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Cannabis is one of the most widely used drugs throughout the world. The psychoactive constituent of cannabis, delta 9-tetrahydrocannabinol (delta 9-THC), produces a myriad of pharmacological effects in animals and humans. Marijuana has been in use for over 4,000 years as a therapeutic and as a recreational drug. It can have both stimulant and sedative properties. In usual intoxicating doses, it produces a sense of well-being, relaxation, a loss of temporal awareness, slowing of thought processes, impairment of short term memory, and a feeling of achieving special insights. At high dosed marijuana can induce panic, toxic delirium, and not often, psychosis.
Marijuana is the term used to describe the leaves and flowering tops of the Cannabis sativa plant. Like other herbal medicines, the Cannabis plant plays host to a number of chemicals. The plant houses approximately 460 known compounds. Sixty of these are unique to the Cannabis plant and are called cannabinoids. The primary psychoactive cannabinoid is delta-9-tetrahydrocannabinol (THC) interacts with cannabinoid receptors to trigger dopamine relase from the mesolimbic reward system. Chemically the cannabinoids are classed as terpenoid (terpene-like). These compounds occur as essential oils within many plants and some are involved in vitamin, steroid and pigment formation.
There are two known endogenous cannabinoid receptors named CB1 and CB2. CB1 receptors are found primarily in the brain. They are most prevalent in the hippocampus, cerebral cortex, basal ganglia, and cerebellum. CB1 receptors in the hippocampus mediate effects on short-term memory. CB2 receptors are also found in the brain, but more so expressed by cells of the immune system, especially B cells. The CB receptor is a G protein mediated receptor that affects primarily calcium and potassium channel activation (Howlett et al, 1995). Both receptors are G protein linked, decrease adenyl cyclase activity, inhibit calcium N channels, and disinhibit potassium channels. Functional changes are most notable in neuronal excitability and neurotransmitter release. Both receptor types selectively bind THC, the active principle in marijuana, and anandamide, an endogenous cannabimimetic eicosanoid (Felder et al, 2000).
As was just mentioned, there is also an endogenous cannabinoid system, the brain’s own marijuana, capable of activating these cannabinoid receptors functionally. These endocannabinoids are synthesized by neurons and inactivated by reuptake systems and enzymes in both neurons and glia. Initially, the receptors were considered orphaned receptors meaning that there were no endogenous ligands. Subsequent research turned up two endogenous cannabinoid ligands, anandamide and 2-arachidonylglycerol, that not only bind to the receptors but also mimic many of the biological actions of plant-derived cannabinoids.

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Anandamide is a member of a new chemicals class of neurotransmitters. It is an endogenous lipid that activates brain cannabinoid receptors and mimics the pharmacological effects of delta-9-THC, the active principle of marijuana. Depolarized neurons release anandamide through a mechanism that may require the calcium-dependent cleavage of a phospholipid precursor in neuronal membranes (Beltramo et al, 1997).
     THC has some therapeutic effects such as pain relief and appetite stimulation. THC also interferes with a process in the hippocampus of the brain called long-term potentiation (LTP), which is important to memory and learning. "Normally, these brain cells would communicate with a certain level of efficacy or strength. However, under certain conditions -- these are the conditions under which we tend to remember things -- the strength of the communication will be increased," explains Daniele Piomelli of the
Neurosciences Institute in San Diego, senior author on the report published in Science. "This phenomenon is called potentiation of synaptic (nerve) transmission. Potentiation that is prolonged for many hours is therefore called long-term potentiation." The fact that the cannabinoid receptors are highly concentrated in the hippocampus is very important in understanding LTP and learning, says Piomelli. "The hippocampus is a small region of the brain present in all mammals, including man, that participates in short-term memory formation and learning. The way people look at the hippocampus is as a 'relay station' where sensory inputs go to become either discarded, or become prolonged memories. In fact, patients who have lesions in the hippocampus, while they can retain old memories, cannot form new memories." By blocking LTP, drugs like THC interfere with this memory-relaying process (Beltramo et al, 1997).
     Research also shows large numbers of the anandamide receptors are in the parts of the brain responsible for short-term memory and motor control. This suggests that anandamide is involved with these two functions. Future medications for the treatment of memory loss may work by stopping the union of anandamide and its receptor. Once the actions of the anandamide system are clear, scientists may be able to manipulate the molecules and create treatments for numerous illnesses perhaps even including Alzheimer's disease.
     Marijuana has been surrounded by a haze of controversy for years. Proponents look past behavioral effects of the drug, including a sense of euphoria, and changes in mood, perception, memory and fine motor skills and point to a long list of potential medical benefits, such as relieving symptoms of glaucoma. Advances in the understanding of the molecular pharmacology and biochemistry of cannabinoid receptors and their lipid endocannabinoids should provide a better approach for further basic research perhaps leading to a more effective therapeutic (Felder, 1998).
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