Author Archives: David Worrell

Amyotrophic lateral sclerosis: delayed disease progression in mice by treatment with a cannabinoid.

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Abstract

“Effective treatment for amyotrophic lateral sclerosis (ALS) remains elusive. Two of the primary hypotheses underlying motor neuron vulnerability are susceptibility to excitotoxicity and oxidative damage. There is rapidly emerging evidence that the cannabinoid receptor system has the potential to reduce both excitotoxic and oxidative cell damage. Here we report that treatment with Delta(9)-tetrahydrocannabinol (Delta(9)-THC) was effective if administered either before or after onset of signs in the ALS mouse model (hSOD(G93A) transgenic mice). Administration at the onset of tremors delayed motor impairment and prolonged survival in Delta(9)-THC treated mice when compared to vehicle controls. In addition, we present an improved method for the analysis of disease progression in the ALS mouse model. This logistic model provides an estimate of the age at which muscle endurance has declined by 50% with much greater accuracy than could be attained for any other measure of decline. In vitro, Delta(9)-THC was extremely effective at reducing oxidative damage in spinal cord cultures. Additionally, Delta(9)-THC is anti-excitotoxic in vitro. These cellular mechanisms may underlie the presumed neuroprotective effect in ALS. As Delta(9)-THC is well tolerated, it and other cannabinoids may prove to be novel therapeutic targets for the treatment of ALS.”

http://www.ncbi.nlm.nih.gov/pubmed/15204022

Cannabis May Extend Life Expectancy Of Lou Gehrig’s Disease Patients, Study Says

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Cannabis therapy may reduce symptoms and prolong survival in patients diagnosed with amyotrophic lateral sclerosis (ALS aka Lou Gehrig’s disease), according to a scientific review published online last week by the American Journal of Hospice & Palliative Medicine.

Investigators at the University of Washington Medical Center in Seattle and Temple University in Pennsylvania reviewed preclinical and anecdotal data indicating that marijuana appears to treat symptoms of ALS as well as moderate the course of the disease.

Authors wrote: “Preclinical data indicate that cannabis has powerful antioxidative, anti-inflammatory, and neuroprotective effects. … Cannabis also has properties applicable to symptom management of ALS, including analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. … From a pharmacological perspective, cannabis is remarkably safe with realistically no possibility of overdose or frank physical addiction. There is a valid, logical, scientifically grounded rationale to support the use of cannabis in the pharmacological management of ALS.”

They added, “Based on the currently available scientific data, it is reasonable to think that cannabis might significantly slow the progression of ALS, potentially extending life expectancy and substantially reducing the overall burden of the disease.”

Investigators concluded, “There is an overwhelming amount of preclinical and clinical evidence to warrant initiating a multicenter randomized, double-blind, placebo-controlled trial of cannabis as a disease-modifying compound in ALS.”

Writing in the March 2004 issue of the journal Amyotrophic Lateral Sclerosis & Other Motor Neuron Disorders, investigators at the California Pacific Medical Center in San Francisco reported that the administration of THC both before and after the onset of ALS symptoms staved disease progression and prolonged survival in animals compared to untreated controls. To date, however, no clinical trials have assessed the use of marijuana or any of the plant’s cannabinoids on patients diagnosed with ALS.

Lou Gehrig’s Disease is a fatal, progressive neurodegenerative disorder that is characterized by the selective loss of motor neurons in the spinal cord, brain stem, and motor cortex. An estimated 30,000 Americans are living with ALS, which often arises spontaneously and afflicts otherwise healthy adults. An estimated 70 to 80 percent of patients with ALS die within three to five years following the onset of disease symptoms.”

By: Paul Armentano, NORML Deputy Director

http://www.medicann.com/conditions-and-diseases/cannabis-may-extend-life-expectancy-of-lou-gehrig%e2%80%99s-disease-patients-study-says/

Article originally available at: http://blog.norml.org/2010/05/19/marijuana-may-extend-life-expectancy-of-lou-gehrig’s-disease-patients-study-says/

 

Survey of cannabis use in patients with amyotrophic lateral sclerosis.

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Abstract

“Cannabis (marijuana) has been proposed as treatment for a widening spectrum of medical conditions and has many properties that may be applicable to the management of amyotrophic lateral sclerosis (ALS). This study is the first, anonymous survey of persons with ALS regarding the use of cannabis. There were 131 respondents, 13 of whom reported using cannabis in the last 12 months. Although the small number of people with ALS that reported using cannabis limits the interpretation of the survey findings, the results indicate that cannabis may be moderately effective at reducing symptoms of appetite loss, depression, pain, spasticity, and drooling. Cannabis was reported ineffective in reducing difficulties with speech and swallowing, and sexual dysfunction. The longest relief was reported for depression (approximately two to three hours).”

http://www.ncbi.nlm.nih.gov/pubmed/15055508

Cannabinol delays symptom onset in SOD1 (G93A) transgenic mice without affecting survival.

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Abstract

“Therapeutic options for amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disorder, remain limited. Emerging evidence from clinical studies and transgenic mouse models of ALS suggests that cannabinoids, the bioactive ingredients of marijuana (Cannabis sativa) might have some therapeutic benefit in this disease. However, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the predominant cannabinoid in marijuana, induces mind-altering effects and is partially addictive, compromising its clinical usefulness. We therefore tested whether cannabinol (CBN), a non-psychotropic cannabinoid, influences disease progression and survival in the SOD1 (G93A) mouse model of ALS. CBN was delivered via subcutaneously implanted osmotic mini-pumps (5 mg/kg/day) over a period of up to 12 weeks. We found that this treatment significantly delays disease onset by more than two weeks while survival was not affected. Further research is necessary to determine whether non-psychotropic cannabinoids might be useful in ameliorating symptoms in ALS.”

http://www.ncbi.nlm.nih.gov/pubmed/16183560

Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice.

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“Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of motoneurons in the spinal cord, brain stem, and motor cortex. However, despite intensive research, an effective treatment for this disease remains elusive. In this study we show that treatment of postsymptomatic, 90-day-old SOD1G93A mice with a synthetic cannabinoid, WIN55,212-2, significantly delays disease progression…

Increasing evidence suggests that cannabinoids might have therapeutic potential in neurodegenerative conditions. In a variety of in vivo and in vitro models, cannabinoids exert neuroprotective effects under excitotoxic, ischemic, and inflammatory conditions. This combination of neuroprotective actions might be particularly relevant to ALS and suggests that cannabinoids might have a greater impact on disease progression than the established therapy that targets excitotoxicity alone.

… the neuroprotective effects observed following pharmacological and genetic augmentation of cannabinoid levels are not necessarily mediated by the CB1 receptor, and indeed inhibition of the CB1 receptor might actually be neuroprotective. Therefore, in contrast to previous studies that have suggested that cannabinoids exert neuroprotection via the CB1 receptor, the present results suggest that activation of CB2 receptors might underlie the beneficial effects of cannabinoids at least in SOD1G93A mice .”

Together these results show that cannabinoids have significant neuroprotective effects in this model of ALS and suggest that these beneficial effects may be mediated by non-CB1 receptor mechanisms.”

http://www.fasebj.org/content/20/7/1003.long

Endocannabinoids accumulate in spinal cord of SOD1 G93A transgenic mice.

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Abstract

“Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are caused by mutations in the super oxide dismutase 1 (SOD1) gene and transgenic mice for these mutations recapitulate many features of this devastating neurodegenerative disease. Here we show that the amount of anandamide (AEA) and 2-arachidonoylglycerol (2-AG), two endocannabinoids that have neuroprotective properties, increase in spinal cord of SOD1(G93A) transgenic mice. This increase occurs in the lumbar section of spinal cords, the first section to undergo neurodegeneration, and is significant before overt motor impairment. Our results show that chronic neurodegeneration induced by a genetic mutation increases endocannabinoid production possibly as part of an endogenous defense mechanism.”

http://www.ncbi.nlm.nih.gov/pubmed/15189359

The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset.

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“Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, paralysis and death within 2-5 years of diagnosis. Currently, no effective pharmacological agents exist for the treatment of this devastating disease. Neuroinflammation may accelerate the progression of ALS. Cannabinoids produce anti-inflammatory actions via cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), and delay the progression of neuroinflammatory diseases…

 …treatment with non-selective cannabinoid partial agonists prior to, or upon, symptom appearance minimally delays disease onset and prolongs survival through undefined mechanisms…

…Δ9-Tetrahydrocannabinol (Δ9-THC) is the main psychoactive constituent in the plant Cannabis sativa (marijuana) and produces its effects by activation of cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) cannabinoid receptors. CB1 receptors are expressed throughout the CNS, while CB2 receptors are expressed predominantly in immune cells and non-neuronal tissues. Therapeutic agents which modulate the cann-abinoid system are effective in treating a wide variety of disorders characterized by inflammation. More specifically, drugs which activate CB2 receptors successfully improve the symptoms of several inflammatory diseases…

More importantly, daily injections of the selective CB2 agonist AM-1241, initiated at symptom onset, increase the survival interval after disease onset by 56%. Therefore, CB2 agonists may slow motor neuron degeneration and preserve motor function, and represent a novel therapeutic modality for treatment of ALS.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819701/

 

AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis.

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“Effective treatment for amyotrophic lateral sclerosis (ALS) remains elusive. Motor neuron degeneration is the primary pathology in ALS; however non-neuronal cells contribute to the disease process. In particular, inflammatory processes have been shown to play an important role. AM1241 is a cannabinoid CB2 receptor selective agonist that has been shown to be effective in models of inflammation and hyperalgesia. Here we report that treatment with AM1241 was effective at slowing signs of disease progression when administered after onset of signs in an ALS mouse model (hSOD1(G93A) transgenic mice)…. As AM1241 was well tolerated by the animals, cannabinoid CB2 receptor-selective compounds may be the basis for developing new drugs for the treatment of ALS and other chronic neurodegenerative diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/16781706

Abnormal sensitivity of cannabinoid CB1 receptors in the striatum of mice with experimental amyotrophic lateral sclerosis.

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“Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons.

The sensitivity of cannabinoid CB1 receptors controlling both glutamate and GABA transmission was remarkably potentiated in ALS mice, indicating that adaptations of the endocannabinoid system might be involved in the pathophysiology of ALS. In conclusion, our data identify possible physiological correlates of striatal dysfunction in ALS mice, and suggest that cannabinoid CB1 receptors might be potential therapeutic targets for this dramatic disease.”

http://www.ncbi.nlm.nih.gov/pubmed/19452308

Identification of receptors and enzymes for endocannabinoids in NSC-34 cells: relevance for in vitro studies with cannabinoids in motor neuron diseases.

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“NSC-34 cells, a hybridoma cell line derived from the fusion of neuroblastoma cells with mice spinal cord cells, have been widely used as an in vitro model for the study of motor neuron diseases [i.e. amyotrophic lateral sclerosis (ALS)]. In the present study, they were used to characterize different elements of the cannabinoid signaling system, which have been reported to serve as targets for the neuroprotective action of different natural and synthetic cannabinoid compounds…

Assuming that glutamate toxicity is one of the major causes of neuronal damage in ALS and other motor neurons diseases, the differentiated NSC-34 cells might serve as a useful model for studying neuroprotection with cannabinoids in conditions of excitotoxic injury, mitochondrial malfunctioning and oxidative stress.”

http://www.ncbi.nlm.nih.gov/pubmed/22206832