Whither Medical Marijuana?
Lester Grinspoon, MD

From Contemporary Drug Problems,
Volume 27, Spring, 2000

Cannabis was first admitted to Western pharmacopoeias one and a half centuries ago. In 1839 W. B. O'Shaughnessy 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.(1) Publication of O'Shaughnessy's paper created a stir within a medical establishment which at that time had access to only a few effective medicines. In the next several decades, many papers on cannabis appeared in the Western medical literature. It was widely used until the first 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.(2)

  Administering a medicine through smoking was unheard of until the late 19th century, when pharmaceutical house prepared coca leaf cigars and cheroots were occasionally used in lieu of cocaine.(3) If physicians had realized that titration of the dose was easier and relief came faster when marijuana was inhaled, they might have preferred to administer it by smoking. However, in the 19th century it was prepared chiefly as a tincture (alcoholic solution), generally referred to as tincture of hemp, tincture of cannabis, or Cannabis indica. The potency and bioavailability of oral cannabis varied widely, and there were no reliable bioassay techniques. Nevertheless, physicians prescribed cannabis without much concern about overdoses or 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, unlike opiates, it could not be used parenterally because it was not water-soluble. Then, at the turn of the century, the first synthetic analgesics and hypnotics (aspirin and barbiturates) became available. Physicians were immediately attracted to these drugs because their potencies were fixed and they were easily dispensed as pills.

  Beginning in the 1920s, interest in cannabis as a recreational drug grew, along with a disinformation campaign calculated to discourage that use. In 1937 the first draconian federal legislation against marijuana, the Marijuana Tax Act, was passed. At that time the medical use of cannabis had already declined considerably; the Act made prescription of marijuana so cumbersome that physicians abandoned it. Now physicians themselves 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.(4)

  The modern renaissance of medicinal cannabis began in the early 1970s, when several 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.(5) 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.(6) 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. The use of marijuana in the symptomatic treatment of convulsive disorders, migraine, insomnia, and dysmenorrhea has been rediscovered.

  We have now identified more than 30 symptoms and syndromes for which patients have found cannabis useful,(7) and others will undoubtedly be discovered. 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 first of the non-steroidal antiinflammatory drugs (NSAIDs), rapidly displaced cannabis as the treatment of choice for this and many other kinds of mild to moderate pain. But NSAIDs now take more than 7,000 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.(8) It is not surprising that many patients now treat their osteoarthritis with cannabis, asserting that it provides a better quality of pain relief than NSAIDs and also elevates their spirits.

  The number of Americans who understand the medical uses of cannabis has grown greatly in the last few years. The passage of initiatives or legislation allowing some restricted legal use of cannabis as a medicine in  eight 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 director of the Office 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 1999.(9)  

The report acknowledged the medical value of marijuana, but grudgingly. One of its most important shortcomings was a failure to put into perspective the vast anecdotal evidence of marijuana's striking medicinal versatility and limited toxicity. The report states that smoking is too dangerous a form of delivery, but this conclusion is based on an exaggerated evaluation of the toxicity of the smoke. The report's Recommendation Six would allow patients with what it calls "debilitating symptoms (such as intractable pain or vomiting)" to use smoked marijuana for only six months, and then only after all other approved medicines have failed. The treatment would have to be monitored with "an oversight strategy comparable to an institutional review board process."(10) This would make legal use of medical cannabis impossible in practice. The IOM would have patients who find cannabis helpful when taken by inhalation wait for years until a means of delivering smoke-free cannabinoids is developed. But there are already prototype devices which take advantage of the fact that cannabinoids vaporize at temperatures below the ignition point of dried cannabis plant material.

  The authors of the IOM report discuss marijuana as if it were a drug like thalidomide, with well-established serious toxicity (phocomelia) and limited clinical usefulness (leprosy). This is inappropriate for a drug with a long history, limited toxicity, unusual versatility, and easy availability. But at least the report confirms that even government officials no longer doubt that cannabis has medical uses. Inevitably, cannabinoids will eventually 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 first 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 flowering tops of female Cannabis indica plants); its toxicity is minimal, its dosage is easily titrated and, once freed of the prohibition tariff, it will be inexpensive. 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 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. 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.

  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 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 efficacy 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 first for safety in animals and then for clinical safety and efficacy. 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 cost of this evaluation exceeds 200 million dollars per drug.

  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 marshalled through the FDA approval process. The patent has long since expired, and with it the incentive to underwrite the enormous cost of this modern seal of approval. Cannabis too is unpatentable, 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 officially approved are today's 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 eight patients under a 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 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 for workers, how would those who use marijuana legally as a medicine be 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 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 first step towards the development of rapid-onset, non-smoked cannabinoid delivery systems."(11) Some cannabinoids and analogs may 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 occasionally prove more useful than marijuana because they can be administered intravenously. For example, 15 to 20 percent of patients lose consciousness after suffering 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 (HU-211) has been shown to protect brain cells from damage by glutamate excitotoxicity in these circumstances, and it will be possible to give it intravenously to an unconscious person.(12) 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, 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 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. THC and cannabidiol, as well as dexanabinol, protect brain cells after a stroke or traumatic injury. Synthetic tetrahydrocannabinol (dronabinol or Marinol) has been available for years, but patients generally find whole smoked marijuana to be more effective.

  The cannabinoids in whole marijuana can be separated from the burnt plant products by vaporization devices 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 a patient who is unconscious or suffering from 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 to 40,000. The therapeutic ratio of a new analog is unlikely to be higher than that; in fact, new analogs may be 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, the manufacturer of Marinol, has recently succeeding in getting it reclassified from Schedule II to Schedule III. 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. Recognizing the great usefulness of naturally occurring cannabinoids, this firm is developing a seed bank of cannabis strains with particular value in the treatment of various symptoms and disorders. They are also attempting to develop products and delivery systems which will skirt the two primary 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 is exploring the possibility of delivering cannabis extracts sublingually or via nebulizers. The company expects its products 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 most or even many cases. Furthermore, the issue is complicated by tolerance. Recreational users soon discover that the more often they use marijuana, the less "high" they feel. A patient who smokes cannabis frequently for the relief of, say, chronic pain or elevated intraocular pressure will not experience a "high" at all. Furthermore, as a clinician who has considerable experience with medical cannabis use, I have to question whether the psychoactive effect is necessarily undesirable. Many patients suffering from serious chronic illnesses say 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.

  In principle, administration of cannabis extracts via a nebulizer has the same advantages as smoked marijuana -- rapid onset and easy titratability of the effect. But the design of the G. W. Pharmaceutical nebulizer negates this advantage. The device has electronic controls that monitor the dose and halt delivery if the patient tries to take more than the physician or pharmacist has set it to deliver. The proposal to use this cumbersome and expensive device apparently reflects a fear that patients cannot accurately titrate the amount or a concern that they might take more than they need and experience some degree of "high" (always assuming, doubtfully, that the two can easily be separated, especially when cannabis is used infrequently). Because these products will be considerably more expensive than natural marijuana, they will succeed only if patients and physicians take the health risks of smoking very seriously and feel that it is necessary to avoid any hint of a psychoactive effect.

  In the end, the commercial success of any 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 price. The number of arrests on marijuana charges has been steadily increasing and has now reached nearly 700,000 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 dronabinol 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 this pharmaceuticalization will never displace natural marijuana for most medical purposes.


Thus two powerful forces are now colliding: the growing acceptance of medical cannabis and the proscription against any use of 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 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 cannabis 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.


    1. W. B. O'Shaughnessy. 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), p. 460.

2. L. Grinspoon. Marihuana Reconsidered. Cambridge, Mass.: Harvard University Press, 1971, pp. 218-230.

3. L. Grinspoon and J. B. Bakalar. Cocaine: A Drug and Its Social Evolution, Revised Edition. New York: Basic Books, 1985, p. 279.

4. Marihuana Problems. Editorial, Journal of the American Medical Association, Vol. 127 (1945), p. 1129.

5. L. Grinspoon and J. B. Bakalar. Marihuana, the Forbidden Medicine, Revised and Expanded Edition. New Haven: Yale University Press, 1997, pp. 25-27.

6. R. S. Hepler and I. M. Frank. Marihuana Smoking and Intraocular Pressure. Journal of the American Medical Association, Vol. 217 (1971), p. 1392.

7. L. Grinspoon and J. B. Bakalar. Marihuana, the Forbidden Medicine, Revised and Expanded Edition. New Haven: Yale University Press, 1997.

8. S. Girkipal, D. R. Ramey, D. Morfeld, G. Singh, H. T. Hatoum, and J. F. Fries. Gastrointestinal Tract Complications of Nonsteroidal Anti-inflammatory Drug Treatment in Rheumatoid Arthritis. Archives of Internal Medicine, Vol. 156 (July 22, 1996), pp. 1530-1536.

9. Marijuana and Medicine: Assessing the Science Base. J. E. Joy, S. J. Watson, Jr., and J. A. Benson, Jr., Editors. Institute of Medicine, Washington, D.C.: National Academy Press (1999).

10. Ibid, pp. 7-8.

11. Ibid, p. 11.

12. R. R. Leker, E. Shohami, O. Abramsky, and H. Ovadia. Dexanabinol; A Novel Neuroprotective Drug in Experimental Focal Cerebral Ischemia. Journal of Neurological Science, Vol. 162, No. 2 (January 15, 1999), pp. 114-119; E. Shohami, M. Novikov, and R. Bass. 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, Vol. 674, No. 1 (March 13, 1995), pp. 55-62.