Tag Archives: Cannabinoids

Cannabis anti-convulsant shakes up epilepsy treatment

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 by Douglas Heaven

“The versatile cannabis plant may have a new use: it could be used to control epileptic seizures with fewer side effects than currently prescribed anti-convulsants.

Ben Whalley at the University of Reading, UK, and colleagues worked with GW Pharmaceuticals in Wiltshire, UK, to investigate the anti-convulsant properties of cannabidivarin (CBDV), a little-studied chemical found in cannabis and some other plants.

There is “big, historical, anecdotal evidence” that cannabinoids can be used to control human seizures, says Whalley, but the “side-effect baggage” means there have been relatively few studies of its pharmaceutical effect on this condition.

The team investigated the effectiveness of CBDV – one of around 100 non-psychoactive cannabinoids found in cannabis – as an anti-convulsant. They induced seizures in live rats and mice that had been given the drug. These animals experienced less severe seizures and lower mortality compared with animals given a placebo. The drug also had fewer side effects and was better tolerated than three of the most widely prescribed anticonvulsants.

Epileptic seizures affect about one per cent of the population. Left uncontrolled, they can lead to depression, cognitive decline and death. If you control the seizures, says Whalley, “the chances of death drop away completely”. The decision about whether to test the drug in humans will be made next year.

“This is a very positive result,” says Ley Sander, an epilepsy specialist at University College London, UK, who was not involved in the study. “We need new drugs,” he says. “For 20-30 per cent of people with epilepsy, nothing seems to work.”

But he urges caution. “The animals in the study are made epileptic,” he says, which is not how epilepsy is acquired in humans. He adds that what you see in animal models doesn’t always translate directly into humans.

“Most compounds showing promise in preclinical studies never reach market,” warns Mark Richardson of the Epilepsy Research Group at King’s College London. “But I agree that these results justify progressing further down the drug development pipeline.””

http://www.newscientist.com/article/dn22263-cannabis-anticonvulsant-shakes-up-epilepsy-treatment.html

Effects of marihuana cannabinoids on seizure activity in cobalt-epileptic rats.

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Abstract

“Rats rendered chronically epileptic by bilateral implantation of cobalt into frontal cortices were simultaneously prepared with permanent electrodes for longitudinal recording of the electroencephalogram (EEG) and electromyogram (EMG). Delta-8-tetrahydrocannabinol (delta-8-THC; 10 mg/kg), delta-9-tetrahydrocannabinol (delta-9-THC; 10 mg/kg), cannabidiol (CBD; 60 mg/kg), or polyvinylpyrrolidone (PVP) vehicle (2 ml/kg) was administered IP twice daily from day 7 through 10 after cobalt implantation, at which time generalized seizure activity in non-treated cobalt-epileptic rats was maximal. Relative to PVP-treated controls, CBD did not alter the frequency of appearance of seizures during the course of repeated administration. In contrast, both delta-8-THC and delta-9-THC markedly reduced the incidence of seizures on the first and second days of administration. Interictal spiking during this period, on the other hand, was actually enhanced. On the third and fourth days, tolerance to the effect on seizures was evident, with a return of seizure frequency of THC-treated rats to values not significantly different from those of controls. Unlike the effect on seizures, no tolerance developed to the marked suppression of rapid eye movement (REM) sleep induces by delta-8-THC and delta-9-THC. REM sleep remained reduced in the treated animals during the first 2 days after termination of THC administration. In contrast, REM sleep time was unaffected by repeated administration of CBD. These results suggest that delta-8-THC and delta-9-THC exert their initial anticonvulsant effect by limiting the spread of epileptogenic activity originating from the cobalt focus.”

http://www.ncbi.nlm.nih.gov/pubmed/6280204

On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures.

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Abstract

“Neurons intensively exchange information among each other using both inhibitory and excitatory neurotransmitters. However, if the balance of excitation and inhibition is perturbed, the intensity of excitatory transmission may exceed a certain threshold and epileptic seizures can occur. As the occurrence of epilepsy in the human population is about 1%, the search for therapeutic targets to alleviate seizures is warranted. Extracts of Cannabis sativa have a long history in the treatment of various neurological diseases, including epilepsy. However, cannabinoids have been reported to exert both pro- and anti-convulsive activities. The recent progress in understanding the endogenous cannabinoid system has allowed new insights into these opposing effects of cannabinoids. When excessive neuronal activity occurs, endocannabinoids are generated on demand and activate cannabinoid type 1 (CB1) receptors. 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, are anti- or pro-convulsive, depending on the seizure model used. The pro-convulsive activity of exogenous cannabinoids might be explained by the notion 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. The concept that the endogenous cannabinoid system is activated on demand suggests that a promising strategy to alleviate seizure frequency is the enhancement of endocannabinoid levels by inhibiting the cellular uptake and the degradation of these endogenous compounds.”

http://www.ncbi.nlm.nih.gov/pubmed/15450934

The Endocannabinoid System Controls Key Epileptogenic Circuits in the Hippocampus

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“Balanced control of neuronal activity is central in maintaining function and viability of neuronal circuits. The endocannabinoid system tightly controls neuronal excitability. Here, we show that endocannabinoids directly target hippocampal glutamatergic neurons to provide protection against acute epileptiform seizures in mice. Functional CB1 cannabinoid receptors are present on glutamatergic terminals of the hippocampal formation, colocalizing with vesicular glutamate transporter 1 (VGluT1). Conditional deletion of the CB1 gene either in cortical glutamatergic neurons or in forebrain GABAergic neurons, as well as virally induced deletion of the CB1 gene in the hippocampus, demonstrate that the presence of CB1 receptors in glutamatergic hippocampal neurons is both necessary and sufficient to provide substantial endogenous protection against kainic acid (KA)-induced seizures. The direct endocannabinoid-mediated control of hippocampal glutamatergic neurotransmission may constitute a promising therapeutic target for the treatment of disorders associated with excessive excitatory neuronal activity.”

“In conclusion, our study reveals a mechanism through which the endocannabinoid system is able to provide on-demand protection against acute behavioral seizures. CB1 expression on hippocampal glutamatergic circuits accounts for this protection and might represent a suitable target for the treatment of neurological disorders associated with excessive neuronal excitation.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1769341/

The Endogenous Cannabinoid System Regulates Seizure Frequency and Duration in a Model of Temporal Lobe Epilepsy

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“Several lines of evidence suggest that cannabinoid compounds are anticonvulsant. However, the anticonvulsant potential of cannabinoids and, moreover, the role of the endogenous cannabinoid system in regulating seizure activity has not been tested in an in vivo model of epilepsy that is characterized by spontaneous, recurrent seizures. Here, using the rat pilocarpine model of epilepsy, we show that the marijuana extract Δ9-tetrahydrocannabinol (10 mg/kg) as well as the cannabimimetic, 4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-i,j]quinolin-6-one [R(+)WIN55,212 (5 mg/kg)], completely abolished spontaneous epileptic seizures. Conversely, application of the cannabinoid CB1 receptor (CB1) antagonist, N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A), significantly increased both seizure duration and frequency. In some animals, CB1 receptor antagonism resulted in seizure durations that were protracted to a level consistent with the clinical condition status epilepticus… These data indicate not only anticonvulsant activity of exogenously applied cannabinoids but also suggest that endogenous cannabinoid tone modulates seizure termination and duration through activation of the CB1 receptor… By demonstrating a role for the endogenous cannabinoid system in regulating seizure activity, these studies define a role for the endogenous cannabinoid system in modulating neuroexcitation and suggest that plasticity of the CB1 receptor occurs with epilepsy.”

“Characterized by spontaneously recurrent seizures, epilepsy is one of the most common neurological conditions. Understanding the factors that contribute to seizure initiation and termination has important implications for our ability to treat epilepsy and for the potential development of novel anticonvulsant agents. Previous evidence has suggested that the endogenous cannabinoid system may be a novel locus of anticonvulsant activity in the brain. Using the maximal electroshock model of short-term seizure, our laboratory determined that cannabinoid compounds block seizure spread via a cannabinoid CB1 receptor-dependent mechanism. Further study revealed that application of a CB1 receptor antagonist lowered the electroshock seizure threshold, indicating that elimination of endogenous cannabinoid tone at the CB1 receptor may increase seizure susceptibility.”

“The CB1 receptor is the most highly expressed G-protein-coupled receptor in brain and has been implicated in regulation of neuronal excitability. The endogenous cannabinoids, arachidonylethanolamine and 2-arachidonylglycerol (2-AG), are synthesized “on demand” in response to sustained neuronal depolarization and elevated intracellular calcium levels; both of these events occur with seizure activity. The neuronal hyperexcitability that accompanies seizure discharge may stimulate endogenous cannabinoid synthesis and subsequently result in CB1 receptor activation. In light of cannabinoid effects on neurotransmission, increased CB1 receptor activation could influence seizure activity. However, no studies have evaluated the role of the endogenous cannabinoid system in an intact model of epilepsy.”

“This study was initiated to evaluate the role of the CB1 receptor and the endogenous cannabinoid system in regulating seizure activity in a long-term model of epilepsy. We used the pilocarpine model of temporal lobe, partial-complex epilepsy; a rat model of acquired, refractory epilepsy that produces spontaneous recurrent seizures for the lifetime of the animal. The pilocarpine model has been shown to closely resemble human refractory partial-complex epilepsy. In this study, seizure frequency and duration were determined by continuous electrographic and video recording of each epileptic animal. The CB1 receptor agonists R(+)WIN55,212 and Δ9-tetrahydrocannabinol (THC) were evaluated for anticonvulsant efficacy. In addition to agonist effects on seizure activity, the effect of CB1 receptor antagonism on seizure frequency and duration was evaluated using the specific antagonist SR141716A. Hippocampal levels of 2-AG during short-term, pilocarpine-induced seizures were measured to determine whether a correlation exists between endogenous cannabinoid synthesis and seizure activity. In addition, Western blot and immunohistochemical analyses were used to evaluate hippocampal CB1 receptor protein expression in the brains of chronically epileptic and sham control rats. The findings presented suggest an anticonvulsant role for the endogenous cannabinoid system and demonstrate that long-term plasticity of the CB1 receptor occurs with epilepsy.”

“Therapeutic Implications for Cannabinoids in the Treatment of Epilepsy. Seizures in patients with refractory, partial-complex epilepsy can be difficult to control despite the use of currently available anticonvulsant medications and surgical interventions. Therefore, there is a clear need for the development of more effective anticonvulsant agents. Some epilepsy patients, seeking alternative treatments, have perceived improvement with marijuana. This has prompted several countries to consider the legalization of marijuana for epilepsy treatment. The pilocarpine model represents a refractory epileptic condition that is not readily treated by conventional anticonvulsants. Our results demonstrate that activation of the CB1 receptor by cannabinoid drugs and possibly endogenous ligands significantly alters seizure activity and is more effective than conventional anticonvulsants in treating the refractory seizures produced in the pilocarpine model. Although the dose dependence and long-term effects of cannabinoid administration on epilepsy must be further investigated, the results presented here provide evidence that warrants a comprehensive assessment of cannabinoid use in the control of refractory epilepsy via the use of animal models and placebo-controlled clinical trials. Although the psychoactive side effects of cannabinoids make their use in the treatment of epilepsy impractical, understanding the mechanisms of endogenous cannabinoid-mediated anticonvulsant action may lead to the development of novel compounds that do not manifest behavioral toxicity. Further investigation of the cannabinoid anticonvulsant phenomenon may illuminate novel therapeutic targets for the treatment of temporal lobe epilepsy as well as more clearly define the physiological function of the endogenous cannabinoid system in brain.”

http://jpet.aspetjournals.org/content/307/1/129.long

Marijuana, endocannabinoids, and epilepsy: Potential and challenges for improved therapeutic intervention.

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Abstract

  “Phytocannabinoids isolated from the cannabis plant have broad potential in medicine that has been well recognized for many centuries. It is presumed that these lipid soluble signaling molecules exert their effects in both the central and peripheral nervous system in large part through direct interaction with metabotropic cannabinoid receptors. These same receptors are also targeted by a variety of endogenous cannabinoids including 2-arachidonoyl glycerol and anandamide. Significant effort over the last decade has produced an enormous advance in our understanding of both the cellular and the synaptic physiology of endogenous lipid signaling systems. This increase in knowledge has left us better prepared to carefully evaluate the potential for both natural and synthetic cannabinoids in the treatment of a variety of neurological disorders. In the case of epilepsy, long standing interest in therapeutic approaches that target endogenous cannabinoid signaling systems are, for the most part, not well justified by available clinical data from human epileptics. Nevertheless, basic science experiments have clearly indicated a key role for endogenous cannabinoid signaling systems in moment to moment regulation of neuronal excitability. Further it has become clear that these systems can both alter and be altered by epileptiform activity in a wide range of in vitro and in vivo models of epilepsy. Collectively these observations suggest clear potential for effective therapeutic modulation of endogenous cannabinoid signaling systems in the treatment of human epilepsy, and in fact, further highlight key obstacles that would need to be addressed to reach that goal.”

http://www.ncbi.nlm.nih.gov/pubmed/22178327

Convulsions associated with the use of a synthetic cannabinoid product.

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Abstract

“INTRODUCTION:

Clinical presentations following the use of various “spice” or synthetic cannabinoids have included agitation, anxiety, emesis, hallucinations, psychosis, tachycardia, and unresponsiveness. Convulsions were described in a one report although there was not laboratory confirmation for synthetic cannabinoids. In another published report laboratory confirmation for a synthetic cannabinoid was done in which the patient manifested activity that was interpreted as a possible convulsion.

CASE REPORT:

We describe a patient who had two witnessed generalized convulsions soon after smoking a “spice” product that we later confirmed to have four different synthetic cannabinoids.

DISCUSSION:

Convulsions have only rarely been associated with marijuana exposures. Recreational use of synthetic cannabinoids is a very recent phenomenon and there is a very limited, albeit burgeoning, literature detailing the associated complications including convulsions we have reported here. The absence of anticonvulsant phytocannabinoids in spice products could potentially be one of multiple unknown mechanisms contributing to convulsions.”

http://www.ncbi.nlm.nih.gov/pubmed/22160733

The cannabinoid acids: nonpsychoactive derivatives with therapeutic potential.

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Abstract

   “The discovery of carboxylic acid metabolites of the cannabinoids (CBs) dates back more than three decades. Their lack of psychotropic activity was noted early on, and this resulted in a total absence of further research on their possible role in the actions of the CBs. More recent studies have revealed that the acids possess both analgesic and anti-inflammatory properties and may contribute to the actions of the parent drug. A synthetic analog showed similar actions at considerably lower doses. In this review, a brief survey of the extensive literature on metabolism of delta 9-tetrahydrocannabinol to the acids is presented, while more emphasis is given to the recent findings on the biological actions of this class of CBs. A possible mechanism involving effects on eicosanoids for some of these actions is also suggested. Finally, an analogy with a putative metabolite of anandamide, an endogenous CB, is discussed.”

http://www.ncbi.nlm.nih.gov/pubmed/10341359

Suppression of human monocyte interleukin-1beta production by ajulemic acid, a nonpsychoactive cannabinoid.

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Abstract

   “Oral administration of ajulemic acid (AjA), a cannabinoid acid devoid of psychoactivity, reduces joint tissue damage in rats with adjuvant arthritis. Because interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNFalpha) are central to the progression of inflammation and joint tissue injury in patients with rheumatoid arthritis, we investigated human monocyte IL-1beta and TNFalpha responses after the addition of AjA to cells in vitro… Reduction of IL-1beta by AjA may help explain the therapeutic effects of AjA in the animal model of arthritis. Development of nonpsychoactive therapeutically useful synthetic analogs of Cannabis constituents, such as AjA, may help resolve the ongoing debate about the use of marijuana as medicine.”

http://www.ncbi.nlm.nih.gov/pubmed/12566094

Cannabimimetic Properties of Ajulemic Acid

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   “Side effects of marijuana-based drugs and synthetic analogs of Δ9-tetrahydrocannabinol (Δ9-THC), including sedation and dysphoria, have limited their therapeutic application. Ajulemic acid (AJA), a side-chain synthetic analog of Δ8-THC-11-oic acid, has been reported to have anti-inflammatory properties without producing undesired psychoactive effects. Moreover, it has been suggested that AJA does not interact with cannabinoid receptors to produce its pharmacological effects. The aim of the present study was to conduct a thorough evaluation of the pharmacological effects of AJA then to determine whether actions at cannabinoid receptor (CB)1 mediated these effects… These studies demonstrated that AJA shares a number of CB1-mediated pharmacological properties with Δ9-THC, including cannabimimetic, discriminative stimulus, and antihyperalgesic effects. Furthermore, a separation between doses that produced antinociception and those that produced the other pharmacological effects in mice was not observed. Moreover, AJA showed nearly equipotency for therapeutic efficacy in the CFA model and for substitution in Δ9-THC discrimination. In summary, this study shows that AJA, like Δ9-THC, exhibits psychoactive and therapeutic effects at nearly equal doses in preclinical models, suggesting similar limitations in their putative therapeutic profiles.”

“Cannabis sativa (marijuana plant) has been used since antiquity for its presumed therapeutic, as well as for its euphoric effects. Although Δ9-tetrahydrocannabinol (Δ9-THC) has been identified as the major psychoactive ingredient in C. sativa, difficulty in dissociating unwanted side effects, such as sedation and psychotropic effects, from therapeutic effects has limited clinical application of Δ9-THC-based drugs. For example, dronabinol, an orally administered synthetic version of Δ9-THC, has been developed as an appetite stimulant and antiemetic for use in chronic diseases such as AIDS and cancer. In addition, recent evidence suggests oral Δ9-THC may be effective as an adjunct to opioid analgesics. The therapeutic utility of Δ9-THC, however, has been limited due to patient complaints of dysphoria and unpleasant subjective effects. Previous research has suggested that Δ9-THC carboxylic acid, one of the acid metabolites of Δ9-THC, lacks psychoactive properties of the parent compound and yet retains antinociceptive and other effects. Since this metabolite has a relatively low potency, structural changes that increased potency and stability of Δ9-THC analogs in previous structure-activity relationship studies were applied to the structure Δ9-THC carboxylic acid. The resulting compound, ajulemic acid (AJA), substitutes a 1′,1-dimethylheptyl side chain for the pentyl group of Δ9-THC and changes the Δ9-THC core structure to a more stable confirmation, Δ8-THC (Fig. 1).”

Fig. 1

 
“To date, the efficacy of AJA has been demonstrated in numerous pain and inflammation studies…”
 
“These findings also underscore the importance of thoroughly evaluating the pharmacological characteristics of novel Δ9-THC-like compounds…”