Perspective

GETTING ON MARIJUANA'S GOOD SIDE

Scientifically Speaking, This Drug Is On Wrong List

The Supreme Court ruling that federal authorities may prosecute
individuals for the possession and use of medical marijuana, even in
the 11 states that permit it, reopened long-standing questions.

What kind of scientific data exist to clarify just how useful -- or
harmful -- marijuana actually is? And why does the Drug Enforcement
Administration assign it to the same class of controlled substances
as heroin and LSD?

As director of a laboratory funded by the National Institutes of
Health to study how drugs act on the brain, I'm committed to
answering that first question, which could help with the second.

When my colleagues and I look dispassionately at the available data
on marijuana, we see a Janus-faced drug with many adverse, even
dangerous properties, even as it presents an exciting and largely
untapped therapeutic potential.

But science's ability to tap marijuana's potential is inhibited by
the DEA's inappropriate classification of it as a Schedule I
controlled substance.

It's true that marijuana and its active ingredient -- a chemical in
the tetrahydrocannabinol (THC) family of compounds -- can produce
undesirable effects in experimental animals and human subjects alike.

A single marijuana cigarette has been shown to impair the judgment of
a professional pilot in a flight simulator, and one injection of THC
significantly reduces a rat's ability to navigate a maze. Long-term
use of these drugs may also have adverse consequences.

Most important perhaps, and contrary to common misconceptions, a
growing number of studies show that prolonged exposure to marijuana
or THC can cause addiction.

This is best seen in lab experiments with monkeys that learn to
self-administer THC by pressing a lever that allows the drug to be
delivered directly into a vein. The animals will work hard to get
that fix, though not as hard as they would for cocaine or other more
addictive drugs.

What's more, a marijuana withdrawal syndrome has been demonstrated in
frequent long-term users of this drug. It is characterized by mild
but distinctive symptoms, including loss of appetite, irritability
and depression.

But marijuana and THC also appear to have significant medical
benefits. As drugs go, THC is a very safe compound.

It would take about 70 pure grams of it -- about the weight of a
chocolate bar -- to seriously harm a 150-pound adult.

Indeed, it has been approved by the Food and Drug Administration for
a human medicine and is currently used, under the trade name Marinol,
to reduce nausea and stimulate appetite in patients suffering from
HIV/AIDS or undergoing chemotherapy.

Medical Applications

Recent tests suggest these drugs may have much broader medical uses.
Marinol has been shown to reduce the physical and vocal tics caused
by Tourette's syndrome, a neurological disorder with no satisfactory
drug treatment. A 2004 report suggests that oral sprays of a
marijuana extract marketed under the name Sativex might reduce muscle
spasms in patients with multiple sclerosis.

Various animal experiments have confirmed the therapeutic
significance of THC and its derivatives, revealing novel potential
applications in such areas as neuropathic pain, cancer, glaucoma and
atherosclerosis.

Nevertheless, ever since the Controlled Substances Act became law in
1970, both marijuana and THC have been listed on Schedule I: the list
of drugs "with a high potential for abuse" and with "no currently
accepted medical use."

The data obviously contradict that assessment. The error was
highlighted by a DEA decision made in 1999 to move Marinol -- but not
THC -- to Schedule III, which includes much less dangerous compounds,
such as the anti-hyperactivity drug Ritalin. As a result, the very
same chemical, THC, is now assigned to two different CSA schedules.

This is patently absurd.

Marijuana, the smokable leaf, may well belong in Schedule I. I'm a
neuroscientist and a pharmacologist, not a medical doctor or
sociologist, and I'm not going to address this issue.

But THC, the chemical compound, does not.

A larger problem is raised by lumping marijuana and THC together with
far more hazardous drugs: If we fail to identify the varying degrees
of danger posed by different substances, we undermine the credibility
of our legislation and hinder its effectiveness. Any young person who
has smoked marijuana and seen a friend ravaged by heroin can tell the
difference between these drugs.

Why can't we?

Actually we can -- at least at a scientific level.

During the past decade the properties of marijuana have been studied
in great detail and its actions are now well understood. When
marijuana smoke enters the lungs, its THC component dissolves into
the blood and spreads rapidly throughout the body. It then combines
with protein molecules present on the surface of many cells in the brain.

These molecules selectively recognize THC, much as a lock fits a key.
They are called cannabinoid receptors (after the Latin name for the
marijuana plant, cannabis).

Heroin binds to a different class of protein molecules, called opiate
receptors -- just as lock-and-key specific as the cannabinoids, but
with different effects.

The two receptors are not interchangeable.

Take, for example, the question of addiction.

Research indicates that when THC stimulates cannabinoid receptors in
the brain, it engages a complex circuit of neural cells and
transmitters that are normally involved in the response to rewarding
stimuli, such as tasty foods.

A brief burst of activity in this circuit produces only a pleasant
sensation, but if the stimulus persists for a long time (as it does
with frequent and heavy marijuana use) it can eventually cause
changes in the neural circuit that result in tolerance -- the need to
take larger amounts to produce the same effect -- and dependence --
the feelings of unease and craving experienced when prolonged drug
use is suddenly stopped.

Heroin's interaction with its opiate receptors triggers a much more
intense sensation of pleasure than does marijuana.

But heroin's withdrawal is far more severe emotionally than
marijuana's, and its myriad physical symptoms including shivering and
pain. It's not a higher degree of the same response; it's a different
response to a different chemical reaction.

Special Delivery

All potential benefits of marijuana, such as its ability to increase
appetite and ease nausea, are also caused by the binding of THC to
its brain receptors.

This is a main trouble with developing medicinal uses for marijuana:
If a single receptor is responsible for all the drug's actions, how
can we tease apart the good from the bad?

One way might be to forgo smoked marijuana and find better methods to
deliver THC -- for example, metered aerosols such as those used in
asthma -- that would allow patients to take just enough to control
their symptoms and minimize unwanted side effects.

Another way may be to take advantage of the fact that cannabinoid
receptors did not evolve in the human brain to give us the
opportunity to experience a high, but to combine with a set of
THC-like chemicals produced by brain cells, whose functions include
the control of pain and anxiety. If we could design chemicals that
tweak the levels of these transmitter substances, we perhaps could
boost their normal effects.

Our lab and others are working in this direction to create new
classes of painkiller, anti-anxiety and antidepressant drugs.

That research sometimes faces extra bureaucratic hurdles because of
THC's Schedule I status.

But that isn't the main reason the drug and its derivatives should be
reclassified; far more important is having realistic drug laws that
penalize drug abuse but also encourage medical progress.

Advocates have pressed for THC to be reclassified since the CSA's
enactment, pleas that have gone unheeded so far. Perhaps the Supreme
Court decision will inspire citizens and medical organizations to
take a fresh look at the scientific evidence without being blinded by
prejudice. This evidence suggests that, while marijuana is an
addictive drug that requires careful monitoring, its active
constituents can be useful in medicine when appropriately employed.

But it's hard to get this message across: All too often, the voice of
science and reason is lost in a polarized shouting match.