Cannabinoid Researchers Meet in Scotland
The International Cannabinoid Research Society held its 18th annual symposium June 26-29, under the craggy Cairngorm Mountains in Aviemore, Scotland. The conference center, one of 60 hotels owned by a plutocrat named Duncan MacDonald, is primarily a ski resort that fills up in the winter. MacDonald has been buying politicians so that he can expand his Aviemore operation onto a flood plain. The U.K. ain't THAT different from the U.S.
More than 200 scientists affiliated with universities and/or pharmaceutical companies presented papers and/or posters, and more than 100 others attended. At least half were women. Labs from all over the world participated. Three pro-cannabis doctors from California made the trip, too, including William Courtney of Ukiah, who is trying to determine why ingesting raw cannabis has helped some of his patients. (THC exists as an acid until cannabis is heated. THC-A is biologically active but its effects haven't been studied much.) Courtney is also interested in the potential of cannabidiol (CBD), a non-psychoactive component found only in trace quantities in strains bred to maximize THC content, i.e almost all the plants grown in California.
"The Italians dominate. Then the Spaniards," said author Martin Lee, surveying the auditorium as if it were the Olympic Stadium. And indeed, the brilliant young scientists and mature superstars gathered in Aviemore are racing one another (while working in teams), and compete for medals, though with more comradeship than prevails in other fields. This may have something to do with a shared sense of indirect connection to the forbidden herb. Acquaintances and even colleagues express amusement when they hear that a scientist is specializing in cannabinoid research. But ICRS scientists are hardly subversive, individually or as a group, except in the sense that their work tends to confirm and explain the medical effectiveness of the "crude" plant.
ICRS scientists accept the constraints of marijuana prohibition. Their practical goal is to develop drugs that exert certain beneficial effects of the plant -countering nausea, inflammation, malignancy, bone loss, etc. -without inducing "euphoria" or other alterations of thought or mood. Their research has yet to yield a blockbuster drug but it has led to the discovery and elucidation of the endocannabinoid system.
 Drs Jeffrey Hergenrather, Ethan Russo and Barbara Costa
Since ananamide has cannabis-like effects, one approach to designing a legal, cannabis-like drug involves blocking production of the enzyme that breaks down anandamide --fatty acid amide hydrolase, or FAAH. Less FAAH means more anandamide available at the synapse. "Endocannabinoid Modulation of Pruritus" was one of many papers touting the promise of FAAH inhibitors. Investigators from Virginia Commonwealth University reported that mice made to itch by injection of a mast-cell degranulator, "Compound 48/80," would reduce their scratching if given a FAAH inhibitor called URB597. And the mice wouldn't get loaded! "The FAAH inhibitor URB597 reduced the response to Compound 48/80 scratching without the increased hypomotility associated with CB1 receptor activity."
Similarly, investigators led by Sandor Batkai of the National Institutes of Health have found that URB597 and another FAAH Inhibitor, AM-3506, lower blood pressure in rats by preventing the breakdown of anandamide. Ingesting herbal cannabis would have the same effect on blood pressure, but... "Because inhibition of FAAH does not elicit behavioral effects predictive of addictive potential, FAAH inhibitors such as AM-3506 may be considered for treatment of hypertension."
Why, I wondered, wouldn't bolstered anandamide levels lead to psychoactive effects? FAAH inhibitors apparently work on systems in the body where anandamide is being actively produced, whereas ingesting THC activates CB1 receptors throughout the body. A concern is that the FAAH enzyme interacts with compounds other than anandamide, and blocking its production might lead to unforeseen side effects.
Almost every West Coast doctor surveyed by O'Shaughnessy's has a few patients using cannabis to treat pruritis. There are undoubtedly many other people out there who wouldn't use cannabis, even to deal with a relentless itch, but would gladly buy a non-psychoactive synthetic sold on TV with a name like Soothex. Or a blood-pressure medication that works by bolstering anandamide levels and doesn't involve ingestion of cannabinoids. Many proponents of medical cannabis, convinced that the herb is benign and outraged by the cruelty of prohibition, assume that legalization for medical use will lead to large-scale renunciation of pharmaceuticals. The drug companies seem to make the same assumption, which is why they pay politicians to uphold prohibition. But the truth is, MOST PEOPLE DON'T WANT TO GET HIGH to control conditions like hypertension or pruritis. They would prefer a drug that didn't alter their thinking or mood in any way -if only the drug companies could come up with one.
URB597 was developed by Daniele Piomelli of Kadmus Pharmaceuticals in Irvine. The patent is now owned by a Organon, a subsidiary of Schering-Plough. URB597 also shows efficacy against intestinal inflammation, according to a paper by Sharkey, et al., "Inhibitors of Endocannabinoid Degradation Reduce Colitis By Activation of CB1 and CB2 Receptors." Jeff Hergenrather, MD, of Sebastopol, who has treated and reported on patients using cannabis to treat Crohn's Disease and inflammatory bowel disorders, got to compare notes with Sharkey in Aviemore.
Basic Science Ultimately Pays Off
At this year's ICRS meeting, Patricia Reggio of the Center for Drug Discovery, University of North Carolina Greensboro, showed a computer simulation of 2-AG being released from a "post-synaptic" cell and moving across the synapse to a CB1 receptor embedded in the membrane of the transmitting cell. Instead of penetrating the CB1 binding pocket from without, according to Reggio's amazing graphic, 2-AG penetrates the cell membrane near the receptor and then shimmies into the binding pocket from within the membrane and deliver its chemical message. Very sexy stuff.
ICRS scientists have been systematically studying the compounds involved in the creation and breakdown of the endocannabinoid agonists and receptors, trying to determine which precursor components and degrading enzymes might be targets for drug development. There was buzz at this year's meeting around a report by Raphael Mechoulam and Itai Bab of Hebrew University in Jerusalem that a byproduct of anandamide, oleoyl serine, which has been found in brain and bone, shows phenomenal efficacy in promoting bone growth and slowing bone resorption. Mechoulam said he deduced that the body would make oleoyl serine by applying "nature's law of stinginess." If a truly effective drug to treat osteoporosis -a natural product- goes on the market in about eight years, you read it here first. Ditto a Nobel Prize for Mechoulam's role in discovering Anandamide and, long before that, the chemical structure of delta-9 THC.
Another offshoot of basic research was described by Christopher Fowler, who studied the role of the endocannabinoid system in prostate cancer. The prognosis in prostate-cancer cases -how advanced and fast-moving the cancer is deemed to be- determines whether invasive treatment is called for. Fowler and colleagues at Umea University in Sweden hypothesized that the expression of CB1 receptors in response to prostate cancer growth would indicate how likely the cancer was to metastasize. They studied preserved tissue samples that had been removed from patients with enlarged prostates, the course of whose cancers was known. They measured the amount of CB1 protein present in the tissue samples and found higher levels in those with poorer prognoses. Doctors and prostate-cancer patients may in the future take into account CB1 level in making treatment decisions.
A final point from Fowler, et al: The proliferation of CB1 receptors triggered by aggressive prostate cancers implies that such cancers may be treatable by cannabinoids. "Given that the endocannabinoid system can affect the invasivity of prostate cancer tumor cells in vitro, its modulation may be a possible therapeutic approach for prostate cancer."
Novel Strategies
Two oompanies with sharply contrasting approaches to drug development have played prominent roles at recent ICRS meetings: Sanofi-Aventis and GW Pharmaceuticals. French-based Sanofi, the sixth-biggest drug company in the world, has gotten approval in some countries (but not the U.S.) to market Rimonabant, also known as Acomplia, a drug that promotes weight loss by blocking the CB1 receptor, and therefore blocking appetite. On the day the ICRS meeting began, the UK National Health Service agreed to reimburse patients taking Acomplia, which will spur its use. The Sanofi team arrived in Aviemore tres joyeux. Some 65,000 patients have now been subject to CB-1 blockade via Rimonabant/Acomplia. The company says no pattern of serious adverse effects has emerged, and will try again for FDA approval.
Dame Fortune has not been smiling on GW Pharmaceuticals, a British company launched in 1998 that grows cannabis under license from the Home Office and makes whole-plant extracts with precise cannabinoid ratios. The company has approval in Canada to market Sativex -a mixture of cannabis extracts high in THC and CBD- for pain brought on by Multiple Sclerosis and cancer. This spring a phase-three trial of Sativex on MS patients for whom conventional therapies were inadequate showed a very high response rate (more than half reported at least 30% pain reduction), but an unexpectedly high response to placebo undercut its statistical significance, and GWP stock plunged. UK/European regulators have asked for a final study of Sativex for MS-spasticity; it is near completion. Backing from the Japanese drug maker Otsuka enables GW to pursue an ambitious research agenda focused on CBD and other cannabinoids usually characterized as "minor."
♦ Dr. Courtney wishes California medical-marijuana growers would try to produce plants high in cannabinoids other than THC. Your local "high-grade" sinsemilla may be 15% THC, 0.1% CBD. A few growers have reportedly obtained seeds that are 4-7% CBD. When their crops start to come in, straightforward popular research into the medical potential of cannabis will become possible. In the meantime, we can only glean the potential of CBD from reports to the ICRS.
♦ Philip Robson of Oxford University, Dept. of Psychiatry, and GW Pharmaceuticals, reviewed psychiatric adverse events in the records of 496 MS patients who had received Sativex and 434 who received placebo. Sativex was found to have induced adverse events at a low rate -disorientation (5.4%), depression (3%), dissociation (2.8%), hallucinations (1.8%), confusional state (1%), and paranoia (.8%). Anxiety and insomnia occurred more frequently following placebo. "There was no evidence from these studies that Sativex poses any long-term psychiatric risks to patients," Robson and co-author Tilden Etges concluded. "The presence of CBD may inhibit some unwanted effects of THC."
♦ A team led by Michael Cawthorne of the Clore Laboratory, University of Buckingham, reported on "The Metabolic Effects of THCV and CBD." THCV is a cannabinoid produced by the plant that is an antagonist at the CB-1 receptor. The investigators conducted a five-week trial treating genetically obese mice with purified THCV, purified CBD, and a 1:1 mix of the two. The mix was most promising. The THCV exerted a thermogenic effect (increased energy expenditure) while the CBD raised plasma HDL-cholesterol concentration and reduced liver triglyceride levels. "This is the first demonstration of potential beneficial effects of CBD in hypercholesterolaemia and non-alcoholic fatty liver disease," the authors concluded. "In combination with THCV, it potentially addresses a number of components of the metabolic syndrome."
♦ Saorise O'Sullivan of the University of Nottingham, Derby City General Hospital, looked at the vascular effects of CBD on rat aorta isolated in vitro. She had previously shown that THC has a relaxant effect that is partially inhibited by the antagonism of a putative third CB receptor. This year she concluded, "CBD causes significant vasorelaxation over time... The majority of the vasorelaxant effects of CBD appear to be through calcium channel inhibition."
♦ A team of Spanish and Scottish researchers used a piglet model of hypoxic-ischemic encephalopathy (brain damage due to insufficient oxygen, which affects an appalling number of premature babies and for which there is no specific treatment). They concluded, "Administration of CBD alone after HI reduced brain damage and was associated with extracerebral benefits." The intellectual duplicity of prohibition is exposed by the presence of non-psychoactive CBD on Schedule 1 (dangerous drugs with no medical potential). CBD modulates the effects of THC by an unknown mechanism. It may be an antagonist at a putative third cannabinoid receptor.
♦ Several investigators are trying to figure out how cannabinoids exert anti-tumor effects. An Italian group studying "Inhibition of Human Glioma Cell Migration and Invasiveness Induced by Cannabidiol" found that CBD inhibits production of an enzyme (Matrix Metalloproteinase-2) required for tumor growth.
CBD Ameliorates Cognitive Impairments Associated with a Model of Chronic Liver Disease in Mice" -the title sums up the results reported by Iddo Magen of the Hadassah Hebrew University Medical. The structure of CBD, Magen noted, "resembles that of resveratrol, which is found in red wine and has anti-inflammatory activity. Resveratrol has also been shown to decrease liver oxidative stress." So let's have a glass of Charles Shaw Merlot before moving on to the posters.
Geoffrey Guy, MD, the founder of GW Pharmaceuticals, observed in a post-conference interview, "CBD was considered a 'minor cannabinoid' when we started looking at it. Now it's the focus of considerable research." Studies sponsored by GW have already established the medical potential of THCV and CBG (Cannabigerol). The company has a three-year plan to produce plant extracts in which other "minor" cannabinoids predominate, and, in concert with Otsuka scientists, to screen their components for biological activity. "We've got to stop thinking of the targets for phytocannabinoids as 'cannabinoid receptors," says Guy. "We should be asking 'Which receptors are activated by the plant polyphenols?'"
Clearly there is more to cannabis than just THC. There are numerous other components --"minor" cannabinoids, terpenoids and flavonoids that affect our bodies through various mechanisms and might be developed into useful medications. The field of cannabis therapeutics is just opening up. |
