Is marijuana a dangerous drug - Essay Example

Is Marijuana a Dangerous Drug Introduction Cannabis is the most commonly used illicit drug. The term cannabis refers to marijuana as well as hashish.Marijuana is a combination of chopped-up dried flowering tops, leaves, and stems of the hemp plant, or Cannabis sativa. Hashish is the brown or black resin from the flowering tops of the same plant, shaped into small rocks. Cannabis is usually smoked, and inhalation produces a state of relaxation and mild euphoria often accompanied by heightened perceptual acuity and intensified sensory inputs. These effects can last up to three hours after taking the drug. The active ingredient in cannabis is delta-9-tetrahydrocannabinol (THC). The effects of cannabis vary greatly depending on the dose and the quality of the drug as well as the users' experience with cannabis and their expectancy about the effects of the drug. Effects About 10% of people who start using cannabis will develop dependence, and frequent use is associated with a higher risk of dependence. Long-term use of cannabis damages short-term memory. The use of cannabis is sometimes associated with violence. It is increasingly being acknowledged that cannabis it is not a safe recreational drug as it was once thought to be. There is increasing evidence that cannabis withdrawal after prolonged use is associated with restlessness, irritability, anger, and sleep problems. Exposure to cannabis use and especially heavy use during adolescence and young adulthood increases the risk of psychotic symptoms later in life. As many as 15% of cannabis users report transient psychotic symptoms directly after use. A number of recent studies investigated prospectively whether cannabis use, at baseline, increases the risk of subsequent development of psychotic symptoms (Howlett et al. 2004). Cannabis use in young people moderately increased the risk of developing psychotic symptoms. The risk for the onset of symptoms was much higher for those who began use at an early age and with a predisposition for psychosis. There is some evidence that early cannabis use facilitates the progression to using drugs such as heroin and cocaine independent of genetic factors (Lundqvist, 2005). Molecular Events The first observed medicinal benefits of cannabis encompassed anesthetic, airway opening, antihypertensive, eye pressure reducing as well as antiemetic actions, but for decades, the underlying physiological and molecular mechanisms were unknown. Important advances have been made in the past decade in understanding how cannabis affects the brain. Research on the psychopharmacology of a plant-derived drug led to the discovery of a naturally occurring cannabinoid system in the brain (Mechoulam and Hanus, 2000). Although tetrahydrocannabinols (THCs) and cannabidiols were discovered and isolated from hemp extracts earlier, the structure and stereochemistry of the naturally occurring active substances in marijuana and hashish were discovered in the 1970s. The major phytocannabinoid structure was identified as a tricyclic ring constituted from a phenol ring, having a 5-carbon alkyl chain meta to the hydroxyl, a central pyran ring, and a mono-unsaturated cyclohexyl ring (Mechoulam and Shvo, 1963). Due to this inherent chemical nature, the active ingredients of cannabis interacts with the cannabinoid system in the brain, and the drug affects psychomotor, cognitive, perceptual and appetitive functions (Sarne & Mechoulam, 2005). Although about 66 different distinctive phytocannabinoid constituents of cannabis have been identified, THCs proved to be the most effective among all phytocannabinoids, whereas among THCs, 9-THC seems to be responsible for the vast majority of effects such as motor disturbances and catalepsy, corneal areflexia, scratching, euphoria and dysphoria, anxiety, drowsiness, altered time and audiovisual perceptions, panic attacks and impaired memory. Later it was shown that the more psychotropic a cannabinoid substance is the greater motor disturbances it causes. Furthermore, among phytocannabinoids, 9-THC is the most potent and effective psychomotor compound. The underlying mechanisms for these effects were mostly believed to result from "non-specific" interactions between the lipophilic 9-THC and the cell membranes, changing the fluidity and structure of the latter, therefore affecting most cell types. However, this hypothesis could not stand the test of time. Further investigations into this area revealed that there are two types of receptors for cannabinoids in the human tissues. One is CB1 cannabinoid receptor expressed in the brain, and the other is CB2, is expressed only in peripheral tissues, principally in the immune system. THC and the synthetic cannabinoids also act to some extent as agonists at the CB2 receptor. A series of synthetic drugs is also now available which act as specific antagonists at CB1 or CB2 receptors (Sarne & Mechoulam, 2005). CB1 receptors are mainly localized to axons and nerve terminals and are largely absent from the neuronal soma or dendrites. Cannabinoid receptors are predominantly presynaptic rather than postsynaptic, and this can provide a plausible explanation as to why cannabinoids are thought to act through modulation of neurotransmitter release. In humans, the cerebral cortex, particularly frontal regions, contains high densities of CB1 receptors. There are also very high densities in the basal ganglia and in the cerebellum. In the limbic forebrain CB1 receptors are found particularly in the hypothalamus and in anterior cingulate cortex. The hippocampus also contains a high density of CB1 receptors. The relative absence of the cannabinoid receptors from brainstem nuclei may account for the low toxicity of cannabinoids when given in overdose. The endocannabinoid system plays important roles in regulating diverse and fundamental processes of pathological and physiologic significance including the control of food intake, pain sensation, inflammation, and cognition. According to the broadly accepted concept, the CB1 receptor is the predominant cannabinoid-sensing receptor subtype expressed on neural cells in the central nervous system. CB1 receptors exhibit highest concentrations on perisynaptic axons segments of both -aminobutyric acid (GABA)- containing and glutamatergic neurons (Sarne & Mechoulam, 2005). The major physiological effect of CB1 receptor activation in the CNS is to modulate synaptic communication between neurons, and this occurs primarily via the presynaptic regulation of neurotransmitter release. In contrast, CB2 receptors are commonly associated with the regulation of immune function. However, although recent findings indicate the presence of CB2 receptors on brainstem neurons making the mechanism of cellular regulation of endocannabinoid functions in the CNS more complex. Interestingly, the CB1 receptor is one of the most abundantly expressed G protein-coupled receptors within the brain. This leads to the propensity of signaling interactions of these receptors with other neurotransmitter systems to establish, maintain, or refine synaptic communication between neurons (Sarne & Mechoulam, 2005). The CB1 receptor belongs to the GPCR superfamily containing seven -helical transmembrane domains with 68% amino acid homology within the transmembrane domains, and with a 44% overall homology to the CB2 receptor. The CB1 receptor signals through the preferential recruitment of Gi/o proteins with a potential switch in G protein coupling to Gs (Gq/11) proteins as determined by ligand availability and receptor interactions. Notably, the CB1 receptor contains a 116 amino acid residue-long N- terminal extracellular domain, which plays a role in determining the efficiency of receptor biogenesis and plasma membrane expression. Classically the CB1 receptor is linked to Gi/o mediated inhibition of adenylyl cyclase activity and a concordant decrease in cytosolic cAMP levels (Gerard, Mollereau, Vassart, Parmentier, 1990). Stimulation of effector kinase cascades, closure of Ca2+ channels, and opening of K+ channels have also been documented. The recruitment of particular signaling mechanisms translating CB1 receptor activity into biological output appears to be dictated by the cellular context at which signaling occurs. Activation of CB1 receptors and the subsequent liberation of Gi/o proteins couples to the inhibition of adenylate cyclases (Howlett, Fleming, 1984). The subsequent depletion of intracellular cAMP levels leads to the inactivation of the protein kinase A phosphorylation pathway. CB1 receptor activation recruits complex networks of intracellular protein kinases that are physiologically critical in producing lasting changes in synaptic strength (Matsuda, Lolait, Brownstein, Young, Bonner, 1990). Cannabinoid agonists are particularly potent in stimulating the extracellular signal-regulated kinase and focal adhesion kinase cascades both in vitro and in vivo. The fundamental roles ERK and FAK kinases play in synaptic plasticity suggests that their cannabinoidinduced activation is a pivotal determinant of synaptic functions with long-term modifications to synaptic structure and efficacy brought about by the selective regulation of several synaptic plasticity-related genes. In addition, 9-THC and endocannabinoids were shown to activate c-Jun N-terminal kinases 1/2 and the p38 mitogen-activated protein kinase with long-term activation of these kinase pathways being involved in 9-THC-induced cell death. Notably, stimulation, rather than inhibition, of adenylyl cyclases via Gs proteins has also been described (Munro, Thomas, Abu-Shaar,1993). Decisions on which of these pathways will be modulated by CB1 receptor activation is critically dependent on the cellular context, interacting proteins, temporal coincidence of active second messenger pathways, and the particular ligands activating the CB1 receptor (Sarne & Mechoulam, 2005). Changes in Brain and Behaviour The presynaptic localization of CB1 receptors suggests a role for cannabinoids in modulating the release of neurotransmitters from axon terminals. THC inhibits acetylcholine release. Similar inhibitory effects of THC and other cannabinoids on the release of a variety of neurotransmitters from CNS neurons have been observed. The neurotransmitters involved include l-glutamate, -aminobutyric acid (GABA), noradrenaline (norepinephrine), dopamine, 5-hydroxytryptamine (5-HT) and acetylcholine. Endocannabinoids are involved in the rapid modulation of synaptic transmission in the CNS by a retrograde signalling system that can influence synapses in a local region of some 40 m diameter, causing inhibitory effects on both excitatory and inhibitory neurotransmitter release that persist for tens of seconds. Retrograde cannabinoid signalling has been likened to a 'molecular coincidence detector' activated by the temporal and spatial convergence of multiple neurochemical signals. Exogenously administered THC or other cannabinoids cannot mimic the physiological effects of locally released endocannabinoids. Exogenous cannabinoids cause a long-lasting activation of CB1 receptors in all brain regions and their overall effect is to cause a persistent inhibition of neurotransmitter release from those nerve terminals which express CB1 receptors (Channabasavanna, Paes, & Hall, W., 1999). CB1 receptors are expressed at particularly high densities in the basal ganglia and cerebellum, so it is not surprising that cannabinoids have complex effects on psychomotor function. The CB1 receptor is expressed particularly by the main output cells of the striatum, GABAergic medium-spiny projection neurons. The receptor is abundant in regions containing the axon terminals of these cells, namely globus pallidus, entopeduncular nucleus and substantia nigra reticulata, and in axon collaterals feeding back to medium-spiny projection neurons in striatum. CB1 receptors are also abundant on the terminals of glutamatergic projection neurons from the subthalamic nucleus to globus pallidus, entopeduncular nucleus and substantia nigra reticulata. Cannabinoids might thus be expected to inhibit GABA release in striatum and GABA and glutamate release in the other nuclei. It has been suggested that the primary role of the endocannabinoid system may be to inhibit tonic release of glutamate inthe substantia nigra, regulating levels of basal motor activity (Deadwyler, Hampson, Porrino, 2004). Exogenous cannabinoids also lead to decreased GABA release in substantia nigra which could lead to a disinhibition of the inhibitory nigral input to the thalamocortical pathway, resulting in inhibition of movement. High-frequency activation of cortical inputs to medium-spiny neurons in the striatum leads to long-term depression of excitatory synaptic transmission (Lundqvist, 2005). Many studies have shown significant effects on short-term memory, particularly when tests were used that depend heavily on attention. THC, synthetic cannabinoids and anandamide cause deficits in short-term memory in spatial learning tasks. CB1 receptors are expressed at high densities in the hippocampus. They are particularly abundant on the terminals of a subset of GABAergic basket cell interneurones which also contain the neuropeptide cholecystokinin, and this is also the case in human hippocampus. Cannabinoids can inhibit the release of both GABA and glutamate in hippocampal circuits. Like other intoxicant drugs, cannabis causes profound changes in a variety of higher brain functions. Most studies in humans have observed changes consistent with a state of drowsiness, with increases in relative and absolute alpha power, particularly in frontal regions of cortex. While users often report a subjective enhancement of visual and auditory perception, sometimes with synaesthesia, laboratory studies have usually not shown marked changes in visual or auditory perception. One subjective effect that has been confirmed is the sensation that cannabis users experience time as passing more quickly relative to real time. Many subjective reports suggest that cannabis intoxication is associated with an increased appetite, particularly for sweet foods, even in subjects who were previously satiated. Nevertheless, controlled clinical trials showed that THC (dronabinol) had significant beneficial effects in counteracting the loss of appetite and reduction in body weight in patients suffering from the acquired immune deficiency syndrome (AIDS)-related wasting syndrome. Cannabinoids may play a role in the regulation of food intake and body weight. There have been many subjective accounts of the cannabis 'high.' The experience is highly variable, depending on the dose of drug, the environment and the experience and expectations of the drug user. A typical 'high' is preceded initially by a transient stage of tingling sensations felt in the body and head, accompanied by a feeling of dizziness or lightheadedness. The 'high' is a complex experience, characterized by a quickening of mental associations and a sharpened sense of humour - sometimes described as a state of 'fatuous euphoria'. The user feels relaxed and calm, in a dreamlike state disconnected from the real world. The intoxicated subject often has difficulty in carrying on a coherent conversation, and may drift into daydreams and fantasies. Drowsiness and sleep may eventually ensue. The feelings of heightened perception, increased appetite and distortion of the sense of time have already been referred to. As with other intoxicant drugs, little is known about the brain mechanisms that underlie the cannabis 'high'. The intoxicant effects are clearly mediated via CB1 receptors (Solowij, 1998). Medicinal Uses Marijuana has been used as an antipsychotic and anxiolytic agent. It has also been shown that it is an effective, safe and well-tolerated alternative treatment for schizophrenic patients. It is also suggested that it may have role in bipolar disorder. It could have potential effects in glaucoma, as a sedative and analgesic, antiemetic, appetiser, anabolic actions. It has therapeutic effects in asthma, insomnia, and is a good anxiolytic. It can minimize spasticity and involuntary movements. Studies are continuing to look for its possible therapeutic effects in seizures, tumors, insomnia, menstrual cramps, premenstrual syndrome, Crohn's disease, tinnitus, adult attention deficit disorder, uncontrollable violent behaviour, post-traumatic stress disorder, and even drug addiction. It has been suggested that it could have therapeutic effects in Alzheimer's disease and in controlling multiple sclerosis (Hayry, 2004). Parkinson's disease and epilepsy might be treated through targeting endocannabinoid system. They can be used in brain tumors, and further research may come up with novel agents to treat schizophrenia and mood disorders (Sundram, 2006). Reference List Channabasavanna, S. M., Paes, M., & Hall, W. (1999). Mental and behavioural disorders due to cannabis use. In H. Kalant, W. Corrigall, W. Hall, & R. Smart (Eds.), The health effects of cannabis (pp. 269-290). Canada: Centre for Addiction and Mental Health. Gerard C, Mollereau C, Vassart G, Parmentier M (1990) Nucleotide sequence of a human cannabinoid receptor cDNA. Nucleic Acids Res 18:7142. Hayry M (2004) Prescribing cannabis: freedom, autonomy, and values. J Med Ethics 30:333-336. Howlett AC, Fleming RM (1984) Cannabinoid inhibition of adenylate-cyclase: pharmacology of the response in neuroblastoma cell membranes. Mol Pharmacol 26:532-538. Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ (2004) Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology 47 Suppl 1:345-358 Lundqvist, T. (2005). Cognitive consequences of cannabis use: Comparison with abuse of stimulants and heroin with regard to attention, memory and executive functions. Pharmacology, Biochemistry and Behavior, 81, 319-330. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561-564 Mechoulam R, Hanus L (2000) A historical overview of chemical research on cannabinoids. Chem Phys Lipids 108:1-13. Mechoulam R, Shvo Y (1963) The structure of cannabidiol. Tetrahedron 19:2073-2078. Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61-65. Robson, P., (2001). Therapeutic aspects of cannabis and cannabinoids. British Journal of Psychiatry; 178: 107-115 Sarne, Y., & Mechoulam, R. (2005). Cannabinoids: Between neuroprotection and neurotoxicity. Current Drug Targets: CNS & Neurological Disorders, 4, 677-84. Solowij, N. (1998). Acute effects of cannabis on cognitive functioning. In Cannabis and cognitive functioning. United Kingdom: Cambridge University Press. Sundram, S. (2006). Cannabis and neurodevelopment: Implications for psychiatric disorders. Human Psychopharmacology, 21, 245-254. Read More