The International Cannabinoid Research
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—2— O’Shaughnessy’s • Leaflet “The field is moving away from the plant...” The International Cannabinoid 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 marijuana 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 cannabidiol (left) and Δ-9 tetrahydrocannabinol (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 Cannabis — 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 hemp when bred for fiber— but ished to find that these receptors, now synthetic cannabinoids 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.