O’Shaughnessy’s • Autumn 2004 —5—

ICRS 2004 from top of previous page for spraying under the tongue for 600 ous years, the brilliant young researchers patient-years. “Consistent maintenance we talked to expressed confidence that of symptom control (pain, spasm, sleep, relying on the U.S. National Institute of bladder disturbances) with stable or even Drug Abuse for funding won’t under- diminishing CBME dosages was noted. mine their objectivity or induce them Sativex in chronic adminsitration dem- to search for adverse effects. They’re onstrates a favorable side-effect profile conducting useful basic research that in comparison with standard medicines will explain the body’s endogenous for neurogenic symptoms, with no toler- system and lead to useful ance developing to its clinical benefits.” new drugs. Sebastopol general practitioner Jef- And yet the net effect of virtually frey Hergenrather, MD, described the all the funding going to people who are health history questionnaire developed trying to develop synthetics, or “eluci- by the California Research date the basic mechanism” by which Medical Group [previewed in the Spring the gets activated, inducing 2004 O’Shaughnessy’s] to facilitate data a chain of chemical events inside the collection and research. California pa- cell... is to deflect research away from tients have reported that cannabis helped the plant itself. ease the symptoms of more than 100 As a biochemistry postdoc at UCSF Arriving to set up posters:Federico Massa and Krysztina Monory of the Max Planck conditions not referred to in the pre-1937 (where not a single investigator studied Institute of Psychiatry in Munich. medical literature. plants) told us in ‘98, “If you care about Tomi Jarvinen of the University of cost-effective treatment for individuals, excitatory effect on nerve cells taken and even account for the rare incidence Kuopio, Finland, reported that THC, then you would be in favor of the classic from the nose of a rat (whereas THC has of seizure episodes in some individuals and other natural cannabi- natural . However, if you a suppressive effect). They know that the taking cannabis recreationally.” noid agonists could be made more water care about drugs that optimally treat the mystery component is working through It may turn out that one of the terpenes that give cannabis flowers their smell soluble by formulating them as phos- various conditions, then you start look- CB1 receptors because its effect can be phate esters or cyclodextrins. As in so ing at receptor distribution and maximiz- blocked by the cannabinoid antagonist is also exerting an effect on the mind many of the earlier talks, the beneficial ing activity and things like that.” SR141716A. The authors infer that a and body! Smell matters —and not just effects Jarvinen was referring to will be Being partial to those classic natural “novel compound” is active in the plant, cosmetically. delivered at some time in the future. And cannabinoids, we were interested in a it does not appear to be CBD, and its Krysztina Monory was a co-author people are hurting in the now. poster by Benjamin J. Whalley and co- potentiating effect at the synapse appears on a poster by Federico Massa and lead workers at the University of London’s to be greater than THC’s. author on another, “Mechanism of Can- Scientific conferences are divided School of Pharmacy: “A Novel Com- The authors conclude, “The po- nabinoid Receptor-Dependent Protection into talks and posters. The talks are 15 ponent of Cannabis Extract Potentiates tentiating effects and enhancement of Against Excitotoxicity.” She is trying to minutes; speakers can use all their time Excitatory Synaptic Transmission in Rat cell excitability of the unkown extract figure out exactly how anadamide and to describe their research or leave a few Olfactory Cortex In Vitro.” constituent(s) on neurotransmission were CB1 receptors are involved in protecting minutes for questions. Everyone shows Smell Matters capable of over-riding the predominantly against nerve damage in mice. slides, and many simply read the same Whalley et al. worked with a “stan- suppressive effects of delta-9-THC on Massa’s group showed that the en- text that’s being shown on the slides. dard cannabis extract” —meaning whole excitatory neurotransmitter release. This dogenous cannabinoid system protects When we first attended an ICRS buds turned into a liquid by a strong phenomenon may possibly explain the against colonic inflammation “both by meeting in ‘98, there were 63 posters; blender— from which they removed the preference by some patients for herbal dampening smooth muscular irritation this year there were 155, which shows delta-9 THC by chemical means. They cannabis rather than isolated delta- caused by inflammation and by control- how the field is burgeoning. As in previ- found that the THC-free extract had a 9-THC (due to attenuation of some of ling cellular pathways leading to inflam- the central delta-nine-THC side effects) matory responses.”

John McPartland of GW Pharma- Betty Yao of Abbott Laboratories. More ceuticals, with Vincenzo Di Marzo, the than 10 major drug companies sent ICRS President-Elect. representatives to the ICRS meeting. California MJ Research Program Stretches Mandate To Hold “Cannabinoid Therapeutics” Event in Italy By Fred Gardner people of California. CMCR arranged after the 2002 ICRS development of synthetic drugs —in- Did the directors of the University of The CMCR was created by the Mari- meeting. cluding “antagonist” drugs that block the California’s Center for Medical Canna- juana Research Act of 1999 and received The CMCR’s 2004 conference was system— by a line bis Research violate their basic mandate a total of $8.7 million from the California funded by the U.S. National Institute in the Marijuana Research Act that refers by arranging a one-day conference in legislature between 2000 and 2002. The on Drug Abuse (NIDA), Health Canada, to “alternate means of administration.” Paestum, Italy? CMCR staff solicited proposals and gave Solvay (makers of Marinol), Lilly, Mer- Wouldn’t most Californians assume The event, entitled “Future Directions grants to 18 scientists to conduct stud- ck, Esteve, Valeant, Indevus, Kadmus, the reference was to vaporizers, tinc- in Cannabinoid Therapeutics II: From ies, some of which won’t be completed and G.W. Pharmaceuticals. tures, and other alternatives to smoking the Bench to the Clinic,” was held on until 2006. The staff designated funds to —not brand-new molecules? June 27, the day after the International pay themselves and to keep the Center, Mattison contends that the The CMCR conference was not pub- which is at UC San Diego, in operation Cannabinoid Research Society’s an- CMCR is mandated to concern licized in advance and as of this writing nual meeting. Participants included through that year. is not reported on their website. Your many prestigious scientists —Raphael Additional funds have been sought itself with synthetic drugs by correspondent first heard about it as Mechoulam, Roger Pertwee, Raj Raz- from foundations, the federal govern- a reference in the Marijuana the ICRS meeting got underway from dan, Alexandros Makriyannis, Daniele ment, and private-sector drug compa- Research Act to “alternate Sumner Burstein, a Univesity of Massa- Piomelli, Cecilia Hillard, Vincenzo di nies —as authorized by the Marijuana chusetts medical school researcher who Marzo, Ester Fride, Natsuo Ueda, Jun Research Act. CMCR co-director Drew means of administration.” has developed a synthetic drug, ajulemic Fu, George Kunos, Geoffrey Guy, and Mattison says that no state funds were acid (named after his granddaughters) Mattison contends that the CMCR others— who had no idea, presumably, spent on the “Cannabinoid Therapeutics” that activates the cannabinoid recep- that the session was unauthorized by the conference in Italy or a previous one that is mandated to concern itself with the continued on next page —6— O’Shaughnessy’s • Autumn 2004

CMCR Conference from previous page tors. Burstein said that a drug company Bentley, a grad student and a distraught contain protocols suitable for research a study designed for 56 patients had called Indevus was testing AJA as a technician who kept scurrying along the on marijuana...” And “Studies conducted signed up only one after almost a year of treatment for pain, and that promising floor trying to get the mikes to work and/ pursuant to this section shall include trying. Given that high-grade cannabis is results would be reported at “the meet- or stop screeching. the greatest amount of new scientific available to patients in California under ing on Sunday.” (The ICRS program ran research possible on the medical uses Prop 215, why would AIDS and cancer through Saturday.) He said he hoped I The talks devoted to of, and medical hazards associated with, patients volunteer for studies in which would cover it. marijuana...” And “The marijuana stud- they receive low-THC cannabis from Next evening two California doctors, antagonist drugs seemed ies shall employ state-of-the-art research NIDA, or —even worse— a placebo? Jeffrey Hergenrather of Sebastopol and furthest afield from what the methodologies.” And so forth. Although the Marijuana Research Act R. Stephen Ellis of San Francisco, were CMCR was created to do. Most of the original CMCR study directs CMCR to conduct studies with seated at dinner with Mattison, who protocols involved smoked marijuana. federally grown marijuana, it provides revealed that CMCR had organized The program was organized into four How did it come to pass that research a loophole. “If federal agencies fail to a meeting on Sunday for companies sections: “Cannabinoid Agonists,” “Can- into the safety and efficacy of smoked provide a supply of adequate quality and developing drugs they hoped to test nabinoid Antagonists,” “New Trends in marijuana got transmuted into studies quantity... the [state] Attorney General and market in the U.S. Mattison said it Cannabinoid Therapeutics,” and “Can- involving synthetics? shall provide an adequate supply pursu- was “by invitation only,” and he did not nabinoid Drug Development.” The talks A key step was the selection of UC ant to Section 11478.” extend an invite to the California docs. devoted to antagonist drugs —which San Diego, where the influence of the The federal agencies have indeed They, being gentlemen, did not protest. work by blocking the body’s cannabi- medical marijuana movement was failed to provide marijuana of adequate The following afternoon I encoun- noid receptors— seemed furthest afield almost nil, to be the headquarters, and quality —which is why CMCR studies tered Mattison outside the lecture hall from what the CMCR was created to Igor Grant ­­—a major recipient of NIDA couldn’t entice enough test subjects— and told him that Burstein had invited do. One paper, by Carl Lupica of NIDA funding throughout his career— to be but Mattison and Grant never asked the me to the CMCR the director. state attorney general to supply medicine session. He said Whereas SB-847 had called for comparable to what Californians are that “since there “Marijuana Research,” the UC center growing in their own gardens. had been so many changed its name to ‘Cannabis’ (Latin complaints,” he’d being so much classier than Mexican). Mattison rejects the notion The launch was accompanied by a self- been forced to that the quality of NIDA’s “open it up” on a congratulatory mission statement that first-come, first- seemed more concerned with fellow bu- marijuana has dissuaded served basis to 20 reaucrats than the people of California: people from enrolling in more participants. “The Center for Medicinal Cannabis CMCR’s clinical trials. I could get in if I Research will conduct high quality scientific studies intended to ascertain showed up early Mattison rejects the notion that the general medical safety and efficacy enough. the quality of NIDA’s marijuana has of cannabis and cannabis products and I asked Mat- ANTAGONIST-DRUG RESEARCH was described by Carl dissuaded people from enrolling in examine alternative forms of cannabis tison if the CMCR Lupica (left) of the U.S. National Institute on Drug Abuse CMCR’s clinical trials. “Our participants administration. The center will be seen might find a way to and Walter Fratta of the University of Cagliari at the have never held that belief,” he said as a model resource for health policy provide analytical- conference in Italy organized by the University of Cali- in a post-conference interview. “Our planning by virtue of its close collabo- lab services so that fornia’s Center for Medicinal Cannabis Research. Fratta participants have not complained about ration with federal, state, and academic California patients, used Sanofi’s SR141716A to reduce craving for heroin in potency except about it being too potent. entities.” doctors and grow- rats. Lupica hopes antagonists can be used to “successfully Some experienced psychoactive effects ers could identify treat marijuana craving.” before they experienced pain relief.” the composition of Who is better positioned Mattison and CMCR Project Manager discussed antagonist drugs as “potential the plants they were using and begin to Heather Bentley have visited the farm treatment” for food, alcohol and nicotine than the CMCR to collect data duplicate, however crudely, the G.W. in Mississippi where NIDA-licensed cravings. “It is also clear that marijuana on the conditions that Cali- approach to research. “The hills are full marijuana is grown, and report that craving may be successfully treated by of Burbanks,” said I. “If only they had fornians have been treating sticks and seeds are now being removed this drug,” according to Lupica. access to an analytical lab, they could on a conveyor belt. Mattison says that Our concern is not that the CMCR with cannabis? begin to develop strains with different NIDA”can provide marijuana blended honchos used California taxpayers’ cannabinoid ratios that patients could use Had the CMCR been based at UC for increased potency,” and did so for at money to organize and stage a “canna- to treat various conditions, and doctors San Francisco, its operation might have least one CMCR study. He adamantly binoid therapeutics” conference in Italy could monitor the results.” been monitored by doctors and cannabis- defends his efforts to build alliances —they say they didn’t and we’re not Mattison exuded impatience and using patients who want and need studies with federal agencies and pharmaceuti- going to ask to see anyone’s time cards. disapproval. Instead of responding, he relevant to their own situation. Who is cal companies. Our concern is that the program itself said “Gerard might be starting his talk” better positioned than the CMCR to col- Bentley also had an answer to our violated the CMCR’s reason for being, and scurried into the hall where Gerard lect data on the conditions that Califor- complaint about CMCR’s failure to which was and is to study “marijuana,” Le Fur of Sanofi was about to describe nians have been treating with cannabis? track which conditions Californians are not ajulemic acid or any other synthetic the effectiveness of a cannabinoid- Who is better positioned to analyze and actually using cannabis to treat. “We cannabinoid, let alone antagonist drugs. antagonist drug in treating obesity. [See provide data on the strains being used didn’t have any applications for such a related story on page 1.] in the here and now? A director whose study,” she said. The CMCR Sunday conference was The Marijuana Research Act ambitions were on the clinical rather than But surely if they can take the initia- held at the Ariston Hotel, same as the of 1999 was drafted explicitly the research side of medicine would have tive to arrange a “Cannabinoid Thera- ICRS meeting. Some 20 distinguished in response to the passage of promoted such studies. peutics” conference in Italy, they could scientists sat around tables with name- Instead we have Igor Grant and Drew suggest that a California researcher get plates, microphones, water, gift note- Prop 215. Mattison “bringing together the major the basic facts on medical marijuana pads, etc. Tables had been added for stakeholders in the development of use in the state. Or the CMCR staff another 20 auditors. Breakfast and lunch The Marijuana Research Act of 1999 cannabinoid therapeutics,” as their con- could do it themselves, as an-in house were provided. was introduced by State Sen. John Vas- ference abstract book put it, “to survey project, while they’re holding the fort At least five people from UC San concellos explicitly in response to the the laboratory compounds that are most through 2006. Diego were involved —Mattison and passage of Prop 215. Enacted as Senate promising for testing in human trials, co-director Igor Grant, staffer Heather Bill 847, it authorized the UC regents confront potential stumbling blocks to to create a “Marijuana Research Pro- testing and develop- gram... (to) develop and conduct studies ment of these com- intended to ascertain the general medical pounds, and identify safety and efficacy of marijuana and, opportunities for pro- if found valuable (sic), shall develop gressing (sic) new medical guidelines for the appropriate compounds to clini- administration and use of marijuana.” cal readiness.” SB-847 refers to “marijuana” as it Another factor was and is being used by Californians that might make under Prop 215 —in other words, the “new compounds” plant. “The crude plant,” that grows in seem more amenable MAHMOUD EL SOHLY, who is licensed the crude soil and that we, the crude to study than smoked by NIDA to grow marijuana at the Univer- people, voted to legalize for medical marijuana is the dif- sity of Mississippi, was an invited partici- use. For example: “Proposals shall con- ficulty that CMCR pant at the CMCR conference. California tain procedures for outreach to patients researchers encoun- doctors R. Stephen Ellis and Jeffrey Her- with various medical conditions who tered recruiting hu- Igor Grant, Director of the UC Center for Medicinal genrather, in background, were allowed to may be suitable participants in research man subjects. In Cannabis Research, and Alexander Makryannis, chairing the audit. Photos by Ed Rosenthal. on marijuana...” And “Proposals shall one egregious case, “Cannabinoid Antagonist” panel at the CMCR conference.