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Autumn 2005
O'Shaughnessy's
Journal of the California Cannabis Research Medical Group

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 tests.

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 pharmacology.

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 receptor that activates the intracellular signaling mediator RhoA. GPR55 is expressed in the brain as well as mesenteric arteries, and regulates blood pressure.

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 selection.

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 THC.

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, and pain.

Markus Leweke and colleagues at Köln conducted a randomized, placebo-controlled study involving 42 patients with acute schizophrenia. CBD significantly 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 subjects.

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 well 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 drug.

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


O'Shaughnessy's
O'Shaughnessy's is the journal of the CCRMG/SCC. Our primary goals are the same as the stated goals of any reputable scientific publication: to bring out findings that are accurate, duplicable, and useful to the community at large. But in order to do this, we have to pursue parallel goals such as removing the impediments to clinical research created by Prohibition, and educating our colleagues, co-workers and patients as we educate ourselves about the medical uses of cannabis.
 
SCC
The Society of Cannabis Clinicians (SCC) was formed in the Autumn of 2004 by the member physicians of CCRMG to aid in the promulgation of voluntary standards for clinicians engaged in the recommendation and approval of cannabis under California law (HSC §11362.5).

As the collaborative effort continues to move closer to issueing guidelines, this site serves as a public venue for airing and discussing these guidelines.

Visit the SCC Site for more information.