A good overview on the state of endocannabinoid research and the development of cannabis-based pharmaceuticals.
Cannabinoid Researchers Won’t Take the High Road
Report from the ICRS Meeting
By FRED GARDNER
July 19 / 20, 2008
The International Cannabinoid Research Society held its 18th annual symposium June 26-29, under the craggy Cairngorm Mountains in Aviemore, Scotland. More than 200 scientists affiliated with universities and/or pharmaceutical companies presented papers and/or posters. At least half were women. (I didn't count.) Labs from all over the world were represented. "The Italians dominate. Then the Spaniards," said Martin Lee, as if we were covering the Olympics. Come to think of it, the stars gathered in Aviemore are racing one another (while working in teams), and winning a medal means a lot to them, though their competition is far less intense than in other scientific fields.
ICRS scientists accept the constraints of marijuana prohibition. Their practical goal is to develop drugs that exert certain beneficial effects of the "crude" plant -countering nausea, inflammation, malignancy, bone loss, etc. -without inducing "euphoria." Their research has yet to yield a blockbuster drug but it has led to the discovery and elucidation of the endocannabinoid system. Since the ICRS was founded in 1990, its members have identified two agonists produced in the body --Anandamide and 2-AG- which work as chemical counterpunches, sent from cells that are receiving chemical signals to cells that are transmitting them (to modulate the rate of transmission). The researchers have identified two kinds of receptors (protein molecules on the outside of certain cells) activated by these endocannabinoids. CB1 is concentrated in the brain and the central and peripheral nervous systems. CB2 is found mainly in tissue associated with the immune system and in nerve tissue associated with inflammation --but is present in brain, too. There are probably other agonists and receptors and chemical players to be named later.
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. Then you can see it lighting up a cigarette.
ICRS scientists have been systematically studying the compounds involved in the creation and breakdown of 2-Ag and anandamide, 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, 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” --and it was subsequently found in brain and bone. 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.
Good news for modern man --or at least a source of guidance with a difficult decision-- was recounted 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, but often the prognosis is indeterminate. 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.
Another 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."
Esther Fride of Ariel University and colleagues had established previously that normal sucking behavior in newborn mice involves activation of the CB1 receptor by the endocannabinoid 2-AG (which is expressed in quantity in mother's milk). Mice treated with a CB1 antagonist at birth will be undernourished and undersized. An analogous syndrome -"non-organic failure-to-thrive," or NOFTT-- occurs among some 4% of human infants. Newborn mice with CBl blockaded -"NOFTT mice," according to Fride's model-- exhibit symptoms, including low weight, short height, anxiety and hyperactivity that last into adulthood. But if 2-AG is administered during the neonatal period, NOFTT symptoms won't develop. Fride and her colleagues tested various infant formulas and found 2-AG to be "absent, or present in low concentrations... as opposed to considerably higher levels in maternal milk." They suggest that NOFTT can be reduced by adding 2-AG or "endocannabinoid-enhancing supplementation" to formulas.
ICRS researchers are testing numerous drugs that inhibit formation of FAAH --fatty acid amide hydrolase, the enzyme that breaks down anandamide. FAAH inhibition means more anandamide available at the synapse. "Endocannabinoid Modulation of Pruritus" was one of several papers on the promise of FAAH inhibitors presented at Aviemore. Investigators from Virginia Commonwealth University found 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 high! "The FAAH inhibitor URB597 reduced the response to Compound 48/80 scratching without the increased hypomotility associated with CB1 receptor activity."
Almost every West Coast doctor surveyed by O'Shaughnessy's has reported a few patients using cannabis as a treatment for pruritis. Which is not to say that there won’t be plenty of customers for a synthetic sold on TV with a name like Soothex. URB597 was developed by Daniele Piomelli of Kadmus Pharmaceuticals in La Jolla. The patent is now owned by a Organon, a subsidiary of Shering-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." [Again, Dr. Hergenrather and colleagues in the Society of Cannabis Clinicians have monitored and reported many cases in which cannabis is used to treat Crohn’s Disease and inflammatory bowel disorders.]
Investigators led by Sandor Batkai of the National Institutes of Health have found that URB597 and another FAAH Inhibitor, AM-3506, effectively lower blood pressure in rats by preventing the breakdown of anandamide. Ingesting THC 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."
CBD Still Waiting at the Altar
Non-psychoactive cannabidiol, not THC, is the predominant cannabinoid when the cannabis plant is in the wild. High-THC strains have been developed over time by growers who valued psychoactivity. CBD modulates the effects of THC by an unknown mechanism. It may be an antagonist at a putative third cannabinoid receptor.
Today, California "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. Here are some highlights from the abstract book:
• 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.”
• 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 (a cannabis-plant extract containing an equal mix of THC and CBD, prescribable in Canada and the UK) 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."
• 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 study 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.
Fred Gardner edits O’Shaughnessy’s, the journal of cannabis in clinical practice. He can be reached at [email protected]