PAST THE SMOKE SCREEN

Forget Your Presumptions. Medical Marijuana Needs the Same Scrutiny as Any
Other Drug

More closely associated with the likes of Cheech and Chong than with
chemotherapy, with pot parties than with pain relief, marijuana is mostly
thought of as an illegal substance. The claim that it might be useful in
treating a variety of medical conditions typically provokes two divergent
and equally unrealistic responses: Opponents argue that the plant offers
little or no therapeutic benefit; advocates see it as a powerfully
effective drug that no one should be denied.

In the United States, the debate about the medical use of marijuana has
become mired in the political arena. Voters in five states (Alaska,
Arizona, Nevada, Oregon and Washington) recently approved medical marijuana
initiatives--despite arguments from federal officials, police chiefs and
some state legislatures that, at best, such a move promotes a mixed message
and, at worst, represents a thinly veiled attempt to legalize marijuana for
recreational use. (In the District, a congressional amendment has blocked
election officials from even counting the votes on Initiative 59, a medical
marijuana referendum that was on the November ballot; the standoff is now
in the hands of a federal judge.)

Lost in the political haze--and in the popular fantasies about the drug's
potency--are the complexities in evaluating marijuana's usefulness as
medicine. The same has been true, in my experience, in trying to assess the
health risks of recreational marijuana use, an issue I addressed in an
article earlier this month in the Lancet, the British medical journal.

Putting politics aside for the moment, let's suppose that prescribing
marijuana in its plant form became legal. How likely would doctors be to
use it? Where does it belong in the array of medications now available for
treating pain or the nausea that often accompanies chemotherapy? In short,
would it benefit or hurt patients?

Physicians and researchers aren't nearly as certain about the answers to
these critical questions as are the advocates and opponents. Definitive
answers are hard to come by, partly because of the absence of scientific
research on the drug's efficacy. Since much of the world's research on
drugs takes place in the United States, the Drug Enforcement Agency's
classification of the marijuana plant (cannabis sativa) as having "no
medical use" has made it difficult to do the clinical trials that usually
provide the best information on a drug's benefits and side effects.

The very nature of marijuana makes it hard to test in clinical trials.
Unlike drugs such as morphine or Viagra, marijuana is a crude plant product
that contains a complex and varied mixture of 60 substances known as
cannabinoids. Before a drug can be registered, the FDA requires that it be
a pure substance of known chemical structure that can be shown in
controlled trials to be safe and effective at particular doses in the
treatment of particular diseases.

Physicians have long had the authority to prescribe painkillers, but
clinical trials have helped clarify the risks and benefits of particular
doses. So, for example, physicians know they can give patients suffering
acute pain an injection of 2.5 to 15 milligrams of morphine, and that their
pain will be relieved for several hours with a low risk of adverse effects.

The point here isn't that marijuana is particularly dangerous. All drugs
pose dangers--that is, all drugs contain risks that must be identified and
weighed. And at this point, we don't know as much about the medical risks
of marijuana as we should.

The difficulties of evaluating the therapeutic uses of marijuana are
amplified by the dizzying variety of medical conditions for which its more
enthusiastic advocates claim it is useful. They include the nausea and
vomiting caused by chemotherapy, AIDS-related wasting caused by loss of
appetite, multiple sclerosis, paraplegia, some forms of chronic pain,
glaucoma and asthma.

For about a decade, doctors have been able to prescribe one of marijuana's
constituents, the cannabinoid tetrahydrocannabinol or THC, which is the
ingredient responsible for many of marijuana's psychological effects, such
as relaxation and euphoria. But THC hasn't proven to be a particularly
useful drug. Now marketed in pill form under the trade name Marinol, THC
can be used to treat the nausea and vomiting experienced by chemotherapy
patients and to stimulate appetite in AIDS patients. These are the only
medical uses of cannabinoids that are supported thus far by evidence from
controlled clinical trials. The DEA has argued that the registration of
Marinol obviates the need to register marijuana itself for medical use.

Despite having been available in the United States for more than a decade,
Marinol is rarely used to treat nausea and vomiting because other drugs
have become available that have proven to be effective, such as ondansetron
and granisetron. And those patients who have taken Marinol as an appetite
stimulant have found it difficult to get the dosage right; the effects of
THC are delayed when taken orally, making it hard to regulate the amount
needed to achieve the desired therapeutic benefit. Some patients report
receiving too little THC to relieve their symptoms; others, in particular
those who have no experience with marijuana, report feeling tired,
lethargic and drowsy after taking the medication.

These sorts of reactions to Marinol contrast sharply with the anecdotal
evidence from AIDS patients who have smoked marijuana. Some of these
patients have reported marked improvements. Smoking marijuana allowed them
to use as much or as little of the drug as they felt they needed to relieve
their symptoms. Experiences like these, reported by Harvard psychiatrist
Lester Grinspoon and his legal colleague James B. Bakalar in their 1997
book "Marijuana, The Forbidden Medicine," led them to conclude that
marijuana smoking should be allowed for medical reasons. Some advocates
also say that smoking is a more sociable way of using medications and might
have advantages over popping a pill--factors that don't normally figure
into regulatory decisions about which drugs to approve for medical use.

But in most developed countries, medical societies and government
regulators have typically rejected medical marijuana smoking. Many doctors
are uncomfortable with promoting any form of smoking, given the risks of
smoking tobacco products. They also point out that the burning of marijuana
and tobacco produces many of the same cancer-causing substances (although
marijuana does not contain nicotine). The cancer risk of marijuana may be
minor for the occasional user, but it becomes a more important question if
marijuana is used to treat a chronic health problem such as glaucoma or
multiple sclerosis--when a patient might smoke it several times a day for
months or years.

In the case of AIDS patients, smoking marijuana may stimulate appetite but
it may also further depress their immune systems, leaving them more
vulnerable to opportunistic infections. The plant also may be contaminated
with microorganisms that can be life-threatening for patients whose immune
systems are already compromised.

For many doctors, the central question is: Should we insist that patients
use only a pure drug, the effects of which are difficult to control, or
should we allow the medical use of smoked marijuana with all its drawbacks?
Neither alternative is ideal. But then, no drug is perfect; all have side
effects, and the side effects of marijuana are arguably no worse than those
of other therapeutic drugs. If marijuana were not an illegal drug, widely
used for recreational reasons, the choice would be left primarily to
doctors and their patients.

Expert opinion may be changing a little on this issue. A panel of experts
convened by the National Institutes of Health to look into these sorts of
questions reported last year that smoking marijuana may be useful for
treating a number of conditions--although it may not be better than other
medications.

In Britain, a subcommittee of the House of Lords suggested in a report
released earlier this month that the medical value of smoked marijuana
should be explored. It recommended that if smoked marijuana proved to be
therapeutically better than oral THC, then methods should be developed to
inhale cannabinoids without the potentially harmful byproducts that are
produced when the leaf is burned. Ironically enough, the tobacco industry's
recent attempts to develop a "smokeless" nicotine delivery system might
provide the means.

Other obstacles would arise if marijuana smoking were approved for medical
purposes. Pharmaceutical companies do not have any commercial incentive to
register and market a non-patentable, naturally occurring plant product.
Similar disincentives delayed, for several years, the use of naturally
occurring pure Lithium salts for the treatment of manic-depressive illness.

The key to moving the current debate forward rests in a better scientific
understanding of the way in which marijuana and its constituent
cannabinoids act in the human brain. In the early 1990s, researchers
identified a receptor in animal and human brains that responds specifically
to THC, as well as a naturally occurring analog of THC, anandamide. These
discoveries have led to the synthesis of new substances that are chemically
related to THC and other cannabinoids. Some of these--and others yet to be
synthesized--may produce the desired therapeutic effects without the side
effects pursued by recreational users.

Not all the consequences of research on the chemistry and pharmacology of
cannabinoids may be desirable. If, for example, it proved easy to
synthesize cannabinoids that had psychoactive effects like THC, then the
opportunities for recreational cannabinoid use would probably increase
markedly. Similarly, if water-soluble cannabinoids are developed for more
efficient oral use, they could also be injected, substantially increasing
the potential for abuse of cannabinoids in much the same way that cocaine
or heroin have done for the coca plant or opium poppy. The price we pay for
medically useful cannabinoid drugs may be more dangerous synthetic
derivatives of marijuana.

The issue of whether to fund clinical trials remains highly controversial;
even if trials were to be funded, the regulatory process would take five to
10 years, at best. Advances in our understanding of cannabinoid chemistry
could dramatically change what we think about marijuana's usefulness.
Meanwhile, I would hazard three predictions about the medical use of
marijuana and cannabinoid drugs over the next 20 years:

First, if marijuana has a medical role, it will be more akin to an herbal
remedy than mainstream treatment. Second, drugs derived from cannabis will
have a medical role but a much more modest one than their more enthusiastic
advocates would have us believe. And third, the development of new and
better drugs may make the current battle over medical marijuana seem like a
puzzling--but fascinating--historical curiosity.

Checked-by: Richard Lake