Spring 2004
O'Shaughnessy's
Journal of the California Cannabis Research Medical
Group
|
"Therapeutic Potential" In
Spotlight at Cannabinoid Researchers' Meeting
By Fred Gardner
The 13th annual meeting of the International Cannabinoid Research Society was
held in late June 2003 in Cornwall, Ontario —a rustbelt city on the St. Lawrence
Seaway about halfway between Toronto and Montreal— at a labyrinthine conference
center built and then sold off by the Canadian Navy.
The ICRS is 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
several from the California Cannabis Research Medical Group (two of whom made
it to Cornwall).
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 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 —herbal, synthetic,
and endogenous. First to be characterized, in the 1930s and ’40s, were
active ingredients of the cannabis plant, hence the name. Some 68 natural
plant cannabinoids have been described to date. Since the 1970s synthetic
compounds have been developed by various labs to exert effects like
those of the plant cannabinoids (synthetic agonists) and to block such
effects (synthetic antagonists). In the 1990s several chemicals in
the body were identified as acting similarly, and dubbed “endocannabinoids” (short
for “endogenous cannabinoids”).
Drugs that cancel the effects of cannabinoids —like Sanofi’s
diet pill— 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 amygdala, which is part
of the limbic system (emotional control, memory of fear, memory of
pain). These receptors are now known as “CB 1” receptors.
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.”
Any alternative to direct activation of the CB1
receptor is considered promising by the drug companies.
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 molecules
that break down anandamide and 2-AG within the cell and create drugs
to block their effect, allowing the endocannabinoids to linger. (This
might sound unnecessarily complicated, but any alternative to direct
activation of the CB1 receptor 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 team’s 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
investigators 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 a lot more to the basic cannabinoid
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 or new understandings — “cannabinoids
modulate neuronal firing in the rat baso-lateral amygdala,” for example.
A talk by Itai Bab of Hebrew University seemed unambiguously significant
to the layman
(me): “Endocannabi-noids 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 a little joke.
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 was a subtle-but-pervasive
shift in focus from the harmful to the helpful potential of cannabinoids.
Adverse effects are still being studied, of course —Sarafian, Tashkin
and colleagues at UCLA’s David Geffen School of Medicine (sic) have
pictures of blistered lung epithelial tissue that could make the joint-smokingest
reprobate invest in a vaporizer. But we heard no dire warnings about
addiction, permanently impaired brain structures, etc. 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, Nora 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.” Fried was always
straining 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?”
The charming professor 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— have repositioned themselves
as the leading pioneers of that most promising new field, the hope of suffering
humanity, cannabis therapeutics!
California Clinicians R. Stephen Ellis and Jeff Hergenrather
at the poster session, keeping abreast of the science on which
cannabis therapeutics is based.
Photos by Fred Gardner |
The glad tidings were not 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 arcane molecular-level
research seemed humanized and ennobled.
And the promising, positive findings just keep 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
• “Blockade of the cannabinoid receptor in one-day-old mouse pups
prevented milk intake and resulted in death within days of birth.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 Hunt-ington’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
• “The endocannabinoids and 2AG inhibit cancer cell proliferation
by acting at cannabinoid receptors. Endocan-nabinoid levels are enhanced
in some tumors, possibly to counteract cancer cell proliferatio2n 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 neuro-protective 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
• “Activity of the CB1 receptor has anticonvulsant effects in animal
models of seizure and epilepsy...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
• “...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.
Probably the most influential report of all was a brief statement
made by Alison Myrden, a radiant Canadian woman, weakened at 37 by
multiple sclerosis, who attend the closing sessions of the conference
at the invitation of Ethan Russo, MD. During a question period Myrden
walked to the mike and explained her situation. She had brought her
mother, whom she pointed out. Her mother (a retired surgical nurse)
had been skeptical about the medicinal validity of cannabis, but was
now convinced by what she’d heard from the scientists. Alison expressed
thanks for the basic research done to date, and her hope that it would
pay off before too long. It was short and simple, but it helped people
in the room reconnect to their mission and their ideals.