IS BIG PHARMA TRYING TO TAKE ALL THE FUN OUT OF POT?

Pricey pharmaceutical-marketing newsletters have touted
cannabis-derived drugs as the next blockbuster for the industry, but
the biggest companies are primarily researching drugs whose effect is
the opposite of the cannabis herb.

Numerous drug researchers are trying to develop medications that
replicate the herb's therapeutic effects without the harm of inhaling
smoke and the side effect of getting people high.

Others are looking into cannabinoid agonists, drugs that enhance the
body's natural cannabinoid system -- or cannabinoid antagonists, which
disrupt it -- and have been the pharmaceutical industry's main focus.
Despite the millions of medical-marijuana users, both U.S. government
restrictions and drug companies' need for exclusive ownership have
limited research into herbal cannabis.

In any case, it will likely be a while before many cannabis-derived
drugs arrive in your local pharmacy.

"There's a lot of interest out there, but there's nothing that's going
to be released in the next week," said a longtime medical-cannabis
researcher who asked to remain anonymous.

So far, only three such drugs are on the market.

Cesamet (Valeant Pharmaceuticals), used for chemotherapy-nausea
treatment, went on sale in the United States in 2006. It contains
nabilone, a synthetic analog of THC, the primary psychoactive
ingredient in cannabis.

Marinol, synthetic THC in capsules, has been on the market since 1986.
It is now manufactured by the Belgian firm Solvay Pharmaceuticals, and
generic versions are beginning to come out.

Sativex, a whole-cannabis-extract spray produced by the British firm
GW Pharmaceuticals, is available in Canada. It is oromucosal, meaning
it is absorbed by the mucous membranes under the tongue and on the
inside of the cheeks, and it contains approximately equal proportions
of THC and cannabidiol (CBD). CBD is a cannabinoid thought to reduce
both pain and the more nerve-jangling aspects of the marijuana high.
The spray is undergoing Phase III trials -- large-scale human studies
of its efficacy -- for multiple sclerosis in Europe and cancer pain in
the U.S.

At least five of the world's top 10 pharmaceutical companies have
looked into the field. In 2006, there were about 18
cannabinoid-related compounds under active pharmaceutical development,
says Dr. George Kunos, scientific director of the National Institute
on Alcohol Abuse and Alcoholism at the National Institutes of Health.
They were primarily cannabinoid antagonists.

Many of those, however, may never make it to market. New drugs need to
be proven safe and effective, drug companies want them to be
profitable, and the approval process can take as long as 10 years.

In January, Novartis announced that it had completed Phase I tests of
a cannabinoid agonist called CRA13, which might be used to treat
chronic pain. Phase I tests are a small-scale study of the drug's
safety, how well human subjects tolerate it, and its
"pharmacokinetics" -- how quickly it gets into the body, where it goes
and how long it stays.

Big Pharma's first move into cannabinoid drugs, however, ended in
failure. In 2006, the French company Sanofi-Aventis began selling in
Europe rimonabant, a cannabinoid antagonist, as an appetite
suppressant under the brand name Acomplia.

By blocking the action of natural cannabinoids at "CB1 receptor" sites
in the brain, Acomplia created the opposite of the "munchies." (As one
drug company put it, activation of CB1 receptors "appears to provoke
food intake even in the setting of satiety.") The drug also showed
promise for diabetes, says Kunos, because it increased the body's
sensitivity to insulin. A British pharmaceutical-business newsletter
predicted that Acomplia would be "the first of the cannabinoid
blockbusters."

The U.S. Food and Drug Administration, however, rejected Acomplia in
2007, because its side effects included suicidal thoughts. Last fall,
the European Medical Agency recommended taking the drug off the market
because it increased the risk of depression. In November,
Sanofi-Aventis announced it was stopping all research on it.

Pfizer and Merck Sharp & Dohme, which had similar drugs in Phase III
trials, suspended their development as well. Solvay, which had had a
marketing deal with Bristol-Myers Squibb for a cannabis antagonist it
called SLV319, also canceled its research. Phase II studies had found
SLV319 an effective anti-obesity drug, but the company's head of
research cited "high regulatory hurdles."

The risks might have been foreseen. Because the endocannabinoid system
was not discovered until the early '90s, its role in regulating
emotions and the effects of disrupting it are far from understood.

In 2003, neurochemist Dale Deutsch, former head of the International
Cannabinoid Research Society, predicted that cannabinoid antagonists
would be effective appetite suppressants, but that people taking them
"might be really irritable."

Drug researchers are now trying to find a cannabinoid antagonist
without the psychiatric side effects. Meanwhile, "online pharmacies"
still advertise rimonabant with "discreet packaging" and "anonymous
delivery."

Johnson & Johnson says it is not researching cannabinoid drugs, and a
company spokesperson said it was "not aware of any" other companies
doing so. On the other hand, drug companies are not likely to tell
competitors about the research they're doing.

"This is all proprietary information," notes Paul Armentano of the
National Organization for the Reform of Marijuana Laws. "I have reason
to believe there has been an explosion in cannabinoid-based drug
research, but we in the general public are not going to be made aware
of it until these drugs are close to market."

5 Types of Pot Drugs

Researchers are looking into five main areas for cannabinoid drugs.
The first two comprise plant extracts and purified forms of THC. The
other three involve drugs that affect the endocannabinoid system.

GW Pharmaceuticals' Sativex is the whole-plant extract closest to U.S.
availability. It has been in development for several years. It was
designed as a spray so it would get into the body and act almost as
quickly as smoked cannabis does. This would avoid the main complaints
patients have about orally administered THC: that it can take an hour
or more to take effect, that it is difficult to calculate whether a
dose will be ineffective or overwhelming, and that oral medications
are useless if you're too nauseous to keep them down.

GW has also just begun research on whether CBD combined with another
cannabinoid, THCV, might help treat Type 2 diabetes.

Longtime medical-marijuana advocates Dr. Robert Melamede, a biologist
at the University of Colorado at Colorado Springs, and California
activist Steve Kubby co-founded Cannabis Science, Inc. The company
says it plans to develop plant-based drugs and proprietary delivery
systems for them, introducing them in the Canadian market first. It
also offered "420 Commemorative Certificates" to anyone who bought
stock before April 20. In early July, however, the company fired Kubby
amid mutual accusations of financial malfeasance.

One major obstacle for U.S. researchers trying to develop plant-based
cannabis drugs is the federal restrictions on the supply of the plant.
The only legal source is the lab of Dr. Mahmoud ElSohly at the
University of Mississippi. He has had an exclusive contract with the
National Institute on Drug Abuse, which must approve researchers'
requests to obtain cannabis, for almost 40 years.

NIDA has had a strong prejudice in favor of studies aimed at
evaluating marijuana's abuse potential. It has denied a supply to
several well-known researchers planning studies on medical cannabis.

The Drug Enforcement Administration has refused to grant anyone else a
license to grow cannabis for research. In January, it denied one to
Lyle Craker, a professor at the University of Massachusetts at
Amherst, who had applied in 2001 and wound up suing to get the agency
to act on his request. The DEA overruled its own administrative judge,
who in 2007 had urged ending the federal monopoly. The judge
summarized the testimony of one medical witness for the DEA as "he
considers medical marijuana an excuse for legalization."

"You can't get permission to even touch the marijuana," says
Armentano.

Fewer obstacles exist in Europe. But when Weleda AG, a German
herbal-medicine and cosmetics company, funded a British study of
THC-CBD extract for multiple-sclerosis spasticity, it was terminated
for lack of volunteers.

Generic forms of Marinol, THC under the name "dronabinol," are
beginning to reach the U.S. market. Two leading generic-drug
manufacturers, Par Pharmaceutical and Watson Pharmaceuticals, began
selling it last year, with Watson the authorized licensee of Solvay.

Bionorica AG, a veteran German herbal-medicine company, is seeking FDA
approval for a version of dronabinol containing THC extracted from
plants. The company has been selling it in pharmacies in Germany and
Austria for the past 10 or 12 years, says Gary Klein, its U.S.
representative. It's also looking at developing THC in droplets that
would be absorbed on the underside of the tongue.

ElSohly, who has the U.S. government monopoly on research cannabis, is
working with Mallinckrodt to develop a plant-extract form of Marinol.
Medical-cannabis advocates sharply criticize him for that. Americans
for Safe Access charges that he "benefits from such a monopoly by
financially profiting from the research and sale of cannabis-based
pharmaceuticals."

ElSohly has also patented a suppository containing THC hemisuccinate,
which breaks down into THC once it is absorbed by the body. That is
"not a popular form of drug delivery," observes the anonymous
medical-marijuana researcher. (The 1960s comedian Lenny Bruce would
disagree; he enjoyed morphine suppositories.)

Cannasat Therapeutics, a Canadian company, is applying to patent a THC
pill called Relivar for neuropathic pain. Like some triptan
migraine-abortive drugs, the pill would melt in the mouth instead of
having to be digested. The company claims that this will make the drug
act faster, get a higher proportion of it into the blood, and make it
less intoxicating than oral THC pills. Cannasat is also working on a
CBD-based treatment for schizophrenia.

Research into the cannabinoid agonists-drugs, which enhance
cannabinoids binding to receptors in the brain and body, has mainly
been "preclinical," with tests on animals instead of humans, according
to Kunos. Drug companies, he adds, have strong objections to them
because they would be psychoactive, essentially mimicking the action
of marijuana in the brain.

Pharmos, an Israeli company, had high hopes for a nonpsychoactive
synthetic cannabinoid called HU-211. Preliminary studies indicated
that it could protect the brain from the cascading neurochemical
inferno set off by a stroke or traumatic injury, but Phase III studies
in 2004 found it not significantly more effective than a placebo.

A fourth area is drugs that inhibit FAAH, the enzyme in the brain that
breaks down the endocannabinoids anandamide and 2AG. These would work
in a manner roughly analogous to antidepressants like Prozac, which
inhibit the reuptake of serotonin. Danielle Piomelli of the University
of California at Irvine has patented several possible FAAH-inhibiting
medications, including an anxiety reducer, a cough suppressor and a
pain reliever.

Finally, research into cannabinoid antagonists continues. Kunos says
the goal now is to find one that's "non-brain-penetrant," a drug that
would affect only cannabinoid receptors outside the brain, and
therefore wouldn't have the psychiatric side effects that derailed
rimonabant. He says the animal models are promising.

7TM Pharma, a Danish company that specializes in drugs for metabolic
disorders, plans to start trials of a cannabinoid antagonist this year
in the treatment of obesity and Type 2 diabetes. It says the drug "has
been designed to exclusively exert its therapeutic effect through CB1
receptors located in the peripheral tissue" instead of those in the
brain.

The Medical Possibilities of Cannabis

Meanwhile, numerous academic researchers are uncovering myriad medical
possibilities for cannabis and the cannabinoids. In one study released
in the last year, researchers at Complutense University in Madrid
found that THC caused brain-cancer cells to destroy themselves.

At the University of Erlangen in Germany, a CB2-receptor agonist
reduced the dermal thickening and fibrosis found in the early stages
of multiple sclerosis, and it also diminished the damage done by
lowered blood supply to the brain in an animal model of stroke.

A Canadian military psychiatrist said that nabilone reduced or
eliminated nightmares in 34 of the 47 post-traumatic stress syndrome
patients he studied.

The University of California at San Diego is currently investigating
whether vaporized cannabis can help relieve diabetic neuropathic pain.

Medical-marijuana advocates maintain that whole-plant drugs will be
the most effective. Research has shown that the synergy of multiple
cannabinoids works better than any single molecule in the plant,
argues Caren Woodson of Americans for Safe Access.

"The strongest drug isn't necessarily the best," adds the anonymous
researcher. The body's systems are subtle and need "a gentle nudge,
not a big shove," he argues, and potent synthetic molecules are more
likely to be toxic than substances people have used for thousands of
years. The liver, he says, will have a hard time processing "a hairy
molecule with lots of fluorine and side chains."

The profit system puts the pure cannabis herb at a disadvantage. Drug
companies are not going to put time and money into a substance they
can't patent, notes Woodson. On the other hand, they can patent
tinctures, methods of extraction, and vaporizers -- which boil the THC
into an inhalable steam instead of burning the herb into a toxic smoke.

Those means of drug administration are also more likely to satisfy the
medical community's anathema to smoking and its desire for precise,
standardized doses.

Woodson suspects that the focus on synthetic cannabinoids may be a
"backdoor way" to deny approval of medical marijuana. On the other
hand, she notes, the FDA has approved four Phase I studies of smoked
marijuana for pain relief in HIV-AIDS patients, and the state of
California is funding them. At this point, she says, "anything that
gets the FDA one step closer to approving cannabis" is a good thing.

"We could be looking at the aspirin of the 21st century," she says,
but it's not going to happen until "pharmaceutical companies can
investigate it in the same way that they investigate any other drug."