Role of CB2 receptors in neuroprotective effects of cannabinoids.

“CB2 receptors, the so-called peripheral cannabinoid receptor type, were first described in the immune system, but they have been recently identified in the brain in healthy conditions and, in particular, after several types of cytotoxic stimuli. Specifically, CB2 receptors were identified in microglial cells, astrocytes and, to a lesser extent, in certain subpopulations of neurons.

Given the lack of psychoactivity demonstrated by selective CB2 receptor agonists, this receptor becomes an interesting target for the treatment of neurological diseases, in particular, the case of certain neurodegenerative disorders in which induction/up-regulation of CB2 receptors has been already demonstrated. These disorders include Alzheimer’s disease, Huntington’s chorea, amyotrophic lateral sclerosis and others. Interestingly, in experimental models of these disorders, the activation of CB2 receptors has been related to a delayed progression of neurodegenerative events, in particular, those related to the toxic influence of microglial cells on neuronal homeostasis.

 The present article will review the evidence supporting that CB2 receptors might represent a key element in the endogenous response against different types of cytotoxic events, and that this receptor type may be a clinically promising target for the control of brain damage in neurodegenerative disorders.”

 http://www.ncbi.nlm.nih.gov/pubmed/18291574

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Cannabinoids and neurodegenerative diseases.

“Although significant advances have taken place in recent years on our understanding of the molecular mechanisms of different neurodegenerative diseases, its translation into effective therapeutic treatments has not been as successful as could be expected. There is still a dramatic lack of curative treatments for the most frequent disorders and only symptomatic relief for many others. Under this perspective, the search for novel therapeutic approaches is demanding and significant attention and efforts have been directed to studying additional neurotransmission systems including the endocannabinoid system (ECS).

The neuroprotective properties of exogenous as well as endogenous cannabinoids have been known for years and the underlying molecular mechanisms have been recently unveiled. As discussed later, antioxidative, antiglutamatergic and antiinflammatory effects are now recognized as derived from cannabinoid action and are known to be of common interest for many neurodegenerative processes.

 Thus, these characteristics make cannabinoids attractive candidates for the development of novel therapeutic strategies.

 The present review will focus on the existing data regarding the possible usefulness of cannabinoid agents for the treatment of relevant neurological pathologies for our society such as Alzheimer’s disease, multiple sclerosis, Huntington’s disease and amyotrophic lateral sclerosis.”

http://www.ncbi.nlm.nih.gov/pubmed/19839933

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Medical Cannabis Helps ALS Patient Outlive her Own Doctors

“In April, Cathy Jordan sat on a panel at the Cannabis Therapeutics Conference in Arizona. Before taking the stage, she discussed the medical use of cannabis for ALS with Jahan Marcu, the Philadelphia Medical Marijuana Examiner.

Cathy Jordan first noticed something was wrong in summer of 1985 when she couldn’t pick things up. Her muscles weren’t responding. In 1986, she was diagnosed with ALS (Amyotrophic Lateral Sclerosis). ALS, also known as Lou Gehrig’s disease, is characterized by the death of motor neurons leading to loss of limb control, breathing, swallowing, speech and widespread cellular dysfunction. Most cases of ALS are sporadic; it is not a viral or autoimmune disease.

Most people start using a feeding tube because they are afraid of choking to death”, says Cathy.

In 1986, she was given 3 – 5 years to live according to her neurologist. Nearly 3 decades later, she is still alive and living with ALS.

“All my docs are retiring or dead. I’ve outlived 5 support groups and 4 neurologists,” said Cathy. This actually posed a problem for Cathy who lost her social security benefits because she lived passed her expiration date. The state of Florida said her ID and regular documentation wasn’t good enough to prove she was alive and to continue to receive benefits. She had to ask her neurologist to fill out paperwork to prove she was still alive.

Mrs. Jordan began using Cannabis from a Florida grower to treat her ALS in the late 80’s. “Donny Clark provided my medicine, grown in the Myakka River Valley…he was busted and sentenced to life in prison, and that strain of Cannabis was lost.”

“You know, they say the fountain of youth is in Florida. Maybe it was something in the soil that made this plant helps me…and I don’t understand why doctors wouldn’t study me. But I still would like to know why this is helping me.”

At first, doctors wouldn’t accept that marijuana could be responsible for Cathy’s extended life span. Other doctors thought that smoking anything would impair her lung function and even threatened to have this paralyzed women committed, simply based on the fact that she thought Cannabis was actually helping her.

“I visited a neurologist at Duke University. When I told him that I was smoking Cannabis, he didn’t know what to do with me. He was afraid. He wouldn’t even take my blood pressure because I was using an illegal drug.”

Cathy adds:

“I asked my docs if they would take a drug if it was neuroprotective, an antioxidant and an anti-inflammatory. They say ‘yes’ and ask me if I know of one. Cannabis, I tell them.”

Nearly three decades later, the science has caught up with this miracle patient. Scientists created a mouse with ALS, which was very exciting for Cathy. Research has shown that THC and other cannabinoids can benefit mice with ALS. The mounting evidence of cannabinoids halting the progression of ALS has started to change the attitudes of doctors and prominent researchers have recently called for ALS clinical trials with Cannabis or cannabinoids.

“They all agree today that I should smoke Cannabis,” says Cathy. “Twenty six years later, my original neurologist fought [successfully] to make sure Cannabis is legal for patients in Delaware.”

Researchers think Cannabis may help ALS patients relieving pain, spasticity, drooling, appetite loss and has minimal drug-drug interactions and toxicity.

“There are ALS patients associations that fight for the right of patients to die with dignity. But what about my right to life?” asks Cathy. “Keeping my medicine illegal removes my right to life.””

By:

http://www.examiner.com/article/medical-cannabis-helps-als-patient-outlive-her-own-doctors

Cathy Jordan’s Story

 
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Cannabinoid Treatments: Amyotrophic Lateral Sclerosis (ALS)

“Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a fatal 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. More than half of ALS patients die within 2.5 years following the onset of symptoms.

A review of the scientific literature reveals an absence of clinical trials investigating the use of cannabinoids for ALS treatment. However, recent preclinical findings indicate that cannabinoids can delay ALS progression, lending support to anecdotal reports by patients that cannabinoids may be efficacious in moderating the disease’s development and in alleviating certain ALS-related symptoms such as pain, appetite loss, depression and drooling.

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.

Additional trials in animal models of ALS have shown that the administration of other naturally occurring and synthetic cannabinoids can also moderate ALS progression but not necessarily impact survival. One recent study demonstrated that blocking the CB1 cannabinoid receptor did extend life span in an ALS mouse model, suggesting that cannabinoids’ beneficial effects on ALS may be mediated by non-CB1 receptor mechanisms.

As a result, experts are calling for clinical trials to assess cannabinoids for the treatment of ALS. Writing in the American Journal of Hospice & Palliative Medicine in 2010, a team of investigators reported, “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.” They 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.”

By braatahon December 25, 2012| From braatah.com
 
 
 
 
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Amyotrophic lateral sclerosis: delayed disease progression in mice by treatment with a cannabinoid.

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

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

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/

 

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Survey of cannabis use in patients with amyotrophic lateral sclerosis.

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

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

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

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

“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

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Endocannabinoids accumulate in spinal cord of SOD1 G93A transgenic mice.

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

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