agonist have been shown to promote mRNA expression of myelin lipid protein. (Kittler et al., 2000; Mollna-Holgado et al., 2002). Taken together, these studies point to the exciting possibility that cannabinoid treatment may not only be able to attenuate the symptoms of multiple sclerosis but also improve oligodendrocyte function (reviewed in Pertwee, 2001; Mollna-Holgado et al., 2002). 2-AG stimulates proliferation of a microglial cell line by a CB2 receptor dependent mechanism, and the number of microglial cells is increased in multiple sclerosis.[41]
Female reproduction[edit]
The developing embryo expresses cannabinoid receptors early in development that are responsive to anandamide secreted in the uterus. This signaling is important in regulating the timing of embryonic implantation and uterine receptivity. In mice, it has been shown that anandamide modulates the probability of implantation to the uterine wall. For example, in humans, the likelihood of miscarriage increases if uterine anandamide levels are too high or low.[42] These results suggest that intake of exogenous cannabinoids (e.g. marijuana) can decrease the likelihood for pregnancy for women with high anandamide levels, and alternatively, it can increase the likelihood for pregnancy in women whose anandamide levels were too low.[43][44]
Autonomic nervous system[edit]
Peripheral expression of cannabinoid receptors led researchers to investigate the role of cannabinoids in the autonomic nervous system. Research found that the CB1 receptor is expressed presynaptically by motor neurons that innervate visceral organs. Cannabinoid-mediated inhibition of electric potentials results in a reduction in noradrenaline release from sympathetic nervous system nerves. Other studies have found similar effects in endocannabinoid regulation of intestinal motility, including the innervation of smooth muscles associated with the digestive, urinary, and reproductive systems.[10]
Analgesia[edit]
At the spinal cord, cannabinoids suppress noxious-stimulus-evoked responses of neurons in the dorsal horn, possibly by modulating descending noradrenaline input from the brainstem.[10] As many of these fibers are primarily GABAergic, cannabinoid stimulation in the spinal column results in disinhibition that should increase noradrenaline release and attenuation of noxious-stimuli-processing in the periphery and dorsal root ganglion. The endocannabinoid most researched in pain is palmitoylethanolamide . Palmitoylethanolamide is a fatty amine related to anandamide, but saturated and although initially it was thought that palmitoylethanolamide would bind to the CB1 and the CB2 receptor, later it was found that the most important receptors are the PPAR-alpha receptor, the TRPV receptor and the GRP55 receptor. Palmitoylethanolamide has been evaluated for its analgesic actions in a great variety of pain indications and found to be safe and effective. Basically these data are proof of concept for endocannabinoids and related fatty amines to be therapeutically useful analgesics; palmitoylethaanolamide is available under the brandnames Normast and PeaPure as neutraceuticals.
Thermoregulation[edit]
Anandamide and N-arachidonoyl dopamine (NADA) have been shown to act on temperature-sensing TRPV1 channels, which are involved in thermoregulation.[45] TRPV1 is activated by the exogenous ligand capsaicin, the active component of chili peppers, which is structurally similar to endocannabinoids. NADA activates the TRPV1 channel with an EC50 of approximately of 50 nM. The high potency makes it the putative endogenous TRPV1 agonist.[46] Anandamide has also been found to activate TRPV1 on sensory neuron terminals, and subsequently cause vasodilation.[10] TRPV1 may also be activated by methanandamide and arachidonyl-2'-chloroethylamide (ACEA).[1]
Sleep[edit]
Increased endocannabinoid signaling within the central nervous system promotes sleep-inducing effects. Intercerebroventricular administration of anandamide in rats has been shown to decrease wakefulness and increase slow-wave sleep and REM sleep.[47] Administration of anandamide into the basal forebrain of rats has also been shown to increase levels of adenosine, which plays a role in promoting sleep and suppressing arousal.[48] REM sleep deprivation in rats has been demonstrated to increase CB1 receptor expression in the central nervous system.[49] Furthermore, anandamide levels possess a circadian rhythm in the rat, with levels being higher in the light phase of the day, which is when rats are usually asleep or less active, since they are nocturnal.
Anyone that came here looking for information on Cancer or Tumor medication, I can not help you. I have personally read anecdotal reports that state because of the mode of action of Cannabinoid Reuptake Inhibitors it helps cancer by helping the body produce more natural Cannabinoids, and others that say they with hurt cancer treatment by not allowing as many Cannabinoids to get out of your brain
But I CAN tell you why I am researching this. My 11 year old brother died from brain swelling that came after a heart attack that was caused by allergies. EndoCannabinoids help with many things that NO OTHER MEDICATION is known to do:
Reduce Brain Swelling (NO OTHER MEDICINE CAN DO THIS, and it is the leading cause of death after stroke, and is the reason my brother died)
Reduce the effect of Brain Trauma (and in some cases when administered late, it even REVERSED the effects. This is according to studies in Israel)
And Even in some cases, bring people out of a Coma
Here is a scholarly article proving that it can help protect your brain, not just cure it:
http://www.sciencemag.org/content/302/5642/84.short
If your loved one is in the hospital because of head trauma or brain swelling, this thread could save their life
The information provided about blood brain barrier boosters should help with people who have a weak heart beat
Your brain has natural Cannabinoids that it produces to regulate MANY things, these are called EndoCannabinoids.
Here is a link to the Wiki about EndoCannabinoids function in the brain: http://en.wikipedia.org/wiki/Endocannabinoid_system#Functions_of_the_endocannabinoid_system
I'm not sure if this is proven, but I have heard that there are studies saying that smoking THC and other Cannabinoids makes your brain feel as if it is unnecessary to produce its own Cannabinoids, since you are activating your CB1 receptor on your own.
But there is now a chem out there that is NOT a cannabinoid (I'm not sure what it is) called LY-2183240. What this chem is said to do is this:
Acts both as a potent inhibitor of the reuptake of the endocannabinoid anandamide, and as an inhibitor of fatty acid amide hydrolase (FAAH), the primary enzyme responsible for degrading anandamide. This leads to markedly elevated anandamide levels in the brain, and LY-2183240 has been shown to produce both analgesic and anxiolytic effects in animal models.
So basically,what this does is GETS YOU HIGH ON YOUR OWN CANNABINOIDS. It creates an environment where when a certain Cannabinoid enters the CB1 & CB2 region of the brain, it has to stay there until it DOES SOMETHING. It can't just go back into your blood and get pissed out.
Firstly, it "is a potent inhibitor of the reuptake of the endocannabinoid Anandamine".
Secondly, it stops your body from producing things that EAT Anandamine.
Thirdly, all of these things could slightly effects other Cannabinoids. As your brain is meant for Endocannabinoids, but when you smoke Marijuana, you add to the supply in a way that the brain isn't exactly meant to handle.
Here is what Anandamine is (a natural Cannabinoid that your brain produces: http://en.wikipedia.org/wiki/Anandamide
In 1992, in Raphael Mechoulam's lab, the first such compound was identified as arachidonoyl ethanolamine and named anandamide, a name derived from the Sanskrit word for bliss and -amide. Anandamide is derived from the essential fatty acid arachidonic acid. It has a pharmacology similar to THC, although its chemical structure is different. Anandamide binds to the central (CB1) and, to a lesser extent, peripheral (CB2) cannabinoid receptors, where it acts as a partial agonist. Anandamide is about as potent as THC at the CB1 receptor.[41] Anandamide is found in nearly all tissues in a wide range of animals.[42] Anandamide has also been found in plants, including small amounts in chocolate.
Mangoes have become pretty well known over the past year or so for helping Cannabinoids cross the blood brain barrier, so that more THC goes from your blood to your brain in the first place, and faster.
Mangoes:
https://www.google.com/search?newwi...1.0....0...1c.1.28.hp..11.25.2354.c59K2M7YJvM
Endocannabinoids play an important role in every day things, as well as important things like your ability to get pregnant. So do not take Endo-Cannabinoid reuptake inhibitors as if they are Marijuana replacements. They should be used as a tool for brain building (like a once a month boost maybe) just to tell your brain "Hey, those natural Cannabinoids are good for you" so it keeps making them.
ALSO, VERY IMPORTANT. Cannabinoid Reuptake Inhibitors are UNDERSTUDIED. So I would suggest not eating a variety of foods while on them. Ex: When you use MAOI, which is another form of inhibitor that CAN effect cannabis, but is not specifically selective of cannabinoids, is safe for humans to ingest. But because of the effects it has on your immune system you can get headaches, or even die if you eat or drink: Chocolate, Cheese or Alcohol. Simply because these things are toxic to our system, until our bodies break it down. So BE CAREFUL.
Here are the things EndoCannabinoids regulate, and these are the ONLY situations they could possibly be viewed useful in. THEY ARE NOT RECREATIONAL DRUGS.
http://en.wikipedia.org/wiki/Endocannabinoid_system#Functions_of_the_endocannabinoid_system
Memory[edit]
Mice treated with tetrahydrocannabinol (THC) show suppression of long-term potentiation in the hippocampus, a process that is essential for the formation and storage of long-term memory.[25] These results concur with anecdotal evidence suggesting that smoking Cannabis impairs short-term memory[26] Consistent with this finding, mice without the CB1 receptor show enhanced memory and long-term potentiation indicating that the endocannabinoid system may play a pivotal role in the extinction of old memories. In contrast, a recent study found that the high-dose treatment of rats with the synthetic cannabinoid HU-210 over several weeks resulted in stimulation of neural growth in the rats' hippocampus region, a part of the limbic system playing a part in the formation of declarative and spatial memories.[27] Taken together, these findings suggest that the effects of endocannabinoids on memory are dependent on what type of neurons are being targeted (excitatory vs. inhibitory) and the location of these networks in the brain.
Role in hippocampal neurogenesis[edit]
In the adult brain, the endocannabinoid system facilitates the neurogenesis of hippocampal granule cells.[27][28] In the subgranular zone of the dentate gyrus, multipotent neural progenitors (NP) give rise to daughter cells that, over the course of several weeks, mature into granule cells whose axons project to and synapse onto dendrites on the CA3 region.[29] NPs in the hippocampus have been shown to possess FAAH and express CB1 and utilize 2-AG.[28] Intriguingly, CB1 activation by endogenous or exogenous cannabinoids promote NP proliferation and differentiation; this activation is absent in CB1 knockouts and abolished in the presence of antagonist.[27][28]
Induction of synaptic depression[edit]
The inhibitory effects of cannabinoid receptor stimulation on neurotransmitter release have caused this system to be connected to various forms of depressant plasticity. A recent study conducted with the bed nucleus of the stria terminalis found that the endurance of the depressant effects was mediated by two different signaling pathways based on the type of receptor activated. 2-AG was found to act on presynaptic CB1 receptors to mediate retrograde short-term depression (STD) following activation of L-type calcium currents, while anandamide was synthesized after mGluR5 activation and triggered autocrine signalling onto postsynapic TRPV1 receptors that induced long-term depression (LTD). Similar post-synaptic receptor dependencies were found in the striatum, but here both effects relied on presynaptic CB1 receptors.[11] These findings provide the brain a direct mechanism to selectively inhibit neuronal excitability over variable time scales. By selectively internalizing different receptors, the brain may limit the production of specific endocannabinoids to favor a time scale in accordance with its needs.
Appetite[edit]
Evidence for the role of the endocannabinoid system in food-seeking behavior comes from a variety of cannabinoid studies. Emerging data suggests that THC acts via CB1 receptors in the hypothalamic nuclei to directly increase appetite.[30] It is thought that hypothalamic neurons tonically produce endocannabinoids that work to tightly regulate hunger. The amount of endocannabinoids produced is inversely correlated with the amount of leptin in the blood.[31] For example, mice without leptin not only become massively obese but express abnormally high levels of hypothalamic endocannabinoids as a compensatory mechanism.[7] Similarly, when these mice were treated with an endocannabinoid inverse agonists, such as rimonabant, food intake was reduced.[7] When the CB1 receptor is knocked-out in mice, these animals tend to be leaner and less hungry than wild-type mice. A related study examined the effect of THC on the hedonic value of food and found enhanced dopamine release in the nucleus accumbens and increased pleasure-related behavior after administration of a sucrose solution.[32] A related study found that endocannabinoids affect taste perception in taste cells [33] In taste cells, endocannabinoids were shown to selectively enhance the strength of neural signaling for sweet tastes, whereas leptin decreased the strength of this same response. While there is need for more research, these results suggest that cannabinoid activity in the hypothalamus and nucleus accumbens is related to appetitive, food-seeking behavior.[30]
Energy balance & metabolism[edit]
The endocannabinoid system has been shown to have a homeostatic role by controlling several metabolic functions, such as energy storage and nutrient transport. It acts on peripheral tissues such as adipocytes, hepatocytes, the gastrointestinal tract, the skeletal muscles and the endocrine pancreas. It has also been implied in modulating insulin sensitivity. Through all of this, the endocannabinoid system may play a role in clinical conditions, such as obesity, diabetes, and atherosclerosis, which may also give it a cardiovascular role.[34]
Stress response[edit]
While the secretion of glucocorticoids in response to stressful stimuli is an adaptive response necessary for an organism to respond appropriately to a stressor, persistent secretion may be harmful. The endocannabinoid system has been implicated in the habituation of the hypothalamic-pituitary-adrenal axis (HPA axis) to repeated exposure to restraint stress. Studies have demonstrated differential synthesis of anandamide and 2-AG during tonic stress. A decrease of anandamide was found along the axis that contributed to basal hypersecretion of corticosterone; in contrast, an increase of 2-AG was found in the amygdala after repeated stress, which was negatively correlated to magnitude of the corticosterone response. All effects were abolished by the CB1 antagonist AM251, supporting the conclusion that these effects were cannabinoid-receptor dependent.[35] These findings show that anandamide and 2-AG divergently regulate the HPA axis response to stress: while habituation of the stress-induced HPA axis via 2-AG prevents excessive secretion of glucocorticoids to non-threatening stimuli, the increase of basal corticosterone secretion resulting from decreased anandamide allows for a facilitated response of the HPA axis to novel stimuli.
Exploration, social behavior, and anxiety[edit]
Prolonged, systemic exposure to cannabinoids has often been associated with anti-social effects. To investigate this theory, a cannabinoid receptor-knockout mouse study examined the effect that these receptors play on exploratory behavior. Researchers selectively targeted glutamatergic and GABAergic cortical interneurons and studied results in open field, novel object, and sociability tests. Eliminating glutamaterigic cannabinoid receptors led to decreased object exploration, social interactions, and increased aggressive behavior. In contrast, GABAergic cannabinoid receptor-knockout mice showed increased exploration of objects, socialization, and open field movement.[36] These contrasting effects reveal the importance of the endocannabinoid system in regulating anxiety-dependent behavior. Results suggest that glutamatergic cannabinoid receptors are not only responsible for mediating aggression, but produce an anxiolytic-like function by inhibiting excessive arousal: excessive excitation produces anxiety that limited the mice from exploring both animate and inanimate objects. In contrast, GABAergic neurons appear to control an anxiogenic-like function by limiting inhibitory transmitter release. Taken together, these two sets of neurons appear to help regulate the organism's overall sense of arousal during novel situations.
Immune function[edit]
Evidence suggests that endocannabinoids may function as both neuromodulators and immunomodulators in the immune system. Here, they seem to serve an autoprotective role to ameliorate muscle spasms, inflammation, and other symptoms of multiple sclerosis and skeletal muscle spasms.[1] Functionally, the activation of cannabinoid receptors has been demonstrated to play a role in the activation of GTPases in macrophages, neutrophils, and BM cells. These receptors have also been implicated in the proper migration of B cells into the marginal zone (MZ) and the regulation of healthy IgM levels.[37] Interestingly, some disorders seem to trigger an upregulation of cannabinoid receptors selectively in cells or tissues related to symptom relief and inhibition of disease progression, such as in that rodent neuropathic pain model, where receptors are increased in the spinal cord microglia, dorsal root ganglion, and thalmic neurons.[9]
Multiple sclerosis[edit]
Historical records from ancient China and Greece suggest that preparations of Cannabis Indica were commonly prescribed to ameliorate multiple sclerosis-like symptoms such as tremors and muscle pain. Modern research has confirmed these effects in a study on diseased mice, wherein both endogenous and exogenous agonists showed ameliorating effects on tremor and spasticity. It remains to be seen whether pharmaceutical preparations such as dronabinol have the same effects in humans.[38][39] Due to increasing use of medical Cannabis and rising incidence of multiple sclerosis patients who self-medicate with the drug, there has been much interest in exploiting the endocannabinoid system in the cerebellum to provide a legal and effective relief.[26] In mouse models of multiple sclerosis, there is a profound reduction and reorganization of CB1 receptors in the cerebellum.[40] Serial sections of cerebellar tissue subjected to immunohistochemistry revealed that this aberrant expression occurred during the relapse phase but returned to normal during the remitting phase of the disease.[40] Other studies suggest that CB1 agonists promote the survival of oligodendrocytes in vitro in the absence of growth and trophic factors; in addition, these agonist have been shown to promote mRNA expression of myelin lipid protein. (Kittler et al., 2000; Mollna-Holgado et al., 2002). Taken together, these studies point to the exciting possibility that cannabinoid treatment may not only be able to attenuate the symptoms of multiple sclerosis but also improve oligodendrocyte function (reviewed in Pertwee, 2001; Mollna-Holgado et al., 2002). 2-AG stimulates proliferation of a microglial cell line by a CB2 receptor dependent mechanism, and the number of microglial cells is increased in multiple sclerosis.[41]
Female reproduction[edit]
The developing embryo expresses cannabinoid receptors early in development that are responsive to anandamide secreted in the uterus. This signaling is important in regulating the timing of embryonic implantation and uterine receptivity. In mice, it has been shown that anandamide modulates the probability of implantation to the uterine wall. For example, in humans, the likelihood of miscarriage increases if uterine anandamide levels are too high or low.[42] These results suggest that intake of exogenous cannabinoids (e.g. marijuana) can decrease the likelihood for pregnancy for women with high anandamide levels, and alternatively, it can increase the likelihood for pregnancy in women whose anandamide levels were too low.[43][44]
Autonomic nervous system[edit]
Peripheral expression of cannabinoid receptors led researchers to investigate the role of cannabinoids in the autonomic nervous system. Research found that the CB1 receptor is expressed presynaptically by motor neurons that innervate visceral organs. Cannabinoid-mediated inhibition of electric potentials results in a reduction in noradrenaline release from sympathetic nervous system nerves. Other studies have found similar effects in endocannabinoid regulation of intestinal motility, including the innervation of smooth muscles associated with the digestive, urinary, and reproductive systems.[10]
Analgesia[edit]
At the spinal cord, cannabinoids suppress noxious-stimulus-evoked responses of neurons in the dorsal horn, possibly by modulating descending noradrenaline input from the brainstem.[10] As many of these fibers are primarily GABAergic, cannabinoid stimulation in the spinal column results in disinhibition that should increase noradrenaline release and attenuation of noxious-stimuli-processing in the periphery and dorsal root ganglion. The endocannabinoid most researched in pain is palmitoylethanolamide . Palmitoylethanolamide is a fatty amine related to anandamide, but saturated and although initially it was thought that palmitoylethanolamide would bind to the CB1 and the CB2 receptor, later it was found that the most important receptors are the PPAR-alpha receptor, the TRPV receptor and the GRP55 receptor. Palmitoylethanolamide has been evaluated for its analgesic actions in a great variety of pain indications and found to be safe and effective. Basically these data are proof of concept for endocannabinoids and related fatty amines to be therapeutically useful analgesics; palmitoylethaanolamide is available under the brandnames Normast and PeaPure as neutraceuticals.
Thermoregulation[edit]
Anandamide and N-arachidonoyl dopamine (NADA) have been shown to act on temperature-sensing TRPV1 channels, which are involved in thermoregulation.[45] TRPV1 is activated by the exogenous ligand capsaicin, the active component of chili peppers, which is structurally similar to endocannabinoids. NADA activates the TRPV1 channel with an EC50 of approximately of 50 nM. The high potency makes it the putative endogenous TRPV1 agonist.[46] Anandamide has also been found to activate TRPV1 on sensory neuron terminals, and subsequently cause vasodilation.[10] TRPV1 may also be activated by methanandamide and arachidonyl-2'-chloroethylamide (ACEA).[1]
Sleep[edit]
Increased endocannabinoid signaling within the central nervous system promotes sleep-inducing effects. Intercerebroventricular administration of anandamide in rats has been shown to decrease wakefulness and increase slow-wave sleep and REM sleep.[47] Administration of anandamide into the basal forebrain of rats has also been shown to increase levels of adenosine, which plays a role in promoting sleep and suppressing arousal.[48] REM sleep deprivation in rats has been demonstrated to increase CB1 receptor expression in the central nervous system.[49] Furthermore, anandamide levels possess a circadian rhythm in the rat, with levels being higher in the light phase of the day, which is when rats are usually asleep or less active, since they are nocturnal.
