CANNABINOIDS AND ANIMAL PHYSIOLOGY
Cannabinoids and Animal Physiology
Much has been learned since the publication of the 1982 IOM report
on Marijuana and Health.a 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 last 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).
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).
a The field of neuroscience has grown substantially since the
publication of the 1982 IOM report. The number of members in the Society
for Neuroscience provide a rough measure of the growth in research and
knowledge about the brain: as of the middle of 1998, there are over 27,000
members, more than triple the number in 1982.
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
specific indications 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 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
non-cannabinoid 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.
Table 2.1 Landmark Discoveries Since the 1982 IOM Report
Since the Previous IOM Report on Marijuana
A Decade of Landmark Discoveries
||Potent cannabinoid agonists are developed the key to discovering
||M.R. Johnson and L.S. Melvin75
||First conclusive evidence of specific cannabinoid receptors
||A. Howlett and W. Devane36
||The cannabinoid brain receptor (CB1) is cloned, its
DNA sequence is identified, and its location in the brain is determined
||L. Matsuda et al,107 and M. Herkenham et al60
||Anandamide is discovered - a naturally occurring substance in
the brain that acts on cannabinoid receptors
||R. Mechoulam and W. Devane37
||A cannabinoid receptor is discovered outside the brain; this receptor
(CB2) is related to the brain receptor but is distinct
||The first specific cannabinoid antagonist, SR141716A, is developed
||The first cannabinoid antagonist, SR144528, that can distinguish
between CB1 and CB2 receptors discovered.
The Value of Animal Studies
Much of the research into the effects of cannabinoids on the brain
is based on animal studies. Many speakers in the public workshops associated
with this study argued that animal studies of marijuana are not relevant
to humans. While animal studies are no substitute for clinical trials,
they are a necessary complement. Ultimately, every biologically active
substance exerts its effects at the cellular and molecular level, and
at this level, the evidence has shown remarkable consistency 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 completely inform us about the full range of psychological
and physiological effects of marijuana or cannabinoids on humans.
The Active Constituents of Marijuana
are the only compounds in the marijuana plant that show all the psychoactive
effects of marijuana. Because 9-THC
is much more abundant than 8-THC,
the psychoactivity of marijuana has been largely attributed to the effects
is the primary product of 9-THC
metabolism by the liver and is about three times as potent as 9-THC.128
There have been considerably fewer experiments with cannabinoids other
although a few studies have been done to examine whether other cannabinoids
modulate the effects of THC or mediate the non-psychological 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 significant effects of cannabidiol (CBD) seem to be its interference
with drug metabolism in the liver, including 9-THC
metabolism.14, 114 CBD exerts this 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
increase in brain levels of THC and its major metabolites, most likely
because of its effects on decreasing the clearance rate of THC from
the body 15
In mice, THC inhibits the release of luteinizing hormone (LH), the
pituitary hormone that triggers the release of testosterone from the
testis in males, this effect is increased when THC is given together
with cannabinol or CBD.113
Cannabinol is considerably less active than THC in the brain, but studies
of immune cells have shown that it can modulate immune function (see
section on Cannabinoids and the Immune System). In mice, cannabinol
lowers body temperature and increases sleep duration.175
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 tool for drug research, which only recently became available
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 receptor functions
by showing what happens when a receptor's 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. 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. 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 so that it can be detected.
Such markers show where in the brain it binds to the receptor, but
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, became the first useful research tool for studying cannabinoid
receptors because of its high potency, and the ability to label it with
a radioactive molecule, which enabled researchers to trace its activity.
Figure 2.1 Diagram of neuron with synapse
How receptors work: 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 (shown as black dots) 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 has bound to the receptor on its surface.
The effects of a transmitted signal include:
·Changing the cell's permeability to ions such as calcium
·Turning a particular gene on or off.
·Sending a signal to another neuron.
·Increasing or decreasing the responsiveness of the cell to other
Those effects can lead to cognitive, behavioral, or physiological changes,
depending on which neuronal system is activated.
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. SR141617A 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; SR141617A 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 have
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 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 intercellular 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
t hat 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
ten times more abundant than mu opioid receptors, the receptors responsible
for the effects of morphine.148
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 largely composed of phospholipids. Like many receptors, the cannabinoid
receptors span the cell membrane; some sections of the receptor protein
are outside the cell membrane (extrucellular), some are inside (intracellular).
THC, anandamide, and other known cannabinoid receptor agonists bind
to the extracellular portion of the receptor, thereby activating the
signal pathway inside the cell.
The CB1 molecule is larger than CB2. The receptor
molecules are most similar in four of the seven regions where they are
embedded in the cell membrane (known as the transmembrane regions).
The intracellular loops of the two cannabinoid receptor sub-types are
quite different, which might affect the cellular response to the ligand,
because these loops are known to mediate G-protein signaling - that
is, the next step in the cell signaling pathway after the receptor.
Receptor homology between the two receptor sub-types is 44 percent for
the full length protein, and 68 percent within the seven transmembrane
regions. The ligand binding sites are typically defined by the extracellular
loops and the transmembrane regions.
Figure 2.3 How cannabinoids affected neuron signals
Figure legend. Intracellular events that happen when cannabinoid agonists
bind to receptors. 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 with 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 potassium (K+) channels which
decreases cell firing, and closing calcium (Ca2+) channels which decreases
the release of neurotransmitters. These changes can influence cellular
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 percent (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 affinityb to both CB1
and CB2 receptors. One exception is the plant-derived compound,
cannabinol, which shows 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
b Affinity is a measure of how avidly a drug binds to
a receptor. The higher the affinity of a drug, the higher its potency;
that is, lower doses are needed to produce its effects.
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 produce
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.
The first endogenous cannabinoid to be discovered was arachidonylethanolamine,
named anandamide from the Sanskrit word ananda, meaning "bliss."37
Compared with THC, anandamide has only moderate affinity for CB1,
and is rapidly metabolized by amidases (enzymes that remove amide groups).
Despite its short duration of action, anandamide shares most of the
pharmacological effects of THC37, 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, which also has high concentrations of CB2 receptors;
and small amounts have been detected in heart.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.c Although
anandamide can be synthesized in a variety of ways, the physiologically
relevant pathway seems to be through enzymatic cleavage of N-arackidonyl-phosphatidyl-ethanolamine
(NAPE), which yields anandamide and phosphatidic acid (reviewed by Childers
Anandamide can be inactivated in the brain via two mechanisms. In one,
anandamide 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-i.e.., by being
transported into the neuron, which prevents its continuing activation
of neighboring neurons.
c Eicosanoids all contain a chain of 20 carbon atoms,
and are named after eikosi, the Greek word for twenty.
Table 2.2 Compounds that bind to cannabinoid receptors
Compounds That Bind to Cannabinoid Receptorsd
Agonists (Receptor activators)
||Main psychoactive cannabinoid in the marijuana plant; largely
responsible for psychological and physiological effects. (Except
in discussions of the different forms of THC, THC is used as a synonym
||Slightly less potent than 9-THC
and much less abundant in the marijuana plant, but otherwise similar.
||Bioactive compound formed when the body breaks down 9-THC.
Presumed to be responsible for some of the effects of marijuana.
|Cannabinoid agonists found in animals
|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.
|Endogenous agonist. Structurally similar to anandamide. More abundant
but less potent than anandamide.
||Synthetic THC. Marketed in the US under the name Marinol®
for nausea associated with chemotherapy and for AIDS-related wasting.
||THC analogue. Marketed in the UK under the name Cesamet® for
the same indications as dronabionol.
||Synthetic cannabinoid; THC analogue; that is, it is structurally
similar to THC
||THC analogue, 100-800 fold greater potency than THC.97
|Chemical structure unlike THC or anandamide
||Chemical structure different from known cannabinoids, but binds
to both cannabinoid receptors. Chemically related to cyclo-oxygenase
inhibitors, which include anti-inflammatory drugs.
Antagonists (Receptor Blockers)
||Synthetic CB1 antagonist, developed in 1994.132
||Synthetic CB2 antagonist; developed in 1997.133
|d Sources: Mechoulam et al. 1998 109,
Felder and Glass 199843; BMA 199717
Figure 2.4 Chemical structures of compounds that bind to cannabinoid
Figure Legend. 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 cannabinoid agonists.
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 (behavioral) or hypothermia (physiological).
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
|Receptor Binding in Brain Tissue124
||Potency Relative to THC
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 time of this writing, all known
endogenous cannabinoid receptor agonists (including anandamide) are
eicosanoids, which are arachidonic acid metabolites. Arachidonic acid
(a free fatty acid) is released via hydrolysis of membrane phospholipids.
Other, non-eicosanoid, 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 can 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
likely by 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 (e.g., 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 and mimic 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
re-uptake inhibitors, or SSRI's. Another way to alter levels of endogenous
cannabinoids would be to develop drugs that act on the enzymes involved
in anandamide synthesis. Some anti-hypertensive drugs work by inhibiting
enzymes involved in the synthesis of endogenous hypertensive agents.
Fore 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
TABLE LEGEND. 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.
|Cellular Processes That Can Be
Targeted for Drug Development
||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
||Chemical breakdown is one method the body uses to inactivate endogenous
||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