"MEDICAL MARIHUANA RECONSIDERED"

The medical value of marihuana has become increasingly clear to many
physicians and patients. There are three reasons for this. First, it is
remarkably non-toxic. Unlike most of the medicines in the present
pharmacopeia, it has never caused an overdose death. Its short-term and
long-term side effects are minimal compared to medicines for which it will
be substituted. Second, once patients no longer have to pay the prohibition
tariff, it will be much less expensive than the medicines it replaces.
Third, it is remarkably versatile, useful in treating a diverse array of
symptoms and syndromes.[1]

As the number of people who have experience with medical marihuana grows,
the discussion is turning away from whether it is effective to how it
should be made available. When I first considered this issue in the early
1970s, 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, because clinical research would be possible and
prescriptions would eventually be allowed.

I was the first witness at a joint meeting of the Drug Enforcement
Administration and the Food and Drug Administration that was convened to
consider a petition for rescheduling introduced by the National
Organization for the Reform of Marijuana Laws in 1972. At that time I had
already come to believe that the greatest harm in recreational use of
marihuana came not from the drug itself but from the effects of
prohibition. But I saw that as a separate issue; I thought that, like
opiates and cocaine, cannabis could be used medically while remaining
outlawed for other purposes. I also thought that once it was transferred to
Schedule II, research on marihuana would be pursued eagerly, since it had
shown such interesting therapeutic properties. From this research we would
eventually be able to determine how prescriptions could be provided and who
would be responsible for quality control.

Now, 25 years later, I have begun to doubt this. Reclassification may turn
out to have more symbolic than practical value. It may be only a
transitional phase in the process that leads to a workable accommodation
for the medical marihuana. It would be highly desirable if marihuana could
be approved as a legitimate medicine within the present federal regulatory
system, but it now seems to me unlikely.

First, I should note that cannabis has already been a legally accepted
medicine in the United States several times. Until 1941, when it was
dropped after the passage of the Marihuana Tax Act, it was one of the drugs
listed in the U.S. Pharmacopeia. If it had not been removed at that time,
it would have been grandfathered into the Comprehensive Drug Abuse and
Control Act as a prescription drug, just a cocaine and morphine were.
Again, in the late 1970s and early 1980s, cannabis was used medically by
hundreds of patients (mainly in the form of synthetic tetrahydrocannabinol)
in projects conducted by several of the states for the treatment of nausea
and vomiting in cancer chemotherapy. This episode ended because each state
program had to comply with an enormous federal paperwork burden that was
more than the physicians and administrators involved could bear. The
federal government itself approved the use of cannabis as a medicine in
1976 by instituting the Compassionate IND program, under which physicians
could obtain an individual Investigational New Drug application (IND) for a
patient to receive cannabis. This program too was so bureaucratically
burdened that in the course of its history only about three dozen patients
ever received marihuana, and only eight are still receiving it. When the
program was discontinued permanently in 1992, the Chief of the Public
Health Service gave the following reason: "If it is perceived that the
Public Health Service is going around giving marihuana to folks, there
would be a perception that this stuff can't be so bad. It gives a bad
signal. I don't mind doing that if there is no other way of helping these
people...But there is not a shred of evidence that smoking marihuana
assists a person with AIDS." In effect, this action was analogous to the
recall of a prescription drug, but without any evidence of toxic effects to
support it.

Today, even transferring marihuana to Schedule II 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 for marketing as medicines. The purpose is to
protect the consumer by establishing safety and efficacy. Because no drug
is completely safe or always efficacious, an approved drug has presumably
satisfied a risk-benefit analysis. When physicians prescribe for individual
patients they conduct an informal analysis of a similar kind, taking into
account not just the drug's overall safety and efficacy, but its risk and
benefits for a given patient with a given condition. The formal drug
approval procedures help to provide physicians with the information they
need to make this analysis.

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 the company has developed and patented. It submits an application
to the Food and Drug Administration and tests it first for safety in
animals and then for clinical efficacy and safety. 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
standards have been tightened since the present system was established in
1962, and few applications that were approved in the early 1960s would be
approved today on the basis of the same evidence.

Certainly we need more laboratory and clinical research to improve our
understanding of medicinal cannabis. We need to know how many patients and
which patients with each symptom or syndrome are likely to find cannabis
more effective than existing drugs. We also need to know more about its
effects on the immune system in immunologically impaired patients, its
interactions with other medicines, and its possible uses for children. But
I have come to doubt whether the FDA rules should apply to cannabis. There
is no question about its safety. It is one of humanity's oldest medicines,
used for thousands of years by millions of people with very little evidence
of significant toxic effects. More is known about its adverse effects than
about those of most prescription drugs. The American government has
conducted a decades-long multimillion dollar research program in a futile
attempt to demonstrate toxic effects that would justify the prohibition of
cannabis as a nonmedical drug.

This is an enormously important consideration in thinking of cannabis as a
medicine. One of its uses, for example, is the treatment of chronic pain.
This symptom is usually treated with opioid narcotics or synthetic
analgesics that are far riskier. Opioids are addictive and tolerance
develops; an overdose can be lethal. The most commonly used synthetic
analgesics -- aspirin, acetaminophen (Tylenol), and nonsteroidal
antiinflammatory drugs (NSAIDs) like ibuprofen and naproxen -- are not
addictive, but they are often insufficiently powerful. Furthermore, they
have serious side effects. Stomach bleeding and ulcer induced by aspirin
and NSAIDs are the most common serious adverse drug reactions reported in
the United States, causing an estimated 7,000 deaths each year.[2]
Acetaminophen can cause liver damage or kidney failure when used regularly
for long periods of time; a recent study suggests it may account for 10% of
all cases of end-stage renal disease, a condition that requires dialysis or
a kidney transplant.[3] Results of comparisons between cannabis and other
drugs are similar, whatever medical use we consider -- anticonvulsant,
antispasmodic, antidepressant, antinauseant. Should time and resources be
wasted to demonstrate for the FDA what is already so obvious?

As for efficacy, some believe that has been proven too, although others
disagree. During the 1970s and '80s several of the state-sponsored research
projects I mentioned suggested that marihuana had advantages over both oral
tetrahydrocannabinol and other medicines in the treatment of nausea and
vomiting from cancer chemotherapy. But as long as the imprimatur of science
can be given only to rigorous double-blind controlled studies, the case for
marihuana has not been made. The assertion that it is a useful medicine
rests almost entirely on case reports and clinical experience, just as it
did in the late 19th and early 20th centuries. A double-blind controlled
study may be the best way to prove the relative value of a new medicine
whose advantages over established drugs are not obvious. But it is not the
only way to demonstrate efficacy. The focus of controlled trials is usually
statistical differences in effects in groups of patients, but medicine has
always been concerned mainly with individuals,whose needs can be obscured
in such experiments, especially when little effort is made to identify
distinctive characteristics that affect their responses.

The value of case reports and clinical experience is often underestimated.
They are the source of much of our knowledge of synthetic medicines as well
as plant derivatives. As Dr. Louis Lasagna has pointed out, controlled
experiments were not needed to recognize the therapeutic potential of
chloral hydrate, barbiturates, aspirin, curare, or insulin.[4] The
therapeutic value of penicillin was widely recognized after it had been
given to only six patients. Similar evidence revealed the use of
propranolol for hypertension, diazepam for status epilepticus (a state of
continuous seizure activity), and imipramine for childhood enuresis
(bedwetting). These drugs had originally been approved by regulators for
other purposes.

As early as 1976 several small and imperfect studies, not widely known in
the medical community, had shown that an aspirin a day could prevent a
second heart attack. In 1988 a large-scale experiment demonstrated effects
so dramatic that the researchers decided to stop the experiment to publish
the life-saving results. On one estimate, as many as twenty thousand deaths
a year might have been prevented from the mid-1970s to the late-1980s if
the medical establishment had been quicker to recognize the value of
aspirin. The lesson is suggestive: marihuana, like aspirin, is a substance
known to be unusually safe and with enormous potential medical benefits.
There is one contrast, however; it was impossible to be sure about the
effect of aspirin on heart attacks without a long-term study involving
large numbers of patients, but innumerable reports show that cannabis often
brings immediate relief of suffering that can be measured in a single person.

Case histories are, in a sense, simply the smallest research studies, and
the case reports on marihuana are numerous and persuasive. There is an
experimental method known as the N-of-1 clinical trial, or the
single-patient randomized trial. In this type of experiment, active and
placebo treatments are administered randomly in alternation or succession
to a patient. The method is often useful when large-scale controlled
studies are impossible or inappropriate because the disorder is rare, the
patient is atypical, or the response to the treatment is idiosyncratic. [5]
Some medical marihuana patients we know of carried out similar experiments
on themselves by alternating periods of cannabis use with periods of no use.

They had such symptoms as nausea and vomiting, muscle spasms, loss of
vision, seizures, and debilitating pruritus (itching). It is certain that
cannabis won its reputation as a medicine partly because many other
patients around the world have carried out the same kind of experiment.
Admittedly, in these experiments cannabis could not be administered
completely at random and there was no placebo, but in any case its
psychoactive effects are usually unmistakable, and few patients or
observers could be deceived by a placebo.

Case histories and other reports of clinical experience are sometimes
disparagingly dismissed as merely "anecdotal" evidence, which is said to be
irrelevant because only apparent successes are counted and failures are
ignored. It is true that cannabis may be useful for some people with, say,
multiple sclerosis, chronic pain, or depression, and not for others. But
cannabis is so safe that if even a few patients with a given symptom could
get that kind of relief, they should be allowed access to it. Even if it
made sense to put marihuana through the FDA process, there would be other
problems in taking the conventional route to medical legitimacy.

As I mentioned, FDA procedures are designed for single chemical compounds,
but marihuana is a plant material containing many chemicals. Also, it is
taken chiefly by smoking, and no other drug in the present pharmacopeia is
delivered by this route. Thousands of people are already getting relief
from cannabis,and they would not be risking severe penalties if they did
not believe that it was more useful than conventional medicines. Can we
expect them to put their pain and suffering on hold for years while the
established procedures grind away?

And where will the money to finance all this come from? New medicines are
usually introduced by drug companies, which spend an estimated two hundred
million dollars on the development of each product. They are willing to
undertake these costs only because they hope for large profits during the
20 years they own the patent. Obviously pharmaceutical companies cannot
patent marihuana, and in fact may oppose its acceptance as a medicine
because it will compete with their own products.

Drug companies may be interested in synthetic cannabinoids and cannabinoid
analogs -- individual chemical compounds that do not have to be smoked and
might be aimed at specific symptoms with little psychoactive effect. But
their patentability and the costs of development would make these drugs
expensive, and many patients would understandably prefer to buy or grow
their own marihuana and endure (or enjoy) the psychoactive effects. Even
now, the minority of cannabis-using patients who find Marinol (dronabinol,
or synthetic tetrahydrocannabinol) useful generally prefer whole smoked
marihuana because it is not only more effective but often less expensive
despite the prohibition tariff.

Only the U.S. government has sufficient resources to explore medical
marihuana, but its record on the matter is, to put it mildly, not
reassuring. The government has opposed any loosening of restrictions on
clinical research with cannabis, including the research needed for FDA
approval. The government will ultimately provide support for this research,
but that will happen only gradually as public pressure increases. A
proposed study of marihuana's safety as a treatment for the AIDS wasting
syndrome has recently been approved and funded, but only after four years
of obstruction -- and not because anything new has been learned about
cannabis, but only because the political climate has changed in the wake of
the recent California initiative.

But just for the sake of argument, let us suppose that government
resistance evaporates and marihuana is approved for, say, the relief of
nausea and vomiting in cancer chemotherapy. Furthermore, we can leave aside
the issue of who would provide the marihuana (the government or marihuana
farmers under contract?) and who would distribute it (pharmacies will need
special facilities to keep fresh supplies). There are other reasons why
making marihuana a Schedule II prescription drug would probably be
unworkable in the long run.

As a Schedule II drug, marihuana would be classified as having a high
potential for abuse and limited medical use. Restrictions on these drugs
are becoming tighter. Nine states now require doctors to make out
prescriptions for many of them in triplicate so that one copy can be sent
to a centralized computer system that tracks every transaction. [6] In 1989
New York state added the benzodiazepines (Valium and related drugs) to the
list of substances monitored in this way. Research has shown that since
then many patients in New York who have a legitimate need for
benzodiazepines are being denied them, and less safe and effective drugs
are being substituted. Increased regulation caused by fear of drug abuse
has been to the disadvantage rather than the advantage of patients.[7]

Obviously, in such situations physicians are often afraid to recommend what
they know or suspect to be the best medicine because they might lose their
reputations, licenses, and careers. Pharmacies might be reluctant to carry
marihuana as a Schedule II drug, and physicians would hesitate to prescribe
it. Through computer-based monitoring, the DEA could know who was receiving
prescription marihuana and how much. It could hound physicians who by its
standards prescribed cannabis too freely or for "off-label" purposes the
government considered unacceptable. The potential for harassment would be
extremely discouraging. Unlike other Schedule II drugs such as cocaine and
morphine, cannabis has many potential medical uses. Many patients might try
to persuade their doctors that they had a legitimate claim to a
prescription. Doctors would not want the responsibility of making such
decisions if they were constantly under threat of discipline by the state.
In fact, since the passage of the medical marihuana initiative in
California, I have received calls from patients who say their doctors are
afraid to recommend (not prescribe) marihuana because of threats from the
federal government -- even though those threats have been declared by the
courts to be legally baseless.

There is actually no case for such restrictions on cannabis -- unless you
think that third-party reefer-madness anxiety qualifies as a risk. Cannabis
is not accurately described as a Schedule II drug. It does not have a high
potential for abuse and, above all, it does not have limited medical uses.
For example, a physician might sensibly and safely prescribe it for muscle
spasms and chronic pain resulting from a variety of conditions, from
paraplegia to premenstrual syndrome. If the government and medical
licensing boards insist on tight restrictions, challenging physicians as
though cannabis were a dangerous drug every time it is used for any new
patient or any new purpose, there will be constant conflict with one of two
outcomes: patients do not get all the benefits they should from this
medicine, or they get the benefits by abandoning the legal system for the
black market or their own gardens.

In fact, the range of beneficial uses of marihuana is so broad that it may
ultimately be wrong to single out the strictly medical uses for approval.
We all know of people who use it to ease everyday discomforts, heighten
creativity, or help them in their work. It can serve as an intellectual
stimulant, and it can also enhance the appreciation of food, sex, natural
beauty, music, and art. It can promote emotional intimacy. Cannabis use
simply cannot be made to conform to the boundaries established by present
medical institutions. In this case the demand for legal enforcement of a
distinction between medical and nonmedical use is incompatible with the
realities of human need.

I know that to say this is to invite the charge that medical marihuana
advocates are only using medicine as a stalking horse for the legalization
of nonmedical use. This false accusation is actually a mirror image of the
view taken by enemies of marihuana. They are unwilling to admit that it can
be a safe and effective medicine largely because they are committed to
exaggerating its dangers when used for other purposes. Nevertheless, it
would be hypocritical to deny that there is a connection. Tolerance for
marihuana use in general is growing as experience of its many medical uses
becomes more widespread, because everyone understands that one important
aspect of its medical usefulness is its safety. For 26 years I have been
urging the legalization of marihuana for general use. That would be
desirable for many reasons I cannot go into here. But at one time I thought
that medical use could be treated as a distinct issue.

Even people who might never see the urgency of legalizing nonmedical use
would be willing to respond to medical need. Now I have come to the
conclusion that this distinction may be invalid, and that on the contrary,
making marihuana fully available as a medicine is another reason for
general legalization.

Ideally, cannabis should be available under more or less the same rules now
applied to alcohol. If the present political and legal system is too
ossified to accommodate that change, as I fear it is, we must at least
encourage a climate of tolerance for all marihuana use, so that the laws
will not be enforced in all their pointless harshness. Doctors must no
longer fear that they have something to lose by recommending marihuana,
even when the law is uncertain, as in the California example I just
mentioned. Patients should no longer have to fear that their motives will
be questioned and they will be charged with "improper" use. That will be
possible only when it is clear that no one is being arrested or persecuted
for any cannabis use. The full potential of this remarkable drug, and its
medical potential in particular, will be realized only when, officially or
unofficially, the present era of prohibition has ended.

References

1.) L. Grinspoon and J. B. Bakalar, Marihuana, the Forbidden Medicine,
revised and expanded edition (New Haven: Yale University Press, 1997).

2.) G. Singh, D. R. Ramey, D. Morfeld, H. Shi, H. T. Hatoum, and J. F.
Fries, "Gastrointestinal Trace Complications of Nonsteroidal
Anti-inflammatory Drug Treatment in Rheumatoid Arthritis," Archives of
Internal Medicine 156 (July 22, 1996): 1530-1536.

3.) T. V. Perneger, P. Whelton, and M. J. Klag, "Risk of Kidney Failure
Associated With the Use of Acetaminophen, Aspirin, and Nonsteroidal
Antiinflammatory Drugs," New England Journal of Medicine 331:25 (December
22, 1994): 1675+1679; P. M. Ronco and A. Flahault, "Drug-induced End-stage
Renal Disease," Editorial, New England Journal of Medicine 331:25 (December
22, 1994): 1711-1712.

4.) L. Lasagna, "Clinical Trials in the Natural Environment," in Drugs
Between Research and Regulations, ed. C. Steichele, W. Abshagen, and J.
Koch-Weser (New York: Springer-Verlag, 1985), 45-49.

5.) E. B. Larson, "N-of-1 Clinical Trials: A Technique for Improving
Medical Therapeutics," Western Journal of Medicine 152 (January 1990):
52-56; G. H. Guyatt, J. L. Keller, R. Jaeschke, et al., "The N-of-1
Randomized Controlled Trial: Clinical Usefulness," Annals of Internal
Medicine 112 (1990): 293-299.

6.) "State Multiple Prescription Programs," State Health Legislation Report
of the American Medical Association 15 (August 1988): 35-339.

7.) H. I. Schwartz, "Negative Clinical Consequences of Triplicate
Prescription Regulation of Benzodiazepines," Hospital and Community
Psychiatry 43 (April 1992): 382-385; M. Weintraub, S. Singh, L. Byrne, et
al., "Consequences of the 1989 New York State Triplicate Benzodiazepine
Prescription Regulations," JAMA 266 (1991): 2392-2397; R. S. Hoffman, M. G.
Wipfler, M.A. Maddaloni, et al.,"Has the New York State Triplicate
Benzodiazepine Prescription Regulation Influenced Sedative-Hypnotic
Overdoses?" New York State Journal of Medicine 91 (1991): 436-439.

Copyright 1996 -- 1998 OPA (Overseas Publishers Association) N.V.

Checked-by: Richard Lake