Who’s Afraid of Cannabidiol?

THC -delta-9 tetrahydrocannabinol is often described inaccurately as “the active ingredient in cannabis.” At least five other cannabinoids (compounds unique to the cannabis plant) have been shown to exhibit biological activity, and so have some of the spicy-smelling terpenes and other compounds found in plants other than cannabis.

CBD -Cannabidiol- is an active ingredient of cannabis that has been suppressed by growers and governments for countless generations. From Marakesh to Mendocino, plants have been bred for maximum psychoactivity, resulting in high THC and low CBD content. In the Prop 215 era, California growers hoping to develop plants with a high CBD-to-THC ratio have been stymied by lack of access to an analytical test lab. Surreptitious tests have been done on “high grade” plants whose buds turned out to be in the range of 15-20% THC and 0.1% CBD.

The U.S. Drug Enforcement Administration has placed CBD on Schedule I even though CBD has no known adverse effects and doesn’t induce “euphoria.” The prohibition of CBD exposes the broader marijuana prohibition as strictly a governmental control tactic having nothing to do with public health or “protecting the children.” The most dire effects attributed to marijuana -tachycardia (accelerated heartbeat), panic, confusion, anxiety, even psychosis- are effects of THC that CBD actually mitigates! By banning CBD outright and denying growers the means to develop high-CBD plant strains, the government is protecting the American people from an immunomodulator with anti-inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, and neuroprotective properties.

A high-CBD cannabis strain was developed in the 1980s by David Watson and Robert Clarke, American naturalists who founded a company called Hortapharm in Amsterdam to pursue their goal of developing plant strains for different purposes. (The day Watson and Clarke became expatriates is the day the U.S. lost its lead in the field of cannabis therapeutics.) In 1998 Hortapharm sold its seed stock to a British start-up, GW Pharmaceuticals, which has since developed a strain that expresses 97% of its cannabinoid content as CBD

GW plans to test its high-CBD strain as a treatment for rheumatoid arthritis, inflammatory bowel diseases, psychotic disorders, and epilepsy. It is now in Phase 2 trials to determine the dose levels to use in clinical trials involving people. GW mixes its high-CBD and high-THC strains in a 1:1 ratio to make Sativex, a plant extract formulated for spraying under the tongue that has been approved in Canada and elsewhere to treat neuropathic pain associated with multiple sclerosis. CBD evidently bolsters the pain-killing effects of THC while moderating its psychoactivity. In various studies, patients with severe pain have reported getting significantly more relief from Sativex, the mixture, than from GW’s high-THC extract.

The 2007 ICRS Meeting

CBD was the subject of several talks and posters that generated buzz at this year’s meeting of the International Cannabinoid Research Society, held June 26-30 at a ski resort in Saint Sauveur, Quebec. Among the promising studies: “CBD and the Neural Correlates of Anxiety,” by Jose Alexandre Crippa and colleagues at King’s College, London, and the Universidade de Sao Paulo. They measured blood flow in various parts of the brain as subjects viewed upsetting images and found that those who had been given an oral dose of CBD had markedly reduced responses. Iddo Magen’s team at Hadassah Hebrew University in Jerusalem showed that CBD and 2-AG (one of the body’s own cannabinoids) improved cognition and neurological function in mice with liver damage. Erica Carrier and co-workers at the Medical College of Wisconsin, Milwaukee, determined that CBD exerts its anti-anxiety effects by activating the adenosine receptors.

Some 350 scientists from university and drug-company laboratories attended. Merck, Pfizer, Eli Lilly, Bristol-Myers Squibb, AstraZeneca, and Allergan (maker of Botox and silicone breast implants) were among the corporate participants. They are all trying to develop synthetic drugs that confer some of the health benefits of cannabis without the psychoactivity. The studies described by representatives of these companies tend not to involve their most promising drugs; or else the speakers are not wholly forthcoming about the structure of the drugs involved.

Other participants included Cayman Chemical (which supplies various companies’ products to research labs), Valeant (now marketing a synthetic cannabinoid called Nabilone, developed by Eli Lilly in the 1980s), ElSohly Laboratories (Mississippi-based, the only company authorized by the DEA to grow cannabis in the U.S.), Bedrocan BV (which grows cannabis for the Dutch Ministry of Health, Welfare and Sport), Cannasat (a Canadian company with three plant-based products in their pipeline), and GW Pharmaceuticals.

Bayer Health Care, which distributes GW’s Sativex in Canada, had set up a large exhibit in one of the rooms dedicated to posters. Geoffrey Guy, the head of GW, expressed embarrassment (“That’s not really the sort of thing to do at a scientific conference”) and pride (“I rather liked it; the materials they distributed were excellent”) in a 1:1 mix.

The meeting’s primary sponsor was Sanofi-Aventis, the world’s third-largest drug company, which had suffered a major setback in mid-June when an FDA advisory panel voted 14-0 against recommending approval of Acomplia (also known as Rimonabant), a weight-loss drug that works by blocking the CB1 receptor. Acomplia has been approved for sale in the UK and elsewhere, and Sanofi and most securities analysts had projected it to be a blockbuster in the U.S. But the FDA advisors were troubled by the number of suicides and seizures in the clinical-trial data.

When Sanofi first announced at the 2004 ICRS meeting that Rimonabant was proving effective in large-scale trials in Europe, Jeffrey Hergenrather, MD, of Sebastopol and other California clinicians warned that reversing the effects of the body’s own cannabinoid system was very likely to cause health problems. Your correspondent had published a piece quoting Hergenrather, slugged “Danger! Danger! Danger!” So it was a little awkward to encounter the charming scientists from Sanofi at this year’s meeting, knowing they had just lost out on millions and might hold us partly responsible (when it fact we are under the radar and politically impotent).

Rimonabant has been used by more than 100,000 people in Europe and Sanofi contends that the safety profile may yet turn out to be satisfactory. They’re also trying to figure out ways to prevent those most at risk -people with epilepsy, MS, a history of serious depression, etc. etc.- from taking Rimonabant. Unfortunately, the et ceteras are numerous. Sanofi’s marketers wish they could sell Rimonabant only to diabetics for whom it would be most beneficial. They dream of applying “genomics” (analyzing every patient’s genetic make-up before prescribing) but the reality is a world in which doctors can prescribe for off-label uses and everyone wants to lose 10 pounds.

The consensus among ICRS scientists is that downward modulation of the CB1 receptor is a feasible strategy for treating diabetes and metabolic syndrome, but that Rimonabant -an “inverse agonist” that doesn’t simply block the receptor but achieves a reverse effect on endocannabinoid tone throughout the body- was too strong a drug. “Inverse agonists of the endocannabinoid system probably do not exist in Nature,” observes Ethan Russo, MD. “Pharmaceuticals that act in such a manner may be outside physiological parameters. The normal order calls for more subtlety of function.

GW is beginning to test a plant strain high in THCV, a neutral antagonist that lightly occupies the receptor but doesn’t reverse its effects on endocannabinoid tone. Guy says, “We may get tarred with the brush by those who don’t understand the difference between an inverse agonist and a neutral antagonist. It’s up to us to present data in due course that reflect those distinctions.”

FRED GARDNER edits O’Shaughnessy’s, the Journal of Cannabis in Clinical Practice. He can be reached at fred@plebesite.com




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