Abstract
Given
the very limited toxicity of marijuana and the growing appreciation of
its therapeutic value, it will undoubtedly find 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 difficulties
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 firms 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.
Introduction
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 (O’Shaughnessy, 1840).
In the next several decades, many papers on cannabis appeared in the European
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 (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 chiefly as a
tincture (alcoholic solution, generally referred to as Cannabis indica).
Because 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 first synthetic
analgesic, aspirin, and the first synthetic hypnotic, phenobarbital, became
available. Physicians were immediately attracted to these drugs because
their potencies were fixed 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 first 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
identified for which patients have found cannabis useful (Grinspoon and
Bakalar, 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 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
cost 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. 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 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 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 1997 (Joy et al. 1999). The report
acknowledged the medical value of marijuana, but begrudgingly. One
of the report's most important shortcomings was its failure to put
into perspective the vast anecdotal evidence of marijuana's 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 find 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 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 and the treatment is
carefully monitored with "an oversight strategy comparable to an institutional
review board process." (Joy et al. 1999: 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 confirms that even government
officials 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 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);
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 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 (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.
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 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. The cost of this evaluation
exceeds 200 million dollars per drug. Case reports, expert opinion,
and clinical experience are not considered sufficient.
It is unlikely that whole
smoked marijuana should or will ever be developed as an officially
recognized medicine via this route. The extensive government-supported
effort of the last three decades to establish a sufficient level of
toxicity to support prohibition has instead provided a record of marijuana's
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-benefit 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 insufficient
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 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 seven patients under a now-discontinued
Compassionate IND (Investigational New Drug) 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? 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?
If the full potential of cannabis as a medicine were to be achieved
in the setting of the present prohibition system, all of these problems
and more would have to be addressed. A delivery system that
successfully navigated this minefield would be 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.
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 first step towards
the development of rapid-onset, non-smoked cannabinoid delivery systems”.
(Joy et al., 1999: 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 to 20 percent 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 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.
There is also the
matter of an analog's classification under the Comprehensive Drug Abuse
and Control Act. It is a rule of thumb that the more restrictive
the classification of a drug the less likely are physicians to prescribe
it. That is why Unimed successfully sought a reclassification 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 field; 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 finds 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
well-being 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 find cannabis useful medicinally choose illegal
marijuana over prescription dronabinol (Marinol) for reasons of efficacy
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.
Unimed's 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 confronts 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 classification, 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 latter's 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 difficult 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: first, the conventional model of modern allopathic medicine
through pharmacy-filled 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 a
reason.
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