Cannabinoid Researchers Won’t Take the High Road

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










Fred Gardner is the managing editor of O’Shaughnessy’s. He can be reached at