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Marijuana Essay, Research Paper

EXECUTIVE SUMMARY

Over the past 18 months there has been wide-ranging public discussion on the potential medical uses of marijuana, particularly smoked marijuana. To contribute to the resolution of the debate, the National Institutes of Health (NIH) held a 2-day scientific meeting on February 19-20, 1997, to review the scientific data concerning the potential therapeutic uses for marijuana and the need for and feasibility of additional research.

Central to the current debate about the therapeutic uses of marijuana is the claim that smoked marijuana offers therapeutic advantages over the currently available oral form (dronabinol capsules) of its most active ingredient, delta-9-tetrahydrocannabinol (_9-THC), for a wide variety of conditions. As the therapeutic claims surrounding marijuana are wide-ranging, 10 separate NIH Institutes (with interest in the relevant areas) selected a group of eight experts with broad experience in clinical studies and therapeutics (and none of whom had a predetermined position on the medical utility of marijuana) to examine the data from the published scientific literature presented by speakers in the various therapeutic fields. The Ad Hoc Group of Experts also considered public comments including those of patients and advocacy groups as well as written material submitted to the Group after the meeting. The Expert Group was asked to focus on four questions:

Question 1 – What research has been done previously and what is currently known about the possible medical uses of marijuana?

Question 2 – What are the major unanswered scientific questions?

Question 3 – What are the diseases or conditions for which marijuana might have potential as a treatment and that merit further study?

Question 4 – What special issues have to be considered in conducting clinical trials of the therapeutic uses of marijuana?

Each presentation of data by a speaker was followed by a question-and-answer session by the Expert Group. There was no requirement that individuals on the Group agree or express a consensus view, although they were free to do so if they so desired. A second day was provided for public comment and further discussion by the Expert Group.

This report is a compilation of the opinions of the Expert Group. Speakers reviewed the literature on the potential efficacy of cannabinoids, including smoked marijuana, in the areas of analgesia, neurological and movement disorders, nausea and vomiting associated with cancer chemotherapy, glaucoma, and appetite stimulation/cachexia. A review of selected aspects of the general clinical pharmacology of marijuana precedes the disorder-specific commentary.

The discovery of receptors in the central nervous system (CNS) for cannabinoid compounds, and the presence of an endogenous ligand for these receptors, is of importance to the debate concerning the potential therapeutic uses of marijuana. This discovery supports a recommendation for more basic research to discover the functional roles of the cannabinoid receptors as a key underpinning for possible therapeutic applications. Such an approach allows the bridging of knowledge from molecular neurobiology to animal studies to human clinical trials.

The scientific process should be allowed to evaluate the potential therapeutic effects of marijuana for certain disorders, dissociated from the societal debate over the potential harmful effects of nonmedical marijuana use. All decisions on the ultimate usefulness of a medical intervention are based on a benefit/risk calculation, and marijuana should be no exception to this generally accepted principle.

The availability of THC in capsule form does not fully satisfy the need to evaluate the potential medical utility of marijuana. The Expert Group noted that, although delta-9-tetrahydrocannabinol (THC, dronabinol, Marinol?, or _9-THC) is the principal psychoactive component of the cannabis leaf, there may be other compounds in the leaf that have useful therapeutic properties. Furthermore, the bioavailability and pharmacokinetics of THC from smoked marijuana are substantially different than those of the oral dosage form. These are the rationales for studying the pharmacological actions of other constituents of the cannabis leaf, as well as determining whether a differential benefit occurs with smoked marijuana rather than oral dronabinol.

The Expert Group noted that even for conditions where good therapies are available, some patients develop adverse reactions or are nonresponders. The needs of this subset of nonresponders must be considered in the deliberations on testing marijuana as a possible therapeutic agent.

The Expert Group also noted that risks associated with marijuana, especially smoked marijuana, must be considered not only in terms of immediate adverse effects on the lung; e.g., bronchi and alveoli, but also long-term effects in patients with chronic diseases. Additionally, age, immune status, the development of intercurrent illnesses, and concomitant diseases should be considered in the determination of the risk calculation. The possibility that frequent and prolonged marijuana use might lead to clinically significant impairments of immune system function is great enough that relevant studies should be part of any marijuana medication development research, particularly when marijuana will be used by patients with compromised immune systems. Concerns were expressed by members of the Expert Group on the use of smoked marijuana because of the combustion byproducts, particularly when marijuana would be used for conditions requiring chronic therapy. Hence, a recommendation was made for the development of insufflation/inhalation devices or dosage forms capable of delivering purer THC or cannabinoids to the lungs free of dangerous combustion byproducts.

The major conclusions in each therapeutic area are summarized below.

Analgesia

No clinical trials involving smoked marijuana have been performed in patients with naturally occurring pain. Two adequate and well-controlled studies in cancer pain compared graded doses of oral _9-THC to placebo, and one of these included graded doses of codeine as a control. Although there was evidence of analgesic efficacy, the studies indicate there is a narrow therapeutic margin between the doses that produce useful analgesia and those producing unacceptable adverse CNS effects.

Neurological and Movement Disorders

Numerous preclinical and clinical studies of the use of cannabinoids in neurological and movement disorders have been reported as accounts of animal experiments, clinical anecdotes, surveys, and clinical studies.

Evidence that marijuana relieves spasticity produced by multiple sclerosis (MS) and partial spinal cord injury is largely anecdotal. Large-scale trials or controlled studies to compare marijuana or THC with currently available therapies have not been performed. There is no published evidence that cannabinoids are superior or equivalent to available therapies.

Preclinical evidence suggests a possible role for cannabinoids in the treatment of the epilepsies, particularly generalized and partial tonic-clonic seizures. There is scant information on the use of marijuana or other cannabinoids for the actual treatment of epilepsy.

Individual case studies have reported some benefit of smoked marijuana in treatment of dystonic states. Smoked marijuana or oral THC administrations for Parkinson?s disease or Huntington?s chorea have not been effective.

Cannabinoids have shown efficacy as immune modulators in animal models of neurological conditions such as experimental allergic encephalomyelitis (EAE) and neuritis. These data suggest that cannabinoids might modify the presumed autoimmune cause of a disease such as MS. However, long-term risks of smoked marijuana need to be quantified when considering chronic therapy for neurological conditions.

Nausea and Vomiting Associated With Cancer Chemotherapy

There is a large body of literature on the effects of cannabinoids on chemotherapy-induced nausea and vomiting. Most of the clinical trials used oral dronabinol rather than smoked marijuana. The oral THC studies showed this dosage form to be superior to placebo and generally equivalent or superior to prochlorperazine, but inferior to metoclopramide. Only one study compared smoked marijuana and dronabinol in a crossover design. Of the 20 patients studied, 9 had no preference, 7 preferred dronabinol, and 4 preferred smoked marijuana.

Since the approval of dronabinol in the mid 1980s for the relief of nausea and vomiting associated with cancer chemotherapy, more effective antiemetics have been developed, such as ondansetron, granisetron, and dolasetron, each combined with dexamethasone. The relative efficacy of cannabinoids versus these newer antiemetics has not been evaluated. Smoked marijuana was tested in one trial in patients who previously had no benefit from older antiemetic agents. Nearly one-quarter of patients who initially agreed to participate later declined citing bias against smoking, the harshness of smoke, and preference for dronabinol. Among the remaining 56 patients, 78 percent rated smoked marijuana very effective or moderately effective. Sedation was seen in 88 percent and dry mouth in 77 percent. It is not known whether smoked marijuana would benefit patients refractory to the current generation of antiemetic therapy.

Glaucoma

Smoked marijuana has been shown to lower intraocular pressure (IOP) in subjects with normal IOP and patients with glaucoma. The duration of the pressure-lowering effect is 3 to 4 hours. Single-administration studies have reported blood pressure falls concurrently with the IOP lowering, raising concern that blood flow to the optic nerve could be compromised. Mitigating this concern are data suggesting that tolerance may develop to cardiovascular effects. Efforts to avoid or reduce side effects led to the development of a topical dosage form of THC. Topically applied THC did not lower IOP.

The mechanism of all IOP-lowering drugs currently used to treat glaucoma is known with the exception of marijuana. The interactive effect of marijuana with currently available IOP-lowering agents is not known but is evaluable. Elucidation of the mechanism of action of marijuana?s IOP-lowering effect is crucial to its potential utilization for treatment of glaucoma; a unique mechanism of action might provide additive benefit whereas a mechanism identical to an available medication would suggest an unfavorable benefit/risk ratio.

Appetite Stimulation/Cachexia

Clinical studies and survey data in healthy populations have shown a strong relationship between marijuana use and increased eating. Marijuana is reported to increase food enjoyment and the number of times individuals eat per day. Mechanistic studies of marijuana on taste and satiety have shown that it does not affect taste or produce a collapse of normal satiety mechanisms. Food intake associated with marijuana use is influenced by the social setting.

There are no controlled studies of marijuana in the AIDS-wasting syndrome, nor have there been any systematic studies of the effects of smoked marijuana on immunological status in HIV-infected patients. Smoking (tobacco, marijuana, or crack cocaine) has been shown to increase the risk of developing bacterial pneumonia in HIV-positive immune-compromised patients. Dronabinol has been shown to increase appetite and produce weight gain in AIDS and cancer patients, although the weight gain is not in lean body mass. Dronabinol is approved for the treatment of anorexia in patients with AIDS-associated weight loss.

Question 3: Which Diseases or Conditions Merit Further Study?

Concerning Question 3, there were varying degrees of enthusiasm to pursue smoked marijuana for several indications. This enthusiasm was tempered by the fact that, for many of these disorders, effective alternative treatments are already available. Given the general consensus among the experts that the number, design and documentation of studies performed to date with smoked marijuana did not provide definitive answers, it was difficult to compare marijuana with products that had received regulatory approval under more rigorous experimental conditions. This does not mean, however, that the issue should be foreclosed. It simply means that in order to evaluate various hypotheses concerning the potential utility of marijuana in various therapeutic areas, more and better studies would be needed. In the words of Dr. William Beaver, Professor of Pharmacology and Anesthesia, Georgetown University School of Medicine, who chaired the workshop, ?For at least some potential indications, marijuana looks promising enough to recommend that there be new controlled studies done.? The indications in which varying levels of interest was expressed are the following:

 Appetite stimulation/cachexia*

 Nausea and vomiting following anticancer therapy**

 Neurological and movement disorders

 Analgesia

 Glaucoma

Accordingly, the NIH should consider relevant administrative mechanisms to facilitate grant applications in each of these areas. Whether or not the NIH is the primary source of grant support for a proposed bona fide clinical research study, if that study meets U.S. regulatory standards (U.S. Food and Drug Administration (FDA) protocol approval and Drug Enforcement Administration (DEA) controlled substances registration) the study should receive marijuana and/or matching placebo supplied by the National Institute on Drug Abuse (NIDA). In this way, a new body of studies may emerge to test the various hypotheses concerning marijuana.

The last question, Question 4, concerning the special issues involved in conducting clinical trials with marijuana, was particularly difficult. There was considerable discussion and debate as to whether smoked marijuana (with the inherent health risks of smoking) would need to demonstrate clear superiority or some unique benefit compared with other medications currently available for these conditions. The Expert Group concluded that smoked marijuana should be held to standards equivalent to other medications for efficacy and safety considerations. Moreover, there might be some patient populations; e.g., cancer patients experiencing nausea and vomiting during chemotherapy, for whom the inhalation route might offer advantages over the currently available capsule formulation. This raises many issues concerning the best mode of administration. Generally accepted pharmacotherapy development schema would favor finding routes of administration under which dosing could be more tightly controlled and easily titrated. Smoking plant material poses difficulties in standardizing testing paradigms, and components of the smoke are hazardous, especially in the immunocompromised patient. Additionally, practical problems exist. Given the no-smoking policy of hospitals and public facilities, it would be difficult to imagine the utility of smoked marijuana in these settings. Therefore, the experts generally favored the development of alternative dosage forms, including an inhaler dosage form into which a controlled unit dose of THC could be placed and volatilized. Other problems noted were the difficulty in attempting to match placebo control against smoked marijuana (especially for those with previous marijuana experience), and the fact that under U.S. law, researchers will need to obtain DEA registration to handle marijuana, which is currently a Schedule I controlled substance (see Appendix).

In summary, the testing of smoked marijuana to evaluate its therapeutic effects is a difficult, but not impossible, task. Until studies are done using scientifically acceptable clinical trial design and subjected to appropriate statistical analysis, the questions concerning the therapeutic utility of marijuana will likely remain much as they have to date?largely unanswered. To the extent that the NIH can facilitate the development of a scientifically rigorous and relevant database, the NIH should do so.

INTRODUCTION

On February 19 and 20, 1997, the National Institutes of Health (NIH) held a meeting concerning the potential medical uses of marijuana. Recent (November 1996) ballot initiatives in California and Arizona had sparked a public health and policy debate on the medical utility of marijuana and the desirability of allowing healthcare providers to prescribe, and patients to receive, marijuana for medicinal purposes.

For some years the principal psychoactive ingredient of marijuana, delta-9-tetrahydrocannabinol (_9-THC), has been available to healthcare providers in an oral form as dronabinol (trade name Marinol) for the treatment of emesis associated with cancer chemotherapy and for appetite stimulation in the treatment of AIDS wasting syndrome. The current debate centers primarily on the potential for other treatment indications and the claims that, when smoked, marijuana offers therapeutic advantages over the currently available oral form. As the Federal Government?s principal biomedical research agency, the NIH believed that the public debate could benefit from an impartial examination of all the data available to date concerning these issues. As the claims for benefits were wide ranging, 10 major components of the NIH participated in the planning for the conference.

The NIH planning group focused the meeting on the following four questions concerning marijuana as a potential therapeutic agent:

Question 1 – What research has been done previously and what is currently known about the possible medical uses of marijuana?

Question 2 – What are the major unanswered scientific questions?

Question 3 – What are the diseases or conditions for which marijuana might have potential as a treatment and that merit further study?

Question 4 – What special issues have to be considered in conducting clinical studies of the therapeutic uses of marijuana?

The meeting was formatted as a scientific workshop. It was not an attempt to render a consensus. Therefore, it was structured so that speakers with experience in the relevant therapeutic areas would present to a group of eight expert consultants who possessed broad expertise in clinical studies and therapeutics and who had no public positions on the potential use of marijuana as a therapeutic agent. Each presentation was followed by a session for questions and answers from the Expert Group. The second day was allotted for the public to present their views and for discussion by the Expert Group. This report represents a compilation of the views of the Expert Group. Since this report was not intended as a general review of the literature on marijuana and THC, only a few selected references from among the thousands that exist are cited. Each of the members in the Expert Group chose those references relevant to their own contributions to the report.

CLINICAL PHARMACOLOGY OF MARIJUANA

The Pharmacology of Natural Products

It is important to keep in mind that marijuana is not a single drug. Marijuana is a mixture of the dried flowering tops and leaves from the plant cannabis sativa (Agurell et al. 1984; Graham 1976; Jones 1987; Mechoulam 1973). Like most plants, marijuana is a variable and complex mixture of biologically active compounds (Agurell et al. 1986; Graham 1976; Mechoulam 1973). Characterizing the clinical pharmacology of the constituents in any pharmacologically active plant is often complicated, particularly when the plant is smoked or eaten more or less in its natural form. Marijuana is not unusual in this respect. Cannabis sativa is a very adaptive plant, so its characteristics are even more variable than most plants (Graham 1976; Mechoulam 1973). Some of the seeming inconsistency or uncertainty in scientific reports describing the clinical pharmacology of marijuana results from the inherently variable potency of the plant material used in research studies. Inadequate control over drug dose when researching the effects of smoked and oral marijuana, together with the use of research subjects who vary greatly in their past experience with marijuana, contribute differing accounts of what marijuana does or does not do.

The Plant

Marijuana contains more than 400 chemicals. Approximately 60 are called cannabinoids; i.e., C21 terpenes found in the plant and their carboxylic acids, analogs, and transformation products (Agurell et al. 1984, 1986; Mechoulam 1973). Most of the naturally occurring cannabinoids have been identified. Cannabinoids appear in no other plant. Cannabinoids have been the subject of much research, particularly since the mid 1960s when Mechoulam and his colleagues first isolated delta-9-tetrahydrocannabinol (_9-THC) (Mechoulam 1973; Mechoulam et al. 1991). THC in the scientific literature is termed _9-THC or _1-THC depending on whether the pyran or monoterpinoid numbering system is used.

Cannabinoids of Importance

THC, the main psychoactive cannabinoid in marijuana, is an optically active resinous substance. THC is not soluble in water but is extremely lipid soluble (Agurell et al. 1984, 1986; Mechoulam 1973). Varying proportions of other cannabinoids, mainly cannabidiol (CBD) and cannabinol (CBN), are also present in marijuana, sometimes in quantities that might modify the pharmacology of THC or cause effects of their own. CBD is not psychoactive but has significant anticonvulsant, sedative, and other pharmacologic activity likely to interact with THC (Adams and Martin 1996; Agurell et al. 1984, 1986; Hollister 1986a).



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