Pubdate: Wed, 09 Jul 2003 Source: Anderson Valley Advertiser (CA) Copyright: 2003 Anderson Valley Advertiser Contact: http://www.mapinc.org/media/2667 Author Fred Gardner 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 - --- MAP posted-by: Jay Bergstrom