Jacob Bell
New Member
The following points are made by Michael D. Roth (Nature 2005 434:708):
1) The discovery of cell-surface receptors that bind to the major active component of marijuana, delta-9-tetrahydrocannabinol (THC), has led to an explosion of research into the biological properties of marijuana and cannabinoids[1]. THC binds with equal affinity to two different receptors -- CB1 and CB2. CB1 is present at high levels on brain cells and at much lower levels on cells outside the nervous system. By contrast, CB2 receptors occur exclusively on cells outside the nervous system and in particular on cells of the immune system. This pattern of distribution suggests different functions for CB1 and CB2 that might be exploited therapeutically.
2) New work by Steffens et al[2] evaluates whether THC can protect against the development of atherosclerosis, a disease in which a combination of fatty deposits and inflammation leads to "plaques" that obstruct coronary arteries, causing angina and heart attacks. The authors suggest that the immunosuppressive properties of THC, and specifically those mediated by CB2 receptors, might be developed to treat heart disease.
3) The capacity of cannabinoids to regulate immune function is now well established. Exposing immune cells to THC alters their ability to produce certain signalling proteins called cytokines. When THC is administered to animals in vivo and to human cells in vitro, it suppresses the production of protective cytokines and increases the production of immunosuppressive cytokines. As a result, mice treated with THC fail to develop protective immunity against opportunistic infections and cancer[3]. Similarly, immune cells collected from the lungs of marijuana smokers produce lower than normal amounts of several cytokines and fail to produce nitric oxide (another intermediary in the immune system), severely limiting their ability to kill bacteria[4].
4) Steffens et al[2] set the stage for their work by demonstrating that immune cells expressing CB2 receptors infiltrate atherosclerotic plaques in humans and in a strain of mice that is used to study atherosclerosis (ApoE-/- mice). In this mouse model, the animals develop progressive narrowing of their arteries as lipids and inflammatory cells called macrophages enter the walls of their blood vessels and produce plaques[5]. When low doses of THC (1 mg per kg body weight per day) were added to their diet, the progression of atherosclerosis was markedly slowed. Mice that were fed THC still had elevated levels of serum lipids but had fewer plaque-infiltrating macrophages when compared with controls, suggesting an effect on immune function.
References (abridged):
1. Di Marzo, V., Bifulco, M. & De Petrocellis, L. Nature Rev. Drug Discov. 3, 771-784 (2004)
2. Steffens, S. et al. Nature 434, 782-786 (2005)
3. Klein, T. W. et al. J. Leukoc. Biol. 74, 486-496 (2003)
4. Shay, A. H. et al. J. Infect. Dis. 187, 700-704 (2003)
5. Meir, K. S. & Leitersdorf, E. Arterioscler. Thromb. Vasc. Biol. 24, 1006-1014 (2004)
Nature Journal home : Nature
--------------------------------
Related Material:
LONG-TERM EFFECTS OF HEAVY MARIJUANA USE
The following points are made by N. Solowij et al (J. Am. Med. Assoc. 2002 287:1123):
1) In the current climate of debate about marijuana laws and interest in marijuana as medicine, one issue remains unresolved: Does heavy, frequent, or prolonged use of cannabis lead to a deterioration in cognitive function that persists well beyond any period of acute intoxication? Is the functioning of the brain altered in the long term? With over 7 million people using cannabis weekly or more often in the US alone, and the potential for increased physician recommendations for select patients to use cannabis therapeutically, answers to these questions are of significant public health concern.
2. Past research suggested that gross impairment related to chronic cannabis use did not occur, but the evidence was inconclusive with regard to the presence of more specific deficits. Recent studies with improved methods have demonstrated changes in cognition and brain function associated with long term or frequent use of cannabis. Specific impairments of attention, memory, and executive function have been found in cannabis users in the unintoxicated state (and in children exposed to cannabis in utero) in controlled studies using brain event-related electric potential techniques and neuropsychological assessments, including complex tasks. In addition, brain imaging studies of cannabis users have demonstrated altered function, blood flow, and metabolism in prefrontal and cerebellar regions.
3) The authors report a multi-site retrospective cross-sectional neuropsychological study conducted in the US between 1997 and 2000, the study involving 102 near-daily cannabis users (51 long-term users; mean, 23.9 years of use; 51 shorter-term users; mean, 10.2 years of use) compared with 33 nonuser controls. The authors report their results confirm that long-term heavy cannabis users show impairments in memory and attention that endure beyond the period of intoxication and worsen with increasing years of regular cannabis use.
J. Am. Med. Assoc. JAMA, the Journal of the American Medical Association, a weekly peer-reviewed medical journal published by AMA – JAMA
--------------------------------
Related Material:
NEUROBIOLOGY: ON MARIJUANA CANNABINOIDS
Notes by ScienceWeek:
The drug "marijuana" is derived from the hemp plant Cannabis sativa. The parts of the plant vary in potency, the resinous exudate of the flowering tops of the female plant the most potent, providing "hashish" and "charas". Next in potency are the dried leaves and flowering shoots of the female plant (providing "bhang"), and the resinous mass from small leaves of inflorescence (providing "ganja"). The drug is usually inhaled by smoking, with marijuana "joints" containing approximately 500 milligrams of marijuana, which in turn contains approximately 5 to 15 milligrams of tetrahydrocannabinol (THC).
With moderate dosage, marijuana produces mild euphoria followed by sleepiness. In the acute state, the user has an altered time perception, less inhibited emotions, psychomotor problems, and impaired immediate memory. High doses produce transient effects resembling psychosis. The drug frequently aggravates existing mental illness, adversely affects motor performance, and slows the learning process in children. Studies of long-term effects have conclusively demonstrated abnormalities in the lungs, laryngitis, rhinitis, and chronic obstructive pulmonary disease. Chronic usage has resulted in depression of plasma testosterone levels and reduced sperm counts. Abnormal menstruation and failure to ovulate have occurred in some female users. Sudden withdrawal produces insomnia, nausea, muscle pain (myalgia), and irritability. In general, marijuana is a potent psychoactive drug acting on the central nervous system and producing both acute and chronic neurophysiological effects.
The most important neuroactive chemical ingredients in marijuana are the lipophilic cannabinoids, especially delta-9-tetrahydrocannabinol. Cannabinoids are believed to act at several specific cannabinoid receptors in the brain. When a human inhales or ingests marijuana, the liver transforms it into a number of metabolites, the most important of which is 11-hydroxy-delta-9-tetrahydrocannabinol, which has effects identical to those of the parent compound. 11-hydroxy-delta-9-THC is in turn converted to more polar and inactive metabolites which are excreted in urine.
Since certain cannabinoids are already present in the nervous system without input of any drug, cannabinoids need to be categorized as "exogenous" (from outside) versus "endogenous" (from inside).
In this context, the term "G-proteins" refers to a family of signal-coupling proteins that act as intermediaries between activated cell receptors and effectors, for example, the transduction of hormonal signals from the cell surface to the cell interior. The G-protein is apparently embedded in the cell membrane with parts exposed on the outside surface and inside surface. The outside moiety is activated by the "first messenger" (e.g., a hormone), and the inside moiety activates a "second messenger", the G-protein thus acting as a trans-membrane signal transducer.
"Neurotransmitters" are chemical substances released at the terminals of nerve axons in response to the propagation of an impulse to the end of that axon. The neurotransmitter substance diffuses into the synapse, the junction between the presynaptic nerve ending and the postsynaptic neuron, and at the membrane of the postsynaptic neuron the transmitter substance interacts with a receptor. Depending on the type of receptor, the result may be an excitatory or an inhibitory effect on the postsynaptic nerve cell.
"GABA" is gamma-amino butyric acid, a neurotransmitter substance. The term "GABA receptor" refers to any of several membrane proteins that bind GABA and mediate its effects as an inhibitory neurotransmitter.
In this context, the term "depolarization" refers to a reduction in the potential difference across the cell membrane. The neuron action potential involves not only a transient depolarization of the membrane but also a transient reversal of polarity of the potential difference, the potential difference across the neuron membrane during an action potential changing from approximately -60 millivolts (inside negative) to approximately +40 millivolts.
The "hippocampus" is a brain cortex structure in the medial part of the temporal lobe. In humans, among other functions, the hippocampus is apparently involved in short-term memory. Analysis of the neurological correlates of learning behavior in the rat indicates that the hippocampus is also involved in memory in that species. Nerve cells in rat brain slices remain active in vitro in appropriate solutions for up to 24 hours, and such slices are convenient tissues for experiments. "Hippocampal pyramidal neurons" are a specific type of nerve cell in the hippocampus.
The term "retrograde signaling" refers to neural information transmission in a direction opposite to the primary signal direction. In this context, the term refers to signaling from postsynaptic neuron to presynaptic neuron. In general, retrograde signaling in neural systems is usually part of a negative feedback process.
In general, an "interneuron" is any neuron that branches locally to innervate other neurons.
In general, in this context, an "agonist" is any substance that binds to and activates a receptor.
The following points are made by R.I. Wilson and R.A. Nicoll (Nature 2001 410:588):
1) Marijuana affects brain function primarily by activating the G-protein-coupled cannabinoid receptor-1 (CB1), which is genetically expressed throughout the brain at high levels. Two endogenous lipids, anandamide and 2-arachidonylglycerol (2-AG), have been identified as cannabinoid receptor-1 ligands, and depolarized hippocampal neurons have been shown to rapidly release both anandamide and 2-AG in a calcium-dependent manner. In the hippocampus, cannabinoid receptor-1 is expressed mainly by GABA-mediated inhibitory interneurons, where cannabinoid receptor-1 apparently clusters on axon terminals of such interneurons. A synthetic cannabinoid receptor-1 agonist has been demonstrated to depress GABA release from hippocampal slices, which suggests that the function of endogenous cannabinoids released by depolarized hippocampal neurons might be to reduce GABA release (down-regulate GABA release).
2) The authors report that their experiments indicate that the transient suppression of GABA-mediated transmission that follows depolarization of hippocampal pyramidal neurons is mediated by retrograde signaling through release of endogenous cannabinoids. Signaling by the endocannabinoid system thus represents a mechanism by which neurons can communicate backwards across synapses to modulate their inputs. The authors suggest this study represents the first identification of a physiological process mediated by endogenous brain cannabinoids. Exogenous cannabinoids such as marijuana may destroy the information contained in endogenous cannabinoid feedback loops and thus promote a more random pattern of synaptic modification.
Source: MEDICAL BIOLOGY: MARIJUANA AND THE HEART
1) The discovery of cell-surface receptors that bind to the major active component of marijuana, delta-9-tetrahydrocannabinol (THC), has led to an explosion of research into the biological properties of marijuana and cannabinoids[1]. THC binds with equal affinity to two different receptors -- CB1 and CB2. CB1 is present at high levels on brain cells and at much lower levels on cells outside the nervous system. By contrast, CB2 receptors occur exclusively on cells outside the nervous system and in particular on cells of the immune system. This pattern of distribution suggests different functions for CB1 and CB2 that might be exploited therapeutically.
2) New work by Steffens et al[2] evaluates whether THC can protect against the development of atherosclerosis, a disease in which a combination of fatty deposits and inflammation leads to "plaques" that obstruct coronary arteries, causing angina and heart attacks. The authors suggest that the immunosuppressive properties of THC, and specifically those mediated by CB2 receptors, might be developed to treat heart disease.
3) The capacity of cannabinoids to regulate immune function is now well established. Exposing immune cells to THC alters their ability to produce certain signalling proteins called cytokines. When THC is administered to animals in vivo and to human cells in vitro, it suppresses the production of protective cytokines and increases the production of immunosuppressive cytokines. As a result, mice treated with THC fail to develop protective immunity against opportunistic infections and cancer[3]. Similarly, immune cells collected from the lungs of marijuana smokers produce lower than normal amounts of several cytokines and fail to produce nitric oxide (another intermediary in the immune system), severely limiting their ability to kill bacteria[4].
4) Steffens et al[2] set the stage for their work by demonstrating that immune cells expressing CB2 receptors infiltrate atherosclerotic plaques in humans and in a strain of mice that is used to study atherosclerosis (ApoE-/- mice). In this mouse model, the animals develop progressive narrowing of their arteries as lipids and inflammatory cells called macrophages enter the walls of their blood vessels and produce plaques[5]. When low doses of THC (1 mg per kg body weight per day) were added to their diet, the progression of atherosclerosis was markedly slowed. Mice that were fed THC still had elevated levels of serum lipids but had fewer plaque-infiltrating macrophages when compared with controls, suggesting an effect on immune function.
References (abridged):
1. Di Marzo, V., Bifulco, M. & De Petrocellis, L. Nature Rev. Drug Discov. 3, 771-784 (2004)
2. Steffens, S. et al. Nature 434, 782-786 (2005)
3. Klein, T. W. et al. J. Leukoc. Biol. 74, 486-496 (2003)
4. Shay, A. H. et al. J. Infect. Dis. 187, 700-704 (2003)
5. Meir, K. S. & Leitersdorf, E. Arterioscler. Thromb. Vasc. Biol. 24, 1006-1014 (2004)
Nature Journal home : Nature
--------------------------------
Related Material:
LONG-TERM EFFECTS OF HEAVY MARIJUANA USE
The following points are made by N. Solowij et al (J. Am. Med. Assoc. 2002 287:1123):
1) In the current climate of debate about marijuana laws and interest in marijuana as medicine, one issue remains unresolved: Does heavy, frequent, or prolonged use of cannabis lead to a deterioration in cognitive function that persists well beyond any period of acute intoxication? Is the functioning of the brain altered in the long term? With over 7 million people using cannabis weekly or more often in the US alone, and the potential for increased physician recommendations for select patients to use cannabis therapeutically, answers to these questions are of significant public health concern.
2. Past research suggested that gross impairment related to chronic cannabis use did not occur, but the evidence was inconclusive with regard to the presence of more specific deficits. Recent studies with improved methods have demonstrated changes in cognition and brain function associated with long term or frequent use of cannabis. Specific impairments of attention, memory, and executive function have been found in cannabis users in the unintoxicated state (and in children exposed to cannabis in utero) in controlled studies using brain event-related electric potential techniques and neuropsychological assessments, including complex tasks. In addition, brain imaging studies of cannabis users have demonstrated altered function, blood flow, and metabolism in prefrontal and cerebellar regions.
3) The authors report a multi-site retrospective cross-sectional neuropsychological study conducted in the US between 1997 and 2000, the study involving 102 near-daily cannabis users (51 long-term users; mean, 23.9 years of use; 51 shorter-term users; mean, 10.2 years of use) compared with 33 nonuser controls. The authors report their results confirm that long-term heavy cannabis users show impairments in memory and attention that endure beyond the period of intoxication and worsen with increasing years of regular cannabis use.
J. Am. Med. Assoc. JAMA, the Journal of the American Medical Association, a weekly peer-reviewed medical journal published by AMA – JAMA
--------------------------------
Related Material:
NEUROBIOLOGY: ON MARIJUANA CANNABINOIDS
Notes by ScienceWeek:
The drug "marijuana" is derived from the hemp plant Cannabis sativa. The parts of the plant vary in potency, the resinous exudate of the flowering tops of the female plant the most potent, providing "hashish" and "charas". Next in potency are the dried leaves and flowering shoots of the female plant (providing "bhang"), and the resinous mass from small leaves of inflorescence (providing "ganja"). The drug is usually inhaled by smoking, with marijuana "joints" containing approximately 500 milligrams of marijuana, which in turn contains approximately 5 to 15 milligrams of tetrahydrocannabinol (THC).
With moderate dosage, marijuana produces mild euphoria followed by sleepiness. In the acute state, the user has an altered time perception, less inhibited emotions, psychomotor problems, and impaired immediate memory. High doses produce transient effects resembling psychosis. The drug frequently aggravates existing mental illness, adversely affects motor performance, and slows the learning process in children. Studies of long-term effects have conclusively demonstrated abnormalities in the lungs, laryngitis, rhinitis, and chronic obstructive pulmonary disease. Chronic usage has resulted in depression of plasma testosterone levels and reduced sperm counts. Abnormal menstruation and failure to ovulate have occurred in some female users. Sudden withdrawal produces insomnia, nausea, muscle pain (myalgia), and irritability. In general, marijuana is a potent psychoactive drug acting on the central nervous system and producing both acute and chronic neurophysiological effects.
The most important neuroactive chemical ingredients in marijuana are the lipophilic cannabinoids, especially delta-9-tetrahydrocannabinol. Cannabinoids are believed to act at several specific cannabinoid receptors in the brain. When a human inhales or ingests marijuana, the liver transforms it into a number of metabolites, the most important of which is 11-hydroxy-delta-9-tetrahydrocannabinol, which has effects identical to those of the parent compound. 11-hydroxy-delta-9-THC is in turn converted to more polar and inactive metabolites which are excreted in urine.
Since certain cannabinoids are already present in the nervous system without input of any drug, cannabinoids need to be categorized as "exogenous" (from outside) versus "endogenous" (from inside).
In this context, the term "G-proteins" refers to a family of signal-coupling proteins that act as intermediaries between activated cell receptors and effectors, for example, the transduction of hormonal signals from the cell surface to the cell interior. The G-protein is apparently embedded in the cell membrane with parts exposed on the outside surface and inside surface. The outside moiety is activated by the "first messenger" (e.g., a hormone), and the inside moiety activates a "second messenger", the G-protein thus acting as a trans-membrane signal transducer.
"Neurotransmitters" are chemical substances released at the terminals of nerve axons in response to the propagation of an impulse to the end of that axon. The neurotransmitter substance diffuses into the synapse, the junction between the presynaptic nerve ending and the postsynaptic neuron, and at the membrane of the postsynaptic neuron the transmitter substance interacts with a receptor. Depending on the type of receptor, the result may be an excitatory or an inhibitory effect on the postsynaptic nerve cell.
"GABA" is gamma-amino butyric acid, a neurotransmitter substance. The term "GABA receptor" refers to any of several membrane proteins that bind GABA and mediate its effects as an inhibitory neurotransmitter.
In this context, the term "depolarization" refers to a reduction in the potential difference across the cell membrane. The neuron action potential involves not only a transient depolarization of the membrane but also a transient reversal of polarity of the potential difference, the potential difference across the neuron membrane during an action potential changing from approximately -60 millivolts (inside negative) to approximately +40 millivolts.
The "hippocampus" is a brain cortex structure in the medial part of the temporal lobe. In humans, among other functions, the hippocampus is apparently involved in short-term memory. Analysis of the neurological correlates of learning behavior in the rat indicates that the hippocampus is also involved in memory in that species. Nerve cells in rat brain slices remain active in vitro in appropriate solutions for up to 24 hours, and such slices are convenient tissues for experiments. "Hippocampal pyramidal neurons" are a specific type of nerve cell in the hippocampus.
The term "retrograde signaling" refers to neural information transmission in a direction opposite to the primary signal direction. In this context, the term refers to signaling from postsynaptic neuron to presynaptic neuron. In general, retrograde signaling in neural systems is usually part of a negative feedback process.
In general, an "interneuron" is any neuron that branches locally to innervate other neurons.
In general, in this context, an "agonist" is any substance that binds to and activates a receptor.
The following points are made by R.I. Wilson and R.A. Nicoll (Nature 2001 410:588):
1) Marijuana affects brain function primarily by activating the G-protein-coupled cannabinoid receptor-1 (CB1), which is genetically expressed throughout the brain at high levels. Two endogenous lipids, anandamide and 2-arachidonylglycerol (2-AG), have been identified as cannabinoid receptor-1 ligands, and depolarized hippocampal neurons have been shown to rapidly release both anandamide and 2-AG in a calcium-dependent manner. In the hippocampus, cannabinoid receptor-1 is expressed mainly by GABA-mediated inhibitory interneurons, where cannabinoid receptor-1 apparently clusters on axon terminals of such interneurons. A synthetic cannabinoid receptor-1 agonist has been demonstrated to depress GABA release from hippocampal slices, which suggests that the function of endogenous cannabinoids released by depolarized hippocampal neurons might be to reduce GABA release (down-regulate GABA release).
2) The authors report that their experiments indicate that the transient suppression of GABA-mediated transmission that follows depolarization of hippocampal pyramidal neurons is mediated by retrograde signaling through release of endogenous cannabinoids. Signaling by the endocannabinoid system thus represents a mechanism by which neurons can communicate backwards across synapses to modulate their inputs. The authors suggest this study represents the first identification of a physiological process mediated by endogenous brain cannabinoids. Exogenous cannabinoids such as marijuana may destroy the information contained in endogenous cannabinoid feedback loops and thus promote a more random pattern of synaptic modification.
Source: MEDICAL BIOLOGY: MARIJUANA AND THE HEART
