TAKE TWO SATIVEX AND CALL ME IN THE MORNING

C-Notes

GW Pharmaceuticals, the British company that has conducted successful
clinical trials of cannabis-based medicines, has signed a deal allowing
Bayer AG to market one of its tinctures in the UK under the Sativex(r)
brand. Bayer also gets a limited-time option to negotiate marketing rights
in Europe and "selected other countries."

GW gets a cash infusion from Bayer to push forward with research,
production, and clinical trials -plus a cut of future sales proceeds. Its
stock on the London Exchange has risen from about 190 to about 250 in
recent weeks. GW stock rose sharply earlier this spring when the company
applied to the Medicines and Healthcare Products Regulatory Agency (the
British equivalent of the USFDA) for approval of Sativex as a treatment for
severe neuropathic pain and multiple-sclerosis symptoms. Bayer is betting
that in the months to come, the MHRA will approve Sativex or kick the
application dossier back to GW with requirements that can be fulfilled
readily.

GW was launched in 1998 by Geoffrey Guy, MD, a pharmaceutical entrepreneur
whose first canny move was to buy all the seed strains collected and
refined over the years by Hortapharm AG, a Dutch firm run by two expatriate
hipster geniuses, Dave Watson and Robert Clarke. (Watson and Clarke had
split California in the mid-1980s, convinced by the FDA's approval of
Marinol that the U.S. government would not allow development of plant
strains for medical use. Serious dudes, and shrewd.)

GW's drug-development strategy was based on the assumption that various
components of the cannabis plant beneficially modulate the effects of THC
and exert helpful effects of their own. Guy inferred from the literature
that the cannabis Queen Victoria smoked to alleviate menstrual cramps was
rich in cannabidiol (CBD), and he hypothesized that CBD, not THC, was the
key anti-convulsant component. To date GW has bred plant strains in which
six different "cannabinoids of interest" predominate. The only ones to have
been tested in clinical trials are high-THC (which GW has dubbed
"Tetranabinex"), high-CBD ("Nabidiolex"), and a 50-50 mix (good old "Sativex").

In addition to 66 known cannabinoids (21-carbon atoms in ring structures,
with hydrogen and oxygen molecules attached at different points), the
cannabis plant contains hundreds of compounds -terpenes, flavonoids, amino
acids, fatty acids, proteins, sugars, hydrocarbons, simple esters,
steroids, nitrogenous compounds, vitamins, elements, and more (as the
pitchmen say)... Terpenes produced in the glandular trichomes are the
essential oils that give cannabis its smell. GW researchers hypothesize
that certain terpenes may have anti-ulcer and anti-mutagenic potential.

So GW's approach has been to grow plants with desired cannabinoid ratios
and blend them -"trace"components and all- into treacley extracts that can
be administered in defined doses by spraying into the mouth. To date the
extracts have been used in randomized double-blind trials involving
patients with multiple sclerosis or neuropathic pain at four UK hospitals.
Significant reductions in pain and spasticity have been reported.

According to GW's May 21 press release, "GW is to be responsible for
commercial product supply and has entered into a supply agreement with
Bayer. GW will manage the supply of product through a range of contract
manufacturing partners, arrangements for which are all in place."

Bayer's Original Blockbuster

One of the first pieces I edited at Scientific American was about aspirin,
Bayer's original blockbuster drug, which is also plant-based. The article
had been written by H.O.J. Collier, an Englishman. The managing editor,
Dennis Flanagan, generalized as he handed it to me that in England (and
other countries of the British empire), scientists got a liberal education
and learned how to write clearly; whereas in the U.S., they -especially the
chemists- had trouble explaining what they did in terms the educated layman
could comprehend. (Our idealized reader was "the educated layman.")

The active ingredient in aspirin, as patented by Bayer in Germany in 1899,
is acetylsalicylic acid. "The name itself," wrote Collier in 1963
"represents one of the first exercises in the peculiar art of applied
etymology that the merchandising specialists of the pharmaceutical industry
have brought to such a high point of elaboration today. The prefix 'a-'
stands for the acetyl group... The root, 'spir,' stands for spirsaure
..(salicylic acid) distilled from the flowers of the meadowsweet (Spiraea
ulmaria)."

Salicylic acid was also derived from willow bark and oil of wintergreen.
The first paper to describe medicinal effects from any of these sources was
read to the Royal Society of London in 1763: "An Account of the Success of
the Bark of the willow in the Cure of Agues," by either Edmund or Edward
Stone (a printer's error in the Philosophical Transactions leaves the
credit up for grabs forever).

A century later the fever-reducing and anti-inflammatory effects of
salicylic acid were well known but "its success was diminished by the
irritation and damage it caused to the moist membranes lining the mouth,
gullet and stomach." It was not until the late 1890s that Bayer chemist
Felix Hofmann found a simple way to make salicylic acid in a less
irritating form by adding an acetyl group.

Aspirin is not entirely benign, however, and to this day it causes
thousands of deaths annually due to allergic reactions and gastrointestinal
bleeding. Advocates of legalizing cannabis for medical use often remark
the irony of aspirin, with its occasionally fatal side effects, being sold
over the counter while their benign herb of choice remains prohibited.

David Hadorn, MD, a physician associated with GW who has recently opened a
practice in Berkeley, observes that "the research dossier on cannabis is
far more robust than for any other long-used drugs, including aspirin,
acetaminophen, digitalis, codeine, morphine, penicillin, thyroxine, and
vitamin B12, which 'grandfathered' onto the FDA's list of approved drugs...
Imagine physicians' reaction to the suggestion that they should stop using
aspirin, codeine, penicillin, etc. until randomized controlled trials are
conducted 'proving' that these medicines 'really' work!"

One of the FDA's present requirements is that a manufacturer seeking
approval for a new drug explain its mechanism of action. The steps by which
aspirin reduces pain and fever are not precisely known. "It has always
been easier to catalogue the wide application of aspirin to man's commonest
ills than to explain its mode of action," wrote Collier. "There is no doubt
about the usefulness of the drug. If the precise nature of its biochemical
action remains a mystery, it is because so little is known about the
biochemistry of the defensive responses, such as pain, fever and
inflammation, evoked in the body by disease."

The same could be said of Sativex in 2003... And the spirit of Dennis
Flanagan has appeared at my side, looking pained and shaking his head over
Hadorn's use of the word "robust."

No Hurry On Guidelines -MBC

In March the California Medical Association resolved to urge the state
Medical Board to issue practice guidelines for doctors approving cannabis
use by their patients. The CMA resolution was a watered-down version of a
motion by Tod Mikuriya and colleagues defining four specific requirements
they thought the guidelines should list. On May 8 about a dozen patients,
accompanied by three physicians, attended a Medical Board meeting in
Sacramento to reiterate the request for guidelines and to express concern
about investigations of doctors who approve cannabis use. On May 21 two
CMA reps and three reps from the Board met to draft guidelines. Or so we
assumed.

According to MBC public information officer Candis Cohen, the reps
agreed to draft an article to appear in the July "Action Report," the
Board's quarterly newsletter. Asked if the article would contain a
proposal for guidelines (which, presumably, a member of the Board's Medical
Quality Division would then move to adopt), Cohen said "I don't think they
committed to actually drafting" a set of guidelines. "It's a work in
progress," she added reassuringly.

The MBC's current "Action Report" includes one of those articles that
medical newsletters are forever running to promote screening for this
condition or that: "Colorectal Cancer Screening Saves Lives -But Too Few
Get Tested," by Diane Fink, MD of the American Cancer Society. The ACS
recommends "flexible sigmoidoscopy every five years" beginning at age
50. Sigmoidoscopy is a painful, humiliating procedure in which the
healthcare provider sticks a camera on a tube up the patient's butt. The
rationale, as stated by Fink, is that they can "find and remove
precancerous polyps before they develop into a serious health problem."

However, a report in the current Journal of the National Cancer
Institute suggests that such frequent screening for colon cancer is "overly
aggressive," and that once every 15 years -or once in a lifetime- would
achieve the same risk reduction. Dr. Polly Newcomb and colleagues at the
Fred Hutchinson Cancer Research Center in Seattle looked at the records of
1668 patients with colorectal cancer and a control group of 1294 healthy
people. They concluded that those who had never had a screening were at
four times greater risk for colorectal cancer than those who had had a
single screening. But the reduction in risk lasted for at least 15 years
(which is about how long it takes for a polyp to progress to cancer).
Getting screened every five years does not appear to provide additional
benefit, according to Newcomb et al.