Cannabinoid Investigations Entering The Mainstream

With the passage last year of Proposition 215 in California and similar measures in Arizona and other states, voters have indicated their belief that marijuana should be made available for medicinal purposes. In response, the Office of National Drug Control Policy requested that the Institute of Medicine of the National Academy of Sciences undertake an 18-month study to assess the science base, the therapeutic use, and the economics of medical marijuana. The study will not be completed until the end of this year, but it is certain to highlight the extent to which research on medical marijuana has entered the mainstream of science. NEW TOOLS: Wake Forest's Steven Childers notes that researchers only recently became able to study the interaction of cannabinoid compounds with their receptors. But it's not just the impetus of political events that is driving the renewed interest in studying marijuana and its active compounds, the cannabinoids. Interest in cannabinoid research started to snowball after some key discoveries in the mid-1980s. As Steven R. Childers, a professor of physiology and pharmacology at Wake Forest University School of Medicine in Winston-Salem, N.C., puts it, "During the late '70s and early '80s, when there was a tremendous explosion of information from other areas of drug abuse-like opiate receptors and enkephalins and endorphins, and the concept that cocaine acts on dopamine transporters-the cannabinoid field was strangely silent." "Before 1990 we really didn't have much of an understanding of how cannabinoids worked," agrees Norbert E. Kaminski, an associate professor of pharmacology, toxicology, and pathology at Michigan State University. "Many, if not most, people in this area of research thought the compounds worked nonspecifically by perturbing cell membranes, because they're very lipophilic compounds." Because of this lipophilicity, delta9-tetra-hydrocannabinol (THC)-the main active ingredient in marijuana-and its derivatives are poorly soluble in water, which makes them difficult to study. According to Childers, it wasn't until the mid-1980s that researchers developed the tools that allow them to study cannabinoid pharmacology-the interaction of the compounds with their specific, membrane-bound receptors-in detail. With the development of these tools came increased funding from the National Institute on Drug Abuse (NIDA), which funds the bulk of basic cannabinoid research. "Until we had the proper pharmacological tools to examine the system from the basic science point of view, it was really very difficult to propose projects," notes Childers, who has been reviewing grants for NIDA for about a dozen years. "There's no question that cannabinoid research funding has increased." With the discovery and cloning of two key cannabinoid receptors, the receptor story has become fairly clear and straightforward, and the field has blossomed. The CB1 receptor, which is found mainly in the brain, was discovered in 1988 (W.A. Devane et al., Molecular Pharmacology, 34:605-13, 1988) and cloned in 1990 (L.A. Matsuda et al., Nature, 346:561-4, 1990). The CB2 receptor, which is found mainly outside the brain, was discovered and cloned in 1993 (S. Munro et al., Nature, 365:61-5, 1993). Both receptors belong to the G-protein-coupled family of receptors. "That very basic finding catapulted this field into the mainstream of neuroscience," notes Childers. When either cannabinoid receptor is activated, there's an intracellular decrease in cyclic AMP production, a decrease in calcium-channel conductance, and an increase in potassium-channel conductance. These actions indicate that cannabinoids have an inhibitory effect on neurotransmission. "CB1 and CB2 are highly homologous to one another, which is very typical for members within the same family of receptors, but there are a number of important differences," Childers points out. "The homologies within CB1 and CB2 are not nearly as great as the homologies within other types of receptor families [the opioid receptors, for example]. The implication [is] that it's quite likely that pharmacological agents can be produced which are highly selective and distinguish between the receptor types." "One of the nice things about these receptors is that they've stimulated chemists around the world to synthesize new and exciting derivatives," observes Childers. Among the plethora of new compounds that interact with cannabinoid receptors, three in particular have emerged as standard research tools. Researchers are using compounds called WIN 55,212-2 and CP 55,940 as standard agonists, and one called SR141716A as the standard receptor antagonist. All three have a higher affinity for cannabinoid receptors than delta9-THC, which turns out to be a weak partial agonist. The field was further energized with the 1992 discovery by a team led by Raphael Mechoulam of Hebrew University in Jerusalem of the first cannabinoid neurotransmitter that is "endogenous"-normally present in the brain (W.A. Devane et al., Science, 258:1946-9, 1992). It's an arachidonic acid derivative, called anandamide. Recently Danieli Piomelli of the Neurosciences Institute in San Diego discovered another endogenous cannabinoid called sn-2 arachidonylglycerol (2-AG). Interestingly, "the endogenous compounds are not particularly potent," Childers points out. "They have about the same affinity for the CB1 receptor as delta9-THC. And they're extremely unstable." The CB1 receptor is exceedingly abundant in the brain. According to Childers, it's by far the brain's most common G-protein-coupled receptor, and it even approaches some of the receptors for excitatory amino acid transmitters, such as glutamate, in quantity. "Certainly no one would ever have predicted that a receptor for marijuana would exist in such high quantities in brain," Childers contends. "We believe there are significant functional consequences to the large amount of receptors that are there." For example, he explains, "if it weren't for the fact that there are so many of these receptors in brain, it's probably likely that cannabis itself would not be an effective drug," since D9-THC is such a weak partial agonist. In terms of the distribution of CB1 receptors, "when you look at an autoradiogram, the thing that really jumps out at you are motor systems," Childers observes. "Motor systems throughout the brain are activated by the agonist." This may provide a partial explanation for the reported ability of marijuana to ease muscle spasticity in disorders like multiple sclerosis. Additionally, he notes, "We know by a variety of animal tests that cannabinoids produce significant effects on short-term memory tasks, and that really makes sense from the very, very high distribution of cannabinoid receptors in the hippocampus," an integral part of the memory system. Researchers are as interested in the areas where cannabinoid receptors cannot be found as in the areas where they exist in high concentration. In contrast to the opioids, for example, there are few cannabinoid receptors in the brainstem nuclei that mediate respiratory depression. Since respiratory depression is one of the main toxic effects of opioid overdose, this suggests that cannabinoids are relatively safe. PROBING THE POSSIBILITIES: Wisconsin's Paul Kaufman hopes to study cannabinoids to learn about the hydrodynamic mechanisms of the eye It's not easy, however, to move from cannabinoid receptor pharmacology to the medical usage of marijuana. Some of marijuana's clearest potential medical effects are seen in glaucoma, a condition in which elevated intraocular pressure (IOP) is associated with damage to the optic nerve and progressive loss of vision. Although smoked marijuana reduces IOP to the same degree as approved medications, the enthusiasm for using marijuana as a front-line treatment has waned since the 1970s, explains Paul L. Kaufman, director of glaucoma services at the University of Wisconsin Medical School in Madison. The main stumbling block is duration of action. Marijuana reduces IOP for only three or four hours, requiring frequent dosing, while some of the newer medications need to be taken only once or twice a day. Another problem, notes Kaufman, is that marijuana's mechanism of action in reducing IOP remains unknown. "People say, 'Let's just legalize marijuana, and it will be the cure for glaucoma.' Well, that's not the way to develop a drug. The way you develop a drug is to understand the mechanism-which we don't for the cannabinoids-and then to take the good points about that mechanism, change the molecule around to give you more of what you want, less of what you don't want, put it through basic studies, put it through clinical trials, and hopefully if you're lucky you wind up with a therapeutically useful compound. And that's the way this should be handled." International Cannabinoid Research Society (ICRS) 98 Brookes Ave. Burlington, Vt. 05401 Phone and Fax: (802) 865-0970 ICRS@together.net http://129.49.19.42/ICRS/ICRS_main.html Roger Pertwee, President Diane Mahadeen, Director 190 members The Institute of Medicine is conducting an 18-month study to assess the therapeutic potential of marijuana and its components. For more information, contact: Janet E. Joy, Study Director Institute of Medicine 2101 Constitution Ave., N.W. Washington, D.C. 20418 (202) 334-1805 Fax: (202) 334-1317 med-mj@nas.edu http://www2.nas.edu/medical-mj/ Review articles are available on several aspects of cannabinoid research. For an article on cannabinoid receptor pharmacology, see R.G. Pertwee, Pharmacology and Therapeutics, 74(2):129-80, 1997. For an article on the cannabinoids in immune function see N.E. Kaminski, Journal of Neuroimmunology, 1998 (in press). Nevertheless, Kaufman remains tantalized by the promise of the cannabinoids. "With the new compounds and the new knowledge of cannabinoid receptor pharmacology, maybe we can use [these agents] as probes to learn something about the hydrodynamic mechanisms of the eye. Whether that would lead to cannabinoids as drugs, or whether that would give us some insight into what other types of noncannabinoid compounds that we might develop to attack those same mechanisms, I think that's exciting." But at least one glaucoma patient, interviewed on condition of anonymity, believes that there's no reason to wait for new compounds, clinical trials, or a refined understanding of marijuana's mechanism of action. He had tried five or six of the standard medications-and experienced unpleasant side effects with each-before trying marijuana. "The marijuana gives me absolutely no side effects," he maintains. Without marijuana, "the pressure builds up in my eye to such a point that . . . it feels like someone has their finger back behind my eye. Marijuana relieves this within seconds." Kaufman acknowledges that marijuana might be useful for people who cannot get relief from the standard medications. Another area of great clinical interest is the cannabinoids' reported ability to alleviate pain. According to Howard L. Fields, a professor of neurology and physiology at the University of California, San Francisco, "I think the recent explosion of knowledge about cannabinoids, in particular the cloning of the receptors and the development of antagonists, is going to allow us to determine a new mechanism for analgesia." Fields's studies have zeroed in on a brainstem nucleus called the rostroventral medulla (RVM). "It's the part of the brainstem that directly controls the pain transmission system at the level of the spinal cord," Fields explains. "And it's a major site of action of endogenous opioids and morphine." In a series of animal experiments Fields injects combinations of cannabinoid and opioid agonists and antagonists into the RVM while simultaneously recording the physiological responses of RVM neurons and monitoring the animal's pain responses. (These experiments have not yet been published, except in abstract form: I. Meng et al., Society for Neuroscience Annual Meeting Abstracts, 1997.) Opioid agonists produce analgesia, and this response is blocked by the opioid antagonist naloxone. Likewise, WIN 55,212-2 produces analgesia that is blocked by SR141716A. But naloxone doesn't block cannabinoid analgesia, and SR141716A doesn't block opioid analgesia. The cellular neurophysiology mirrors the behavioral responses. "In every way, from an electrical standpoint, cannabinoids and opioids are the same," explains Fields. "However, they're acting at different molecular sites, and they're acting on the cell by different mechanisms." Moreover Fields can prove that the RVM is essential for cannabinoid analgesia even when the compounds are administered systemically. Inactivating the RVM with the local anesthetic lidocaine blocks the cannabinoids' analgesic effects. WINNING COMBINATION? Sandra Welch of the Medical College of Virginia hopes to use cannabinoids and opioid for analgesia without development of tolerance. "We clearly have a new bullet for treating pain," Fields rhapsodizes. But how will this weapon be used? Sandra P. Welch, an associate professor of pharmacology and toxicology at the Medical College of Virginia in Richmond, thinks that cannabinoids might be used in combination with opioids. "Our goal is to determine whether one can lower the dose of cannabinoids down to such a low level that you would not see any other side effects," she elaborates, "nor would you get tolerance to that cannabinoid, and combine it with an opioid at very, very low therapeutic levels where you would not get tolerance to the opioid. By the combination of these two [perhaps the researchers would] get an enhanced effect such that you'd see an analgesic effect for the two in combination and not see tolerance development." Cannabinoids clearly affect tissues outside the brain as well. In the immune system, for example, cannabinoids-at much higher doses than recreational marijuana users normally experience-inhibit many different immune functions, including lymphokine production by T cells and nitric oxide production by macrophages. But paradoxically, notes Kaminski, "there is some evidence that at lower doses these cannabinoids can enhance immune responses." "The problem in trying to correlate that to people actually smoking marijuana is that there are over 60 cannabinoid compounds in the smoked material," Kaminski points out. "We really don't know what concentration of cannabinoids these people are getting." Kaminski thinks cannabinoid effects on the immune system may well turn out to be of more than academic interest. "I think there's some indication that these might be useful as relatively weak immune modulators, perhaps to be used as anti-inflammatory agents or even maybe for asthma," which is thought to be an autoimmune disease. In addition to its effects on glaucoma, pain, motor systems, and the immune system, researchers are examining marijuana's potential as an antinausea drug for use with chemotherapy and as an appetite stimulant, for use in AIDS wasting and other such conditions. Childers summarizes cannabinoid research by saying, "I think that what we've seen here is a dramatic transformation of this field. Twenty years ago cannabinoid research was dealing with a fairly innocuous drug of abuse, looking into . . . how it produces its psychological effects. We now see the research in this area has been transformed into mainstream neuroscience, where now we're not just looking at a drug of abuse but we're looking at a major neurotransmitter system in the brain." Robert Finn, a freelance science writer based in Long Beach, Calif., can be reached online at finn@nasw.org.

Cannabinoid Investigations Entering The Mainstream

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