The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters. The discovery of endocannabinoids has raised the question of their potential involvement in the physiological control of appetite and energy metabolism. But did you know you also have an endocannabinoid system (ECS)? You probably didn't because unless you are a research scientist or work.
The classic behavioral effects of marijuana also provided early clues about potential therapeutic targets, such as the control of pain or appetite. The role of the endocannabinoid system in the pathogenesis and treatment of specific CNS diseases is discussed below.
The endocannabinoid system plays an important role in neuroprotection both in acute neuronal injury e. Although the underlying mechanisms are not fully understood, multiple cannabinoid receptor-dependent as well as receptor-independent processes have been implicated. These include, but are not limited to 1 modulation of excitatory glutamatergic transmissions and synaptic plasticity via presynaptic CB 1 receptors Molina-Holgado et al. Excitotoxicity, the toxic effects of an overactivation of glutamate receptors, and the resulting oxidative stress may contribute to the pathological processes eventually leading to cellular dysfunction or death in both acute and chronic forms of neurodegeneration Coyle and Puttfarcken, ; McNamara, ; Lutz, Dexanabinol HU , a behaviorally inactive cannabinoid and noncompetitive antagonist of NMDA receptors, protects primary rat neuronal cultures against NMDA and glutamate exposure in vitro Eshhar et al.
THC protects primary cultured neurons against kainate-mediated toxicity in a CB 1 -dependent manner Abood et al. Palmitoylethanolamide also improves neuronal survival in a glutamate-induced cell death model Skaper et al.
Intracerebral injection of NMDA in neonatal rats results in a fold increase of cortical anandamide concentrations Hansen et al. Both THC and anandamide exerted CB 1 -mediated neuroprotective effects in an ouabain-induced rat model of in vivo excitotoxicity van de Stelt et al.
Anandamide and synthetic agonists of CB 1 receptors also protected the newborn brain against AMPA-kainate receptor-mediated excitotoxic damage in mice Shouman et al.
Traumatic brain injury TBI is one of the leading causes of disability and mortality in young individuals Holm et al. TBI is characterized by cerebral edema, axonal and neuronal injury, increased permeability of the blood-brain barrier, and post-traumatic changes in cognitive and neurological functions Bayir et al. TBI can trigger glutamate-induced excitotoxicity, oxidative stress, release of inflammatory cytokines from brain-resident cells microglia, neurons, and astrocytes , programmed cell death, and cortical blood flow dysregulation reviewed in Wang and Feuerstein, ; Gentleman et al.
The protective effect of cannabinoids in traumatic brain injury was first indicated in studies with the nonpsychotropic cannabinoid dexanabinol HU Fig. These studies have demonstrated reduced brain damage and improved motor and cognitive function in HUtreated animals in a rat model of TBI.
The favorable effects of a single injection of HU on learning and neurological deficits lasted up to 30 days and could be achieved within a therapeutic window of 6 h Shohami et al. Beneficial effects of HU were also demonstrated in an axonal injury model Yoles et al. In mice with closed head injury, brain levels of 2-AG increased, and exogenous 2-AG administered 1 h after the head injury reduced infarct size and improved neurological outcome Panikashvili et al.
A multicenter, double-blind, randomized, placebo-controlled phase II trial conducted in 67 patients with severe closed head injury found dexanabinol to be safe and well tolerated. However, a double-blind, randomized, placebo-controlled phase III clinical trial of dexanabinol, conducted in 15 countries in 86 specialized centers and involving patients failed to demonstrate any favorable effects Maas et al.
Ischemic stroke is the most common form of stroke, mostly caused by a transient interruption of blood supply to the brain by thrombotic occlusion of blood vessels. It is an important cause of death and disability in industrialized countries, affecting up to 0.
One in six patients die in the 1st month after ischemic stroke, and half of the survivors are permanently disabled despite the best efforts to rehabilitate them and to prevent complications Klijn and Hankey, One of the first indications of the neuroprotective effect of cannabinoids came from the field of stroke research, using various in vitro and in vivo models of ischemic injury.
Anandamide, 2-AG, and WIN 55, protected cultured cortical neurons against hypoxia and glucose deprivation Nagayama et al. The effects of various cannabinoid ligands were also investigated in in vivo models of global cerebral ischemia induced by two-vessel occlusion with hypotension or by four-vessel occlusion, or in focal ischemia induced by occlusion of the middle cerebral artery MCAo , with or without reperfusion.
Importantly, this protective effect was observed even when the drug was administered 60 to min after the insult Vered et al. WIN 55,, at doses of 0. It also reduced infarct size after permanent focal cerebral ischemia induced by MCAo, when given 40 min before 30 min after the occlusion, and these effects were prevented by SR Nagayama et al.
WIN 55, also protected cultured cerebral cortical neurons from in vitro hypoxia and glucose deprivation, but in contrast to the receptor-mediated neuroprotection observed in vivo, this in vitro effect was not stereoselective and was insensitive to CB 1 and CB 2 receptor antagonists Nagayama et al. BAY also decreased infarct size in rats with permanent MCAo even when given intravenously 4 h after the occlusion Mauler et al.
The protective effect of HU was partially reversed by pretreatment with SR, indicating CB 1 receptor involvement. Surprisingly, all protection could be abolished by warming the animals to the body temperature of controls, indicating that CB 1 -mediated hypothermia contributed to the neuroprotection Leker et al. Consistent with these findings, CB 1 knockout mice had increased mortality from permanent focal cerebral ischemia, increased infarct size, more severe neurological deficits after transient focal cerebral ischemia, and decreased cerebral blood flow in the ischemic penumbra during reperfusion, compared with wild type controls subjected to the same insult Parmentier-Batteur et al.
Further evidence for a role of CB 1 receptors is their increased expression on neurons in the arterial boundary zone of cortical infarction Jin et al. Finally, brain levels of endocannabinoids are increased during ischemic Schmid et al. Other studies do not support the neuroprotective role of CB 1 receptor activation.
Thus, it appears that both CB 1 agonists and antagonists can be neuroprotective in cerebral ischemia. The reason for the opposite effects of pharmacological blockade versus genetic knockout of CB 1 receptors is not clear and may be related to the CB 1 receptor-independent effects of antagonists Begg et al. Clearly, evaluating the potential usefulness of cannabinoid ligands in the treatment of stroke warrants future studies. Multiple sclerosis MS is a complex, immune-mediated, inflammatory disease of the white matter of the brain, which compromises impulse conduction due to the loss of the myelin sheath of neurons and the secondary axonal loss Sospedra and Martin, MS affects 2 to 5 million people worldwide and commonly presents with an unpredictable, relapsing-remitting course and a range of clinical symptoms depending on where the demyelination and axonal loss have occurred Compston and Coles, Some patients become disabled within a short period of time, whereas others can live their entire lives with only negligible or no disability.
The symptoms of MS typically involve tremor, ataxia, visual loss, double vision, weakness or paralysis, difficulty in speaking, loss of bladder control and constipation, cognitive impairment, and painful muscle spasms. Muscle spasticity often leads to reduced mobility, considerable distress from pain, and interference with daily living activities. Spasticity, neuropathic and nociceptive pain, and some of the above symptoms are also common in spinal cord injury SCI.
Although there are numerous drugs available that target the immune system to slow down the progression of the disease, they are only moderately effective, and the treatment of MS remains mostly symptomatic and far from satisfactory Killestein and Polman, Cannabis had been used in ancient Greece, Rome, China, and India for relieving muscle cramps, spasm, and pain reviewed in Mechoulam, , Mechoulam et al.
THC treatment not only reduced CNS inflammation and improved neurological outcome but also improved survival compared with placebo. The nonpsychotropic dexanabinol also suppressed inflammatory responses in the brain and spinal cord of rats with EAE and improved their neurological symptoms Achiron et al. Although CB 1 receptor density is decreased in the striatum and cortex of EAE rats, this is compensated for by increased coupling to G protein-mediated signaling, ensuring the effectiveness of treatment with cannabinoid agonists Berrendero et al.
Furthermore, spasticity could be relieved not only by administration of exogenous anandamide, 2-AG, or PEA but also by selective inhibitors of endocannabinoid transport or hydrolysis, which suggests tonic control of muscle tone by the endocannabinoid system in EAE Baker et al. Additional evidence for this has emerged through the use of CB 1 -deficient mice, which tolerated inflammatory and excitotoxic insults poorly and developed substantial neurodegeneration after the induction of EAE Pryce et al.
Interestingly, CB 1 knockout mice had increased caspase 3 levels before the induction of EAE, suggesting a neuroprotective tone mediated by CB 1 receptors Jackson et al. These changes were paralleled by extensive remyelination Arevalo-Martin et al. Consistent with the animal data, cannabinoids have shown promise in the treatment of MS in humans Table 1. There have been anecdotal reports of the effectiveness of marijuana smoking in relieving symptoms of MS and SPI Grinspoon and Bakalar, , , which were supported by the results of early open or single-blind observations with orally given THC or smoked marijuana, involving small numbers of patients Dunn and Davis, ; Petro, ; Petro and Ellenberger, ; Clifford, ; Meinck et al.
The most consistent finding was a subjective improvement in spasticity, although benefits for mobility, tremor, nystagmus, mood, and bladder control were also reported. In a double-blind crossover study of a single MS patient, nabilone treatment improved muscle spasms, nocturia, and general well-being Martyn, In contrast, Greenberg et al.
These encouraging reports have triggered numerous larger, population-based clinical trials of cannabis-based medicines in MS, which have yielded mixed results. Using a randomized, double-blind, placebo-controlled, crossover design, Killestein et al. Spasticity and disability, quantified using the objective Ashworth scale Ashworth, and the Expanded Disability Status Scale were not improved. However, a significant improvement in the subjective rating of spasm frequency and trends toward improved mobility were noted, with no effect on tremor, sleep quality, or lower urinary tract symptoms.
It should be mentioned, however, that the dose of THC used was lower than that in subsequent studies with more positive outcome, and as was noted in an accompanying editorial Thompson and Baker, , the study was not powered to detect efficacy. There was no change in Ashworth score, tremor, irritability, depression, or tiredness after 15 weeks of treatment with Marinol or Cannador.
However, there were significant improvements in patient-reported spasticity, pain, and sleep quality. Unexpectedly, there was also a reduction in hospital admissions for relapse in the two active treatment groups. Adverse side effects were generally minor and similar to those with placebo. Remarkably, in the month follow-up of the original CAMS study of patients, muscle spasticity measured by the Ashworth scale was significantly improved in the THC-treated group. The Rivermead Mobility Index was also improved, indicative of reduced disability.
The effect of Cannador on tremor was also studied in a randomized, double-blind, placebo-controlled, crossover trial in 14 patients with MS. Consistent with an earlier report Zajicek et al. In another study of similar design, administration of oral capsules containing 2. In a double-blind, placebo-controlled study involving 18 patients with MS, THC and CBD decreased self-reported spasticity and pain and improved bladder symptoms, whereas spasticity measured by the Ashworth scale was not significantly improved Wade et al.
The therapeutic effect of Sativex delivered by oromucosal spray 2. Patients were allowed to self-titrate the dose to achieve optimal effects, up to a maximal daily dose of mg of THC and CBD.
Efficacy was assessed by using a modified Ashworth scale to assess spasticity, whereas daily living, mobility, cognitive function, and tremor were quantified through the use of various scales and questionnaires Wade et al. There was no significant difference in the Ashworth scale, tremor, and pain at 6 weeks between the Sativex and placebo groups.
However, visual analog scales showed significant improvement in patients whose primary symptom had been spasticity Wade et al. Sativex was well tolerated and effective against central neuropathic pain and sleep disturbances associated with MS in a randomized, controlled trial involving 66 patients Rog et al.
Sativex was approved and launched in Canada in for the treatment of neuropathic pain associated with MS and is currently being investigated for various other therapeutic indications Russo, , In a recent case report, a year-old woman was diagnosed with MS after having entered treatment with the CB 1 receptor antagonist rimonabant for obesity, and recovery to near normal was noted within weeks after discontinuation of the treatment van Oosten et al.
This report, coupled with the more severe neurodegenerative process when MS is induced in CB 1 knock-out mice or in mice treated with a CB 1 receptor antagonist, could suggest that CB 1 antagonism may exacerbate inflammatory demyelinating diseases in humans van Oosten et al. However, the occurrence of MS in this one patient may have been purely coincidental. Although the results of the above clinical studies Table 1 are somewhat equivocal, patients treated with cannabis experienced improvements in the most disturbing symptoms including pain and spasticity compared with those receiving placebo, without experiencing significant side effects.
These studies also suggest that the Ashworth scale as a primary measure of spasticity in MS does not accurately assess the complex collection of symptoms associated with spasticity, which may be more accurately evaluated using subjective measures.
Indeed, the use of the Ashworth scale as a primary measure of spasticity in MS has often being criticized, and many commonly used antispasticity medications have also failed to generate statistically significant improvements according to this scale Hinderer and Gupta, ; Shakespeare et al. Accurate assessment of the clinical effectiveness of cannabinoids in MS may be complicated by the difficulty in achieving the most appropriate individual oral dose Table 1.
Peak plasma concentrations and their timing vary greatly because of the low water solubility of cannabis components and the large variability in their absorption from the gastrointestinal tract. An additional disadvantage of oral administration is the hepatic first-pass effect.
This can result in the formation of large quantities of the psychoactive metabolite OH-THC, which may be responsible for some of the side effects observed Table 1. Delivery of cannabis-based extracts as an oromucosal spray may minimize these drawbacks and may allow patients to better optimize their individual daily dose by self-titration Russo, In conclusion, controlled clinical trials with cannabinoids have demonstrated their efficacy in eliciting symptomatic improvements in MS patients.
These results suggest that there is place for the use of cannabis in the treatment of MS, which should be confirmed in further larger-scale clinical trials. Endocannabinoid involvement in the central regulation of motor functions and in movement disorders is based on multiple lines of evidence. First, CB 1 receptors are highly expressed in the basal ganglia, especially in the substantia nigra and in the cerebellum Herkenham et al.
Second, endocannabinoids are also abundant in these brain regions Bisogno et al. Third, endogenous, plant-derived, and synthetic cannabinoids have potent, mostly inhibitory, effects on motor activity Crawley et al. Fourth, CB 1 receptor and endocannabinoid levels are altered in the basal ganglia both in experimental models Zeng et al.
Fifth, the endocannabinoid system interacts with several neurotransmitter pathways at various levels of the basal ganglia circuitry Glass et al. PD is caused by a severe loss of dopaminergic neurons in the substantia nigra pars reticulata SNr , resulting in reduced dopamine levels and a loss of dopaminergic neurotransmission in the striatum, which interferes with motor function and coordination. Although excitotoxicity, oxidative stress, inflammation, mitochondrial dysfunction, and environmental and hereditary factors have all been implicated in the pathogenesis of PD, the exact cause of the loss of dopaminergic neurons remains elusive Hattori and Mizuno, ; Eriksen et al.
Current therapies include oral dopamine replacement via the dopamine precursor levodopa, anti-cholinergic agents, and monoamine oxidase B inhibitors Horn and Stern, Although dopamine replacement therapy can be effective in most patients by controlling the symptoms in the short term, their long-term use is associated with diminishing efficacy and severe side effects such as levodopa-induced dyskinesia LID involuntary movements , which often lead to treatment discontinuation and severe disability.
In PD, there are secondary abnormalities in nondopaminergic transmission within the basal ganglia that are thought to contribute to the inhibition of motor function. This results in decreased GABAergic input from the GPe to the subthalamic nucleus which, together with increased activity of glutamatergic efferents to this nucleus, results in its hyperactivity. In turn, the hyperactive subthalamic nucleus increases the activity of the SNr and internal globus pallidus GPi through glutamatergic efferents.
Because both the SNr and GPi provide inhibitory output to motor nuclei outside the basal ganglia e. In general, changes opposite to those described above are likely to be involved in LID. The final outcomes of the dysregulation of neuronal circuits are abnormal patterning, firing rate, and synchronization of basal ganglia outputs Obeso et al. They may also attenuate the severity of symptoms once symptoms develop.
As discussed below, the endocannabinoid system may play an important regulatory role in PD,PD and LID as well as in the compensatory mechanisms. Overactivity of endocannabinoid transmission, as reflected by increased tissue levels of endocannabinoids and CB 1 receptors as well as decreased rates of endocannabinoid transport and degradation by FAAH, have been found in the basal ganglia in the 6-hydroxydopamine-lesioned or reserpine-treated rat models of PD Mailleux and Vanderhaeghen, ; Romero et al.
In basal ganglia from 1-methylphenyl-1,2,3,6-tetrahydropyridine-lesioned marmosets, a primate model of PD, and in basal ganglia of PD patients, the density of striatal CB 1 receptors and CB 1 receptor-G-protein coupling were found to be increased Lastres-Becker et al. The above changes in 1-methylphenyl-1,2,3,6-tetrahydropyridine-treated marmosets and 6-hydroxydopamine-lesioned rats were reversible by chronic L-dopa treatment, which indicates that the similar changes observed in PD patients were unlikely to have been induced by the replacement therapy Lastres-Becker et al.
There is broad agreement that the endocannabinoid system becomes overactive in the basal ganglia in PD reviewed in Brotchie, , although some studies report a reduction Silverdale et al. If the enhanced CB 1 receptor signaling in the striatum is viewed as an attempt of the dopamine-deficient brain to normalize striatal function, the pharmacological amplification of this signaling might alleviate symptoms of PD, e.
On the other hand, enhanced CB 1 receptor signaling, if focused on the other part of the circuitry e. Likewise, CB 1 antagonism could have either pro-parkinsonian effects, if it targets the striatum, or antiparkinsonian effects, if it targets the GPe. Accordingly, both agonists and antagonists might have therapeutic potential, both in PD and LID reviewed in Brotchie, On the other hand, dysfunction of nigrostriatal dopaminergic neurons can be associated with overactivity of endocannabinoid transmission in the basal ganglia see above.
Mailleux and Vanderhaeghen, ; Di Marzo et al. Notwithstanding the above, studies using SR in rat Di Marzo et al. Rimonabant treatment also failed to influence dyskinesia in the first small-scale, randomized, double-blind, placebo-controlled human study Mesnage et al. However, the dose used in this human study was approximately fold lower 0. As suggested by a recent report Fernandez-Espejo et al. More recently, using Park-2 knockout mice, a genetic model of early PD, Gonzalez et al.
Taken together, although the above studies do not offer a complete understanding of the role of endocannabinoids and cannabinoid receptors in PD and LID, they support the notion that the endocannabinoid system plays an important role in movement disorders, including PD, and may provide the framework for novel therapeutic approaches in the future. The disease is characterized by motor disturbances, such as chorea involuntary movements and dystonia, psychiatric symptoms, and dementia Melone et al.
The prevalence of HD is similar to that of ALS see below , but much lower than that of most of the other neurodegenerative illnesses discussed above or below. The therapy of HD is very limited and includes antidopaminergic drugs to reduce the hyperkinesias and antiglutamatergic agents to reduce excitotoxicity Melone et al.
It has been clearly demonstrated, both in postmortem human tissue Glass et al. Furthermore, decreased levels of anandamide and 2-AG in the striatum and an increase of anandamide in the ventral mesencephalon, where the substantia nigra is located, have been documented in a rat model of HD Lastres-Becker et al.
Thus, it appears that endocannabinoid signaling in the basal ganglia is hypofunctional in HD, which probably contributes to the hyperkinesia associated with the disease. This finding raises the intriguing possibility that these cells could be a source of replacement of cells lost due to neurodegenerative disease Curtis et al.
Indeed, data from animal models demonstrated that both CB 1 agonists and inhibitors of endocannabinoid transport are able to reduce hyperkinesia Lastres-Becker et al.
Interestingly, direct agonists of CB 1 receptors, such as CP55,, only produced a very modest effect compared with the anandamide transport inhibitor AM, which also exhibits affinity for the VR 1 receptor Zygmunt et al.
This latter property of AM may account for its ability to reduce hyperkinesia Lastres-Becker et al. Arvanil, a hybrid endocannabinoid and vanilloid compound, was also reported to alleviate hyperkinesias in a rat model of HD de Lago et al.
There have been few human trials on the effects of cannabinoid agonists in HD, and the results do not live up to the promise of the animal data. Small trials with the synthetic THC analog nabilone and with the nonpsychoactive cannabidiol showed no efficacy or even increased choreic movements in HD patients Consroe et al.
These negative results could be related to dosing issues, to the lack of TRPV 1 receptor activity of the compounds tested, or to the advanced stage of the disease. Nevertheless, further studies are warranted to explore the therapeutic potential of cannabinoids in HD. TS is a neurological syndrome that becomes evident in early childhood and is characterized by multiple motor and vocal tics lasting for more than 1 year.
In addition, as described in the sections above, cannabinoids have potential in the management of the LID in PD and of the spasticity and tremor in MS. On the other hand, in patients chronically treated with neuroleptic drugs, a correlation between chronic cannabis use and the presence of tardive dyskinesia has been described previously Zaretsky et al. It is characterized by rapid, progressive degeneration of motor neurons in the brain and spinal cord, which ultimately leads to progressive weakness, paralysis, and premature death Rowland and Shneider, Although weak, patients are cognitively intact and thus are completely aware of their progressive disability.
The disease strikes adults at any age, and most patients die within 3 to 5 years after the onset of symptoms. Despite a variety of putative underlying mechanisms, including oxidative stress, neuroinflammation, autoimmunity, a defect in neuronal glutamate transport and glutamate toxicity, neurofilament accumulation, exogenous factors virusesor toxins , mitochondrial dysfunction, and mutations in the superoxide dismutase SOD1 gene, the pathogenesis of ALS is incompletely understood Barnham et al.
Tragically, available treatment options are limited and do not prevent disease progression and death Rowland and Shneider, Based on the well-known protective effect of cannabinoids against oxidative cell damage and excitotoxicity Hampson et al. Indeed, in a pilot study of the safety and tolerability of THC in ALS patients, symptomatic benefits were seen for spasticity, insomnia, and appetite Gelinas et al. Furthermore, THC potently reduced oxidative and excitotoxic damage in spinal cord cultures in vitro and prolonged survival in SOD1 mutant mice Raman et al.
These results suggest that cannabinoids have significant neuroprotective effects in a mouse model of ALS but that these beneficial effects may be mediated by non-CB 1 receptor mechanisms.
These studies have engendered new perspectives on the possible role of the endocannabinoid system in neurodegenerative processes associated with inflammation reviewed in Walter and Stella, , including those in AD reviewed in Pazos et al.
However, analyses of brain tissue samples obtained from AD patients Westlake et al. Senile plaques in AD patients express both CB 1 and CB 2 receptors together with markers of microglial activation, and CB 1 -positive neurons, present in high numbers in control cases, are greatly reduced in areas of microglial activation Ramirez et al. CB 1 receptor protein levels and G protein coupling were also markedly decreased in AD brains, coupled with increased nitration of the CB 1 and CB 2 receptor proteins Ramirez et al.
Although there are no data available on the endocannabinoid content in AD brain tissue are available, increased levels have been reported in the brain after inflammatory events and in neurodegenerative disorders associated with inflammation reviewed in Walter and Stella, and see also sections above.
Intriguingly, in a recent open-label pilot study of six patients in the late stages of dementia five patients with AD and one patient with vascular dementia , treatment with 2.
If the balance between inhibitory and excitatory communications among neurons is disturbed, the intensity of excitatory transmission may exceed a certain threshold, leading to epileptic seizures. Thereafter, endocannabinoids are released and reach presynaptic CB 1 receptors retrogradely to modulate both inhibitory GABAergic and excitatory glutamatergic transmissions via multiple mechanisms Marsicano and Lutz, ; Alger, , ; Gerdeman et al.
Multiple pathways, eventually culminating in neuronal death, are triggered by excessive excitatory activity through a process known as excitotoxicity McNamara, Epileptic syndromes are classified as generalized seizures, which affect the entire forebrain, or partial seizures, which occur within localized brain regions. Cannabis has been used to treat epilepsy for centuries. Hashish was reported to cure the sick son of the chamberlain of the Caliphate Council in Baghdad by the medieval Arab writer Ibn al-Badri Mechoulam, ; Iversen, Almost four centuries later, W.
The benefit of cannabis in epilepsy was also reported by a British neurologist Reynolds, , but the medicinal use of cannabis was prohibited in the early 20th century in most countries.
After the identification of the structure of THC Gaoni and Mechoulam, , several groups investigated its antiepileptic effects reviewed in Gordon and Devinsky, ; Lutz, THC was originally characterized as an anticonvulsant, but it has a variety of excitatory and depressant effects, ranging from convulsions to ataxia, depending on the dose, experimental model, and the animal species used Karler and Turkanis, ; reviewed in Gordon and Devinsky, ; Lutz, Further complicating the picture, animal studies also document a rebound effect to THC with enhanced CNS excitability and increased sensitivity to convulsions Chiu et al.
This withdrawal hypersensitivity implies that in susceptible patients, the use of marijuana may be associated with withdrawal seizures Karler and Turkanis, Only case reports on the effects of THC in epileptic patients are currently available.
Two reports described decreased seizure frequency after marijuana use Consroe et al. According to a questionnaire completed by epileptic patients using marijuana regularly, 7. In contrast, marijuana smoking was associated with an increase in seizure frequency in another study Keeler and Reifler, Small-scale clinical studies have shown that the nonpsychotropic cannabidiol either reduced seizure frequency or had no significant effect on it Cunha et al.
As in human studies, cannabinoids were found to exert both anti- and proconvulsive activity in animal models of epilepsy, largely depending on the stimulus applied to induce seizures chemical, electrical, light, or fever and the species used Johnson et al. Anandamide and its metabolically stable analog, O, dose dependently inhibited electroshock-induced seizures in rats, and this effect was abolished by SR Wallace et al. In a rat model of febrile seizures, the expression of presynaptic CB 1 receptors in hippocampal GABAergic interneurons was increased Chen et al.
Remarkably, in a rat model of pilocarpine-induced status epilepticus, CB 1 receptor agonists were more effective in reducing seizure frequency than clinically used anticonvulsants, such as phenytoin or phenobarbital. Consistently, CB 1 receptor blockade increased seizure frequency, and the seizure activity was associated with increased brain levels of CB 1 receptors and 2-AG Wallace et al.
With use of the kainic acid-induced excitotoxic epileptiform seizure model in wild type and CB 1 knockout mice, recent studies have established that the seizure-induced increase of intracellular calcium, a hallmark of epilepsy Raza et al. In contrast to these findings, FAAH knockout mice or mice treated with a CB 1 agonist were found to have increased sensitivity to kainic acid-induced seizures Clement et al. The lack of protection in this latter study may be related to the nonselective activation of CB 1 receptors on both inhibitory proconvulsive effect and excitatory neurons anticonvulsive effect and by the life-long rather than on-demand activation of CB 1 receptors present in FAAH knockout animals.
In summary, the use of cannabinoids for the treatment of epilepsy is still controversial, although recent experimental studies provide some new insight. To date, there have been no large-scale, controlled clinical trials to examine the beneficial effects of cannabinoids in various forms of epilepsy.
The potential use of the nonpsychotropic cannabidiol and of inhibitors of anandamide transport or degradation warrants further investigation. The well-known psychotropic effects of cannabinoids and the distribution of cannabinoid receptors across important emotional circuits in the brain suggest that the endocannabinoid system may be involved in various psychiatric disorders such as schizophrenia and mood disorders reviewed in van der Stelt and Di Marzo, ; Hall et al.
Schizophrenia is the second most common mental disorder with a lifetime prevalence of approximately 0. The psychotic episodes are separated by periods with negative symptoms consisting of apathy, anhedonia, reduced social drive, loss of motivation, poverty of speech and thought, and blunting of affect.
With disease progression, behavioral impairment can lead to complete social isolation. Although recent advances in the pharmacotherapy of schizophrenia produced great improvement in the clinical symptoms and the quality of life of patients, there is room for further improvements Ban et al.
Numerous theories have been put forth regarding the etiology of schizophrenia, ranging from developmental or neurodegenerative processes, environmental factors, neurotransmitter abnormalities dopamine or glutamate , and infectious or autoimmune processes, but also including the cannabinoid hypothesis reviewed in Thaker and Carpenter, ; Lewis et al. It appears that hypoglutamatergic and hypodopaminergic transmission in the prefrontal cortex is involved in the negative symptoms, whereas hyperactivity of dopamine neurotransmission in the mesencephalic projections to the nucleus accumbens may underlie the positive symptoms Thaker and Carpenter, ; Lewis et al.
According to the endocannabinoid hypothesis of schizophrenia, overactivity of the endocannabinoid system may lead to a hyperdopaminergic and hypoglutamatergic state, which may underlie some of the symptoms Emrich et al.
The endocannabinoid hypothesis is supported by multiple lines of evidence. First, the use of large amounts of cannabis and THC may produce psychotic symptoms in normal individuals, including delusions, hallucinations, and cognitive impairment, which resemble schizophrenia Spencer, ; Halikas et al. Second, cannabis and THC may worsen psychotic symptoms in schizophrenic patients, contribute to poor outcome, increase the possibility of relapse, and decrease the effectiveness of antipsychotic drugs Breakey et al.
Third, the use of cannabis may precipitate the onset of schizophrenia in individuals susceptible to psychosis Andreasson et al. Fourth, postmortem radioligand studies document increased CB 1 receptor density in the dorsolateral and anterior cingular regions and subregions of the prefrontal cortex in schizophrenia Dean et al.
Fifth, the levels of anandamide are increased in cerebrospinal fluid or blood from schizophrenic patients Leweke et al. Sixth, treatment with neuroleptics appears to normalize the imbalance in endocannabinoid signaling in blood cells in schizophrenic patients De Marchi et al. Last, the hebephrenic type of schizophrenia shows a strong association with polymorphisms in the CNR1 gene encoding CB 1 receptors Leroy et al.
Taken together, the above evidence suggests that the endocannabinoid system may be a novel therapeutic target in schizophrenia. It is also tempting to speculate that CB 1 antagonists may be beneficial against some, most likely the negative, symptoms of the disease. Some preclinical and clinical evidence also suggests that cannabidiol may have antipsychotic potential reviewed in Zuardi et al. Mood disorders such as generalized anxiety or panic disorder, major depressive disorder and bipolar disorder manic depressive illness are very common, often serious, and potentially life-threatening conditions.
Many of the psychological effects of cannabis and THC are biphasic and bidirectional, depending on mode of administration, dose, personality, time frame, degree of tolerance, and various other environmental and individual factors Paton and Pertwee, ; Ashton et al.
The acute effects in normal subjects can range from euphoria, relaxation, excitation, heightened perception, and increased motor activity to dysphoria, anxiety, sedation, perceptual distortion, and incoordination.
THC, under certain conditions and at certain doses, exerts anxiolytic, antidepressant, and hypnotic effects in patients suffering from pain associated with cancer or multiple sclerosis and improves mood and general well-being in normal subjects Regelson et al. However, under different conditions and at higher doses, cannabis or THC can produce dysphoric reactions, anxiety, panic paranoia, and psychosis Spencer, ; Halikas et al.
CBD also possesses anxiolytic, antipsychotic and anticonvulsant properties, which are not mediated by classic cannabinoid receptors Carlini et al. The mode of action of CBD is not completely understood; it may involve blockade of anandamide and serotonin reuptake Bisogno et al. Animal studies yielded further support to the biphasic and bidirectional effects of cannabinoids on anxiety, with low doses being anxiolytic and high doses being anxiogenic.
Indeed, low doses of CP55, Genn et al. Low-dose CP55, was also anxiolytic in other models of anxiety in adult, juvenile, or infant rodents Romero et al.
In contrast, at medium to high doses, CP55, or HU displayed anxiogenic effects in the same or other experimental paradigms in adult as well as in juvenile or infant animals McGregor et al. Although several hypotheses have been proposed to explain the biphasic effects of cannabinoids on anxiety, including distinct receptors Haller et al.
The high level of CB 1 receptors in the hippocampus, amygdala, and prefrontal and anterior cingular cortex, key regions in the regulation of anxiety, may suggest that the endocannabinoid system plays a role in the control of anxiety Herkenham et al. Further support of this theory came from studies using CB 1 receptor antagonists or CB 1 receptor knockout mice. SR produced anxiogenic effects in the elevated plus-maze and the defensive withdrawal tests in adult rats Navarro et al.
Furthermore, SR not only reversed the anxiolytic effects of the CB 1 agonist CP55, but also was anxiogenic in the ultrasonic vocalization test in rat pups when administered alone McGregor et al. In contrast, Haller et al. Furthermore, another selective CB 1 receptor antagonist, AM, increased anxiety-like behavior in wild-type mice but had no effect in the knockouts, in support of a CB 1 receptor-mediated anxiolysis. Thus, the findings of Haller et al.
CB 1 knockout mice displayed increased anxiogenic responses in the light-dark box, plus-maze, and social interaction tests, an increased aggressive response in the resident-intruder test, and marked alterations in the hypothalamic-pituitary-adrenal HPA axis coupled with impaired action of known anxiolytic drugs such as buspiron and bromazepam Haller et al.
However, Marsicano et al. The importance of the latter is also indicated by the confounding effect of stress on anxiogenic behaviors and their modulation by endocannabinoids Haller et al. Stress-induced down-regulation of hippocampal endocannabinoid signaling may contribute to problems in behavioral flexibility and may play a role in the development of perseveratory and ruminatory behaviors in stress-related neuropsychiatric disorders Hill et al.
Collectively, a majority of evidence supports a role for CB 1 receptors in the control of emotional behavior and suggests the existence of an anxiolytic endocannabinoid tone. Facilitation of such a tone by inhibiting the degradation of endocannabinoids in vivo may be therapeutically exploited, as indicated by the reduced anxiety-like behavior and potent antidepressant-like effects in mice and rats treated with a FAAH or anandamide transport inhibitor and the blockade of this effect by SR or AM Kathuria et al.
The mechanisms responsible for the effects of cannabinoids on anxiety-related responses are complex and may involve modulation of numerous neurotransmitter systems. In contrast, there are also examples of negative modulation of HPA function by endocannabinoids Di et al.
Cannabinoids also modulate GABAergic transmission and the release of the peptide cholecystokinin, which may contribute to both anxiolytic and anxiogenic effects Onaivi et al. Furthermore, cannabinoids enhance the release of endogenous opioids and a functional interplay between the endocannabinoid and opioid systems modulates analgesic responses and is involved in antidepressant-like effects and in various addiction-related processes Pugh et al.
There are also interactions between the endocannabinoid and serotonergic systems Arevalo et al. In contrast to earlier dogma, recent findings indicate that neurogenesis occurs in the adult brain. Furthermore, stress and depression decrease neurogenesis, particularly in the hippocampus, whereas electroconvulsive therapy and chronic treatment with conventional antidepressants increases this process reviewed in Pacher et al.
It has been recently demonstrated that the endocannabinoid system drives neural progenitor cell proliferation Aguado et al. Furthermore, CB 1 receptors appear to be required for neuronal survival in the hippocampus Bilkei-Gorzo et al. These findings are particularly exciting, as they raise the possibility of a role for endocannabinoids in antidepressive drug action.
Indeed, CB 1 receptor density in the hippocampus and hypothalamus is increased by chronic tricyclic antidepressant treatment Hill et al. It should not be surprising, however, that based on the basis of the bimodal action of cannabinoids on mood and anxiety, a case could be made for the opposite, i. CB 1 antagonists were reported to elicit antidepressant-like behavioral effects in rodents and can increase the synaptic concentration of biogenic amines, much like antidepressants do reviewed in Witkin et al.
Thus, pharmacological modulation of the endocannabinoid system holds considerable promise in the treatment of both anxiety-related and mood disorders. The results of a recent study implicated endocannabinoids and CB 1 receptors in the extinction of aversive memories by demonstrating that CB 1 knockout mice show impaired extinction in auditory fear-conditioning tests, and this could be mimicked in wild-type mice by treatment with SR Marsicano et al.
These exciting findings raise the possibility that pharmacological amplification of CB 1 signaling, for example, by FAAH inhibitors, may have therapeutic value in obsessive-compulsive disorder or post-traumatic shock syndrome. Insomnia, the most common sleep disorder, is defined as difficulty with the initiation, maintenance, duration, or quality of sleep that results in the impairment of daytime functioning, despite adequate opportunity and circumstances for sleep Silber, The cause for insomnia is often not known, but frequently it may be a consequence of a chronic disease associated with pain or depression.
Early studies documented the fact that marijuana and THC affect sleep patterns both in humans Freemon, , ; Pivik et al.
More recently, Nicholson et al. They found that 15 mg of THC was sedative, whereas 15 mg of CBD had alerting properties as it increased wake activity during sleep and counteracted the residual sedative activity of THC Nicholson et al. Anandamide was also found to modulate sleep by increasing slow-wave sleep two and rapid eye movement sleep in a CB 1 receptor-dependent manner in rats Murillo-Rodriguez et al.
Interestingly, a recent study has demonstrated that anandamide not only induced sleep but also increased levels of the sleep-inducing substance adenosine in the basal forebrain, and both of these effects were blocked by SR Murillo-Rodriguez et al.
Oleamide is a fatty acid amide with a variety of in vitro effects, including inhibition of gap junction-mediated cell-cell communication Boger et al. Oleamide accumulates in the cerebrospinal fluid of sleep-deprived cats Cravatt et al. Initially, it was suggested that inhibition of anandamide degradation by FAAH rather than the activation of CB 1 receptors was responsible for the sleep-inducing effect of oleamide Boring et al.
Although little is known about the role of the endocannabinoid system in the pathophysiology of sleep disorders, clinical studies uniformly report significantly improved sleep quality in patients taking cannabinoids for symptomatic treatment of multiple sclerosis, cancer, chronic pain, or intractable pruritus. Although psychotropic cannabinoids are unlikely to gain acceptance for the treatment of insomnia, FAAH inhibitors were shown to enhance certain endocannabinoid-mediated behaviors without evidence for addictive properties Kathuria et al.
Nausea and vomiting can present as symptoms of a variety of diseases or as secondary consequences of chemotherapy or radiotherapy of cancer. It is for this latter indication that THC has gained acceptance as a highly efficacious therapeutic agent, often effective in cases resistant to other, more conventional, medications reviewed by Martin and Wiley, ; Aapro, ; Hall et al.
Emesis is thought to involve activation of specific receptors on sensory nerve endings in the gut and also in brainstem regions including the medullary chemoreceptor trigger zone and the lateral reticular formation. Activation of 5-HT 3 receptors appears to play a dominant role in acute emesis, whereas activation of NK 1 substance P receptors is more important in the delayed emesis after chemotherapy, as indicated by the effectiveness of the respective receptor antagonists in controlling these different stages of the emetic response Aapro, Also, cannabinoids may directly inhibit 5-HT 3 -gated ion currents by a mechanism not involving CB 1 receptors Fan, ; Barann et al.
Such a CB 1 receptor-independent effect is also suggested by the ability of cannabidiol, a natural constituent of marijuana which does not bind to the CB 1 receptor, to reduce lithium-induced vomiting in the house musk shrew Parker et al. Nevertheless, the involvement of CB 1 receptors is clearly indicated by the ability of SR to reverse the effects of THC and synthetic agonists in suppressing vomiting caused by cisplatin Darmani, b or lithium chloride Parker et al.
These latter findings suggest that the emetic circuitry is tonically controlled by endocannabinoids. In line with such a possibility, a recent human study found an association between chronic marijuana use, which probably results in desensitization of cannabinoid receptors, and cyclical hyperemesis: A meta-analysis of 30 randomized comparisons of cannabis nabilone, dronabinol, or levonantradol with placebo or standard antiemetics, involving a total of patients, concluded that cannabinoids are slightly more effective than conventional antiemetics, and the patients prefer them because of their mood enhancing and sedative effects.
This led to the recommendation to limit the use of cannabinoids as antiemetics to patients with chemotherapy-related sickness, in whom their mood-enhancing effects would be of added benefit. Neuroanatomically, this circuitry consists of three series of coupled pathways.
First-order neurons project from structures in the ventral limbic forebrain orbitofrontal cortex and anterior cingulate area to the mesencephalic ventral tegmental area VTA where they synapse onto dopaminergic neurons. These second-order neurons project primarily to neurons in the shell of the nucleus accumbens nAc , but also to cortical areas and to the amygdala. Third-order neurons in the nAc, some of which are GABAergic, project to the ventral pallidum and other regions involved in mediating reward-related behaviors recently reviewed by Lupica et al.
Genetic vulnerability to drug addiction has been linked to a functional deficiency in the second-order dopaminergic neurons at their interface with third-order neurons in the nAc Nestler, In human subjects prone to addiction, a deficiency in D 2 dopamine receptors in the nAc could be documented by brain imaging Volkow et al. A common denominator among different addictive drugs interacting with distinct receptors is their ability to activate the mesolimbic dopaminergic reward pathway and increase dopamine levels in the nAc, which is believed to be responsible for their addictive properties Koob, ; Wise, THC also increases the firing rate of the second-order VTA-nAc dopaminergic neurons via CB 1 but not opiate receptors French, , and withdrawal from THC increases corticotropin-releasing factor levels in the central nucleus of the amygdala Rodriguez de Fonseca et al.
THC and related synthetic cannabinoid agonists also fulfill the reward-related behavioral criteria for drugs of abuse: An issue of intense interest is the location of the CB 1 receptors mediating these effects. Similar to cannabinoids, opiates also increase the activity of dopaminergic neurons in the VTA. A similar mechanism has been postulated for cannabinoids by Cheer et al. In line with this, WIN 55, was found to suppress electrically evoked, but not muscimol-induced, inhibitory postsynaptic currents via CB 1 receptors in brain slices containing the VTA Szabo et al.
However, cannabinoids also inhibit glutamate release in the VTA, which would have an opposite effect on dopaminergic activity Melis et al. This pathway may be activated by ethanol, as indicated by the ability of the GABA B agonist baclofen to antagonize the increase in ethanol drinking caused by WIN 55, treatment of alcohol-preferring rats Colombo et al. Indeed, both the VTA and the nAc may be sites of the rewarding effects of cannabinoids, as documented by the propensity of rats to self-administer THC into either site Zangen et al.
Regardless of the exact location of presynaptic CB 1 receptors, their natural activation occurs through retrograde transmission, with their endogenous ligands being released from postsynaptic cells Kreutzer and Regehr, ; Ohno-Shosaku et al. For example, in rodents, the highest concentration of cannabinoid binding sites are in the basal ganglia and cerebellum , regions of the brain involved in the initiation and coordination of movement.
A recent analysis of cannabinoid binding in CB 1 and CB 2 receptor knockout mice found cannabinoid responsiveness even when these receptors were not being expressed, indicating that an additional binding receptor may be present in the brain.
CB1 has also been noted to form a functional human receptor heterodimer in orexin neurons with OX1 , the CB1—OX1 receptor, which mediates feeding behavior and certain physical processes such as cannabinoid-induced pressor responses which are known to occur through signaling in the rostral ventrolateral medulla.
During neurotransmission, the pre-synaptic neuron releases neurotransmitters into the synaptic cleft which bind to cognate receptors expressed on the post-synaptic neuron.
Based upon the interaction between the transmitter and receptor, neurotransmitters may trigger a variety of effects in the post-synaptic cell, such as excitation, inhibition, or the initiation of second messenger cascades. Based on the cell, these effects may result in the on-site synthesis of endogenous cannabinoids anandamide or 2-AG by a process that is not entirely clear, but results from an elevation in intracellular calcium.
This exclusion is based on synthesis-specific channel activation: Evidence suggests that the depolarization-induced influx of calcium into the post-synaptic neuron causes the activation of an enzyme called transacylase.
This enzyme is suggested to catalyze the first step of endocannabinoid biosynthesis by converting phosphatidylethanolamine , a membrane-resident phospholipid, into N -acyl-phosphatidylethanolamine NAPE.
Once released into the extracellular space by a putative endocannabinoid transporter, messengers are vulnerable to glial cell inactivation. Endocannabinoids are taken up by a transporter on the glial cell and degraded by fatty acid amide hydrolase FAAH , which cleaves anandamide into arachidonic acid and ethanolamine or monoacylglycerol lipase MAGL , and 2-AG into arachidonic acid and glycerol.
Such approaches could lead to the development of new drugs with analgesic, anxiolytic-like and antidepressant-like effects, which are not accompanied by overt signs of abuse liability. Cannabinoid receptors are G-protein coupled receptors located on the pre-synaptic membrane.
While there have been some papers that have linked concurrent stimulation of dopamine and CB 1 receptors to an acute rise in cyclic adenosine monophosphate cAMP production, it is generally accepted that CB 1 activation via cannabinoids causes a decrease in cAMP concentration by inhibition of adenylyl cyclase and a rise in the concentration of mitogen-activated protein kinase MAP kinase.
Results from rat hippocampal gene chip data after acute administration of tetrahydrocannabinol THC showed an increase in the expression of transcripts encoding myelin basic protein , endoplasmic proteins, cytochrome oxidase , and two cell adhesion molecules: In addition, CB1 activation has been demonstrated to increase the activity of transcription factors like c-Fos and Krox Graham et al.
The molecular mechanisms of CB 1 -mediated changes to the membrane voltage have also been studied in detail. Recent studies have found that CB 1 activation specifically facilitates potassium ion flux through GIRKs , a family of potassium channels. In the central nervous system , CB 1 receptors influence neuronal excitability, reducing the incoming synaptic input. CB 1 receptors then reduce the amount of neurotransmitter released, so that subsequent excitation in the presynaptic neuron results in diminished effects on the postsynaptic neuron.
It is likely that presynaptic inhibition uses many of the same ion channel mechanisms listed above, although recent evidence has shown that CB 1 receptors can also regulate neurotransmitter release by a non-ion channel mechanism, i.
Mice treated with tetrahydrocannabinol THC show suppression of long-term potentiation in the hippocampus, a process that is essential for the formation and storage of long-term memory.
One study found that the high-dose treatment of rats with the synthetic cannabinoid HU over several weeks resulted in stimulation of neural growth in the rats' hippocampus region, a part of the limbic system playing a part in the formation of declarative and spatial memories , but did not investigate the effects on short-term or long-term memory.
In the adult brain, the endocannabinoid system facilitates the neurogenesis of hippocampal granule cells.
The inhibitory effects of cannabinoid receptor stimulation on neurotransmitter release have caused this system to be connected to various forms of depressant plasticity. A recent study conducted with the bed nucleus of the stria terminalis found that the endurance of the depressant effects was mediated by two different signaling pathways based on the type of receptor activated.
Similar post-synaptic receptor dependencies were found in the striatum, but here both effects relied on presynaptic CB 1 receptors. By selectively internalizing different receptors, the brain may limit the production of specific endocannabinoids to favor a time scale in accordance with its needs. Evidence for the role of the endocannabinoid system in food-seeking behavior comes from a variety of cannabinoid studies.
Emerging data suggests that THC acts via CB 1 receptors in the hypothalamic nuclei to directly increase appetite. The amount of endocannabinoids produced is inversely correlated with the amount of leptin in the blood. A related study examined the effect of THC on the hedonic pleasure value of food and found enhanced dopamine release in the nucleus accumbens and increased pleasure-related behavior after administration of a sucrose solution.
While there is need for more research, these results suggest that cannabinoid activity in the hypothalamus and nucleus accumbens is related to appetitive, food-seeking behavior. The endocannabinoid system has been shown to have a homeostatic role by controlling several metabolic functions, such as energy storage and nutrient transport.
It acts on peripheral tissues such as adipocytes , hepatocytes , the gastrointestinal tract , the skeletal muscles and the endocrine pancreas. It has also been implied in modulating insulin sensitivity.
Through all of this, the endocannabinoid system may play a role in clinical conditions, such as obesity , diabetes , and atherosclerosis , which may also give it a cardiovascular role.
While the secretion of glucocorticoids in response to stressful stimuli is an adaptive response necessary for an organism to respond appropriately to a stressor, persistent secretion may be harmful. The endocannabinoid system has been implicated in the habituation of the hypothalamic-pituitary-adrenal axis HPA axis to repeated exposure to restraint stress. Studies have demonstrated differential synthesis of anandamide and 2-AG during tonic stress.
A decrease of anandamide was found along the axis that contributed to basal hypersecretion of corticosterone ; in contrast, an increase of 2-AG was found in the amygdala after repeated stress, which was negatively correlated to magnitude of the corticosterone response. All effects were abolished by the CB 1 antagonist AM , supporting the conclusion that these effects were cannabinoid-receptor dependent.
These contrasting effects reveal the importance of the endocannabinoid system in regulating anxiety -dependent behavior. Results suggest that glutamatergic cannabinoid receptors are not only responsible for mediating aggression, but produce an anxiolytic-like function by inhibiting excessive arousal: In contrast, GABAergic neurons appear to control an anxiogenic-like function by limiting inhibitory transmitter release.
Taken together, these two sets of neurons appear to help regulate the organism's overall sense of arousal during novel situations. Evidence suggests that endocannabinoids may function as both neuromodulators and immunomodulators in the immune system. Here, they seem to serve an autoprotective role to ameliorate muscle spasms, inflammation, and other symptoms of multiple sclerosis and skeletal muscle spasms.
These receptors have also been implicated in the proper migration of B cells into the marginal zone MZ and the regulation of healthy IgM levels. Historical records from ancient China and Greece suggest that preparations of Cannabis indica were commonly prescribed to ameliorate multiple sclerosis-like symptoms such as tremors and muscle pain.
Modern research has confirmed these effects in a study on diseased mice, wherein both endogenous and exogenous agonists showed ameliorating effects on tremor and spasticity.
It remains to be seen whether pharmaceutical preparations such as dronabinol have the same effects in humans. Taken together, these studies point to the exciting possibility that cannabinoid treatment may not only be able to attenuate the symptoms of multiple sclerosis but also improve oligodendrocyte function reviewed in Pertwee, ; Mollna-Holgado et al.
The developing embryo expresses cannabinoid receptors early in development that are responsive to anandamide secreted in the uterus. This signaling is important in regulating the timing of embryonic implantation and uterine receptivity. In mice, it has been shown that anandamide modulates the probability of implantation to the uterine wall.
For example, in humans, the likelihood of miscarriage increases if uterine anandamide levels are too high or low. Peripheral expression of cannabinoid receptors led researchers to investigate the role of cannabinoids in the autonomic nervous system. Research found that the CB 1 receptor is expressed presynaptically by motor neurons that innervate visceral organs. Cannabinoid-mediated inhibition of electric potentials results in a reduction in noradrenaline release from sympathetic nervous system nerves.
Other studies have found similar effects in endocannabinoid regulation of intestinal motility, including the innervation of smooth muscles associated with the digestive, urinary, and reproductive systems. At the spinal cord, cannabinoids suppress noxious-stimulus-evoked responses of neurons in the dorsal horn, possibly by modulating descending noradrenaline input from the brainstem.
The endocannabinoid most researched in pain is palmitoylethanolamide. Palmitoylethanolamide is a fatty amine related to anandamide, but saturated and although initially it was thought that palmitoylethanolamide would bind to the CB1 and the CB2 receptor, later it was found that the most important receptors are the PPAR-alpha receptor , the TRPV receptor and the GPR55 receptor.
Palmitoylethanolamide has been evaluated for its analgesic actions in a great variety of pain indications  and found to be safe and effective. Basically these data are proof of concept for endocannabinoids and related fatty amines to be therapeutically useful analgesics; palmitoylethanolamide is available under the brand names Normast and PeaPure as nutraceuticals. Endocannabinoids are involved in placebo induced analgesia responses. Increased endocannabinoid signaling within the central nervous system promotes sleep-inducing effects.
Intercerebroventricular administration of anandamide in rats has been shown to decrease wakefulness and increase slow-wave sleep and REM sleep. Anandamide is an endogenous cannabinoid neurotransmitter that binds to cannabinoid receptors. In mice it was demonstrated that certain features of a runner's high depend on cannabinoid receptors. Pharmacological or genetic disruption of cannabinoid signaling via cannabinoid receptors prevents the analgesic and anxiety-reducing effects of running.
Neuroscientists often utilize transgenic CB 1 knockout mice to discern novel roles for the endocannabinoid system. While CB 1 knockout mice are healthy and live into adulthood, there are significant differences between CB 1 knockout and wild-type mice. When subjected to a high-fat diet, CB 1 knockout mice tend to be about sixty percent leaner and slightly less hungry than wildtype.
The endocannabinoid system is by molecular phylogenetic distribution of apparently ancient lipids in the plant kingdom, indicative of biosynthetic plasticity and potential physiological roles of endocannabinoid-like lipids in plants,  and detection of arachidonic acid AA indicates chemotaxonomic connections between monophyletic groups with common ancestor dates to around million years ago silurian ; devonian.
From Wikipedia, the free encyclopedia.
There was a problem providing the content you requested
Humans and animals alike naturally synthesize endocannabinoids, chemical compounds that activate the same receptors as. And the same endocannabinoid system that translates marijuana's buzz-inducing compounds into a high plays crucial roles in health and. The endocannabinoid system is found throughout the brain and nervous system and is involved with things like appetite, pain modulation.