What the General Will Learn

by Lester Grinspoon, M.D. and James B. Bakalar*

*Members of the faculty of the Harvard Medical School and coauthors of Marihuana, the Forbidden Medicine (Yale University Press, Revised and Expanded Edition, 1997).

In November, 1996, the people of California endorsed a change in the state's drug laws that is not welcome to the federal government's Drug Enforcement Administration and its Office of National Drug Control Policy, headed by General Barry McCaffrey. The voters approved Proposition 215, an initiative that could make marihuana legally available as a medicine in the United States for the first time in two generations. Under the new law, patients or their caregivers who possess or cultivate marihuana for medical treatment recommended by a doctor will not be subject to criminal prosecution. The recommendation may be either written or oral, and doctors cannot be penalized by the state for making it. A similar but more restrictive initiative was passed in Arizona at the same time.

The campaign for these laws and their passage drew a strong and mostly sympathetic reaction from the press and public. That should not have been surprising to anyone. For several years public opinion surveys have indicated a growing impatience with the ban on medical marihuana. According to a 1995 poll conducted by the American Civil Liberties Union, for example, 85% of Americans believe marihuana should be available as a medicine.

The federal government and its drug agencies responded predictably at first to the California and Arizona laws and the prospect of similar actions in other states. General McCaffrey tried to coordinate a campaign against the California initiative, calling it "Cheech and Chong medicine," a hoax perpetrated on the people of the state. After the law was passed, the government threatened doctors who recommended marihuana with loss of their federal licenses to prescribe controlled substances, and even hinted at criminal prosecution.

Since then federal officials have been backing off. Maybe they were surprised by the volume and intensity of the support for medical marihuana and its basis in informed opinion. Thousands of patients, with the backing of hundreds of doctors, have been using marihuana medically for a variety of purposes. Not only the patients and their friends and families, but their physicians have begun to speak out. The California initiative was supported by several medical societies. In February of this year, Jerome Kassirer, editor of the nation's leading medical journal, the New England Journal of Medicine, endorsed medical marihuana in an editorial.

Whether he is chagrined by the recognition of his ignorance or just trying to buy time, the General has agreed to the appropriation of a million dollars for the study of marihuana's medical uses by the Institute of Medicine, a branch of the National Academy of Sciences. The reviewers will have 18 months to consider short-term and long-term effects of marihuana on health and behavior, its mechanisms of action in the body, the scientific literature on its therapeutic uses, and its costs and benefits when compared with other drugs used for the same purposes.

We can anticipate much of what the Institute of Medicine's committee, if it is dispassionate and objective, will tell the General and the nation. So much research has been done on marihuana, often in unsuccessful efforts to show serious health hazards and addictive potential, that we know more about it than about most prescription drugs. When the committee examines the effects of marihuana on health and human behavior, it will almost certainly come to the same conclusions reached by a previous committee of the IOM in 1982: there is no great reason for concern. Every government commission that has ever studied the question has given the same answer. To name a few: the Indian Hemp Drugs Commission, reporting to the British government of India in 1894; the Commission on the Marihuana Problem in the City of New York, reporting to Mayor LaGuardia in 1944; the National Commission on Marihuana and Drug Abuse, reporting to President Nixon in 1973; and the Le Dain Commission, reporting to the government of Canada in 1974.

What these reviews and others show is, first, that marihuana is remarkably safe. In 5,000 years of medical and nonmedical use, it has never been known to cause a single overdose death. A medicine's lethal potential is often measured by a number called the therapeutic ratio. This is calculated by dividing the amount of a drug that would kill half of the people using it by the amount needed for a therapeutic effect. The higher the ratio, the safer the drug. For example, it takes from 3 to 50 times the therapeutic (sedative) dose of the barbiturate secobarbital (Seconal) to kill half the people using it. Since no one has ever died from taking marihuana, the therapeutic ratio might be said to be infinite.

The commission will also undoubtedly find, as previous commissions have, that the other alleged risks of marihuana -- psychotic reactions, addiction and dependence, the so-called amotivational syndrome, and reputed effects on the immune system, sex hormones, and the reproductive system -- are either nonexistent or have been greatly exaggerated. Marihuana has fewer serious side effects than most prescription drugs and is far less addictive or subject to abuse than many drugs now used as muscle relaxants, sedatives, and painkillers. In 1988 the Drug Enforcement Administration (DEA) was obliged to consider a petition to make marihuana available as a prescription drug. The DEA's own Administrative Law Judge, after hearing dozens of witnesses and reading thousands of pages of testimony during two years of hearings, declared marihuana to be "one of the safest therapeutically active substances known to man."

The only serious concern is the effect of smoking. Marihuana smoke, like tobacco smoke, carries irritating and possibly cancer-causing particles of burned plant matter into the lungs. But there are important differences. First, even people who use marihuana for pleasure are rarely exposed to as much smoke as tobacco addicts. Medical users will generally need still less. Second, marihuana users usually take only as much as they need to achieve the desired effect, which they can judge quite precisely. That means medical marihuana can be made safer if its potency is increased, reducing the amount of contaminants in a given dose. Finally, technical innovations could allow the active ingredients in marihuana, the cannabinoids, to be heated and vaporized without burning plant material. Once marihuana is approved as a medicine and inventive people are allowed to develop a practical vaporizing apparatus, we will no longer have to worry about the dangers of smoking.

The commission will find much less in the recent scientific literature that indicates marihuana's therapeutic value, partly because the federal government has discouraged such research. There are few controlled studies of the kind contemporary scientific medicine relies on. But the history of medical marihuana goes back to ancient China, and Western physicians have generated a mass of reports and case histories beginning in the middle of the 19th century. Between 1840 and 1900, European and American medical journals published more than 100 articles on the therapeutic uses of marihuana, which was known then as Indian hemp. It was mentioned as an appetite stimulant, muscle relaxant, sedative, painkiller, and treatment for opium addiction and epilepsy. As late as 1913 Indian hemp was recommended as the best remedy for migraine in an authoritative textbook written by one of the most highly respected physicians of his time. We can assure General McCaffrey that the author of this text, Sir William Osler, had never heard of Cheech and Chong. We can also assure him that many migraine sufferers today agree with Osler.

The evidence for medical uses of marihuana is still mostly of the kind sometimes disparaged as merely anecdotal -- individual reports and case histories. But many of the medicines in common use today were accepted long before the advent of modern controlled studies because of convincing anecdotal evidence that they worked -- aspirin, insulin, and penicillin, to name three. Besides, individual responses are often obscured in large group experiments. There is a growing number of successful formal and informal tests of the kind researchers call N of 1 studies -- experiments in which the patient takes marihuana in alternation with a placebo or standard medicine for comparison.

The medical use of marihuana declined in the early 20th century. The old method of application, an alcohol solution taken with a dropper, was unreliable in its effects. Synthetic alternatives, including aspirin, barbiturates, and injectable opiates, were substituted for some of the most common uses of marihuana. When nonmedical use began to appear in the United States, mainly among Mexican-Americans and African-Americans in the Southwest, the states passed a series of anti-marihuana laws. After a campaign by Harry Anslinger, the first Director of the Federal Bureau of Narcotics, the federal government introduced the Marihuana Tax Act of 1937. That law was supposed to prevent so-called recreational use but had the effect of making medical use so difficult that marihuana was soon removed from the standard pharmaceutical references.

Many of the medical uses known to 19th century physicians have come to light again in the last 20 years, and new uses are being developed. But this time, instead of doctors telling patients about marihuana, patients are telling their doctors about it. In a 1995 poll, 22% of the people surveyed said they had learned about the medical benefits of marihuana from personal experience or from friends and family members who used it. People with glaucoma learned that marihuana could relax the pressure on the optic nerve that causes blindness. Patients in cancer chemotherapy discovered that a few puffs of a marihuana cigarette halted the devastating nausea and vomiting that made some of them want to die rather than continue the torture of treatment. Paraplegics, people with multiple sclerosis, and others suffering from spastic disorders found that marihuana relieved their muscle spasms. Amputees reported relief from phantom limb pain. People with AIDS discovered that marihuana restored their appetite and prevented the AIDS weight loss syndrome. In the revised and enlarged edition of our book, Marihuana, the Forbidden Medicine, to be published in July of this year, we cite 30 potential medical uses, and the list is undoubtedly not exhaustive.

Professionals in the field of health care are listening. The California initiative was endorsed by the California Nurses' Association, the California Nurses' Alliance, the San Francisco Medical Society, and the California Academy of Family Physicians. Forty-four percent of cancer specialists responding to a 1990 survey said they had suggested marihuana to a patient at some time. Yet, according to federal law, this drug is unsafe for use even under medical supervision. Doctors and patients are obviously trying to tell the government that, to use a politically popular phrase, mistakes are being made.

In comparing marihuana with other medicines used for the same purposes, the IOM committee will find that a major advantage is its safety and freedom from side effects. For example, marihuana sometimes relieves the pain and stiffness of arthritis. The standard treatments are aspirin and other nonsteroidal antiinflammatory drugs, which can cause serious digestive complications and lead to several thousand deaths a year from internal bleeding. Some people with multiple sclerosis find that marihuana eases their pain and muscle spasms. The standard alternatives are large doses of the stupefying and sometimes addictive diazepam (Valium), along with dantrolene and baclofen, two potentially toxic drugs that are marginally useful. We have also seen cases (confirming 19th century reports) in which marihuana serves as a benign substitute for alcoholics and heroin addicts. Of course, it will not help every patient with one of these disorders, but it is safe enough to be worth trying even if only a few benefit.

When the commission makes its comparisons, the General may also learn that legal marihuana would be less expensive than most conventional medicines. If there were no "prohibition tariff", its cost would be $20 to $30 an ounce, or about 30 cents a cigarette, as compared with the present street price of $200 to $500 an ounce. One marihuana cigarette usually relieves the nausea and vomiting of cancer chemotherapy. So does a standard dose of ondansetron (Zofran), the best present legally available treatment, at a price of up to $100 for every episode of nausea and vomiting -- $600 or more if the patient is too nauseated to swallow a pill and has to take the drug intravenously in a hospital bed.

A synthetic form of delta-9-tetrahydrocannabinol (THC), the main active chemical in marihuana, is legally available in the form of a capsule for limited medical purposes under the name of dronabinol or Marinol. Patients and doctors agree that marihuana is usually more effective, even apart from problems created by nausea. THC is absorbed slowly and unreliably by mouth, and users often find out hours later that they have taken too much or too little. Smokers can judge the correct dose more easily because they receive immediate feedback. Besides, Marinol makes some patients uncomfortable, possibly because it contains only one of the many related cannabinoids in marihuana. Some of these substances may modify the effects of THC, which occasionally causes anxiety, mainly in new users.

Once the General learns about marihuana's safety, versatility, and low cost as a medicine, he will probably want it to run the gauntlet of multi-million dollar controlled studies required by the Food and Drug Administration (FDA) for approval of a new drug (although, as we have pointed out, marihuana is hardly new). The question is who is going to pay for those studies. The cost of new drugs is ordinarily borne by pharmaceutical companies, which invest millions because they hope to win a 20-year patent that will make them millions more. Marihuana, of course, cannot be patented, since it is a plant that grows freely all

over the world and has been used as a medicine for thousands of years. Drug companies may even have something to lose if marihuana competes with their expensive products. So the government will have to pay for the tests -- at least two large studies for each of the many potential medical uses. It will take a great deal of time as well as money.

It will also require a change in the government's attitude. One reason for the scarcity of controlled scientific research on medical marihuana is the federal government's determination to block the way. For example, in 1994 Donald Abrams, a physician at the University of California at San Francisco, tried to win approval for a study comparing smoked marihuana with Marinol in the treatment of the AIDS weight loss syndrome. He faced obstacles at every turn as he worked his way through the state and federal bureaucracies. Eventually the project was approved by the Food and Drug Administration and by several institutional review boards and advisory committees, but the National Institute on Drug Abuse and the Drug Enforcement Administration would not provide the marihuana he needed -- the marihuana many of his patients were undoubtedly finding on the streets.

Even if federal authorities relent, the research will take so long that other ways must be found to accommodate patients who cannot wait. The main purpose of the FDA drug approval process is to protect consumers from drugs that are ineffective or toxic. We know that marihuana is not highly toxic (partly because of the substantial time, money, and effort that have been expended on attempts to prove the opposite), and the anecdotal evidence of its effectiveness is persuasive. More scientific research would certainly help; we need to learn which patients with which disorders will benefit most. But meanwhile patients should not be prevented from using and doctors should not be prevented from prescribing a relatively harmless drug that might be more effective and less expensive than conventional medicines. Even cocaine and morphine are legally available on prescription. As Dr. Kassirer pointed out in his editorial, it is hypocritical to forbid the prescription of marihuana while allowing the use of much more dangerous drugs.

That is not the only example of the federal government's hypocrisy. It is a little-known fact that the government first acknowledged marihuana's medical usefulness more than 20 years ago. In 1976 growing demand persuaded the FDA to institute the Individual Treatment Investigational New Drug Application, commonly referred to as the Compassionate IND, a permit for the use of individual doctors whose patients needed marihuana. Even with the best intentions on the part of everyone involved, this arrangement would never have worked for large numbers of patients. In practice, the complicated application process seemed almost designed to discourage, and physicians were reluctant to become entangled in the paperwork, especially since many of them thought there was a stigma attached to prescribing marihuana.

The government awarded only about a half dozen of these permissions in 13 years. Then, in 1989, the FDA was deluged with applications from people with AIDS. In June 1991, when the number of Compassionate INDs had risen to 34, the program was suspended, with an announcement by the chief of the Public Health Service that it gave a "bad signal" by suggesting that "this stuff can't be so bad." The program was permanently discontinued in 1992. The eight remaining patients whose doctors hold pre-1991 applications are the only ones in the country for whom marihuana is not a forbidden medicine.

When General McCaffrey injected himself into the debate on the California initiative by declaring that medical marihuana was a fraud, he was plausibly criticized for trying to tell physicians how to conduct their business. Although we may be risking the same mistake, we would like to suggest to him that a good general knows when to retreat and cut his losses. The Administration does not have to wait for the Institute of Medicine's report. It can free itself now from the need to defend the untenable position that medical marihuana is a hoax. As Senator George Aiken of Vermont suggested to the President during the Vietnam War, the government could declare victory and withdraw, by announcing that the medical value of marihuana has been established and a workable accommodation will be made now for patients who need it.