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2
CANNABINOIDS AND ANIMAL PHYSIOLOGY

Introduction

Much has been learned since the publication of the 1982 Institute of Medicine (IOM) report Marijuana and Health.* Although it was clear then that most of the effects of marijuana were due to its actions on the brain, there was little information about how THC acted on brain cells (neurons), which cells were affected by THC, or even what general areas of the brain were most affected by THC. Too little was known about cannabinoid physiology to offer any scientific insights into the harmful or therapeutic effects of marijuana. That is no longer true. During the past 16 years, there have been major advances in what basic science discloses about the potential medical benefits of cannabinoids, the group of compounds related to THC. Many variants are found in the marijuana plant, and other cannabinoids not found in the plant have been chemically synthesized. Sixteen years ago it was still a matter of debate as to whether THC acted nonspecifically by affecting the fluidity of cell membranes or whether a specific pathway of action was mediated by a receptor that responded selectively to THC (Table 2.1).

*The field of neuroscience has grown substantially since the publication of the 1982 IOM report. The number of members in the Society for Neuroscience provides a rough measure of the growth in research and knowledge about the brain: as of the middle of 1998, there were over 27,000 members, more than triple the number in 1982.



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Page 33 2 CANNABINOIDS AND ANIMAL PHYSIOLOGY Introduction Much has been learned since the publication of the 1982 Institute of Medicine (IOM) report Marijuana and Health.* Although it was clear then that most of the effects of marijuana were due to its actions on the brain, there was little information about how THC acted on brain cells (neurons), which cells were affected by THC, or even what general areas of the brain were most affected by THC. Too little was known about cannabinoid physiology to offer any scientific insights into the harmful or therapeutic effects of marijuana. That is no longer true. During the past 16 years, there have been major advances in what basic science discloses about the potential medical benefits of cannabinoids, the group of compounds related to THC. Many variants are found in the marijuana plant, and other cannabinoids not found in the plant have been chemically synthesized. Sixteen years ago it was still a matter of debate as to whether THC acted nonspecifically by affecting the fluidity of cell membranes or whether a specific pathway of action was mediated by a receptor that responded selectively to THC (Table 2.1). *The field of neuroscience has grown substantially since the publication of the 1982 IOM report. The number of members in the Society for Neuroscience provides a rough measure of the growth in research and knowledge about the brain: as of the middle of 1998, there were over 27,000 members, more than triple the number in 1982.

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Page 34 TABLE 2.1  Landmark Discoveries Since the 1982 IOM  Report Year Discovery Primary Investigators 1986 Potent cannabinoid agonists are developed; they are the key to discovering the receptor. M. R. Johnson and L. S. Melvin75       1988 First conclusive evidence of specific   cannabinoid receptors. A. Howlett and W. Devaneh36 1990 The cannabinoid brain receptor (CB,) is cloned, its DNA sequence is identified, and its location in the brain is determined. L. Matsuda107 and M. Herkenham     et al60 1992 Anandamide is discovered—a naturally occurring substance in the brain that acts on cannabinoid receptors. R. Mechoulam and W. Devane37       1993 A cannabinoid receptor is discovered outside the brain; this receptor (CB2) is related to the brain receptor but is distinct. S. Munro112                   1994 The first specific cannabinoid antagonist, SR 141716A, is developed. M. Rinaldi-Carmonal32       1998 The first cannabinoid antagonist, SR144528, that can distinguish between CB1 and CB2 receptors discovered. M. Rinaldi-Carmona133       Basic science is the wellspring for developing new medications and is particularly important for understanding a drug that has as many effects as marijuana. Even committed advocates of the medical use of marijuana do not claim that all the effects of marijuana are desirable for every medical use. But they do claim that the combination of specific effects of marijuana enhances its medical value. An understanding of those specific effects is what basic science can provide. The multiple effects of marijuana can be singled out and studied with the goals of evaluating the medical value of marijuana and cannabinoids in specific medical conditions, as well as minimizing unwanted side effects. An understanding of the basic mechanisms through which cannabinoids affect physiology permits more strategic development of new drugs and designs for clinical trials that are most likely to yield conclusive results. Research on cannabinoid biology offers new insights into clinical use, especially given the scarcity of clinical studies that adequately evaluate the medical value of marijuana. For example, despite the scarcity of sub-

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Page 35 stantive clinical data, basic science has made it clear that cannabinoids can affect pain transmission and, specifically, that cannabinoids interact with the brain's endogenous opioid system, an important system for the medical treatment of pain (see chapter 4). The cellular machinery that underlies the response of the body and brain to cannabinoids involves an intricate interplay of different systems. This chapter reviews the components of that machinery with enough detail to permit the reader to compare what is known about basic biology with the medical uses proposed for marijuana. For some readers that will be too much detail. Those readers who do not wish to read the entire chapter should, nonetheless, be mindful of the following key points in this chapter: ·      The most far reaching of the recent advances in cannabinoid biology are the identification of two types of cannabinoid receptors (CB1 and CB2) and of anandamide, a substance naturally produced by the body that acts at the cannabinoid receptor and has effects similar to those of THC. The CB1 receptor is found primarily in the brain and mediates the psychological effects of THC. The CB2 receptor is associated with the immune system; its role remains unclear. ·      The physiological roles of the brain cannabinoid system in humans are the subject of much active research and are not fully known; however, cannabinoids likely have a natural role in pain modulation, control of movement, and memory. ·      Animal research has shown that the potential for cannabinoid dependence exists, and cannabinoid withdrawal symptoms can be observed. However, both appear to be mild compared to dependence and withdrawal seen with other drugs. ·      Basic research in cannabinoid biology has revealed a variety of cellular pathways through which potentially therapeutic drugs could act on the cannabinoid system. In addition to the known cannabinoids, such drugs might include chemical derivatives of plantderived cannabinoids or of endogenous cannabinoids such as anandamide but would also include noncannabinoid drugs that act on the cannabinoid system. This chapter summarizes the basics of cannabinoid biology—as known today. It thus provides a scientific basis for interpreting claims founded on anecdotes and for evaluating the clinical studies of marijuana presented in chapter 4.

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Page 36 The Value of Animal Studies Much of the research into the effects of cannabinoids on the brain is based on animal studies. Many speakers at the public workshops associated with this study argued that animal studies of marijuana are not relevant to humans. Animal studies are not a substitute for clinical trials, but they are a necessary complement. Ultimately, every biologically active substance exerts its effects at the cellular and molecular levels, and the evidence has shown that this is remarkably consistent among mammals, even those as different in body and mind as rats and humans. Animal studies typically provide information about how drugs work that would not be obtainable in clinical studies. At the same time, animal studies can never inform us completely about the full range of psychological and physiological effects of marijuana or cannabinoids on humans. The Active Constituents of Marijuana D9-THC and D8-THC are the only compounds in the marijuana plant that produce all the psychoactive effects of marijuana. Because D9-THC is much more abundant than D8-THC, the psychoactivity of marijuana has been attributed largely to the effects of D9-THC. 11-OH-D9-THC is the primary product of D9-THC metabolism by the liver and is about three times as potent as D9-THC.128 There have been considerably fewer experiments with cannabinoids other than A9-THC, although a few studies have been done to examine whether other cannabinoids modulate the effects of THC or mediate the nonpsychological effects of marijuana. Cannabidiol (CBD) does not have the same psychoactivity as THC, but it was initially reported to attenuate the psychological response to THC in humans;81,177 however, later studies reported that CBD did not attenuate the psychological effects of THC.11,69 One double-blind study of eight volunteers reported that CBD can block the anxiety induced by high doses of THC (0.5 mg/kg).177 There are numerous anecdotal reports claiming that marijuana with relatively higher ratios of THC:CBD is less likely to induce anxiety in the user than marijuana with low THC:CBD ratios; but, taken together, the results published thus far are inconclusive. The most important effect of CBD seems to be its interference with drug metabolism, including D9-THC metabolism in the liver.14, 114 It exerts that effect by inactivating cytochrome P450s, which are the most important class of enzymes that metabolize drugs. Like many P450 inactivators, CBD can also induce P450s after repeated doses.13 Experiments in which mice were treated with CBD followed by THC showed that CBD treatment was associated with a substantial increase in brain concentrations of

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Page 37 THC and its major metabolites, most likely because it decreased the rate of clearance of THC from the body.15 In mice, THC inhibits the release of luteinizing hormone, the pituitary hormone that triggers the release of testosterone from the testes; this effect is increased when THC is given with cannabinol or CBD.113 Cannabinol also lowers body temperature and increases sleep duration in mice.175 It is considerably less active than THC in the brain, but studies of immune cells have shown that it can modulate immune function (see ''Cannabinoids and the Immune System'' later in this chapter). The Pharmacological Toolbox A researcher needs certain key tools in order to understand how a drug acts on the brain. To appreciate the importance of these tools, one must first understand some basic principles of drug action. All recent studies have indicated that the behavioral effects of THC are receptor mediated.27 Neurons in the brain are activated when a compound binds to its receptor, which is a protein typically located on the cell surface. Thus, THC will exert its effects only after binding to its receptor. In general, a given receptor will accept only particular classes of compounds and will be unaffected by other compounds. Compounds that activate receptors are called agonists. Binding to a receptor triggers an event or a series of events in the cell that results in a change in the cell's activity, its gene regulation, or the signals that it sends to neighboring cells (Figure 2.1). This agonist-induced process is called signal transduction. Another set of tools for drug research, which became available only recently for cannabinoid research, are the receptor antagonists, so-called because they selectively bind to a receptor that would have otherwise been available for binding to some other compound or drug. Antagonists block the effects of agonists and are tools to identify the functions of a receptor by showing what happens when its normal functions are blocked. Agonists and antagonists are both ligands; that is, they bind to receptors. Hormones, neurotransmitters, and drugs can all act as ligands. Morphine and naloxone provide a good example of how agonists and antagonists interact. A large dose of morphine acts as an agonist at opioid receptors in the brain and interferes with, or even arrests, breathing. Naloxone, a powerful opioid antagonist, blocks morphine's effects on opiate receptors, thereby allowing an overdose victim to resume breathing normally. Naloxone itself has no effect on breathing. Another key tool involves identifying the receptor protein and determining how it works. That makes it possible to locate where a drug activates its receptor in the brain—both the general region of the brain and

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Page 38 Figure 2.1   Diagram of neuron with synapse. Individual nerve cells, or neurons, both send and receive  cellular signals to and from neighboring neurons, but for the purposes of this diagram  only one activity is indicated for each cell. Neurotransmitter molecules are released from  the neuron terminal and move across the gap between the "sending" and "receiving"  neurons. A signal is transmitted to the receiving neuron when the neurotransmitters have  bound to the receptor on its surface. The effects of a transmitted signal include: ·      Changing the cell's permeability to ions, such as calcium and potassium. ·      Turning a particular gene on or off. ·      Sending a signal to another neuron. ·      Increasing or decreasing the responsiveness of the cell to other cellular signals. Those effects can lead to cognitive, behavioral, or physiological changes, depending on which neuronal system is activated. Continued on bottom of p. 39

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Page 39 the cell type where the receptor is located. The way to find a receptor for a drug in the brain is to make the receptor "visible" by attaching a radioactive or fluorescent marker to the drug. Such markers show where in the brain a drug binds to the receptor, although this is not necessarily the part of the brain where the drug ultimately has its greatest effects. Because drugs injected into animals must be dissolved in a waterbased solution, it is easier to deliver water-soluble molecules than to deliver fat-soluble (lipophilic) molecules such as THC. THC is so lipophilic that it can stick to glass and plastic syringes used for injection. Because it is lipophilic, it readily enters cell membranes and thus can cross the blood brain barrier easily. (This barrier insulates the brain from many bloodborne substances.) Early cannabinoid research was hindered by the lack of potent cannabinoid ligands (THC binds to its cannabinoid receptors rather weakly) and because they were not readily water soluble. The synthetic agonist CP 55,940, which is more water soluble than THC, was the first useful research tool for studying cannabinoid receptors because of its high potency and ability to be labeled with a radioactive molecule, which enabled researchers to trace its activity. Cannabinoid Receptors The cannabinoid receptor is a typical member of the largest known family of receptors: the G protein-coupled receptors with their distinctive pattern in which the receptor molecule spans the cell membrane seven times (Figure 2.2). For excellent recent reviews of cannabinoid receptor biology, see Childers and Breivogel,27 Abood and Martin,1 Felder and Glass,43 and Pertwee.124 Cannabinoid receptor ligands bind reversibly (they bind to the receptor briefly and then dissociate) and stereoselectively (when there are molecules that are mirror images of each other, only one The expanded view of the synapse illustrates a variety of ligands, that is, molecules that bind to receptors. Anandamide is a substance produced by the body that binds to and activates cannabinoid receptors; it is an endogenous agonist. THC can also bind to and activate cannabinoid receptors but is not naturally found in the body; it is an exogenous agonist. SR 141716A binds to but does not activate cannabinoid receptors. In this way it prevents agonists, such as anandamide and THC, from activating cannabinoid receptors by binding to the receptors without activating them; SR 141716A is an antagonist, but it is not normally produced in the body. Endogenous antagonists, that is, those normally produced in the body, might also exist, but none has been identified.

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Page 40 Figure  2.2   Cannabinoid receptors. Receptors are proteins, and proteins are  made up of strings of amino acids. Each circle in the diagram represents one amino  acid. The shaded bar represents the cell membrane, which like all cell membranes  in animals is composed largely of phospholipids. Like many receptors, the cannabinoid  receptors span the cell membrane; some sections of the receptor protein are outside  the cell membrane (extracellular); some are inside (intracellular). THC, anandamide,  and other known cannabinoid receptor agonists bind to the extracellular portion of the  receptor, thereby activating the signal pathway inside the cell. The CB1  molecule is  larger than CB2. The receptor molecules are most similar in four of the seven regions  where they are embedded in the cell membrane (known as the transmembrane regions).  The intracellular loops of the two receptor subtypes are quite different, which might  affect the cellular response to the ligand because these loops are known to mediate  G protein signaling, the next step in the cell signaling pathway after the receptor. Receptor  homology between the two receptor subtypes is 44% for the full-length protein  and 68% within the seven transmembrane regions. The ligand binding sites are typically  defined by the extracellular loops and the transmembrane regions.   version activates the receptor). Thus far, two cannabinoid receptor subtypes (CB1 and CB2) have been identified, of which only CB1 is found in the brain. The cell responds in a variety of ways when a ligand binds to the cannabinoid receptor (Figure 2.3). The first step is activation of G proteins, the first components of the signal transduction pathway. That leads to changes in several intracellular components-such as cyclic AMP and calcium and potassium ions—which ultimately produce the changes in cell functions. The final result of cannabinoid receptor stimulation de-

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Page 41   Figure 2.3  Cannabinoid agonists trigger a series of reactions within cells.  Cannabinoid receptors are embedded in the cell membrane, where they are  coupled to G proteins (G) and the enzyme adenylyl cyclase (AC). Receptors  are activated when they bind to ligands, such as anandamide or THC in this  case. This triggers a variety of reactions, including inhibition (-) of AC,  which decreases the production of cAMP and cellular activities dependent on  cAMP; opening of potassium (K+) channels, which decreases cell firing; and  closing of calcium (Ca2+) channels, which decreases the release of neurotransmitters.  Each of those changes can influence cellular communication.   pends on the particular type of cell, the particular ligand, and the other molecules that might be competing for receptor binding sites. Different agonists vary in binding potency, which determines the effective dose of the drug, and efficacy, which determines the maximal strength of the signal that they transmit to the cell. The potency and efficacy of THC are both relatively lower than those of some synthetic cannabinoids; in fact, synthetic compounds are generally more potent and efficacious than endogenous agonists. CB1 receptors are extraordinarily abundant in the brain. They are more abundant than most other G protein-coupled receptors and 10 times more abundant than mu opioid receptors, the receptors responsible for the effects of morphine.148

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Page 42 The cannabinoid receptor in the brain is a protein referred to as CB,. The peripheral receptor (outside the nervous system), CB2, is most abundant on cells of the immune system and is not generally found in the brain.43,124 Although no other receptor subtypes have been identified, there is a genetic variant known as CB1A (such variants are somewhat different proteins that have been produced by the same genes via alternative processing). In some cases, proteins produced via alternative splicing have different effects on cells. It is not yet known whether there are any functional differences between the two, but the structural differences raise the possibility. CB1 and CB2 are similar, but not as similar as members of many other receptor families are to each other. On the basis of a comparison of the sequence of amino acids that make up the receptor protein, the similarity of the CB1 and CB2 receptors is 44% (Figure 2.2). The differences between the two receptors indicate that it should be possible to design therapeutic drugs that would act only on one or the other receptor and thus would activate or attenuate (block) the appropriate cannabinoid receptors. This offers a powerful method for producing biologically selective effects. In spite of the difference between the receptor subtypes, most cannabinoid compounds bind with similar affinity* to both CB1 and CB2 receptors. One exception is the plant-derived compound CBD, which appears to have greater binding affinity for CB2 than for CB1,112 although another research group has failed to substantiate that observation.129 Other exceptions include the synthetic compound WIN 55,212-2, which shows greater affinity for CB2 than CB,, and the endogenous ligands, anandamide and 2-AG, which show greater affinity for CB1, than CB2.43 The search for compounds that bind to only one or the other of the cannabinoid receptor types has been under way for several years and has yielded a number of compounds that are useful research tools and have potential for medical use. Cannabinoid receptors have been studied most in vertebrates, such as rats and mice. However, they are also found in invertebrates, such as leeches and mollusks.156 The evolutionary history of vertebrates and invertebrates diverged more than 500 million years ago, so cannabinoid receptors appear to have been conserved throughout evolution at least this long. This suggests that they serve an important and basic function in animal physiology. In general, cannabinoid receptor molecules are similar among different species.124 Thus, cannabinoid receptors likely fill many similar functions in a broad range of animals, including humans. *Affinity is a measure of how avidly a compound binds to a receptor. The higher the affinity of a compound, the higher its potency; that is, lower doses are needed to produce its effects.

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Page 43 The Endogenous Cannabinoid System For any drug for which there is a receptor, the logical question is, "Why does this receptor exist?" The short answer is that there is probably an endogenous agonist (that is, a compound that is naturally produced in the brain) that acts on that receptor. The long answer begins with a search for such compounds in the area of the body that produces the receptors and ends with a determination of the natural function of those compounds. So far, the search has yielded several endogenous compounds that bind selectively to cannabinoid receptors. The best studied of them are anandamide37 and arachidonyl glycerol (2-AG).108 However, their physiological roles are not yet known. Initially, the search for an endogenous cannabinoid was based on the premise that its chemical structure would be similar to that of THC; that was reasonable, in that it was really a search for another "key" that would fit into the cannabinoid receptor "keyhole," thereby activating the cellular message system. One of the intriguing discoveries in cannabinoid biology was how chemically different THC and anandamide are. A similar search for endogenous opioids (endorphins) also revealed that their chemical structure is very different from the plant-derived opioids, opium and morphine. Further research has uncovered a variety of compounds with quite different chemical structures that can activate cannabinoid receptors (Table 2.2 and Figure 2.4). It is not yet known exactly how anandamide and THC bind to cannabinoid receptors. Knowing this should permit more precise design of drugs that selectively activate the endogenous cannabinoid systems. Anandamide The first endogenous cannabinoid to be discovered was arachidonyl-ethanolamine, named anandamide from the Sanskrit word ananda, meaning "bliss."37 Compared with THC, anandamide has only moderate affinity for CB1 receptor and is rapidly metabolized by amidases (enzymes that remove amide groups). Despite its short duration of action, anand-amide shares most of the pharmacological effects of THC.37,152 Rapid degradation of active molecules is a feature of neurotransmitter systems that allows them control of signal timing by regulating the abundance of signaling molecules. It creates problems for interpreting the results of many experiments and might explain why in vivo studies with anandamide injected into the brain have yielded conflicting results. Anandamide appears to have both central (in the brain) and peripheral (in the rest of the body) effects. The precise neuroanatomical localiza-

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Tab/e 2.8 Historical comparisons between cannabinoicis and opiates Comparisons between cannabinoids and opiates Cannabinoids Pharmacological Discoveries Discovery of receptor existence identification of receptor anfagonisf Discovery of tsf enclogenous ligand Ask Receptor cloned Natural functions of cannabinoic] / opiate systems 1988 (Howlett and Devane)36, 40 1994 SR141716A (Rinaldi Carmona)l32 1992 Anandamide (Devane and Mechoulam)37 1990 (Matsuda)l07 Unknown Opiates 1973 (Pert and Snyder, Terenius, and Simon)123, 149, 162 pre-1973 Naloxone 1975 Met- and Leu-enkephalin (Hughes et al)70 1992 (Evans et al. and Kieffer et al.)41, 82 Pain, reproduction, mood, movement, and others There are several research tools that will greatly aid such investigations in particular, a greater selection of agonists and antagonists that permit discrimination between the activation of CB~ versus CB2 receptors; hydrophilic agonists (that can be delivered to animals or cells more effectively than hydrophobic compounds). In the area of drug development, fixture progress should continue to provide more specific agonists and antagonists for CB~ and CB2 receptors, with varying potential for therapeutic uses. There are certain areas that wall provide keys to a better understanding of the potential therapeutic value of cannabinoids. For example, basic biology indicates a role for cannabinoids in pain and control of movement, which is consistent with a possible therapeutic role in these areas. The evidence is relatively strong for the treatment of pain, and intriguingly, although less well-established, for movement disorders. The neuroprotective properties of cannabinoids might prove therapeutically useful, although it should be noted that this is a new area and other, better studied, neuroprotective drugs have not yet been shown to be therapeutically useful. Cannabinoid research is clearly relevant not only to drug abuse, but also to 2.44