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Category: Neurochemistry

Term Paper Code: 168

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Since ancient times, people have been using marijuana for their beneficial effects. Marijuana (also referred to as "pot", "grass", "bhang", "weed", "hashish"), which may be any variety of mixtures from the Cannabis sativa plant, has its roots in various places in time and part of the globe. For example, ancient texts have recorded the use of marijuana by the Chinese Emperor Shen as medicine in 2737 BC (WWW1). It is also known that Queen Victoria was regularly treated with marijuana for various illnesses (WWW1). Even though it has proven its medical effectiveness throughout history, the United States has branded the use of cannabis, even for health promoting factors, as illegal by federal law. It is categorized as a schedule I drug due to its addiction and abuse potentials. But this categorization also means that marijuana has no accepted medical uses. According to this classification, marijuana cannot be prescribed by a doctor even though he feels that the use of this substance is in the best interest of the patient. Within weeks after voters in Arizona and California approved propositions allowing

physicians in their states to prescribe marijuana for medical indications, federal officials sprang into action, reiterating their support against the legalization of marijuana. For example, attorney General Janet Reno announced that physicians in any state who prescribed the drug could lose the privilege of writing prescriptions, be excluded from Medicare and Medicaid reimbursement, and even be prosecuted for a federal crime (Kassirer, 1997). This is one reason why many feel that marijuana should be legalized. They want the people who are in medical need to have access to the drug. General Barry R. McCaffrey, director of the Office of National Drug Control Policy indicated that it is always possible to study the effects of any drug, including marijuana, but that the use of marijuana by seriously ill patients would require, at the least, scientifically valid research. This is another reason why people feel that legalization of marijuana is a valid claim. Due to such strict regulation of schedule I imposed upon marijuana, it is near impossible to do any sort of scientific research. So there seems to be a counterintuitive aspect in the logic of those opposing the legalization the marijuana.

Opponents of marijuana claim that it is not an innocent drug and that it can have detrimental effects. For one, it has psychoactive effects and potential for abuse. They feel that legalization will only aggravate the drug problem since there have been reports that marijuana can lead to the use of other drugs such as cocaine and amphetamine. Long-term studies of high school students and their patterns of drug use show that very few young people use other illegal drugs without first trying marijuana. For example, the risk of using cocaine is 104 times greater for those who have tried marijuana than for those who have never tried it. Using marijuana puts children and teens in contact with people who are users and sellers of other drugs. So there is more of a risk that a marijuana user will be exposed to and urged to try more drugs (WWW2).

To settle the debate, one must consider the scientific evidence of the effects of cannabinoids (the family of active chemical substances found in the cannabis plant). The proceeding discussion will weigh health-promoting effects of cannabinoids against possible detrimental consequences. For example, cannabinoids have been effective in lowering the intraoccular pressure in glaucoma patients (Green, 1998; Marmor, 1998). It has also been useful in counteracting the nausea associated with cancer chemotherapy and in stimulating appetite (Voth, 1997). But how do some of these beneficial effects weigh against some of the detrimental effects such as potential addiction, problems with memory and learning, and inability to perform complex mental and physical tasks (WWW2)? Research is beginning to uncover the functionality of cannabinoids but there is still much to learn. By learning as much as we can about the action of cannabinoids can we make a valid decision as to whether the helpful aspect of this drug outweighs the harmful effects. Yet, with the knowledge of this drug that we currently have, one will see that the reclassification of marijuana into a less restrictive schedule would be the wisest decision. The access to cannabinoids should not be denied to those who are genuinely in medical need, but it should not be available to those who seek this substance simply for recreational use. Hence a good compromise would be to reschedule it into a less prohibitory category.

The debate:

Marijuana addiction

The dominant fear about marijuana in the 20th century has been that its effects were somehow similar to the dangerously addictive effects of opiates such as morphine and heroin. Despite widespread decriminalization of marijuana in the United States in the 1970s, this concern has remained the basis for federal law and policies regarding the use and study of marijuana (WWW3). Even today, there are doubts about the addictive nature of cannabinoids and this may be one of the reason why it is still considered as a schedule I drug by the law makers. In the past, those individuals who were against marijuana were successful in debunking the argument made by some proponents of legalization that marijuana has no addictive properties. For years, proponents were convinced that marijuana had no addictive properties mainly because there were no scientific evidence refuting their claim.

Many important functions of the brain, which dictate our behavior, involve dopamine. It is known that highly addictive drugs such as cocaine and heroin interfere with this dopamine and alter the individual. Hence, the abuse potentials of drugs are measured on the extent to which they interfere with dopamine regulation (i.e. production, release, or re-uptake). Dopamine is believed to be a neurotransmitter associated with the brain reward system, which is responsible for pleasure sensations. An integral part of this system is the mesolimbic pathway in which the nucleus accumbens of the limbic system produce dopamine.

The proponents of marijuana believed that cannabinoids did not act on the mesolimbic pathway. They believed that cannabinoids did not act on the dopaminergic synapses. Today we know that this is not the case. Experiments have shown that delta-9-tetrahydrocannabinol (delta-9-THC), the major active chemical in cannabis (cannabidiol and cannabinol are also prominent ingredients of cannabis plant), does increase the extracellular concentrations of dopamine in the "shell" [the nucleus accumbens consists of a "shell" and a "core" which is distinct from one another anatomically and histochemically (Pontier et al. 1995)] of nucleus accumbens (Tanda et al. 1997; Diana et al. 1998). Tanda et al. found that delta-9-THC utilized the same pathway as that utilized by opioids, such as heroin which utilizes the opioid receptors. It was found that heroin and delta-9-THC utilized the same opioid receptor, mu-1, which eventually causes the increase in concentration of dopamine in the nucleus accumbens. Diana et al. also found similar results concerning the dopamine concentration increase in response to delta-9-THC. The administration of this chemical along with a synthetic cannabinoid agonist (WIN 55212,2) produced a dose-related increase in the firing rate in dopaminergic neurons. From such experiments, the claim that marijuana has no effect on dopamine concentration can be refuted.

Though this may lend support to the idea that marijuana has some addictive properties, there have not been any incontrovertible evidence proposing that marijuana is addictive. There are numerous investigations that suggest marijuana’s addictive properties but there are also studies that suggest otherwise. There are various studies on marijuana withdrawal. One study showed dependence and withdrawal symptoms after frequent administration of high doses of oral delta-9-THC (Haney et al. 1999). Active administration of the substance increased the rating of "high," "good drug effect," and "willingness to take dose again." Abstinence from delta-9-THC increased ratings of "anxious," "depressed," and "irritable." Withdrawal dysphoria is an addiction-related phenomenon. Hence, evidence of marijuana withdrawal leads one to believe that cannabinoids do indeed possess addictive qualities. On the other hand, there is evidence that suggests the opposite to be true. To test for abuse potential of a drug, scientists will administer the drug to mice and see whether or not the mice will repeatedly self-administer the drug to a point where it becomes obsessive and harmful. In the case of delta-9-THC, it has been reported that the animals will not self-administer the substance (Eliot et al. 1999). This lends support to the idea that marijuana does not have addictive properties. So, what can explain these incongruent reports?

The answer is not known. Different investigations into this subject have resulted in varying results. For example, one study administered this test on monkeys and found that they self-administered delta-9-THC only after cannabinoid physical dependence had been established. Another investigation performed on mice reported that only food-deprived mice self-administered delta-9-THC (Eliot et al. 1999). Nevertheless, the previous claim of the proponents of marijuana that cannabinoids lack pharmacological interaction with the brain reward substrates appears no longer tenable. It is clear that cannabinoids activate these brain substrates and induce reward-related behavior. Presumably, the abuse potential derives from these actions.

From current knowledge, one may assume that marijuana does have some addictive qualities but are limited in its potencies. Hence they should not be classified with some of the most addictive drugs of today. With the information acquired, one may infer that cannabinoids act upon dopamine by an indirect route. Cannabinoid neurons interact with the opioid neurons, which, in turn, stimulate the release of dopamine by another indirect connection to dopaminergic neurons. Advances in the characterization of cannabinoid receptors have revealed that there are cannabinoid receptors in the ventromedial striatum and basal ganglia, which are associated in the dopamine production, but no cannabinoid receptors were found in the dopaminergic neurons (Axelrod et al. 1998). Therefore, among the most controversial addictive drugs, cocaine and amphetamine, which are dopaminergic stimulant, have direct access to the increase of dopamine. Opioids, such as heroin, utilize a more indirect route through the mu-1 receptor. And cannabinoids are the least direct in their action (Tanda et al. 1997). This may be a reason why the addictive properties of cannabinoids are much more limited than cocaine, for example. Though delta-9-THC has been proven to have the neurochemical functions characteristic of an addictive substance, one must realize that marijuana is not a "hard" drug and should not be categorized with such drugs.

Psychoactive effects of marijuana

It has been found that there are high densities of cannabinoid receptors in the forebrain and cerebellum. This has implicated cannabinoids in cognition and movement (Axelrod et al 1998). Opponents of marijuana also attack its psychoactive effects. They say that this side effect of marijuana use is not only detrimental to the user but also to society. Few can dispute this point. Most users of marijuana are young adults who recreationally use this substance just for the psychoactive effects. Marijuana tends to generate a sense of euphoria and a dream-like state. The user feels completely relaxed (WWW4). Also, cases of marijuana heightening the senses and distorting time and space is not uncommon.

Cannabinoid receptors are sparse in the area of the brain stem, medulla, and thalamus. Hence binding is minimal in these areas and may explain the general lack of serious effects of marijuana abuse on the autonomic nervous system (Axelrod et al. 1998). This may be the reason why toxic overdose is rare and death resulting from marijuana use is unheard of. A study done on mortality rates and marijuana use proved that the two factors are not correlated (Sidney et al. 1997). Though death from marijuana use alone is very rare, marijuana related deaths are not as rare. For example, driving is impaired and marijuana related car accidents are common. Marijuana has serious harmful effects on the skills required to drive safely: alertness, the ability to concentrate, coordination, and the ability to react quickly, difficulty in judging distance, and reacting to signals and signs on the road. These effects can last up to 24 hours after smoking marijuana (WWW2). There also have been cases where people who were high on marijuana have fallen off windows and balconies. Such unwanted side effects of marijuana have hindered its legalization.

Other criticisms of marijuana

Opponents of marijuana also criticize its effects on the body. The concentration of carcinogens in marijuana smoke is higher than that in tobacco smoke. Though there isn’t enough scientific evidence to link marijuana smoke with lung cancer, there are many accounts where chronic use of marijuana has lead to laryngitis and bronchitis (Roth et al. 1998; Morris, 1997)

Marijuana has also been implicated with immune suppression. Though definitive proof is not currently available, studies have shown that it has immunosuppressive qualities. For example, a study performed on lab animals show that marijuana decreases the resistance to bacterial, protozoan, and viral infections. Macrophages, T-lymphocytes, and natural killer cells appear to be major targets of the immunosuppressive effects of THC (Cabral et al. 1998). Though investigators do not have definite proof, it is believed that similar effects occur in humans. Investigations into cannabinoid receptors have revealed that cannabinoids bind to selective binding sites in the brain, regulating second-messenger formation. Three cannabinoid receptors have been cloned, CB1, CB2, and CB1A (Axelrod et al. 1998). CB2, or the peripheral cannabinoid receptor, has been detected in spleen and in several cells of the immune system. Various studies have given promise to the idea that CB2 activation by cannabinoids is responsible for immunosuppression action. For example, Klein et al. reviewed data concerning the role of cannabinoid receptors in the cells of the immune system. In summary, the literature to supports the role of cannabinoids as an immunomodulator capable of suppressing resistance to infection but the mechanisms has yet to be determined. (As a note, studies have given way to the idea that it probably isn’t THC that binds to CB2 but some other cannabinoid. In the study done by Bayewitch et al., it was concluded that delta-9-THC constitutes a weak antagonist for the CB2 receptor).

This aspect of marijuana can pose problems because medical-marijuana patients are often those suffering from diseases like cancer and AIDS. Such patients already have immune deficiency so smoking marijuana may exacerbate the problem. But there is evidence that seem to contradict this idea. Studies have shown that cannabinoid CB2 agonist can down-modulate mast cell activation and control inflammation (Mazzari et al. 1996). While cannabinoids can suppress the immune system, scientists argue that CB2 agonist can control unwanted inflammation. Hence CB2 agonists have the potential to substitute antihistamines. And since delta-9-THC is not an agonist of CB2, psychoactive effects can be neglected. The idea that marijuana harms the immune system and therefore should not be legalized is an invalid one. This concept is still premature and there is evidence that it can be used for a beneficial cause.

Opponents of marijuana have cited other studies to claim that marijuana is detrimental to health. For example, studies have shown that marijuana affects short term memory. This may be attributed to the high densities of the central cannabinoid receptor, CB1, in the hippocampus, which is believed to be involved in the control memory. "The most consistent effect of delta-9-THC on performance is disruption of selective aspects of short-term memory tasks" (Herkenham et al. 1990). An investigation into this matter has shown that THC neurotoxicity may be responsible for memory loss. In the study, treatment of cultured neurons of hippocampal slices with THC caused shrinkage of neuronal cell bodies and nuclei as well as genomic DNA strand breaks (Cadena et al. 1996).

Critics also cite studies in which chronic use of marijuana lead to "antimotivational syndrome"(WWW2). This syndrome has been characterized by apathy, lethargy, lack of focus, decreased concentration, and decrease ambition. There also have been studies that suggest cannabinoids implication with fertility and endocrine functions. Cannabinoids have been shown to decrease the plasma levels of leutenizing hormone and increase the level of ACTH in female rats (Cadena et al.).

Medical uses of marijuana

The concerns about marijuana’s implications with immunosuppression, memory loss, and endocrine functions are valid. As mentioned, there is good evidence that support these ideas. Hence, those patients who wish to use this substance and the physicians who wish to prescribe it should be wary of these possible detrimental effects. Nevertheless, the idea of using marijuana for medical purposes seems a good idea. Cannabinoids have been shown to be effective drugs with analgesic, antiemetic, sedative-hypnotic and appetite stimulating properties. There are studies that prove cannabinoids help nausea induced by chemotherapy. For example, Meng et al. found that cannabinoids produce analgesia by modulating the rostral ventromedial medulla neuronal activity in a manner similar to, but pharmacologically dissociable from, morphine.

Also, McCallum et al. investigated the effects of THC on chemotherapy-induced nausea and vomiting. It was found that gastric emptying after THC administration was slower than with placebo administration.

Other people who suffer from chronic diseases such as AIDS have found that marijuana can help them deal with the effects of the disease. For AIDS patients, many have found that the usage of marijuana helped in stress reduction, pain relief, elimination of nausea, and increase in appetite (WWW5). It has also been found that as AIDS progresses and the medical therapies utilized intensify, marijuana provided patients with help in easing joint and muscle pain and reducing the stomach cramps associated with morphine use (WWW5). But as mentioned, marijuana can suppress the immune system. And the AIDS patients who wish to use marijuana as medical therapy must deal with the possibility that their already weakened immune system may be further suppressed. Nevertheless, AIDS patients continue to use marijuana because they feel that the beneficial effects outweigh the negative ones. There needs to be further investigation in this area in order to substantiate this idea. But the decision to use marijuana should be made by the patient and the physician who would know the individual situations the best.

Marijuana can be used not only as therapy for cancer and AIDS patients but also for variety of other conditions. Marijuana may be used by glaucoma patients. Studies have shown that cannabinoids lower the intraocular pressure in the eye of glaucoma patients. A study has shown that smoking marijuana caused a fall in the intraocular pressure in 60 percent to 65 percent of users (Green, 1998).

There is also promise of marijuana use in treating head trauma. A study looked at 45Ca accumulation as a marker for lethally injured brain tissue following closed head injury (Nadler et al. 1995). Investigation into the neuroprotective effect of the non-psychoactive cannabinoid, (+)-(3S, 4S)-7-hydroxy-D-6 tetrahydro-cannabinol 1,1-dimethylheptyl (HU-211), showed promise as a therapeutic agent for head trauma in humans. In this study 45Ca accumulation was examined in rat brains after closed head trauma. Observations revealed the accumulation of 45Ca in various regions of the brain and expansion of accumulation with time. It was found that injection of HU-211 significantly decreased the volume of 45Ca accumulation in the various regions of the brain. The ability of HU-211 to decrease 45Ca accumulation after head trauma is thought to be due to its ability to attenuate Ca2+ fluxes through the N-methyl-D-aspartate receptor-mediated calcium channels and to reduce the depolarization evoked Ca2+ fluxes.

Marijuana has also been investigated as a possible therapy for Parkinson’s disease (Maneuf et al. 1997). There are reports that say cannabinoids are beneficial for some forms of dystonia, tremor, and spasticity (Herkenham et al. 1990). The ability of cannabinoids to control muscle is no surprise because there is a localization of cannabinoid receptors in the motor areas of the brain. Also, the idea that cannabinoids exacerbates hypokinesia is being challenged. The study done by Maneuf et al. showed that while cannabinoid receptor agonists alone don’t have any effect in alleviating akinesia, when it is administered in combination with a dopamine D2 agonist, the cannabinoid receptor agonist can have antiparkinsonian effects. If further investigations confirm these findings, it will lend support to the idea of legitimizing marijuana.

Although there is much evidence of the benefits of marijuana, some critics still oppose its legalization. Some refer to dronabinol to affirm their opposition. Dronabinol (Marinol) is an oral form of THC indicated for the treatment of weight loss associated with anorexia and AIDS and nausea and vomiting associated with cancer chemotherapy. Some critics feel that legalizing marijuana would be useless since there already is a pill form of THC on the market. The fact is that dronabinol acknowledged a good idea. But the effects produced by this pill form compare poorly with the smoked form. First, the effect of dronabinol is slow and gradual, taking hours to take effect. Smoking takes effect in minutes and can provide instant relief for those who are in medical need. Also an oral treatment for nausea and vomiting can prove to be ineffective because the user may regurgitate the drug. Also, oral administration means that the drug must go through the liver before it can reach the bloodstream, which can neutralize the chemical, resulting in poor alleviation of pain and other ailments of the patient. Also, dronabinol can cost upwards of $600 for a month’s supply. This can pose a problem of availability for those that are not financially secure. On the other hand, marijuana would be quite cheap if it were legalized.

Marijuana certainly has numerous effects on the human body. Some if these actions are still unresolved and deserve further investigation before this substance can be deemed as good or bad. Nevertheless, lawmakers seem to have already branded this substance as malevolent. It is true that investigations show that "weed" is addictive and psychoactive. And it is also true that numerous individuals who seek to get "high" by using marijuana not only harm themselves but may also harm society. But marijuana has numerous beneficial effects as well. Research has shown marijuana’s beneficial effects on those individuals suffering from a variety of diseases and ailments. 

Marijuana uses by patients with cancer or AIDS have alleviated some of the pain that is involved in these conditions. Marijuana uses among patients with Parkinson’s disease, glaucoma and migraine headaches have shown positive effects. The actions of marijuana in producing these beneficial effects need further investigation but the patients’ testimonials seem proof enough at this time to maintain marijuana’s effectiveness. Hence it would be wise for the lawmakers to remove the brand on marijuana that says it is a drug with malevolent qualities similar to heroin and reclassify it into a less strict schedule.

 Although reclassification may make marijuana more available to those who are not in medical need, the needs of those suffering from diseases and ailments should be the primary concern. Besides, reclassification would not mean complete deregulation. It would not make it readily available like cigarettes. The government and responsible medical doctors would still be able to regulate the distribution. Hopefully in the future, scientific evidence that supports the positive actions of marijuana will force the courts to judge in favor of the rights of those at death’s door over the absolute power of bureaucrats whose decisions are based more on ideology and political correctness than on compassion.

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