Saturday, December 6, 2008
How Marijuana can help with Epilepsy
For thousands of years cannabis sativa and its extracts have been used to treat a variety of illnesses ranging from epilepsy to gastrointestinal issues. Unfortunately, during the early 20th century cannabis came under the attack of yellow journalism, and was renamed marijuana by the media. Through a series of smear campaigns driven by racism, fear, and politics, slogans such as “smoke one joint and you will want to kill your brother” and movies like Reefer Madness marijuana was made illegal. Eventually it reached the status of a schedule I drug, which according to the FDA means that it has a high potential for abuse, no currently accepted medical, value and a lack of safety. This scheduling has been highly controversial, and due to its legal status research has been difficult. Little research has been done and very few clinical trials have ever been conducted on humans in the United States. The focus of this paper is to evaluate the efficacy of cannabinoid receptor agonists on their ability to prevent or treat epileptic seizures.
In order to understand how a cannabinoid receptor agonist can have an effect on epilepsy it is important to be familiar with the basics of the endocannabinoid system in the brain. The endocannabinoid system is a recently discovered signaling system. Cannabinoid receptors in the brain were discovered in 1990[1]. These are G-coupled receptors with seven transmembrane regions. There are two known cannabinoid receptors: CB1 and CB2. CB1 is heavily concentrated in the central nervous system and is coupled with ion channels[2]. It is also the most ample G-coupled protein receptor in the mammalian brain although this receptor is also found in other tissues. CB2 on the other hand is more localized, found to be associated with immune cells, the pancreas and the lymphoid system. The two endogenous ligands to which these receptors are agonized were not discovered until 1992. Anandamide was the first endocannabinoid to be classified, followed by 2-arachidonoyl glycerol. Both of these compounds are derivatives of arachidonic acid and both endocannabinoids appear to bind to CB1 and CB2.
The activation of the endocannabinoid system is similar to other G coupled protein receptors in the way it produces a cascade involving protein kinase A, and cyclic AMP[3]. During high levels of neural activity calcium ion concentrations increase in the cytoplasm which promote N-acyltransferase to produce N-arachidonoyl phosphatidyl ethanolamine from phosphatidyl ethanolamine. This intermediate is further processed by phospholipase D to form anandamide. Anandamide, which is now free in the synapse, is subject to degradation by the enzyme fatty acid amide hydrolase (FAAH). However, if it is not degraded anandamide will bind to and activate CB1 . The G-protein dissociates from the receptor and inhibits adenylyl cyclase. Because of this, cytoplasmic concentrations of cAMP decrease, which in turn decrease the levels of PKA. PKA can stimulate the ryanodine, which mediate the release of Ca2+ from the endoplasmic reticulum. Therefore reducing the amount of PKA will reduce the amount of calcium leaking from the ER into the cytoplasm, which will reduce the neurons ability to become depolarized. The bound CB1 receptor activates the extra cellular signal regulated kinase pathway (ERK) which stimulates the transcription of genes encoding transcription factors c-fos, zif268, and BDNF. These transcription factors are known to help ameliorate the effects of excitotoxic damage caused by excessive neural activity[4]. This sequence has the effect of decreasing the likelihood of further neural excitation and putting in motion the creation of gene products that can dampen the effects of excitotoxic events. Furthermore, CB1 receptor stimulation has also been shown to reduce inflammation and promote neurogenesis[5]. The overall view of the endocannabinoid system is that it mediates the effects of over stimulation, reduces inflammation, and promotes growth of new neurons in response to overstimulation.
Epilepsy is a disorder which is characterized by excessive synchronized neuronal activity particularly in the cortical, hippocampal, and thalamocortical networks. Certain pathways in a person with epilepsy are prone to becoming repeatedly activated and can cause excitotoxic damage. In total over seventy genes have been identified as epilepsy susceptibility genes. Interestingly, none of the genes coding for the CB receptors have been found to be mutated in people with epilepsy. Several genes that encode for subunits of voltage gated ion channels have been found to be correlated with epilepsy[6]. This would make sense because if the voltage gated ion channels are not working properly, the state of polarization, or depolarization, could be effected dramatically. The progression of the disease is fairly simple. Epileptic seizures can be triggered by reading, sleeping, flickering lights, or often times, without a known trigger. Once an individual has one seizure, it becomes much more likely that they will experience more within their lifetime. This has been attributed to the hotly debated kindling theory of seizure progression [7]. Additionally, excessive neural activity can trigger molecular pathways that lead to neuronal death. This is called an excitotoxic event. If a cure is to be found, research into what causes seizures and what can stop them is necessary. However, using humans as research subjects can be unethical, therefore animal models are needed.
In order to study epilepsy in greater detail, animal models have been used to simulate epileptic seizures. Three in particular provide good insight into epilepsy: the maximal electroshock model, the pilocarpine model, and the kainic acid model. The maximal electroshock model is exactly what it sounds like: an electric shock is applied so that a maximal amount of test subjects, mice in this scenario, are sent into seizure. This model is most useful in determining seizure threshold, that is, how much electric shock is needed in order to induce seizure. During this procedure, an electric shock is admistered via corneal electrodes to mice who have either received a dose of anandamide or nothing (placebo), in order to determine how anandamide affects the seizure threshold. In the pilocarpine model, a special type of seizure is emulated called “status epilepticus” which is a seizure that lasts for at least thirty minutes before the subject regains consciousness. In this model, prolonged seizing is induced by intraperitoneal injection of pilocarpine, which is a muscarinic acetylcholine receptor agonist. This causes prolonged seizure, only to be stopped after thirty minutes when the mice are injected several times with diazepam. This model is useful for seeing the effects of prolonged seizing on neural tissue. The third model of importance is the kainic acid model, which is simply an injection of kainic acid. Kainic acid induces activation of excitatory pathways which lead to seizure. This model was used in order to specifically see if the CB1 receptors were important in the neuroprotective effects of endocannabinoids. All three of these models are also used to determine the relative efficacy of currently prescribed drugs for epilepsy versus the efficacy of cannabinoids, either endogenous or exogenous.
The most commonly prescribed drugs for epilepsy are the benzodiazepines, such as diazepam and lorazepam[8]. These drugs act by binding to the calcium ion channels and block them from allowing calcium ion entry[9]. This protects the neurons from further depolarization and therefore inhibits seizures[10]. Unfortunately derivatives of benzodiazepines have little to no beneficial effect on approximately one third of the epileptic population. In addition to this, a tolerance can result and the beneficial effects are eventually overcome by the negative effects of increasing the dosage, such as extreme prolonged drowsiness, suppression of REM sleep, and depression. As a result of these shortcomings, development of better anticonvulsants are warranted.
A popular alternative medication for epilepsy is Δ9- Tetrahydrocannabinol(THC).
THC acts as a cannabinoid receptor agonist binding to both CB1 and CB2. This binding produces a cascade of events leading to a decrease in cytoplasmic Ca2+ concentration which reduces a neurons ability to become excited. This could prevent or treat seizures by reducing the probability a neuron will come into over excessive stimulation leading to an excitotoxic event. In addition THC being a CB1 receptor agonist could reduce inflammation caused by over stimulation, thereby providing a neuroprotective effect[11]. However, evidence is more important than what seems to make sense.
There is a body of evidence suggesting that both endogenous and exogenous cannabinoids can regulate epilepsy. For instance, in the maximal electroshock model, a 300mg/kg dose of anandamide reduced the amount of convulsions by 12.5%. More impressive however is that a 300mg/kg dose mixed with a fatty acid amide hydrolase inhibitor, phenylmethylsulfonyl fluoride (PMSF), reduced the amount of convulsions by 100%. This would appear to indicate that much of the anandamide is broken down before it can activate the CB1 receptors. This is confirmed when using a synthetic cannabinoid dubbed O-1812. This compound, which is not hydrolyzed by FAAH, produces 100% reduction in convulsions without any PMSF. This would suggest that other exogenous compounds that activate the CB1 receptor and are not susceptible to hydrolysis by FAAH would produce similar results given that binding affinities are similar. In addition, when using a CB1 antagonist like SR141716A, the amount of electric current necessary to produce convulsions in 50% of test animals drops significantly, from 17.57mA to 14.27mA in test mice. Basically, this means that if the cannabinoid receptors are not working, or if there is an insufficient concentration of cannabinoids, the possibility of seizure increases. In the pilocarpine model it was found that treating the rats with CB1 receptor agonists strongly reduced seizure frequency, and that CB1 agonists were more efficient in their ability to reduce the seizures than phenobarbital and phenytoin, which are two prescribed anti-convulsants. The CB1 receptor agonist in this model was 10mg/kg THC. The kainic acid model confirmed that it is through the CB1 receptor mechanism that cannabinoids direct their anti-convulsant properties. To do this, the researchers engineered mice without CB1 receptors and then injected them and their wild-type litter mates with kainic acid. The results showed that the mice without CB1 receptors were much more prone to convulsions due to kainic acid injection versus the wild-type mice. In cell cultures of hippocampal neurons with low Mg2+ treatment, which induces seizure, it was found that treating the cultures with concentrations of anandamide as low as 1μM was able to completely stop seizures, whereas phenobarbital was not able to stop seizures until a concentration of 100μM was applied.
It is clear that the endocannabinoid system is involved in the regulation of neural stimulation through the CB1 receptor cascade. The evidence shows that manipulation of the endocannabinoid system can stop seizures. The evidence also seems to warrant further investigation into the ability of synthetic or natural exogenous cannabinoids to prevent or treat seizures. However as the evidence stands, it appears that there is some validity in the use of THC as an anti-convulsant but should not be recommended because of the lack of clinical trials with humans. Also it has been postulated that prolonged activation of the endocannabinoid system could actually contribute to epilepsy[12]. Further research using double blind clinical trials with humans are necessary in order to determine the efficacy of CB1 receptor agonists on reducing epileptic seizures within humans, specifically using THC as the receptor agonist.
Cited Sources
[1]Lutz, Beat. "On-Demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures." Biochemical Pharmacology 68(2004): 1691-1698.
[2]Croxford, J. Ludovic. "Cannabinoids and the immune system: Potential for the treatment of inflammatory diseases?." Journal of Neuroimmunology 166(2005): 3-18.
[3]Grant, Igor. "Cannabis and endocannabinoid modulators: Therapeutic promises and challenges." Clinical Neuroscience Research 5(2005): 185-199.
[4]Mechoulam R, Spatz M Endocannabinoids and neuroprotection. Sci STKE 2002;2002(129):RE5
[5]Marchalant, Yannick. "Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats." Neurobiology of Aging (2007):
[6]Miriam H. Meisler and Jennifer A. Kearney (2005). "Sodium channel mutations in epilepsy and other neurological disorders". Journal of Clinical Investigation 115 (8): 2010–2017.
[7]Goddard, G.V. (1967). Development of epileptic seizures through brain stimulation at low intensity. Nature, 214, 1020-1021.
[8]Deshpande, Laxmikant. "Endocannabinoids block status epilepticus in cultured hippocampal neurons." European Journal of Pharmacology 558(2007): 52-59.
[9]Taft WC; DeLorenzo RJ (May 1984). "Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations". Proc Natl Acad Sci U S A 81 (10): 3118-22.
[10]Wallace, Melisa. "Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity." European Journal of Pharmacology 452(2002): 295-301.
[11]Eljaschewitsch , Eva. "The Endocannabinoid anandamide protects neurons during CNS Inflammation by induction of MKP-1 in Microglial cells." Neuron 49(2006): 67-79.
[12]Bisogno, Tiziana. "Short- and long-term plasticity of the endocannabinoid system in neuropsychiatric and neurological disorders." Pharmacological Research 56(2007): 428-442.
Uncited Sources
Marchalant, Yannick. "Inflammation and aging: Can endocannabinoids help?." Biomedicine & Pharmacotherapy (2008): 1-6.
Optiz, Christiane. "Production of the endocannabinoids anandamide and 2-arachidonoylglycerol by endothelial progenitor cells." Federation of European Biochemical Societies 581(2007): 4927-4931.
Marchalant, Yannick. "Anti-Inflammatory property of the cannabinoid agonist win-55212-2 in a rodent model of chronic brain inflammation." Neuroscience 144(2007): 1516-1522.
Panikashvili, David. "The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines." Neurobiology of Disease 22(2006): 257-264.
In order to understand how a cannabinoid receptor agonist can have an effect on epilepsy it is important to be familiar with the basics of the endocannabinoid system in the brain. The endocannabinoid system is a recently discovered signaling system. Cannabinoid receptors in the brain were discovered in 1990[1]. These are G-coupled receptors with seven transmembrane regions. There are two known cannabinoid receptors: CB1 and CB2. CB1 is heavily concentrated in the central nervous system and is coupled with ion channels[2]. It is also the most ample G-coupled protein receptor in the mammalian brain although this receptor is also found in other tissues. CB2 on the other hand is more localized, found to be associated with immune cells, the pancreas and the lymphoid system. The two endogenous ligands to which these receptors are agonized were not discovered until 1992. Anandamide was the first endocannabinoid to be classified, followed by 2-arachidonoyl glycerol. Both of these compounds are derivatives of arachidonic acid and both endocannabinoids appear to bind to CB1 and CB2.
The activation of the endocannabinoid system is similar to other G coupled protein receptors in the way it produces a cascade involving protein kinase A, and cyclic AMP[3]. During high levels of neural activity calcium ion concentrations increase in the cytoplasm which promote N-acyltransferase to produce N-arachidonoyl phosphatidyl ethanolamine from phosphatidyl ethanolamine. This intermediate is further processed by phospholipase D to form anandamide. Anandamide, which is now free in the synapse, is subject to degradation by the enzyme fatty acid amide hydrolase (FAAH). However, if it is not degraded anandamide will bind to and activate CB1 . The G-protein dissociates from the receptor and inhibits adenylyl cyclase. Because of this, cytoplasmic concentrations of cAMP decrease, which in turn decrease the levels of PKA. PKA can stimulate the ryanodine, which mediate the release of Ca2+ from the endoplasmic reticulum. Therefore reducing the amount of PKA will reduce the amount of calcium leaking from the ER into the cytoplasm, which will reduce the neurons ability to become depolarized. The bound CB1 receptor activates the extra cellular signal regulated kinase pathway (ERK) which stimulates the transcription of genes encoding transcription factors c-fos, zif268, and BDNF. These transcription factors are known to help ameliorate the effects of excitotoxic damage caused by excessive neural activity[4]. This sequence has the effect of decreasing the likelihood of further neural excitation and putting in motion the creation of gene products that can dampen the effects of excitotoxic events. Furthermore, CB1 receptor stimulation has also been shown to reduce inflammation and promote neurogenesis[5]. The overall view of the endocannabinoid system is that it mediates the effects of over stimulation, reduces inflammation, and promotes growth of new neurons in response to overstimulation.
Epilepsy is a disorder which is characterized by excessive synchronized neuronal activity particularly in the cortical, hippocampal, and thalamocortical networks. Certain pathways in a person with epilepsy are prone to becoming repeatedly activated and can cause excitotoxic damage. In total over seventy genes have been identified as epilepsy susceptibility genes. Interestingly, none of the genes coding for the CB receptors have been found to be mutated in people with epilepsy. Several genes that encode for subunits of voltage gated ion channels have been found to be correlated with epilepsy[6]. This would make sense because if the voltage gated ion channels are not working properly, the state of polarization, or depolarization, could be effected dramatically. The progression of the disease is fairly simple. Epileptic seizures can be triggered by reading, sleeping, flickering lights, or often times, without a known trigger. Once an individual has one seizure, it becomes much more likely that they will experience more within their lifetime. This has been attributed to the hotly debated kindling theory of seizure progression [7]. Additionally, excessive neural activity can trigger molecular pathways that lead to neuronal death. This is called an excitotoxic event. If a cure is to be found, research into what causes seizures and what can stop them is necessary. However, using humans as research subjects can be unethical, therefore animal models are needed.
In order to study epilepsy in greater detail, animal models have been used to simulate epileptic seizures. Three in particular provide good insight into epilepsy: the maximal electroshock model, the pilocarpine model, and the kainic acid model. The maximal electroshock model is exactly what it sounds like: an electric shock is applied so that a maximal amount of test subjects, mice in this scenario, are sent into seizure. This model is most useful in determining seizure threshold, that is, how much electric shock is needed in order to induce seizure. During this procedure, an electric shock is admistered via corneal electrodes to mice who have either received a dose of anandamide or nothing (placebo), in order to determine how anandamide affects the seizure threshold. In the pilocarpine model, a special type of seizure is emulated called “status epilepticus” which is a seizure that lasts for at least thirty minutes before the subject regains consciousness. In this model, prolonged seizing is induced by intraperitoneal injection of pilocarpine, which is a muscarinic acetylcholine receptor agonist. This causes prolonged seizure, only to be stopped after thirty minutes when the mice are injected several times with diazepam. This model is useful for seeing the effects of prolonged seizing on neural tissue. The third model of importance is the kainic acid model, which is simply an injection of kainic acid. Kainic acid induces activation of excitatory pathways which lead to seizure. This model was used in order to specifically see if the CB1 receptors were important in the neuroprotective effects of endocannabinoids. All three of these models are also used to determine the relative efficacy of currently prescribed drugs for epilepsy versus the efficacy of cannabinoids, either endogenous or exogenous.
The most commonly prescribed drugs for epilepsy are the benzodiazepines, such as diazepam and lorazepam[8]. These drugs act by binding to the calcium ion channels and block them from allowing calcium ion entry[9]. This protects the neurons from further depolarization and therefore inhibits seizures[10]. Unfortunately derivatives of benzodiazepines have little to no beneficial effect on approximately one third of the epileptic population. In addition to this, a tolerance can result and the beneficial effects are eventually overcome by the negative effects of increasing the dosage, such as extreme prolonged drowsiness, suppression of REM sleep, and depression. As a result of these shortcomings, development of better anticonvulsants are warranted.
A popular alternative medication for epilepsy is Δ9- Tetrahydrocannabinol(THC).
THC acts as a cannabinoid receptor agonist binding to both CB1 and CB2. This binding produces a cascade of events leading to a decrease in cytoplasmic Ca2+ concentration which reduces a neurons ability to become excited. This could prevent or treat seizures by reducing the probability a neuron will come into over excessive stimulation leading to an excitotoxic event. In addition THC being a CB1 receptor agonist could reduce inflammation caused by over stimulation, thereby providing a neuroprotective effect[11]. However, evidence is more important than what seems to make sense.
There is a body of evidence suggesting that both endogenous and exogenous cannabinoids can regulate epilepsy. For instance, in the maximal electroshock model, a 300mg/kg dose of anandamide reduced the amount of convulsions by 12.5%. More impressive however is that a 300mg/kg dose mixed with a fatty acid amide hydrolase inhibitor, phenylmethylsulfonyl fluoride (PMSF), reduced the amount of convulsions by 100%. This would appear to indicate that much of the anandamide is broken down before it can activate the CB1 receptors. This is confirmed when using a synthetic cannabinoid dubbed O-1812. This compound, which is not hydrolyzed by FAAH, produces 100% reduction in convulsions without any PMSF. This would suggest that other exogenous compounds that activate the CB1 receptor and are not susceptible to hydrolysis by FAAH would produce similar results given that binding affinities are similar. In addition, when using a CB1 antagonist like SR141716A, the amount of electric current necessary to produce convulsions in 50% of test animals drops significantly, from 17.57mA to 14.27mA in test mice. Basically, this means that if the cannabinoid receptors are not working, or if there is an insufficient concentration of cannabinoids, the possibility of seizure increases. In the pilocarpine model it was found that treating the rats with CB1 receptor agonists strongly reduced seizure frequency, and that CB1 agonists were more efficient in their ability to reduce the seizures than phenobarbital and phenytoin, which are two prescribed anti-convulsants. The CB1 receptor agonist in this model was 10mg/kg THC. The kainic acid model confirmed that it is through the CB1 receptor mechanism that cannabinoids direct their anti-convulsant properties. To do this, the researchers engineered mice without CB1 receptors and then injected them and their wild-type litter mates with kainic acid. The results showed that the mice without CB1 receptors were much more prone to convulsions due to kainic acid injection versus the wild-type mice. In cell cultures of hippocampal neurons with low Mg2+ treatment, which induces seizure, it was found that treating the cultures with concentrations of anandamide as low as 1μM was able to completely stop seizures, whereas phenobarbital was not able to stop seizures until a concentration of 100μM was applied.
It is clear that the endocannabinoid system is involved in the regulation of neural stimulation through the CB1 receptor cascade. The evidence shows that manipulation of the endocannabinoid system can stop seizures. The evidence also seems to warrant further investigation into the ability of synthetic or natural exogenous cannabinoids to prevent or treat seizures. However as the evidence stands, it appears that there is some validity in the use of THC as an anti-convulsant but should not be recommended because of the lack of clinical trials with humans. Also it has been postulated that prolonged activation of the endocannabinoid system could actually contribute to epilepsy[12]. Further research using double blind clinical trials with humans are necessary in order to determine the efficacy of CB1 receptor agonists on reducing epileptic seizures within humans, specifically using THC as the receptor agonist.
Cited Sources
[1]Lutz, Beat. "On-Demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures." Biochemical Pharmacology 68(2004): 1691-1698.
[2]Croxford, J. Ludovic. "Cannabinoids and the immune system: Potential for the treatment of inflammatory diseases?." Journal of Neuroimmunology 166(2005): 3-18.
[3]Grant, Igor. "Cannabis and endocannabinoid modulators: Therapeutic promises and challenges." Clinical Neuroscience Research 5(2005): 185-199.
[4]Mechoulam R, Spatz M Endocannabinoids and neuroprotection. Sci STKE 2002;2002(129):RE5
[5]Marchalant, Yannick. "Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats." Neurobiology of Aging (2007):
[6]Miriam H. Meisler and Jennifer A. Kearney (2005). "Sodium channel mutations in epilepsy and other neurological disorders". Journal of Clinical Investigation 115 (8): 2010–2017.
[7]Goddard, G.V. (1967). Development of epileptic seizures through brain stimulation at low intensity. Nature, 214, 1020-1021.
[8]Deshpande, Laxmikant. "Endocannabinoids block status epilepticus in cultured hippocampal neurons." European Journal of Pharmacology 558(2007): 52-59.
[9]Taft WC; DeLorenzo RJ (May 1984). "Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations". Proc Natl Acad Sci U S A 81 (10): 3118-22.
[10]Wallace, Melisa. "Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity." European Journal of Pharmacology 452(2002): 295-301.
[11]Eljaschewitsch , Eva. "The Endocannabinoid anandamide protects neurons during CNS Inflammation by induction of MKP-1 in Microglial cells." Neuron 49(2006): 67-79.
[12]Bisogno, Tiziana. "Short- and long-term plasticity of the endocannabinoid system in neuropsychiatric and neurological disorders." Pharmacological Research 56(2007): 428-442.
Uncited Sources
Marchalant, Yannick. "Inflammation and aging: Can endocannabinoids help?." Biomedicine & Pharmacotherapy (2008): 1-6.
Optiz, Christiane. "Production of the endocannabinoids anandamide and 2-arachidonoylglycerol by endothelial progenitor cells." Federation of European Biochemical Societies 581(2007): 4927-4931.
Marchalant, Yannick. "Anti-Inflammatory property of the cannabinoid agonist win-55212-2 in a rodent model of chronic brain inflammation." Neuroscience 144(2007): 1516-1522.
Panikashvili, David. "The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines." Neurobiology of Disease 22(2006): 257-264.
How Marijuana Works in the Brain
Medical Marijuana: A Biochemical Approach
Introduction
For thousands of years cannabis sativa and its extracts have been used to treat a variety of illnesses ranging from epilepsy to gastrointestinal issues. Unfortunately, during the early 20th century cannabis came under the attack of yellow journalism, and was renamed marijuana by the media. Through a series of smear campaigns driven by racism, fear, and politics, slogans such as “smoke one joint and you will want to kill your brother” and movies like Reefer Madness marijuana was made illegal. Eventually it reached the status of a schedule I drug, which according to the FDA means that it has a high potential for abuse, no currently accepted medical, value and a lack of safety. This scheduling has been highly controversial, and due to its legal status research has been difficult. Little research has been done and very few clinical trials have ever been conducted on humans in the United States.
Chapter 1: The Endocannabinoid System in the Brain
In order to understand how a cannabinoid receptor agonist like those found in marijuana can have an effect on medical conditions it is important to be familiar with the basics of the endocannabinoid system in the brain. The endocannabinoid system is a recently discovered signaling system. Cannabinoid receptors in the brain were discovered in 1990[1]. These are G-coupled receptors with seven transmembrane regions. There are two known cannabinoid receptors: CB1 and CB2. CB1 is heavily concentrated in the central nervous system and is coupled with ion channels[2]. It is also the most ample G-coupled protein receptor in the mammalian brain although this receptor is also found in other tissues. CB2 on the other hand is more localized, found to be associated with immune cells, the pancreas and the lymphoid system. The two endogenous ligands to which these receptors are agonized were not discovered until 1992. Anandamide was the first endocannabinoid to be classified, followed by 2-arachidonoyl glycerol. Both of these compounds are derivatives of arachidonic acid and both endocannabinoids appear to bind to CB1 and CB2.
The activation of the endocannabinoid system is similar to other G coupled protein receptors in the way it produces a cascade involving protein kinase A, and cyclic AMP[3]. During high levels of neural activity calcium ion concentrations increase in the cytoplasm which promote N-acyltransferase to produce N-arachidonoyl phosphatidyl ethanolamine from phosphatidyl ethanolamine. This intermediate is further processed by phospholipase D to form anandamide. Anandamide, which is now free in the synapse, is subject to degradation by the enzyme fatty acid amide hydrolase (FAAH). However, if it is not degraded anandamide will bind to and activate CB1 . The G-protein dissociates from the receptor and inhibits adenylyl cyclase. Because of this, cytoplasmic concentrations of cAMP decrease, which in turn decrease the levels of PKA. PKA can stimulate the ryanodine receptor, which will mediate the release of Ca2+ from the endoplasmic reticulum. Therefore reducing the amount of PKA will reduce the amount of calcium leaking from the endoplasmic reticulum into the cytoplasm, which will reduce the neurons ability to become depolarized. The bound CB1 receptor activates the extra cellular signal regulated kinase pathway (ERK) which stimulates the transcription of genes encoding transcription factors c-fos, zif268, and BDNF. These transcription factors are known to help ameliorate the effects of excitotoxic damage caused by excessive neural activity[4]. This sequence has the effect of decreasing the likelihood of further neural excitation and putting in motion the creation of gene products that can dampen the effects of excitotoxic events. Furthermore, CB1 receptor stimulation has also been shown to reduce inflammation and promote neurogenesis[5]. The overall view of the endocannabinoid system is that it mediates the effects of over stimulation, reduces inflammation, and promotes growth of new neurons in response to overstimulation.
Introduction
For thousands of years cannabis sativa and its extracts have been used to treat a variety of illnesses ranging from epilepsy to gastrointestinal issues. Unfortunately, during the early 20th century cannabis came under the attack of yellow journalism, and was renamed marijuana by the media. Through a series of smear campaigns driven by racism, fear, and politics, slogans such as “smoke one joint and you will want to kill your brother” and movies like Reefer Madness marijuana was made illegal. Eventually it reached the status of a schedule I drug, which according to the FDA means that it has a high potential for abuse, no currently accepted medical, value and a lack of safety. This scheduling has been highly controversial, and due to its legal status research has been difficult. Little research has been done and very few clinical trials have ever been conducted on humans in the United States.
Chapter 1: The Endocannabinoid System in the Brain
In order to understand how a cannabinoid receptor agonist like those found in marijuana can have an effect on medical conditions it is important to be familiar with the basics of the endocannabinoid system in the brain. The endocannabinoid system is a recently discovered signaling system. Cannabinoid receptors in the brain were discovered in 1990[1]. These are G-coupled receptors with seven transmembrane regions. There are two known cannabinoid receptors: CB1 and CB2. CB1 is heavily concentrated in the central nervous system and is coupled with ion channels[2]. It is also the most ample G-coupled protein receptor in the mammalian brain although this receptor is also found in other tissues. CB2 on the other hand is more localized, found to be associated with immune cells, the pancreas and the lymphoid system. The two endogenous ligands to which these receptors are agonized were not discovered until 1992. Anandamide was the first endocannabinoid to be classified, followed by 2-arachidonoyl glycerol. Both of these compounds are derivatives of arachidonic acid and both endocannabinoids appear to bind to CB1 and CB2.
The activation of the endocannabinoid system is similar to other G coupled protein receptors in the way it produces a cascade involving protein kinase A, and cyclic AMP[3]. During high levels of neural activity calcium ion concentrations increase in the cytoplasm which promote N-acyltransferase to produce N-arachidonoyl phosphatidyl ethanolamine from phosphatidyl ethanolamine. This intermediate is further processed by phospholipase D to form anandamide. Anandamide, which is now free in the synapse, is subject to degradation by the enzyme fatty acid amide hydrolase (FAAH). However, if it is not degraded anandamide will bind to and activate CB1 . The G-protein dissociates from the receptor and inhibits adenylyl cyclase. Because of this, cytoplasmic concentrations of cAMP decrease, which in turn decrease the levels of PKA. PKA can stimulate the ryanodine receptor, which will mediate the release of Ca2+ from the endoplasmic reticulum. Therefore reducing the amount of PKA will reduce the amount of calcium leaking from the endoplasmic reticulum into the cytoplasm, which will reduce the neurons ability to become depolarized. The bound CB1 receptor activates the extra cellular signal regulated kinase pathway (ERK) which stimulates the transcription of genes encoding transcription factors c-fos, zif268, and BDNF. These transcription factors are known to help ameliorate the effects of excitotoxic damage caused by excessive neural activity[4]. This sequence has the effect of decreasing the likelihood of further neural excitation and putting in motion the creation of gene products that can dampen the effects of excitotoxic events. Furthermore, CB1 receptor stimulation has also been shown to reduce inflammation and promote neurogenesis[5]. The overall view of the endocannabinoid system is that it mediates the effects of over stimulation, reduces inflammation, and promotes growth of new neurons in response to overstimulation.
Stop The Lies: Legalize it Already
Imagine a naturally occurring plant that when consumed kills cancer cells, grows new brain cells, can stop seizures, relieves nausea during chemotherapy, treats pain more effectively than morphine, reduces muscle spasticity for people with multiple sclerosis, slows the onset of blindness in people with glaucoma, can treat tourettes syndrome, is impossible to overdose on, and makes people who use it really happy. It almost sounds too good to be true, yet it is. The plant is called Cannabis Sativa, or what is known on the streets as “marijuana.”
This November people in Michigan will have the choice to vote on whether or not a doctor can prescribe marijuana to sick people who would benefit from its use. Many have been told for years that marijuana is a dangerous drug that causes brain damage, violence, and insanity. Many wonder how it is possible that a dangerous illegal drug like marijuana could ever be considered medicine when the federal government says that it is not medicine. The truth is, the American people, and much of the world have been lied to about Cannabis Sativa and anyone with a casual interest in the subject that has access to a database of medical journals knows that.
The current medical marijuana debate began in 1996 when Californian voters passed proposition 215. This allowed doctors to prescribe marijuana to patients they thought would benefit from the drug. Since this time debate has raged among the people of this nation about whether or not marijuana could be considered medicine. Doctors and scientists invested a lot of time and money researching marijuana and the chemicals that give it its special properties.
The chemicals that give marijuana its medical and recreational properties are called cannabinoids. There are sixty-six known cannabinoids in marijuana each with slightly different biochemical effects. In the 1990's researchers discovered that the brain and body actually has receptors for cannabinoids. The two receptors are called CB1 and CB2. Shortly after the discovery of their receptors two endogenous cannabinoids also known as endocannabinoids were discovered. Their names are anandamide and 2-arachidonoyl glycerol. Both of these compounds are derivatives of arachidonic acid and both endocannabinoids appear to bind to CB1 and CB2. Biochemical research into these receptors and their agonists reveal the exact biochemical cascade of events that happens when these receptors are agonized. The overall view of the endocannabinoid system is that it mediates the effects of over stimulation, reduces inflammation, and promotes growth of new neurons in response to overstimulation.
Over the past several years researchers have been finding more and more evidence that the most prominent cannabinoid in marijuana THC can actually destroy cancer cells(Jia, 2006). When cells become cancerous their cellular clocks are damaged. Most cells go through a cycle where they grow, divide, then die. In cancer cells the cycle is broken and the cancer cells do not die. When THC is injected into cancer cells, the cancer cells cycle is reactivated and cancer cells commit apoptosis, which is just a fancy word for cellular suicide(Athanasiou, 2007). Far more research has been done on the destruction of cancer cells via marijuana than has been presented here, yet the federal government denies that there is any possible medical use for marijuana.
For most of the twentieth century our government has been claiming that marijuana kills brain cells, and that medicine shouldn't destroy your brain. The problem with the assertion the government is making is that it is patently false. There has never been any studies accepted by the medical community that proves marijuana kills brain cells. In fact recent research has suggested the exact opposite, THC actually stimulates the brain to grow new neurons in a process called neurogenesis. In a study done at the Neuropsychiatry Research Unit at the University of Saskatchewan researchers found that “Cannabinoids promote embryonic and adult hippocampus neurogenesis...”(Jiang, 2005). The hippocampus is the part of the brain responsible for forming new memories. If the underlying assumption is that the destruction of brain cells results in stupidity then is it also true that the creation of new brain cells results in superior intelligence? Maybe, because according to research done by the Department of Psychology at Ohio State University, activation of cannabinoid receptors in older mice improved their spatial memory(Yannick, 2007) . This would explain how it is possible that intellectuals like science popularizer and astronomer Carl Sagan can use marijuana regularly and still retain their brilliance. Yet despite this evidence the federal government still believes that marijuana is just as dangerous as heroin, and that anyone who uses it is so dangerous that they belong in a cage.
In addition to marijuana being able to grow new brain cells the cannabinoid THC is able to stop a seizure dead in its tracks and reduce the number of them. Research at the Department of Pharmacology and Toxicology at Virginia Commonwealth University found that if THC is given to rats before a seizure is induced the rats have fewer seizures than they do if they are given standard anti-seizure medication like phenobarbital(Wallace, 2002). Also researchers at the same university but in the department of neurology found that cannabinoid receptor agonists stopped seizures in cultures of hippocampal neurons where seizure was induced at 1% the concentration of the leading anti-convulsant pharmaceutical phenobarbital (Deshpande, 2007). A statement from a medical marijuana patient who goes by the name buzz at the medical marijuana community at www.marijuana.com says it all.
“I have had epilpesy for a while. Four years ago my sezuires were out of control. All my meds made me sucidal and I tried to take my own life. Now I use weed instead of the pills and I have taken back my life. I had both grand and petite. Some times petite as high as 20 per day. Now I can go for days sezuire free”
Yet despite this overwhelming evidence the federal government routinely breaks into medical marijuana pharmacies, steals the medicine, and then arrests the pharmacists.
Marijuana, in addition to treating epilepsy can also treat multiple sclerosis. Many patients with multiple sclerosis have reported relief of pain far superior than the relief experienced due to morphine or other dangerous legal drugs. Is there more than just pain relief? Research done in 2008 published in the Journal of Neuroimmunology found that high doses of cannabinoids actually reduces the disease, and at lower doses cannabinoids “slowed the accumulation of nerve loss and disability.”(Croxford, 2008). Furthermore a study published in 2005 in the journal Trends in Neuroscience stated, that after reviewing the literature on the subject concluded “cannabis not only relieves symptoms [of MS] but also is potentially neuroprotective and is involved in synaptic plasticity.” (Pryce, 2005). Disregarding this evidence the federal government still considers medical marijuana patients like Montel Williams, a talk show host with MS, a criminal that is a danger to society.
So what if marijuana can cure cancer, grow new brain cells, treat epilepsy and MS, the medical marijuana community is just a bunch of hippies that want to get high right? Well, thats not what was observed at the medical marijuana forums at marijuana.com. The community is incredibly diverse as it is composed of people from all across the United States and Canada. The people within the community typically range from fifteen to fifty years old. These people stand out from their other subcultures in a fairly uniform way, they are all criminals in the eye of the federal government. Therefore many are secretive about their involvement in this subculture. An example of this is a conversation in the community in which a student with ADHD describes how cannabis has helped him focus on his studies and has also helped him get along better with his family and friends. He goes as far as saying that his family and friends have complimented him on his strongly positive behavior change. However he is afraid to tell them that this positive behavioral change is due to marijuana. There is an intense paranoia about being “found out” within the community. Many people will say that marijuana makes people paranoid, this is not true. Marijuana prohibition makes marijuana users paranoid, consider that in 2007 marijuana arrests reached record breaking levels of 872,721 and cost the tax payers $41.8billion that year alone, for comparison 597,447 people were arrested for violent crimes in 2007. Nearly 300,000 more people are arrested for marijuana each year than for all violent crimes combined. It is for this reason that the vast majority of the medical marijuana community are silent observers and only a few actively contribute to the discussion.
Prohibition of medical marijuana makes people within the community skeptical of all government activity. These people know that marijuana is not anywhere near as harmful as heroin, and they know they aren't a danger to society that needs to be locked up. They know that the things the government says about marijuana are lies that medical science has disproved. When a mountain of research by medical science completely contradicts the claims of the government whose claims are not backed up by research it creates skepticism by anybody within the know. For instance during an interview with a member who goes by the name SpiralArchitect he said the government “should be [working in the best interests of the people]. It currently isn't ; private interests and personal agendas have taken priority.” and when further questioned about whether or not the government would knowingly lie to a person he simply said “Look at History.” Indeed this is a strong statement. Governments have been knowingly deceiving people for thousands of years, and the United States is no exception. Surprisingly this sort of sentiment is creeping its way into mainstream society an interview with an outsider about whether the government is looking out for the best interests of the people yielded this response “I think that the government, in general, takes advantage of its citizens. I think that if the government truly had the best interested of their people in mind, many things in society would be different. The government is just like any other business in the world - it is out to make a profit at the expense of the worker.”
There is ample evidence to suggest that marijuana has therapeutic potential. Marijuana has the ability to kill cancer cells through apoptosis. The ability to promote the growth of new neurons in the learning center of the brain. The ability to treat epilepsy, the ability to treat MS and slow its progression, and many others. Cannabis is a safe non-toxic plant that grows like a weed. It remains illegal because it would destroy the pharmaceutical companies ability to profit because none of their drugs can compete with cannabis. Next time you have severe pain try vaporizing some medical grade cannabis and see the difference for yourself. Its safe, non-toxic, and is not physically addicting unlike morphine and Vicodin.
Cited Sources:
Athanasiou, Andriani . "Cannabinoid receptor agonists are mitochondrial inhibitors: A unified hypothesis of how cannabinoids modulate mitochondrial function and induce cell death." Biochemical and Biophysical Research Communications 364(2007): 131-137 .
Croxford, Ludovic J.. "Cannabinoid-mediated neuroprotection, not immunosuppression, may be more relevant to multiple sclerosis." Journal of Neuroimmunology 193(2008): 120-129.
Deshpande, Laxmikant. "Endocannabinoids block status epilepticus in cultured hippocampal neurons." European Journal of Pharmacology 558(2007): 52-59.
Jia, Wentao . "{Delta}9-Tetrahydrocannabinol-Induced Apoptosis in Jurkat Leukemia T Cells Is Regulated by Translocation of Bad to Mitochondria ." Molecular Cancer Research 4(2006): 549-562.
Jiang, Wen. "Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects." The Journal of Clinical Investigation 115(2005): 3104–3116 .
Marchalant, Yannick. "Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats." Neurobiology of Aging (2007):
Wallace, Melisa. "Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity." European Journal of Pharmacology 452(2002): 295-301.
This November people in Michigan will have the choice to vote on whether or not a doctor can prescribe marijuana to sick people who would benefit from its use. Many have been told for years that marijuana is a dangerous drug that causes brain damage, violence, and insanity. Many wonder how it is possible that a dangerous illegal drug like marijuana could ever be considered medicine when the federal government says that it is not medicine. The truth is, the American people, and much of the world have been lied to about Cannabis Sativa and anyone with a casual interest in the subject that has access to a database of medical journals knows that.
The current medical marijuana debate began in 1996 when Californian voters passed proposition 215. This allowed doctors to prescribe marijuana to patients they thought would benefit from the drug. Since this time debate has raged among the people of this nation about whether or not marijuana could be considered medicine. Doctors and scientists invested a lot of time and money researching marijuana and the chemicals that give it its special properties.
The chemicals that give marijuana its medical and recreational properties are called cannabinoids. There are sixty-six known cannabinoids in marijuana each with slightly different biochemical effects. In the 1990's researchers discovered that the brain and body actually has receptors for cannabinoids. The two receptors are called CB1 and CB2. Shortly after the discovery of their receptors two endogenous cannabinoids also known as endocannabinoids were discovered. Their names are anandamide and 2-arachidonoyl glycerol. Both of these compounds are derivatives of arachidonic acid and both endocannabinoids appear to bind to CB1 and CB2. Biochemical research into these receptors and their agonists reveal the exact biochemical cascade of events that happens when these receptors are agonized. The overall view of the endocannabinoid system is that it mediates the effects of over stimulation, reduces inflammation, and promotes growth of new neurons in response to overstimulation.
Over the past several years researchers have been finding more and more evidence that the most prominent cannabinoid in marijuana THC can actually destroy cancer cells(Jia, 2006). When cells become cancerous their cellular clocks are damaged. Most cells go through a cycle where they grow, divide, then die. In cancer cells the cycle is broken and the cancer cells do not die. When THC is injected into cancer cells, the cancer cells cycle is reactivated and cancer cells commit apoptosis, which is just a fancy word for cellular suicide(Athanasiou, 2007). Far more research has been done on the destruction of cancer cells via marijuana than has been presented here, yet the federal government denies that there is any possible medical use for marijuana.
For most of the twentieth century our government has been claiming that marijuana kills brain cells, and that medicine shouldn't destroy your brain. The problem with the assertion the government is making is that it is patently false. There has never been any studies accepted by the medical community that proves marijuana kills brain cells. In fact recent research has suggested the exact opposite, THC actually stimulates the brain to grow new neurons in a process called neurogenesis. In a study done at the Neuropsychiatry Research Unit at the University of Saskatchewan researchers found that “Cannabinoids promote embryonic and adult hippocampus neurogenesis...”(Jiang, 2005). The hippocampus is the part of the brain responsible for forming new memories. If the underlying assumption is that the destruction of brain cells results in stupidity then is it also true that the creation of new brain cells results in superior intelligence? Maybe, because according to research done by the Department of Psychology at Ohio State University, activation of cannabinoid receptors in older mice improved their spatial memory(Yannick, 2007) . This would explain how it is possible that intellectuals like science popularizer and astronomer Carl Sagan can use marijuana regularly and still retain their brilliance. Yet despite this evidence the federal government still believes that marijuana is just as dangerous as heroin, and that anyone who uses it is so dangerous that they belong in a cage.
In addition to marijuana being able to grow new brain cells the cannabinoid THC is able to stop a seizure dead in its tracks and reduce the number of them. Research at the Department of Pharmacology and Toxicology at Virginia Commonwealth University found that if THC is given to rats before a seizure is induced the rats have fewer seizures than they do if they are given standard anti-seizure medication like phenobarbital(Wallace, 2002). Also researchers at the same university but in the department of neurology found that cannabinoid receptor agonists stopped seizures in cultures of hippocampal neurons where seizure was induced at 1% the concentration of the leading anti-convulsant pharmaceutical phenobarbital (Deshpande, 2007). A statement from a medical marijuana patient who goes by the name buzz at the medical marijuana community at www.marijuana.com says it all.
“I have had epilpesy for a while. Four years ago my sezuires were out of control. All my meds made me sucidal and I tried to take my own life. Now I use weed instead of the pills and I have taken back my life. I had both grand and petite. Some times petite as high as 20 per day. Now I can go for days sezuire free”
Yet despite this overwhelming evidence the federal government routinely breaks into medical marijuana pharmacies, steals the medicine, and then arrests the pharmacists.
Marijuana, in addition to treating epilepsy can also treat multiple sclerosis. Many patients with multiple sclerosis have reported relief of pain far superior than the relief experienced due to morphine or other dangerous legal drugs. Is there more than just pain relief? Research done in 2008 published in the Journal of Neuroimmunology found that high doses of cannabinoids actually reduces the disease, and at lower doses cannabinoids “slowed the accumulation of nerve loss and disability.”(Croxford, 2008). Furthermore a study published in 2005 in the journal Trends in Neuroscience stated, that after reviewing the literature on the subject concluded “cannabis not only relieves symptoms [of MS] but also is potentially neuroprotective and is involved in synaptic plasticity.” (Pryce, 2005). Disregarding this evidence the federal government still considers medical marijuana patients like Montel Williams, a talk show host with MS, a criminal that is a danger to society.
So what if marijuana can cure cancer, grow new brain cells, treat epilepsy and MS, the medical marijuana community is just a bunch of hippies that want to get high right? Well, thats not what was observed at the medical marijuana forums at marijuana.com. The community is incredibly diverse as it is composed of people from all across the United States and Canada. The people within the community typically range from fifteen to fifty years old. These people stand out from their other subcultures in a fairly uniform way, they are all criminals in the eye of the federal government. Therefore many are secretive about their involvement in this subculture. An example of this is a conversation in the community in which a student with ADHD describes how cannabis has helped him focus on his studies and has also helped him get along better with his family and friends. He goes as far as saying that his family and friends have complimented him on his strongly positive behavior change. However he is afraid to tell them that this positive behavioral change is due to marijuana. There is an intense paranoia about being “found out” within the community. Many people will say that marijuana makes people paranoid, this is not true. Marijuana prohibition makes marijuana users paranoid, consider that in 2007 marijuana arrests reached record breaking levels of 872,721 and cost the tax payers $41.8billion that year alone, for comparison 597,447 people were arrested for violent crimes in 2007. Nearly 300,000 more people are arrested for marijuana each year than for all violent crimes combined. It is for this reason that the vast majority of the medical marijuana community are silent observers and only a few actively contribute to the discussion.
Prohibition of medical marijuana makes people within the community skeptical of all government activity. These people know that marijuana is not anywhere near as harmful as heroin, and they know they aren't a danger to society that needs to be locked up. They know that the things the government says about marijuana are lies that medical science has disproved. When a mountain of research by medical science completely contradicts the claims of the government whose claims are not backed up by research it creates skepticism by anybody within the know. For instance during an interview with a member who goes by the name SpiralArchitect he said the government “should be [working in the best interests of the people]. It currently isn't ; private interests and personal agendas have taken priority.” and when further questioned about whether or not the government would knowingly lie to a person he simply said “Look at History.” Indeed this is a strong statement. Governments have been knowingly deceiving people for thousands of years, and the United States is no exception. Surprisingly this sort of sentiment is creeping its way into mainstream society an interview with an outsider about whether the government is looking out for the best interests of the people yielded this response “I think that the government, in general, takes advantage of its citizens. I think that if the government truly had the best interested of their people in mind, many things in society would be different. The government is just like any other business in the world - it is out to make a profit at the expense of the worker.”
There is ample evidence to suggest that marijuana has therapeutic potential. Marijuana has the ability to kill cancer cells through apoptosis. The ability to promote the growth of new neurons in the learning center of the brain. The ability to treat epilepsy, the ability to treat MS and slow its progression, and many others. Cannabis is a safe non-toxic plant that grows like a weed. It remains illegal because it would destroy the pharmaceutical companies ability to profit because none of their drugs can compete with cannabis. Next time you have severe pain try vaporizing some medical grade cannabis and see the difference for yourself. Its safe, non-toxic, and is not physically addicting unlike morphine and Vicodin.
Cited Sources:
Athanasiou, Andriani . "Cannabinoid receptor agonists are mitochondrial inhibitors: A unified hypothesis of how cannabinoids modulate mitochondrial function and induce cell death." Biochemical and Biophysical Research Communications 364(2007): 131-137 .
Croxford, Ludovic J.. "Cannabinoid-mediated neuroprotection, not immunosuppression, may be more relevant to multiple sclerosis." Journal of Neuroimmunology 193(2008): 120-129.
Deshpande, Laxmikant. "Endocannabinoids block status epilepticus in cultured hippocampal neurons." European Journal of Pharmacology 558(2007): 52-59.
Jia, Wentao . "{Delta}9-Tetrahydrocannabinol-Induced Apoptosis in Jurkat Leukemia T Cells Is Regulated by Translocation of Bad to Mitochondria ." Molecular Cancer Research 4(2006): 549-562.
Jiang, Wen. "Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects." The Journal of Clinical Investigation 115(2005): 3104–3116 .
Marchalant, Yannick. "Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats." Neurobiology of Aging (2007):
Wallace, Melisa. "Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity." European Journal of Pharmacology 452(2002): 295-301.
Medical Marijuana on a Personal Level
“There has never been a single death in all of recorded history attributed to acute marijuana intoxication.” To some this may appear to be a bizarre and inaccurate statement; to others this is simply the tip of the iceberg of truth regarding marijuana. In this paper I will attempt to explain why the subject of medical marijuana is of great interest to me, what I know about this issue, and what communities I could possibly study in order to gain further insight.
When I was twelve and on a summer vacation with my parents in Maine, I began to get incredibly painful stomach cramps that would leave me incapacitated for hours in pain, and then incapacitated for hours due to sheer exhaustion from said pain. The cramps came to me shortly after most meals. Because of this I subconsciously associated eating with pain. Subsequently I lost forty pounds over a period of about one year. I went to the doctor many times, had many different scans and tests performed, all of them inconclusive, so my doctor told me I have Irritable Bowel Syndrome, or IBS. This basically means they don't know what is causing the pain, but that it is real. I was prescribed a medication which did not work and did not make me feel too well in general, so I stopped taking it after about two weeks. This pain after eating continued all the way through high school, until the summer of 2005, the summer before I entered college. It was during this period I began experimenting with cannabis. I had always been heavily anti-drug, so much so that at one point in high school I ratted out a few of my friends for smoking a joint, because I thought doing so was in their best interest. However, after experimenting with cannabis, I noticed that I no longer would get sick after most meals. During my freshmen year in college I bought a vaporizer so that I could use cannabis without burning it. A vaporizer simply heats up the medically active chemicals to their boiling point and then they can be breathed into the lungs without any tar or carcinogens. My life had greatly improved because of cannabis consumption; I could eat without getting sick and I could eat with other people in a social setting. Unfortunately due to the fact that medical marijuana is illegal in the state of Michigan currently, I decided that my health was not worth risking prison time, so I had to stop using medical marijuana. After about two weeks of stopping my medication the cramping after meals began starting again and it is incredibly difficult for me to maintain a healthy weight.
Because the incapacitating pain and wasting syndrome subsided during my exposure to cannabis, I became incredibly interested in the subject and began doing research at an intense pace. I knew that newspapers, television, and websites were not good sources of information, so I used my university's databases to find medical and scientific journals on the subject. I wanted to find out what doctors and scientists have to say about the drug as opposed to politicians and journalists. Medical marijuana is a term that sprung up sometime after 1937 when marijuana became illegal as a result of H.R. 6385. Before that point in time, medical marijuana was called cannabis. Preparations of cannabis were sold in pharmacies across the United States for a variety of symptoms such as: epilepsy, stomach pain, social anxiety, PMS, and as a general pain reliever. In 1930 after alcohol prohibition had failed, a smear campaign against cannabis was launched by Harry J. Ansligner who was the commissioner of the U.S. Bureau of Narcotics. Harry referred to the plant as “marijuana”, which is what the Mexicans called it, in order to play into the xenophobia of the uneducated American masses. A few quotes from him taken from the “gore files” which is a compiled list of “facts” on why it should become and remain illegal is enough to convince anyone that Harry was producing propaganda and not looking out for the best interests of Americans.
“There are 100,000 total marijuana smokers in the US, and most are Negroes, Hispanics, Filipinos, and entertainers. Their Satanic music, jazz, and swing, result from marijuana use.”
“This marijuana causes white women to seek sexual relations with Negroes, entertainers, and any others."
"...the primary reason to outlaw marijuana is its effect on the degenerate races."
After seven years of slinging this propaganda, he was able to make cannabis, and more importantly hemp, illegal. The reasons he produced these outright lies are out of the scope of this paper I believe, however the reason is well documented and complicated, but it boils down to protecting the financial interests of himself and his friends the DuPonts, and William Randolph Hearst.
Not too much happened in the area of marijuana or medical marijuana between 1937 and 1970. In 1971 Richard Nixon wanted to have scientific justification for his tough on drugs policies that were going to require lots of taxpayer money. Nixon decided a group of independent scientists should evaluate marijuana and its dangers, this was dubbed “The Shafer Commission.” In a taped declassified conversation between Richard Nixon and House Representative Robert “Bob” Haldeman discussing the purpose of the Shafer Commission on May 26, 1971, between 10 and 11 am, the following conversation took place:
RN: "Now, this is one thing I want. I want a Goddamn strong
statement on marijuana. Can I get that out of this
sonofabitching, uh, Domestic Council?"
HRH: "Sure."
RN: "I mean one on marijuana that just tears the ass out of them.
I see another thing in the news summary this morning about it.
You know it's a funny thing, every one of the bastards that are
out for legalizing marijuana is Jewish. What the Christ is the
matter with the Jews, Bob, what is the matter with them? I
suppose it's because most of them are psychiatrists, you know,
there's so many, all the greatest psychiatrists are Jewish. By
God we are going to hit the marijuana thing, and I want to hit it
right square in the puss, I want to find a way of putting more on
that. More [ unintelligible ] work with somebody else with this."
HRH: "Mm hmm, yep."
RN: "I want to hit it, against legalizing and all that sort of
thing."
Nixon however, was furious when the commission recommended that marijuana be legalized because it is a safe non-toxic drug that is impossible to overdose on. There are many good quotes from the Shafer Commissions report “Marihuana: A signal of misunderstanding,” but perhaps one of the better ones is:“Objective studies of chronic, heavy smokers of potent preparations have not causally linked this drug with the amotivational syndrome which has been described by many clinicians. Almost all chronic, heavy hashish smokers are indistinguishable from their peers in the lower socioeconomic strata of their respective societies in social behavior, work performance, mental status and overall life style.”[Emphasis added]
The report was ignored by the Nixon administration, the War on Drugs began, and so did a bottomless pit of taxpayer money. At this point in time about 100,000 people a year were being arrested for crimes related to marijuana possession. Over the next twenty years marijuana arrests continued to climb. In 1990, 260,390 people were arrested for crimes related to marijuana possession.
Then in the 1990s, researchers discovered that the brain and body actually has receptors for the compounds in marijuana called cannabinoids. The two receptors are called CB1 and CB2. Shortly after the discovery of their receptors, two endogenous cannabinoids, also known as endocannabinoids, were discovered. Their names are anandamide and 2-arachidonoyl glycerol. Both of these compounds are derivatives of arachidonic acid, and both endocannabinoids appear to bind to CB1 and CB2. Biochemical research into these receptors and their agonists revealed the exact biochemical cascade of events that happens when these receptors are agonized. The overall view of the endocannabinoid system is that it mediates the effects of over stimulation, reduces inflammation, and promotes growth of new neurons in response to overstimulation. On going research is finding that marijuana can reduce tumor growth, help people resist staph infections, and alleviate chronic pain far better with far fewer side effects than opium derivatives. [start new paragraph here ->] In 2007 marijuana arrests reached record breaking levels of 872,721 that year alone and cost the tax payers $41.8billion. In comparison 597,447 people were arrested for violent crimes in 2007. Nearly 300,000 more people are arrested for marijuana each year than for all violent crimes combined. In 2008, I wrote a lengthy research paper analyzing the biochemistry of the endocannabinoid system for my second biochemistry class entitled “The Endocannabinoid System and Implications in Epilepsy.” The findings of this paper was that essentially there is a great deal of biochemical and animal model evidence that suggests the compounds in marijuana can treat acute epileptic seizures better than the conventional pharmaceutical medications.
In addition to my factual knowledge relating to medical marijuana, I also have subjective opinions on the subject that although based on factual information are simply opinions. I am of the opinion that marijuana should be legalized for medical and recreational purposes and taxed like tobacco and alcohol. I am of the opinion that regular responsible use of marijuana is beneficial to a person physically, mentally, and spiritually.
I would be considered an insider on this issue. However, I also know what it feels like to be on the outside of this issue because for the majority of my life I was strongly anti-cannabis. As an anti-cannabis outsider, I was encouraged by my pro-cannabis friends to do research on the issue. Because I value the objective eye of science over subjective debates on the issue, I simply started doing research in large databases of medical and scientific journals. As I read article after article on the subject I was beginning to see a trend: that marijuana is non-toxic, has never killed a single person in all of recorded history, actually promotes the growth of brain cells, and promotes the destruction of tumors. Over the next few years I continued doing more and more research on the subject and I have yet to see any scientific or medical data that confirms that marijuana is more dangerous than aspirin. My research into the subject allowed me to transition from being an outsider, to an insider. Now as an insider my questions regarding this topic are more fine tuned. I am now very interested in the biochemical mechanisms through which cannabis is able to alleviate pain, grow new neurons, and provide relief from many medical conditions.
I hoped you enjoyed reading this article about marijuana and I hope you start asking some of your own serious questions on this issue. Remember “Believe nothing, no matter where you read it or who has said it, not even if I have said it, unless it agrees with your own reason and your own common sense.” – Buddha
Uncited Sources: (not in correct format, sorry will add in later)
Lutz, Beat. "On-Demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures." Biochemical Pharmacology 68(2004): 1691-1698.
Croxford, J. Ludovic. "Cannabinoids and the immune system: Potential for the treatment of inflammatory diseases?." Journal of Neuroimmunology 166(2005): 3-18.
Grant, Igor. "Cannabis and endocannabinoid modulators: Therapeutic promises and challenges." Clinical Neuroscience Research 5(2005): 185-199.
Mechoulam R, Spatz M Endocannabinoids and neuroprotection. Sci STKE 2002;2002(129):RE5
Marchalant, Yannick. "Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats." Neurobiology of Aging (2007):
Miriam H. Meisler and Jennifer A. Kearney (2005). "Sodium channel mutations in epilepsy and other neurological disorders". Journal of Clinical Investigation 115 (8): 2010–2017.
Goddard, G.V. (1967). Development of epileptic seizures through brain stimulation at low intensity. Nature, 214, 1020-1021.
Deshpande, Laxmikant. "Endocannabinoids block status epilepticus in cultured hippocampal neurons." European Journal of Pharmacology 558(2007): 52-59.
Taft WC; DeLorenzo RJ (May 1984). "Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations". Proc Natl Acad Sci U S A 81 (10): 3118-22.
Wallace, Melisa. "Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity." European Journal of Pharmacology 452(2002): 295-301.
Eljaschewitsch , Eva. "The Endocannabinoid anandamide protects neurons during CNS Inflammation by induction of MKP-1 in Microglial cells." Neuron 49(2006): 67-79.
Bisogno, Tiziana. "Short- and long-term plasticity of the endocannabinoid system in neuropsychiatric and neurological disorders." Pharmacological Research 56(2007): 428-442.
Marchalant, Yannick. "Inflammation and aging: Can endocannabinoids help?." Biomedicine & Pharmacotherapy (2008): 1-6.
Optiz, Christiane. "Production of the endocannabinoids anandamide and 2-arachidonoylglycerol by endothelial progenitor cells." Federation of European Biochemical Societies 581(2007): 4927-4931.
Marchalant, Yannick. "Anti-Inflammatory property of the cannabinoid agonist win-55212-2 in a rodent model of chronic brain inflammation." Neuroscience 144(2007): 1516-1522.
Panikashvili, David. "The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines." Neurobiology of Disease 22(2006): 257-264.
Marihuana:A signal of Misunderstanding
CSDP Research Report
March 2002
Nixon Tapes Show Roots of Marijuana Prohibition:
Misinformation, Culture Wars and Prejudice
Lost Taxes and Other Costs
of Marijuana Laws
by Jon Gettman, Ph.D.
Sidney, S. The British Medical Journal, Sept. 20, 2003; vol 327: pp 635-636.
When I was twelve and on a summer vacation with my parents in Maine, I began to get incredibly painful stomach cramps that would leave me incapacitated for hours in pain, and then incapacitated for hours due to sheer exhaustion from said pain. The cramps came to me shortly after most meals. Because of this I subconsciously associated eating with pain. Subsequently I lost forty pounds over a period of about one year. I went to the doctor many times, had many different scans and tests performed, all of them inconclusive, so my doctor told me I have Irritable Bowel Syndrome, or IBS. This basically means they don't know what is causing the pain, but that it is real. I was prescribed a medication which did not work and did not make me feel too well in general, so I stopped taking it after about two weeks. This pain after eating continued all the way through high school, until the summer of 2005, the summer before I entered college. It was during this period I began experimenting with cannabis. I had always been heavily anti-drug, so much so that at one point in high school I ratted out a few of my friends for smoking a joint, because I thought doing so was in their best interest. However, after experimenting with cannabis, I noticed that I no longer would get sick after most meals. During my freshmen year in college I bought a vaporizer so that I could use cannabis without burning it. A vaporizer simply heats up the medically active chemicals to their boiling point and then they can be breathed into the lungs without any tar or carcinogens. My life had greatly improved because of cannabis consumption; I could eat without getting sick and I could eat with other people in a social setting. Unfortunately due to the fact that medical marijuana is illegal in the state of Michigan currently, I decided that my health was not worth risking prison time, so I had to stop using medical marijuana. After about two weeks of stopping my medication the cramping after meals began starting again and it is incredibly difficult for me to maintain a healthy weight.
Because the incapacitating pain and wasting syndrome subsided during my exposure to cannabis, I became incredibly interested in the subject and began doing research at an intense pace. I knew that newspapers, television, and websites were not good sources of information, so I used my university's databases to find medical and scientific journals on the subject. I wanted to find out what doctors and scientists have to say about the drug as opposed to politicians and journalists. Medical marijuana is a term that sprung up sometime after 1937 when marijuana became illegal as a result of H.R. 6385. Before that point in time, medical marijuana was called cannabis. Preparations of cannabis were sold in pharmacies across the United States for a variety of symptoms such as: epilepsy, stomach pain, social anxiety, PMS, and as a general pain reliever. In 1930 after alcohol prohibition had failed, a smear campaign against cannabis was launched by Harry J. Ansligner who was the commissioner of the U.S. Bureau of Narcotics. Harry referred to the plant as “marijuana”, which is what the Mexicans called it, in order to play into the xenophobia of the uneducated American masses. A few quotes from him taken from the “gore files” which is a compiled list of “facts” on why it should become and remain illegal is enough to convince anyone that Harry was producing propaganda and not looking out for the best interests of Americans.
“There are 100,000 total marijuana smokers in the US, and most are Negroes, Hispanics, Filipinos, and entertainers. Their Satanic music, jazz, and swing, result from marijuana use.”
“This marijuana causes white women to seek sexual relations with Negroes, entertainers, and any others."
"...the primary reason to outlaw marijuana is its effect on the degenerate races."
After seven years of slinging this propaganda, he was able to make cannabis, and more importantly hemp, illegal. The reasons he produced these outright lies are out of the scope of this paper I believe, however the reason is well documented and complicated, but it boils down to protecting the financial interests of himself and his friends the DuPonts, and William Randolph Hearst.
Not too much happened in the area of marijuana or medical marijuana between 1937 and 1970. In 1971 Richard Nixon wanted to have scientific justification for his tough on drugs policies that were going to require lots of taxpayer money. Nixon decided a group of independent scientists should evaluate marijuana and its dangers, this was dubbed “The Shafer Commission.” In a taped declassified conversation between Richard Nixon and House Representative Robert “Bob” Haldeman discussing the purpose of the Shafer Commission on May 26, 1971, between 10 and 11 am, the following conversation took place:
RN: "Now, this is one thing I want. I want a Goddamn strong
statement on marijuana. Can I get that out of this
sonofabitching, uh, Domestic Council?"
HRH: "Sure."
RN: "I mean one on marijuana that just tears the ass out of them.
I see another thing in the news summary this morning about it.
You know it's a funny thing, every one of the bastards that are
out for legalizing marijuana is Jewish. What the Christ is the
matter with the Jews, Bob, what is the matter with them? I
suppose it's because most of them are psychiatrists, you know,
there's so many, all the greatest psychiatrists are Jewish. By
God we are going to hit the marijuana thing, and I want to hit it
right square in the puss, I want to find a way of putting more on
that. More [ unintelligible ] work with somebody else with this."
HRH: "Mm hmm, yep."
RN: "I want to hit it, against legalizing and all that sort of
thing."
Nixon however, was furious when the commission recommended that marijuana be legalized because it is a safe non-toxic drug that is impossible to overdose on. There are many good quotes from the Shafer Commissions report “Marihuana: A signal of misunderstanding,” but perhaps one of the better ones is:“Objective studies of chronic, heavy smokers of potent preparations have not causally linked this drug with the amotivational syndrome which has been described by many clinicians. Almost all chronic, heavy hashish smokers are indistinguishable from their peers in the lower socioeconomic strata of their respective societies in social behavior, work performance, mental status and overall life style.”[Emphasis added]
The report was ignored by the Nixon administration, the War on Drugs began, and so did a bottomless pit of taxpayer money. At this point in time about 100,000 people a year were being arrested for crimes related to marijuana possession. Over the next twenty years marijuana arrests continued to climb. In 1990, 260,390 people were arrested for crimes related to marijuana possession.
Then in the 1990s, researchers discovered that the brain and body actually has receptors for the compounds in marijuana called cannabinoids. The two receptors are called CB1 and CB2. Shortly after the discovery of their receptors, two endogenous cannabinoids, also known as endocannabinoids, were discovered. Their names are anandamide and 2-arachidonoyl glycerol. Both of these compounds are derivatives of arachidonic acid, and both endocannabinoids appear to bind to CB1 and CB2. Biochemical research into these receptors and their agonists revealed the exact biochemical cascade of events that happens when these receptors are agonized. The overall view of the endocannabinoid system is that it mediates the effects of over stimulation, reduces inflammation, and promotes growth of new neurons in response to overstimulation. On going research is finding that marijuana can reduce tumor growth, help people resist staph infections, and alleviate chronic pain far better with far fewer side effects than opium derivatives. [start new paragraph here ->] In 2007 marijuana arrests reached record breaking levels of 872,721 that year alone and cost the tax payers $41.8billion. In comparison 597,447 people were arrested for violent crimes in 2007. Nearly 300,000 more people are arrested for marijuana each year than for all violent crimes combined. In 2008, I wrote a lengthy research paper analyzing the biochemistry of the endocannabinoid system for my second biochemistry class entitled “The Endocannabinoid System and Implications in Epilepsy.” The findings of this paper was that essentially there is a great deal of biochemical and animal model evidence that suggests the compounds in marijuana can treat acute epileptic seizures better than the conventional pharmaceutical medications.
In addition to my factual knowledge relating to medical marijuana, I also have subjective opinions on the subject that although based on factual information are simply opinions. I am of the opinion that marijuana should be legalized for medical and recreational purposes and taxed like tobacco and alcohol. I am of the opinion that regular responsible use of marijuana is beneficial to a person physically, mentally, and spiritually.
I would be considered an insider on this issue. However, I also know what it feels like to be on the outside of this issue because for the majority of my life I was strongly anti-cannabis. As an anti-cannabis outsider, I was encouraged by my pro-cannabis friends to do research on the issue. Because I value the objective eye of science over subjective debates on the issue, I simply started doing research in large databases of medical and scientific journals. As I read article after article on the subject I was beginning to see a trend: that marijuana is non-toxic, has never killed a single person in all of recorded history, actually promotes the growth of brain cells, and promotes the destruction of tumors. Over the next few years I continued doing more and more research on the subject and I have yet to see any scientific or medical data that confirms that marijuana is more dangerous than aspirin. My research into the subject allowed me to transition from being an outsider, to an insider. Now as an insider my questions regarding this topic are more fine tuned. I am now very interested in the biochemical mechanisms through which cannabis is able to alleviate pain, grow new neurons, and provide relief from many medical conditions.
I hoped you enjoyed reading this article about marijuana and I hope you start asking some of your own serious questions on this issue. Remember “Believe nothing, no matter where you read it or who has said it, not even if I have said it, unless it agrees with your own reason and your own common sense.” – Buddha
Uncited Sources: (not in correct format, sorry will add in later)
Lutz, Beat. "On-Demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures." Biochemical Pharmacology 68(2004): 1691-1698.
Croxford, J. Ludovic. "Cannabinoids and the immune system: Potential for the treatment of inflammatory diseases?." Journal of Neuroimmunology 166(2005): 3-18.
Grant, Igor. "Cannabis and endocannabinoid modulators: Therapeutic promises and challenges." Clinical Neuroscience Research 5(2005): 185-199.
Mechoulam R, Spatz M Endocannabinoids and neuroprotection. Sci STKE 2002;2002(129):RE5
Marchalant, Yannick. "Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats." Neurobiology of Aging (2007):
Miriam H. Meisler and Jennifer A. Kearney (2005). "Sodium channel mutations in epilepsy and other neurological disorders". Journal of Clinical Investigation 115 (8): 2010–2017.
Goddard, G.V. (1967). Development of epileptic seizures through brain stimulation at low intensity. Nature, 214, 1020-1021.
Deshpande, Laxmikant. "Endocannabinoids block status epilepticus in cultured hippocampal neurons." European Journal of Pharmacology 558(2007): 52-59.
Taft WC; DeLorenzo RJ (May 1984). "Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations". Proc Natl Acad Sci U S A 81 (10): 3118-22.
Wallace, Melisa. "Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity." European Journal of Pharmacology 452(2002): 295-301.
Eljaschewitsch , Eva. "The Endocannabinoid anandamide protects neurons during CNS Inflammation by induction of MKP-1 in Microglial cells." Neuron 49(2006): 67-79.
Bisogno, Tiziana. "Short- and long-term plasticity of the endocannabinoid system in neuropsychiatric and neurological disorders." Pharmacological Research 56(2007): 428-442.
Marchalant, Yannick. "Inflammation and aging: Can endocannabinoids help?." Biomedicine & Pharmacotherapy (2008): 1-6.
Optiz, Christiane. "Production of the endocannabinoids anandamide and 2-arachidonoylglycerol by endothelial progenitor cells." Federation of European Biochemical Societies 581(2007): 4927-4931.
Marchalant, Yannick. "Anti-Inflammatory property of the cannabinoid agonist win-55212-2 in a rodent model of chronic brain inflammation." Neuroscience 144(2007): 1516-1522.
Panikashvili, David. "The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines." Neurobiology of Disease 22(2006): 257-264.
Marihuana:A signal of Misunderstanding
CSDP Research Report
March 2002
Nixon Tapes Show Roots of Marijuana Prohibition:
Misinformation, Culture Wars and Prejudice
Lost Taxes and Other Costs
of Marijuana Laws
by Jon Gettman, Ph.D.
Sidney, S. The British Medical Journal, Sept. 20, 2003; vol 327: pp 635-636.
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