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Institute of Medicine (US); Joy JE, Watson SJ Jr., Benson JA Jr., editors. Marijuana and Medicine: Assessing the Science Base. Washington (DC): National Academies Press (US); 1999.

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Marijuana and Medicine: Assessing the Science Base.

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2Cannabinoids and Animal Physiology


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).

TABLE 2.1. Landmark Discoveries Since the 1982 IOM Report.


Landmark Discoveries Since the 1982 IOM Report.

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 substantive 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 plant-derived 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.

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

Δ9-THC and Δ8-THC are the only compounds in the marijuana plant that produce all the psychoactive effects of marijuana. Because Δ9-THC is much more abundant than Δ8-THC, the psychoactivity of marijuana has been attributed largely to the effects of Δ9-THC. 11-OH-Δ9-THC is the primary product of Δ9-THC metabolism by the liver and is about three times as potent as Δ9-THC.128

There have been considerably fewer experiments with cannabinoids other than Δ9-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 Δ9-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 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.

FIGURE 2.1. Diagram of neuron with synapse.


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 (more...)

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 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 water-based 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 blood-borne 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.


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,27Abood 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 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.

FIGURE 2.2. Cannabinoid receptors.


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 (more...)

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 depends 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.

FIGURE 2.3. Cannabinoid agonists trigger a series of reactions within cells.


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, (more...)

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

The cannabinoid receptor in the brain is a protein referred to as CB1. 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 CB1, 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.


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.

TABLE 2.2. Compounds That Bind to Cannabinoid Receptors.


Compounds That Bind to Cannabinoid Receptors.

FIGURE 2.4. Chemical structures of selected cannabinoid agonists or molecules that bind to and activate cannabinoid receptors.


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 (more...)


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 localization 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 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).

TABLE 2.3. Comparison of Cannabinoid Receptor Agonists.


Comparison of Cannabinoid Receptor Agonists.

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 seems to be through enzymatic cleavage of N-arachidonyl-phosphatidyl-ethanolamine (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 fast-moving 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.

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.

TABLE 2.4. Cellular Processes That Can Be Targeted for Drug Development.


Cellular Processes That Can Be Targeted for Drug Development.


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

TABLE 2.5. Brain Regions in Which Cannabinoid Receptors Are Abundant.


Brain Regions in Which Cannabinoid Receptors Are Abundant.

FIGURE 2.5. Locations of brain regions in which cannabinoid receptors are abundant.


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

TABLE 2.6. Cannabinoid Receptors.


Cannabinoid Receptors.

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.


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

FIGURE 2.6. Diagrams showing motor regions of the brain.


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 (more...)

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


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.

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.

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.64-66,131 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 un-measured 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 increase 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.


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.


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 ex-creted) 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 concentrations 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 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 reinforce-ment.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 Δ9-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-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.


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.

TABLE 2.7. Effects of Cannabinoids on the Immune System.


Effects of Cannabinoids on the Immune System.

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-lymphocyte-enriched 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.

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).53,79,91,122,139,151,167 Increases 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 HU-210.61,89,93,99,127,155 In contrast, one study testing anandamide revealed little or no effect on T cell proliferation.93

Box Icon

Box 2.1

Cells of the Immune System. The various organs of the immune system are positioned throughout the body and include bone marrow, thymus, lymph nodes, and spleen. The cells of the immune system consist of white blood cells, or leukocytes, which are formed (more...)

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 μM in cell culture studies and greater than 5 mg/kg in whole-animal studies.85 By 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 μM had no effect on NK cell activity in mouse cell cultures.98


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


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-γ and interleukin-2 (IL-2), are produced by T helper-1 (Th1) 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-OH-THC, 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 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 pneumonia-causing 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 HU-211. CT-3, another atypical cannabinoid, suppresses acute and chronic joint inflammation in animals.178 It is a nonpsychoactive synthetic derivative 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 μM in vitro and over 5 μg/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 low-dose 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.


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.

TABLE 2.8. Historical Comparisons Between Cannabinoids and Opiates.


Historical Comparisons Between Cannabinoids and Opiates.

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

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 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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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.


Affinity is a measure of how avidly a compound binds to a receptor. The higher the affin ity of a compound, the higher its potency; that is, lower doses are needed to produce its effects.


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


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.


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.


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


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.


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.

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