Mechoulam on Cannabidiol by Fred Gardner a Lipid

O’Shaughnessy’s • Winter/Spring 2008 —31— An Overview at the IACM meeting in Cologne Mechoulam on Cannabidiol By Fred Gardner a lipid. Sophisticated analytical tech- wonder, then, that CBD plays a role in The emerging significance of can- niques and brilliant, dedicated lab work- many clinical conditions. nabis components other than THC was ers (“They should not be married so they Conditions treatable by CBD again a prominent theme when the can work 24 hours a day, seven days a Mechoulam described an experiment International Association of Cannabis week”) enabled Mechoulam to isolate a led by Paul Consroe and colleagues in as Medicine met in Cologne in early cannabinoid produced by the body itself Brazil in which CBD was tested as a October, 2007. The IACM was founded —arachidonoyl-ethanolamide or AEA, treatment for intractable epilepsy. Pa- in 1997 by Franjo Grotenhermen, MD which his colleague William Devane tients stayed on the anticonvulsants they (as the German ACM); it is a smaller dubbed “anandamide,” incorporating the had been on (which hadn’t eliminated organization than the ICRS and its focus Sanskrit word for “bliss.” their seizures) and added 200mg/day of is more clinical, less pharmacological. CBD or a placebo. Of the seven patients “There is almost no physi- getting CBD over the course of several Mechoulam thought his ological system that has been months, only one showed no improve- study of cannabis would be “a ment; three became seizure-free; one looked into in which endocan- experienced only one or two seizures,

minor project, it will be finished nabinoids don’t play a certain Mechoulam recalled; and two experi- photo by by photo Alon Weinstock off in six months.” part.” enced reduced severity and occurrence of seizures. Raphael Mechoulam of the Hebrew Mechoulam’s lab isolated a second University, Jerusalem, Faculty of Medi- endogenous compound, arachidonoyl “Nobody has done any work cine gave a talk on cannabidiol on the glyceride, or 2-AG, which is more on cannabidiol in the clinic occasion, he noted, of his 45th year of abundant in the body but less potent than involvement in the field. In October, anandamide. Although their structures on epilepsy, and I just wonder 1962 Mechoulam had just gotten his are different, AEA, 2-AG and THC have why.” PhD in chemistry and was looking for a similar pharmacological effects. research project that might lead to tenure The receptors to which they bind “So it seemed a very promising ap- ‘let’s have more CBD,’” Mechoulam at the Weizmann Institute. He chose to weave in and out of the cell membrane proach,” said Mechoulam, “but unfor- said. “We should try it with humans in analyze the components of cannabis, he and are coupled to a protein that triggers tunately, nothing has been done ever a few years.” said, thinking “it’s a minor project, it will events within the cell leading to slowed since. To the best of my knowledge, He went on: “What about sleep? I’m be finished off in six months.” release of neurotransmitters. (Think of nobody has done any work on cannabi- jumping from thing to thing to show you a tiny doorknob twisting on the outside diol in the clinic on epilepsy, and I just that CBD does quite a lot of things and “There is a fantastic collabo- of a frenzied beehive and starting a wonder why.” I’m not sure that all of them are accord- sequence of events on the inside that A colleague of Mechoulam’s, Marc ing to the same mechanism.” ration between Arabs and Jews results in fewer bees departing the hive.) Feldman at Imperial College, London, Mechoulam was part of a group led in smuggling,” Mechoulam Because the cannabinoids affect the tested CBD on mice who had a version by Eric Murillo-Rodriguez that admin- observed. intensity with which other neurotrans- of rheumatoid arthritis and found that it istered CBD to rats and determined that mitters are firing, they modulate numer- reduced inflammation by almost 50% at while THC caused sleepiness, CBD Hashish of Lebanese origin was ous systems within the body. Mechoulam the right dose —5mg/kg of body weight. increased wakefulness and significantly obtained from the police —“There is a said, “There is almost no physiological But this “beautiful antiinflammatory decreased REM sleep. According to fantastic collaboration between Arabs system that has been looked into in reaction was lost if we went up to, say, Mechoulam, “When one says ‘cannabis and Jews in smuggling,” Mechoulam which endocannabinoids don’t play a 25 mg/kg,” Mechoulam said. Drug causes sleep,’ one should think really of observed— and a dozen constituents certain part.” developers must bear in mind and cope two compounds, one that causes sleep were then identified by two types of CBD binds to a second cannabinoid with the fact that cannabinoids have a and one that causes awakening.” chromatography. (Some cannabis con- receptor —CB2—originally found in finite “therapeutic window” and may be stituents had been identified previously, spleen cells by S. Munro of Cambridge ineffective at low and high doses. Anti-nausea including CBD, which Roger Adams of University in 1993 and subsequently The anti-nausea and memory extinc- the University of Illinois isolated in the found in the stomach, liver, heart, kid- CBD for Diabetes tion effects of CBD “seem to be closely early 1940s.) ney, lymph and immune cells, bones, Mechoulam has been testing CBD related,” Mechoulam said. He described Mechoulam and his co-workers endocrine glands, and throughout the on mice bred to have a version of type- the problem of anticipatory nausea, for elucidated the exact chemical structure peripheral nervous system. 1 diabetes that manifests around age 14 which no good drugs are available. (The of CBD in 1963 and of THC the fol- In his IACM talk Mechoulam re- weeks. He and his co-workers treated effects of chemotherapy can be so nau- lowing year. It was generally assumed viewed research in recent years that these mice with CBD for their first 6-7 seating that patients start vomiting when for almost two decades that the canna- has shed light on aspects of CBD’s weeks of life, then tested them 6-7 weeks they see the doctor or nurse who is going binoids exerted effects not by binding to mechanism of action. Its lipid-solubility later and found that only 30% had devel- to administer the treatment.) a specific receptor but “nonspecifically” enables it to get into places in the brain oped diabetes (compared to 90-100% Linda Parker at the University of by altering the lipid structure of cellular that conventional neurotransmitters can- given placebo). Guelph conditioned shrews to start vom- membranes. Mechoulam established that not reach. It is a potent anti-oxidative iting by administering lithium fluoride at the action was specific by purifying THC agent. It turns out to be an antagonist CBD did not just prevent a certain location. When the shrews were and showing that only the natural version to a recently discovered receptor called onset but blocked development subsequently placed in that location they of the molecule —and not its synthetic GPR-55 to which THC and 2-AG bind of diabetes. began vomiting. But if given CBD, they mirror image— was exerting the effect. as agonists. It blocks the uptake of ad- could be moved to the dreaded location In 1988 Alynn Howlett found that enosine, an inhibitory neurotransmitter In a follow-up experiment the mice without vomiting. [THC is anti-emetic, THC was indeed activating a receptor. that may promote sleep. It blocks the weren’t given a course of CBD until age too; the advantage of CBD in this in- It was dubbed “CB1” and was found formation of various cytokines (signal- 14 weeks, when they were developing stance may be legal rather than medical.] in those areas of the brain involved in ing compounds not released by nerves diabetes. They were then tested at age “The conditioned-wretching reaction movement, stress, cognitive function or glands) under certain circumstancs. 24 weeks, and again only 30% of the was completely abolished,” Mechoulam — “everywhere it would be expected,” It activates the serotonin receptors. No treated mice were found to have diabe- declared. “Can we abolish other kinds of said Mechoulam, giv- tes. In other words, CBD did not just conditoning?” en what was known prevent onset but blocked development He described an experiment in which about the effects of of diabetes. rats had a choice of two paths, one lead- cannabis on people. Examination of the insulin-producing ing to cocaine. Rats like cocaine (and “A receptor doesn’t islets showed that only 8% were intact amphetamine) and will learn to choose exist in the brain just in the untreated diabetic mice, whereas the path leading to it. But if injected with because there’s a plant 77% were intact in the mice treated CBD, they no longer show a preference out there,” Mechoul- with CBD. “I believe that here we have for cocaine! am reasoned, “chances something very promising,” Mechoulam Mechoulam characterized post- are there are endog- said. “We plan to have a clinical trial traumatic stress disorder, certain phobias enous compounds that starting next week treating patients, and and forms of chronic pain as “human will act on these recep- hopefully at the next meeting I will tell situations which are conditioned” and tors —so we went after you that all of them are cured.” might be amenable to treatment with them.” “Let’s have some more CBD” CBD. “I know that many patients with Whereas others Cardiologists working with mice PTSD take cannabis, self administered,” were looking for pep- at Hebrew University have found that Mechoulam said. He has been trying to tides, Mechoulam fig- At the IACM meeting: Mechoulam and Christian Steup, interest the Israeli Ministry of Health in director of THC-Pharm, a Frankfurt company that synthe- CBD treatment at the time of a heart ured the CB1 receptor attack can reduce infarct size by about testing CBD and THC at various ratios would be activated by sizes CBD and other chemicals for clinical and research purposes. 66%. “So now they’re pushing me, to treat PTSD.