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Medical Marihuana
 in a Time of Prohibition

International Journal of Drug Policy, April, 1999.

Lester Grinspoon, M.D.

"A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die and a new generation grows up that is familiar with it."—Max Planck

The medical value of marihuana has become increasingly clear to many physicians and patients. There are three reasons for this. First, it is remarkably non-toxic. Unlike most of the medicines in the present pharmacopeia, it has never caused an overdose death. Its short-term and long-term side effects are minimal compared to medicines for which it will be substituted. Second, once patients no longer have to pay the prohibition tariff, it will be much less expensive than the medicines it replaces. Third, it is remarkably versatile. Case histories and clinical experience suggest that it is useful in the treatment of more than two dozen symptoms and syndromes, and others will undoubtedly be discovered in the future.

As clinical evidence of marihuana's medical efficacy and safety accumulates and first-hand experience of its value becomes more common, the discussion is turning to how it should be made available. When I first considered this issue in the early 1970s, I thought the main problem was its classification in Schedule I of the Comprehensive Drug Abuse and Control Act of 1970, which describes it as having a high potential for abuse, no accepted medical use in the United States, and lack of accepted safety for use under medical supervision. At that time I naively believed that a change to Schedule II would overcome a major obstacle, because clinical research would be possible and prescriptions would eventually be allowed.

I was the first witness at a joint meeting of the Drug Enforcement Administration and the Food and Drug Administration that was convened to consider a petition for rescheduling introduced by the National Organization for the Reform of Marijuana Laws in 1972. At that time I had already come to believe that the greatest harm in recreational use of marihuana came not from the drug itself but from the effects of prohibition. But I saw that as a separate issue; I thought that, like opiates and cocaine, cannabis could be used medically while remaining outlawed for other purposes. I also thought that once it was transferred to Schedule II, research on marihuana would be pursued eagerly, since it had shown such interesting therapeutic properties. From this research we would eventually be able to determine how it should be used medicinally, how prescriptions could be provided, and who would be responsible for quality control. Twenty-five years later, I have begun to doubt this. It would be highly desirable if marihuana could be approved as a legitimate medicine within the present federal regulatory system, but it now seems to me unlikely.

First, I should note that cannabis has already been a legally accepted medicine in the United States several times. Until 1941, when it was dropped after the passage of the Marihuana Tax Act, it was one of the drugs listed in the U.S. Pharmacopeia. If it had not been removed at that time, it would have been grandfathered into the Comprehensive Drug Abuse and Control Act as a prescription drug, just as cocaine and morphine were. Again, in the late 1970s and early 1980s, cannabis was used medically by hundreds of patients (mainly in the form of synthetic tetrahydrocannabinol) in projects conducted by several of the states for the treatment of nausea and vomiting in cancer chemotherapy. This episode ended because each state program had to comply with an enormous federal paperwork burden that was more than the physicians and administrators involved could bear. The federal government itself approved the use of cannabis as a medicine in 1976 by instituting the Compassionate IND program, under which physicians could obtain an individual Investigational New Drug application (IND) for a patient to receive cannabis. This program too was so bureaucratically burdened that in the course of its history only about three dozen patients ever received marihuana, and only eight are still receiving it. When the program was discontinued permanently in 1992, James O. Mason, the chief of the Public Health Service, gave the following reason: "If it is perceived that the Public Health Service is going around giving marihuana to folks, there would be a perception that this stuff can't be so bad. It gives a bad signal. I don't mind doing that if there is no other way of helping these people...But there is not a shred of evidence that smoking marihuana assists a person with AIDS." In effect, this action was analogous to the recall of a prescription drug, without any evidence of toxic effects to support it.

Today, even transferring marihuana to Schedule II would not be enough to make it available as a prescription drug. Such drugs must undergo rigorous, expensive, and time-consuming tests before they are approved by the Food and Drug Administration for marketing as medicines. The purpose is to protect the consumer by establishing safety and efficacy. Because no drug is completely safe or always efficacious, an approved drug has presumably satisfied a risk-benefit analysis. When physicians prescribe for individual patients they conduct an informal analysis of a similar kind, taking into account not just the drug's overall safety and efficacy, but its risk and benefits for a given patient with a given condition. The formal drug approval procedures help to provide physicians with the information they need to make this analysis.

This system is designed to regulate the commercial distribution of drug company products and protect the public against false or misleading claims about their efficacy and safety. The drug is generally a single synthetic chemical the company has developed and patented. It submits an application to the Food and Drug Administration and tests it first for safety in animals and then for clinical efficacy and safety. The company must present evidence from double-blind controlled studies showing that the drug is more effective than a placebo and as effective as available drugs. Case reports, expert opinion, and clinical experience are not considered sufficient. The standards have been tightened since the present system was established in 1962, and few applications that were approved in the early 1960s would be approved today on the basis of the same evidence.

Certainly we need more laboratory and clinical research to improve our understanding of medicinal cannabis. We need to know how many patients and which patients with each symptom or syndrome are likely to find cannabis more effective than existing drugs. We also need to know more about its effects on the immune system in immunologically impaired patients, its interactions with other medicines, and its possible uses for children.

But I have come to doubt whether the FDA rules should apply to cannabis. There is no question about its safety. It is one of humanity's oldest medicines, used for thousands of years by millions of people with very little evidence of significant toxic effects. More is known about its adverse effects than about those of most prescription drugs. The American government has conducted a decades-long multimillion-dollar research program in a futile attempt to demonstrate toxic effects that would justify the prohibition of cannabis as a nonmedical drug. Should time and resources be wasted to demonstrate for the FDA what is already so obvious?

As for efficacy, some believe that has been proven too, although most disagree. During the 1970s and '80s several of the state-sponsored research projects I mentioned suggested that marihuana had advantages over both oral tetrahydrocannabinol and other medicines in the treatment of nausea and vomiting from cancer chemotherapy. But as long as the imprimatur of science can be given only to rigorous double-blind controlled studies, the case for marihuana has not been made. The assertion that it is a useful medicine rests almost entirely on case reports and clinical experience, just as it did in the late 19th and early 20th centuries.

A double-blind controlled study may be the best way to prove the relative value of a new medicine whose advantages over established drugs are not obvious. But it is not the only way to demonstrate efficacy. The focus of controlled trials is usually statistical differences in effects in groups of patients, but medicine has always been concerned mainly with individuals, whose needs can be obscured in such experiments, especially when little effort is made to identify distinctive characteristics that affect their responses. The value of case reports and clinical experience is often underestimated. They are the source of much of our knowledge of synthetic medicines as well as plant derivatives. Controlled experiments were not needed to recognize the therapeutic potential of chloral hydrate, barbiturates, aspirin, curare, or lithium. The therapeutic value of penicillin was widely recognized after it had been given to only six patients. Similar evidence revealed the use of propranolol for hypertension, diazepam for status epilepticus, and imipramine for childhood enuresis. These drugs had originally been approved by regulators for other purposes.

As early as 1976 several small and imperfect studies, not widely known in the medical community, had shown that an aspirin a day could prevent a second heart attack. In 1988 a large-scale experiment demonstrated effects so dramatic that the researchers decided to stop the experiment to publish the life-saving results. On one estimate, as many as twenty thousand deaths a year might have been prevented from the mid-1970s to the late-1980s if the medical establishment had been quicker to recognize the value of aspirin. The lesson is suggestive: marihuana, like aspirin, is a substance known to be unusually safe and with enormous potential medical benefits. There is one contrast, however; it was impossible to be sure about the effect of aspirin on heart attacks without a long-term study involving large numbers of patients, but innumerable reports show that cannabis often brings immediate relief of suffering that can be measured in a single person.

Case histories are, in a sense, simply the smallest research studies, and the case reports on marihuana are numerous and persuasive. There is an experimental method known as the N-of-1 clinical trial, or the single-patient randomized trial. In this type of experiment, active and placebo treatments are administered randomly in alternation or succession to a patient. The method is often useful when large-scale controlled studies are impossible or inappropriate because the disorder is rare, the patient is atypical, or the response to the treatment is idiosyncratic.

Some medical marihuana patients I know of carried out similar experiments on themselves by alternating periods of cannabis use with periods of no use. They had such symptoms as nausea and vomiting, muscle spasms, compromised vision, seizures, and debilitating pruritus. It is certain that cannabis won its reputation as a medicine partly because many other patients around the world have carried out the same kind of experiment. Admittedly, in these experiments cannabis could not be administered completely at random and there was no placebo, but in any case its psychoactive effects are usually unmistakable, and few patients or observers could be deceived by a placebo. Case histories and other reports of clinical experience are sometimes disparagingly dismissed as merely "anecdotal" evidence, which is said to be irrelevant because only apparent successes are counted and failures are ignored. It is true that cannabis may be useful for some people with, say, multiple sclerosis, chronic pain, or depression, and not for others. But cannabis is so safe that if even a few patients with a given symptom could get that kind of relief, they should be allowed access to it.

Even if it made sense to put marihuana through the FDA process, there would be other problems in taking the conventional route to medical legitimacy. As I have mentioned, FDA procedures are designed for single chemical compounds, but marihuana is a plant material containing many chemicals. Also, it is taken chiefly by smoking, and no other drug in the present pharmacopeia is delivered by this route. Furthermore, thousands of people are already getting relief from cannabis, and they would not be risking severe penalties if they did not believe that it was more useful than conventional medicines. Can we expect them to put their pain and suffering on hold for years while the established procedures grind away?

Patients, their families, and others are becoming increasingly impatient for a legal means of obtaining medical cannabis. The most dramatic manifestation of this impatience has been the referenda allowing distribution of medicinal cannabis that have been passed in several states. In 1996 California became the first state to approve such a law. Within weeks of the vote, more than a dozen cannabis clubs opened to help sick people in need of relief, and the membership of one quickly grew to 8,000. Many Americans believe that this is the best temporary approach to the problem of making medical cannabis available.

Among those who understand the present importance of the cannabis clubs or cooperatives, there are two views on their organization. One model follows the conventional delivery system for medicine: the patient who needs medicinal cannabis (read medicine) goes to the buyers club (read pharmacy) and presents a note from a physician which certifies that the patient has a condition for which the physician recommends cannabis (read prescription) to the staff of the buyers club (read pharmacist). If both the doctor and the buyers club behave responsibly and ethically, only those who have a certified need for the medicine can receive it, and those who are certified now have a reliable source. They are relieved of the anxiety of having to find it on the street or grow their own.

In a buyers club of this kind, the patient is of course not expected to take the medicine on the premises. In contrast, the second distribution model resembles a social club more than a pharmacy. The dispensing area is plastered with menus offering types, grades, and prices. Large rooms are filled with brightly colored posters, lounge chairs and sofas, tables, magazines, and newspapers. While some people remain only long enough to buy their medicine, most stay to smoke and talk. There are animated conversations, laughter, music, and the pervasive pungent odor of cannabis. The atmosphere is informal, welcoming, and warm, providing support for patients who may be socially isolated and have little opportunity to share concerns and feelings about their illnesses. This type of club is a blend of Amsterdam-style coffeehouse, American bar, and medical support group.

Most people who recognize the importance of the buyers clubs believe that the first model, epitomized by the now closed Oakland Club, is preferable to the second model, represented by the now closed San Francisco Cultivators' Club. The San Francisco model, largely because of the on-site cannabis smoking and relaxed atmosphere, seems more casual in its commitment to confirming medical need, and this has made even the supporters of buyers clubs a little nervous. Yet the importance of the social aspect cannot be underestimated. It is becoming increasingly clear that emotional support—contacts with and help from friends, family, co-workers, and others—plays an important role in battling illness. This support improves the quality of life and may even prolong the life of people with various illnesses, including cancer. The San Francisco buyers club was not designed by psychiatrists and social scientists to provide supportive group therapy, but there is reason to believe it did. One of the properties of marihuana may have contributed to its effectiveness: when people use cannabis, they tend to be more sociable and find it easier to share difficult thoughts and feelings. If there is even a kernel of truth to the idea that talking about the stress, setbacks, and triumphs in the battle against an illness can help a patient cope and recover, it is clear that the San Francisco model provides the best kind of environment for the dispensing of marihuana.

Unfortunately, even many supporters of medical cannabis regarded the language of California Proposition 215 as permitting the legal use, cultivation, and distribution of marihuana too broadly. The initiatives passed more recently in several states have more tightly drawn limitations. They will not permit cannabis clubs with the medical and psychiatric advantages of the San Francisco model, and they allow such a short list of medical uses that only a few of the patients who could find marihuana helpful will be allowed to use it. But in any case, buyers clubs have to be regarded as a stopgap measure. The federal government is not going to allow the development of a separate distribution system for one medicine. It has already succeeded in closing most of the California buyers clubs, and if it is as successful elsewhere, they will not long endure.

Other present approaches to making marihuana medically available have even more serious drawbacks. Marihuana is now classified as a Schedule I drug, which means that it is legally defined as too dangerous for use even under medical supervision. But for the sake of argument, let us suppose that the government comes to its senses and marihuana is moved to Schedule II. This would allow investigators to do the studies which lead to FDA approval for medical use. But where will the money to finance these studies come from? New medicines are usually introduced by drug companies, which spend an estimated two hundred million dollars or more on the development of each product. They are willing to undertake these costs only because they hope for large profits during the 20 years they own the patent. Obviously pharmaceutical companies cannot patent marihuana and, in fact, may oppose its acceptance as a medicine because it will compete with their own products. Only the U.S. government has sufficient resources to explore medical marihuana. But its record on the matter is, to put it mildly, not reassuring. The government has opposed any loosening of restrictions on clinical research with cannabis, including the research needed for FDA approval. I believe the government will ultimately have to provide some support for this research because of public pressure, but it will arrive slowly. A study of marihuana in the treatment of the AIDS wasting syndrome has recently been approved and funded after four years of obstruction. But this happened only because the political climate had changed after the California initiative, and even so, the main subject of the study had to be changed from medical efficacy to safety.

But let us suppose that studies are somehow completed showing that marihuana is safe and effective as a treatment for the weight reduction syndrome of AIDS, and physicians are able to prescribe it for that condition. This will present unique problems. When a drug is approved for one medical purpose, physicians are generally free to write off-label prescriptions—that is, prescribe it for other conditions as well. Dronabinol (Marinol), a synthetic form of tetrahydrocannabinol, was approved as a prescription drug in 1986 for the treatment of nausea and vomiting in cancer chemotherapy, and later for the treatment of the weight reduction syndrome of AIDS. However, presumably because it was thought to be susceptible to medically questionable use, it became the first FDA-approved drug for which off-label use was forbidden. The ban has proved too difficult to enforce, and doctors have prescribed it off-label, although somewhat timidly. If marihuana is approved as a medicine, how will this concern about off-label prescriptions be dealt with?

Present state and federal schemes for making cannabis medically available invariably specify that it must be used for the treatment of illnesses defined as "serious", "life-threatening", "terminal", or "debilitating." Which of the many symptoms and syndromes for which cannabis is useful should be considered "serious?" For example, what about premenstrual syndrome? Surely women who suffer from this disorder consider it a serious problem, and many of them find that marihuana is the most useful treatment. What about intractable hiccups or the loss of erectile capacity in paraplegics? The people who suffer from these rare problems know how debilitating they can be.

Generally speaking, the more dangerous a drug is, the more serious or debilitating must be the symptom or illness for which it is approved. Conversely, the more serious the health problem, the more risk is tolerated. If the benefit is very large and the risk very small, the medicine is distributed over the counter (OTC). OTC drugs are considered so useful and safe that patients are allowed to use their own judgment without a doctor's permission or advice. Thus, today anyone can buy and use aspirin for any purpose at all. This is permissible because aspirin is considered so safe; it takes "only" one to two thousand lives a year in the United States. The remarkably versatile ibuprofen and other NSAIDs can also be purchased over the counter, because they too are considered very safe; "only" 7,000 Americans lose their lives to these drugs annually. Acetaminophen, another useful OTC drug, is responsible for about 10% of cases of end-stage renal disease. The public is also allowed to purchase many herbal remedies whose dangers have not been determined and which probably have only placebo effects.

Compare these drugs with marihuana. Today no one can doubt that it is, as DEA Administrative Judge Francis L. Young put it, "among the safest therapeutic substances known to man." If it were now in the official pharmacopeia, it would be a serious contender for the title of least toxic substance in that compendium. In its long history, marihuana has never caused a single overdose death. Yet government schemes for its medical use are always cloaked in language suggesting that it is too dangerous to be used except under the most stringent limitations. In several states, medical marihuana initiatives require patients to register, and in two states they will need identification cards to protect them from arrest.

As a Schedule II drug, marihuana would be classified as having a high potential for abuse and limited medical use. Restrictions on these drugs are becoming tighter. Nine states now require doctors to make out prescriptions for many of them in triplicate so that one copy can be sent to a centralized computer system that tracks every transaction. In 1989 New York State added the benzodiazepines (Valium and related drugs) to the list of substances monitored in this way. Research has shown that since then many patients in New York who have a legitimate need for benzodiazepines are being denied them, and less safe and effective drugs are being substituted. Increased regulation caused by fear of drug abuse has been to the disadvantage rather than the advantage of patients.

In such situations physicians are often afraid to recommend what they know or suspect to be the best medicine because they might lose their reputations, licenses, and careers. Pharmacies might be reluctant to carry marihuana as a Schedule II drug, and physicians would hesitate to prescribe it. Through computer-based monitoring, the DEA could know who was receiving prescription marihuana and how much. It could hound physicians who by its standards prescribed cannabis too freely or for off-label purposes the government considered unacceptable. The potential for harassment would be extremely discouraging. Unlike other Schedule II drugs such as cocaine and morphine, cannabis has many potential medical uses. Many patients might try to persuade their doctors that they had a legitimate claim to a prescription. Physicians would not want the responsibility of making such decisions if they were constantly under threat of discipline by the state. A physician who prescribed marihuana for chronic pain, for example, might be subjected to the same harassment as those whom the DEA considers to be dispensing opioids too liberally. Since the passage of the medical marihuana initiative in California, I have heard from many patients who say their doctors are afraid to recommend (not prescribe) marihuana because of threats from the federal government—even though those threats have been declared by the courts to be legally baseless.

There is actually no case for the present restrictions—unless third-party reefer-madness anxiety counts as a risk. The Schedule II classification of cannabis would not be accurate. It does not have a high potential for abuse, and above all, it does not have limited medical uses. For example, a physician might sensibly and safely prescribe it for muscle spasms and chronic pain resulting from a variety of conditions, from paraplegia to premenstrual syndrome. If the government and medical licensing boards insist on tight restrictions, challenging physicians as though cannabis were a dangerous drug every time it is used for any new patient or any new purpose, there will be constant conflict with one of two outcomes: patients do not get all the benefits they should from this medicine, or they get the benefits by abandoning the legal system for the black market or their own outdoor or closet gardens.

Then there is the question of who will provide the cannabis. The federal government now provides cannabis from its farm in Mississippi to eight patients who have residual Compassionate INDs. But surely the government could not or would not produce marihuana for many thousands of patients receiving prescriptions, any more than it does for other prescription drugs. But if production is contracted out, will the farmers have to enclose their fields with security fences? How would the marihuana be distributed? If through pharmacies, how would they provide secure facilities capable of keeping fresh supplies? When urine tests are demanded for workers, how would patients who use marihuana legally as a medicine be distinguished from those who use it for other (disapproved) purposes?

If the full potential of cannabis as a medicine were to be achieved in the setting of the present prohibition system, all of these problems and more would have to be addressed. A delivery system that successfully navigated this minefield would be so cumbersome, inefficient, and bureaucratically top-heavy that patients would continue to grow their own or buy it on the illicit market. The authorities could claim that a legal medical distribution apparatus existed, but most patients would find themselves in the same situation they are in today. The Compassionate IND program, the federal government's last scheme to satisfy these needs, lasted from 1976 to 1992 but never supplied more than a few dozen patients with cannabis.

Some believe a solution to the "medical marihuana problem" (restricting the use of cannabis for medical purposes only) will be found in the isolation of individual cannabinoids, the manufacture of synthetic cannabinoids, and the development of analogs (chemical cousins of cannabinoids). Supposedly, these drugs, sometimes in combination, will make the natural product superfluous. Their use in the form of parenterals, nasal sprays, vaporizers, skin patches, pills, and suppositories will allegedly make it unnecessary to expose the lungs to the particulate matter in marihuana smoke. Furthermore, the commercial products may lack psychoactive effects, which is apparently very important to some people. A pain researcher at the Memorial Sloan-Kettering Cancer Institute recently said that he was excited by the new analogs because "the euphoria sparked by cannabinoids…is undesirable in chronically ill patients."

Not everyone will agree that freedom from the psychoactive effects is an advantage, but some cannabinoids and analogs may be preferable to whole smoked or ingested marihuana for other reasons. For example, cannabidiol may be more effective as an anti-anxiety drug when it is taken without THC, which sometimes generates anxiety. Other cannabinoid analogs may occasionally prove more useful than marihuana because they can be administered intravenously. For example, loss of consciousness occurs in 15% to 20% of patients who suffer a thrombotic or embolic stroke, an even higher proportion after a hemorrhagic stroke, and some who develop a brain syndrome after a severe blow to the head. The cannabinoid analog dexanabinol (HU 211) has recently been shown to limit brain swelling and protect brain cells from damage in these circumstances. It is apparently not psychoactive and can be given intravenously to an unconscious person.

The modern pharmaceutical laboratory will undoubtedly develop other cannabinoid-related products with properties that whole marihuana and marihuana extracts lack. There are already two known receptors for cannabinoids with different anatomical distributions and only partially overlapping functions. New agonists, antagonists, and inverse agonists will be developed for these receptors (and possibly for others still to be discovered), some of which may have therapeutic potential. For example, tetrahydrocannabinol and possibly other cannabinoids enhance appetite. Perhaps pharmacologists will develop cannabinoid inverse tagonists which inhibit appetite and act as nontoxic weight reduction medicines. A better understanding of brain functions will also result from this kind of research.

But these encouraging developments have a worrisome downside. South American Indians have chewed the coca leaf for thousands of years with little apparent abuse and few ill effects, but since the isolation of methylbenzoylecgonine (cocaine) from the leaf's other natural alkaloids, some users have developed serious problems. Similarly, opium in its natural form is less risky than, say, the potent synthetic opioid fentanyl. HU 211 (dexanabinol) is not psychoactive, but its stereoisomer, HU 210, synthesized in the same laboratory, is hundreds of times more psychoactive than THC. Other analogs may be equally potent. The danger is that they will bear the same relationship to marihuana that fentanyl bears to opium.

There are other reasons why isolated cannabinoids and cannabinoid analogs will probably never completely displace marihuana itself as a medicine. It was once widely believed that the availability of dronabinol would make medical marihuana superfluous. Dronabinol is packed in sesame oil, partly for easier absorption, but also because it makes smoking impossible and therefore was thought to make nonmedical use unlikely. But patients have generally not found dronabinol to be nearly as useful as whole smoked marihuana. Even among those who judge it equally effective, many find that street marihuana is less expensive. If the advent of prescribable dronabinol did not make marihuana medically obsolete, it is hard to believe that the arrival of new analogs will do so. I believe that many if not most patients who could get benefits from the new analogs will choose instead to smoke the more easily accessible and less expensive marihuana.

In evaluating the prospects for cannabis analogs, we must consider what a pharmaceutical product requires for economic success.

(1) It must be as useful as or more useful than competitive medicines for a particular symptom or syndrome, or it must have a wide variety of approved medicinal uses.

    1. It must not have more undesirable side effects than competitive medicines.
    2. It must have a mode of delivery which is as good as or better than available alternatives.
    3. It must be priced competitively.
    4. It must have a risk-benefit ratio which is at least as good as that of competitive medicines.
    5. It must not be restrictively scheduled under the federal Comprehensive Drug Abuse and Control Act. The more restrictive the schedule, the more serious impact on marketability and the cost of development.

Now compare the anticipated analogs with whole marihuana:

    1. Except in a few situations, such as intravenous injection in an unconscious person, analogs or combinations of analogs are unlikely to be more useful than natural cannabis for most specific symptoms. Nor are they likely to have a much wider spectrum of therapeutic uses than the natural product, which contains the cannabinoids (and synergistic combinations of cannabinoids) from which the analogs are derived. In fact, one result of the development of new analogs may be to identify new medical uses for marihuana in its natural form. Shortly after dexanabinol, which is both a potent antoxidant and an NMDA antagonist, was found to protect brain cells against damage after a stroke or trauma, it was shown that THC and cannabidiol, also potent antoxidants, provide the same kind of protection. In fact, given the urgency of retarding the pathological process set in motion by a stroke or brain trauma, it may be more medically sensible to allow patients with closed head injuries to smoke the more accessible marihuana immediately upon regaining consciousness as they await transportation to a hospital to receive dexanabinol.
    2. The analogs may not cause such minor side effects as inflammation of the sclera of the eyes or increased heart rate, but these are not medically significant. Except for infrequent orthostatic hypotension (faintness on standing up), pulmonary exposure to smoke and, in the opinion of some, the psychoactive effect (the high), marihuana has few medically significant side effects.
    3. Inhalation devices now being perfected protect the lungs by separating the cannabinoids in whole marihuana from burnt plant products. When these devices are manufactured in large numbers, they will provide an inexpensive, safe, and highly effective means of delivery. Again, except for a few situations such as unconsciousness and pulmonary impairment, it is doubtful that a better means of delivery will be available for analogs.
    4. Given the cost of development, the new analogs will be expensive. They will probably cost much more than whole smoked marihuana even at the inflated prices imposed by the prohibition tariff. Suppose, for example, that a new analog is an antinauseant comparable to the prescription drug ondansetron in effectiveness and price. Today a patient suffering from the nausea of cancer chemotherapy might require one to four 8-mg ondansetron pills at $30 to $40 apiece. Many patients will probably get equally effective relief from a few puffs of a marihuana cigarette—cost $5 at today's street price, 30 cents if marihuana is produced as a medicine.
    5. The potential benefits of whole smoked marihuana are extraordinarily high compared to the risks. For example, the therapeutic ratio of marihuana is not known because it has never caused an overdose death. It has been estimated on the basis of extrapolation from animal data to be 20,000 to 40,000 to 1. Even if the therapeutic ratio of a new analog is also high, it is unlikely to be as safe as whole marihuana because it will be physically possible to ingest much more of the analog.
    6. Any new cannabinoid analog with psychoactive properties would presumably have to be placed in a restricted schedule by the federal government. The Unimed Corporation, which makes dronabinol, is now attempting to have it transferred from Schedule II to Schedule III. That would allow physicians to write prescriptions which could be refilled up to three times, reducing the inconvenience and cost to the patient. Yet THC in the form of dronabinol is chemically the same as the THC in whole marihuana, which remains in Schedule I. It will become increasingly difficult to justify such inconsistencies, which might be regarded as hypocritical.

Ultimately, I do not believe the full potential of cannabinoids as medicines can be realized through the use of prescription analogs as long as the crushing, costly prohibition on natural marihuana is maintained. Will prescription analogs be approved for all of the present and future medical uses of whole cannabis? If not, will off-label prescriptions of the analogs be allowed? And if prescription drugs are available, will they always be sought? For example, minor stomach upset is almost always quickly relieved with a few puffs of cannabis. Will people suffering from this symptom go to the trouble and expense of seeking a prescription? When it is generally appreciated that marihuana usually relieves not only gastric distress, but many other common symptoms such as headache, insomnia, tension, pain and dysphoria, it may come to be regarded much as aspirin is today.

In fact, the range of beneficial uses of marihuana is so broad that it may ultimately be wrong to single out the strictly medical uses for approval. Many people use it not only to ease everyday discomforts, but also to heighten creativity or help them in their work. It can serve as an intellectual stimulant, promote emotional intimacy, or enhance the appreciation of food, sex, natural beauty, music, and art. Cannabis use simply cannot be made to conform to the boundaries established by present medical institutions. In this case the demand for legal enforcement of a distinction between medical and nonmedical use may be incompatible with the realities of human need. I know that to say this is to invite the charge that medical marihuana advocates are only using medicine as a stalking horse for the legalization of nonmedical use. This false accusation is actually a mirror image of the view taken by enemies of marihuana. They are unwilling to admit that it can be a safe and effective medicine largely because they are committed to exaggerating its dangers when used for other purposes. Nevertheless, it would be hypocritical to deny that there is a connection. For 28 years I have been urging the legalization of marihuana for general use. At one time I thought medical use could be treated as a distinct issue, because even people who might never see the urgency of legalizing nonmedical use would respond to medical need. Now I have changed my mind. On the contrary, I believe that making marihuana fully available as a medicine is one of the reasons for general legalization.

Ideally, cannabis should be available under more or less the same rules now applied to alcohol. At present, I fear, the political and legal system is too ossified to accommodate that change. But I believe enforcement of the laws against marihuana will be increasingly neglected because of the same kind of public pressure that has led to the enactment of the medical marihuana initiatives in five states. If I am correct, anti-marihuana statutes will come to resemble the laws against oral sex which still exist in several states but are ignored so totally that most people do not even know they exist. As the number of people arrested for possession declines, cannabis in its natural form, along with isolated cannabinoids and analogs, will be used more freely as a medicine. As a result, the public will be in a better position to learn about its virtues, and our understanding of those virtues will in turn make the laws more difficult to enforce. I hope and expect that this process will bring the era of prohibition to a de facto end. Only then will it be possible to realize the full potential of this remarkable substance, and its medical potential in particular.