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)
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.
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
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
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)
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.
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
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.
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?
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.
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.
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.
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").
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.
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.
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
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.
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.
L. Grinspoon. Marihuana Reconsidered. Cambridge, Mass.: Harvard
University Press, 1971, pp. 218-230.
L. Grinspoon and J. B. Bakalar. Cocaine: A Drug and Its Social
Evolution, Revised Edition. New York: Basic Books, 1985, p. 279.
Marihuana Problems. Editorial, Journal of the American Medical
Association, Vol. 127 (1945), p. 1129.
L. Grinspoon and J. B. Bakalar. Marihuana, the Forbidden Medicine,
Revised and Expanded Edition. New Haven: Yale University Press, 1997, pp.
R. S. Hepler and I. M. Frank. Marihuana Smoking and Intraocular Pressure. Journal
of the American Medical Association, Vol. 217 (1971), p. 1392.
L. Grinspoon and J. B. Bakalar. Marihuana, the Forbidden Medicine,
Revised and Expanded Edition. New Haven: Yale University Press, 1997.
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.
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).
Ibid, pp. 7-8.
Ibid, p. 11.
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.