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Marijuana and Medicine: Assessing the Science Base (1999)

Chapter: 2 Cannabinoids and Animal Physiology

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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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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.

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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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-

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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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.

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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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

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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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

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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image

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

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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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.

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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image

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 CB 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-

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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image

  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

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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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.

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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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-

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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TABLE 2.2  Compounds That Bind to Cannabinoid Receptors

Compound

Properties

Agonists (receptor activators)

 

Plant-derived compounds

 

D9-THC

Main psychoactive cannabinoid in marijuana plant; largely responsible for psychological and physiological effects (except in discussions of the different forms of THC, THC is used as a synonym for D9-THC).

   
   

D8-THC

Slightly less potent than D9-THC and much less abundant in marijuana plant but otherwise similar.

   

11-OH-D9-THC

Bioactive compound formed when body breaks down D9-THC; presumed to be responsible for some effects of marijuana.

   

Cannabinoid agonists found in animals

 

Anandamide

Found in animals ranging from mollusks to mammals; appears to be primary endogenous cannabinoid agonist in mammals; chemical structure very different from plant cannabinoids and related to prostaglandins.

(arachidonyl-

 

ethanolamide)

 
   

2-AG (arachidonyl

Endogenous agonist; structurally similar to anandamide; more abundant but less potent than anandamide.

glycerol)

 

THC analogues

 

Dronabinol

Synthetic THC; marketed in the United States as Marinol for nausea associated with chemotherapy and for AIDS- related wasting.

   

Nabilone

THC analogue; marketed in the United Kingdom as Cesamet for same indications as dronabionol.

   

CP 55,940

Synthetic cannabinoid; THC analogue; that is, it is structurally similar to THC.

   

Levonantradol

THC analogue.

HU-210

THC analogue, 100- to 800-fold greater potency than THC97.

Chemical structure unlike THC or anandamide

 

WIN-55,212-2

Chemical structure different from known cannabinoids, but binds to both cannabinoid receptors; chemically related to cyclo-oxygenase inhibitors, which include antiinflammatory drugs.

   
   

Antagonists (receptor blockers)

 

SR 141716A

Synthetic CB1 antagonist; developed in 1994132.

SR 144528

Synthetic CB2 antagonist; developed in 1997133.

SOURCES: Mechoulam et al., 1998;109 Felder and Glass, 1998;43 and British Medical Association.17

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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image

Figure 2.4 
Chemical structures of selected cannabinoid agonists 
or molecules that bind to and activate cannabinoid receptors. 
THC  is the primary psychoactive molecule found in marijuana. 
CP 55,940 is a THC analogue; that is, its chemical structure is 
related to THC.  Anandamide and 2-arachidonyl glycerol (2-AG) are
 endogenous molecules, meaning they are naturally produced 
in the body. Although the chemical structure of  WIN 55,212 is 
very different from either THC or anandamide, it is also a canabinoid agonist.

tion of anandamide and the enzymes that synthesize it are not yet known. This information will provide essential clues to the natural role of anandamide and an understanding of the brain circuits in which it is a neurotransmitter. The importance of knowing specific brain circuits that involve anandamide (and other endogenous cannabinoid ligands) is that such circuits are the pivotal elements for regulating specific brain functions, such as mood, memory, and cognition. Anandamide has been found in numerous regions of the human brain: hippocampus (and

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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TABLE 2.3  Comparison of Cannabinoid Receptor Agonists

 

Potency can be measured in a variety of ways, from behavioral to physiological to cellular. This table shows potency in terms of receptor binding, which is the most broadly applicable to the many possible actions of cannabinoids. For example, anandamide binds to the cannabinoid receptor only about half as avidly as does THC. Measures of potency might include effects on activity (behavior) or hypothermia (physiologic).  The apparently low potency of 2-AG may, however, be misleading. A study published late in 1998 reports that 2-AG is found with two other closely related compounds that by themselves are biologically inactive; but in the presence of those two compounds, 2-AG is only three times less active than THC.9 Further, 2-AG is much more abundant than anandamide, although the biological significance of this remains to be determined.

 

Receptor Binding in Brain Tissue124

   

Potency Relative

 

Compound

to D9-THC

     
 

CP 55,940

59

 

D9-THC

1

 

Anandamide

0.47

 

2-AG

0.08

     

parahippocampic cortex), striatum, and cerebellum; but it has not been precisely identified with specific neuronal circuits. CB1 receptors are abundant in these regions, and this further implies a physiological role for endogenous cannabinoids in the brain functions controlled by these areas. But substantial concentrations of anandamide are also found in the thalamus, an area of the brain that has relatively few CB1 receptors.124

Anandamide has also been found outside the brain. It has been found in spleen tissue, which also has high concentrations of CB2 receptors, and small amounts have been detected in heart tissue.44

In general, the affinity of anandamide for cannabinoid receptors is only one-fourth to one-half that of THC (see Table 2.3). The differences depend on the cells or tissue that are tested and on the experimental conditions, such as the binding assay used (reviewed by Pertwee124).

The molecular structure of anandamide is relatively simple, and it can be formed from arachidonic acid and ethanolamine. Arachidonic acid is a common precursor of a group of biologically active molecules known as eicosanoids, including prostaglandins.*  Although anandamide can be synthesized in a variety of ways, the physiologically relevant pathway

*Eicosanoids all contain a chain of 20 carbon atoms and are named after eikosi, the Greek word for 20.

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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seems to be through enzymatic cleavage of N-arachidonyl-phosphatidylethanolamine (NAPE), which yields anandamide and phosphatidic acid (reviewed by Childers and Breivogel27).

Anandamide can be inactivated in the brain via two mechanisms. In one it is enzymatically cleaved to yield arachidonic acid and ethanolamine-the reverse of what was initially proposed as its primary mode of synthesis. In the other it is inactivated through neuronal uptake—that is, by being transported into the neuron, which prevents its continuing activation of neighboring neurons.

Other Endogenous Agonists

Several other endogenous compounds that are chemically related to anandamide and that bind to cannabinoid receptors have been discovered, one of which is 2-AG.108 2-AG is closely related to anandamide and is even more abundant in the brain. At the time of this writing, all known endogenous cannabinoid receptor agonists (including anandamide) were eicosanoids, which are arachidonic acid metabolites. Arachidonic acid (a free fatty acid) is released via hydrolysis of membrane phospholipids.

Other, noneicosanoid, compounds that bind cannabinoid receptors have recently been isolated from brain tissue, but they have not been identified, and their biological effects are under investigation. This is a fastmoving field of research, and no review over six months old will be fully up to date.

The endogenous compounds that bind to cannabinoid receptors probably perform a broad range of natural functions in the brain. This neural signaling system is rich and complex and has many subtle variations, many of which await discovery. In the next few years much more will probably be known about these naturally occurring cannabinoids.

Some effects of cannabinoid agonists are receptor independent. For example, both THC and CBD can be neuroprotective through their antioxidative activity; that is, they can reduce the toxic forms of oxygen that are released when cells are under stress.54 Other likely examples of receptor-independent cannabinoid activity are modulation of activation of membrane-bound enzymes (such as ATPase), arachidonic acid release, and perturbation of membrane lipids. An important caution in interpreting those reports is that concentrations of THC or CBD used in cellular studies, such as these, are generally much higher than the concentrations of THC or CBD in the body that would likely be achieved by smoking marijuana.

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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TABLE 2.4 Cellular Processes That Can Be Targeted for Drug Development

Drug Action

 

Biological Result

Block synthesis  

Synthesis of bioactive compounds is a continuous process and is one means by which concentrations of that compound are regulated.

Weaker signal, due to decreased agonist concentration.

     
     

Inhibit degradation

Chemical breakdown is one method the body uses to inactivate endogenous substances.

Stronger signal, due to increased agonist concentration.

Facilitate neuronal uptake

Neuronal uptake is one of the natural ways in which a receptor agonist is inactivated.

Stronger signal, due to increased amount of time during which agonist is present in the synapse where it can stimulate the receptor.

     
     

NOTE: Endogenous cannabinoids are part of a cellular signaling system. This table lists categories of natural processes that regulate such systems and shows the results of altering those processes.

Novel Targets for Therapeutic Drugs

Drugs that alter the natural biology of anandamide or other endogenous cannabinoids might have therapeutic uses (Table 2.4). For example, drugs that selectively inhibit neuronal uptake of anandamide would increase the brain's own natural cannabinoids, thereby mimicking some of the effects of THC. A number of important psychotherapeutic drugs act by inhibiting neurotransmitter uptake. For example, antidepressants like fluoxetine (Prozac) inhibit serotonin uptake and are known as selective serotonin reuptake inhibitors, or SSRIs. Another way to alter levels of endogenous cannabinoids would be to develop drugs that act on the enzymes involved in anandamide synthesis. Some antihypertensive drugs work by inhibiting enzymes involved in the synthesis of endogenous hypertensive agents. For example, anti-converting enzyme (ACE) inhibitors are used in hypertensive patients to interfere with the conversion of angiotensin I, which is inactive, to the active hormone, angiotensin II.

Sites Of Action

Cannabinoid receptors are particularly abundant in some areas of the brain. The normal biology and behavior associated with these brain areas

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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TABLE 2.5 Brain Regions in Which Cannabinoid Receptors Are Abundant

Brain Region

Functions Associated with Region

Brain regions in which cannabinoid receptors are abundant

Basal ganglia 

Movement control

Substantia nigra pars reticulata

 

Entopeduncular nucleus

 

Globus pallidus

 

Putamen

 

Cerebellum

Body movement coordination

Hippocampus

Learning and memory, stress

Cerebral cortex, especially cingulate,

Higher cognitive functions

frontal, and parietal regions

 

Nucleus accumbens

Reward center

Brain regions in which cannabinoid brain receptors are moderately concentrated

Hypothalamus 

Body housekeeping functions (body temperature regulation, salt and water balance, reproductive function)

   

Amygdala

Emotional response, fear

Spinal cord

Peripheral sensation, including pain

Brain stem

Sleep and arousal, temperature regulation, motor control

Central gray

Analgesia

Nucleus of the solitary tract

Visceral sensation, nausea and vomiting

SOURCES: Based on reviews by Pertwee (1997b)124 and Herkenham (1995).57

are consistent with the behavioral effects produced by cannabinoids (Table 2.5 and Figure 2.5). The highest receptor density is found in cells of the basal ganglia that project locally and to other brain regions. These cells include the substantia nigra pars reticulata, entopeduncular nucleus, and globus pallidus, regions that are generally involved in coordinating body movements. Patients with Parkinson's or Huntington's disease tend to have impaired functions in these regions.

CB1 receptors are also abundant in the putamen, part of the relay system within the basal ganglia that regulates body movements; the cerebellum, which coordinates body movements; the hippocampus, which is involved in learning, memory, and response to stress; and the cerebral cortex, which is concerned with the integration of higher cognitive functions.

CB1 receptors are found on various parts of neurons, including the

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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image

Figure 2.5 
Locations of brain regions in which cannabinoid receptors are abundant. 
See Table 2.5 for a summary of functions associated with those regions.  

axon, cell bodies, terminals, and dendrites.57,165 Dendrites are generally the ''receiving'' part of a neuron, and receptors on axons or cell bodies generally modulate other signals. Axon terminals are the "sending" part of the neuron.

Cannabinoids tend to inhibit neurotransmission, although the results are somewhat variable. In some cases, cannabinoids diminish the effects of the inhibitory neurotransmitter, g-aminobutyric acid (GABA);144 in other cases, cannabinoids can augment the effects of GABA.120 The effect of activating a receptor depends on where it is found on the neuron: if cannabinoid receptors are presynaptic (on the "sending" side of the synapse) and inhibit the release of GABA, cannabinoids would diminish GABA effects; the net effect would be stimulation. However, if cannabinoid receptors are postsynaptic (on the "receiving" side of the synapse) and on the same cell as GABA receptors, they will probably mimic the effects of GABA; in that case, the net effect would be inhibition.120,144,160

CB1 is the predominant brain cannabinoid receptor. CB2 receptors have not generally been found in the brain, but there is one isolated report suggesting some in mouse cerebellum.150 CB2 is found primarily on cells

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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TABLE 2.6 Cannabinoid Receptors

   
 

CB1

CB2

Effects of various cannabinoids

   

D9-THC

Agonist

Weak antagonist

Anandamide

Agonist

Agonist

Cannabinol

Weak agonist

Agonist; greater affinity for CB2 than

   

for CB1

Cannabidiol

Does not bind to receptor

Does not bind to receptor

Receptor distribution

   

Areas of greatest

Brain

Immune system, especially B cells and

abundance

 

natural killer cells

of the immune system. CB1 receptors are also found in immune cells, but CB2 is considerably more abundant there (Table 2.6) (reviewed by Kaminski80 in 1998).

As can be appreciated in the next section, the presence of cannabinoid systems in key brain regions is strongly tied to the functions and pathology associated with those regions. The clinical value of cannabinoid systems is best understood in the context of the biology of these brain regions.

Cannabinoid Receptors and Brain Functions

Motor Effects

Marijuana affects psychomotor performance in humans. The effects depend both on the nature of the task and the experience with marijuana. In general, effects are clearest in steadiness (body sway and hand steadiness) and in motor tasks that require attention. The results of testing cannabinoids in rodents are much clearer.

Cannabinoids clearly affect movement in rodents, but the effects depend on the dose: low doses stimulate and higher doses inhibit locomotion.111,159 Cannabinoids mainly inhibit the transmission of neural signals, and they inhibit movement through their actions on the basal ganglia and cerebellum, where cannabinoid receptors are particularly abundant (Figure 2.6). Cannabinoid receptors are also found in the neurons that project from the striatum and subthalamic nucleus, which inhibit and stimulate movement, respectively.58,101

Cannabinoids decrease both the inhibitory and stimulatory inputs to the substantia nigra and therefore might provide dual regulation of move-

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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image

image

 Figure 2.6  
Diagrams showing motor regions of the brain. Basal ganglia 
are a group of three brain regions, or nuclei —caudate, putamen, 
and globus pallidus.  Figure 2.6a is a three-dimensional view showing the 
location of those nuclei in the brain. Figure 2.6b shows those structures 
in a vertical cross-sectional view. The major output pathways of the 
basal ganglia arise from the globus pallidus and pars reticulata of the 
substantia nigra.  Their main target is the  thalamus.  SOURCE: Figure 
2.6a is reprinted from  Principles of Neural Science,  2nd ed., 1985 (E.R. 
Kandel and J.H. Schwartz, eds.), with permission from the copyright holder, 
Appleton and Lange.

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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ment at this nucleus. In the substantia nigra, cannabinoids decrease transmission from both the striatum and the subthalamic nucleus.141 The globus pallidus has been implicated in mediating the cataleptic effects of large doses of cannabinoids in rats.126 (Catalepsy is a condition of diminished responsiveness usually characterized by trancelike states and waxy rigidity of the muscles.) Several other brain regions—the cortex, the cerebellum, and the neural pathway from cortex to striatum—are also involved in the control of movement and contain abundant cannabinoid receptors.52, 59, 101 They are therefore possible additional sites that might underlie the effects of cannabinoids on movement.

Memory Effects

One of the primary effects of marijuana in humans is disruption of short-term memory.68 That is consistent with the abundance of CB1 receptors in the hippocampus, the brain region most closely associated with memory. The effects of THC resemble a temporary hippocampal lesion.63 Deadwyler and colleagues have demonstrated that cannabinoids decrease neuronal activity in the hippocampus and its, inputs.23,24, 83 In vitro, several cannabinoid ligands and endogenous cannabinoids can block the cellular processes associated with memory formation.29,30,116,157,163 Furthermore, cannabinoid agonists inhibit release of several neurotransmitters: acetylcholine from the hippocampus,49- 51 norepinephrine from human and guinea pig (but not rat or mouse) hippocampal slices,143 and glutamate in cultured hippocampal cells.144 Cholinergic and noradrenergic neurons project into the hippocampus, but circuits within the hippocampus are glutamatergic.* Thus, cannabinoids could block transmission both into and within the hippocampus by blocking presynaptic neurotransmitter release.

Pain

After nausea and vomiting, chronic pain was the condition cited most often to the IOM study team as a medical use for marijuana. Recent research presented below has shown intriguing parallels with anecdotal reports of the modulating effects of cannabinoids on pain—both the effects of cannabinoids acting alone and the effects of their interaction with opioids.

*Neurons are often defined by the primary neurotransmitter released at their terminals. Thus, cholinergic neurons release acetylcholine, noradrenergic neurons release noradrenalin (also known as norepinephrine), and glutamergic neurons release glutamate.

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Behavioral Studies

Cannabinoids reduce reactivity to acute painful stimuli in laboratory animals. In rodents, cannabinoids reduced the responsiveness to pain induced through various stimuli, including thermal, mechanical, and chemical stimuli.12, 19,46, 72, 96,154, 174 Cannabinoids were comparable with opiates in potency and efficacy in these experiments.12,72

Cannabinoids are also effective in rodent models of chronic pain. Herzberg and co-workers found that cannabinoids can block allodynia and hyperalgesia associated with neuropathic pain in rats.62 This is an important advance because chronic pain frequently results in a series of neural changes that increase suffering due to allodynia (pain elicited by stimuli that are normally innocuous), hyperalgesia (abnormally increased reactivity to pain), and spontaneous pain; furthermore, some chronic pain syndromes are not amenable to therapy, even with the most powerful narcotic analgesics.10

Pain perception is controlled mainly by neurotransmitter systems within the central nervous system, and cannabinoids clearly play a role in the control of pain in those systems.45 However, pain-relieving and pain-preventing mechanisms also occur in peripheral tissues, and endogenous cannabinoids appear to play a role in peripheral tissues. Thus, the different cannabinoid receptor subtypes might act synergistically. Experiments in which pain is induced by injecting dilute formalin into a mouse's paw have shown that anandamide and palmitylethanolamide (PEA) can block peripheral pain.22,73 Anandamide acts primarily at the CB1 receptor, whereas PEA has been proposed as a possible CB2 agonist; in short, there might be a biochemical basis for their independent effects. When injected together, the analgesic effect is stronger than that of either alone. That suggests an important strategy for the development of a new class of analgesic drug: a mixture of CB1 and CB2 agonists. Because there are few, if any, CB2 receptors in the brain, it might be possible to develop drugs that enhance the peripheral analgesic effect while minimizing the psychological effects.

Neural Sites of Altered Responsiveness to Painful Stimuli

The brain and spinal cord mediate cannabinoid analgesia. A number of brain areas participate in cannabinoid analgesia and support the role of descending pathways (neural pathways that project from the brain to the spinal cord).103,105 Although more work is needed to produce a comprehensive map of the sites of cannabinoid analgesia, it is clear that the effects are limited to particular areas, most of which have an established role in pain.

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Specific sites where cannabinoids act to affect pain processing include the periaqueductal gray,104 rostral ventral medulla,105, 110 thalamic nucleus submedius,102 thalamic ventroposterolateral nucleus,102 dorsal horn of the spinal cord,64,65 and peripheral sensory nerves.64,65,66,131 Those nuclei also participate in opiate analgesia. Although similar to opiate analgesia, cannabinoid analgesia is not mediated by opioid receptors; morphine and cannabinoids sometimes act synergistically, and opioid antagonists generally have no effect on cannabinoid-induced analgesia.171 However, a kappa-receptor antagonist has been shown to attenuate spinal, but not supraspinal, cannabinoid analgesia.153,170,171 (Kappa opioid receptors constitute one of the three major types of opioid receptors; the other two types are mu and delta receptors.)

Neurophysiology and Neurochemistry of Cannabinoid Analgesia

Because of the marked effects of cannabinoids on motor function, behavioral studies in animals alone cannot provide sufficient grounds for the conclusion that cannabinoids depress pain perception. Motor behavior is typically used to measure responses to pain, but this behavior is itself affected by cannabinoids. Thus, experimental results include an unmeasured combination of cannabinoid effects on motor and pain systems. The effects on specific neural systems, however, can be measured at the neurophysiological and neurochemical levels. Cannabinoids decrease the response of immediate-early genes (genes that are activated in the early or immediate stage of response to a broad range of cellular stimuli) to noxious stimuli in the spinal cord, decrease response of pain neurons in the spinal cord, and decrease the responsiveness of pain neurons in the ventral posterolateral nucleus of the thalamus.67,102 Those changes are mediated by cannabinoid receptors, are selective for pain neurons, and are unrelated to changes in skin temperature or depth of anesthesia, and they follow the time course of the changes in behavioral responses to painful stimuli but not the time course of motor changes.67 On-cells and off-cells in the rostral ventral medulla control pain transmission at the level of the spinal cord, and cannabinoids also modulate their responses in a manner that is very similar to that of morphine.110

Endogenous Cannabinoids Modulate Pain

Endogenous cannabinoids can modulate pain sensitivity through both central and peripheral mechanisms. For example, animal studies have shown that pain sensitivity can be increased when endogenous cannabinoids are blocked from acting at CB1 receptors.22,62,110,130,158 Administration of cannabinoid antagonists in either the spinal cord130 or paw22 in-

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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crease the sensitivity of animals to pain. In addition, there is evidence that cannabinoids act at the site of injury to reduce peripheral inflammation.131

Current data suggest that the endogenous cannabinoid analgesic system might offer protection against the long-lasting central hyperalgesia and allodynia that sometimes follow skin or nerve injuries.130,158 These results raise the possibility that therapeutic interventions that alter the levels of endogenous cannabinoids might be useful for managing pain in humans.

Chronic Effects of THC

Most substances of abuse produce tolerance, physical dependence, and withdrawal symptoms. Tolerance is the most common response to repetitive use of a drug and is the condition in which, after repeated exposure to a drug, increasing doses are needed to achieve the same effect. Physical dependence develops as a result of a resetting of homeostatic mechanisms in response to repeated drug use. Tolerance, dependence, and withdrawal are not peculiar to drugs of abuse. Many medicines that are not addicting can produce these types of effects; examples of such medications include clonidine, propranolol, and tricyclic antidepressants. The following sections discuss what is known about the biological mechanisms that underlie tolerance, reward, and dependence; clinical studies about those topics are discussed in chapter 3.

Tolerance

Chronic administration of cannabinoids to animals results in tolerance to many of the acute effects of THC, including memory disruption,34 decreased locomotion,2,119 hypothermia,42,125 neuroendocrine effects,134 and analgesia.4 Tolerance also develops to the cardiovascular and psychological effects of THC and marijuana in humans (see also discussion in chapter 3).55,56,76

Tolerance to cannabinoids appears to result from both pharmacokinetic changes (how the drug is absorbed, distributed, metabolized, and excreted) and pharmacodynamic changes (how the drug interacts with target cells). Chronic treatment with the cannabinoid agonist, CP 55,940, increases the activity of the microsomal cytochrome P450 oxidative system,31 the system through which drugs are metabolized in the liver; this suggests pharmacokinetic tolerance. Chronic cannabinoid treatment also produces changes in brain cannabinoid receptors and cannabinoid receptor mRNA concentrations—an indication that pharmacodynamic effects are important as well.

Most studies have found that brain cannabinoid receptor concentra-

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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tions usually decrease after prolonged exposure to agonists,42,119,136,138 although some studies have reported increases137 or no changes2 in receptor binding in brain. Differences among studies could be due to the particular agonist tested, the assay used, the brain region examined, or the treatment time. For example, the THC analogue, levonantradol, produces a greater desensitization of adenylyl cyclase inhibition than does THC in cultured neuroblastoma cells.40 This might be explained by differences in efficacy between these two agonists.18,147 A time course study revealed differences among brain regins in the rates and magnitudes of receptor down regulation.16 Those findings suggest that tolerance to different effects of cannabinoids develops at different rates.

Chronic treatment with THC also produces variable effects on cannabinoid-mediated signal transduction systems. It produces substantial desensitization of cannabinoid-activated G proteins in a number of rat brain regions.147 The time course of this desensitization varies across brain regions.16

It is difficult to extend the findings of short-term animal studies to human marijuana use. To simulate long-term use, higher doses are used in animal studies than are normally achieved by smoking marijuana. For example, the average human will feel "high" after injection of THC at a level of 0.06 mg/kg,118 compared with the 10-20 mg/kg per day used in many chronic rat studies. At the same time, doses of marijuana needed to observe behavioral changes in rats (usually changes in locomotor behavior) are substantially higher than doses at which people feel "high." The pharmacokinetics of THC distribution in the body are also dramatically different between rats and humans and depend heavily on whether it is inhaled, injected, or swallowed. It is likely that some of the same biochemical adaptations to chronic cannabinoid administration occur in laboratory animals and humans, but the magnitude of the effects in humans might be less than that in animals in proportion to the doses used.

Reward and Dependence

Experimental animals that are given the opportunity to self-administer cannabinoids generally do not choose to do so, which has led to the conclusion that they are not reinforcing and rewarding.38 However, behavioral95 and brain stimulation94 studies have shown that THC can be rewarding to animals. The behavioral study used a "place preference" test, in which an animal is given repeated doses of a drug in one place, and is then given a choice between a place where it received the drug and a place where it did not. The animals chose the place where they received the THC. These rewarding effects are highly dose dependent. In all models studied, cannabinoids are only rewarding at midrange; doses that are

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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too low are not rewarding; doses that are too high can be aversive. Mice will self-administer the cannabinoid agonist WIN 55,212-2 but only at low doses.106 This effect is specifically mediated by CB1 receptors and indicates that stimulation of those receptors is rewarding to the mice. Antagonism of cannabinoid receptors is also rewarding in rats; in conditioned place preference tests, animals show a preference for the place they receive the cannabinoid antagonist SR 141716A at both low and high doses.140 Cannabinoids increase dopamine concentrations in  the mesolimbic dopamine system of rats, a pathway associated with reinforcement.25,39,161 However, the mechanism by which THC increases dopamine concentrations appears to be different from that of other abused drugs51 (see chapter 3 for further discussion of reinforcement). THC-induced increases in dopamine are due to increases in the firing rate of dopamine cells in the ventral tegmental area by D9-THC.47 However, these increases in firing rate in the ventral tegmental area could not be explained by increases in the firing of the A10 dopamine cell group, where other abused drugs have been shown to act.51

Physical dependence on cannabinoids has been observed only under experimental conditions of "precipitated withdrawal" in which animals are first treated chronically with cannabinoids and then given the CB1 antagonist SR 141716A.3,166 The addition of the antagonist accentuates any withdrawal effect by competing with the agonist at receptor sites; that is, the antagonist helps to clear agonists off and keep them off receptor sites. This suggests that, under normal cannabis use, the long half-life and slow elimination from the body of THC and the residual bioactivity of its metabolite, 11-OH-THC, can prevent substantial abstinence symptoms. The precipitated withdrawal produced by SR 141716A has some of the characteristics of opiate withdrawal, but it is not affected by opioid antagonists, and it affects motor systems differently. An earlier study with monkeys also suggested that abrupt cessation of chronic THC is associated with withdrawal symptoms.8 Monkeys in that study were trained to work for food after which they were given THC on a daily basis; when the investigators stopped administering THC, the animals stopped working for food.

A study in rats indicated that the behavioral cannabinoid withdrawal syndrome is consistent with the consequences of withdrawal from other drugs of abuse in that it correlates with the effects of stimulation of central amygdaloid corticotropin-releasing hormone release.135 However, the withdrawal syndrome for cannabinoids and the corresponding increase in corticotropin-releasing hormone are observed only after administration of the CB1 antagonist SR 141716A to cannabinoid-tolerant animals.3,166 The implications of data based on precipitated withdrawal in animals for human cannabinoid abuse have not been established.166 Furthermore, acute administration of THC also produces increases in corticotropin-

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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releasing hormone and adrenocorticotropin release; both are stress-related hormones.71 This set of withdrawal studies may explain the generally aversive effects of cannabinoids in animals and could indicate that the increase in corticotropin-releasing hormone is merely a rebound effect. Thus, cannabinoids appear to be conforming to some of the neurobiological effects of other drugs abused by humans, but the underlying mechanisms of these actions and their value for determining the reinforcement and dependence liability of cannabinoids in humans remain undetermined.

Cannabinoids and the Immune System

The human body protects itself from invaders, such as bacteria and viruses through the elaborate and dynamic network of organs and cells referred to as the immune system. Cannabinoids, especially THC, can modulate the function of immune cells in various ways-in some cases enhancing and in others diminishing the immune response85 (summarized in Table 2.7). However, the natural function of cannabinoids in the immune system is not known. Immune cells respond to cannabinoids in a variety of ways, depending on such factors as drug concentration, timing of drug delivery to leukocytes in relation to antigen stimulation, and type of cell function. Although the chronic effects of cannabinoids on the immune system have not been studied, based on acute exposure studies in experimental animals it appears that THC concentrations that modulate immunological responses are higher than those required for psychoactivity.

The CB2 receptor gene, which is not expressed in the brain, is particularly abundant in immune tissues, with an expression level 10-100 times higher than that of CB1. In spleen and tonsils the CB2 mRNA* content is equivalent to that of CB1 mRNA in the brain.48 The rank order, from high to low, of CB2 mRNA levels in immune cells is B-cells > natural killer cells >> monocytes > polymorphonuclear neutrophil cells > T8 cells > T4 cells. In tonsils the CB2 receptors appear to be restricted to B-lymphocyteenriched areas. In contrast, CB1 receptors are mainly expressed in the central nervous system and, to a lesser extent, in several peripheral tissues such as adrenal gland, heart, lung, prostate, uterus, ovary, testis, bone marrow, thymus, and tonsils.

*After a gene is transcribed, it is often spliced and modified into mRNA, or message RNA. The CB-2 mRNA is the gene "message" that moves from the cell nucleus into the cytoplasm where it will be translated into the receptor protein.

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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TABLE 2.7 Effects of Cannabinoids on the Immune System

Drug Tested

Cell Types Tested or
Type of Animal Experiment

Drug
Concentration*

THC, 2-AG,
II-OH-THC, CBN

Lymphocytes and splenocytes in vitro

0.1-30 mM

THC, 2-AG

Lymphocytes and splenocytes

0.1-25 mM

Anandamide

Splenocytes in vitro

1-25 mM

THC, 11-OH-THC, 2-AG

Splenocytes in vitro

3-30 mM

THC, CP 55,940,
WIN 55,212-2

Lymphocytes in vitro

0.1-100 nM
(0.0001-0.1 PM)

THC

Drug injected into mice

>5 mg/kg

HU-210

Drug injected into mice

>0.05 mg/kg

THC, 11-OH-THC,
CBD, CP 55,940, CBN

Splenocytes in vitro

1-30 mM

THC

Drug injected into rodent

3 mg/kg per day for
25 days, 40 mg/kg
per day for 2 days

THC, 11-OH-THC

Natural killer cells in vitro

0.1-32 mM

THC

Peritoneal macrophages and

3-30 mM

 

monocytes

 

THC, CBD

Drug injected into mice; in one case,
in vitro tests done on spleens

>5 mg/kg per day for
4 days or 50 mg/kg
every 5 days for up
to 8 weeks

THC, CBD

Peripheral blood mononuclear cells
in vitro

<0.1 mM

30 mM

THC, CBD

Splenocytes and T cells in vitro

10 PM

THC

Phorbol myristate acetate-
differentiated macrophage in vitro

10-20 mM

     

THC

Endotoxin-activated macrophages
in vitro

10-30 mM

     

THC

Peritoneal macrophages in vitro

10-30 mM

(Table continued on next page)

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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(Table continued from the previous page)

TABLE 2.7 Effects of Cannabinoids on the Immune System

Drug Tested

Result

Reference

THC, 2-AG,
11-OH-THC, CBN

Higher doses suppressed T cell proliferation

Luo, 1992; Pross, 1992;'bKlein, 1985;c
Specter, 1990;d Lee, 1995,a Herring, 1998

THC, 2-AG

Lower doses increased T cell proliferation
in vitro

Luo, 1992; Lee, 1995;a Pross, 1992'b

Anandamide

Little or no effect on T cell proliferation

Lee, 1995;a Devane, 1992

THC, 11-OH-THC, 2-AG

Decreased B cell proliferation

Klein, 1985;c Lee, 1995c

THC, CP 55,940,
WIN 55,212-2

Increased B cell proliferation

Derocq, 1995

THC

Antibody production suppressed

Baczynsky, 1983; Schatz, 1993

HU-210

Antibody production suppressed

Titishov, 1989

HC, 11-OH-THC,
CBD, CP 55,940, CBN

Antibody production suppressed

Klein, 1990; Baczynsky, 1983; Kaminski,
1992, 1994; Herring, 1998

THC

Repeated low doses or a high dose of THC
suppressed the activity of natural killer cells

Patel, 1985; Klein, 1987

THC, 11-OH-THC

Doses of >10 }M suppressed natural killer
cell cytolytic activity; doses <10 pM
produced no effect

Klein, 1987; Luo, 1989

THC

Variable doses of THC suppressed
macophage functions in vitro

Lopez-Cepero, 1986; Specter, 1991;
Tang, 1992

THC, CBD

THC suppressed normal immune response;
interferons failed to increase when
exposed to cytokine inducer; CBD had no
suppressive effect

Cabral, 1986; Blanchard, 1986

THC, CBD

Increased interferon production

Watzl, 1991

 

Decreased interferon production

 

THC, CBD

Both THC and CBD suppressed
interleukin-2 secretion and number of
interleukin-2 transcripts

Condie, 1996

     
     

THC

Increased tumor necrosis factor production
and interleukin-1 supernatant bioactivity

Shivers, 1994

     

THC

Increased processing and release of
interleukin-1 rather than cellular
production of interleukin-1

Zhu, 1994

     
     

THC

Increased interleukin-1 bioactivity

Klein, 1990

(Table continued on next page)

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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TABLE 2.7  Continued

Drug Tested

Cell Types Tested or
Type of Animal Experiment

Drug
Concentration*

THC

Drug and sublethal or lethal dose of
Legionella pneumophilia
injected in mice

8 mg/kg before and
after bacterial
infection

     
     
   

<5 mg/kg doses
or one 8 mg/kg or
4 mg/kg dose before
bacteria infection

     
     
     

THC

Drug and herpes simplex virus

100 mg/kg before
and after viral
infection
100 mg/kg before
virual infection

 

injected in immunodeficient mice

 
     
     
     

aCell density dependent.

bMitogen dependent.

cDependent on serum concentration in cell culture medium.

dDependent on timing of drug exposure relative to mitogen exposure.

*Drug concentrations are given in the standard format of molarity (M). A 1-M solution is the molecular weight of the compound (in grams) in 1 liter (L) of solution. The molecular

Box 2.1 Cells of the Immune system

The various organs of the immune system are positioned throughout the body and include b one marrow, thymus, lymph nodes, and spleen.  the cells of the immune system consist of white blood cells, or leukocytes, which are formed in the bone marrow from stem cells—so called because a great variety of cells descend from them (see below). There are two kinds of leukocytes: lymphocytes and phagocytes. Lymphocytes consist of B cells, T cells (B and T refer to where the cells mature, either in the bone marrow [B] or thymus [T]), and natural killer (NK) cells; the major phagocytes are monocytes, macrophages, and neutrophils.  Phagocytes have many important roles in the immune response; most important is that they initiate the response by engulfing and digesting foreign substances, or antigens (such as bacteria, viruses, and foreign proteins), that enter the body.  Once digested, the antigens are exposed to specialized lymphocytes, some of which produce antibodies and effector T cells, which help destroy any antigens remaining in the body.  Antibodies are proteins produced by B cells that bind to antigens and promote antigen destruction.  Effector T cells include killer T cells, which attack and kill antigen laden cells, and helper T cells, which secrete special proteins called cytokines that promote antigen elimination. NK cells are specialized lymphocytes that are also activated by antigen to either kill infected targets or secrete immunoregulatory cytokines.

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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(Table continued from previous page)

Drug Tested

Result

Reference

THC

Cytokine-mediated septic shock and death occurred with exposure to sublethal dose of bacteria

Klein, 1993, 1994; Newton, 1994

 

Survival occurred, but with greater susceptiblity to infection when challenged with bacteria and death when challenged with a lethal dose of bacteria

 

THC

Two high doses of THC potentiated the effects of herpes simplex and enhanced the progression of death

Specter, 1991

 

Single dose did not promote death

weight of THC is 314, so a 1-M solution would be 314 g of THC in 1 L of solution, and a 10-mM solution would be 3.14 mg THC/L. A 1- to 10-mM concentration will generally elicit a physiologically relevant response in immune cell cultures. Higher doses are often suspected of not being biologically meaningful because they are much larger than would ever be achieved in the body. The doses listed in this table are, for the most part, very high. See text for further discussion.

image

 
Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Cannabinoid Receptors and Intracellular Action in Immune Cells

CB2 appears to be the predominant gene expressed in resting leukocytes.78,112 The level of CB1 gene activity is normally low in resting cells but increases with cell activation.32 Thus the CB1 receptor might be important only when immune responses are stimulated, but the physiological relevance of this observation remains to be determined. Some of the cannabinoid effects observed in immune systems, especially at high drug concentrations, are likely mediated through nonreceptor mechanisms, but these have not yet been identified.4

Ligand binding to either CB1 or CB2 inhibits adenylate cyclase, an enzyme that is responsible for cAMP production and is, thus, an integral aspect of intracellular signal transduction (see Figure 2.3).53,79,91,122,139,151,167Increases in intracellular cAMP concentrations lead to immune enhancement, and decreases lead to an inhibition of the immune response.77 Cannabinoids inhibit the rise in intracellular cAMP that normally results from leukocyte activation, and this might be the pathway through which cannabinoids suppress immune cell functions.28,74,167 In addition, cannabinoids activate other molecular pathways such as the nuclear factor-kB pathway, and therefore these signals might be modified in drug-treated immune cells.33,74

T and B Cells

When stimulated by antigen, lymphocytes (see Box 2.1) first proliferate and then mature or differentiate to become potent effector cells, such as B cells that release antibodies or T cells that release cytokines. The normal T-cell proliferation that is seen when human lymphocytes and mouse splenocytes (spleen cells) are exposed to antigens and mitogens* can be inhibited by THC, 11-OH-THC, cannabinol, and 2-AG, as well as synthetic cannabinoid agonists such as CP 55,940; WIN 55,212-2; and HU210.61,89,93,99,127,155 In contrast, one study testing anandamide revealed little or no effect on T cell proliferation.93

However, these drug effects are variable and depend on experimental conditions, such as the experimental drug dose used, the mitogen used, the percentage of serum in the culture, and the timing of cannabinoid drug exposure. In general, lower doses of cannabinoids increase proliferation and higher doses suppress proliferation. Doses that are effective in suppressing immune function are typically greater than 10 mM in cell culture studies and greater than 5 mg/kg in whole-animal studies.85 By

*Mitogens are substances that stimulate cell division (mitosis) and cell transformation.

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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comparison, at 0.05 mg/kg, people will experience the full psychoactive effects of THC; however, because of their high metabolic rates, small rodents frequently require drug doses that are 100-fold higher than doses needed for humans to achieve comparable drug effects. Thus, the immune effects of doses of cannabinoids higher than those ever experienced by humans should be interpreted with caution.93

As with T cells, B cell proliferation can be suppressed by various cannabinoids, such as THC, 11-OH-THC, and 2-AG, but B cell proliferation is more inhibited at lower drug concentrations than T cell proliferation.89,93 Conversely, low doses of THC, CP 55,940 and WIN 55,212-2 increase B cell proliferation in cultured human cells exposed to mitogen.35 This effect possibly involves the CB2 receptor, because the effect appears to be the same when the CB1 receptor was blocked by the antagonist SR 141716A (which does not block the CB2 receptor). The reason for the differences in B cell responsiveness to cannabinoids is probably due to differences in cell type and source; for example, B cells collected from mouse spleen might respond to cannabinoids somewhat differently than B cells from human tonsils.

Natural Killer Cells

Repeated injections of relatively low doses of THC (3 mg/kg/day121*) or two injections of a high dose (40 mg/kg86) suppress the ability of NK cells to destroy foreign cells in rats and mice. THC can also suppress cytolytic activity of the NK cells in cell cultures; 11-OH-THC is even more potent.86 In contrast, THC concentrations below 10 mM had no effect on NK cell activity in mouse cell cultures.98

Macrophages

Macrophages perform various functions, including phagocytosis (ingestion and destruction of foreign substances), cytolysis, antigen presentation to lymphocytes, and production of active proteins involved in destroying microorganisms, tissue repair, and modulation of immune cells. Those functions can be suppressed by THC doses similar to those capable of modulating lymphocyte functions (see above).88,109

*While 3 mg/kg would be a high dose for humans (see Table 3.1), in rodents, it is a low dose for immunological effects and a moderate dose for behavioral effects.

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Cytokines

Cytokines are proteins produced by immune cells. When released from the producing cell, they can alter the function of other cells they come in contact with. In a sense they are like hormones. Thus, cannabinoids can either increase or decrease cytokine production depending upon experimental conditions.

Some cytokines, such as interferon-y and interleukin-2 (IL-2), are produced by T helper-1 (Thl) cells. These cytokines help to activate cell-mediated immunity and the killer cells that eliminate microorganisms from the body (see Box 2.1). When injected into mice, THC suppresses the production of those cytokines that modulate the host response to infection (see below).115 Cannabinoids also modulate interferons induced by viral infection,21 as well as other interferon inducers.85 Furthermore, in human cell cultures, interferon production can be increased by low concentrations but decreased by high concentrations of either THC or CBD.168 In addition to Th1 cytokines, cannabinoids modulate the production of cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and interleukin-6 (IL-6).145,176 At 8 mg/kg, THC can increase the in vivo mobilization of serum acute-phase cytokines, including IL-1, TNF, and IL-6.90 Finally, although these studies suggest that cannabinoids can induce an increase in cytokines, other studies suggest that they can also suppress cytokine production.85 The different results might be due to different cell culture conditions or because different cell lines were studied.

Antibody Production

Antibody production is an important measure of humoral immune function as contrasted with cellular (cell-mediated) immunity. Antibody production can be suppressed in mice injected with relatively low doses of THC (>5 mg/kg) or HU-210 (>0.05 mg/kg) and in mouse spleen cell cultures exposed to a variety of cannabinoids, including THC, 11-OHTHC, cannabinol, cannabidiol, CP 55,940, or HU-210.5,6,61,78,79,84,85,142,164 However, the inhibition of antibody response by cannabinoids was only observed when antibody-forming cells were exposed to T-cell-dependent antigens (the responses require functional T cells and macrophages as accessory cells). Conversely, antibody responses to several T-cell-independent antigens were not inhibited by THC; this suggests that B cells are relatively insensitive to inhibition by cannabinoids.142

Resistance to Infection in Animals Exposed to Cannabinoids

Evaluation of bacterial infections in mice that received injections of

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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THC can suppress resistance to infection, although the effect depends on the dose and timing of drug administration. Mice pretreated with THC (8 mg/kg) one day before infection with a sublethal dose of the pneumoniacausing bacteria Legionella pneumophilia and then treated again one day after the infection with THC developed symptoms of cytokine-mediated septic shock and died; control mice that were not pretreated with THC became immune to repeated infection and survived the bacterial challenge.90 If only one injection of THC was given or doses less than 5 mg/kg were used, all the mice survived the initial infection but failed to survive later challenge with a lethal dose of the bacteria; hence, these mice failed to develop immune memory in response to the initial sublethal infection.87 Note that these are very high doses and are considerably higher than doses experienced by marijuana users (see Figure 3.1).115 In rats, doses of 4.0 mg/kg THC are aversive.95

Few studies have been done to evaluate the effect of THC on viral infections, and this subject needs further study.20 Compared to healthy animals, THC might have greater immunosuppressive effects in animals whose immune systems are severely weakened. For example, a very high dose of THC (100 mg/kg) given two days before and after herpes simplex virus infection was shown to be a cofactor with the virus in advancing the progression to death in an immunodeficient mouse model infected with a leukemia virus.85 However, THC given as a single dose (100 mg/kg) two days before herpes simplex virus infection did not promote the progression to death. Hence, whether THC is immunosuppressive probably depends on the timing of THC exposure relative to an infection.

Antiinflammatory Effects

As discussed above, cannabinoid drugs can modulate the production of cytokines, which are central to inflammatory processes in the body. In addition, several studies have shown directly that cannabinoids can be antiinflammatory. For example, in rats with autoimmune encephalomyelitis (an experimental model used to study multiple sclerosis), cannabinoids were shown to attenuate the signs and the symptoms of central nervous system damage.100, 172 (Some believe that nerve damage associated with multiple sclerosis is caused by an inflammatory reaction.) Likewise, the cannabinoid, HU-211, was shown to suppress brain inflammation that resulted from closed-head injury146 or infectious meningitis7 in studies on rats. HU-211 is a synthetic cannabinoid that does not bind to cannabinoid receptors and is not psychoactive;7 thus, without direct evidence, the effects of marijuana cannot be assumed to include those of HU211. CT-3, another atypical cannabinoid, suppresses acute and chronic joint inflammation in animals.178 It is a nonpsychoactive synthetic deriva-

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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tive of 11-THC-oic acid (a breakdown product of THC) and does not appear to bind to cannabinoid receptors.129 Cannabichromene, a cannabinoid found in marijuana, has also been reported to have antiinflammatory properties.173 No mechanism of action for possible antiinflammatory effects of cannabinoids has been identified, and the effects of these atypical cannabinoids and effects of marijuana are not yet established.

It is interesting to note that two reports of cannabinoid-induced analgesia are based on the ability of the endogenous cannabinoids, anandamide and PEA, to reduce pain associated with local inflammation that was experimentally induced by subcutaneous injections of dilute formalin.22,73 Both THC and anandamide can increase serum levels of ACTH and corticosterone in animals.169 Those hormones are involved in regulating many responses in the body, including those to inflammation. The possible link between experimental cannabinoid-induced analgesia and reported antiinflammatory effects of cannabinoids is important for potential therapeutic uses of cannabinoid drugs but has not yet been established.

Conclusions Regarding Effects on the Immune System

Cell culture and animal studies have established cannabinoids as immunomodulators—that is, they increase some immune responses and decrease others. The variable responses depend on such experimental factors as drug dose, timing of delivery, and type of immune cell examined. Cannabinoids affect multiple cellular targets in the immune system and a variety of effector functions. Many of the effects noted above appear to occur at concentrations over 5 mM in vitro and over 5 mg/kg in vivo.* By comparison, a 5-mg injection of THC into a person (about 0.06 mg/kg) is enough to produce strong psychoactive effects. It should be emphasized, however, that little is known about the immune effects of chronic lowdose exposure to cannabinoids.

Another issue in need of further clarification involves the potential usefulness of cannabinoids as therapeutic agents in inflammatory diseases. Glucocorticoids have historically been used for these diseases, but nonpsychotropic cannabinoids potentially have fewer side effects and might thus offer an improvement over glucocorticoids in treating inflammatory diseases.

*In vitro studies are those in which animal cells or tissue are removed and studied outside the animal; in vivo studies are those in which experiments are conducted in the whole animal.

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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TABLE 2.8 Historical Comparisons Between Cannabinoids and Opiates

Pharmacological
Discoveries

Cannabinoids

Opiates

Discovery of receptor existence

1988 (Devane et al. and Dill and Howlett )36,40

1973(Pert and Snyder, Simon, and Terenius )123,149,162

     

Identification of receptor antagonist

1994SR 141716A (Rinaldi-Carmona et al.)132

Before 1973: naloxone

Discovery of first endogenous ligand

1992anandamide (Devane et al.)37

1975met- and leu-enkephalin (Hughes et al.)70

First receptor cloned

1990(Matsuda et al.)107

1992(Evans et al. and Kieffer et al.)41,82

Natural functions

Unknown

Pain, reproduction, mood,

movement, and others

Conclusions and Recommendations

Given the progress of the past 15 years in understanding the effects of cannabinoids, research in the next decade is likely to reveal even more. It is interesting to compare how little we know about cannabinoids with how much we know about opiates. Table 2.8 suggests good reason for optimism about the future of cannabinoid drug development. Now that many of the basic tools of cannabinoid pharmacology and biology have been developed, one can expect to see rapid advances that can begin to match what is known of opiate systems in the brain.

Despite the tremendous progress in understanding the pharmacology and neurobiology of brain cannabinoid systems, this field is still in its early developmental stages. A key focus for future study is the neurobiology of endogenous cannabinoids; establishing the precise brain localization (in which cells and where) of cannabinoids, cellular storage and release mechanisms, and uptake mechanisms will be crucial in determining the biological role of this system. Technology needed to establish the biological significance of these systems will be broad based and include such research tools as the transgenic or gene knockout mice, as has already been accomplished for various opioid-receptor types.26 In 1997, both CB1 and CB2 knockout mice were generated by a team of scientists at the National Institutes of Health, and a group in France has developed another strain of CB1 knockout mice.92

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Several research tools will greatly aid such investigations, in particular a greater selection of agonists and antagonists that permit discrimination in activation between CB1 and CB2 and hydrophilic agonists that can be delivered to animals or cells more effectively than hydrophobic compounds. In the area of drug development, future progress should continue to provide more specific agonists and antagonists for CB1 and CB2 receptors, with varying potential for therapeutic uses.

There are certain areas that will 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, intriguing 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 understanding basic human biology. Further, it offers the potential for the discovery and development of new therapeutically useful drugs.

CONCLUSION: At this point, our knowledge about the biology of marijuana and cannabinoids allows us to make some general conclusions:

·      Cannabinoids likely have a natural role in pain modulation, control of movement, and memory.

·      The natural role of cannabinoids in immune systems is likely multi-faceted and remains unclear.

·      The brain develops tolerance to cannabinoids.

·      Animal research has demonstrated the potential for dependence, but this potential is observed under a narrower range of conditions than with benzodiazepines, opiates, cocaine, or nicotine.

·      Withdrawal symptoms can be observed in animals but appear mild compared with those of withdrawal from opiates or benzodiazepines, such as diazepam (Valium).

CONCLUSION: The different cannabinoid receptor types found in the body appear to play different roles in normal physiology. In addition, some effects of cannabinoids appear to be independent of those receptors. The variety of mechanisms through which cannabinoids can influence human physiology underlies the variety

Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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of potential therapeutic uses for drugs that might act selectively on different cannabinoid systems.

RECOMMENDATION: Research should continue into the physiological effects of synthetic and plant-derived cannabinoids and the natural function of cannabinoids found in the body. Because different cannabinoids appear to have different effects, cannabinoid research should include, but not be restricted to, effects attributable to THC alone.

This chapter has summarized recent progress in understanding the basic biology of cannabinoids and provides a foundation for the next two chapters which review studies on the potential health risks (chapter 3) and benefits of marijuana use (chapter 4).

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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Suggested Citation:"2 Cannabinoids and Animal Physiology." Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. doi: 10.17226/6376.
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Marijuana and Medicine: Assessing the Science Base Get This Book
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The medical use of marijuana is surrounded by a cloud of social, political, and religious controversy, which obscures the facts that should be considered in the debate.

This book summarizes what we know about marijuana from evidence-based medicine--the harm it may do and the relief it may bring to patients. The book helps the reader understand not only what science has to say about medical marijuana but also the logic behind the scientific conclusions.

Marijuana and Medicine addresses the science base and the therapeutic effects of marijuana use for medical conditions such as glaucoma and multiple sclerosis. It covers marijuana's mechanism of action, acute and chronic effects on health and behavior, potential adverse effects, efficacy of different delivery systems, analysis of the data about marijuana as a gateway drug, and the prospects for developing cannabinoid drugs. The book evaluates how well marijuana meets accepted standards for medicine and considers the conclusions of other blue-ribbon panels.

Full of useful facts, this volume will be important to anyone interested in informed debate about the medical use of marijuana: advocates and opponents as well as policymakers, regulators, and health care providers.

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