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The medical marijuana problem is a Janus-like conundrum; one view of the problem is seen through the eyes of patients and another through those of their government. One face regards with dismay the problem of denying marijuana to the growing number of pained, impatient patients who find it useful, often more useful, less toxic and cheaper than the legally available medications. Through the patients’ eyes the problem is, of course, how to acquire and use this medicine without swelling the ranks of those who are arrested for using this illegal substance and how to avoid jeopardizing job security through random urine testing. The other face, the backward looking one, is that of an obdurate government as it defensively and inconsistently insists that “marijuana is not a medicine”, and backs up this ill-informed, arrogant position with the full force of its vast legal power as it is presently doing in the state of California.
In 1985 the Food and Drug Administration (FDA) approved dronabinol (Marinol) for the treatment of the nausea and vomiting of cancer chemotherapy. Marinol is a solution of synthetic tetrahydrocannabinol in sesame oil (the sesame oil is meant to protect against the possibility that the contents of the capsule could be smoked). Marinol was developed by Unimed Pharmaceuticals Inc. with the approval of and a great deal of financial support from the United States government. This was the first hint that the “pharmaceuticalization” of cannabis might be what the government hoped would solve its problem with marijuana as medicine, the problem of how to make the medicinal properties of cannabis widely available while at the same time prohibiting its use for any other purpose. But Marinol did not displace marijuana as “the treatment of choice”; most patients found the herb itself much more useful than Marinol in the treatment of the nausea and vomiting of cancer chemotherapy. In 1992, the treatment of the AIDS wasting syndrome was added to Marinol’s labeled uses; again, patients reported that it was inferior to smoked marijuana. Because it was thought that it would sell better if it were placed in a less restrictive Drug Control Schedule, it was moved from Schedule 2 to Schedule 3 in the year 2000. But Marinol has not solved the marijuana-as-a-medicine problem because so few of the patients who have discovered the therapeutic usefulness of marijuana use Marinol. In general, they find it less effective than smoked marijuana, it cannot be titrated because it has to be taken orally, it takes at least an hour for the therapeutic effect to manifest itself and even with the prohibition tariff on street marijuana, Marinol is more expensive. Thus, the first attempt at the pharmaceuticalization of marijuana proved not to be the answer. In practice, for many patients who use marijuana as a medicine the doctor-prescribed Marinol serves primarily as a cover from the threat of the growing ubiquity of urine tests.
Most of the patients who use cannabis as a medicine smoke or ingest it in some form. In so doing they are in violation of federal law throughout the USA and of state laws in all but eleven states. In those states, notably California, which allow for doctor-recommended use of cannabis, buyers’ clubs or compassion clubs have evolved as cannabis pharmacies for patients with appropriate physician documentation. Two distribution models have evolved. One is based on the conventional delivery system for medicine: a patient visits a buyers’ club (read: pharmacy), where he or she presents a note from a physician
certifying that the patient has a condition for which the physician recommends cannabis (read: prescription). The proprietor of the club (read: pharmacist) fills the prescription and the patient leaves to use the medicine, presumably at home. This model preserves the medical profession’s authority to decide who shall use a medicine and for how long. The “pharmacy” provides a source — — in this case a nonprofit one — — for the medicine. If the doctor and the “pharmacist” behave ethically, only those who have a medical need for marijuana can receive it. In turn, patients have a reliable source for the drug, relieving them of the stress of buying it on the street or secretly growing their own. The staid set-up of the club and the attitudes of the proprietors make it clear that the patient is no more expected to use his medicine on the premises than he would be in a conventional pharmacy.
The second buyer’s club distribution model resembles a social club more than it does a pharmacy. The dispensing area is plastered with marijuana menus offering types, grades and prices. Large rooms are filled with brightly colored posters, lounge chairs and sofas, tables, magazines and newspapers. While some patients 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, often much needed, for many of these 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.
Until some kind of legal accommodation makes it possible for patients to obtain marijuana without violating the law, buyers’ clubs are the best approach to the problem. Yet the federal government, including the White House, the Drug Enforcement Administration and federal law enforcement at all levels, remains opposed to the idea and they are now working diligently to close these compassion clubs.
Now that the federal government has embarked on a cruel and so far successful campaign to close down buyers’ clubs, what options are available to the many thousands of patients who find cannabis of great importance, even essential, to the maintenance of their health? They can either use Marinol, which most find unsatisfactory, or they can break the law and use marijuana. Why is a government which considers itself compassionate criminalizing these patients? What is the government’s problem with medical marijuana? The problem as seen through the eyes of the government is the belief that as growing numbers of people observe relatives and friends using marijuana as a medicine, they will come to understand that this is a drug which does not conform to the description the government has been pushing for years. They will first come to appreciate what a remarkable medicine it really is; it is less toxic than almost any other medicine in the pharmacopoeia; it is, like aspirin, remarkably versatile; and it is less expensive than the conventional medicines it displaces. They will then begin to wonder if there are any properties of this drug which justify denying it to people who wish to use it for any reason, let alone arresting almost 800,000 citizens annually. The federal government sees the acceptance of marijuana as a medicine as the gateway to catastrophe, the repeal of its prohibition. In so far as the government views as anathema any use of plant marijuana, it is difficult to imagine it accepting a legal arrangement that would allow for its use as a medicine, while at the same time vigorously pursuing a policy of prohibition of any other use. Yet, there are many who believe this type of arrangement is possible and workable. In fact, this is the option the Canadian and Dutch governments are presently pursuing as are eleven states in the United States. Let us consider what might be involved in establishing and maintaining such a legal arrangement in the USA.
The first requirement at this time is that the Food and Drug Administration (FDA) approve marijuana as a medicine. One can argue, however, that FDA approval is superfluous where cannabis is concerned. Drugs must undergo rigorous, expensive, and time-consuming tests before they are approved by the FDA 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. This system is designed to regulate the commercial distribution of drug company products and protect the public against false or misleading claims about the efficacy and safety. The drug is generally a single synthetic chemical that a pharmaceutical company has acquired or developed and patented. It submits an application to the FDA and tests it first for safety in animals and then for clinical efficacy. The company must present evidence from double-blind controlled studies showing that the drug is more effective than a placebo. Case reports, expert opinion, and clinical experience ( anecdotal data ) 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 ’60s 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 government of the United States has conducted through its National Institute of Drug Abuse (NIDA) a decades-long multimillion-dollar research program in a futile attempt to demonstrate significant toxic effects that would justify the prohibition of cannabis as a non-medical drug. Should time and resources be wasted to demonstrate for the FDA what is already so obvious?
But even if it were legally and practically possible to do the various phased studies to win FDA approval, where would the money to finance these studies come from? New medicines are almost invariably introduced by drug companies that spend many millions of dollars on the development of each product. They are willing to undertake these costs only because of the anticipated large profits during the 20 years they own the patent. Obviously pharmaceutical companies cannot patent marijuana. In fact they are very much opposed to its acceptance as a medicine because it will compete with their own products.
It is unlikely that whole smoked marijuana should or will ever be developed as an officially recognized medicine via this route. Thousands of years of use have demonstrated its medical value; the extensive government-supported effort of the last three decades to establish a sufficient level of toxicity to support the harsh prohibition has instead provided a record of safety that is more compelling than that of most approved medicines. The modern FDA protocol is not necessary to establish a risk-benefit estimate for a drug with such a history. To impose this protocol on cannabis would be like making the same demand of aspirin, which was accepted as a medicine more than 60 years before the advent of the double-blind controlled study. Many years of experience have shown us that aspirin has many uses and limited toxicity, yet today it could not be marshaled through the FDA approval process. The patent has long since expired, and with it the incentive to underwrite the substantial cost of this modern seal of approval. Cannabis, too, is unpatentable, so the only sources of funding for a “start-from-scratch” approval would be non-profit organizations or the government, which is, to put it mildly, unlikely to be helpful. Other reasons for doubting that marijuana would ever be officially approved are today’s anti-smoking climate and, most important, the widespread use of cannabis for purposes disapproved by the government.
To see some of the obstacles to this approach to the problem, consider the effects of granting marijuana legitimacy as a medicine while prohibiting it for any other use. How would the appropriate “labeled” uses be determined and how would “off-label” uses be monitored? Let us suppose that studies satisfactory to the FDA are somehow completed affirming that marijuana is safe and effective as a treatment for the AIDS wasting syndrome and/or AIDS-related neuropathy, and physicians are able to prescribe it for those conditions. 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. If marijuana is approved as a medicine, how will off-label prescribing play out? Surely, knowledgeable physicians will want to prescribe it for some patients with multiple sclerosis, Crohn’s disease, migraine, convulsive disorders, spastic symptoms, and other conditions for which the use of cannabis is well established by a mountain of anecdotal evidence. But what about premenstrual syndrome? Surely women who suffer from this disorder consider it a serious problem, and many of them find cannabis the most useful and least toxic treatment. What about the loss of erectile capacity in paraplegics? What about intractable hiccups? And then there is depression, not the DSM-IV defined major affective disorder, but the common low-level dysphoric condition for which general practitioners frequently prescribe SSRI’s such as Prozac? What about bipolar disorder?
Generally speaking, the more dangerous a drug is, the more serious or debilitating must be a 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 to be so safe; it takes “only” one to two thousand lives a year in the United States. The remarkably versatile ibuprofen (Advil) and other non-steroidal anti-inflammatory drugs (NSAIDs) can also be purchased OTC because they, too, are considered very safe; “only” 10,000 Americans lose their lives to these drugs annually. Acetaminophen (Tylenol), another useful OTC drug, is responsible for about 10 percent of cases of end-stage renal disease. The public is also allowed to purchase many herbal remedies whose dangers and efficacies have not been well determined. Compare these drugs with marijuana. 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 pharmacopoeia, it would be a serious contender for the title of least toxic substance in that compendium. In its long history, cannabis has never caused a single overdose death.
Then there is the question of who will provide the cannabis. The federal government now provides marijuana from its farm in Mississippi to the five surviving patients covered by the now-discontinued Compassionate IND program. But surely the government could not or would not produce marijuana for many thousands of patients receiving prescriptions, any more than it does for other prescription drugs. If production is contracted out, will the farmers have to enclose their fields with electrified security fences and protect them with security guards? How would the marijuana be distributed? If through pharmacies, how would they provide secure facilities capable of keeping fresh supplies? Would the price of pharmaceutical marijuana have to be controlled: not too high, lest patients be tempted to buy it on the street or grow their own; not too low, lest people with marginal or fictitious “medical” conditions besiege their doctors for prescriptions? What about the parallel problems with potency? When urine tests are demanded of workers, what would be the bureaucratic and other costs of identifying those who use marijuana legally as a medicine as distinguished from those who use it for other purposes?
To realize the full potential of cannabis as a medicine in the setting of the present prohibition system, we would have to address all these problems and more. A delivery system that successfully navigated this minefield would be cumbersome, inefficient, and bureaucratically top-heavy. Government and medical licensing boards would insist on tight restrictions, challenging physicians as though cannabis were a dangerous drug every time it was used for any new patient or purpose. There would be constant conflict with one of two outcomes: patients would not get all the benefits they should, or they would get the benefits by abandoning the legal system for the black market or their own gardens and closets.
A solution now being proposed, notably in the Institute of Medicine (IOM) Report(1999), is what might be called the “pharmaceuticalization” of cannabis: prescription of isolated individual cannabinoids, synthetic cannabinoids, and cannabinoid analogs. The IOM Report states that “…if there is any future for marijuana as a medicine, it lies in its isolated components, the cannabinoids, and their synthetic derivatives.” It goes on: “Therefore, the purpose of clinical trials of smoked marijuana would not be to develop marijuana as a licensed drug, but such trials could be a first step towards the development of rapid-onset, non-smoked cannabinoid delivery systems.” This position was echoed by Antonio Maria Costa, Executive Director, Office on Drugs and Crime, the United Nations at the International Symposium on Cannabis in Stockholm in 2003.
Some cannabinoid analogs may indeed have advantages over whole smoked or ingested marijuana in limited circumstances. For example, cannabidiol may be more effective as an anti-anxiety medicine and an anticonvulsant when it is not taken along with THC, which sometimes generates anxiety. Other cannabinoids and analogs may prove more useful than marijuana in some circumstances because they can be administered intravenously. Presumably other analogs may offer related advantages. Some of these commercial products may also lack the psychoactive effects which make marijuana useful to some for non-medical purposes. Therefore, they will not be defined as “abusable” drugs subject to the constraints of the Comprehensive Drug Abuse and Control Act. Nasal sprays, vaporizers, nebulizers, skin patches, pills, and suppositories can be used to avoid exposure of the lungs to the particulate matter in marijuana smoke.
The question is whether these developments will make marijuana itself medically obsolete. Surely many of these new products would be useful and safe enough for commercial development. It is uncertain, however, whether pharmaceutical companies will find them worth the enormous development costs. Some may be (for example, a specific cannabinoid inverse agonist that reduces appetite might be highly lucrative), but for most specific symptoms, analogs or combinations of analogs are unlikely to be more useful than natural cannabis. Nor are they likely to have a significantly wider spectrum of therapeutic uses, since the natural product contains the compounds (and synergistic combinations of compounds) from which they are derived.
The cannabinoids in whole marijuana can be separated from the burnt plant products (which comprise the smoke) by vaporization devices that will be inexpensive when manufactured in large numbers. These devices take advantage of the fact that finely chopped marijuana releases the cannabinoids by vaporization when air flowing through the marijuana is held within a fairly large temperature window below the ignition temperature of the plant material. Inhalation is a highly effective means of delivery, and faster means will not be available for analogs (except in a few situations such as parenteral injection in a patient who is unconscious or suffering from pulmonary impairment). It is the rapidity of the response to inhaled marijuana from a joint, a pipe or a vaporizer which makes it possible for patients to titrate the dose so precisely. Furthermore, any new analog will have to have an acceptable therapeutic ratio. The therapeutic ratio (an index of the drug’s safety) of marijuana is not known because it has never caused an overdose death, but it is estimated, on the basis of extrapolation from animal data, to be an almost unheard of 20,000 to 40,000. The therapeutic ratio of a new analog is unlikely to be higher than that; in fact, new analogs may be much less safe than smoked marijuana because it will be physically possible to ingest more of them. And there is the problem of classification under the Comprehensive Drug Abuse and Control Act for analogs with psychoactive effects. The more restrictive the classification of a drug, the less likely drug companies are to develop it and physicians to prescribe it. Recognizing this economic fact of life, Unimed Pharmaceuticals Inc. has fairly recently succeeding in getting Marinol (dronabinol) reclassified from Schedule 2 to Schedule 3. Nevertheless, many physicians will continue to avoid prescribing it for fear of the drug enforcement authorities.
A somewhat different approach to the pharmaceuticalization of cannabis is being taken by a British company, G. W. Pharmaceuticals. It is attempting to develop products and delivery systems which will skirt the two primary popular concerns about the use of marijuana as a medicine: the smoke and the psychoactive effects (the “high”). To avoid the need for smoking, G. W. Pharmaceuticals has developed a cannabis extract to be taken sublingually in carefully controlled doses. The company expects its extract of marijuana (Sativex) to be effective therapeutically at doses too low to produce the psychoactive effects sought by recreational and other users. My clinical experience leads me to question whether this is possible in many or even most cases. The issue is complicated by tolerance to the psychoactive effects. Recreational users soon discover that the more often they use marijuana, the less “high” they experience. A patient who smokes cannabis frequently for the relief of, say, chronic pain or elevated intraocular pressure will experience little or no “high”. Furthermore, as a clinician who has considerable experience with medical cannabis use, I have to question whether the psychoactive effect is always separable from the therapeutic. And I strongly question whether the psychoactive effects are necessarily undesirable. Many patients suffering from serious chronic illnesses report that cannabis generally improves their spirits. If they note psychoactive effects at all, they speak of a slight mood elevation — certainly nothing unwanted or incapacitating.
The great advantage of the administration of cannabis through the pulmonary system is the rapidity (a few minutes) with which its effects are experienced. This in turn allows for the self-titration of dosage, the best way of adjusting individual dosage. With other routes of delivery the response time is longer and self-titration becomes more difficult. Thus, because the response time is about an hour and a half, self-titration is not possible with oral ingestion of cannabis. While the response time for sublingual or oral mucosal administration of cannabis (such as with Sativex) is shorter than it is with oral ingestion, it is significantly longer than that from absorption through the lungs and therefore a considerably less useful route of administration for self-titration. (And, because Sativex tastes so bad and cannot be held under the tongue for long, much of it goes down the esophagus and to that extent it can be titrated no more accurately than any other oral form of cannabis). Because these pharmaceutical industry products will be considerably more expensive than natural marijuana, they will succeed only if patients are intimidated by the legal risks, and if patients and physicians consider the health risks of smoking marijuana (with and without a vaporizer) much more compelling than is justified by either the medical or epidemiological literature, and they believe that it is essential to avoid any hint of a psychoactive effect.
In the end, the commercial success of any psychoactive cannabinoid product will depend on how vigorously the prohibition against marijuana is enforced. It is safe to predict that new analogs and extracts will cost much more than whole smoked or ingested marijuana even at the inflated prices imposed by the prohibition tariff. I doubt that pharmaceutical companies would be interested in developing cannabinoid products if they had to compete with natural marijuana on a level playing field. The most common reason for using Marinol is the illegality of marijuana, and many patients choose to ignore the law for reasons of efficacy and cost. The number of arrests on marijuana charges has been steadily increasing and has now reached almost 800,000 annually, yet patients continue to use smoked cannabis as a medicine. I wonder whether any level of enforcement would compel enough compliance with the law to embolden drug companies to commit the many millions of dollars it would take to develop new cannabinoid products. Unimed is able to profit from the exorbitantly priced Marinol only because the United States government underwrote much of the cost of development. Pharmaceutical companies will undoubtedly develop useful cannabinoid products, some of which may not be subject to the constraints of the Comprehensive Drug Abuse and Control Act. But, it is unlikely that this pharmaceuticalization will displace natural marijuana for most medical purposes.
It is also clear that the realities of human need are incompatible with the demand for a legally enforceable distinction between medicine and all other uses of cannabis. Marijuana use simply does not conform to the conceptual boundaries established by twentieth century institutions. It enhances many pleasures and it has many potential medical uses, but even these two categories are not the only relevant ones. The kind of therapy often used to ease everyday discomforts does not fit any such scheme. In many cases what lay people do in prescribing marijuana for themselves is not very different from what physicians do when they provide prescriptions for psychoactive or other drugs. The only workable way of realizing the full potential of this remarkable substance, including its full medical potential, is to free it from the present dual set of regulations — those that control prescription drugs in general and the special criminal laws that control psychoactive substances. These mutually reinforcing laws established a set of social categories that strangle its uniquely multifaceted potential. The only way out is to cut the knot by giving marijuana the same status as alcohol — legalizing it for adults for all uses and removing it entirely from the medical and criminal control systems.
Two powerful forces are now colliding: the growing acceptance of medical cannabis and the proscription against any use of the plant marijuana, medical or non-medical. There are no signs that we are moving away from absolute prohibition to a regulatory system that would allow responsible use of marijuana. As a result, we are going to have two distribution systems for medical cannabis: the conventional model of pharmacy-filled prescriptions for FDA-approved cannabinoid medicines, and a model closer to the distribution of alternative and herbal medicines. The only difference, an enormous one, will be the continued illegality of whole smoked or ingested cannabis. In any case, increasing medical use by either distribution pathway will inevitably make growing numbers of people familiar with marijuana and its derivatives. As they learn that its harmfulness has been greatly exaggerated and its usefulness underestimated, the pressure will increase for drastic change in the way we as a society deal with this drug.
