December 3, 2009 – Marijuana is a complex substance containing over 60 different forms of cannabinoids, the active ingredients. Cannabinoids are now known to have the capacity for neuromodulation, via direct receptor-based mechanisms at numerous levels within the nervous system. These have therapeutic properties that may be applicable to the treatment of neurological disorders; including anti-oxidative, neuroprotective, analgesic and anti-inflammatory actions; immunomodulation, modulation of glial cells and tumor growth regulation. This article reviews the emerging research on the physiological mechanisms of endogenous and exogenous cannabinoids in the context of neurological disease.

Introduction
Over the past few decades, there has been widening interest in the viable medicinal uses of cannabis. The National Institutes of Health, the Institute of Medicine, and the Food and Drug Administration have all issued statements calling for further investigation. The discovery of an endogenous cannabinoid system with specific receptors and ligands has led the progression of our understanding of the actions of cannabis from folklore to valid science. It now appears that the cannabinoid system evolved with our species and is intricately involved in normal human physiology, specifically in the control of movement, pain, memory and appetite, among others. The detection of widespread cannabinoid receptors in the brain and peripheral tissues suggests that the cannabinoid system represents a previously unrecognized ubiquitous network in the nervous system. Dense receptor concentrations have been found in the cerebellum, basal ganglia and hippocampus, accounting for the effects on motor tome, coordination and mood state. Low concentrations are found in the brainstem, accounting the remarkably low toxicity. Lethal doses in humans has not been described.

The Chemistry of Cannabis
Marijuana is a complex plant, with several subtypes of cannabis, each containing over 400 chemicals. Approximately 60 are chemically classified as cannabinoids. The cannabinoids are 21 carbon terpenes, biosynthesized predominantly via a recently discovered deoxyxylulose phosphate pathway. The cannabinoids are lipophilic and not soluble in water. Among the most psychoactive is D9-tetrahydrocannabinol (THC), the active ingredient in dronabinol (Unimed Pharmaceuticals Inc). Other major cannabinoids include cannabidiol (CBD) and cannabinol (CBN), both of which may modify the pharmacology of THC or have distinct effects of their own. CBD is not psychoactive but has significant anticonvulsant, sedative and other pharmacological activity likely to interact with THC. In mice, pretreatment with CBD increased brain levels of THC nearly 3-fold and there is strong evidence that cannabinoids can increase the brain concentrations and pharmacological actions of other drugs.

Two endogenous lipids, anandamide (AEA) and 2-aracidonylglycerol (2-AG), have been identified as cannabinoids, although there are likely to be more. The physiological roles of these endocannabinoids have been only partially clarified but available evidence suggests they function as diffusible and short-lived intercellular messengers that modulate synaptic transmission. Recent studies have provided strong experimental evidence that endogenous cannabinoids mediate signals retrogradely from depolarized post synaptic neurons to presynaptic terminals to suppress subsequent neurotransmitter release, driving the synapse into an altered state. In hippocampal neurons, depolarization of postsynaptic neurons and the resultant elevation of calcium lead to transient suppression of inhibitory transmitter release. Depolarized hippocampal neurons rapidly release both AEA and 2-AG in a calcium-dependent manner. In the hippocampus, cannabinoid receptors are expressed mainly by GABA-mediated inhibitory interneurons. Synthetic cannabinoid agonists depress GABAA release from hippocampal slices. However, in cerebellar Purkinje cells, depolarization-induced elevation of calcium causes transient suppression of excitatory transmitter release. Thus endogenous cannabinoids released by depolarized hippocampal neurons may function to downregulate GABA release. Further, signaling by the endocannabinoid system appears to represent a mechanism enabling neurons to communicate backwards across synapses in order to modulate their inputs.

There are two known cannabinoid receptor subtypes; subtype 1 (CB1) is expressed primarily in the brain, whereas subtype 2 (CB2) is expressed primarily in the periphery. Cannabinoid receptors constitute a major family of G protein-coupled, 7-helix transmembrane nucleotides, similar to the receptors of other neurotransmitters such as dopamine, serotonin and norepinephrine. Activation of protein kinases may be responsible for some of the cellular responses elicited by the CB1 receptor.

Neuromodulation and neuroprotection
As we are developing an increased cognizance of the physiological function of endogenous and exogenous cannabinoids it is becoming evident that they may be involved in the pathology of certain diseases, particularly neurological disorders. Cannabinoids may induce proliferation, growth arrest or apoptosis in a number of cells, including neurons, lymphocytes and various transformed neural and non-neural cells. In the CNS, most of the experimental evidence indicates that cannabinoids may protect neurons from toxic insults such as glutamatergic overstimulation, ischemia and oxidative damage. The neuroprotective effect of cannabinoids may have potential clinical relevance for the treatment of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson.s disease, cerebrovascular ischemia and stroke. Both endogenous and exogenous cannabinoids apear to have neuroprotective and antioxidant effects. Recent studies have demonstrated the neuroprotective effects of synthetic, non-psychotropic cannabinoids, which appear to protect neurons from chemically-induced excitotoxicity. Direct measurement of oxidative stress reveals that cannabinoids prevent cell death by antioxidation. The antioxidative property of cannabinoids is confirmed by their ability to antagonize oxidative stress and consequent cell death induced by the powerful oxidant, retinoid anhydroretinol. Cannabinoids also modulate cell survival and the growth of B-lymphocytes and fibroblasts.

The neuroprotective actions of cannabidiol and other cannabinoids have been examined in rat cortical neuron cultures exposed to toxic levels of the exitatory neurotransmitter glutamate. Glutamate toxicity was reduced by both CBD (non-psychoactive) and THC. The neuroprotection observed with CBD and THC was unaffected by a cannabinoid receptor antagonist, indicating it to be cannabinoid receptor-independent. CBD was more protective against glutamate neurotoxicity than either ascorbate (vitamin C) or a-tocopherol (vitamin E).

Cannabinoids have demonstrated efficacy as immune modulators in animal models of neurological conditions such as MS and neuritis. Current data suggests that the naturally occurring, non-psychotropic cannabinoid, CBD, may have a potential role as a therapeutic agent for neurodegenerative disorders produced by excessive cellular oxidation, such as ALS, a disease characterized by excess glutamate activity in the spinal cord.

It is not yet known how glutamatergic insults affect in vivo endocannabinoid homeostasis, including AEA, 2-AG, as well as other constituents of their lipid families, N-acylethanolamines (NAEs) and 2-monoacylglycerols (2-MAGs). Hansen et al used three in vivo neonatal rat models characterized by widespread neurodegeneration as a consequence of altered glutamatergic neurotransmission and assessed changes in endocannabinoid homeostasis. A 46-fold increase in cortical NAE concentration and a 13-fold increase in AEA was noted 24 h after intracerebral NMDA injection, while less severe insults triggered by mild concussive head trauma or NDMA receptor blockade produced a less pronounced NAE accumulation. In contrast, levels of 2-AG and other 2-MAGs were unaffected by the insults employed, rendering it likely that key enzymes in biosynthetic pathways of the two different endocannabinoid structures are not equally associated with intracellular events that cause neuronal damage in vivo. Analysis of cannabinoid CB1 receptor mRNA expression and binding capacity revealed that cortical subfields exhibited an upregulation of these parameters following mild concussive head trauma and exposure to NMDA receptor blockade. This suggests that mild-to-moderate brain activity via concomitant increase of anandamide levels, but not 2-AG, and CB1 receptor density. Panikashvili et al demonstrated that 2-AG has an important neuroprotective role. After closed head injury (CHI) in mice, the level of endogenous 2-AG was significantly elevated. After administering synthetic 2-AG to mice following CHI, a significant reduction of brain edema, better clinical recovery, reduced infarct volume and reduced hippocampal cell death compared with controls occurred. When 2-AG was administered together with additional inactive 2-acyl-glycerols that are normally present in the brain, functional recovery was significantly enhanced. The beneficial effect of 2-AG was dose-dependently attenuated by SR-141716A (Sanofi-Synthélabo), an antagonist of the CB1 receptor [30]. Ferraro et al looked at the effects of the cannabinoid receptor agonist WIN-55212-2 (Sanofi Winthrop Inc) on endogenous extracellular GABA levels in the cerebral cortex of the awake rat using microdialysis. Win-55212-2 was associated with a concentration-dependent decrease in dialysate GABA levels. Win-55212-2 induces inhibition was counteracted by the CB1 receptor antagonist SR-141716A, which by itself was without effect on cortical GABA levels. These findings suggest that cannabinoids decrease cortical GABA levels in vivo.

Sinor has shown that AEA and 2-AG increase cell viability in cerebral cortical neuron cultures subjected to 8 h of hypoxia and glucose deprivation. This effect was observed at nanomolar concentrations, was reproduced by a non-hydrolyzable analog of anandamide, and was unaltered by CB1 or CB2 receptor antagonists. In the immune system, low doses of cannabinoids may enhance cell proliferation, whereas high doses of cannabinoids usually induce growth arrests or apoptosis.

In addition, cannabinoids produce analgesia by modulating rostral ventromedial medulla neuronal activity in a manner similar to, but pharmacologically distinct from, that of morphine. Cannabinoids have been shown to produce an anti-inflammatory effect by inhibiting the production and action of tumor necrosis factor (TNF) and other acute phase cytokines. These areas are discussed in great detail in a recent paper by Rice.
Glia as the cellular targets of cannabinoids

There is now accumulating in vitro evidence that glia (astrocytes and microglia in particular) have cannabinoid signaling systems. This provides further insight into the understanding of the therapeutic effects of cannabinoid compounds. Glial cells are the non-neuronal cells of the CNS. In humans they outnumber neurons by a factor of about 10:1. Because of their smaller average size they make up about 50% of the cellular volume of the brain. Glial cells of the CNS fall into three general categories: astrocytes, oligodendrocytes and microglia. Schwann cells and the less well-recognized enteric glia are their counterparts in the peripheral nervous system. Glia are ubiquitous in the nervous system and are critical in maintaining the extracellular environment, supporting neurons, myelinating axons and immune surveillance of the brain. Glia are involved, actively or passively, in virtually all disorders or insults involving the brain. This makes them logical targets for therapeutic pharmacological interventions in the CNS. Astrocytes are the most abundant cell type of the CNS. They express CB1 receptors, and take up and degrade the endogenous cannabinoid anandamide. The expression of CB2 receptors in this population appears to be limited to gliomas and may be an indicator of tumor malignancy. Two recent studies suggest that some of the anti-inflammatory effects of cannabinoids, such as the inhibition of nitric oxide (NO) and TNF release are mediated by CB1 receptors on astrocytes.

The most recent therapeutic role for cannabinoids in the CNS evolved from the discovery that cannabinoids selectively induce apoptosis in glioma cells in vitro and that THC and other cannabinoids lead to a spectacular regression of malignant gliomas in immune-compromised rats in vivo. The mechanism underlying this is not yet clear but it appears to involve both CB1 and CB2 receptor activation. A recent study comparing the antiproliferative effects of cannabinoids on C6 glioma cells suggests the involvement of vanilloid receptors.

Microglia are the tissue macrophages of the brain. In variance from other immune tissue but in accordance with their place in the CNS microglia appear to lack CB2 receptors on protein and RNA levels. Similar to their effect on peripheral macrophages, cannabinoids inhibit the release of NO and the production of various inflammatory cytokines in microglia. Interestingly, the inhibition of NO release seems to be CB1 receptor- mediated, whereas the differential inhibition of cytokines is not mediated by either CB1 or CB2 receptors, suggesting as yet unidentified receptors or a receptor independent mechanism. Irrespective, the potential of cannabinoids on inflammatory processes such as a mouse model of MS or future experiments on brain tumors in immunocompetent animal.

Nothing is known of the effects of cannabinoids on oligodendroglia. In the light of the clinical and experimental evidence suggesting the beneficial effects of cannabinoids in MS, investigations in this direction appear promising.

Future trends

A growing number of strategies for separating the sought-after therapeutic effects of cannabinoid receptor agonists from the unwanted consequences of CB1 receptor activation are now emerging. However, further improvements in the development of selective agonists and antagonists for CB1 and CB2 receptors are needed. This would allow for the refinement of cannabinoids with good therapeutic potential and would facilitate the design of effective therapeutic drugs from the cannabinoid family. Customized delivery systems are also needed; as the cannabinoids are volatile, they will vaporize at a temperature much lower than actual combustion. Thus heated air can be drawn through marijuana and the active compounds will vaporize and can easily be inhaled. Theoretically this removes most of the wealth hazards of smoking, although this has not been well studied. Recently, pharmacologically active, aerosolized forms of THC have been developed. This form of administration is achieved via a small particle nebulizer that generates an aerosol which penetrates deeply into the lungs.

From a regulatory perspective, the scientific process should be allowed to evaluate the potential therapeutic effects of cannabis, dissociated from the societal debate over the potentially harmful effects of non-medical marijuana use. This class of compounds not only holds tremendous therapeutic potential for neurological disease but is also confirmed as having remarkably low toxicity. Source.

Benefits of Cannabis Use

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