Tag Archives: marijuana

Marijuana use and epilepsy: prevalance in patients of a tertiary care epilepsy center.

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Abstract

“The authors sought to determine the prevalence of marijuana use in patients with epilepsy by performing a telephone survey in a tertiary care epilepsy center. Twenty-one percent of subjects had used marijuana in the past year with the majority of active users reporting beneficial effects on seizures. Twenty-four percent of all subjects believed marijuana was an effective therapy for epilepsy. Despite limited evidence of efficacy, many patients with epilepsy believe marijuana is an effective therapy for epilepsy and are actively using it.”

http://www.ncbi.nlm.nih.gov/pubmed/15184622

Endocannabinoids and Their Implications for Epilepsy

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“This review covers the main features of a newly discovered intercellular signaling system in which endogenous ligands of the brain’s cannabinoid receptors, or endocannabinoids, serve as retrograde messengers that enable a cell to control the strength of its own synaptic inputs. Endocannabinoids are released by bursts of action potentials, including events resembling interictal spikes, and probably by seizures as well. Activation of cannabinoid receptors has been implicated in neuroprotection against excitotoxicity and can help explain the anticonvulsant properties of cannabinoids that have been known since antiquity.”

“Cannabis in its various forms, including marijuana and hashish, is produced from the flowers and leaves of the hemp plant, Cannabis sativa. Through their primary psychoactive ingredient, Δ9-tetrahydrocannabinol (THC), these drugs affect the central nervous system by activating specific membrane-bound receptors. The primary brain receptors, cannabinoid receptors type 1 (CB1), are G protein–coupled, seven-transmembrane domain proteins that share numerous similarities with heterotrimeric G protein–coupled receptors for conventional neurotransmitters such as γ-aminobutyric acid (GABA) and glutamate. The CB1s bind THC with a high degree of selectivity and are heterogeneously distributed throughout the brain. Inasmuch as THC is a plant-derived compound not produced in mammals, endogenous ligands must exist for the cannabinoid receptor, that is, endocannabinoids. Indeed, several endogenous ligands for CB1 have been discovered, with anandamide being the first. Anandamide and 2-arachidonoyl glycerol (2-AG), are thought to be the major brain endocannabinoids, with regional differences in which one or the other predominates. Endocannabinoids have been strongly implicated in a growing variety of physiologic phenomena, including regulation of eating, anxiety, pain, extinction of aversive memories, and neuroprotection. Potent agonists and antagonists for CB1 exist and may serve as the foundation of new therapeutic strategies for treating pathologies. The voluminous work summarized here has been extensively covered in recent reviews on cannabinoid neurochemistry and pharmacology as well as neurophysiology. This review focuses on the neurophysiology of the endocannabinoid systems.”

“Conclusion

From what is known about their synthesis and release, endocannabinoids should be produced under many conditions of increased neuronal excitability and specific intercellular signaling. For example, an epileptic seizure, with its large swings in transmembrane voltage, increases in intracellular calcium, and marked release of neurotransmitters, such as acetylcholine and glutamate, should prominently release endocannabinoids. Indeed, seizures induced by kainic acid (a glutamate agonist) increase hippocampal levels of anandamide in normal and wild-type mice. Intriguingly, CB1 knockout mice and normal mice treated with a CB1 antagonist had more pronounced seizures and more severe excitotoxic cell death than untreated normal mice. Although the detailed mechanisms of neuroprotection have not been worked out, the rapid increases in expression of the immediate early genes, c-fos and zipf268, and subsequent increase in brain-derived neurotrophic factor (BDNF) normally induced by kainic acid, were absent in the CB1 knockout mice. The results complement previous evidence that exogenous cannabinoids can be neuroprotective and show that CB1 activation by seizure-induced release of endocannabinoids also is normally neuroprotective.”

“The important new directions being opened by investigations of endocannabinoids underscore the prescient opinion of Robert Christison, who, in 1848, noting its various beneficial effects, argued that cannabis “is a remedy which deserves a more extensive inquiry…””

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1176361/

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

Marijuana: an effective antiepileptic treatment in partial epilepsy? A case report and review of the literature.

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Abstract

“Although more data are needed, animal studies and clinical experience suggest that marijuana or its active constituents may have a place in the treatment of partial epilepsy. Here we present the case of a 45-year-old man with cerebral palsy and epilepsy who showed marked improvement with the use of marijuana. This case supports other anecdotal data suggesting that marijuana use may be a beneficial adjunctive treatment in some patients with epilepsy. Although challenging because of current federal regulations, further studies are needed to examine the role of marijuana in the treatment of this disorder.”

http://www.ncbi.nlm.nih.gov/pubmed/17609644

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

Marijuana-Derived Compound Targets Pain, Inflammation

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   “Researchers are developing a marijuana-derived synthetic compound to relieve pain and inflammation without the mood-altering side effects associated with other marijuana based drugs.

  They say the compound could improve treatment of a variety of conditions, including chronic pain, arthritis and multiple sclerosis. Their findings were presented at the 224th national meeting of the American Chemical Society, the world’s largest scientific society.

   The compound, called ajulemic acid, has produced encouraging results in animal studies of pain and inflammation. It is undergoing tests in a group of people with chronic pain and could be available by prescription within two to three years, the researchers say.

 “We believe that [the compound] will replace aspirin and similar drugs in most applications primarily because of a lack of toxic side effects,” says Sumner Burstein, Ph.D., lead investigator in the study and a professor in the department of biochemistry and molecular pharmacology at the University of Massachusetts Medical School in Worcester. “The indications so far are that it’s safe and effective,” he added.”

Read more: http://www.sciencedaily.com/releases/2002/08/020822071026.htm

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…”
 

Activation and Binding of Peroxisome Proliferator-Activated Receptor γ by Synthetic Cannabinoid Ajulemic Acid

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   “Ajulemic acid (AJA) is a synthetic analog of the tetrahydrocannabinol (THC) metabolite THC-11-oic acid; THC is a major active ingredient of the drug marijuana derived from the plant cannabis. AJA has potent analgesic and anti-inflammatory activity without the psychotropic action of THC. Unlike the nonsteroidal anti-inflammatory drugs, AJA is not ulcerogenic at therapeutic doses, making it a promising anti-inflammatory drug. However, the mechanism of AJA action remains unknown. Here we report that AJA binds directly and specifically to the peroxisome proliferator-activated receptor γ (PPARγ), a pharmacologically important member of the nuclear receptor superfamily. Functional assay indicates that AJA activates the transcriptional activity of both human and mouse PPARγ at pharmacological concentrations. Activation of PPARγ by AJA requires the AF-2 helix of the receptor, suggesting that AJA activates PPARγ through the ligand-dependent AF-2 function. AJA binding consistently enables PPARγ to recruit nuclear receptor coactivators. In addition, we show that AJA inhibits interleukin-8 promoter activity in a PPARγ-dependent manner, suggesting a link between the anti-inflammatory action of AJA and the activation of PPARγ. Finally, we find that AJA treatment induces differentiation of 3T3 L1 fibroblasts into adipocytes, a process mediated by PPARγ. Together, these data indicate that PPARγ may be a molecular target for AJA, providing a potential mechanism for the anti-inflammatory action of AJA, and possibly other cannabinoids. These studies also implicate other potential therapeutic actions of AJA through PPARγ activation in multiple signaling pathways.”

“The mood-altering drug marijuana derived from the hemp plant Cannabis sativa contains a group of biosynthetically related substances known collectively as cannabinoids. Tetrahydrocannabinol (THC), one of the major cannabinoids in marijuana, has potent analgesic and anti-inflammatory activities, but it also exhibits psychotropic effects, which limit its clinical application. Considerable effort has been expended toward the goal of creating nonpsychotropic cannabinoid derivatives that retain therapeutic actions but are free of psychotropic activity. A useful template for this search is the THC metabolite THC-11-oic acid…”

http://molpharm.aspetjournals.org/content/63/5/983.long