How does marijuana work?
Presented by: Dr. Gary B. Whitman
Marijuana has been used for over 2500 years. The first written record of its use comes from Central Asia. However, it is only within the last 2 decades that scientists have been able to determine specific and precise pharmacologic mechanisms of action. Such elegant scientific work lends merit to the rational utilization of marijuana.
There are specific receptors within the brain as well as other organs to which the most important marijuana compounds bind. These are known as Cannabinoid Receptors.
Knowledge of these receptors is essential for understanding the benefits associated with usage of marijuana. Based upon this knowledge, one can then make a rational decision as to whether use can be justified. One premise which is well known is that the cannabinoid receptors inhibit the accumulation of cyclic AMP within cells. These receptors are important for cognition, memory, appetite control, emesis, motor activity, sensory, neuroendocrine and inflammatory responses. Such is the power of the cannabinoid receptor system.
What are cannabinoid receptors? These are specific binding receptors which work in a “lock and key” binding method. When a drug binds to its specific receptor it causes a transformational change which then leads to a subsequent biological event. It is this biological event which is the consequence of the administration of the drug compound. Compounds which bind to the receptor and enhance its activity are known this agonists. Compounds which block the effects of the receptor are known as antagonists. Both agonists and antagonists have been identified and characterized for the cannabinoid receptor system.
The cannabinoid receptors are G protein couple receptors capable of binding to 3 different types of agents. The first type are plant cannabinoids such as are found in marijuana. THC is primarily 9—D tetrahydrocannabinol, which is the most powerful agent in terms of providing neurological benefits in the central nervous system. The second type of cannabinoid is a class known as endocannabinoids and are produced by the mammalian body as well as other parts of the central nervous system The third type of cannabinoid is synthetic, with the best known synthetic cannabinoid agent being HU—210. These synthetic compounds represent multiple chemicals and are not necessarily structurally related to other cannabinoids.
There are 2 well characterized subtypes of cannabinoid receptors—these are known as CB—I and CB—2. These receptors share more than 40% of their protein structures but are found in different parts of the body. The CB-I receptors are found primarily in the brain, while the CB-2 receptors are found primarily in cells of the immune system as well as cells responsible for the production of blood cells. Additionally, novel cannabinoid receptors have recently been identified, many of which have novel chemical structures as well as possessing mechanisms of action that have yet to be fully characterized. Even after 50 years of careful study the role of THC and its effect within the cannabinoid receptor system is yet to be fully elucidated. Of great importance but underwent is the fact that there are strains of marijuana which contain very little in the way of THC and yet may provide extraordinary therapeutic benefits. 2500 years of usage and it is only now that scientists are capable of figuring out how things work.
Because the CB 1 receptors have been characterized it is now possible to create synthetic antagonists. These antagonists bind to the receptor with greater selectivity than available drugs. The first of these is rimonabant. This agent helps to regulate weight gain and also leads to decreased food intake. The CB 1 receptor is found in the highest concentration in an area of the brain known as the hypothalamus, which is the part of the brain responsible for feeding regulation. The CB 1 receptors are also found in peripheral tissue with high concentrations within the gastrointestinal tract. Specific effects include changes in gastric emptying and peristalsis and have effects upon insulin sensitivity and the oxidation of fatty acids in muscle tissue as well as in the liver.
From all of these physiological effects one can begin to recognize the power of the cannabinoid receptor system. The creation of a synthetic cannabinoid antagonist binding with high affinity to a receptor leading to usage for weight control and which has no side effects is the goal of many a medicinal chemist. It is beyond the intentions of this treatise for Dr. Greenleaf to describe with precision the molecular mechanism of action of the binding process between the agonist and the cannabinoid receptor. What is important is for you to know that this mechanism has been fully worked out. Even more powerful synthetic antagonist compounds have been created with longer durations of action and which also can be given orally. The best characterized of these is the new drug surinabant.
However, these powerful compounds have been associated with significant clinical adverse effects. Side effects have included changes in mentation. It is for this reason that the European Regulatory Agencies have recommended the discontinuation of rimonabant, marketed under the brand name of Acornplia and that the FDA rejected the application because of concerns regarding anxiety and depression as a consequence of drug administration.
This may mean that the cannabinoid system is an important regulator of the anxiety coping behavior of the body. THC use appears to overcome the anxiety and depression associated with cannabinoid antagonists and therefore offers extraordinary therapeutic benefits. Through its effects in the midbrain region, THC leads to an increase in the neurotransmitters serotonin and nortriptyline, and is able to modulate pain control.
Many of the effects of THC appear to occur in a part of the brain known as the striatum. A majority of the neural outputs from this region of the brain are inhibitory in nature. For this reason THC is being administered for the treatment of Huntington’s chorea, a disorder in which muscle activity is hyperactive. Furthermore, preliminary data appears to indicate that THC is able to retard the progression of this devastating illness.
Dr. Greenleaf will present shortly the data demonstrating the benefits of modulating CD 2 receptors through the use of cannabinoid receptor interaction with marijuana.