Click "Read More" to Learn about Marijuana Legalization and Why it Matters!
In plain language, here is what Initiative 502 will do:
Washington State Initiative Measure No. 502 (I-502) would license and regulate marijuana production, distribution, and possession for persons over twenty-one; remove state-law criminal and civil penalties for activities that it authorizes; tax marijuana sales; and earmark marijuana-related revenues.
This law legalizes the possession of marijuana for adults age 21 and older. The only marijuana that would be legal to sell in this state would be grown by specially-licensed Washington farmers and sold in standalone, marijuana-only stores operated by private Washington businesses licensed and regulated by the state. There would be a 25% sales tax, with 40% of the new revenues going to the state general fund and local budgets, and the remainder dedicated to substance-abuse prevention, research, education and health care. Advertising would be restricted. A new marijuana DUI standard that operates like the alcohol DUI standard would be established.
This law legalizes the possession of marijuana for adults age 21 and older. The only marijuana that would be legal to sell in this state would be grown by specially-licensed Washington farmers and sold in standalone, marijuana-only stores operated by private Washington businesses licensed and regulated by the state. There would be a 25% sales tax, with 40% of the new revenues going to the state general fund and local budgets, and the remainder dedicated to substance-abuse prevention, research, education and health care. Advertising would be restricted. A new marijuana DUI standard that operates like the alcohol DUI standard would be established.
The Facts
We stand to gain hundreds of millions in state tax revenue. We stand to gain tight regulatory control so that Marijuana becomes an age restricted 21+ product. We stand to gain quality control and product labels so that consumers know what they are buying. We stand to liberate the courts and law enforcement so that they can focus on mail theft, identify theft, property theft, rape, assault, murder and other crimes that have victims.
The primary opponents of marijuana legalization are from Big Alcohol companies that fear marijuana will give alcohol products competition in the "Relaxant" product markets.... Within consumers the primary opponents to marijuana legalization are those who fear the impacts of legalization. They hold fear, uncertainty and doubt about the impacts of legalization.
We know exactly what will happen if I-502 passes
Everyone in Washington State will benefit from the tighter regulatory controls and taxes of marijuana. Hundreds of millions of dollars in tax revenue will be generate to benefit every aspect of the state budget, giving more resources to law enforcement, schools and infrastructure. The age restrictions will reduce child and teen access to marijuana. At my middle and high schools, it was far easier to get illegal marijuana that it was to get legal age restricted alcohol. Drug dealers dont check ID's. The DUI regulations in I-502 are such that it encourages people to use marijuana in their homes during leisure time when they will not be operating heavy machinery or a vehicle while under the influence, employing the same kind of DUI technology used to combat alcohol drunken driving problems. I-502 will create labels and product information so that consumers of marijuana can enjoy the kind of product knowledge that alcohol consumers enjoy: they be able to know the exact kind of marijuana they are buying and its relative strength, flavor, organic or not, ect. I-502 will liberate more resources so that we can educate each other about the negative effects of abusing marijuana. Almost anything is unhealthy when it is abused, not just marijuana.
We need a rational and reasonable marijuana law, and the overwhelming majority of Washington State residents now understand that we stand to gain a lot by passing I-502 and stand to lose nothing.
Prohibition has been a long costly miserable failure
It is time to embrace the truth, freedom and accountability. Each person has to have personal accountability. We are not going to outlaw cough syrup because a few people abuse it. We are not going to outlaw beer or wine or distilled spirits because a few people abuse them. We are not to outlaw coffee because some people abuse caffeinated beverages. The states continued prohibition against marijuana does not make sense either. This is exactly why normal rational people are voting Yes for I-502.
Law Enforcement Supports the end of Prohibition
When law enforcement professionals are openly endorsing I-502 on National Television, only the most confused people continue to oppose it!
Law Enforcement Against Prohibition (LEAP)
http://www.leap.cc/
The Science
Against the Prohibition of Marijuana
by Aaron Schwarz on Wednesday, December 15, 2010 at 6:40pm
Law Enforcement Supports the end of Prohibition
When law enforcement professionals are openly endorsing I-502 on National Television, only the most confused people continue to oppose it!
Law Enforcement Against Prohibition (LEAP)
http://www.leap.cc/
The Science
An Overview of the Endogenous Cannabinoid System
Its Components and Possible Roles of this Recently Discovered Regulatory System
v1.3 Apr 2011
Citation: Goodman N. "An Overview of the Endogenous Cannabinoid System: Components and Possible Roles of this Recently Discovered Regulatory System".
Contact: goodman_neil@hotmail.com
1.0 Introduction #
Cannabis sativa is one of the most widely used psychoactives and has a documented history of use going back thousands of years; however, the mechanisms of its actions are only just being elucidated. Until relatively recently, the intoxicating effect of cannabis was thought to act in a way similar to ethanol. The active principle, Δ9-tetrahydrocannabinol (THC), a highly lipophilic molecule, was thought to insert itself into the lipid cell membrane of nerve cells. However, it is now known that a specific receptor in the brain selectively binds this ligand. The characteristic effects of cannabis intoxication are thus generated by intracellular changes and altered signalling of the neurons.
Different subtypes of this receptor are known to be present in the body. When these receptors were first discovered, there were no naturally-occurring molecules in the body that were known to bind them. Early fringe speculation suggested that the receptor system might have co-evolved with the ancient use of cannabis, but its natural function is not to mediate the effects of the most widely distributed and used drug of plant origin, but to interact with naturally occurring, or endogenous, cannabinoids. These cannabinoids, their receptors, and their possible roles in the normal functioning of the body are the focus of intensive research. Present evidence suggests that the endocannabinoids and their receptors constitute a widespread modulatory system that fine tunes bodily responses to a number of stimuli.
This short review article outlines what is currently known about this system from experiments undertaken by scientists in a range of fields. The purpose of this article is not to provide a comprehensive review of all research and knowledge in the field of endocannabinoid research, but to give an overview of the system as it is currently known and to highlight several interesting areas. First, the cannabinoid receptors shall be discussed, followed by the molecules thought to selectively bind them (their ligands) under normal physiological conditions. The final section of this review focuses on some of the possible functions this recently discovered system could perform and the individual roles that the endocannabinoids and their receptors could play. An outline of the optimistic outlook for cannabinoid therapies is then given.
The first cannabinoid receptor to be discovered was characterized and cloned in 1990 from the mammalian brain1. Its structure and function resembles that of other known hormone receptors2. As of May 2003, two subtypes of the cannabinoid receptor, CB1 and CB2, have been distinguished and are expressed both in the nervous system and peripheral tissues and organs. Both subtypes belong to the seven transmembrane spanning receptor family with seven a-helices spanning the cell membrane. The intracellular loops of the receptor protein are involved with G-proteins responsible for the transduction of the intercellular signal. This G-protein-coupled receptor causes the inhibition of the enzymatic activity of adenylate cyclase responsible for the production of cyclic adenosine monophosphate (cAMP) in the cell. A large number of hormones act through G-protein-coupled receptors and so cAMP has been termed a 'second messenger' because it transmits signals originating at the surface of cells from a variety of 'first messengers' to the interior of cells.
The CB1 receptor is also present in the cerebellum, throughout the cerebral cortex and also in many parts of the body including both the male and female reproductive systems. The scarcity of receptors in the medulla oblongata, responsible for controlling respiratory and cardiovascular functions, explains the virtual absence of reports of fatal cannabis overdose in humans5.
The existence of two homologous receptor subtypes, with moderate to low sequence identity, allowed for the development of both agonists and antagonists selective for either type. THC is known to act as a weak, but functional, agonist of the CB2 receptor10. Exciting research is being undertaken into the possibility of developing therapeutically useful compounds that selectively bind the CB2 receptor. These compounds could perform their beneficial function without their potentially unwanted, psychotropic side effects.
Although there has been no progress in finding CBn receptors, a functionally active short isoform has been characterized called CB1A12. The distribution of mRNA for both the CB1 and CB1A receptor has been found throughout the brain and in all peripheral tissues examined. The putative CB1A receptor is present in amounts of up to 20% that of CB1 and has been shown to exhibit all the known properties of CB1 to a slightly attenuated extent13.
We have seen that receptors for cannabinoids exist in the body. The presence of these receptors that selectively bind THC and other cannabinoids could only be explained by the presence of endogenous ligands that can bind them. Otherwise, it would indeed be strange that receptors exist in the body, having as their only function the binding of molecules of plant origin. Researchers thus looked for molecules in the body that utilized these orphan receptors and thereby discovered their natural functions.
This putative endocannabinoid caused the typical behavioral reactions in mice, affected levels of cAMP17 and had similar effects to some actions of THC in the periphery18. It has also been shown to be present in the brain of rats, at levels higher than those of anandamide19 and also in dog spleen and pancreas20.
The cannabimimetic actions of oleamide, however, cannot have been mediated though any of the known cannabinoid receptor types. Oleamide can only bind CB1 or CB2 receptors at very high concentrations never present under physiological conditions26. [This statement on oleamide binding has been disputed, see Comments.] An indirect way that oleamide could exert its cannabimimetic action could be through the competitive inhibition of the enzyme responsible for the degradation of anandamide27. This action would thus raise the concentration of the latter cannabinoid, causing its actions to be recorded. Other long-chain fatty acid ethanolamides, co-synthesized with anandamide in neurons, are also thought to have a similar function28.
Although the distribution of receptors in the body is becoming clearer and their putative ligands becoming more fully characterized, the correlation between pathophysiological responses and the production and activation of these ligands is by no means certain. Nevertheless, from the existing data, it is possible to suggest a widespread modulatory role for the cannabinoid system, responsible for regulating a number of tasks. This system is not limited to the central nervous system but is also concerned with peripheral processes and could act to modulate neurotransmitter release and action from autonomic and sensory nerve fibers. Functions within the control of immunological, gastrointestinal, reproductive and cardiovascular performance are also indicated.
It has recently been shown that the endogenous cannabinoid system has a central function in the extinction of aversive memories42. Aversive memories are important for the survival of an organism. These memories are kept by reinforcement but if reinforcement does not occur, the resulting behavioral response to the noxious stimuli will diminish until it no longer exists. This extinction process is also important but its mechanism is not fully known. Endocannabinoids acting through the CB1 receptor in the amygdala of the limbic system (which is known to be involved in this process43) are now thought to facilitate the memory loss through an inhibitory effect on local inhibitory networks (possibly GABA-using neurons).
The actions of endocannabinoids may be mediated by cannabinoid receptors located both pre- and post- synaptically. The activation of pre-synaptic receptors could lead to such intracellular changes that modulate the release and/or actions of other neurotransmitters, such as dopamine, acetylcholine and glutamate44, 45, 46, 47 and thereby have even further-reaching effects. In such a way, THC has been found to facilitate the release of dynorphins (endogenous opiate-like molecules), which act at opioid receptors. This action may have a role to play in the pain-reducing, or analgesic, properties of both THC and anandamide.
Recent research has tentatively shown that THC does not affect the VR1 receptor. In other studies, when the CB1 receptor of mice was genetically eliminated, the CB1 knockout mice did not exhibit significant alterations of pain indicators49. These results, however, appear to contradict other studies that demonstrate anti-nociceptive activity produced by marijuana or THC. One possibility that may explain these apparently contradictive data may lie in the fact that THC has a high affinity for the CB1 receptor. Exogenously applied THC, such as when a subject smokes marijuana, may compete with other agonists of the CB1 receptor thus competing with anandamide for binding to the CB1 receptor. This would free endogenous anandamide and increase the concentration available to bind to the VR1 receptor and therefore provide the reported pain relief. Some anecdotal evidence suggests that users of medical marijuana become insensitive to the euphoric effects of marijuana after sustained use while still benefiting from its pain relieving properties. The mechanism proposed above may underlie this action, although the question will have to await further research before being fully clarified.
Anandamide from basophils might also increase the production of prostaglandin E2 from macrophages, which suppresses the activity and proliferation of both lymphocytes and macrophages. Anandamide could also directly inhibit the recruitment of lymphocytes during the late phase of the allergic response and induce their cell death61. It would thus appear that both palmitoyl-ethanolamide and anandamide could help to prevent the excessive propagation of the inflammatory response. This would reduce the risk of subsequent hypersensitivity to the initial stimulus and prevent the development of allergic disease54, 62. Further research is needed to determine which receptor types are expressed in the different sub-populations of each immune cell-type. It is, at present, unclear which of the immunological actions of the endocannabinoids are mediated by which cannabinoid receptor. Research directed into giving a clearer picture of receptor expression would certainly help clarify their immunomodulatory role.
It is conceivable that endocannabinoids in the reproductive system act as local hormones and evidence exists for an anandaminergic system in the rat testes and mouse vas deferens that controls spermatogenesis and male fertility63, 64, 65. THC and anandamide are also both thought to inhibit the acrosome reaction through cannabinoid receptors on the sperm cell membrane66, 67, 68. These receptors have been found on the sperm cell of the sea urchin, and the ovaries from the same species are known to synthesize and degrade both anandamide and palmitoyl-ethanolamide69. It is therefore conceivable that the sea urchin synthesizes anandamide during the acrosome reaction in order to prevent fertilization by more than one sperm. It is not yet known whether an analogous system also occurs in mammals although some evidence does point towards an increased infertility among chronic cannabis users.
Anandamide may also play another interesting role in the female reproductive system. CB1 and CB2 receptors are present in the embryos of mice from the very early stages of their development and also in the adult uterus70. Due to the inhibitory effect of anandamide on embryonic cell division, anandamide might act as a negative signal for embryonic development and implantation71. High levels of the synthesizing enzyme, and low levels of the degrading enzyme exist at the time when the uterus is the least receptive for embryo implantation. The uterus may therefore utilize anandamide in order to direct both the location and timing of embryo implantation.
In just over one decade, the abundance of quality research has changed our basic views of the mechanism of cannabis intoxication. It has also unveiled a new and extensive regulatory system within the body. Further multidisciplinary research must be undertaken to improve our understanding of these functions and provide more data on the expression and inactivation of the components of this system. It will then be possible to exploit this knowledge in order to make therapeutic compounds for the treatment of symptoms, and possible prevention, of a number of disorders.
One of the most interesting potential therapeutic actions of cannabinoids reported to date is the ability of cannabinoids to inhibit the growth of cancerous, or transformed, cells in culture. Anandamide can inhibit breast cancer cell proliferation74 and THC can cause the programmed cell death, or apoptosis, of transformed neural cells in vitro75. In vivo research has also begun to elucidate the biochemical mechanisms involved in the anti-tumoral actions of CB1 agonists, including THC76. These experiments have shown that it is possible to completely eradicate malignant brain tumors in rats by THC administration.
Cannabinoids have also been found to protect neurons in culture from glutamate-induced excitotoxicity77, 78 and from ischaemic death (lack of oxygen)79. These ligands are currently under test as therapeutic agents in the treatment of neurodegenerative diseases such as multiple sclerosis and Parkinson's Disease. Research is also being directed into the possibility of using cannabinoids as drugs that could stop the growth and spread of cancer cells, based on the research mentioned above.
A prominent researcher in the field described the discovery of anandamide as a 'new dawn for cannabinoid pharmacology'7. Although a lot of work has been conducted, we can expect far more research in the near future that could revolutionize the way we view our bodies and the treatments we use to prevent their malfunction.
Different subtypes of this receptor are known to be present in the body. When these receptors were first discovered, there were no naturally-occurring molecules in the body that were known to bind them. Early fringe speculation suggested that the receptor system might have co-evolved with the ancient use of cannabis, but its natural function is not to mediate the effects of the most widely distributed and used drug of plant origin, but to interact with naturally occurring, or endogenous, cannabinoids. These cannabinoids, their receptors, and their possible roles in the normal functioning of the body are the focus of intensive research. Present evidence suggests that the endocannabinoids and their receptors constitute a widespread modulatory system that fine tunes bodily responses to a number of stimuli.
This short review article outlines what is currently known about this system from experiments undertaken by scientists in a range of fields. The purpose of this article is not to provide a comprehensive review of all research and knowledge in the field of endocannabinoid research, but to give an overview of the system as it is currently known and to highlight several interesting areas. First, the cannabinoid receptors shall be discussed, followed by the molecules thought to selectively bind them (their ligands) under normal physiological conditions. The final section of this review focuses on some of the possible functions this recently discovered system could perform and the individual roles that the endocannabinoids and their receptors could play. An outline of the optimistic outlook for cannabinoid therapies is then given.
2.0 Cannabinoid receptors #
The first cannabinoid receptor to be discovered was characterized and cloned in 1990 from the mammalian brain1. Its structure and function resembles that of other known hormone receptors2. As of May 2003, two subtypes of the cannabinoid receptor, CB1 and CB2, have been distinguished and are expressed both in the nervous system and peripheral tissues and organs. Both subtypes belong to the seven transmembrane spanning receptor family with seven a-helices spanning the cell membrane. The intracellular loops of the receptor protein are involved with G-proteins responsible for the transduction of the intercellular signal. This G-protein-coupled receptor causes the inhibition of the enzymatic activity of adenylate cyclase responsible for the production of cyclic adenosine monophosphate (cAMP) in the cell. A large number of hormones act through G-protein-coupled receptors and so cAMP has been termed a 'second messenger' because it transmits signals originating at the surface of cells from a variety of 'first messengers' to the interior of cells.
2.1 The CB1 receptor #
The CB1 receptor is present in both the nervous system and other tissues and organs of the body. By using the imaging technique called quantitative radiography, researchers have determined that this receptor is responsible for the psychotropic actions of THC and other cannabinoids3. The primary regions where cannabinoids bind in the human brain are the basal ganglia, which control unconscious muscle movements, and the limbic system, including the hippocampus, which is involved in integrating memory. It is this last distribution that points to the reason why the most consistent effect of THC on performance is the disruption of selective aspects of short-term memory tasks, similar to patients with damage to the limbic cortical areas4.The CB1 receptor is also present in the cerebellum, throughout the cerebral cortex and also in many parts of the body including both the male and female reproductive systems. The scarcity of receptors in the medulla oblongata, responsible for controlling respiratory and cardiovascular functions, explains the virtual absence of reports of fatal cannabis overdose in humans5.
2.2 The CB2 receptor #
Three years after the discovery of CB1, a second human cannabinoid receptor, CB2, was identified in the marginal zone of the spleen6. The CB2 receptor is homologous to the CB1 receptor, sharing an overall 44% homology with CB17. It is confined to the immune system with its greatest density in the region where it was first discovered8. It is this form of the receptor that is expressed on T-cells of the immune system9 but is not expressed in the central nervous system (CNS) or, like the CB1 receptor, in the liver, lungs or kidneys.The existence of two homologous receptor subtypes, with moderate to low sequence identity, allowed for the development of both agonists and antagonists selective for either type. THC is known to act as a weak, but functional, agonist of the CB2 receptor10. Exciting research is being undertaken into the possibility of developing therapeutically useful compounds that selectively bind the CB2 receptor. These compounds could perform their beneficial function without their potentially unwanted, psychotropic side effects.
2.3 The possibility of CBn receptors #
Although no further subtypes have been discovered, it is possible that other cannabinoid receptors may exist. Advances in molecular biology, including the possibility of in silico screening of complete gene libraries, may uncover CBn (that is, neither CB1, nor CB2) receptors with low amino acid sequence homology to the cloned receptors. Indirect evidence also supports the existence of as yet undiscovered receptors both in the periphery and the brain. It has been shown that certain compounds exert typical cannabimimetic actions, such as the down-regulation of mast cells, but this cannot be reproduced in cells transfected with either the CB1 or CB2 receptors11.Although there has been no progress in finding CBn receptors, a functionally active short isoform has been characterized called CB1A12. The distribution of mRNA for both the CB1 and CB1A receptor has been found throughout the brain and in all peripheral tissues examined. The putative CB1A receptor is present in amounts of up to 20% that of CB1 and has been shown to exhibit all the known properties of CB1 to a slightly attenuated extent13.
3.0 Endocannabinoids #
We have seen that receptors for cannabinoids exist in the body. The presence of these receptors that selectively bind THC and other cannabinoids could only be explained by the presence of endogenous ligands that can bind them. Otherwise, it would indeed be strange that receptors exist in the body, having as their only function the binding of molecules of plant origin. Researchers thus looked for molecules in the body that utilized these orphan receptors and thereby discovered their natural functions.
3.1 Anandamide #
In 1992, Devane et al., identified the first putative endocannabinoid from porcine brain14. This ligand was later called anandamide, which is derived from the Sanskrit word for bliss (ananda) due to its possible cannabimimetic, psychotropic properties. Anandamide, or N-arachidonylethanolamine, is a modified form of arachidonic acid. It is a polyunsaturated fatty acid that serves as a common precursor for many biologically active metabolites. Although the structure of anandamide is quite different from THC, experiments have shown that it binds to cannabinoid receptors. It has also been shown to share with THC, and other cannabinoids, most of the pharmacological properties exerted both in the CNS and peripheral system. These include the basic characteristic actions in behavioral tests on rodents15. Cross-tolerance to THC also substantiates the evidence that anandamide works through the same mechanism as THC and, like THC, anandamide also increases both the affinity and number of rat cerebellum and hippocampal receptors after chronic and acute exposure16.
3.2 2-arachidonoyl-glycerol #
Because anandamide, like THC, behaves as a weak agonist at CB2 receptors, the question arose whether there may be other endogenous cannabinoids more selective for the CB2 receptor and produced in the peripheral tissues. Investigations led to the discovery of 2-arachidonoyl-glycerol from the canine gut17. This derivative of arachidonic acid was shown to bind to both CB1 and CB2 receptors.This putative endocannabinoid caused the typical behavioral reactions in mice, affected levels of cAMP17 and had similar effects to some actions of THC in the periphery18. It has also been shown to be present in the brain of rats, at levels higher than those of anandamide19 and also in dog spleen and pancreas20.
3.3 Palmitoyl-ethanolamide #
Palmitoyl-ethanolamide, or N-(2-Hydroxyethyl)hexadecamide, is an N-acyl-ethanolamide. It is co-synthesized with anandamide in all tissues so far examined and possibly acts as an endogenous CB2 ligand. Its proposed role is that of an autocoid, or 'local hormone', capable of negatively regulating mast cell activation and inflammation [21]. It has also been reported that palmitoyl-ethanolamide can down-regulate IgE-triggered activation of cultured mast cells through the CB2 receptor present on these cells21.
3.4 Docosatetraenylethanolamide and Homo-γ-linoenylethanolamide #
Researchers looking for further endocannabinoids reasoned that other classes of chemical mediators originating from the precursor arachidonic acid, such as prostaglandins and leukotrienes, do not exist as single entities but as large families of chemically-related substances. They therefore expected that anandamide was only the first identified representative of a class of unsaturated fatty acid-derived ethanolamides that bind to the cannabinoid receptor22. Within a short period of anandamide being identified, two analogues of anandamide -- docosatetraenylethanolamide (DTEA) and homo-g-linoenylethanolamide (HLEA) were also isolated and identified. They were found to exert similar effects to both anandamide and THC in behavioral tests on rodents and also inhibited the action of adenylate cyclase through G-proteins, the action of which could be blocked by the highly specific CB1 antagonist SR 141716A 23, 24. It was therefore proposed that these substances might function as endogenous agonists at the neuronal CB1 receptor.
3.5 Oleamide #
Another putative endogenous cannabinoid, oleamide, or cis-9-octadecenoamide, has also been isolated and shown to have similar actions to anandamide in the behavioral rodent tests. This molecule is a long-chain fatty acid derivative that was first isolated from the cerebrospinal fluid of cats and humans deprived of sleep. This extract had a sleep-inducing action in mammals25, which has often been suggested for anandamide and THC because of their sedative and motor inhibitory properties.The cannabimimetic actions of oleamide, however, cannot have been mediated though any of the known cannabinoid receptor types. Oleamide can only bind CB1 or CB2 receptors at very high concentrations never present under physiological conditions26. [This statement on oleamide binding has been disputed, see Comments.] An indirect way that oleamide could exert its cannabimimetic action could be through the competitive inhibition of the enzyme responsible for the degradation of anandamide27. This action would thus raise the concentration of the latter cannabinoid, causing its actions to be recorded. Other long-chain fatty acid ethanolamides, co-synthesized with anandamide in neurons, are also thought to have a similar function28.
4.0 Proposed roles of the endogenous cannabinoid system #
Although the distribution of receptors in the body is becoming clearer and their putative ligands becoming more fully characterized, the correlation between pathophysiological responses and the production and activation of these ligands is by no means certain. Nevertheless, from the existing data, it is possible to suggest a widespread modulatory role for the cannabinoid system, responsible for regulating a number of tasks. This system is not limited to the central nervous system but is also concerned with peripheral processes and could act to modulate neurotransmitter release and action from autonomic and sensory nerve fibers. Functions within the control of immunological, gastrointestinal, reproductive and cardiovascular performance are also indicated.
4.1 Learning and synaptic plasticity #
It has been shown that, in the brain, the CB1 receptor is one of the most abundant G-protein coupled receptors present29. Activation of these CB1 receptors suppresses the release of a number of nerotransmitters including acetylcholine, noradrenaline, dopamine, serotonin, GABA, glutamate and aspartate30, 31, 32, 33 and cannabimimetic drugs are known to produce a number of behavioral effects including the impairment of memory34, 35, 36. This could be due to CB1 receptors modulating cAMP-dependent synaptic plasticity and thereby preventing the recruitment of new synapses by inhibiting the formation of cAMP37. Due to both functional and anatomical evidence suggesting that CB1 receptors are present pre-synaptically30, 38, 39, cannabinoids may therefore act at this site to inhibit new synapse formation. This is further suggested by the observation that hippocampal presynaptic boutons assemble before the postsynaptic assembly40. Synaptic plasticity is an important property involved in a number of processes and the possibility therefore exists that endocannabinoids act to modulate changes in neuronal communication associated with brain development, learning, and also pain41.It has recently been shown that the endogenous cannabinoid system has a central function in the extinction of aversive memories42. Aversive memories are important for the survival of an organism. These memories are kept by reinforcement but if reinforcement does not occur, the resulting behavioral response to the noxious stimuli will diminish until it no longer exists. This extinction process is also important but its mechanism is not fully known. Endocannabinoids acting through the CB1 receptor in the amygdala of the limbic system (which is known to be involved in this process43) are now thought to facilitate the memory loss through an inhibitory effect on local inhibitory networks (possibly GABA-using neurons).
The actions of endocannabinoids may be mediated by cannabinoid receptors located both pre- and post- synaptically. The activation of pre-synaptic receptors could lead to such intracellular changes that modulate the release and/or actions of other neurotransmitters, such as dopamine, acetylcholine and glutamate44, 45, 46, 47 and thereby have even further-reaching effects. In such a way, THC has been found to facilitate the release of dynorphins (endogenous opiate-like molecules), which act at opioid receptors. This action may have a role to play in the pain-reducing, or analgesic, properties of both THC and anandamide.
4.2 Pain #
Pain is initiated when a variety of physical stimuli activate specific pain receptors. The endogenous cannabinoid, anandamide, can inhibit the stimulation of one such pain receptor, the vanilloid receptor (VR1), which results in an analgesic effect. Anandamide and structurally-related lipids may also act as vanilloid receptor modulators in the regulation of various afferent stimuli such as pain reception and visceral reflexes and also efferent actions such as vasodilation and inflammation arising from the nervous signals. However, this research is currently in the preliminary stages and the natural occurrence in vivo has yet to be determined48.Recent research has tentatively shown that THC does not affect the VR1 receptor. In other studies, when the CB1 receptor of mice was genetically eliminated, the CB1 knockout mice did not exhibit significant alterations of pain indicators49. These results, however, appear to contradict other studies that demonstrate anti-nociceptive activity produced by marijuana or THC. One possibility that may explain these apparently contradictive data may lie in the fact that THC has a high affinity for the CB1 receptor. Exogenously applied THC, such as when a subject smokes marijuana, may compete with other agonists of the CB1 receptor thus competing with anandamide for binding to the CB1 receptor. This would free endogenous anandamide and increase the concentration available to bind to the VR1 receptor and therefore provide the reported pain relief. Some anecdotal evidence suggests that users of medical marijuana become insensitive to the euphoric effects of marijuana after sustained use while still benefiting from its pain relieving properties. The mechanism proposed above may underlie this action, although the question will have to await further research before being fully clarified.
4.3 Vision #
A large amount of anecdotal evidence and several published scientific reports describe numerous effects of cannabinoids on visual perception. This includes altered thresholds of light detection and recovery from glare. The possible positions within the brain and/or retina of the eye responsible for these changes in perception are, as yet, unknown, although research has found that CB1 receptors are found in the retina of many vertebrate species50. This report also presents strong evidence for an endogenous cannabinoid signalling system in the vertebrate retina utilizing 2-arachidonoyl-glycerol and palmitoyl-ethanolamide which may act pre-synaptically to regulate the release of the neurotransmitter glutamate across synapses.
4.4 Neuroprotection #
A neuroprotective role may also exist for the acyl-ethanolamides in general and palmitoyl-ethanolamide in particular, due to their production at the sites of neuronal damage and cell death51, 52, 53, 54, 55. It is also becoming clear that CB1 receptors are present in the hypothalamus and may be responsible for the fine-tuning of pituitary hormone secretion56, 57, 58. Injection of anandamide into the ventricles of the brain led to the release of the hypothalamic hormone, corticotrophin-releasing factor-4156. This hormone ultimately leads to the production of corticosterone, a regulator of carbohydrate and protein metabolism, from the adrenal gland. Anandamide working at the hypothalamus may also inhibit the release of other hormones, such as prolactin and the luteinising, follicle stimulating and growth hormones57, 58.
4.5 Allergy and regulation of inflammation #
In addition to modulating the release of neurotransmitters and hormones, it is becoming increasingly clear that the endocannabinoid system is intimately linked to other processes in the periphery. A system may exist where endocannabinoids mediate chemical communication between different types of immune cells and between sensory fibers and blood cells. They have also been found to play an important role in acute inflammatory reactions. The standard picture of inflammatory reactions is that binding of an allergen to IgE receptors on immune cells leads to the activation of basophil and mast cells. These cells then release histamine, serotonin and leukotrienes. Within this mixture of inflammatory mediators, palmitoyl-ethanolamide and anandamide have also been discovered59. Palmitoyl-ethanolamide is thought to act as an autocoid on the same, or neighboring, basophilic or mast cells and thereby inhibits the further release of mediators60, thereby keeping the inflammatory reaction in check.Anandamide from basophils might also increase the production of prostaglandin E2 from macrophages, which suppresses the activity and proliferation of both lymphocytes and macrophages. Anandamide could also directly inhibit the recruitment of lymphocytes during the late phase of the allergic response and induce their cell death61. It would thus appear that both palmitoyl-ethanolamide and anandamide could help to prevent the excessive propagation of the inflammatory response. This would reduce the risk of subsequent hypersensitivity to the initial stimulus and prevent the development of allergic disease54, 62. Further research is needed to determine which receptor types are expressed in the different sub-populations of each immune cell-type. It is, at present, unclear which of the immunological actions of the endocannabinoids are mediated by which cannabinoid receptor. Research directed into giving a clearer picture of receptor expression would certainly help clarify their immunomodulatory role.
4.6 Reproduction #
There are a number of other ideas for possible roles for the endocannabinoid system based on the expression of the ligands, and/or their receptors in the body. These include the very interesting observation that tissues of the reproductive system also contain receptors and are able to synthesize and degrade endocannabinoids.It is conceivable that endocannabinoids in the reproductive system act as local hormones and evidence exists for an anandaminergic system in the rat testes and mouse vas deferens that controls spermatogenesis and male fertility63, 64, 65. THC and anandamide are also both thought to inhibit the acrosome reaction through cannabinoid receptors on the sperm cell membrane66, 67, 68. These receptors have been found on the sperm cell of the sea urchin, and the ovaries from the same species are known to synthesize and degrade both anandamide and palmitoyl-ethanolamide69. It is therefore conceivable that the sea urchin synthesizes anandamide during the acrosome reaction in order to prevent fertilization by more than one sperm. It is not yet known whether an analogous system also occurs in mammals although some evidence does point towards an increased infertility among chronic cannabis users.
Anandamide may also play another interesting role in the female reproductive system. CB1 and CB2 receptors are present in the embryos of mice from the very early stages of their development and also in the adult uterus70. Due to the inhibitory effect of anandamide on embryonic cell division, anandamide might act as a negative signal for embryonic development and implantation71. High levels of the synthesizing enzyme, and low levels of the degrading enzyme exist at the time when the uterus is the least receptive for embryo implantation. The uterus may therefore utilize anandamide in order to direct both the location and timing of embryo implantation.
5.0 Concluding remarks #
In just over one decade, the abundance of quality research has changed our basic views of the mechanism of cannabis intoxication. It has also unveiled a new and extensive regulatory system within the body. Further multidisciplinary research must be undertaken to improve our understanding of these functions and provide more data on the expression and inactivation of the components of this system. It will then be possible to exploit this knowledge in order to make therapeutic compounds for the treatment of symptoms, and possible prevention, of a number of disorders.
5.1 Therapeutic possibilities #
Such therapies could act through the agonistic/antagonistic properties of the novel compounds acting at cannabinoid receptors, or by targeting the synthesizing, or degrading, enzymes responsible for endocannabinoids. As cannabinoids are effective at countering muscle spasms, this property could be exploited to provide relief for sufferers of multiple sclerosis and patients who suffer from chronic tremors, or other involuntary movements. Ongoing research is presently determining whether cannabinoid ligands are effective agents in the treatment of chronic pain, glaucoma, spasms, and the wasting and emesis associated with AIDS and cancer chemotherapy72, 73. This latter property is currently being exploited and a cannabinoid called Nabilone is on the market, indicated for the suppression of nausea and vomiting during cytotoxic chemotherapy. The potential therapeutic application of cannabinoids is, however, controversial and constitutes a widely debated issue with relevance in both scientific and social circles.One of the most interesting potential therapeutic actions of cannabinoids reported to date is the ability of cannabinoids to inhibit the growth of cancerous, or transformed, cells in culture. Anandamide can inhibit breast cancer cell proliferation74 and THC can cause the programmed cell death, or apoptosis, of transformed neural cells in vitro75. In vivo research has also begun to elucidate the biochemical mechanisms involved in the anti-tumoral actions of CB1 agonists, including THC76. These experiments have shown that it is possible to completely eradicate malignant brain tumors in rats by THC administration.
Cannabinoids have also been found to protect neurons in culture from glutamate-induced excitotoxicity77, 78 and from ischaemic death (lack of oxygen)79. These ligands are currently under test as therapeutic agents in the treatment of neurodegenerative diseases such as multiple sclerosis and Parkinson's Disease. Research is also being directed into the possibility of using cannabinoids as drugs that could stop the growth and spread of cancer cells, based on the research mentioned above.
A prominent researcher in the field described the discovery of anandamide as a 'new dawn for cannabinoid pharmacology'7. Although a lot of work has been conducted, we can expect far more research in the near future that could revolutionize the way we view our bodies and the treatments we use to prevent their malfunction.
Against the Prohibition of Marijuana
by Aaron Schwarz on Wednesday, December 15, 2010 at 6:40pm
There are many reasons to support marijuana legalization. In the following I will present some of these ideas and outline the reasoning and ideologies that gives rational reasons to change the current prohibition laws. I include some links in most of the sections so that you can use this document as a springboard to other literature on this subject and issue. Enjoy
Inconsistent Laws
The federal statute placing marijuana as a Schedule I substance is inconsistent with the scientific findings that marijuana and its active constituents are effective at treating hundreds of medical conditions; findings that are supported by 16 states who's medical marijuana laws confirm the science. http://www.mpp.org/library/policy-analysis-alternatives.html
The Facts:
Millions of arthritis, glaucoma, cancer, pain, HIV and Chrones patients: millions of people who suffer from a wide range of medical/ psychological ailments can benefit from the use of cannabis products. The cannabinoids in the cannabis plant are useful in the treatment and prophylaxis of wide variety of oxidation associated diseases, such as ischemic, age-related, inflammatory and autoimmune diseases. The cannabinoids in marijuana are found to have particular application as neuroprotectants, for example in limiting neurological damage following ischemic insults, such as stroke and trauma, or in the treatment of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Dementia.
The History: A brief example...
Focus On Real Crimes
For common goods sake would the state please focus their resources on catching criminals who violate other peoples rights; rapists, murderers, pedophiles, identity thieves, financial fraud and other forms of anti-freedom/ hate and violence that hurts our country and society; focus on the hard drugs and real criminals.
The Reasons People Use It
Modes of Use
Marijuana can be cooked into foods, vaporized, smoked or extracted and or consumed as a liquid;the versatility of active delivery methods means flexible options for medical treatment and recreation use alike.
There are thousands of strain types, each with a unique medicinal, flavor, color and quality profile; different kinds have different medicinal and social applications based on their strength and flavor; similar to how there are many kinds of beer, wine and mixed drinks for different settings and different applications.
Lost Source of Tax Revenue
We could have legal marijuana generating billions of tax revenue for the states and federal government; where labels would clearly indicate the strength, potency and strain type, and recommended use; but under the current federal statute, billions of dollars are diverted into the grey market where organized criminals are forced to supply the innocent customers who prefer this plant flower over the alternatives intoxicants that are legal: namly alcohol, and prescribed anxiolytic drugs of the benzodiazepine class (xanax et. al.)
My Position on the Laws
I cannot understand nor will I ever endorse or support any law against marijuana except those that govern its access to adults; the same way that we have common sense laws restricting alcohol and tobacco products to adults. I also do not advocate violation of the federal statute as doing so is dangerous because of the legal risks of arrest, prosecution and incarceration.
The fact that their is a federal law restricting patients from access to their preferred highly effective and safe medicine is an absurdity. Please join me and millions of others in saying no to prohibition and yes to freedom for marijuana: vote yes for marijuana legalization.
Sincerely,
Aaron Kenneth Schwarz
Legal Disclaimer: For Clarity
I do not use marijuana or any derivatives of the cannabis plant and I furthermore do not condone or endorse the violation of any laws. Those who do have a legitimate medicinal reason for using marijuana as a medicine may contact the green cross of washington state to establish contact with doctor.
If you live in one of these other states: Alaska, Arizona, California, Colorado, Hawaii, Maine, Michigan, Montana, Nevada, New Jersey, New Mexico, Oregon, Rhode Island, Vermont, or Virginia; then you may contact local medical cannabis organizations to locate doctors that you can work with.
Just watch this (http://www.youtube.com/watch?v=LayaGk0TMDc) and then post something about why prohibition is effective ?
Law Enforcement Agrees
LEAP, former police officers who had to administer the backward draconian drug laws come forward and speak out to describe how the war on drugs was is and always will be a miserable failure that wastes tax money, divert billions of dollars into organized crime, jams up the courts, jails and prisons with non violent offenders who violate no other laws than those related to controlled substances. They openly recognize as I do that drugs like methamphetamine, cocaine and heroin are incredibly destructive to users that abuse these substances. They are suggesting as I have suggested that the state would be better off prescribing these drugs to their users and then administering treatment and help for the addicts who suffer from all forms of addiction and substance abuse. http://www.leap.cc/cms/index.php
Benefits of Legalization
When marijuana is legal, it can be controlled by the state, regulated, taxed and sold to adults with valid ID. Ironically, most of the hard dangerous drugs are already prescription drugs, while marijuana is flat prohibited by federal law.
If marijuana is legalized it can be taxed and controlled; regulated for potency and labeling for consumer safety. If criminals are forced to supply the market, then all sorts of nasty things will continue happening.
The Costs of The Backward Laws
For the state to continue waging a war against its own people is absurd, and no amount of backward Rhetoric will prove otherwise. The fact is that when Drugs Lords and Criminals control drugs, then children end up with them, then they are cut with nasty substances which harm users more than the drugs, then people end up diverting capital into the hands of the criminal entrepreneurs who produce, distribute and administer the sales of illicit substances.
Prohibition Does Not Work
Education and Freedom are the Answers
What we need is honesty and education: so that people can make rational choices about what to smoke or not to smoke, about what to drink or not to drink. We need adults to have the medical, spiritual and personal freedom to choose what they do with their bodies (abortion, prostitution, tatoos, substance use, piercings, BSDM, or whatever else consenting adults choose to do with themselves and other willing parties) so long as they do not violate any law on infringe on the rights of other free people. http://www.usconstitution.net/const.html
All Drugs are Dangerous
An Ineffective War Against Freedom
Good Intentions Gone Astray
What I am hoping for is that the courts and law enforcement systems can send drug abuser to treatment, not to prison or jail. I am worried about the security of our borders from terrorist agents; so the DEA agents who stop working on marijuana can work on improving national security by redirecting their talents and capacities to stopping the infiltration of illegal aliens and terrorist agents into our nation. I support their effort where they operate to increase public safety; to protect communities from dangerous criminal networks.
Promoting Progressive Public Policy
I am only involved in promoting healthy intelligent public policy based on rational science and information. I do not participate or have an connections or information about people in the narcotics trade. Of the few friends I used to know that were involved with marijuana, I have lost contact with them and know nothing of their activities, whereabouts or current modes of employment. I am a law abiding citizen who is politically active and I only seek to address change with conversations by encouraging public discourse.
Others Agree:
1. Shock: Christian Coalition founder Pat Robertson favors marijuana legalization | Raw Story
700 Club founder Pat Robertson, one of the cornerstone figures of America's Christian right movement, has come out in favor of legalizing marijuana: because its prohibition criminalizes innocent people who then loose opportunities and turn to lives in crime.
Why I Support Legal Marijuana
We should invest in effective education rather than ineffective arrest and incarceration.
By GEORGE SOROS
Our marijuana laws are clearly doing more harm than good. The criminalization of marijuana did not prevent marijuana from becoming the most widely used illegal substance in the United States and many other countries. But it did result in extensive costs and negative consequences.
Law enforcement agencies today spend many billions of taxpayer dollars annually trying to enforce this unenforceable prohibition. The roughly 750,000 arrests they make each year for possession of small amounts of marijuana represent more than 40% of all drug arrests.
Regulating and taxing marijuana would simultaneously save taxpayers billions of dollars in enforcement and incarceration costs, while providing many billions of dollars in revenue annually. It also would reduce the crime, violence and corruption associated with drug markets, and the violations of civil liberties and human rights that occur when large numbers of otherwise law-abiding citizens are subject to arrest. Police could focus on serious crime instead.
The racial inequities that are part and parcel of marijuana enforcement policies cannot be ignored. African-Americans are no more likely than other Americans to use marijuana but they are three, five or even 10 times more likely—depending on the city—to be arrested for possessing marijuana. I agree with Alice Huffman, president of the California NAACP, when she says that being caught up in the criminal justice system does more harm to young people than marijuana itself. Giving millions of young Americans a permanent drug arrest record that may follow them for life serves no one's interests.
Racial prejudice also helps explain the origins of marijuana prohibition. When California and other U.S. states first decided (between 1915 and 1933) to criminalize marijuana, the principal motivations were not grounded in science or public health but rather in prejudice and discrimination against immigrants from Mexico who reputedly smoked the "killer weed."
Who most benefits from keeping marijuana illegal? The greatest beneficiaries are the major criminal organizations in Mexico and elsewhere that earn billions of dollars annually from this illicit trade—and who would rapidly lose their competitive advantage if marijuana were a legal commodity. Some claim that they would only move into other illicit enterprises, but they are more likely to be weakened by being deprived of the easy profits they can earn with marijuana.
This was just one reason the Latin American Commission on Drugs and Democracy—chaired by three distinguished former presidents, Fernando Henrique Cardoso of Brazil, César Gaviria of Colombia and Ernesto Zedillo of Mexico—included marijuana decriminalization among their recommendations for reforming drug policies in the Americas.
Like many parents and grandparents, I am worried about young people getting into trouble with marijuana and other drugs. The best solution, however, is honest and effective drug education. One survey after another indicates that teenagers have better access than most adults to marijuana—and often other drugs as well—and find it easier to buy marijuana than alcohol. Legalizing marijuana may make it easier for adults to buy marijuana, but it can hardly make it any more accessible to young people. I'd much rather invest in effective education than ineffective arrest and incarceration.
California's Proposition 19, which would legalize the recreational use and small-scale cultivation of marijuana, wouldn't solve all the problems connected with the drug. But it would represent a major step forward, and its deficiencies can be corrected on the basis of experience. Just as the process of repealing national alcohol prohibition began with individual states repealing their own prohibition laws, so individual states must now take the initiative with respect to repealing marijuana prohibition laws. And just as California provided national leadership in 1996 by becoming the first state to legalize the medical use of marijuana, so it has an opportunity once again to lead the nation.
In many respects, of course, Proposition 19 already is a winner no matter what happens on Election Day. The mere fact of its being on the ballot has elevated and legitimized public discourse about marijuana and marijuana policy in ways I could not have imagined a year ago.
These are the reasons I have decided to support Proposition 19 and invite others to do so.
Mr. Soros is chairman of Soros Fund Management and founder of the Open Society Foundations.
Clearly as you have stated it makes since to legalize and the rest of Washington and Colorado agreed :)
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