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. 2006 May 12;26(4-6):577–589. doi: 10.1007/s10571-006-9070-8

Implication of Cannabinoids in Neurological Diseases

Angela Alsasua del Valle 1,✉
PMCID: PMC11520754  PMID: 16699878

Abstract

1. Preparations from Cannabis sativa (marijuana) have been used for many centuries both medicinally and recreationally.

2. Recent advances in the knowledge of its pharmacological and chemical properties in the organism, mainly due to Δ9-tetrahydrocannabinol, and the physiological roles played by the endocannabinoids have opened up new strategies in the treatment of neurological and psychiatric diseases.

3. Potential therapeutic uses of cannabinoid receptor agonists include the management of spasticity and tremor in multiple sclerosis/spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, cancer, and vasodilation that accompanies advanced cirrhosis. CB1 receptor antagonists have therapeutic potential in Parkinson's disease.

4. Dr. Julius Axelrod also contributed in studies on the neuroprotective actions of cannabinoids.

KEY WORDS: cannabinoids, tetrahydrocannabinol, epilepsy, neurological diseases, multiple sclerosis, neuroprotective effects

INTRODUCTION

The main active psychotropic constituent in Cannabis sativa, Δ9-tetrahydrocannabinol, (Δ9-THC), was isolated in its pure form and its structure elucidated in the 1960s (Mechoulam and Gaoni, 1965). The discovery of an endogenous cannabinoid system consisting of two receptors (CB1 and CB2) and two endogenous ligands advanced the knowledge of the effects of Δ9-THC on the body (Martin et al., 1999). There is emerging evidence, however, that current cannabinoid receptor classification may be incomplete with the identification of non-CB1 non-CB2 cannabinoid-receptor induced responses in a variety of tissues (Jarai et al., 1999; White et al., 2001; Kunos et al., 2002; Zygmunt et al., 2002). This system appears to be involved in normal physiology, specifically in the control of movement, formation of memories (Piomelli et al., 2000) and appetite control.

Cannabinoids act through the G-protein-coupled receptors, CB1 (Matsuda et al., 1990) and CB2 (Munro et al., 1993). After many years of studies involving marijuana and cannabinoids, unequivocal evidence for a cannabinoid receptor in brain was reported in the late 1980s (Devane et al., 1988). Subsequent cloning indicated that this receptor belonged to a family of G-protein-coupled receptors, whose actions involve the inhibition of cyclic AMP and downregulation of calcium channels (-N and -P/Q) (Howlett et al., 1988; Matsuda et al., 1990; Pertwee, 1997; Netzeband et al., 1999).

Cannabinoid CB1 receptors are highly localised in the central nervous system (CNS) and are also found in some peripheral tissues (Pertwee, 1997, 1998). Cannabinoid CB2 receptors are found outside the central nervous system, in particular in association with immune tissues. Although anandamide can act through CB1 and CB2 receptors, it is also a vanilloid receptor agonist (Zygmunt et al., 1999; Smart et al., 2000).

Endogenous agonists for cannabinoid receptors (endocannabinoids) have also been discovered, the most important being arachidonoyl ethanolamide (anandamide), and 2-arachidonoylglycerol (2AG) (Devane et al., 1992; Mechoulam et al., 1995; Stella et al., 1997). Although other endocannabinoids and cannabinoid receptor types may also exist, these are the best-studied ones. Endocannabinoids are chemical compounds derived from arachidonic acid, which are released upon demand from lipid precursors in a receptor-dependent manner, and serve as retrograde signalling messengers in GABAergic and glutamatergic synapses, as well as modulators of post-synaptic transmission, interacting with other neurotransmitters, including norepinephrine and dopamine (Miller and Walker, 1995).

Endocannabinoids are transported into cells by a specific uptake system and degraded by two well-characterized enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase.

The discovery of the endocannabinoid system has prompted the development of CB1- and CB2-selective agonists and antagonists/inverse agonists that may be used in the treatment of some motor and neurological pathologies (Williamson and Evans, 2000).

In spite of preclinical data being presented, which could provide a rationale for the clinical use of cannabinoids in the fields of multiple sclerosis (MS), spasticity, epilepsy, movement disorders, and neuroprotection after traumatic head injury or ischemic stroke, at present, clinical data are insufficient to recommend the use of cannabinoids in any neurological disease as standard therapy. Nevertheless, they can be of the utmost use in the treatment of degenerative diseases for which there are no other effective treatments. Several questions still need to be answered, such as the route of administration, the type of cannabinoid or the use of endogenous cannabinoid system stimulation. However, agonists of cannabinoid receptors with low psychoactive effects are needed, and controlled studies are still required to clarify the potential therapeutical role of cannabinoids in neurology (Schwenkreis and Tegenthoff, 2003)

BRAIN CB1 RECEPTORS

Cannabinoid CB1 receptors are found on neurons, including the axons, cell bodies, terminals and dendrites. They are densely distributed in areas of the brain related to motor control, like cortex, basal ganglia and cerebellum 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 (Tsou et al., 1998).

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.

Particularly important classes of neurons that express high levels of CB1 receptors are GABAergic interneurons in hippocampus, amygdala and cerebral cortex. Activation of CB1 receptors leads to inhibition of amino acid and monoamine neurotransmitter release as occurs with the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) (Iversen, 2003; Engler et al., 2005; Kofalvi et al., 2005).

Cannabinoids tend to inhibit neurotransmission, although the results are somewhat variable. In some cases, cannabinoids diminish the effects of GABA, while in others they can augment the effects of GABA. The effect of activating a receptor depends on where it is found on the neuron: if cannabinoid receptors are presynaptic and inhibit the release of GABA, cannabinoids would diminish GABA effects; the net effect would be stimulation. However, if cannabinoid receptors are post-synaptic and on the same cell as GABA receptors, they would probably mimic the effects of GABA; in that case, the net effect would be inhibition.

In addition, at least in some areas of the brain, activation of the CB1 cannabinoid receptor has been shown to block pre-synaptic release of glutamate. The glutamatergic neurons are part of the excitatory system in the brain; thus, inhibition of glutamate reduces the activity of other neurons. Cannabinoids can tonically regulate N-methyl-d-aspartate (NMDA) glutamate receptor activity in vitro and support the in vivo observation that CB1 regulates NMDA-induced and ischaemic excitotoxicity (Nagayama et al., 1999).

These findings have led to a remarkable expansion of basic cannabinoid research as well as to a renaissance in the study of the therapeutic value of cannabinoids (Rodriguez de Fonseca et al., 2005).

Neuroprotector Effects of Cannabinoids

Since their pronounced psychoactive effects have been known for centuries through the medicinal and recreational use of the cannabis plant C. sativa, much of the interest in cannabinoids has focussed on their actions on the CNS.

Thus, cannabinoids have been shown to protect neurons from toxic insults such as excitotoxicity, traumatic injury and ischaemia both in vitro and in vivo (Mechoulam et al., 2002; van der Stelt et al., 2002).

Research on cannabinoids, conducted in mice, rats and isolated tissues, has begun to accumulate over the past few years showing that cannabinoids are neuroprotective against brain injury resulting from injected toxins, hypoxia and head trauma (Mechoulam et al., 2002). Researchers have found protective effects not only from the plant-derived cannabinoids such as Δ9-THC, but also from endogenous cannabinoids (Baker et al., 2001). Anandamide levels in the brains of rats rise after brain injury or neuronal death, and the cannabinoid system may play a primary role in limiting brain damage (Marsicano et al., 2003).

The mechanisms by which the cannabinoids reduce damage from both toxic and traumatic injury to the brain are not yet fully understood. It is accepted that CB1-mediated neuroprotective mechanisms are related to enhanced GABAergic tone, reducing glutamate activity, as well as to inhibition of nitric oxide and TNFα production (Molina-Holgado et al., 1997).

The best current hypothesis for how these chemicals provide their protective effects is perhaps that their general dampening of neural activity reduces excitotoxicity. Activation of the CB1 cannabinoid receptor has been shown to block pre-synaptic release of glutamate. Neuroprotective effects of the cannabinoid agonists WIN55212-2 and CP55940 have been demonstrated. Both produce protection against neuronal death induced by glutamate in hippocampal neuronal cultures. This effect is blocked by SR141716A, a CB1 receptor antagonist (Shen et al., 1996; Shen and Thayer, 1998). Similar results are reported by Martínez-Orgado et al. (2003) with the cannabinoid agonist WIN55212-2 inhibiting glutamate release in an in vivo model of acute severe asphyxia in newborn rats. This effect is not exclusively mediated by CB1 receptors. The prevention of early neuronal death was unmodified by SR171416 coadministration, revealing that the protective effect was not fully dependent on CB1 receptor activation.

Morisset and Laszlo (2001) report the inhibition of glutamatergic neurotransmission and proinflammatory cytokines as the mechanism of the neuroprotective action of anandamide and the synthetic agonist, WIN55212-2, in the spinal cord slice preparation, using whole cell patch-clamp recording.

Dr. Julius Axelrod also contributed to studies on the neuroprotective actions of cannabidiol (the non-psychoactive marijuana constituent, non-CB1–CB2 receptor agonist) and other cannabinoids. Cannabidiol was found to prevent both glutamate neurotoxicity and ROS-induced cell death in rat cortical neuron cultures exposed to toxic levels of the excitatory neurotransmitter glutamate. Δ9-THC, also blocked glutamate neurotoxicity, with a similar potency to cannabidiol. In both cases, neuroprotection was unaffected by cannabinoid receptor antagonists. This suggests that cannabinoids may have potentially useful therapeutic effects that are independent of psychoactivity-inducing cannabinoid receptors and so are not necessarily accompanied by psychotropic side effects (Hampson et al., 1998).

CB1 receptor activation is also known to inhibit certain calcium channels, directly reducing the production of nitric oxide and other potentially damaging reactive oxygen species (Shen et al., 1996; Shen and Thayer, 1998; van der Stelt et al., 2002).

Cannabinoid neuroprotection is usually more evident in whole-animal than in cultured-neuron models, which may result from their impact on various brain cell types (neurons, glia, vascular endothelium). Cannabinoids may exert dual effects on neural cell fate depending on signal input (e.g. agonist dose and time of exposure) with high inputs usually exerting growth inhibition or death. Endocannabinoids and exogenous cannabinoids may display distinct pharmacological behaviour (e.g. agonistic potency and stability) and the origin of the neural cell and its stage of differentiation may affect sensitivity to death. Besides the well-established neuromodulatory events such as its activation reducing the release of neurotransmitters such as dopamine and GABA, the cannabinoid system may control the survival/death of neurons (Guzmán, 2003).

NEUROLOGICAL DISEASES

Cannabis-derived compounds have the potential to be used medicinally in the treatment of degenerative diseases for which there are no other effective treatments.

Due to an increased understanding of the physiological role of endocannabinoids, it is becoming clear that they may be involved in the pathology of several neurological diseases (Glass, 2001): Parkinson's and Huntington's disease, MS and epilepsy.

Parkinson Disease

Parkinson's disease (PD) is a chronic, progressive neurodegenerative movement disorder. In PD, dopamine production in the basal ganglia is altered. Dopamine is the neurotransmitter that stimulates motor neurons, the nerve cells that control movement. PD results from the degeneration of dopamine-producing neurons in the brain, specifically in the substantia nigra and the locus coeruleus. When dopamine production is depleted, the motor system nerves are unable to control movement and coordination. Characteristic primary symptoms of PD are tremor, rigidity, slow movement (bradykinesia) and difficulty walking.

Patients with Parkinson and Huntington disease tend to have impaired functions in these regions. Oxidative damage of dopaminergic neurons has been postulated as a mechanism of neuronal degeneration.

The cannabinoid system, therefore, might play some physiological role in the control of movement by the basal ganglia. The globus pallidus and substantia nigra pars reticulata contain the highest density of CB1 receptors in the body. CB1 receptors are also abundant in the putamen, part of the relay system within the basal ganglia that regulates body movements, and in the cerebellum, which coordinates body movements. Cannabinoid receptors are also found in the neurons that project from the striatum and subthalamic nucleus, which inhibit and stimulate movement, respectively. They are, therefore, possible additional sites that might underlie the effects of cannabinoids on movement. This is supported by the finding that CB1 knockout mice exhibit lower locomotor activity (Zimmer et al., 1999). Furthermore, the concentration of anandamide in the globus pallidus and substantia nigra is three times higher than in other brain regions.

The evidence of the implication of cannabinoids in PD is based on the demonstration of a powerful action, mostly inhibitory, of synthetic, plant-derived and endogenous cannabinoids on motor activity. In addition, the fact that CB1 receptor binding was altered in the basal ganglia of humans affected by several neurological diseases and, also of rodents with experimentally induced motor disorders, further supports this contention (Sañudo-Peña et al., 1998; Romero et al., 2002).

Furthermore, evidence suggests that cannabinoids may prove useful in Parkinson's disease by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor suggests that they may be potent neuroprotective agents (Molina-Holgado et al., 1997).

Current treatments for PD, based on the replacement of dopamine in the brain, are often not satisfactory, due mostly to dyskinesic motor side effects, and new approaches are needed.

Cannabis-derived compounds may be used medicinally in the treatment of PD mainly because they 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 (Venderova et al., 2004). Cannabinoids decrease both the inhibitory and stimulatory inputs to the substantia nigra, and therefore might provide dual regulation of movement at this nucleus, producing an upregulation of CB1 receptors. In an early clinic report, however, no effects of smoked cannabis were observed in parkinsonian tremor (Frankel et al., 1990). Treatment with CB1 receptor antagonists may also be used to control akinesia in PD (Lastres-Becker et al., 2001).

Standard treatments of PD with levodopa may be constrained in the long term by the development of dyskinesia. In a randomized, double-blind, placebo-controlled, crossover trial, the authors demonstrate that the cannabinoid receptor agonist Nabilone (a THC synthetic derived) significantly reduces levodopa-induced dyskinesia in PD (Sieradzan et al., 2001).

The lateral segment of the globus pallidus is thought to be overactive in levodopa-induced dyskinesia in PD. Some authors suggest that CB1 receptor agonists could have value only in reducing L-dopa-induced dyskinesia (Brotchie et al., 1997; Fox et al., 2002; Brotchie, 2003; Carroll et al., 2004) and antagonists could prove useful in the treatment of parkinsonian symptoms, which was also demonstrated in a recent clinical study (Sieradzan et al., 2001).

The antidyskinetic function of cannabinoid agonists may be exerted through inhibition of GABA reuptake in the lateral part of the globus pallidus. Augmentation of GABAergic transmission in the indirect pathway may alleviate dyskinesia (Venderova et al., 2005). This issue is supported clinically by the finding that 14% of PD patients self-report improvement in their dyskinesia with cannabis use.

Huntington's Chorea

Huntington's disease is a neurodegenerative disorder characterized by a selective degeneration of striatal projection neurons, which deal with choreic movements. Huntington's chorea is a fatal degenerative condition inherited via sex chromosomes, which usually develops in middle-aged males. It is rare in women who may nevertheless carry the disease. There is a gradual loss of mental and cognitive function, commonly associated with depression and progressive loss of voluntary motor control.

It has been suggested that the neuronal degeneration caused by the disease results from an excess of free radical oxidation or glutamate. Excitotoxicity has been implicated in the etiology of Huntington's disease, because intrastriatal injection of glutamate receptor agonists reproduces some of the neuropathological features of this disorder. Activation of glutamate receptors in the striatum differentially regulates the expression of neurotrophins, such as glial cell line-derived neurotrophic factor (GDNF), in the striatum and in its connections, cortex, and substantia nigra, showing a selective trophic response against excitotoxic insults (Muller-Vahl et al., 1999).

A selective loss (≈97%) of cannabinoid receptors and neurotransmitters alterations in specific regions of the brain, like the corpus striatum, substantia nigra and globus pallidus of Huntington's patients has been demonstrated (Glass et al., 1993, 2000). NMDA receptor antagonists have been shown to delay neurodegeneration, and a synthetic cannabinoid (+)-HU-210 has been found to be a potent antagonist of the NMDA receptor (Richfield and Herkenham, 1994). The mechanism is not clear because synthetic cannabinoids, but not anandamide, protect against glutamate-mediated neurotoxicity (Skaper et al., 1996).

However, the massive depletion of cannabinoid receptors, coupled with the neuroprotective effects of cannabidiol, would suggest that cannabinoids potentially have a major future role in treating the symptomatology of Huntington's chorea (e.g. uncontrolled muscle spasms/movements) by two mechanisms: (1) Direct stimulation of the remaining receptors by Δ9-THC or by other CB1 receptor agonists and (2) by delaying the development of the disease due to the neuroprotective effects of Δ9-THC and cannabidiol.

This is an emerging area of research but clearly more research is needed.

Multiple Sclerosis

MS is a disease of the nervous system that affects as many as one person/800 in the population, especially young adults. MS has being recognized as a neurodegenerative disease that is triggered by inflammatory attack of the CNS. When MS has been active for some years it can cause muscle stiffness and spasms, pain, fatigue, difficulty passing urine and tremors.

CB1 cannabinoid receptors are involved in the pathophysiology of MS. The nature of the endogenous neuroprotective cannabinoid has yet to be definitively resolved and may involve more than one CB1-mediated pathway. In addition, cannabinoids exert a neuromodulatory effect on neurotransmitters and hormones involved in the neurodegenerative phase of the disease. Furthermore, the cannabinoid system acts as a regulator of many different neurotransmitters and ion (K+ and particularly Ca2+) channels (Twitchell et al., 1997; Howlett et al., 2002) and appears to be particularly important when CNS homeostasis is disrupted, as occurs in MS (Baker et al., 2000). Cannabinoids also have antioxidant properties that could further limit damaging events during inflammation (Hampson et al., 1998; Howlett et al., 2002).

Therefore, the CB1 receptor can act at many levels within the neuronal death cascade, which would otherwise ultimately lead to toxic ion influxes, cell metabolic failure and activation of death effector molecules, such as caspase-3 (Jackson et al., 2005). This would be consistent with the rapid neurodegeneration that occurs in CB1-deficient mice, and also implies a role for endocannabinoids in neuroprotection.

The cannabinoid system is neuroprotective in an animal model of MS, the allergic encephalomyelitis (EAE) model (Pryce et al., 2003). Mice deficient in the cannabinoid receptor CB1 tolerate inflammatory and excitotoxic insults poorly and develop substantial neurodegeneration following immune attack in EAE.

Several studies suggest that cannabinoids and endocannabinoids may have a key role in the pathogenesis and therapy of MS. In EAE and, at least initially, in MS, axonal damage occurs at least concurrently with inflammation (Ferguson et al., 1997; Killestein et al., 2004), which produces many potentially damaging elements such as cytokines and oxidative stress (Koprowski et al., 1993). Indeed, they can down-regulate the production of pathogenic T helper 1-associated cytokines enhancing the production of T helper 2-associated protective cytokines (Malfitano et al., 2005). A shift towards T helper 2 has been associated with therapeutic benefit of cannabinoids in MS.

Ionotropic glutamate receptor systems can also signal damaging mechanisms at the blood–brain barrier and within the neural microenvironment in EAE and MS. CB1 receptor activity regulates kainate glutamate receptor activity in vitro and in vivo (Nagayama et al., 1999; Pryce et al., 2003).

In addition, exogenous CB1 agonists can provide significant neuroprotection from the consequences of inflammatory CNS disease in an experimental allergic uveitis model. This will be elucidated once suitable agents to dissect these pathways become available.

As yet, there is no satisfactory treatment for this condition, although there are an increasing number of treatments to help relieve some of the distressing symptoms. In vivo studies using mice with EAE, suggest that the increase in circulating levels of endocannabinoids might have a therapeutic effect, and that agonists of endocannabinoids with low psychoactive effects (such as cannabidiol) could open new strategies for the treatment of MS (Malfitano et al., 2005). As both anandamide and 2-AG are elevated in chronic EAE lesions (Baker et al., 2001), both may participate in endogenous neuroprotective mechanisms.

Recently many sufferers from MS have reported that using cannabis (illegally) has helped their symptoms, especially muscle spasms. Therefore, in addition to symptom management, cannabis-derivative compounds may slow the neurodegenerative processes that ultimately lead to chronic disability in MS and, probably, other diseases (Croxford and Miller, 2004). This might provide a new therapeutic route in MS and could be combined with therapies that target the immunological elements of the disease. In neurodegenerative diseases including MS, signs appear once significant damage has already accumulated. Slowing the degenerative process early following diagnosis may help improve quality of life for many more years.

Epilepsy

Epilepsy is a chronic, often hereditary condition, characterized by the unprovoked recurrence of seizures following excessive or disordered firing of neurons. The normal pattern of neuronal activity becomes disturbed, causing strange sensations, emotions and behaviour, or sometimes convulsions, muscle spasms and loss of consciousness.

In epilepsy, if the balance of excitation and inhibition is perturbed, the intensity of excitatory transmission may exceed a certain threshold and epileptic seizures can occur. Abnormally high spiking activity can damage neurons.

It has been known for centuries that exogenous cannabinoids have anti-convulsant activity, but little is know about of its molecular mechanism. However, cannabinoids have been reported to exert both pro- and anti-convulsive activities. The recent progress in understanding of the endogenous cannabinoid system has revealed new insights into these opposing effects of cannabinoids (Gross et al., 2004).

The pro-convulsive activity of exogenous cannabinoids might be explained by the fact that CB1 receptors expressed on inhibitory GABAergic neurons are also activated, leading to a decreased release of GABA, and to a concomitant increase in seizure susceptibility.

When excessive neuronal activity occurs, endocannabinoids are generated on demand and activate the CB1 receptor. Using mice lacking CB1 receptors in principal forebrain neurons in a model of epileptiform seizures, it was shown that CB1 receptors expressed on excitatory glutamatergic neurons mediate the anti-convulsive activity of endocannabinoids. Systemic activation of CB1 receptors by exogenous cannabinoids, however, is anti- or pro-convulsive, depending on the seizure model used. The concept that the endogenous cannabinoid system is activated on demand suggests that a promising strategy to alleviate seizure frequency might be the enhancement of endocannabinoid levels by inhibiting the cellular uptake and the degradation of these endogenous compounds (Lutz, 2004).

The anti-convulsant activity of exogenously applied cannabinoids was also demonstrated by Wallace et al. (2003) using the rat pilocarpine model of epilepsy, suggesting that endogenous cannabinoid tone modulates seizure termination and duration through activation of the CB1 receptor. Western blot and immunohistochemical analyses revealed that CB1 receptor protein expression was significantly increased throughout the same regions of epileptic hippocampi. These studies define a role for the endogenous cannabinoid system in modulating neuroexcitation and suggest that plasticity of the CB1 receptor occurs with epilepsy.

Marsicano et al. (2003) also measured levels of endogenous cannabinoids in the hippocampus of mice after kainic acid-induced seizures and showed levels of anandamide but not 2AG transiently increased. These studies show that seizures rapidly activate the endogenous cannabinoid system, which provides protection against excessive neuronal activity by reducing excitability of hippocampal pyramidal neurons and activating intracellular signalling cascades.

Furthermore, CB1 receptors on principal neurons of the forebrain are primarily responsible for this action. These studies have improved our knowledge of the endocannabinoid system, but further investigation is required.

PSYCHIATRIC APPLICATIONS

Various authors have expressed different viewpoints concerning psychiatric syndromes and cannabis. While some emphasize the problems caused by cannabis, some describe the therapeutic possibilities. Cannabis products may be either beneficial or harmful, depending on the particular case. However, it is difficult to measure the placebo effect of smoking cannabis (Kirk et al., 1998).

Acute psychosis has been cited as a consequence of cannabis use, but there is no evidence that use of cannabis induced psychosis in previously asymptomatic individuals (Pope et al., 1995). In patients with existing psychiatric disorders, cannabis use may exacerbate psychotic symptoms (Ries, 1993).

The evidence for cannabis as an antidepressant is conflicting. Recent biochemical and behavioural findings have demonstrated that blockade of CB1 receptors engenders antidepressant-like neurochemical changes (increases in extracellular levels of monoamines in cortical but not subcortical brain regions) and behavioural effects consistent with antidepressant/antistress activity in rodents (Witkin et al., 2005).

Although data point to the involvement of the endocannabinoid system in anxiety states, the pharmacological evidence seems contradictory: Both anxiolytic- and anxiogenic-like effects have been reported with both endocannabinoid neurotransmission enhancers and blockers (Witkin et al., 2005).

There are additional case reports claiming benefits of cannabinoids in other psychiatric symptoms and diseases, such as sleep disorders, anxiety disorders, bipolar disorders and dysthymia (Gruber and Poper, 1994).

CONCLUSIONS

In summary, based on the available data, cannabinoids exhibit an interesting therapeutic potential in the treatment of neurological diseases such as multiple sclerosis, and Parkinson's and Huntington's diseases. There is insufficient evidence on the efficacy of cannabis and its derivatives in controlling epilepsy. Further clinical trials, well-designed, carefully executed for efficacy, are essential to clearly define the pharmacological role of cannabinoids. They should not be used as first-line. They may prove effective as adjuvants to other medications or to treat pathologies refractory to standard treatments. It is necessary to determine what type of cannabinoid and what route of administration are the best to maximize the beneficial effects and minimize the incidence of undesirable reactions. Future clinical investigation should focus on the development of novel synthetic agents with more specific actions and fewer side-effects that would broaden their therapeutic applications.

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