International Journal of Drug Policy 12 (2001) 377 383 www.elsevier.

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Commentary

On the pharmaceuticalization of marijuana

Lester Grinspoon
Medical School, Uni6ersity of Har6ard, 74 Fenwood Road, Boston, MA 02115, USA Received 5 February 2001; accepted 31 August 2001

Abstract Given the very limited toxicity of marijuana and the growing appreciation of its therapeutic value, it will undoubtedly nd increasing application as a medicine in the coming years. But there is uncertainty about the forms in which it will be made available. Governments are hesitant to approve it because of concern about its use for nonmedical purposes and the difculties of distributing as a medicine a substance that is already easily available. An alternative is the development of commercial cannabis pharmaceuticals that can be regulated and controlled. But pharmaceutical rms will be reluctant to invest the necessary money if they believe they cannot compete successfully with marijuana. Some of these products may have advantages over whole smoked or ingested marijuana, but most will not, and they will all be quite expensive. Ultimately, we can anticipate two medical distribution networks, a legal one for cannabinoid pharmaceuticals and an illegal one for street or homegrown marijuana. 2001 Published by Elsevier Science B.V.
Keywords: Marijuana; Cannabis; Pharmaceuticals

Introduction Cannabis was rst admitted to Western pharmacopoeias one and a half centuries ago. In 1839 W.B. OShaughnessy at the Medical College of Calcutta observed its use in the indigenous treatment of various disorders and found that tincture of hemp was an effective analgesic, anticonvulsant, and muscle relaxant (OShaughnessy, 1840). In the next several decades, many papers on cannabis appeared in the European medical liter-

ature. It was widely used until the rst decades of the 20th century, especially as an analgesic and hypnotic. Symptoms and conditions for which it was found helpful included tetanus, neuralgia, labor pain, dysmenorrhea, convulsions, asthma, and rheumatism (Grinspoon, 1971). If physicians had realized that the titration of the dose was easier and relief came faster when marijuana was inhaled, they might have preferred to administer it by smoking. However, at the time it was prepared chiey as a tincture

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(alcoholic solution, generally referred to as Cannabis indica ). Since there were no reliable bioassay techniques, potency and bioavailability varied widely, yet physicians prescribed cannabis without much concern about side effects, because they knew how safe it was. But understandably, they considered it less reliable as an analgesic than opium and opium derivatives. Furthermore, it could not be injected into the blood because it was not water-soluble. Then, at the turn of the century, the rst synthetic analgesic, aspirin, and the rst synthetic hypnotic, phenobarbital, became available. Physicians were immediately attracted to these drugs because their potencies were xed and they were easily dispensed as pills. Meanwhile, interest in cannabis as a recreational drug grew from the 1920s on, and so did a disinformation campaign calculated to discourage that use. In 1937 in the USA, the rst federal legislation against marijuana, the Marijuana Tax Act, was passed. At that time the medical use of cannabis had already declined considerably, and the Act made prescription of marijuana so cumbersome that physicians abandoned it and soon became victims of the Reefer Madness madness. Beginning with an editorial published in the Journal of the American Medical Association in 1945, the medical establishment became one of the most effective agents of cannabis prohibition (Journal of the American Medical Association, 1945). The modern renaissance of medicinal cannabis began in the early 1970s, when a number of young patients who were being treated with the recently developed cancer chemotherapies discovered that marijuana was much more effective than conventional medicines for the relief of the intense and prolonged nausea and vomiting induced by some of these agents. Word spread rapidly over the cancer treatment grapevine. By mid-

decade, the capacity of marijuana to lower intraocular pressure had been observed, and patients suffering from glaucoma began to experiment with it (Hepler and Frank, 1971). As the AIDS epidemic gathered momentum, many patients who suffered HIV-associated weight loss learned that marijuana was the most effective and least toxic treatment for this life-threatening symptom. These three new medical uses of cannabis have led to wider folk experimentation, and a substantial body of anecdotal evidence has now accumulated. The usefulness of marijuana in the symptomatic treatment of convulsive disorders, migraine, insomnia, and dysmenorrhea was rediscovered. More than 30 symptoms and syndromes have now been identied for which patients have found cannabis useful (Grinspoon and Balakar, 1997). Many patients regard it as more effective than conventional medicines, with fewer or less disturbing side effects. Consider the pain of osteoarthritis, which was often treated in the 19th century with tincture of cannabis. Aspirin, the rst of the non-steroidal antiinammatory drugs (NSAIDs), rapidly displaced cannabis as the treatment of choice for this and many other kinds of mild to moderate pain. But NSAIDs now cost more than 7000 lives annually in the United States alone; cannabis, by contrast, has never killed anyone using it for the relief of pain or any other purpose. It is not surprising that many patients are now treating their osteoarthritis with cannabis (Girkipal et al. 1996). They claim that it provides a better quality of pain relief and also elevates their spirits.

The legitimacy of marijuana as medicine The number of Americans who understand the medical uses of cannabis has grown greatly in the last few years. The passage of

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initiatives allowing some restricted legal use of cannabis as a medicine in nine states is the most striking political manifestation of this growing interest. The state laws have led to a battle with federal authorities who, until recently, proclaimed medical marijuana to be a hoax. Under public pressure to acknowledge the medical potential of marijuana, the then director of the Ofce of National Drug Policy, Barry McCaffrey, authorized a review by the Institute of Medicine of the National Academy of Science which was published in March of 1997 (Joy et al., 1999). The report acknowledged the medical value of marijuana, but begrudgingly. One of the reports most important shortcomings was its failure to put into perspective the vast anecdotal evidence of marijuanas striking medicinal versatility and limited toxicity. The report states that smoking marijuana is too dangerous a form of delivery, but this conclusion is based on an exaggerated evaluation of the toxicity of the smoke. The IOM would have patients who nd cannabis helpful when taken through the respiratory system wait for years until a means of delivering smoke-free cannabinoids is developed. But there are already prototype vaporizers, which take advantage of the fact that cannabinoids vaporize at a temperature below the ignition point of dried cannabis plant material. The reports Recommendation Six would allow patients with what it calls debilitating symptoms (such as intractable pain or vomiting) to use smoked marijuana for only 6 months, and then only after all other approved medicines have failed and the treatment is carefully monitored with an oversight strategy comparable to an institutional review board process. (Joy et al., 1999 pp.7 8). This makes legal use of medicinal cannabis practically impossible. The authors of the report are treating marijuana as if it were a

drug like thalidomide, with well-established serious toxicity (phocomelia) and limited clinical usefulness (leprosy). This is inappropriate and unworkable for a drug with limited toxicity, unusual clinical versatility, and easy availability. At least the IOM Report conrms that even government ofcials no longer doubt that cannabis has medical uses. Inevitably, cannabinoids will be allowed to compete with other medicines in the treatment of a variety of symptoms and conditions; the only uncertainty involves the form in which they will be delivered. When I rst considered this issue in the early 1970s, I assumed that cannabis as medicine would be identical to the marijuana that is used for other purposes (the dried owering tops of female C. indica plants); toxicity is minimal, dosage is easily titrated and, once freed of the prohibition tariff, it will be inexpensive. I thought the main problem was its classication 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 to its legal availability as a medicine. I had already come to believe that the greatest harm in recreational use of marijuana came not from the drug itself but from the effects of prohibition (Grinspoon, 1971). But I saw that as a separate issue; I believed that, like opiates and cocaine, cannabis could be used medically while remaining outlawed for other purposes. I thought that once it was transferred to Schedule II, clinical research on marijuana would be pursued eagerly. A quarter of a century later, I have begun to doubt this. It would be highly desirable if marijuana could be approved as a legitimate medicine within the present federal regulatory system, but it now seems to me unlikely.

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Today, transferring marijuana to Schedule II (high potential for abuse, limited medical use) 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 (FDA). This system is designed to regulate the commercial distribution of drug company products and protect the public against false or misleading claims about their efcacy and safety. The drug is generally a single synthetic chemical that a pharmaceutical company has developed and patented. The company submits an application to the FDA and tests it rst for safety in animals and then for clinical safety and efcacy. 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. The cost of this evaluation exceeds 200 million dollars per drug. Case reports, expert opinion, and clinical experience are not considered sufcient. It is unlikely that whole smoked marijuana should or will ever be developed as an ofcially recognized medicine via this route. The extensive government-supported effort of the last three decades to establish a sufcient level of toxicity to support prohibition has instead provided a record of marijuanas safety that is more compelling than that of many, if not most, approved medicines, while thousands of years of medical use have demonstrated its value. The modern FDA protocol is not the only way to establish a risk-benet estimate for a drug with such a long 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.

Even if we thought that this experience was insufcient to establish its credentials by modern standards, it would not be possible to marshal it through the FDA approval process. The patent has long since expired, and with it the enormous economic incentive to underwrite the cost of this modern seal of approval. The plant cannabis too cannot be patented, so the only source of funding for a start-from-scratch approval would be the government, which is, to put it mildly, unlikely to be helpful. Other reasons for doubting that marijuana would ever be ofcially approved are todays anti-smoking climate and, most important, the widespread use of cannabis for purposes disapproved by the government. To see the importance of this obstacle, 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 proscribed? Then there is the question of who will provide the cannabis. The federal government now provides marijuana from its farm in Mississippi to seven patients under a now-discontinued Compassionate Investigational New Drug (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 elds with security fences? 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 ctitious medical conditions besiege their doctors for prescriptions. What

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about the parallel problems with potency? When urine tests are demanded for workers, how would those who use marijuana legally as a medicine be distinguished from those who use it for other 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 mineeld would be cumbersome, inefcient, and bureaucratically topheavy. 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 conict with one of two outcomes: patients would not get all the benets they should, or they would get the benets by abandoning the legal system for the black market or their own gardens and closets.

The pharmaceuticalization of cannabis A solution now being proposed, notably in the IOM Report, 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 rst step towards the development of rapid-onset, non-smoked cannabinoid delivery systems (Joy et al., 1999 pp.11). Some cannabinoids and analogs may have advantages over whole smoked or ingested marijuana in certain circumstances.

For example, cannabidiol may be more effective as an anti-anxiety drug when it is not taken along with delta-9-tetrahydrocannabinol (THC), which sometimes generates anxiety. Other cannabinoids and analogs may occasionally prove more useful than marijuana because they can be administered intravenously. For example, 15 20% of patients lose consciousness after suffering from a thrombotic or embolic stroke, and some people who suffer brain syndrome after a severe blow to the head become unconscious. The new analog dexanabinol has been shown to protect brain cells from damage by glutamate excitotoxicity in these circumstances, and it can be given intravenously to an unconscious person (Leker et al., 1999; Shohami et al., 1995). 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, and therefore will not be dened as abusable drugs subject to the constraints of the Comprehensive Drug Abuse and Control Act. Nasal sprays, nebulizers, skin patches, pills, and suppositories can be used to avoid exposure of the lungs to the particulate matter in marijuana smoke. Will these developments make marijuana itself medically obsolete? Surely many of these substances will be useful and safe enough for commercial development. The question is whether pharmaceutical companies will nd them worth the enormous cost of development. Some may; for example, an inverse cannabinoid agonist that reduces appetite might be highly lucrative, but for most specic symptoms, analogs or combinations of analogs are unlikely to be more useful than natural cannabis. Nor are they likely to have a signicantly wider spectrum of therapeutic uses, since the natural product contains the compounds (and synergistic combinations of compounds) from which

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they are derived. THC and cannabidiol, for example, provide the same protection for brain cells that dexanabinol provides after a stroke or traumatic injury. Synthetic tetrahydrocannabinol (Marinol) has been available for years, but patients generally nd whole smoked marijuana to be more effective. The cannabinoids in whole mariuana can be separated from the burnt plant products by devices already being perfected that will be inexpensive when manufactured in large numbers. 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 an unconscious patient or one with pulmonary impairment). Furthermore, any new analog will have to have an acceptable therapeutic ratio. The therapeutic ratio 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 20 000 40 000. The therapeutic ratio of a new analog is unlikely to be higher than that; in fact, it may be less safe because it will be physically possible to ingest more. There is also the matter of an analogs classication under the Comprehensive Drug Abuse and Control Act. It is a rule of thumb that the more restrictive the classication of a drug the less likely are physicians to prescribe it. That is why Unimed successfully sought a reclassication of Marinol from Schedule II to Schedule III. As with Marinol, the commercial success of new cannabinoid products will depend to a considerable extent on how vigorously the prohibition against marijuana is enforced. While the pharmaceutical companies are less likely to be interested in developing medicines which are restrictively scheduled or even scheduled at all, one wonders how motivated they would be to develop cannabinoid products if they had to compete with natural marijuana on a level playing

eld; that is, if marijuana were legally available as a medicine. I have yet to examine a patient who has used both smoked marijuana and Marinol who nds the latter more useful; the most common reason for using Marinol is the illegality of marijuana, and many patients choose to ignore the law when they believe that the difference between the two puts their health, comfort or economic wellbeing at risk. If patients were legally allowed to use marijuana, relatively few would choose Marinol. With the present prohibition in place, the economic viability of pharmaceutical-industry-generated cannabinoid products and the motivation to develop them will be directly proportional to the vigor with which the marijuana prohibition is enforced. One of the prices of the present level of enforcement is the more than 700 000 marijuana arrests annually; and the collateral costs are enormous. And still most patients who nd cannabis useful medicinally choose illegal marijuana over prescription dronabinol (Marinol) for reasons of efcacy and cost. One has to ask whether there is any level of enforcement which would compel enough compliance to embolden drug companies to commit the many millions of dollars it will take to develop new cannabinoid products. Unimeds developmental costs for dronabinol were relatively small because the United States government underwrote much of it and it involved a substance which already existed. We can safely predict that new products will be more expensive than the exorbitantly priced Marinol. It appears, then, that in the United States two powerful forces are colliding over the issue of medicinal cannabis. On the one hand, there is a growing interest in and acceptance of the medicinal importance of cannabis, and there is every reason to believe that this development will continue to gain momentum. As it does so it increasingly con-

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fronts the proscription against any use of marijuana. At the same time, there does not appear to be widespread interest in moving from an absolute prohibition against cannabis to a regulatory system which would allow for the responsible use of this drug. The federal government, until recently, has denied any medical utility to cannabis, and it appears to be vehemently opposed to any relaxation of the prohibition. There is little doubt that pharmaceutical companies will develop some cannabinoid products which will be at least as useful as marijuana, and some will be uniquely so. Also, some may be expected to be free or nearly so of psychoactivity; this will allow them to be placed outside of the constraints of the Comprehensive Drug Abuse Act classication, or at most assignment to Categories IV or V. They will require prescription and they will be expensive, but there will be a market. What is uncertain, and of course critical to a decision to develop new cannabinoid products, is the anticipated size of the market. The pharmaceuticalization of marijuana will only succeed if the pharmaceutical products displace marijuana as a medicine. This seems unlikely in view of the latters limited toxicity, easy availability, low cost relative to pharmaceuticals, ease with which it can be self-titrated, growing access to vaporization devices, and its remarkable medical versatility. And if the legal costs of using marijuana are presently not so high that most people choose marijuana over dronabinol, it is difcult to imagine a level of enforcement, which would eliminate use of the plant material. It seems inevitable that at least for some period of time there will coexist two distribution pathways for this medicine: rst, the conventional model of modern allopathic medicine through pharmacy-lled prescriptions for FDA-approved medicines; and second, a model closer to the distribution of

alternative and herbal medicines, where there is little if any quality or quantity control. Either way, growing numbers of people will become familiar with cannabis and its derivative products. They will learn that its harmfulness has been greatly exaggerated and its usefulness underestimated. We can expect that with this growing sophistication about cannabis there is likely to be growing pressure to change the way we as a society deal with people who use this drug for any reason. References
Girkipal GS, Ramey DR, Morfeld D, Singh G, Hatoum HT, Fries JF. Gastrointestinal tract complications of nonsteroidal Anti-Inammatory Drug Treatment in Rheumatoid Arthritis. Archives of Internal Medicine 1996;156:1530 6. Grinspoon L. Marijuana Reconsidered. Cambridge, MA: Harvard University Press, 1971:218 30. Grinspoon L, Bakalar JB. Marijuana, the Forbidden Medicine. New Haven: Yale University Press, 1997 Revised and expanded edition. Hepler RS, Frank IM. Marijuana smoking and intraocular pressure. Journal of the American Medical Association 1971;217:1392. Journal of the American Medical Association. Marijuana Problems. Editorial, Journal of the American Medical Association 1945;127:1129. Joy JE, Watson SJ Jr, Benson JA Jr, editors. Marijuana and Medicine: Assessing the Science Base. Institute of Medicine, Washington, DC: National Academy Press, 1999. Leker RR, Shohami E, Abramsky O, Ovadia H. Dexanabinol; a novel neuroprotective drug in Experimental Focal Cerebral Ischemia. Journal of Neurological Science 1999;162(2):114 9. OShaughnessy WB. On the preparations of the Indian Hemp, or Gunjah (Cannabis indica ): the effects on the animal system in health, and their utility in the treatment of tetanus and other convulsive diseases, Transactions of the Medical and Physical Society of Bengal, 1838 1840:460. Shohami E, Novikov M, Bass R. Long-term effect of HU-211, a novel non-competitive NMDA antagonist, on motor and memory functions after closed head injury in the rat. Brain Research 1995;674(1):55 62.