WHO'S AFRAID OF CANNABIDIOL?

THC -delta-9 tetrahydrocannabinol is often described inaccurately as
"the active ingredient in cannabis." At least five other cannabinoids
(compounds unique to the cannabis plant) have been shown to exhibit
biological activity, and so have some of the spicy-smelling terpenes
and other compounds found in plants other than cannabis.

CBD -Cannabidiol-is an active ingredient of cannabis that has been
suppressed by growers and governments for countless generations. From
Marakesh to Mendocino, plants have been bred for maximum
psychoactivity, resulting in high THC and low CBD content. In the
Prop 215 era, California growers hoping to develop plants with a high
CBD-to-THC ratio have been stymied by lack of access to an analytical
test lab. Surreptitious tests have been done on "high grade" plants
whose buds turned out to be in the range of 15-20% THC and 0.1% CBD.

The U.S. Drug Enforcement Administration has placed CBD on Schedule I
even though CBD has no known adverse effects and doesn't induce
"euphoria." The prohibition of CBD exposes the broader marijuana
prohibition as strictly a governmental control tactic having nothing
to do with public health or "protecting the children." The most dire
effects attributed to marijuana -tachycardia (accelerated heartbeat),
panic, confusion, anxiety, even psychosis- are effects of THC that
CBD actually mitigates! By banning CBD outright and denying growers
the means to develop high-CBD plant strains, the government is
protecting the American people from an immunomodulator with
anti-inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, and
neuroprotective properties.

A high-CBD cannabis strain was developed in the 1980s by David Watson
and Robert Clarke, American naturalists who founded a company called
Hortapharm in Amsterdam to pursue their goal of developing plant
strains for different purposes. (The day Watson and Clarke became
expatriates is the day the U.S. lost its lead in the field of
cannabis therapeutics.) In 1998 Hortapharm sold its seed stock to a
British start-up, GW Pharmaceuticals, which has since developed a
strain that expresses 97% of its cannabinoid content as CBD

GW plans to test its high-CBD strain as a treatment for rheumatoid
arthritis, inflammatory bowel diseases, psychotic disorders, and
epilepsy. It is now in Phase 2 trials to determine the dose levels to
use in clinical trials involving people. GW mixes its high-CBD and
high-THC strains in a 1:1 ratio to make Sativex, a plant extract
formulated for spraying under the tongue that has been approved in
Canada and elsewhere to treat neuropathic pain associated with
multiple sclerosis. CBD evidently bolsters the pain-killing effects
of THC while moderating its psychoactivity. In various studies,
patients with severe pain have reported getting significantly more
relief from Sativex, the mixture, than from GW's high-THC extract.

The 2007 ICRS Meeting

CBD was the subject of several talks and posters that generated buzz
at this year's meeting of the International Cannabinoid Research
Society, held June 26-30 at a ski resort in Saint Sauveur, Quebec.
Among the promising studies: "CBD and the Neural Correlates of
Anxiety," by Jose Alexandre Crippa and colleagues at King's College,
London, and the Universidade de Sao Paulo. They measured blood flow
in various parts of the brain as subjects viewed upsetting images and
found that those who had been given an oral dose of CBD had markedly
reduced responses. Iddo Magen's team at Hadassah Hebrew University in
Jerusalem showed that CBD and 2-AG (one of the body's own
cannabinoids) improved cognition and neurological function in mice
with liver damage. Erica Carrier and co-workers at the Medical
College of Wisconsin, Milwaukee, determined that CBD exerts its
anti-anxiety effects by activating the adenosine receptors.

Some 350 scientists from university and drug-company laboratories
attended. Merck, Pfizer, Eli Lilly, Bristol-Myers Squibb,
AstraZeneca, and Allergan (maker of Botox and silicone breast
implants) were among the corporate participants. They are all trying
to develop synthetic drugs that confer some of the health benefits of
cannabis without the psychoactivity. The studies described by
representatives of these companies tend not to involve their most
promising drugs; or else the speakers are not wholly forthcoming
about the structure of the drugs involved.

Other participants included Cayman Chemical (which supplies various
companies' products to research labs), Valeant (now marketing a
synthetic cannabinoid called Nabilone, developed by Eli Lilly in the
1980s), ElSohly Laboratories (Mississippi-based, the only company
authorized by the DEA to grow cannabis in the U.S.), Bedrocan BV
(which grows cannabis for the Dutch Ministry of Health, Welfare and
Sport), Cannasat (a Canadian company with three plant-based products
in their pipeline), and GW Pharmaceuticals.

Bayer Health Care, which distributes GW's Sativex in Canada, had set
up a large exhibit in one of the rooms dedicated to posters. Geoffrey
Guy, the head of GW, expressed embarrassment ("That's not really the
sort of thing to do at a scientific conference") and pride ("I rather
liked it; the materials they distributed were excellent") in a 1:1 mix.

The meeting's primary sponsor was Sanofi-Aventis, the world's
third-largest drug company, which had suffered a major setback in
mid-June when an FDA advisory panel voted 14-0 against recommending
approval of Acomplia (also known as Rimonabant), a weight-loss drug
that works by blocking the CB1 receptor. Acomplia has been approved
for sale in the UK and elsewhere, and Sanofi and most securities
analysts had projected it to be a blockbuster in the U.S. But the FDA
advisors were troubled by the number of suicides and seizures in the
clinical-trial data.

When Sanofi first announced at the 2004 ICRS meeting that Rimonabant
was proving effective in large-scale trials in Europe, Jeffrey
Hergenrather, MD, of Sebastopol and other California clinicians
warned that reversing the effects of the body's own cannabinoid
system was very likely to cause health problems. Your correspondent
had published a piece quoting Hergenrather, slugged "Danger! Danger!
Danger!" So it was a little awkward to encounter the charming
scientists from Sanofi at this year's meeting, knowing they had just
lost out on millions and might hold us partly responsible (when it
fact we are under the radar and politically impotent).

Rimonabant has been used by more than 100,000 people in Europe and
Sanofi contends that the safety profile may yet turn out to be
satisfactory. They're also trying to figure out ways to prevent those
most at risk -people with epilepsy, MS, a history of serious
depression, etc. etc.- from taking Rimonabant. Unfortunately, the et
ceteras are numerous. Sanofi's marketers wish they could sell
Rimonabant only to diabetics for whom it would be most beneficial.
They dream of applying "genomics" (analyzing every patient's genetic
make-up before prescribing) but the reality is a world in which
doctors can prescribe for off-label uses and everyone wants to lose 10 pounds.

The consensus among ICRS scientists is that downward modulation of
the CB1 receptor is a feasible strategy for treating diabetes and
metabolic syndrome, but that Rimonabant -an "inverse agonist" that
doesn't simply block the receptor but achieves a reverse effect on
endocannabinoid tone throughout the body-was too strong a drug.
"Inverse agonists of the endocannabinoid system probably do not exist
in Nature," observes Ethan Russo, MD. "Pharmaceuticals that act in
such a manner may be outside physiological parameters. The normal
order calls for more subtlety of function.

GW is beginning to test a plant strain high in THCV, a neutral
antagonist that lightly occupies the receptor but doesn't reverse its
effects on endocannabinoid tone. Guy says, "We may get tarred with
the brush by those who don't understand the difference between an
inverse agonist and a neutral antagonist. It's up to us to present
data in due course that reflect those distinctions."