—2— O’Shaughnessy’s • Leaflet

“The field is moving away from the plant...” The International Research Society Convenes in France; Focus is on Pharmacology By Fred Gardner reduced pain, body temperature, spon- What scientists really know about taneous activity and motor control. The how exerts its effects is up- researchers call these four “the classic dated every summer at the International tetrad” of cannabinoid effects. Cannabinoid society’s annual meeting. In 1974 Eli Lilly produced a synthetic In late July, 1998, with no one from the THC which has been marketed in Eng- news media showing the slightest inter- land and elsewhere as Nabilone. In the est, some 200 ICRS members convened mid-1980s Pfizer produced a synthet- in a resort town on the French Mediter- ic cannabinoid suitable for research. Molecular structures of (left) and Δ-9 (right) ranean called La Grande Motte to re- Pfizer’s synthetic, CP-55940, proved were worked out by Raphael Mechoulam and Yechiel Gaoni at Hebrew University in view their latest findings. Part of the to be highly psychoactive and couldn’t Jerusalem in the 1960s. tab was picked up by Sanofi Recherche, be marketed as a medicine. But unlike a large pharmaceutical company with THC, which exerts a weak, fleeting ef- extremely weak agonists. (An agonist is Sanofi also has several promising headquarters in nearby Montpelier. fect, CP-55940 would bind long enough a drug that binds to and activates a re- agonist drugs in the pipeline, accord- The ICRS was organized in 1990 by to reveal where in the body it acted. ceptor.) They have a slightly weaker af- ing to rechercheur Francis Barth. The scientists who had been following each finity for the CB-1 receptor than THC, company has decided to position itself others’ work in the literature and con- Receptors in the Brain which itself is a low-efficacy partial at the forefront of cannabinoid research ferring informally for years. The first The existence of cannabinoid recep- agonist. This makes the endocannabi- because the therapeutic potential out- meeting, held on Crete in 1990, drew tors in the brain —proteins on the out- noids hard to study and helps explain weighs the political constraints. As 45 participants and was chaired by Rik side of certain cells to which cannabi- the preference for stronger, longer-last- Barth put it in a recent review paper, Musty, a professor of psychology at noids bind, inducing a squaredance of ing synthetics as receptor probes in the “Potential therapeutic applications the University of Vermont. Originally molecular events within the cells— was research labs. range from the well-described analge- the C in ICRS stood for — established in 1988 by Alynn Howlett sia, anti-emesis, appetite stimulation the Latin name of the plant known as and William Devane at St. Louis Uni- Synthetics and antiglaucoma properties to the less marijuana when bred for psychoactiv- versity. The researchers were aston- Researchers now have 10 different documented antirheumatic, antipyretic ity and when bred for fiber— but ished to find that these receptors, now synthetic at their dispos- and bronchodilatory effects.” What in 1995, because so few members were known as CB-1 receptors, are at least al. WIN 55212-2, an aminoalkylindole drug company can ignore such a range actually conducting research with the 20 times more prevalent in the brain developed by Sterling Winthrop in the of applications? plant, a vote was taken to change the than opioid receptors. 1980s, is considerably stronger than “They all have their toes in the wa- C-word to “Cannabinoid.” CB1 receptors are concentrated in THC. (Sterling Winthrop is now owned ter,” says Lesley Iverson, a British “Cannabinoid” refers to chemicals the cerebellum and the basal ganglia by Sanofi, which in turn has merged scientist sent to the ICRS conference from three sources —extracted from (regions responsible for motor control, with Synthelabo.) The rights to distrib- as an observer by the House of Lords. the plant, synthesized in the lab, or which may explain why marijuana re- ute WIN 55212-2 are owned by RBI Glaxo Wellcome, Roche, and Bayer produced by the body of man, mouse, portedly eases muscle spasticity); in the Neurochemicals of Cambridge, Mass. A.G. were all represented by men and or lower animal. The body’s own can- hippocampus (storage of short-term Mechoulam’s lab at Hebrew University women in their twenties and early thir- nabinoids are said to be “endogenous,” memory); and in the limbic system has created several synthetic agonists. ties who are designing and testing can- and are now being called “endocannab- (emotional control). Cannabinoids act- In addition to the synthetic agonists nabinoid drugs. inoids,” just as the body’s own chemi- ing through the CB1 receptors seem to that bind to and activate the cannabi- Merck Frosst has developed two po- cals with morphine-like effects were play a role in the processes of reward, noid receptors, researchers have been tent agonists, which were described at dubbed “endorphins.” cognition, and pain perception, as well employing two antagonist drugs from the meeting as being selective for the The first plant cannabinoids were as motor control. Sanofi —one that blocks the CB-1 re- CB-2 receptor. Eli Lilly has a synthetic identified in the early 1940s by Roger In 1992 a second cannabinoid recep- ceptor and one that blocks the CB-2 THC drug called Nabilone on the mar- Adams, a University of Illinois chem- tor was found in cells of the immune receptor. Antagonists enable research- ket in Switzerland, England, Ireland ist who isolated cannabinol, cannabi- system in “peripheral” areas of the ers to see what the body does when it and Canada to combat nausea (although diol (CBD), and a crude form of delta- body. The discovery of this second re- is deprived of cannabinoid activation. it is less efficacious than smoked mari- 9-tetrahydrocannabinol (THC). CBD is ceptor type —called the CB-2 receptor, The effectiveness of a new antagonist juana and failed US FDA toxicity tests). the predominant compound in cannabis or the “peripheral receptor”— strongly from Pfizer was discussed in a paper Companies that for years saw nothing plants that have been bred for fiber, i.e., implied that effective non-psychoactive at the 1998 ICRS meeting. Sanofi has but potential competition in cannabis hemp. THC is the predominant com- drugs involving the immune system an antagonist drug in clinical trials in now see a source of marketable synthet- pound in cannabis plants that have been could be developed. Europe. It is being tested as an antipsy- ics. One young scientist from a private- bred for psychoactive potency, i.e., Also in ‘92, Devane and Lumir Hanus, chotic, but other effects —on appetite, sector firm said he’d been advised by marijuana. working together at Hebrew University, memory, etc.—will be assessed. continued on next page To date more than 60 cannabinoids identified an endogenous cannabinoid, have been found, most of them chemi- a relatively simple molecule called ara- Glossary cally inactive when inhaled or ingested chidonyl ethanolamine, or AEA, which into the body. The cannabis plant also they named “anandamide” after the Cannabis is the Latin name of the plant known as hemp when bred for fiber and contains hundreds of chemical sub- Sanskrit word for “bliss.” Devane re- known as marijuana when bred for psychoactive effects. stances that are not unique to it. portedly came up with the name after A receptor is a protein on the outside of a cell that recognizes and responds to In 1964 the precise structure of del- Mechoulam said he “couldn’t think of a a chemical signal, such as a hormone or a drug, to initiate events within the cell, ta-9 THC was described in a paper by single happy word in Hebrew.” leading to a response by the cell. Raphael Mechoulam and Y. Gaoni of A second endogenous agonist, 2-ara- An agonist is a molecule that activates a receptor. Think of the receptor as a lock, the Weissmann Institute of Science in chidonyl glycerol (2-AG), has been the agonist as a key, and the door opening as the physiological response. Morphine Rehovoth, Israel. This triggered a long found in the brain at concentrations 170 is an agonist which acts at opioid receptors to decrease pain. More than one agonist search in Mechoulam’s lab and else- times greater than anandimide. can act at a given receptor. where for synthetics that would have The endocannabinoids are said to be An antagonist is the opposite of an agonist —it thwarts the activity of the recep- the therapeutic effects of THC with- tor, either by binding to it directly and blocking the agonist, or by other means that out the psychoactivity. (A drug was cancel out the agonist effect. For example, the opioid antagonist naloxone prevents determined to be a cannabinoid if it morphine from relieving pain. Neurons are nerve cells that transmit signals to other nerve cells by chemicals called neurotransmitters. The gap between a neuron sending a signal and the neuron receiving it is called a synapse, and the two neurons are called “presynaptic” and “postsynaptic,” respectively. More than 100 different neurotransmitters have been identified to date. Cannabinoids are chemicals that activate the cannabinoid receptors. There are three types. First to be discovered were certain active ingredients of the cannabis plant —hence the name. Sixty-six different plant cannabinoids have been identified to date. Plant cannabinoids have 21 carbon atoms in ring structures, with hydrogen and oxygen molecules attached at different points. Endogenous cannabinoids are chemicals occuring naturally in the body that have effects similar to those of the plant cannabinoids. are made in the laboratory and have effects similar to the plant cannabinoids. At least 10 are currently in use by researchers. The Endogenous cannabinoids anandamide synthetics and the endogenous cannabinoids look nothing like the 21-carbon plant (AEA) and 2-Arachidonyl Glycerine (2- cannabinoids; but they have “active sites” that bind to the cannabinoid receptors AG) are produced in the body to activate and produce similar effects. Raphael Mechoulam cannabinoid receptors. O’Shaughnessy’s • Leaflet —3—

ICRS continued from previous page the head of drug development, as he left drugs. Nevertheless, the net effect of with HU-211, which we know exerts a tem,” Bisogno et al described how anti- for the conference, “If it ends in -oid, virtually all the funding going to people strong antioxidant effect and we hope pain and anti-inflammatory effects are you must avoid.” But he seemed more who are trying to develop synthetics or will prevent strokes and lower blood triggered by the inhibition of endoge- amused than threatened. “elucidate the basic mechanism” is to pressure. It also has potent anti-pain nous AEA inactivation by mast cells. If deflect research away from the plant effects in chronic pain,” Mechoulam capsaicin inhibits the normal inactiva- Logistics itself. said. “But it doesn’t bind to the recep- tion of anandamide... this may be why The job of organizing the annual A postdoc rationalized his choice tor. How does it act?” He shrugged. people enjoy eating hot foods. meeting is handled by Diane Maha- thus: “If you care about cost-effective “We’re missing something. My impres- • David Mason’s talk about “The deen, an experienced publicist who treatment for individuals, then you sion is that it’s either a third cannabi- Role of Dynorophin A Peptides...” im- served for five years as a consultant to would be in favor of the classic natu- noid receptor or there is some specific plied that THC works because it’s do- the ICRS before she was formally hired ral cannabinoids. However, if you care membrane effect.” ing what the body’s chemical messen- as director in 1997. She is married to about drugs that optimally treat the var- HU-211 is the mirror image of a ger system was designed to do in the an ICRS prime mover, Rik Musty, and ious conditions, then you start looking high-potency synthetic analog of the first place. Because there are almost no operates out of an office in Burlington, at receptor distribution and maximizing THC molecule, but has no psychoac- cannabinoid receptors in the brainstem Vermont. activity and things like that.” tive effects whatsoever, according to to mediate respiratory depression —the Mahadeen was surprised when the All but a very few of the ICRS Mechoulam. A small Israeli-American most dangerous side-effect of the opi- number of members registering for members in La Grande Motte fell into company called Pharmos has spent ods— cannabinoids are relatively safe the meeting in La Grande Motte ap- the latter category. “The field is mov- more than $8 million testing its anti- in treating pain. proached 200. Recent meetings had all ing away from the plant,” is how Dale stroke effects in animals, and a num- • In “Functional Cannabinoid Recep- been in North America, where most of Deutsch, a biochemist who edits the ber of papers have been published on tors in Human Sperm” Herbert Schuel the members lived, and she’d expected ICRS Newsletter, summed up the trend. its neuroprotective properties. Recently of the University of Buffalo, SUNY, a drop in the number attending. Instead U.S. Army researchers tested HU-211 watched sperm interact with eggs in vi- there’d been a 75-member jump from The first two days of the meeting as a treatment for the effects of nerve tro. When the sperm reaches the egg, it the previous year. So Mahadeen was were devoted mainly to reports from gas and found a 70% reduction in brain needs to “acrosomes” —mole- still trying to book extra rooms on the pharmacologists and biochemists on damage. cules that enable penetration of the egg evening everyone was due to arrive. the processes by which cannabinoids Pharmos is taking HU-211 through wall. Very often the sperm release their The town to which Sanofi had invited are made, exert their effects, and get the trials required by the FDA so that acrosomes en route to the egg, which is the cannabinoid researchers, La Grande broken down. The focus was on the it can be marketed in the U.S. [Phase I called “premature AR.” (No kidding.) Motte, was built in the 1960s on a san- molecular level. For example, Romelda tests are for toxicity in humans. Phase THC and a synthetic cannabinoid dy marsh reclaimed from the mosqui- Omeir, a graduate student in Deutsch’s II seeks to determine optimum dosage were found to “significantly reduce the toes in an attempt to increase tourism lab at SUNY Stony Brook, reported on levels. Phase III is an effiicacy trial incidence of premature ARs.” Schuel, in the Languedoc region. The architect, her study of how anandamide gets bro- against placebo or other medications who is funded in part by NIDA, notes Jean Balladur, was in his pyramid peri- ken down. —the key step in obtaining a license that “the smoking of marijuana by od, and the downtown skyline consists The enzyme that does the dismantling to market the drug. Phase IV involves women could affect these processes in of 8- to 10-story hotels that slope away had been identified in ‘93. An enzyme thousands of patients followed over vivo.” His paper implied that it affected from the observer as they rise. Balla- is a large protein molecule consisting of time to assess longterm toxicity.] the processes positively, i.e., increased dur is quoted in the Office de Tourisme hundreds of amino acids that catalyzes The Phase I tests of HU-211 showed the likelihood of fertility. brochure saying “La Grande Motte will a biochemical reaction. Omeir used a no toxicity in humans. Results are due Schuel, who has found a cannabinoid- enter the 21st century young and new, technique called mutagenesis analysis in September from a Phase II trial in- type receptor system in sea urchins rising out of the sand like a problem- —altering the amino acids one by one volving 60 patients with brain dam- ,comments, “The presence of canna- free child.” until the enzyme ceases to work. After age -considered similar to the damage binoid receptors and anandamides in The buildings already showed more much painstaking benchwork she found caused by stroke- or from car crashes gametes and somatic cells of verte- signs of deterioration than the centu- the “active site” —Serine 241— the ami- and other closed head injuries. The brates and invertebrates indicates that ries-old ones we’d been admiring en no acid that actually snips anandamide, patients were all treated after their in- this signal system has been highly route, but we had a problem-free time making it dysfunctional. Someone else juries, 30 with HU-211 and 30 with a conserved during evolution.” His work there, saw the only flamingoes in - Eu in Deutsch’s lab is studying the part of placebo. They were to be assessed one seems to lend itself to a cannabinoid- rope gulping shrimp in the lagoons, the enzyme that holds anandamide in week, one month and six months after based birth-control drug (for males!), and heard a hot blues trio at a sidewalk place while Serine 241 is snipping it. their injuries. but Schuel said no backers were on the cafe around midnight. La Grande Motte And so it went (mostly over our If HU-211 passes its clinical trials, horizon for such a project. draws a lively crowd of French families heads). Razdan described an effort to Pharmos intends to market it as “Dex- whose four-week vacations are subsi- make the anandamide molecule less inabinol,” dex being a reference to its • A group at the University of Kuo- dized by their employers and govern- susceptible to chemical breakdown by chemical righthandedness. pio (Finland), headed by David Pate, ment. “A little bit of socialism goes a replacing the amide bond with urea or “If we see that HU-211 works and we an American scientist associated with long way,” Rosie observed. carbamate derivatives... Meschler and get a lot of money,” Mechoulam adds, the Dutch medical cannabinoid firm The ICRS members were staying at Howlett described a new antagonist for “then we can conduct trials on a long HortaPharm, showed that intraocular the Hotel Mercure, a U-shaped 10-sto- the CB-1 receptor, manufactured by list of compounds that are just waiting pressure could be lowered in rabbits by ry building near the beach. The meeting Pfizer, called CP-272871... Piomelli around to be developed. We also want either anandamide, the Pfizer synthetic was a long block away at the “Palais of the Neurosciences Institute in San to test HU-211 as a drug for chronic CP-55,940, or a metabolically stable des Congres,” an auditorium that, from Diego (funded by Novartis) has deter- pain. We’ve known for five or six years anandamide analog. Pre-treatment with afar, looks like a giant oil can laid on mined how the production of the en- that it seems to reduce pain in animals, the Sanofi CB-1 antagonist blocked the its side. Johnny Clegg and Juluka had dogenous cannabinoid 2-AG in neurons but we don’t understand the mecha- effect of the two man-made variants, played there a few nights before the is controlled by NMDA receptors. nism.” but did not block the effect of anan- cannabinoid researchers hit town. damide, suggesting that applied doses The schedule called for 70 papers to Medicinal Benefit Good News for Medical Marijuana of the latter drug don’t function at the be presented over the course of three There was no reference to a promis- Much of the research seemed like CB-1 receptor. days. Speakers get a total of 15 minutes ing new medication —no mention of good news for the medical marijuana It is widely acknowledged that can- to describe their research and answer “patients”— until Raphael Mechoulam movement, albeit indirectly. The work- nabis reduces intraocular pressure in questions. They were supposed to talk read a paper describing “A Novel Group ings of the endogenous cannabinoid glaucoma sufferers unresponsive to for 10 and leave five for questions. All of Stable, Non-Hydrolysable Endocan- neurotransmitter system, the potency of other drugs, but this is the first work relied on slides to help tell their stories nabinoid Analogs.” The grand old man the synthetics, the modulating effects that implies that at least some cannabi- —the standard scientific-meeting for- of the field, now in his mid-60s, talks of other cannabinoids on THC —stud- noids lower intra-ocular pressure at the mat. and gestures with a charming Israeli ies in all these areas help to explain and eye’s own cannabinoid receptor. The details of another 63 studies were lilt. For some reason he reminded me substantiate what Californians with a • Claire Williams and co-workers at described on posters tacked to parti- of Robert Crumb’s Mr. Natural, clean- wide range of conditions have been re- the British Institute of Food Research tions in a large room where coffee was shaven. porting about safety and efficacy. and the University of Reading sought served during the breaks. A few hours Mechoulam reported that his group, • In “Anandamide Synthesis in Cells to determine whether THC-induced were set aside for sessions at which the by adding an ether group to 2-AG, had of the Immune System,” Burstein ob- eating is caused by “amplication of the authors stood by their posters and an- created a variant that is more than three served that THC stimulates production rewarding properties of the food” or swered questions. times as strong (in mice tested for the of anandamide —and that anandamide “an inhibition of satiety mechanisms.” ICRS members are university-con- classic tetrad of effects) and lasts longer can stimulate its own synthesis— sug- It appears to be both —“some inter- nected scientists. Many are funded by (40 minutes compared to six). They had gesting a positive feedback mechanism. action between postingestive factors, the National Institute on Drug Abuse, a named it HU —for Hebrew Universi- Being happy makes you happy. cannabinoid activity and the intermeal U.S. government agency whose stated ty—310. “HU-310 causes a reduction • In “Activity-Dependent Release of satiation process. Possibly, endogenous interest for years has been to prove the of blood pressure which is considerably Anandamide in Basal Ganglia of Freely cannabinoid activity occurs [after feed- harmfulness of marijuana. Some of the more potent than that observed with Moving Rats” a group from the Scripps ing] to inhibit satiety in preparation for brilliant young researchers we met in anandamide or 2-AG,” Mechoulam Research Institute in La Jolla found that a recurrence of eating. Attenuation of La Grande Motte said, sincerely, that said like a throwaway line. running induces production of anan- THC feeding by naloxone implies an taking NIDA money doesn’t influence I caught up with him during a break damide, just as marathoners have re- important cannabinoid-opioid interac- their objectivity, they’re conducting ba- and asked if I had heard right. Yes, he ported analgesia and altered conscious- tion. As opiods are believed to mediate sic scientific research that will explain said, “We might have a very useful ness from endorphins after exercise. food reward, it is possible that cannabi- the body’s endogenous cannabinoid medicine here... But this is still pre- • In “Interactions Betwen Vanilloids noids act indirectly to inhibit satiety by system and lead to useful synthetic liminary. We’re much further along and the Endogenous Cannabinoid Sys- continued on next page —4— O’Shaughnessy’s • Leaflet

ICRS continued from previous page increasing the incentive to eat and the section of the meeting, however, some suspect...” hedonic value of food.” Bottom line: good news about medical marijuana Far from treating Nahas as a THC makes food taste better. was revealed. In fact, if the press were political enemy, Mechoulam • Lester Bornheim, a UCSF phar- on the case, the headlines would have seemed to be responding to macologist who was funded by NIDA read: the anguish he’d shown on in 1985 to study the adverse effects of stage, trying to soothe him. marijuana, has shown that cannabidiol Canadian Study Finds: Now there’s a real therapist, I —CBD— can inactivate an enzyme in Kids Whose Moms Smoked MJ thought. But Nahas was hav- the liver involved in the metabolism of Do Better in School, Socially ing none of it. He whipped out most clinically useful drugs. If you in- Gabriel Nahas said that Tibor Wenger’s work was a notebook and started illus- activate an enzyme involved in a drug’s The frontal lobe symposium closed based on “totally false premises.” trating his points, punching the breakdown, you prolong the amount with a report by Peter Fried of the John McPartland to his wife. “Every pad emphatically with his pen- of time the drug continues to function Department of Psychology, Carleton time something comes out about why cil, insisting that THC operates through and increase its efficacy. Bornheim is University, Ottawa. Since 1978 Fried marijuana works, Nahas is there to re- a “direct effect on cell membranes that currently trying to define the molecular has been conducting a study designed fute it...” deregulates cell function!” mechanism of this inactivation. Previ- to measure “The impact of prenatal Nahas had been scheduled to give a ous studies have shown that CBD may marijuana exposure on executive func- paper on the unsuitability of THC as Therapeutic Potential work as an anti-epileptic either directly tioning (EF) in offspring.” Executive an adjunct to anesthesia. But he said, When the final session began —the or by enhancing the effects of other Functioning is defined by Fried as “a when he got to the lectern, that he had general topic was “Therapeutic Poten- drugs. shorthand for a set of processes that more important findings to share. Hav- tial”— Nahas did not return to the au- One of the posters described the op- are involved in future-oriented behav- ing just spent three months reviewing ditorium. He sat for a long while with erations of Maripharm, a Dutch firm iors that include aspects of attention, the literature, he had come to inform his wife, a beautiful woman who is that provides standardized cannabis to judgment, planning and decision mak- his colleagues that their recent dis- obviously devoted to him, on a bench rural pharmacists whose patients don’t ing. EF involves the identification of coveries were all wrong, right down in the lobby of the Palais des Congres, have access to the clubs of Amsterdam. subgoals, conjuring up and mentally to their nomenclature. “THC does not while Hampson and Di Marzo read the Maripharm placed a stack of cans os- assessing different response options, interact directly with neurotransmitters most encouraging papers of the confer- tensibly containing their product along and concomitant self-monitoring and or neuromodulators,” Nahas asserted, ence. When I interviewed him after the with their brochures on the floor in front self-correction...” Who would have “but acts directly on cell membranes meeting, Nahas would reiterate, “The of their poster. They contained “patient thought that when the social scientists in the manner of an anesthetic to al- endogenous cannabinoid neurotrans- information” literature, in Dutch. took the floor the material would- be ter their response.” He said that THC mitter system is an ego trip on the part come even harder to grasp? “deregulates” the signals that are con- of Raphael Mechoulam.” Bad News for Medical MJ? Fried concluded that prenatal mari- stantly being regulated by arachidonyl Most of the papers that fell into the juana exposure adversely affects chil- ethanolamine. (Nahas hates the name CBD is a plant cannabinoid dren starting at about age six. “In category of Bad News for Medical “anandamide.” He says, “Bliss has that doesn’t bind to the CB-1 MJ were funded, not surprisingly, by early adolescence these offspring were nothing to do with it!”) NIDA. The only one that got picked up negatively impacted on tasks requiring Mechoulam rose to restate the evi- receptors and has no psycho- by the dailies was a report by UCLA impulse control and visual analysis/ dence for cannabinoids functioning as active effects. pulmonologists on the ostensible mu- hypothesis testing...” Between 12 and neuromodulators. “It is not just a mem- tagenic effects of smoked marijuana. 16 they “differed from controls on di- brane effect,” he said. “There is an in- Aidan Hampson —who got his PhD (Somehow the dailies didn’t pick up mensions of behavior, attention and terplay of effects on the receptor and from UCSF in 1996 and is now work- on the large silver lining reported the certain tasks requiring visual analy- membrane.” This drew an outburst of ing at the National Institutes of Health next day: cannabinoids that are found ses...” Fried’s data revealed that the in Bethesda— reported results with in MJ smoke were found to have anti- children of women who used marijuana cannabidiol and THC that seem to par- oxidative properties that protect against moderately while pregnant had higher allel Mechoulam’s with HU-211. cellular damage.) I.Q.s and more friends than the children CBD is a plant cannabinoid that Some studies seemed like a dubious of the non-users at age 12. “If the press doesn’t bind to the CB-1 receptors and use of taxpayers money. David Gore- ever gets wind of this,” he said “the has no psychoactive effects. (California lick of NIDA had come all the way to game is over!” Was this an attempt at growers have long been breeding for France with a poster entitled “Charac- wry humor or a Friedian slip? high THC content.) teristics of Marijuana Users Presenting Hampson and co-workers in Bethes- to an Urban Hospital Emergency De- Fried had come up with a dubious da showed that both THC and CBD, partment.” His team interviewed 826 explanation for this troubling data. The administered to rats after they’d been drug-using patients. Only 35 were iden- success of the potsmoking moms’ kids exposed to toxic levels of a neurotrans- tified as marijuana users. Of these, four must be attributable, not to cannabis ex- mitter called glutamate, significantly used marijuana exclusively; 21 also posure, but what he dubbed “the earth- reduced the resulting brain damage. used cocaine and other illicit drugs, mother effect.” The potsmoking moms, That CBD had the same effect as THC six also used prescription drugs. The he explained in professorial cadences, Mechoulam restated the evidence. suggests that the mechanism does not nursed their kids longer, and gave them entire 18-month study involved only applause that was cut short by the chair, involve the CB-1 receptors. When the better diets and more attention. So their four marijuana users —while providing UCLA pulmonologist Donald Tashkin. rats were treated with an antagonist offspring were superior despite the employment for Gorelick and five co- Nahas repeated that the evidence was drug, the neuroprotection provided by moms having smoked pot! (Fried’s authors! all in the literature and cited studies THC and CBD did not diminish —fur- Ottawa Prenatal Prospective Study Gorelick also had a poster on “Mari- done in the 1970s. As Mechoulam was ther proof that they weren’t function- has been supported for many years by juana Dependence Among Inpatients asking “What receptor is it that you il- ing at the receptor level. Hampson et NIDA grant RO1 DAO4874.) at a Regional Training Center,” which lustrate in your slide there?” Dr. Tash- al found that THC and CBD had an In a question session, Ed Rosenthal of contained the finding: “Current mari- kin said that “in the interests of time,” antioxidant effect 20-30% greater than bluntly asked the speakers juana addicts (sic) were less likely than the discussion should be continued that of Vitamins C and E. (Antioxidants who had participated in the frontal lobe patients without any current substance elsewhere. are capable of soaking up the “free radi- symposium, “Do any of you think your dependence to have been in a single During the break Mechoulam found cals” that kill brain cells.) work is influenced by Alan Leshner’s vehicle accident (52% vs 69%) or been Nahas seated by himself at a coffee ta- Equally promising was a talk by Vin- bias?” There was a pause as the pan- wearing seat belts (13% to 63%).” We ble in the room where the posters were cenzo Di Marzo of the Instituto per la elists looked at each other to see who translated this as “Less respect for the displayed. Mechoulam sat down next to Chimica di Molecole di Interesse Bio- would respond. After a few beats the law, but better drivers.” him. I heard him say, “The field moves logico in Naples entitled “Anandamide diplomatic Rik Musty remarked, “Sci- Gorelick confirmed my reading of it, on. We’re old men coming to the end Potently and Selectively Inhibits Hu- ence is always influenced by the - cul but dismissed the significance of his of our careers, these young people will man Breast Cancer Cell Proliferation ture in which it’s conducted.” And so own poster. soon know much more than we even Through Interference With Endog- ended day two. enous Prolactin Ac- NIDA provided “special support” for tion.” (Prolactin is a a section of the program designated Confrontation hormone that stimu- “The Frontal Lobe Symposium” —six On the third and final day of the ICRS lates lactation.) talks held on the afternoon of the sec- meeting, as gentlemanly Tibor Wenger Di Marzo’s group ond day. NIDA director Alan Leshner finished reporting that anandamide found that anan- had been scheduled to make the intro- stimulates release of the pituitary hor- damide slowed the ductory remarks, but instead faxed a mones via a yet-unknown CB receptor growth of three dif- statement to be read aloud by Monique that is not activated by THC—a scien- ferent lines of human Braude, a past ICRS president, recently tist who had only just arrived, angrily breast cancer cells in retired after years of employment by informed Wenger that his research was vitro. They could not NIDA. “based on totally false premises.” get the same anti- Leshner struck the first blatantly po- A buzz of recognition went through proliferative effect litical note of the conference when he the audience: this was the famous Ga- when they tried anan- urged the researchers to get “into the briel Nahas, an anesthesiologist now damide on several fray” by publicizing “the harm involved at NYU who had spent most of his ca- other non-mammary in using marijuana” and supporting reer trying to prove and publicize the tumor cell lines. Donna Shalala’s Marijuana Prevention health hazards of marijuana. “Nancy Nahas making his point to Mechoulam, does not accept the They established that Reagan’s favorite scientist,” whispered Initiative. Even in NIDA’s own special reality of cannabinoid receptors. continued on next page O’Shaughnessy’s • Leaflet —5—

the effect was not due to toxicity but and other components of the cannabis to a receptor-mediated blockade of the plant beneficially modulate the effects prolactin receptor. The presence of the of THC and exert helpful effects of enzyme responsible for breaking down their own. anandamide within the cancer cells In an interview with your correspon- implied “that the endogenous cannabi- dent at the ICRS meeting, Guy ex- noid may act as a local inhibitory sig- plained his long-range plan: GW would nal for human breast cancer cell prolif- grow plants under controlled condi- eration.” tions in which various cannabinoids of Auditing the ICRS talks with an ac- interest (THC, cannabidiol, and several tive interest were representatives of a others) were predominant. Then they British start-up called GW Pharma- would blend uniform, pharmaceutical- ceuticals. In addition to the co-found- grade extracts containing different can- ers, Geoffrey W. Guy, MD, and Brian nabinoid ratios and provide them to in- Whittle, PhD, there were three Ameri- vestigators for use in clinical trials. can ex-pats based in Amsterdam: Da- Guy could promise the Home Office vid Watson, Robert C. Clarke, and Da- that his products would not induce eu- vid Pate, PhD. phoria because cannabidiol —CBD— Watson and Clarke are old friends is not psychoactive and actually coun- from California, devoted to the Can- ters the psychoactivity of THC. GW’s nabis plant. Back in the 1970s they had breeding program had been jumpstarted the insight that compounds in differ- David Watson and Geoffrey Guy at the 1998 meeting of the International Cannabinoid by a Hortapharm strain in which CBD ent strains exert different effects. They Research Society in La Grand Motte, France. was strongly predominant. traveled the world collecting seeds Guy thought it unlikely that cannabis from “landrace” varieties. erful “Skunk.” They sold seeds. esized that CBD, not THC, was the key plants now being grown in California Watson says they gave up hope that Geoffrey Guy’s interest in cannabis anti-convulsant component. would have more than trace amounts of the research they had in mind would was piqued in 1997 when he attended Guy then obtained licenses from the CBD. “When you breed for psychoac- be allowed in the U.S. when Marinol a meeting in London of multiple sclero- Home Office to grow cannabis at a tivity you’re elevating THC and reduc- (synthetic THC) was approved by the sis patients demanding access to legal secure 20,000-square-foot glasshouse ing CBD levels,” he explained. FDA in 1984. They moved to Am- medicine. (The MS patients had been complex, purchased Hortapharm’s “ge- But we know that the hills are full sterdam, where they started a com- inspired by the passage of Prop 215 in netic library” —the seed strains collect- of hippies who kept seeds from plants pany called Hortapharm B.V. and were California!) ed and refined over the years by Watson with unusual effects... What a shame granted a license to grow cannabis. Guy inferred from the literature that and Clarke—and hired them and Pate that, due to Prohibition, no analytic In a large greenhouse near the airport the cannabis Queen Victoria smoked as consultants. chemistry labs are testing marijuana in Hortapharm hybridized plants, creating to alleviate menstrual cramps was rich GW’s drug-development strategy was the state where legalization for medical numerous varieties, including the pow- in cannabidiol (CBD), and he hypoth- based on the assumption that terpenes use in ‘96 inspired the MS patients in England who inspired Geoffrey Guy! Scrapbook: Reno Sur-la-Mer

Vacationing French workers get four-weeks of paid time off. “A little bit of socialism goes a long way,” Rosie observed.

Mechoulam and rosie: “He discovered THC in 1964, and she discovered THC in 1964.”

Monique Braude and Gabriel Nahas

John McPartland agreed that the French do ancien better than they do moderne.