THE DOPE ON MEDICAL MARIJUANA

Legend has it that the Chinese Emperor Shen Nung discovered the medicinal
properties of marijuana almost 5,000 years ago, observing that it was not
only psychoactive but useful for pain control. A physician in ancient
Greece, Dioscorides, noted that cannabis could treat pain, rheumatism, and
gout. Queen Victoria's physician recommended it for insomnia, migraines,
menstrual cramps, and muscle spasms. One neurologist estimates that today,
perhaps as many as 50,000 Americans with multiple sclerosis illegally smoke
marijuana to alleviate their symptoms.

Despite such historical and anecdotal reports of marijuana's medical
benefits, scientists say far more research needs to be done before the drug
can be considered a viable treatment. Yet governmental reviewers have all
but shut down clinical trials, basing their decisions on politics rather
than science, some researchers charge. Some scientists interested in
studying medical marijuana say they won't bother to apply to hold clinical
trials because of the difficulty of obtaining federal approval.

Indeed, today, only one clinical trial of the plant's medical effects is
under way in the United States, involving fewer than 70 volunteers. By
contrast, the government permitted 21 clinical trials involving more than
3,000 men in the years leading up to Viagra's approval in 1998.

"The government is much more interested in preserving the purity of its
ideology than it is in allowing patients to get effective medicine," says
Ethan B. Russo, a neurologist at Western Montana Clinic, who has been denied
access to the National Institute on Drug Abuse's supply of marijuana, the
only legal source in the country. "I think it's a moralistic stance rather
than a scientifically based one," Dr. Russo says.

But Steven W. Gust, the special assistant to the director of the drug-abuse
institute, says that's not true. "There seems to be a consensus of opinion
[among scientists] that more research should be done," he says. "It's just a
matter of getting it done."

Dr. Russo, who is also an adjunct associate professor at the University of
Montana, has been submitting proposals to study marijuana's effects on
migraine headaches since 1997, without success. Most recently, despite
unanimous approval from the review board of the Missoula hospital where he
hoped to conduct his study, and approval from the Food and Drug
Administration last year, the drug-abuse institute rejected his proposal to
use federal supplies of marijuana. "The criticisms indicated that [the
federal reviewers had] a poor understanding of issues with cannabis and
migraines," he says.

Dr. Russo and others insist that more research on marijuana's possible
health benefits is important not only because legalized medicinal cannabis
could relieve symptoms for patients who have little other recourse, but also
because the many ailing people who already smoke marijuana for its medical
benefits need better information about its effects.

It hasn't always been so hard to study the plant. Research, including six
trials run by state public-health departments to look at marijuana's
effectiveness in staving off nausea caused by chemotherapy, was done as
recently as the 1970's and early 1980's -- before the government's war on
drugs kicked into high gear. More research is needed, say proponents,
because the state studies were never published and some of them failed to
compare cannabis to a placebo or make sure that all trial participants had
the same medical conditions.

However, those studies and others did suggest that marijuana or other drugs
containing cannabinoids, marijuana's major psychoactive ingredients, could
treat a number of conditions, according to a report published last year by
the Institute of Medicine, an independent organization that studies health
issues that have implications for federal policies. The report concluded
that cannabinoids can relieve pain, reduce vomiting, and stimulate appetite
in people with diseases, such as AIDS, that cause them to lose weight. It
found the data on marijuana's effectiveness for treating muscle spasticity,
as in multiple sclerosis, only "moderately promising," and was less
encouraging about its use to treat glaucoma, epilepsy, and movement
disorders such as Huntington's and Parkinson's diseases.

No matter how effective it is, smoked marijuana is unlikely to be approved
as a medicine in the United States. Public resistance -- reflected in Al
Gore's recent waffling on the issue, despite his sister's having tried the
drug when she was fighting lung cancer -- is based in part on longstanding
social concerns. Legalization of medical marijuana, goes one popular
theory, might open the door to recreational use. It could even lead people
to more harmful substances like cocaine or heroin, a claim that published
research on drug use casts into doubt, says Janet E. Joy, director of the
Institute of Medicine's study.

Other concerns about marijuana use are grounded in physiology. It has long
been known that cannabis interferes with cognition, at least in the short
term, so that people under the influence should not drive cars, for example.
Smoking it also causes the heart to beat faster for a few hours, which could
cause problems for people with heart disease. But Ms. Joy dismissed some
other physiological objections. The possibility that users could become
dependent is "well within the risks we already tolerate" with other
medicines, she said. And claims that marijuana suppresses the immune system
are "not well established."

The strongest objection to marijuana is that it is smoked. "There's no
F.D.A.-approved product, to my knowledge, that's delivered in a smoked
form," says Mr. Gust, of the National Institute on Drug Abuse. As with
tobacco, smoking marijuana can damage the lungs. In fact, marijuana
cigarettes generate more tar than tobacco cigarettes, and marijuana smokers
exacerbate the problem by holding their breath longer. However, no studies
have directly linked smoking marijuana to cancer.

Lung disease is a concern for people who would be using marijuana long-term
to fight chronic illness. For patients with terminal diseases, though, "the
medical benefits of smoked marijuana might outweigh the harm," says the
Institute of Medicine report.

Still, a nonsmoked medication stands a much better chance of being accepted
by the medical establishment and approved by the government. The Food and
Drug Administration has approved one such drug for appetite stimulation and
relief of vomiting in AIDS and cancer patients. The drug, Marinol, comes as
pills that contain tetrahydrocannabinol, or THC, the main psychoactive
component of marijuana.

Marinol does not satisfy all proponents of medical marijuana, however. They
say that the way the body receives the drug can, in many cases, make it less
effective. Keeping a pill down can be difficult or impossible for patients
with severe nausea. And it takes hours for Marinol to take effect, whereas
with smoked marijuana's instant hit of cannabinoids in the bloodstream,
patients can monitor their own dose and simply stop smoking when they feel
their symptoms receding.

Some activists say Marinol has become an obstacle to studying marijuana.
"The federal government was able to stall progress on the medical-marijuana
issue for almost a decade simply by approving the THC pill in 1986," says
Chuck Thomas, the director of communications at the Marijuana Policy
Project, a Washington-based lobbying organization. Others blame the 1980's
Just Say No movement and the rise of government opposition to drugs.

Whatever the reason, running a clinical trial to test marijuana's medical
properties in humans has become a Herculean labor, as the experience of
Donald I. Abrams demonstrates.

An AIDS specialist at the University of California at San Francisco, Dr.
Abrams is the only researcher in the United States currently doing such
experiments. He became interested in studying marijuana's effects on AIDS
wasting, the sometimes life-threatening weight reduction that results from a
loss of appetite in people with AIDS, because many of his patients were
already smoking marijuana.

In 1992, Dr. Abrams designed a study with assistance from the Food and Drug
Administration to compare smoked marijuana to Marinol in 40 patients with
AIDS wasting. He planned to get marijuana from a Dutch growing company. His
proposal won approval from the university's institutional-review board, as
well as from the Research Advisory Panel of California, which must approve
clinical trials of controlled substances.

Next, Dr. Abrams and his colleagues applied to the Drug Enforcement Agency
for a license to prescribe the illegal drug. Under the Controlled Substances
Act, marijuana, like heroin and LSD, is a Schedule I drug, which means that
it has a high potential for abuse and no accepted medical use. Schedule II
drugs, which have a high potential for abuse but also have a medical use and
are easier to prescribe, include cocaine and methamphetamine.

The application was rejected. "The message I got was they didn't want me
importing marijuana across international borders," Dr. Abrams says. In
August of 1994, he sent his F.D.A.-approved protocol to the National
Institute on Drug Abuse requesting use of the institute's supply of
cannabis. Nine months later, he received a letter from the institute's
director, Alan I. Leshner, denying his request. "I think he said he
regretted he couldn't [supply marijuana], but the study was not scientific."

"I wrote him back and said, well gee, it's been approved by a number of
august bodies, and for you to tell me that it's not scientific was a little
bizarre," he says. "We finally heard that Alan Leshner said that if our
study received favorable peer review, he would reconsider providing us with
marijuana. I've been around long enough to understand that favorable peer
review means submit it to the [National Institutes of Health] for a grant."

Taking into account some of Mr. Leshner's criticisms, such as his
requirement that the trial be performed in the hospital rather than on an
outpatient basis, Dr. Abrams redesigned the study and applied for N.I.H.
support in 1996. He planned to study 15 patients, in the hospital, for two
15-day periods of smoking either marijuana or the plant minus its active
ingredients. Those periods would be separated by a three-week "washout,''
when the patients smoked nothing.

The institute turned him down. "The media was saying to me by this time,
'Donald, surely this is political.' And I was saying, 'No, no, this is
scientific, this is a review by my peers.'" But when he received the
reviewers' comments, he decided he had been naive.

Two of the reviewers were concerned about marijuana's toxicity -- which,
many researchers point out, is far lower than that of most prescription
medications. The third was concerned about the patients' risks of high
cholesterol due to their increased appetites. "This is really not something
that people with AIDS wasting have the luxury of worrying about," Dr. Abrams
says.

His team applied again, changing the focus of the study to examining the
negative effects of marijuana. They would look at whether it interferes with
the body's processing of widely used AIDS drugs called protease inhibitors,
since cannabinoids are metabolized by the same system in the liver. They
planned to study 63 people: One third would smoke marijuana, one third would
take the Marinol pill, and one third would take a placebo pill.

Asking to study the downside of medical marijuana seemed to do the trick. In
1997, five years after Dr. Abrams first applied to do research, the National
Institutes of Health awarded him a grant and 1,400 marijuana cigarettes. He
applied for and received a license from the Drug Enforcement Agency, and
enrolled the first patient on May 12, 1998. Just a few weeks ago, the last
patient returned home.

But Dr. Abrams has not analyzed the data. "I didn't want any perception of
having any bias or doing anything un-kosher" during the trial, he explains.
He hopes to analyze the data in time to present them at the International
AIDS Conference in Durban, South Africa, this summer. Although his trial was
designed to look for negative effects, if he finds a trend toward weight
gain, he plans to submit proposals to run trials looking specifically at
that benefit.

Despite several rejected applications, Dr. Russo, of Western Montana Clinic,
says he will not change his proposed migraine study to look at safety, as
Dr. Abrams did. "This is a compromise I personally will not make." Even with
new regulations allowing researchers to apply for federal supplies of
marijuana without financing from the National Institutes of Health, he is
pessimistic about his chances of gaining access.

His proposed trial, he says, "presents a pitfall for the government." If the
trial is successful, "it immediately blows out of the water the governmental
argument that there is no therapeutic value to cannabis."

But Mr. Gust, of the National Institute on Drug Abuse, insists that the
government's procedures are based on science alone. The N.I.H. finances only
about one in four applications in any field, he says. And procedures for
researchers with other sources of funds are only meant to give scientists
"some feedback on how to make their protocol a rigorous one."

"I've been kind of surprised there haven't been more requests and
applications," Mr. Gust says. "We are open for business and I've been
anticipating some requests, but they haven't come in."

Researchers may be reluctant to go through tribulations like Dr. Abrams's,
especially if they question whether even successful trials will affect
marijuana's legal status. 'It'll never get approved" as a medicine, says
Juan Sanchez-Ramos, a professor of neurology, pharmacology, and psychiatry
at the University of South Florida.

Dr. Sanchez-Ramos and other scientists may have recourse to a new drug being
produced by GW Pharmaceuticals Ltd. The British company has developed an
extract of marijuana -- the whole plant, not just THC -- that is sprayed
under a patient's tongue. That allows it to reach the bloodstream quickly,
without being metabolized in the liver, as pills are.

The company began studies in April to test their cannabis extract on
patients with multiple-sclerosis pain and spasticity. Dr. Sanchez-Ramos says
he hopes to study the extract in Parkinson's-disease patients, and Dr.
Russo's next step might be using it in his migraine studies.

Dr. Abrams is also eager to study the extract. But he cautions that, as a
pharmaceutical product, its cost may discourage many potential users. "There
are always going to be people who are going to perhaps grow their own and
use their own medicine," he says. For that reason, "it's still worthwhile
looking at the medical effects of smoked marijuana."