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Summer 2003
O'Shaughnessy's
Journal of the California Cannabis Research Medical Group

What Every Doctor Should Know About Cannabinoids

What scientists really know about how marijuana exerts its effects is updated every summer at the Inter-national Cannabinoid Society’s annual meeting.
The ICRS was organized in 1990. Originally the “C” stood for “cannabis,” but so few members were working with the plant itself that in ‘95 it was decided to change the C-word to “Cannabinoid,” which refers to chemicals synthesized in the lab and produced by the body as well as those found in the plant.
The 2002 ICRS meeting was held at Asilomar. Twenty-six nations were represented. A dozen corporate sponsors, including Eli Lilly, Johnson & Johnson, Merck, Pfizer, and Schering Plough provided scholarships enabling 40 graduate students to attend. Also taking part were several California physicians whose patients have been using marijuana medicinally.
Although chemists have studied cannabis since the mid-1800s, the first plant cannabinoids were identified in the early 1940s by Dr. Roger Adams, a University of Illinois researcher. Adams identified cannabinol (CBN) and cannabidol (CBD), which tend to be the predominant cannabinoids in strains grown for fiber, a.k.a. hemp (which had been a significant crop in Illinois). The distillation techniques available to Adams did not enable him to fully isolate and identify tetrahydrocannabi-nol (THC).
To date some 66 cannabindoids have been found, most of them chemically in-active when inhaled or ingested into the body. The cannabis plant also contains hundreds of chemical substances that are not unique to it, including terpenes and flavinoids known to exert biological effects.
In 1964 the precise structure of the main psycho-active cannab-inoid, delta-9 THC, was described in a paper by Raphael Mechoulam and Y. Gaoni of the Weissmann Institute of Science in Rehovoth, Israel. (Chromatography had enabled them to isolate it.)

Raphael Mechoulam


There followed a long search in Mechoulam’s lab and elsewhere for synthetics that would have the therapeutic effects of THC without the psychoactivity. (A drug was defined as a cannabinoid if it reduced pain and body temperature, and induced spontaneous activity in low doses and catalepsy at high doses in test animals.)
In 1974 Pfizer produced a synthetic cannabinoid, CP-55,940, which is about 40 times stronger than delta-9 THC. Although its psychoactivity kept it from being marketed as a medicine, CP-55,940 became a widely used research tool. Unlike THC, which exerts a weak, rapidly fleeting effect, a synthetic “supercannabinoid” binds strongly enough to the cannabinoid receptors so that, when labeled radioactively, it can reveal their locations in various tissues of the body.


Cannabinoid Receptors
In the late ’80s, Alynn Howlett and William Devane at the University of Washington in St. Louis reported finding cannabinoid receptors in the brain proteins on the outside of certain cells to which cannabinoids bind, inducing a cascade of molecular events within the cell.
Researchers were surprised to find that these receptors, now known as CB1receptors, are much more prevalent in the brain than the opioid receptors. High concentrations of CB1 receptors were found in the cerebellum and the basal ganglia (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).
In 1992 a second cannabinoid receptor was found 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, or the “peripheral receptor”— strongly implied that effective non-psychoactive drugs involving the immune system could be developed.
Mechoulam and Devane, working together at Hebrew University, also identified a cannabinoid produced by the body itself, a molecule called arachidonyl ethanolamine, which they named “anandamide” after the Sanskrit word for “bliss.” The body’s own endogenous cannabinoids are called “endocannabinoids,” (just as the body’s endogenous morphine-like chemicals are called “endorphins”).

Other endogenous cannabinoids have been discovered in recent years: 2-arachidonyl glycerol (2-AG) and and perhaps palmitoylethanolamide (PEA). The endocannabinoids have a slightly weaker affinity for the CB1 receptor than THC (which itself has a weak affinity for the receptor). This makes the endo-cannabinoids hard to study and helps explain the researchers’ preference for stronger, longer-lasting synthetics as receptor probes.
In addition to the synthetic drugs that bind to and activate the CB1 and CB2 receptors, there are antagonist drugs that block the activity of the receptors, enabling researchers to see what the body does when deprived of CB1 or CB2 activation. A French pharmaceutical firm, Sanofi-Synthelabo, has a cannabinoid-antagonist drug in Phase-III clinical trials in Europe as a treatment for obesity.


Technical Updates
In recent years ICRS researchers have determined that cannabinoids modulate the activity of virtually every messenger system in the brain —GABA, dopamine, acetylcholine, the endorphins, prolactin, glutamate, serotonin… This may explain why cannabis has an impact on so many medical conditions.
There is growing evidence that anandamide works as a “retrograde messenger,” causing the other receptors to slow down when they’re firing too much.
Endogenous cannabinoids may or may not rely on a “transporter” molecule to enter cells they activate (instead of going through the membrane by passive diffusion). Existence of a transporter would provide a strategy for drug companies: block the action of the transporter and keep anandamide in the synapse, firing away at the cell (instead of entering and getting digested by it).
Several labs are honing in on which specific amino acids in the receptor are critical for selectively binding cannabinoids.


Therapeutic Potential
Among the findings reported at the 2002 meeting:
• Rats, when stressed, increase their production of anandamide, according to Andrea Hohman. The implication is that it serves to reduce stress.
• Anandamide may oppose the growth of colorectal cancers in rats, reported Vincenzo Di Marzo.
• Anandamide induces sleep. Cecilia Hillard reported that the general anesthetic propofol works by inducing a 10-15 fold increase in anandamide and 2-AG. When people wake up from propofol they’ve had nice dreams and may be euphoric. “One physiological role of the endocannabinoids is in the induction of natural sleep,” Hillard suggested.
• Anandamide binds to both the cannabinoid and the vanilloid receptors. The vanilloid receptor is activated by capsaicin (which has a vanilloid active group). Can one receptor signal “pain” when activated by capsaicin and “analgesia” when activated by anandamide? A push-pull mechanism?
• Giovanni Marsicano reported that “extinction of aversive memories is controlled by the endogenous cannabinoid system.” His group found that the cannabinoid receptor is necessary for synaptic plasticity in the amygdala, a part of the brain where memory of pain and fear resides.
• Several papers and posters focused on cannabidiol (CBD), the non-psychoactive component of the plant that has been bred out of the high-THC strains available in California. CBD reportedly has anti-convulsant, neuro-protective, and anti-inflammatory effects.

GW Pharmaceuticals
The final day of the conference —devoted to “therapeutic potential” —featured kept promises by GW Pharmaceuticals, the British company founded in 1998 by Geoffrey W. Guy, MD. Guy is a pharmaceutical entre-preneur in his late 40s whose interest in cannabis was piqued when he attended a meeting in London of multiple sclerosis patients demanding access to legal medicine. (The patients had been inspired by the passage of Prop 215 in California.)
Guy then obtained licenses from the Home Office to grow cannabis at a secure 20,000-square-foot glasshouse complex, and purchased the seed strains collected and refined over the years by two American expatriates —Robert Clarke and David Watson— who had relocated to Amsterdam and founded a company called HortaPharm. Talk about a “brain drain...”
At the 1999 ICRS meeting Guy laid out his long-range plan: GW would grow plants under controlled conditions in which various cannabinoids of interest (THC, CBD, and several others) were predominant. Then they would blend uniform, pharmaceutical-grade extracts containing different cannabinoid ratios and provide them to investigators for use in clinical trials. This has now been done and two English physicians were able to report promising results at the Asilomar meeting.
William Notcutt and colleagues at the James Paget Hospital in Great Yarmouth used GW’s extracts —formulated for spraying under the tongue- in clinical trials involving 29 chronic pain patients. Initially patients were given a 1:1 mix of THC and CBD for two weeks. The 27 who reported benefits then received, over the next eight weeks, one-week treatments with high-THC, high-CBD, placebo, and 1:1 THC/CBD extracts. The order in which patients used the various extracts was unknown to either them or the doctors.
Patients were assessed weekly. This method, in which each patient is his/her own control, is called an “N=1” trial.
Notcutt reported that 24 of the 27 patients showed consistent benefit: “Improvements in pain, sleep, depression, activity and general health were the most important… All of the 24 patients who showed benefit have started a long-term safety extension of the study.”
P.J. Robson and his group at the Oxford University Department of Psychiatry tested GW’s plant extracts on 24 patients with multiple sclerosis and spinal cord injuries whose pain, spasticity, and other symptoms would not respond to standard treatments. After two weeks on the THC:CBD 1:1 mix, patients were given the three extracts and placebo in two-week blocks. Four patients dropped out due to adverse affects. “Unequivocal alleviation of at least one target symptom (pain, spasticity, muscle spasms, bladder-related symptoms, tremor) was seen in all of the remaining 20 patients… Both THC and CBD significantly improved pain and stimulated appetite, while THC:CBD 1:1 significantly improved sleep. Intoxication occurred most frequently after THC… Larger scale studies are warranted in a variety of neurological conditions.”

The GW contingent included John McPartland, co-author of a textbook on pests of the cannabis plant, who debunked the assumption that homo sapiens evolved CB receptors that bind to cannabis compounds. By measuring dissimilarities between genes that express cannabinoid receptors in various animals, McPartland estimated that cannabinoid receptors have been evolving for “at least 600 million years.” Fossil records don’t pinpoint the epoch when the cannabis plant appeared, but the fossils of related plants should provide a rough estimate.
The closest relatives to Cannabis are probably plants in the family Urticacea (nettles), based on their morphology, chemistry, gene structure, and the fact that seven obligate parasites of Cannabis ar shared by hosts in the Urticaceae. The fossil record of the Urticaceae goes back 34 million years, so cannabis is a relatively young plant species.
McPartland concludes, “CB receptors evolved long before cannabis.” The plant developed compounds that bind to CB receptors, a very successful evolutionary strategy that has resulted in its cultivation everywhere on the planet.
Geoffrey Guy and his partner Brian Whittle co-authored a poster suggesting that cannabinoids might treat motion sickness effectively. They worked with the Japanese House Musk shrew (rats don’t vomit). Animals given CBD and THC extracts and placebo were placed in cages that could be mechanically shaken to induce nausea. The CBD extract was found to significantly delay the onset of an “emetic episode,” and to reduce the number of emetic episodes observed.
As GW expands its operations, the company is also beginning to influence the research agenda, Most ICRS members still rely on grants and research materials provided by NIDA —the National Institute on Drug Abuse, a U.S. government agency whose stated interest is to prove the harmfulness of marijuana. At every ICRS meeting there’s an enticing talk by NIDA bureaucrat —this year it was Hari H. Singh— listing all the hard-to-get substances that only the government can supply. But with GW beginning to offer support and pharmaceutical-grade drugs that can be worked with legally, the picture is changing. A number of speakers thanked GW for providing their substrates. “G.W. is single-handedly forcing the research away from the super-THC synthetics and back into natural cannabinoids,” McPartland exulted.

Three California doctors who have recommended cannabis for thousands of patients —Tod Mikuriya, David Bearman and R. Stephen Ellis— followed the proceedings with interest. Mikuriya presented two posters: one listing 147 conditions for which cannabis reportedly provides relief, and one reviewing cases of patients who’ve attempted to substitute cannabis for alcohol (see article in this issue).
It was clear at Asilomar that the passage of Prop 215 has inspired much more progress in Europe than in the U.S., where the forces of reaction simply defy the will of the people when they think the people are being disobedient. In California, six and a half years after Prop 215 became law, the individuals most willing and able to explore the medical potential of cannabis are on the defensive, their funds and energy tied up in courtroom fights.

 

 

O'Shaughnessy's
O'Shaughnessy's is the journal of the CCRMG/SCC. Our primary goals are the same as the stated goals of any reputable scientific publication: to bring out findings that are accurate, duplicable, and useful to the community at large. But in order to do this, we have to pursue parallel goals such as removing the impediments to clinical research created by Prohibition, and educating our colleagues, co-workers and patients as we educate ourselves about the medical uses of cannabis.
 
SCC
The Society of Cannabis Clinicians (SCC) was formed in the Autumn of 2004 by the member physicians of CCRMG to aid in the promulgation of voluntary standards for clinicians engaged in the recommendation and approval of cannabis under California law (HSC §11362.5).

As the collaborative effort continues to move closer to issueing guidelines, this site serves as a public venue for airing and discussing these guidelines.

Visit the SCC Site for more information.