Journal of the California Cannabis Research Medical
Dr. X's Talks of Special Interest
The most interesting talks at the 2005 ICRS meeting were a mix of
basic science and clinical science. The numbers are somewhat arbitrary —they
were all amazing.
1. Krisztina Monory and colleagues at the Max Planck
Institute in Germany unveiled dazzling expertise with the latest “conditional knockout” technology.
Monory created a series of mutant mice and subjected them to behavioral
With conditional knockouts, she dissected the involvement of different
neuronal subpopulations colocalizing with cannabinoid 1 (CB1) receptors.
Provocatively, her results suggested that GABAergic forebrain interneurones
are not required for the manifestation of typical symptoms produced
by THC treatment, paving the way for a novel interpretation of cannabinoid
2. Patti Reggio has long researched the mechanisms by which THC, anandamide,
and other cannabinoids bind to the CB1 receptor, the “key-in-lock” analogy.
Her research indicated that the “lock” has more than one
keyhole; THC and anandamide may share one binding site, and this differs
from binding sites for WIN55 and other cannabinoids.
In fact, the binding site for THC may be a “side door,” a
part of the receptor that faces the lipid bilayer, rather than the
extracellular portion of the receptor. Reggio identified two beta-branching
amino acid residues on the receptor that specifically interact with
THC (which she wonderfully called “groove residues,” because
of their chemical structure).
3. Many scientists have suspected the presence of a third cannabinoid
receptor. Two research groups converged upon a molecular entity called “GPR55” as
the long-sought “CB3” receptor. GPR55 was identified six
years ago, but was labeled an “orphan receptor” because
its endogenous ligand was unknown.
A team at GlaxoSmithKline went “ligand fishing” and discovered
that GPR55 has affinity for anandamide, CP55,940, and SR141716A.
Simultaneously, a team at AstraZeneca reported GPR55 is a G13-coupled
activates the intracellular signaling mediator RhoA. GPR55 is expressed
in the brain as well as mesenteric arteries, and regulates blood
4. The efficacy of THC at CB1 is modulated by other proteins. Chris
Breivogel gave an update on beta-arrestin 2 (BA2), a protein implicated
in the desensitization of CB1 and other G-protein-coupled receptors.
Experiments with mice suggested that BA2 shuts down CB1 signaling by
THC, yet does not affect other cannabinoid ligands. Whether BA2 shuts
down THC in humans remains to be seen; the BA2 gene is actively evolving,
its sequence differs in humans, and the gene is undergoing positive
Deborah Lewis presented research on CRIP (cannabinoid receptor interacting
protein) 1a and 1b. CRIP1b may regulate the membrane localization of
CB1. Intriguingly, CRIP 1b has only been identified in human and chimpanzee
genomes, it may be unique to primates.
Several studies supported the notion that cannabis is more than simply
5. Several studies supported the notion that cannabis is more than
simply THC. This should be no surprise, given the number of people
who consume medical cannabis yet cannot tolerate Marinol (pure THC).
Richard Musty and coworkers showed that anxiety induced by THC alone
is mitigated by the addition of cannabichromene (CBC).
Ethan Russo showed that cannabidiol (CBD) acts at the 5HT1a receptor,
a serotonin receptor targeted for the treatment of anxiety, depression,
Markus Leweke and colleagues at Köln conducted a randomized,
placebo-controlled study involving 42 patients with acute schizophrenia.
reduced psychopathological symptoms of acute psychosis, on par
with Amisulpride (a new antipsychotic medicine not available
in the U.S.,
said to be as effective as Clozapine).
CBD produced significantly less severe side effects than amisulpride.
Stephan Wright and colleagues at GW Pharmaceuticals showed that a combination
of CBD and THC was better than THC alone in the relief of refractory
cancer pain, based upon a randomized clinical trial of 177 subjects.
6. In a similar “synergy” theme, Roger Pertwee and his
team reported a unique characteristic of tetrahydrocannabivarin (THCV),
a minor variant of THC (THC has a five carbon tail, THCV has a three
carbon tail). THCV selectively antagonized the effects of anandamide,
with little antagonism of THC. It’s as if cannabis was formulated
by a pharmaceutical company, and designed as a combination remedy that
simultaneously gave our endogenous mechanism a rest (shutting down
anandamide) and supplemented with an exogenous remedy (THC).
7. Donald Tashkin and colleagues at UCLA conducted a large, case-control
study of marijuana smokers in Los Angeles. They determined that longterm
heavy use of marijuana was not a risk for cancer of the lung, upper
airwaves, or esophagus. This surprised Tashkin, whose lab previously
demonstrated that marijuana smoke harbors potent carcinogens, and smoking
damages airway tissues.
Tashkin’s team interviewed over 1,200 L.A. patients with cancer,
and compared them to an equal number of “controls” matched
for age, gender, ethnicity, tobacco and alcohol use, diet, family history
of cancer, and other socio-demographic factors. The relative risk of
marijuana smoking, calculated as a statistical odds ratio, was < 1
(1 = the control group’s chances of cancer). In contrast, heavy
tobacco smokers had a 21-fold greater risk of cancer than control
Given the statistics, Donald Abrams posed a question from the floor,
asking Tashkin to comment on the possibility that marijuana might
provide a protective effect against lung cancer. Tashkin tried
to back himself
out of a corner, then concluded, “That is not an unreasonable
hypothesis.” The anti-inflammatory and anti-tumor effects
of THC, terpenoids, and flavonoids in marijuana smoke may very
provide a protective effect against toxic L.A. air pollution!
8. Donald Abrams and colleagues at San Francisco General Hospital
conducted a randomized, placebo-controlled study involving 50 patients
with HIV-related peripheral neuropathy. Marijuana cigarettes supplied
by NIDA provided pain relief comparable to Neurontin (gabapentin),
the most widely used treatment for peripheral neuropathy. Given the
poor worth of NIDA ganja, patient response to quality cannabis should
be even better.
A questioner criticized the use of marijuana as medicine, brandishing
the often-cited shibboleth, “you can’t separate the high
from the clinical benefits.” Abrams deadpanned his reply, “I
am an oncologist as well as a specialist in AIDS, and I don’t
think that a drug that creates euphoria in patients with terminal
diseases is having an adverse effect.”
9. Ethan Russo of GW Pharmaceuticals showed that abrupt cessation
of a medicinal cannabis extract was not associated with a withdrawal
syndrome. A series of 25 patients with multiple sclerosis who took
Sativex (50% THC and 50% CBD) for over one year experienced minor and
transient disturbances of sleep and appetite when withdrawn from the
Abstinence from Sativex was associated with re-emergence of MS-related
symptoms, however. The study also showed that long-term treatment with
Sativex did not result in dose escalation or tolerance.
Patients have never responded consistently to treatment. Every
time a prescription is written (except for identical twins) what
effectively begins is a clinical trial with n=1.
-Alfred PJ Lake, MD