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THE CURRENT STATUS OF
MARIJUANA CANNABIS RESEARCH
Category: Neurochemistry
Term Paper Code: 737
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Introduction
The subject of marijuana is a very charged topic, both politically and socially. Because of its status as a DSM IV Schedule One drug, much of the arguments for or against marijuana use have been the result of speculation and anecdotes. Recently, however, scientists have been able to study the molecular biology of some of the chemicals in marijuana and elucidate some of the biochemical pathways which they affect. Despite the intense controversy surrounding the subject, there have been quite a few breakthroughs in the past decade. The most notable being the identification of the endogenous cannabinoid ligand. In social and political discussions one often hears two extreme opinions on opposite ends of the spectrum with regard to this subject. Some people feel that marijuana is a dangerous drug which should be kept at its current status as a Schedule One controlled substance. Others feel that the drug should be made available for both medical and recreational purposes.
Many people make claims of the extreme benefits or detriments of marijuana; some claim that marijuana is a useful analgesic, anti-inflammatory agent, sedative hypnotic, or appetite stimulant. Others assert that it causes memory loss or cancer. Unfortunately, most people are unable to point to scientific research to back up their claims on either side if the debate. This is due to several reasons: not enough research has been done on the subject, many people have extreme biases, and many people are ignorant to the research that has been done. The fact of the matter is we still know very little about the possible dangers or benefits of marijuana. At this point in time, both of the previously mentioned views are probably unacceptable until further research is done. It is the goal of this paper to outline and explain the current status of research related to marijuana and discuss some of the implications. In doing so, perhaps some of the myths about marijuana will be dispelled.
Background
Marijuana is obtained from Cannabis sativa, the hemp plant. As many as sixty different cannabinoid substances have been identified in marijuana. Its use as a psychoactive agent was noted as early as 2737 B.C. in ancient China, and has been seen in many cultures throughout history. It was used recreationally by Muslims over a thousand years ago and spread into the Middle East and North Africa. Marijuana was also believed to have many medicinal properties in combating rheumatism, gout, and malaria. It was brought to the western hemisphere by the Spanish in the mid 1500’s. Hemp was for a long time a major cash crop in the United States, beginning in 1611 in Jamestown. Although it was smoked, it was also used to make paper, rope, and textiles because of the strong fibers it contained, and the relative ease of growing the plant. During the 1920’s it is believed that smoking marijuana began to become popular, possibly because of Prohibition. During the 1930’s, the use of marijuana became associated with certain minority groups and violence.
The overall prejudices of American society at the time caused all of the states to make marijuana illegal by 1936. By the 40’s and 50’s, very little research was done on marijuana. The view that marijuana caused violent behavior became replaced with the gateway theory. This theory stated that marijuana use could lead to the use of more dangerous drugs such as cocaine and heroin. This theory had little data to back it up, but because research was not being carried out it became widely accepted. It was not until the 1980’s and 1990’s that research pertaining to marijuana experienced a rebirth. Cannabinoid receptors were identified and scientists began to understand how marijuana might cause certain effects (WWW 1). There are currently two known cannabinoid receptors, CB1 and CB2. CB1 is found in the brain, while CB2 is found in many immune tissues including the spleen, tonsils, B cells, and monocytes.
Recent Research
The identification of anandamide (Devane et al. 1992) and 2-arachidonoyl glycerol as the endogenous cannabinoid receptor ligands was a major stepping stone in this area of research. Several years ago, results were published stating that the biosynthesis of cannabinoid precursors was dependent on both calcium and cyclic-AMP concentrations (Cadas et al. 1996). Endogenous cannabinoids are believed to be formed from a precursor molecule called N-acylphosphatidylethanolamine (NAPE). One model suggests that when the calcium concentration rises due to neuronal depolarization, N-acyltransferase is stimulated to transfer a fatty acid group from a membrane lipid such as phosphatidylcholine to phosphatidylethanolamine yielding NAPE. Another molecule, protein kinase A, is able to enhance this process. Protein kinase A activity is largely dependent on cyclic-AMP. At this point, NAPE can be cleaved into anandamide and N-palmitoylethanolamine (a CB2 ligand) by phospholipase D, which is stimulated by calcium influx. All of these molecules that are being enzymatically modified are membrane bound. It is still unknown how these cannabinoids leave the membranes to act as neurotransmitters. It is known that cAMP is involved in the reward systems in the brain and these results provide a clear link between cannabinoids and cAMP levels as well as linking them to calcium levels.
This link was further strengthened by a recent publication explaining the role of anandamide in the brain (Ishioka and Bukoski 1999). In this study the anandamide was tested to see if it is involved in relaxation. Using rat mesenteric branch arteries, contraction was induced using norepinephrine. Chemicals that block calcium channels, such as iberiotoxin, were able to inhibit this relaxation. Both calcium and anandamide were shown to be able to induce relaxation in these tissues, supporting the hypothesis that anandamide mediates nerve-dependent calcium-induced relaxation.
While the discovery of anandamide is quite recent, scientists are still only starting to understand the functioning of a molecule which was identified some time ago:*-9-tetrahydrocannabinol, a major active chemical in marijuana. Although it is difficult to determine exactly how the molecule functions in vivo, many studies have been carried out in vitro. In 1996, it was reported that cannabinoids, such as THC, could inhibit the release of presynaptic glutamate (Shen et al. 1996). This study done by a group at the University of Minnesota provides an extensive look at one of the possible mechanisms by which cannabinoids function. All of their experiments were carried out on rat hippocampal cell cultures. Initially, they showed that a cannabinoid receptor agonists, including Win 55,212, were able to stereospecifically inhibit calcium ion spiking in cells that were undergoing a pattern of repetitive calcium spiking. They also showed that the anandamide, the endogenous cannabinoid ligand, was able to have a similar inhibitory effect on calcium spiking. Many cannabinoid effects have been shown to be the result of G-protein coupled reactions (CB1 and CB2 are G-protein coupled receptors).
As expected, the inhibition shown in their experiments was also due to a G-protein coupled reaction. Finally, they demonstrate that the release of glutamate at presynaptic neurons is inhibited by agonists of the cannabinoid receptor, while there is no effect on neurotransmission through GABA. These obdervations provide some explanation as to how marijuana and cannabinoids in general can produce their known anticonvulsant and analgesic effects. Glutamate is a very prevalent excitatory neurotransmitter; therefore, we would expect that interfering with glutamatergic signaling could have such effects. With this knowledge, we can further take advantage of the cannabinoid receptor and its ligands and eventually use them for medical purposes.
Although the ability of cannabinoids to block glutamate may prove to be useful, some cannabinoids may also have harmful effects. Recently, it has been demonstrated that *-9-THC could have neurotoxic effects on the hippocampus (Chan et al. 1998). The experiments supporting this were also carried out on rat hippocampal cultures by a group at the University of Washington. The initial results showed quite clearly that treatments of cells with THC caused cell death. This alone does not tell much. However, they were able to show that such results were seen at relatively low concentrations, and were not simply due to overwhelming the cell. Additionally, cannabinoid antagonists were able to completely block this effect. Still, the term "cell death" is quite broad and can be caused by a number of things. Therefore, this research group looked at how exactly such cell death was being caused.
They noticed several physical and molecular changes resulting from the THC treatment. The cells as a whole underwent shrinkage; the nuclei were observed to contract and there were clear breaks in the genomic DNA following the treatment. Although it is difficult to correlate results from rat cell culture experiments with what is actually occurring in a human brain, such data provide strong evidence that long term repeated use of marijuana might have similar harmful effects. Since the hippocampus is known to be involved in memory, it has been postulated that the cell death observed here might explain apparent short term memory problems seen in some users of marijuana.
It has often been claimed that marijuana is not addictive and that there are no withdrawal symptoms. A group from Spain and the Scripps Institute attempted to address this by looking at the effects of cannabinoids on the limbic system (Fonesca et al. 1997). The limbic system, also called the reward pathway, is known to be involved in causing the addictive nature of many drugs. Corticotropin-releasing factor is believed to play a role in the negative consequences of withdrawal from substances such as alcohol and cocaine. Rats were treated with a cannabinoid receptor agonist for two weeks. When withdrawal was induced by administration of a cannabinoid receptor antagonist, corticotropin-releasing factor levels increased. Additionally, these rises corresponded with the peak in behavioral withdrawal symptoms. These are quite convincing results that show that marijuana is capable of having both addictive effect and symptoms of withdrawal. The authors do make attempts to tie this into the gateway theory, as others have. In this case, they state that drugs that have such effects on the limbic system can induce "neuroadaptive processes," which make one vulnerable to future drug dependence.
All of the studies discussed thus far have been have been carried out on rats or rat cell cultures with specific cannabinoid molecules in a very controlled manner. This, however, is no substitute for research involving the use of actual marijuana by human subjects. Such experiments are very difficult to carry out, and involve a lot of bureaucratic red tape. Research groups are only now starting to gain approval for controlled studies of marijuana use. For instance, a group at UCSF recently obtained funding and marijuana to carry out studies looking at the interactions between THC and HIV protease inhibitors (Abrams 1998). Numerous studies have already been carried out using marijuana users in the general public. Such studies can provide important information on the effects of smoking the drug.
There is much debate about how harmful marijuana smoke is. Some people claim that it is much safer than cigarette smoke, while others state that more carcinogens are released in marijuana smoke than in cigarette smoke. A group at UCLA looked closely at the functioning of certain immune cells in response to smoking different drugs (Baldwin et al. 1997). They were able to show convincing evidence that alveolar macrophages from marijuana smokers had reduced ability to kill bacteria. The same was not observed in tobacco smokers, cocaine smokers, or nonsmokers. This was tested by mixing macrophages from the various people in the study with Staphylococcus aureus, a common bacterial strain. The macrophages from nonsmokers, cocaine smokers, and tobacco smokers showed very similar phagocytic levels, while those from marijuana smokers showed markedly lower phagocytic levels.
In terms of the macrophages’ cytotoxic abilities to deal with tumor cell, marijuana smokers showed decreased levels as compared to tobacco smokers and nonsmokers. Interestingly, macrophages from cocaine smokers had even lower levels of tumor cytotoxicity than those from marijuana smokers. Additionally, users of marijuana showed decreased levels of several important molecules including interleukin-6, tumor necrosis factor-a, and granulocyte-macrophage colony-stimulating factor. In this study a marijuana smoker was defined as someone who smokes marijuana at least five times per week, while a tobacco smoker is someone who smokes at least ten cigarettes per day (both for a minimum of five years).
These experiments support the hypothesis that marijuana can have immunosuppressive effects. The alveolar macrophages are the predominant leukocytes of the lungs, and are the main defense system against bacteria and fungi. The cells secrete many molecules which are important in immune functioning, some of which showed sharp decreases in the tests mentioned above. The results of this study closely match those that were predicted based on previous animal studies. Although these harmful effects are seen most clearly in heavy users, this does show that the risk of damage is present in humans. This study points out that we still know very little about the possible harmful effects of marijuana, though it is clear that there are some immunosuppressive properties of *-9-THC.
There has also been convincing research done showing that smoking marijuana may not be as harmful on the lungs as some would claim. Another study involving some of the same investigators from UCLA demonstrated that marijuana smokers showed no observable decline in lung function over time, while a significant decline was seen in tobacco smokers (Tashkin et al. 1997). Additionally, in those who smoked both tobacco and marijuana, results were the same as those seen in smokers of tobacco alone. Lung function for these purposes was measured by lung capacity. It should also be noted that in this set of experiments a marijuana smoker was someone who smoked an average of 3.5 joints per day. This appears to support the notion that marijuana is safe to smoke. The investigators, however, also mention that the habitual marijuana smokers had other lung problems that contrasted these results. Many of the marijuana smokers had symptoms of chronic bronchitis.
The proportion of marijuana smokers who had such problems closely matched the proportion in tobacco smokers. Additionally, it was noted that both marijuana and tobacco smokers showed "extensive histopathologic alterations on bronchial mucosa biopsies." Obviously, there are quite a few similarities and differences between the effects of marijuana and tobacco smoke and further studies will be necessary before anyone can convincingly talk about the safety of marijuana smoking.
It has been asserted that marijuana can have even more harmful effect during growth and development. This was partially addressed in a study published this past April on mouse embryonic development (Wang et al. 1999). It had been observed that mouse embryos express both the CB1 and CB2 receptors before implanting in the uterine wall. It was also noted that the highest level of anandamide seen anywhere in the body is in the uterus before embryonic implantation. This study showed that early mouse embryonic cells (blastocysts) showed accelerated growth and differentiation when cultured in media containing anandamide. They went on to show that this is a direct result of interactions with the CB1 receptor. It was also demonstrated that the effects seen on embryonic cells were concentration dependent. Because the anandamide levels in the uterus were found to be lowest at the implantation site, it has been postulated that anandamide might be involved in the spatial regulation of the site of implantation. With the possibility that the cannabinoid pathway is involved in development, it is not unreasonable to wonder if THC can interfere with this regulation and lead to birth defects.
Earlier this year, another group addressed whether marijuana can have adverse effects in later developmental stages in humans, such as puberty. This study compared the attention levels of people who began using marijuana early (before age 16), late (after age 16), and people who have not used marijuana (Ehrenreich et al. 1999). Subjects were tested for visual scanning, alertness, divided attention, flexibility, and working memory. They found that reaction times in visual scanning were significantly lower in cases of early onset of use than in cases of late onset. This suggests that the human brain is still developing well into puberty. Therefore, we can see that marijuana use in children can lead to problems later in life. These developmental studies are among the most recent research published in this area. There is still much to be learned from studies on cannabinoid involvement and marijuana’s effect on development.
Conclusion
We see that in terms of basic science research done on the cannabinoids and their receptors, there is great potential for research and medical uses of marijuana and related chemical derivatives. It is also evident that in some respects, marijuana use may be safer than cigarettes and other common drugs, in other respects it can be much worse. Therefore, rather than adopting either of the extreme viewpoints in regard to the subject, it would probably be most helpful to delay making policies on "recreational" use of marijuana. Meanwhile, intensive research can be carried out to further understand the possible harmful and beneficial effects of the drug. It is important that we not underestimate the importance of basic science and medical research. Even if we are not ready to legalize marijuana, we should certainly make efforts to further ascertain whether there are benefits of using marijuana and its derivatives medically, or even merely to gain further knowledge on neuronal function. Much of the research that has been done to this point has been done on THC. The above studies have shown several potentially harmful effects on the central nervous system, immune system, and lungs that can result from abuse of marijuana, as well as some possible medical and scientific uses for cannabinoids. There is a wealth of other active chemicals found in marijuana that should be studied. It is clear that the scientific community should continue its work on marijuana and other cannabinoids, in order to know exactly what we are dealing with and possibly reap the benefits.
References
Abrams, D.I. Medical Marijuana: Tribulations and Trials. Journal of Psychoactive Drugs 30: 163-169 (1998).
Baldwin, G.C., Tashkin, D.P., Buckley, D.M., Park, A.N., Dubinett, S.M., & Roth, M.D. Marijuana and Cocaine Impair Alveolar Macrophage Function and Cytokine Production. American Journal of Respiratory Critical Care Medicine 156: 1606-1613 (1997).
Cadas, H., Gaillet, S., Beltramo, M., Venance, L., & Piomelli, D. Biosynthesis of an Endogenous Cannabinoid Precursor in Neurons and its Control by Calcium and cAMP. Journal of Neuroscience 16: 3934-3942 (1996).
Chan, G.C., Hinds, T.R., Imprey, S., & Storm, D.R. Hippocampal Neurotoxicity of *9-Tetrahydrocannabinol. Journal of Neuroscience 18: 5322-5332 (1998).
Devane W.A., Hanus L., Breuer A., Pertwee R.G., Stevenson L.A., Griffin G., Gibson D., Mandelbaum A., Etinger A., & Mechoulam R. Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptor. Science 258: 1946-1949 (1992).
Ehrenreich, H., Rinn, T., Kunert, H.J., Moeller, M.R., Poser, W., Schilling, L., Gigerenzer, G., & Hoehe, M.R. Specific Attentional Dysfunction in Adults Following Early Start of Cannabis Use. Psychopharmacology 142: 295-301 (1999).
Fonesca, F.R., Carrera, M.R.A., Navarro, M., Koob, G.F., & Weiss, F. Activation of Corticotropin-Releasing Factor in the Limbic System During Cannaboid Withdrawal. Science 276: 2050-2054 (1997).
Ishioka, N., & Bukoski, R.D. A Role for N-arachidonylethanolamine (Anandamide) as the Mediator of Sensory Nerve-Dependent Ca2+-Induced Relaxation. J Pharmacol Exp Ther 289: 245-250 (1999).
Presti, D. Lectures from MCB 165: Molecular Neurobiology and Neurochemistry UC Berkeley Spring 1999.
Shen, M., Piser, T.M., Seybold, V.S., & Thayer, S.A. Cannabinoid Receptor Agonists Inhibit Glutamatergic Synaptic Transmission in Rat Hippocampal Cultures. Journal of Neuroscience 16: 4322-4334 (1996).
Tashkin, D. P., Simmons, M.S., Sherrill, D.L., & Coulson, A.H. Heavy Habitual Marijuana Smoking Does Not Cause an Accelerated Decline in FEV1 With Age. American Journal of Respiratory Critical Care Medicine 155: 141-148 (1997).
Wang, J., Paria, B.C., Dey, S.K., & Armant, D.R.Stage-specific Excitation of Cannabinoid Receptor Exhibits Differential Effects on Mouse Embryonic Development. Biol Reprod 60: 839-844 (1999).
WWW 1. The History and Effects of Marijuana.
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