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congruent with these observations. The GABA function in the basal

ganglia is enhanced by CB1 agonists (Consroe, 1998). Cannabimimetics

seem to exert an important modulatory action in basal ganglia output

nuclei by inhibiting both inhibitory striatal input, which is tonically

inactive, and excitatory subthalamic input, which is tonically active

(Sanudo-Pena, 1999). The net cannabimimetic effect on motor activity

depends on the level of activity of each of these two functions. This may

explain the biphasic effect of cannabimimetics on motor behavior.

An important recent discovery has advanced the current understanding of how cannabimimetics are implicated in the control of motor

behavior (Giuffrida, 1999). Giuffrida et al. have reported that D2 activation in the striatum results in release of the endocannabinoid anandamide,

which in turn seems to mediate a negative feedback control, counteracting

dopamine-induced facilitation of motor activity (Giuffrida, 1999). Because

of these effects of cannabinergics on the basal ganglia and subsequently on

motor activity, it has been suggested that cannabinergics may be useful

agents in the treatment of motor disorders such as choreas, Tourette’s

syndrome, dystonias, and Parkinson’s disease (Consroe, 1998). In general,

by increasing hypokinetic features in the basal ganglia, CB1 agonists may

alleviate the various hyperkinetic manifestations, such as choreic movements, that characterize basal ganglia disorders. Direct evidence suggesting the involvement of CB1 in Huntington’s chorea is the extensive loss of

CB1 receptors in the substantia nigra and lateral globus pallidus (Glass,

1993). It is still unclear whether these observations are causative of

Huntington’s disease or its results. However, this finding alone argues that

a suitable CB1 ligand could potentially be useful as a diagnostic agent for

this chorea.

Furthermore, the presence of CB1 in the structures and pathways

associated with the pathophysiology of Tourette’s syndrome, and especially the functional link between CB1 and D1, D2, also argues that the

endocannabinoid system may have some involvement in this disorder as

well (Consroe, 1998). In addition, it has been suggested that activation of

CB1 receptors, also owing to their link with the dopaminergic system, may

reduce dyskinesia produced by L-DOPA in patients with Parkinson’s

disease (Brotsie, 1998).

The CB1 receptors present in the hippocampus, amygdala, and

cerebral cortex may be responsible for observations that cannabimimetics

are effective against some types of seizures (Consroe, 1998). The anticonvulsant and antispastic effects of cannabinoids are well documented,

however the mechanisms of these effects are still unclear (Nahas, 1999).

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Orally administered cannabimimetics can relieve some of the symptoms of

multiple sclerosis and spinal cord injury such as muscle spasticity, pain,

tremor, nystagmus, and nocturia (Pertwee, 2000). Recent studies (Baker,

2000; Baker, 2001) have shown that exogenously administered cannabimimetics control spasticity in a multiple sclerosis (MS) model. Possible

implication of both CB1 and CB2 receptors has been suggested. Agents

that elevate anandamide levels by inhibiting AEAase (AM374) or AT

(AM404) also produced these antispastic effects indirectly. Cannabinoid

receptor antagonists blocked these antispastic effects. Respectively,

SR141716A and SR1445228, selective CB1 and CB2 antagonists/inverse

agonists, produced enhanced spasticity when administered alone to the

same animal model (Baker, 2000). Furthermore, it was evident that

endocannabinoids are released during episodes of MS, during which they

alleviate the spastic effects of the disease (Pertwee, 2000). These findings

confirm, at least to some extent, the anecdotal reports that marijuana

smoking alleviates the symptoms in MS patients and establishes cannabimimetics as exciting candidates for the development of agents that control

spasticity and other abnormalities resulting from some neurodegenerative

diseases. These agents may also control spasticity produced by spinal cord

injury by acting on spinal as well as on supraspinal mechanisms (Consroe,

1998). It has been suggested that the effect of cannabimimetics on the

release of glutamate in the substantia nigra appears to be the most

important supraspinal mechanism of cannabimimetic-induced control of

spasticity (Consroe, 1998).

The CB1-mediated inhibition of glutamate release in the hippocampus was also suggested to be the most likely mechanism of the neuroprotective effects of WIN5521,2 observed in both the global and focal

cerebral ischemia animal models (Nagayama, 1999). These effects were

stereoselective and were blocked by SR141716A. Therefore, cannabimimetics may find potential therapeutic utility in the treatment of disorders

resulting from cerebral ischemia, including stroke.

Another neuroprotective activity of cannabimimetics was shown to

be associated with the CB1-mediated inhibition of nitric oxide (NO) release

from rat microglial cells (Waksman, 1999). This study suggests cannabimimetics as potentially useful agents in brain injury resulting from

inflammatory neurodegenerative processes, especially those involving

activation of microglial cells, such as AIDS-encephalitis.

Another significant cannabinoid activity that is mediated by the

nervous system arises from the antinociceptive properties of these agents.

Compelling evidence suggests that cannabimimetics are effective in the

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

control of acute and chronic pain in a variety of antinociceptive tests in

animals (Martin, 1998). Synthetic cannabimimetics have been classified as

equal to morphine in potency and efficacy (Walker, 1999). The mechanism

of the cannabimimetic-induced analgesia is multifaceted and occurs at

several levels: (1) directly on spinal cord mechanisms (Walker, 1999); (2) in

supraspinal mechanisms, specifically in the thalamus and the periaqueductal gray (PAG) matters (Walker, 1999; Martin, 1998); and (3) in the

periphery, possibly involving CB1-like and CB2-like receptors (Calignano,

1998). Other systems, such as n and A opiate receptors, as well as spinal

noradrenergic mechanisms, seem to be involved in the cannabimimeticproduced analgesia (Walker, 1999). Evidence supports the suggestion that

cannabimimetics are effective in animal models of chronic pain, a type of

pain that is poorly managed by opioids (Walker, 1999). It has also been

suggested that CB1 agonists may be superior to morphine in suppressing

pain caused by nerve damage (Pertwee, 2000). This type of pain is signaled

by abnormal discharges of Ah and Adelta fibers, which are much more

populated by CB1 than A-opioid receptors.

Another category of CNS-mediated cannabinoid effects includes

alterations in cognition and memory. Cannabimimetics have been shown

to interfere with the mechanisms of long-term potentiation (LTP), a

candidate mechanism for learning and memory. They also alter presynaptic release of GABA and glutamate from hippocampal neurons (Hampson,

1998). Hippocampus, a structure rich in CB1, plays a major role in memory

processing, especially by enabling memory retrieval, whereas retrohippocampal areas with fewer CB1 receptors are responsible for memory

storage. Hippocampal lesions in rodents impair short-term memory.

Several behavioral studies have exhibited that cannabinoids disrupt information processing in the hippocampus, acting as ‘‘reversible’’ hippocampal lesions (Hampson, 1999). It is suggested that the role of CB1 in

these regions is to regulate storage information by switching hippocampal memory circuits (Hampson, 1998). The role of the cannabinoid

system in memory and cognition renders it a possible target for memory

and cognition enhancing agents. This possibility is strongly supported

by some recent advances in understanding the neurobiology of the

endocannabinoid system (Wilson, 2001; Christie, 2001; Kreitzer, 2001;

Ohno-Shosaku, 2001). Endocannabinoids were found to be the neurotransmitters responsible for the depolarization-induced suppression of

inhibition (DCI) and excitation (DCE). Since DCI enhances memory in

the hippocampus, drugs that inhibit the metabolism and especially the

transport of endocannabinoids are very likely to have a beneficial effect on

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

memory by increasing the levels of endocannabinoids at the sites where

DCI takes place (Christie, 2001). Direct cannabinoid receptor agonists

flood the endocannabinoid system, resulting in the well-known overall

disruptive effect in memory and cognition.

Cannabinoids are long known for their psychoactive and euphoric

‘‘high’’ effects and have been used for these properties for centuries. Their

addictive potential and mechanisms appear to be qualitatively and quantitatively different from those of other drugs of abuse. However, recent

studies indicate that cannabimimetics, similar to other addictive drugs,

activate the brain reward/reinforcement circuit (ventral tegmental area,

nucleus pallidus, and ventral pallidum) and produce reward-related

behaviors in laboratory animals (Gardner, 1998). Efforts to separate these

unwanted effects from the desired ones have had only limited success thus

far. This fact, along with the negative social perception of these drugs, has

been a major hindrance to the development of cannabinergic therapeutics.

However, the increasing understanding of the endocannabinoid system

presents us with possibilities for the design of selective agents. Indirect

activation of this system by increasing endocannabinoid levels only at the

sites where they are physiologically produced through inhibition of

endocannabinoid catabolism or transport may lead to increased selectivity

and fewer undesired effects than activation of the cannabinoid receptors

with direct agonists (Pertwee, 2000). Endocannabinoids such as anandamide were shown to have a much lower physical dependence potential

(Aceto, 1998).

Other well-known central cannabimimetic effects that nevertheless

are not well understood are hypothermia, appetite stimulation, and

antiemetic effects. Cannabimimetic-induced hypothermia is thought to

occur by decreasing the thermoregulatory set point through interactions

with the relevant hypothalamic centers (Pertwee, 1995b). Cannabimimetics also stimulate hunger in humans and animals, particularly for solid,

sweet tasting foods (Pertwee, 1995b). For this property, delta-9-THC

(marinol) is clinically used today for the management of AIDS-wasting

syndrome (Nahas, 1999). The advent of potent and CB1-selective ligands

lacking the CB2-mediated immunosuppressive properties may present

significant advantages over the currently used delta-9-THC in the treatment of AIDS patients who are already severely immunocompromised. It

is also conceivable that cannabinoid receptor antagonists may be proven

effective as appetite suppressants, as suggested by the results of a study

showing that SR141716A, a selective CB1 antagonist/inverse agonist,

suppressed rodent appetite for sucrose and ethanol (Arnone, 1998).

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

A second current clinical indication of cannabimimetics is their

antiemetic and antinausea effects, especially in cancer chemotherapy

patients. These effects are mediated above the level of vomiting reflex

and possibly through descending inhibitory connections to the lower brain

stem centers (Levitt, 1986).

B. Immune System

The discovery of the peripheral CB2 receptor, which localizes in cells of the

immune system, is very likely linked to the well-known immunosuppression of marijuana smokers.

Miskin (1985) found that delta 9-THC decreases host resistance to

herpes virus type 2 in mice and guinea pigs by decreasing both cellular and

humoral immunity. In vivo and in vitro studies indicate that macrophages

are the major targets of cannabinoids. delta 9-THC inhibits, in a dosedependent manner, the extrinsic antiviral activity of macrophages (Cabral,

1991). It was also shown that cannabinoids cause morphological changes

in macrophages (Cabral, 1991) and affect their phagocytic and spreading

ability (Spector, 1991).

The involvement of CB2 (and possibly of CB1) receptor(s) in the

immunosuppressive effects of cannabinoids is not proven yet. The localization of CB2 in cells of the immune system and especially in macrophages

and lymphocytes suggests that this receptor serves some immunoregulatory role(s). The first strong piece of evidence that implicates CB2 in such a

function came from Kaminski et al. (1994), who demonstrated that

cannabinoid-induced suppression of humoral immunity was partially

mediated through inhibition of adenylyl cyclase by a G-protein-coupled

mechanism that is pertussis toxin sensitive. Involvement of a membrane

perturbation mechanism in cannabinoid-induced immunosuppression is

also possible, especially in areas exposed to high drug concentrations, such

as lung alveolar macrophages of marijuana smokers (Cabral, 1999). The

involvement of the cannabinoid system in the regulation of the immune

system may suggest that cannabinergics could potentially serve as immunomodulatory agents. Although CB2 selective agents already exist, their

clinical potential in some immunomodulatory role will not be realized until

the CB2 physiological functions are better understood. Cannabidiol, a

cannabis terpenoid ingredient lacking the pyran ring as well as significant

binding affinity for CB1 and CB2, was shown to be an active antiinflammatory agent in the murine model of arthritis (Pertwee, 2000). The

molecular basis of this observation is still unknown.

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

C. Cardiovascular System

Cannabinoids reduce platelet aggregation and also produce tachycardia

and orthostatic hypotension due to peripheral vasodilation. A distinct,

CB1-like, receptor is found in the endothelium of rat mesenteric arteries

(Jarai, 1999). This receptor mediates a remarkable vasodilating effect after

activation by any of several CCs, anandamide, or some CB1-inactive CClike analog. This effect is NO independent and is inhibited by the CB1

antagonists, SR141716A and AM251 (Batkai, 2001), and also by cannabidiol. It is possible that exploitation of this new cannabinoid target may

lead to new types of hypotensive agents.

D. Reproductive System

Cannabinoids produce increased ring and chain chromosomal translocations and morphological abnormalities in mouse sperm, as well as reduction of sperm concentration in humans (Zimmerman, 1999). Strong

evidence indicates the presence of functional CB1, or CB1-like receptors,

in human sperm (Schuel, 1999). Furthermore, the endogenous cannabimimetic anandamide is produced in the human uterus and testes (Schuel,

1999). These findings along with several observations on cannabinoidinduced effects on reproductive functions suggest that the cannabinoid

system may be directly involved in the regulation of sperm production,

sperm motility, the acrosome reaction, and prevention of polyspermy

(Schuel, 1999). The endocannabinoid system in the uterus appears to play

a fundamental role in embryo implantation and early development.

Anandamide inhibits these processes and, therefore, regulation of its

levels seems to control the timing of these events (Paria, 1995). These

findings are also in line with recent clinical observations that correlate the

levels of AEAase expression with miscarriages in pregnant women

(Maccarone, 2000). Further understanding of the endocannabinoid functions in the reproductive system will open perspectives for exploitation of

cannabinergics for the treatment of some types of infertility or the development of contraceptives.

Cannabimimetics are also shown to affect reproductive and

metabolic functions indirectly by hormonal modulation through the

hypothalamic and pituitary regulatory centers. They are found to

reduce serum levels of the luteinizing hormone, prolactin, growth

hormone, and thyroid-stimulating hormone, and to increase corticotropin (Murphy, 1998).

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

E. Eye

Cannabinoids reduce intraocular pressure, probably by directly affecting

ocular fluid outflow pathways. The mechanism of this effect is unknown,

and its link to cannabinoid receptors has yet to be established (Green,

1999). Marijuana smoking is allegedly helpful to glaucoma patients, and

the potential use of cannabimimetics for the treatment of glaucoma has

long been recognized. New formulation technologies, as well as the advent

of less hydrophobic cannabimimetics, present us with opportunities to

overcome the challenge of local drug delivery to the eye.

F. Respiratory System

Cannabimimetics are known to produce bronchodilation, which is manifested by a marked increase in airway conductance and reduction in

airway resistance (Vachon, 1973). Although the mechanism of this activity

is not known, it probably does not directly involve adrenergic receptors.

Possible involvement of CB1A (a CB1 variant found in the lung) in

cannabinoid-induced bronchodilation is still unexplored (Shire, 1995).

Recently, it was shown that anandamide is released in the lung upon

Ca2+ stimulation and exerts a dual effect on bronchial response. It strongly

inhibits capsaicin-evoked bronchospasm and cough; however, it causes

bronchoconstriction in vagotomized rodents (Calignano, 2000). These

effects are mediated by CB1 receptors present in axon terminals of airway

nerves since they are blocked by SR141716A. This endocannabinoidmediated control of airway responsiveness may be exploited in the development of new antiasthmatic agents.

G. Gastrointestinal System

Cannabimimetics reduce the intestinal motility by a CB1-mediated inhibitory activity on acetylcholine release from autonomic fibers. An endocannabinoid, 2-AG, was isolated from dog intestine; however, its role there

remains unknown (Mechoulam, 1995a).


With the discovery of anandamide and 2-arachidonyl glycerol as two new

families of endocannabinoids, cannabinoid research has taken major

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

strides toward arriving at an understanding of the molecular mechanism of

cannabinoid action. Currently, there are multiple characterized endocannabinoid proteins [at least two receptors, CB1 and CB2; an enzyme,

arachidonylethanolamide amidohydrolase (AEAase); and a transport

protein, anandamide transporter (AT)] as potential therapeutic targets

for the development of useful medications in the treatment of a multitude

of conditions such as drug addiction, pain, and motor disorders. A number

of ligands (receptor-selective agonists/antagonists, inverse agonists,

enzyme inhibitors, transport inhibitors) are also available which can serve

as important research tools for exploring the endocannabinoid biochemical pathways and their role in the modulation of behavior, memory,

cognition, and pain perception. This is significant progress, considering

that only about a decade ago the sites of action of cannabinoids had not yet

been identified and their molecular mechanism of action was still under

question. The future of endocannabinoid research is undoubtedly very

exciting and full of promise.


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