I

MARIJUANA, MEDICINE, AND SCIENCE



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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy I MARIJUANA, MEDICINE, AND SCIENCE

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy 1 INTRODUCTION There are many reasons for wanting to understand what science has so far revealed—and what remains unknown—about marijuana's medical potential. Can marijuana really help people with AIDS (acquired immune deficiency syndrome), cancer, glaucoma, multiple sclerosis, or any of several other conditions it is purported to relieve? How does marijuana affect the human body? Could the potential benefits of legalizing marijuana for medicinal use possibly outweigh the risk of encouraging drug abuse? All of these questions remain to be answered completely, but over the past two decades scientists have made significant progress in revealing how chemicals in marijuana act on the body. Researchers have also studied how marijuana use affects individuals and society as a whole. Unfortunately, much of what scientists have learned about the medical use of marijuana has been obscured by highly polarized debate over the drug's legal status. At times advocates for medical marijuana have appeared to be discussing a different drug than their opponents. Consider the following statements: There are over ten thousand documented studies available that confirm the harmful physical and psychological effects of . . . marijuana. —from the California Narcotic Officers' Association Marijuana is NOT a Medicine, Santa Clarita, CA (1996), p. 2.

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy The cannabis plant (marijuana) . . . [has] therapeutic benefits and could ease the suffering of millions of persons with various illnesses such as AIDS, cancer, glaucoma, multiple sclerosis, spinal cord injuries, seizure disorders, chronic pain, and other maladies. —from the editor's introduction to Cannabis in Medical Practice, by Mary Lynn Mathre, R.N. Conflicts regarding the legitimacy of medical marijuana use extend even to the level of state versus federal law. Between 1996 and 1999, voters in eight states (Alaska, Arizona, California, Colorado, Maine, Nevada, Oregon, and Washington) and the District of Columbia* registered their support for the prescription of marijuana by physicians, defying the policies of the federal government and the convictions of many of its leaders. Prior to the 1998 election, former Presidents Ford, Carter, and Bush released a statement urging voters to reject state medical marijuana initiatives because they circumvented the standard process by which the Food and Drug Administration (FDA) tests medicines for safety and effectiveness. “Compassionate medicine,” these leaders insisted, “must be based on science, not political appeals. ” Nevertheless, medical marijuana initiatives proceeded to pass in every state in which they appeared on the ballot. Both those who advocate and those who oppose the medical use of marijuana claim to have science on their side. Each camp selectively cites research that supports its position, and each occasionally misrepresents study findings. Unfortunately, these skewed interpretations have frequently served as the main source of scientific information on the subject. Until now it has been difficult for people other than scientists to find unbiased answers to questions about the medical use of marijuana—questions that have often drawn conflicting responses from either side of the debate. * The Colorado vote was later disallowed after a court determined that the petition to place the initiative on the ballot did not have enough valid signatures. Congress has prohibited the counting of actual ballots in the District of Columbia referendum, but exit polls indicated that a majority of voters approved the measure. Nevada voters must reapprove their proposal in the year 2000 before it becomes law.

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy But the public controversy over the medical use of marijuana does not reflect scientific controversy. Scientists who study marijuana and its effects on the human body largely agree about the risks posed by its use as well as the potential benefits it may provide. That is what researchers at the Institute of Medicine (IOM) learned when they undertook the study on which this book is based. The goal of the study, performed at the request of the White House Office of National Drug Control Policy, was to conduct a critical review of all scientific evidence pertaining to the medical use of marijuana and its chemical components. For more than a year, researchers from the IOM—an arm of the National Academy of Sciences, which acts as an independent adviser to the federal government—compiled and assessed a broad range of information on the subject. One of us (Janet E. Joy) coordinated the IOM study. John A. Benson, Jr., dean and professor of medicine emeritus from the Oregon Health Sciences University School of Medicine and Stanley J. Watson, Jr., codirector and research scientist at the University of Michigan's Health Research Institute in Ann Arbor, served as its chief investigators. Nine other medical scientists with expertise concerning the medical use of marijuana served as technical advisers throughout the project. In the course of its work, the study team examined research on how marijuana exerts its effects in the body and its ability to treat a wide variety of medical conditions. Team members compared the effectiveness of using marijuana versus approved medicines to treat numerous specific disorders. They also evaluated the effects of chronic marijuana use on physical and mental health as well as its possible role as a “gateway” drug to cocaine, heroin, and other illicit drugs. To gather this information, the researchers analyzed scientific publications, consulted extensively with biomedical and social scientists, and conducted public scientific workshops. They also visited four so-called cannabis buyers' clubs and two HIV-AIDS clinics. Organizations and individuals were encouraged to express their views on the medical use of marijuana at the public workshops as well as via the Internet, by mail, and by telephone. The team's draft report was reviewed and critiqued anonymously by more than a dozen experts, whose comments were addressed

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy in preparing the final version of the document. Entitled Marijuana and Medicine: Assessing the Science Base, the final report was released in March 1999. The report was subsequently published as a clothbound book by the National Academy Press; it can also be viewed on the Press's web site. At the time of its release, the study received considerable attention from the news media. For example, the next week more than 50 U.S. newspapers carried stories on the study. While many of the articles reflected the balanced nature of the report's findings, most of the headlines—which tend to stick in readers' minds—gave the impression that the IOM had fully endorsed the medical use of marijuana. Scores of editorials followed suit, including several expressing uncritical acceptance of marijuana as a medicine. In fact, the IOM researchers found little reason to recommend crude marijuana as a medicine, particularly when smoked, but they did conclude that active ingredients in marijuana could be developed into a variety of promising pharmaceuticals. Responding to the report's call for clinical trials on such marijuana-based medications, the National Institutes of Health and the Canadian equivalent of that agency, Health Canada, subsequently announced new policies intended to encourage medical research on marijuana (see Chapter 11). While the IOM report was directed at policymakers, the purpose of this book is to present the main findings of that study for use by anyone who wants unbiased, scientifically sound medical information on marijuana. To adapt the IOM's publication for a general audience, considerable technical detail has been removed and in-depth explanations added of several key studies reviewed in the original report. For studies discussed in detail, references are provided in the form of footnotes. When the results of a group of studies are summarized, readers are referred to the relevant pages of the IOM report for more information and complete references. In a few instances, where more recent survey data became available after the IOM report was published, the most current information is used. This book is divided into three parts, each of which offers a different perspective on marijuana as medicine. Along with this introduction, Chapter 2 and Chapter 3 lay out the scientific and historical

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy foundation of current knowledge on the potential benefits and dangers of marijuana-based medicines. The second section—Chapter 4, Chapter 5, Chapter 6, Chapter 7, Chapter 8 through Chapter 9—focuses on specific diseases, including cancer, AIDS, glaucoma, and a variety of movement and neurological disorders. In each case, the current state of knowledge regarding marijuana's effectiveness in treating symptoms of specific disorders is described and compared with conventional therapies. We explain why some marijuana-related studies that may seem convincing are actually inconclusive and what evidence is needed to support various claims about marijuana's harms or benefits. Finally, although this is primarily a book about science, two chapters in Part III are devoted to related issues: the economic prospects for developing pharmaceuticals from marijuana (Chapter 10) and the complex legal environment surrounding the medical use of marijuana (Chapter 11). Much of the information that is included about the legal status of marijuana did not appear in the IOM report but was added here to place the science of medical marijuana in a broader social context. In addition to providing a critical and up-to-date summary of scientific knowledge that pertains to the medical use of whole marijuana, chemicals derived from the marijuana plant are also discussed, as well as synthetic compounds that represent “improved” versions of marijuana derivatives. This information can help readers evaluate future research news and participate in the ongoing public discussion of medical marijuana. At the same time, it is important to recognize that science is but one aspect of the medical marijuana controversy. Ultimately, drug laws must address moral, social, and political concerns as well as science and medicine. Although we present scientific evidence related to the social impact of medical marijuana, the intent is not to prescribe policy but to encourage continued debate based on a firm understanding of scientific knowledge. As you read, please bear this in mind, along with the following caveats: Neither this book, nor the IOM study on which it is based, is intended to promote specific social policies. Both were designed to provide an objective scientific analysis of marijuana's current and potential usefulness in treating a variety of symptoms. In no way do we wish to suggest that patients should, un-

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy der any circumstance, medicate themselves with marijuana, an illegal drug. The medical information in this book is not intended to substitute for the advice of a physician or other health care professional. Now that you know where this book came from and where it's going, we offer a few guideposts to aid your journey through it. Because the following key concepts underlie our discussion of medical marijuana, familiarizing yourself with them will help you make the most of your reading. Marijuana contains a complex mixture of chemicals. Marijuana leaves or flower tops can be smoked, eaten, or drunk as a tea (see Figure 1.1). People who use marijuana in these ways expose themselves to the complex mixture of chemical compounds present in the plant. One of these chemicals, tetrahydrocannabinol (THC), is the main cause of the marijuana “high.” Thus, the effects of marijuana on the body include those of THC, but not all of marijuana's effects are necessarily due to THC alone. According to federal law, marijuana belongs to a category of substances that have a high potential for abuse and no accepted medical use. Other drugs in this category include LSD (lysergic acid diethylamide) and heroin. By contrast, doctors can legally prescribe THC, in the form of the medicine Marinol (a brand name for a specific formulation of the generic drug dronabinol), under highly regulated conditions. Dronabinol, the “synthetic” THC in Marinol, is identical in every way to the “natural” THC in marijuana. The FDA has approved Marinol for the treatment of nausea and vomiting associated with cancer chemotherapy and also to counteract weight loss in AIDS patients. Currently classified with controlled substances such as anabolic steroids, Marinol was moved from a more restrictive category, which included cocaine and morphine, in July 1999. Some of the medical studies discussed in later chapters deal with the effects of marijuana, while others focus on specific chemicals present in the marijuana plant. This distinction should be kept in mind when considering the results of these studies. The psychoactive chemicals in marijuana are members of a family of mol-

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy FIGURE 1.1 Leaves and flower tops of female marijuana plants. (Photo by Andr é Grossman.) ecules known as cannabinoids, derived from the plant's scientific name, Cannabis sativa. Most cannabinoids are closely related to THC. Scientists also refer to chemicals that are not found in marijuana but that resemble THC either in their chemical structure or the way they affect the body as cannabinoids. Occasionally, we also refer to “marijuana-based medicines.” These encompass the entire spectrum of potential medications derived from marijuana, from whole-plant remedies to extracts to individual cannabinoids, both natural and synthetic. Marijuana is not a modern medicine. Although people have used marijuana for centuries to soothe a variety of ills, it cannot be considered a medicine in the same sense as, for example, aspirin. Aspirin's chemical cousin, found in willow bark, was long used as a folk remedy for pain. But unlike marijuana, aspirin has been proven safe and effective through rigorous testing. Aspirin tablets contain a pure measured dose of medicine, so they can be relied on to give consistent and predictable results. By contrast, two identical-looking marijuana cigarettes could produce quite different effects, even if smoked by the same per-

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy son. If one of the cigarettes were made mostly from leaves and the other from flower tops, for instance, they would probably contain different amounts of active chemicals. Growing conditions also affect marijuana's potency, which can vary greatly from region to region and even from season to season in the same place. This variability makes marijuana at best a crude remedy, more akin to herbal supplements such as St. John's wort or ginkgo than to conventional medications. To date, few herbal supplements have been tested for safety and efficacy in the United States, nor are such products subject to mandatory quality controls. Yet despite these drawbacks, increasing numbers of consumers are using herbal treatments, prompted by their desire for “natural” alternatives to man-made medicines. However, another way to view herbal remedies is to recognize that if they are effective, they contain specific active ingredients. Willow bark contains a pain-relieving compound; marijuana contains cannabinoids such as THC, which lessens nausea. Once identified, chemists can duplicate active compounds in the laboratory. Scientists can also use natural compounds as a basis for creating new medicines. By introducing subtle structural changes in natural molecules, chemists have produced drugs that are more effective and easier to administer and that have fewer side effects than their natural counterparts. So far, a few such analogs or derivatives of cannabinoids are known to exist; others are currently under investigation. Marijuana used as medicine is not a recreational drug. People who use marijuana solely as a medication do so in order to relieve specific symptoms of AIDS, cancer, multiple sclerosis, and other debilitating conditions. Some do so under the advice or consent of doctors after conventional treatments have failed to help them. In mentioning medical marijuana users, we are referring to people who smoke or eat marijuana exclusively as a treatment for medical symptoms. The fact that many such patients may have prior recreational experience with the drug does not mean that they are using illness as an excuse to get high, although it is possible that some patients might do so. Surveys of marijuana buyers' clubs indicate that most of their members do, in fact, have serious medical conditions. Medical marijuana users tend to come from different seg-

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy ments of the population than recreational users. In the United States recreational marijuana use is most prevalent among 18 to 25 year olds and declines sharply after age 34. By contrast, reports on medical marijuana users indicate that most are over 35, as are typical consumers of herbal medicine and other alternative therapies. Most tend to suffer from chronic illnesses or pain that defy conventional treatments. Medical marijuana advocates assert that patients usually obtain relief with smaller doses of the drug than would be used recreationally and that they rarely feel high when treating their symptoms with marijuana; however, no objective study has tested this claim. As discussed in detail in Chapter 3, marijuana and its constituent chemicals can produce both physical and psychological dependence. These risks must be taken into account if marijuana or cannabinoids are to be used as medicines. Many effective medicines have side effects. The fact that marijuana affects the human body adversely does not preclude its use as a source of useful medicines. Many legitimate drugs—including opiates, chemotherapy agents, and steroids—have side effects ranging from the dangerous to the merely unpleasant. When used carefully, though, the benefits of these medications far outweigh their drawbacks. Patients may also develop tolerance, dependence, and withdrawal—conditions associated with marijuana use —when taking proper doses of several commonly prescribed medications. For example, the correct use of some prescription medicines for pain, anxiety, and even hypertension normally produces tolerance and some physiological dependence. As researchers learn more about the chemicals present in marijuana and their effects on the body, it may be possible to identify beneficial compounds and separate them from harmful substances in the plant. Finding a rapid way to deliver cannabinoids to the body, other than smoking, could lessen some of marijuana's worst side effects. It may also be possible to reduce the adverse effects of specific cannabinoids through chemical modification, as previously noted. Marijuana's effects vary with different delivery methods. Traditionally, medicinal marijuana has not been smoked but rather swallowed in the form of an extract or applied to the underside of the tongue in the form of an alcohol-based tincture. Although the lat-

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy ter method allows the THC to pass directly into the bloodstream, it is far less efficient than smoking. When swallowed, drugs pass through the stomach, intestine, and liver before entering the bloodstream, so they act slowly. This is especially true of the main active ingredient in marijuana. Because THC is barely soluble in water, the body absorbs only a small fraction of the available drug when it is swallowed. The same is true of Marinol, which is simply THC in capsule form. Marijuana smoke, on the other hand, efficiently delivers THC into the bloodstream via the lungs. Inhaled THC takes effect quickly, allowing patients to use just enough to relieve their symptoms; it is not so easy to fine-tune the dose of oral medications. For this reason, pharmaceutical firms are investigating the use of smokeless inhalers and nasal sprays to deliver THC and possibly other cannabinoids.