REPORT FROM THE ICRS MEETING

C-Notes

The International Cannabinoid Research Society met June 25-28 in Cornwall,
Ontario -a rustbelt city on the St. Lawrence Seaway about halfway between
Toronto and Montreal- at a labrynthine conference center built and then
sold off by the Canadian Navy. It was the 13th annual meeting of the ICRS,
a group made up mainly of university-connected scientists, many of whom
receive support from the U.S. National Institute on Drug Abuse. ICRS
members also include drug-company researchers and a small number of
physicians, including two from the California Cannabis Research Medical Group.

Abbott, Allergan, AstraZeneca, Cayman Chemical, Johnson & Johnson, Eli
Lilly, Merck, Pfizer, Schering Plough and Solvay (makers of Marinol,
synthetic THC in sesame oil) were among the drug companies represented at
this year's meeting. "None of them are presenting data," a university
researcher observed, "They're all just here to keep an eye on one another
and stay abreast of the science."

Also in attendance were reps from Sanofi-Synthelabo (a giant French company
hoping to market a cannaboind "antagonist" drug that blocks the
appetite-inducing effects of the body's own cannabinoids); GW
Pharmaceuticals (the British firm awaiting government approval to market a
cannabis-plant extract in alliance with Bayer); and Elsohly Laboratories (a
company owned by America's only legal grower, Mahmoud Elsohly,.who has
devised a test that can distinguish between traces of Marinol and natural
cannabis in the urine. Elsohly also has patented a novel THC delivery
system, the suppository. "And he is the friendliest gentleman you'd ever
want to meet," said a Californian who knows somebody who is doing time
thanks to the Elsohly test.)

There are three types of cannabinoids. First to be discovered, in the 1930s
and '40s, were active ingredients of the cannabis plant, hence the name.
Since the 1970s compounds have been developed by various labs to exert
effects like those of the plant cannabinoids (synthetic agonists). In the
1990s several chemicals occurring naturally in the body were identified as
acting similarly, and dubbed "endocannabinoids" (short for "endogenous
cannabinoids").

Drugs that cancel the effects of cannabinoids are called cannabinoid
"antagonists."

Receptors activated by cannabinoids are highly concentrated in the
cerebellum and the basal ganglia (areas of the brain responsible for motor
control, which may help explain why marijuana eases muscle spasticity in
disorders like multiple sclerosis), the hippocampus (responsible for
storage of short-term memory), and the limbic system (emotional control).

A second cannabinoid receptor was initially detected in spleen cells, white
blood cells, and other tissues associated with the immune system. The
discovery of this second receptor type -called the CB2 receptor-suggested a
product-development strategy for the drug companies: create a molecule
that, by activating only the CB2 receptor, won't induce the nasty
side-effect known as "euphoria."

The first endogenous cannabinoid, arachidonyl ethanolamine (AEA), was
identified by Raphael Mechoulam and William Devane of Hebrew University.
They named it "anandamide" after the Sanskrit word for "bliss." The
discovery of anandamide and then another endocannabinoid, 2-AG, suggested a
different commercial drug-development strategy: find the molecule that
breaks down anandamide and 2-AG within the cell and create a drug to block
its effect, allowing the endocannabinoids to linger. (This might sound
unnecessarily complicated, but any alternative to direct infusion of THC is
considered promising by the drug companies.)

ICRS meetings adhere to a standard scientific-meeting format. Over the
course of three-and-a-half days researchers presented 67 papers. Each had
15 minutes to describe their work (aided by computer-generated graphics).
Another 86 studies were recounted on posters tacked to partitions in a
large gymnasium. Each day there was a two-hour session at which the authors
stood by their posters to answer questions.

The first day and a half of talks -and a proportional number of
posters-were devoted to studies elucidating the chemical mechanisms by
which cannabinoid compounds exert their effects in the body and get broken
down. Several groups presented evidence that there is more to the
cannabinoid receptor signaling system than two receptors and two endogenous
cannabinoids. (For example, Breivogel has found that the brains of mice
lacking CB1 receptors still respond to stimulation by endogenous and
synthetic cannabinoids; Kunos et al have found a receptor in epithelial
tissue that is neither CB1 or CB2.)

"Any blockbuster talks?" we were asked when we got back. Time will have to
tell. Dramatic announcements are rare in any field of science; most studies
contribute a finite bit of information that might or might not result in
significant applications -"cannabinoids modulate neuronal firing in the rat
baso-lateral amygdala," for example.

A talk by Itai Bab of Hebrew University seemed significant to your
correspondent: "Endocannabinoids stimulate bone formation," according to
Bab, "and possibly inhibit bone resorption directly by activating
osteoblastic and osteoclastic CB2 receptors." (Osteoblasts are bone-forming
cells, osteoclasts are bone-removing cells.) What do the Bab Lab's
findings -based on work with mice-imply for the homo sapien cannabis user?
"Stoned heads equal stone bones," said Bab, making a joke for the lame-man.

Irv Rosenfeld, the Florida stockbroker who is one of seven patients
receiving U.S. government-issued cannabis, was told about Bab's results.
Rosenfeld has a rare disorder characterized by tumor formation at the ends
of his bones. "My doctors warned me to expect thinning of the bones," he
said. "They told me it was a certainty, but it hasn't happened. Maybe now
we know why."

The real news at the 2003 ICRS meeting -subtle but pervasive-was a shift in
focus from the harmful to the helpful potential of cannabinoids. Adverse
effects are still being studied -Sarafian and Tashkin at UCLA showed
pictures of blistered lung epithelial tissue that could make the
joint-smokingest reprobate invest in a vaporizer- but we heard no dire
warnings about permanently impaired brain structures. The glad tidings, as
in the case of Bab's, weren't confined to the last-day set of talks on
"Therapeutic Potential." Indeed, therapeutic benefit has been so firmly
established in recent years -thanks in part to California physicians and
patients, and thanks, also, to G.W. Pharmaceuticals-that even the
molecular-level research seemed humanized and ennobled. And the positive
data just keeps coming in:

"...2-AG may regulate sperm functions in male and female reproductive
tracts... human sperm may produce and degrade AEA to modulate their own
swimming behavior via cannabinoid receptors." -Burkman et al.

"...The endocannbinoid receptor system plays a critical role in milk
ingestion and survival of the newborn." -Fride, et al

"...These results provide a neural basis for previous studies that showed
potent suppression of the abnormal pain responses of nerve-injured rats."
- -Liu and Walker

"...This work could imply that combination treatment for pain, using
cannabinoids jointly with opioids, may be more effective than opiods alone
while utilizing lower doses and attenuating side effects" -Cichewitz et al

"... Delaying the loss of CB1 receptors, either by environmental
stimulation or pharmacologically, may be beneficial in delaying disease
progression in Huntington's Disease patients." -Glass et al.

"...This work may help to understand the mechanism of cannabinoid
anti-tumoral action, and provides a novel pharmacological target for
cannabinoid-based anti-tumoral therapies." -Blazquez et al

"... Endocannabinoid levels are enhanced in some tumors, possibly to
counteract cancer cell proliferation via cannabinoid receptors. Inhibitors
of endocannabinoid inactivation, by enhancing this endogenous tumor
suppressing tone, may provide useful, non-psychotropic agents against
cancer growth." -Di Marzo et al

"... CBD (cannabidiol) acts to produce a significant antitumor activity
inducing apoptosis [programmed cell death] ... the present results further
confirm the possible application of cannabinoid compounds as antineoplastic
agents." [neoplastic refers to unregulated growth] -Massi et al

"... Our results indicate that THC may reduce the progressive degeneration
of... neurons occuring in Parkinson's Disease... The fact that the same
neuroprotective effects were elicited by cannabidiol, a cannabinoid with
negligible affinity for the CB1 receptors, suggests that both cannabinoids
protect... neurons from death because of their antioxidant (and CB1
receptor-independent) properties." -Fernandez-Ruiz et al

"... The results of this study provide evidence that, in the hippocampus,
plasticity of the endogenous cannabinoid system occurs in response to
epilepsy." -Wallace, et al.

"...We propose that the endogenous cannabinoid system plays a fundamental
role in the physiological protection against excitotoxicity by dampening
neuronal excitability and activating protective molecular cascades."
- -Monory et al

"...There is rapidly emerging evidence that the cannabinoid receptor system
has the potential to reduce both excitotoxic and oxidative cell damage...
Here we report that treatment with D9-THC was effective if administered
either before or after onset of signs in the ALS mouse model... To our
knowledge, this is the first time a compound has been shown to be effective
in this model when administered after onset of disease signs... This
profound anti-oxidant effect was not blocked by the CB1 receptor
antagonist... suggesting the anti-oxidant effect was not receptor mediated.
Additionally, D9-THC is anti-excitotoxic in vitro. These cellular
mechanisms may underly the presumed neuroprotectitive effect in ALS. As
D9-THC is well tolerated, it and other cannabinoids may prove to be novel
therapeutic targets for the treatment of ALS." -Abood et al.

At this year's meeting there was no pitch from the director of NIDA urging
ICRS members to renew their efforts to prove the harmful effects of
cannabis. (Alan Leshner sent such a motivational message to the assembled
scientists in 1998.) The new head of NIDA, Nina Volkow, who happens to be
Leon Trotsky's great-granddaughter, has done some work in the cannabinoid
field, and is said to understand its potential.

Another indicator of the political winds shifting: Peter Fried, an
Ottawa-based professor who has conducted a 25-year, NIDA-funded study of
the children of women who smoked marijuana while pregnant, has apparently
given up trying to prove "cognitive dysfunction." It was always a strain,
because much of his data actually suggested that marijuana smoking had a
positive impact, cognitively and socially. Fried's latest study compared
the cognitive abilities of heavy users, quitters, and non-users among the
kids (now adolescents and young adults). He reports that heavy use impairs
cognition (slightly), but quitting restores it fully in a matter of months.
In fact, the quitters wind up scoring better than the non-users!

Fried's tone has changed over the years. When we first heard him in 1998,
the subtext was "Danger! Beware! Marijuana use is associated with concealed
pitfalls..." This time the subtext was: "So nu?" And at the grand finale
awards dinner Saturday night, Dr. Fried and other stars of the NIDA
constellation -people who had spent a good part of their careers funding or
carrying out the decades-long, inevitably futile search for adverse
effects-were honoring one another as the leading pioneers of that most
promising new field, cannabis therapeutics!

"Were there any blockbuster talks?..." The most influential, we thought,
was a brief statement made by Allsion NAME, a Canadian woman weakened by
multiple sclerosis, who attend the closing sessions of the conference.
During a question period she walked to the mike and explained her
situation, and said she had brought her mother, who had been skeptical
about the medicinal validity of cannabis, but now was convinced. Allison
thanked the scientists for their work and expressed hope that it would pay
off for her before too long.

Next week: An interview with Geoffrey Guy of G.W. Pharmaceuticals