ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

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“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27086601

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Quantification of pain in sickle mice using facial expressions and body measurements.

“Pain is a hallmark feature of sickle cell disease (SCD). Subjects typically quantify pain by themselves, which can be biased by other factors leading to overtreatment or under-treatment. Reliable and accurate quantification of pain, in real time, might enable to provide appropriate levels of analgesic treatment.

The mouse grimace scale (MGS), a standardized behavioral coding system with high accuracy and reliability has been used to quantify varied types of pain. We hypothesized that addition of the objective parameters of body length and back curvature will strengthen the reproducibility of MGS.

We examined MGS scores and body length and back curvature of transgenic BERK sickle and control mice following cold treatment or following treatment with analgesic cannabinoid CP55,940. We observed that sickle mice demonstrated decreased length and increased back curvature in response to cold. These observations correlate with changes in facial expression for the MGS score.

CP55,940 treatment of sickle mice showed an increase in body length and a decrease in back curvature concordant with MGS scores indicative of an analgesic effect. Thus, body parameters combined with facial expressions may provide a quantifiable unbiased method for objective measure of pain in SCD.”

http://www.ncbi.nlm.nih.gov/pubmed/26852657

http://www.thctotalhealthcare.com/category/sickle-cell-disease/

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Cannabinoid receptor-specific mechanisms to ameliorate pain in sickle cell anemia via inhibition of mast cell activation and neurogenic inflammation.

“Sickle cell anaemia is a manifestation of a single point mutation in haemoglobin, but inflammation and pain are the insignia of this disease which can start in infancy and continue throughout life.

Earlier studies showed that mast cell activation contributes to neurogenic inflammation and pain in sickle mice.

Morphine is the common analgesic treatment but also remains a major challenge due to the side effects and ability to activate mast cells. Therefore, we examined the cannabinoid receptor-specific mechanisms to ameliorate mast cell activation, neurogenic inflammation and hyperalgesia, using HbSS-BERK sickle and cannabinoid receptor 2 deleted sickle mice.

We show that cannabinoids ameliorate mast cell activation, inflammation and neurogenic inflammation in sickle mice via both cannabinoid receptors 1 and 2.

Thus, cannabinoids influence systemic and neural mechanisms, ameliorating the disease pathobiology and hyperalgesia in sickle mice.

This study provides a “proof of principle” for the potential of cannabinoid/cannabinoid receptor-based therapeutics to treat several manifestations of sickle cell anaemia.”

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Cannibinoids offer novel treatment for pain in sickle cell disease, study suggests

ScienceDaily: Your source for the latest research news

“Researchers have discovered that cannibinoids offer a novel approach to ease the chronic and acute pain caused by sickle cell disease.

“This paper provides proof that we can use other classifications of drugs to treat pain in patients with sickle cell disease,” Gupta said.

“Cannibinoids offer great promise in the treatment of chronic and acute pain, and they’re effective in much lower amounts than opioids — the only currently approved treatment for this disease.”

http://www.sciencedaily.com/releases/2010/07/100722121225.htm

Pain-related behaviors and neurochemical alterations in mice expressing sickle hemoglobin: modulation by cannabinoids… Our observations in these mice suggest that both systemically administered and locally applied cannabinoids may be beneficial in treating pain in SCD.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913454/

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Vaporized Cannabis for Chronic Pain Associated With Sickle Cell Disease (Cannabis-SCD) -ClinicalTrials.gov Identifier: NCT01771731

“Cannabinoid-Based Therapy and Approaches to Quantify Pain in Sickle Cell Disease.

Our primary objective is to assess whether inhaling vaporized cannabis ameliorates chronic pain in patients with sickle cell disease (SCD). As these patients will all be on chronic opioid analgesics, the investigators will also assess the possible synergistic affect between inhaled cannabis and opioids.

The investigators will also assess the clinical safety of the concomitant use of cannabinoids and these opioids in patients with SCD by monitoring the short-term side effects associated with combined therapy.

Finally, the investigators will evaluate the short-term effects of inhaled cannabis on markers of inflammation and disease progression in patients with SCD.

Hypotheses are as follows:

  1. Inhaled cannabis will significantly reduce chronic pain in patients with SCD.
  2. Inhaled cannabis will significantly alter the short-term side effects experienced by patients who take opioids for SCD.
  3. Inhaled cannabis will significantly alter markers of inflammation and disease progression in patients with SCD compared to placebo.
Subjects will complete a 5-day pain diary prior to admission to the Clinical Research Center (CRC) to establish a baseline of pain. They will then be assigned to inhale either vaporized cannabis of mixed THC/CBD content (4.7% THC/5.1% CBD) or placebo cannabis (0% THC/0% CBD). Participants and personnel will be blinded as to assignment. Pain will be evaluated during the 5-day inpatient exposure. Participants will be asked to participate in two such 5-day sessions separated by at least a 2-week washout so that each will be exposed to the two experimental conditions.
Detailed Description:

This is a proof-of-principle investigation of the safety and potential effectiveness of inhaled vaporized cannabis when added to a stable analgesic regimen in sickle cell disease (SCD) patients with chronic pain. The study will be comprised of two 5-day intervention periods in the inpatient setting (the Clinical Research Center at SFGH), with completion of a 5-day daily pain diary prior to admission to establish an outpatient baseline. Participants will be randomly assigned, in double-blind fashion, to treatment with (A) vaporized cannabis with an approximately 1:1 ration of delta-9-tetrahydrocannabinol:cannabidiol or (B) vaporized placebo. Those who receive treatment A during the first admission will receive treatment B in the second, and those who receive treatment B during the first admission will receive treatment A in the second. The two admissions will be spaced at least 14 days apart.

On Day 1 of each admission, subjects will provide blood samples for baseline markers of inflammation and SCD disease progression. They will undergo assessments of pain, mood, and quality of life. At 12 pm on Day 1, they will inhale vaporized study agent (equivalent to 1 cannabis/placebo cigarette) using the Volcano® vaporizer; on Days 2-4 they will inhale study agent at 8 am, 2 pm, and 8 pm, and they will inhale their final dose on Day 5 at 8 am. Subjects will continue their pre-study analgesic regimen while in the study. If additional analgesia is required, supplemental therapy will be administered and the dose recorded. Pain measurements by visual analogue scale will be obtained every 2 hours while subjects are awake. On Day 5 a second set of blood samples for inflammation markers and disease progression will be obtained, and subjects will again complete pain, mood, and quality of life assessments.”

http://www.clinicaltrials.gov/ct2/show/study/NCT01771731#contacts

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THC Can Manage Sickle Cell Disease

“Cannabinoids, the active ingredients in pot offer a new way to treat chronic and acute pain from sickle cell disease, ScienceDaily reports.

Currently the only treatment for the blood disease is opiods.

“Pain in SCD is described to be more intense than labor pain. The pain starts early in a patient’s life, often during infancy, and increases in severity with age.

[Cannibinoids are] effective in much lower amounts than opioids — the only currently approved treatment for this disease.”

http://www.eastbayexpress.com/LegalizationNation/archives/2010/07/23/daily-roundup-thc-can-manage-sickle-cell-disease-oakland-tweaks-medical-cannabis-taxes

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Sickle Cell Pain May be Managed with Cannabis

“Can Medical Cannabis Help to Cure SCD?”

Sickle Cell Disease Pain May Be Managed 2

“Sickle cell disease (SCD) is a hereditary condition caused by a mutation in the haemoglobin gene, which leads to symptoms of anaemia, extreme pain, and organ damage if unmanaged.”

Sickle Cell Disease Pain May Be Managed 1

“Individuals suffering from SCD are far more likely to use cannabis than the general population, potentially for its analgesic properties.

In 2010, researchers at the University of Minnesota found that the synthetic THC analogue CP 55,940 was as effective as morphine sulphate in treating SCD-related severe pain in transgenic mice expressing human sickle haemoglobin, and that it was effective at smaller doses than the opioid.

In 2011, a further paper submitted by the same researchers to Blood (the Journal of the American Association of Hematology) indicated that CP 55,940 ameliorated severe pain associated with the hypoxia/reoxygenation cycle. CP 55,940 is a full agonist of both CB receptors, and is thought to act as an antagonist at the GPR55 receptor.

As well as this, cannabis has been repeatedly shown to act as a vasodilator, which could in itself assist in easing the blockages caused by build-up of sickle cells…

SCD is a painful and debilitating disease, and the overall inefficacy of opioid treatments and resultant poor quality of life for many sufferers is an indication that our approach to it is far from perfect.

If cannabis is a good candidate to replace opioids, it should be implemented forthwith to prevent ongoing suffering for existing patients.”

http://sensiseeds.com/en/blog/sickle-cell-pain-may-managed-cannabis/

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Medical Marijuana Could Help Treat Sickle Cell Disease

sickle cell marijuana

“People who suffer from sickle cell disease have to deal with a lot of pain.

Patients with sickle cell disease have crescent shaped blood cells, compared to disc shaped blood cells in people who don’t suffer from sickle cell disease. These cells block blood flow, which causes pain, fatigue, and organ damage. I’ve heard people that suffer from sickle cell disease describe the pain as being like nails poking their entire body.

Doctors usually prescribe opiate based pain killers like morphine for sickle cell disease. Opiate prescriptions have a lot of side effects including respiratory issues, damage to organs, and addiction to name a few. Compare that to medical marijuana, which has far less harmful side effects, especially if consumed in food or vapor form. Patients should have the option to choose medical marijuana if they want to. From Minnesota Daily:

School of Dentistry professor and pain expert Donald Simone, who is also working on the research project, said opiates sometimes have “problematic” side effects, such as respiratory depression. And Gupta said patients sometimes receive incorrect dosages of the drugs because their exact amount of pain is unknown.

Medical marijuana is promising for sickle cell patients because it has a pain-relieving effect without as many severe side effects as morphine, Simone said.

Right now researchers in California are teaming up with researchers at the University of Minnesota to find out how medical marijuana can help those suffering from sickle cell disease. Right now, sickle cell patients can get safe access to medical marijuana if they are in California. However, patients in Minnesota will have to wait until the condition is added to the list of approvable conditions in Minnesota, which could take awhile.”

http://www.theweedblog.com/medical-marijuana-could-help-treat-sickle-cell-disease/

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Cannabis use in sickle cell disease: a questionnaire study.

“Cannabinoids are increasingly being considered for the management of various painful conditions, and could be considered as an option for treating acute pain in sickle cell disease (SCD).

The objective of this study was to determine the extent of use of cannabis in the community for pain and other symptom relief, and its side effects during self-administration in patients with SCD…

The main reasons for use were to reduce pain in 52%, and to induce relaxation or relieve anxiety and depression in 39%. Symptoms related to sedation and mood effects were reported in 77% of patients. The majority of patients (58%) expressed their willingness to participate in studies of cannabis as a medicine.

We conclude that research in the use of cannabinoids for pain relief in SCD would be both important and acceptable to adult patients.”

http://www.ncbi.nlm.nih.gov/pubmed/16173972

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Medical marijuana could treat pain caused by sickle cell disease

“A group of University of Minnesota researchers is testing to see if medical marijuana can help treat chronic pain caused by sickle cell disease, but state and federal laws are putting a hitch in their study.

As researchers continue with the study’s next step — conducting human trials — they’re heading to California, as Minnesota doesn’t easily allow testing cannabis on people. The state’s recently passed medical marijuana law doesn’t include sickle cell disease as a qualifying medical condition, but the University’s current research could play a role in how that law changes in the future.

“We find that cannabinoids have good outcomes in treating pain [in mice with sickle cell disease],” said chief researcher and associate professor of medicine Kalpna Gupta.

Gupta said the researchers are now ready to expand their study to patients. And in doing so, they will move to California, where medical marijuana became legal nearly two decades ago. Minnesota’s stricter version of that law will take effect next summer.

Right now, the Minnesota Department of Health is working to appoint members to a task force that will oversee medical cannabis therapeutic research in the coming months. The department is also fine-tuning the rules that outline patient access and qualifications.

Qualifying health conditions to receive medical cannabis in the Minnesota law include cancer, glaucoma, HIV/AIDS and seizures. Patients also qualify for the drug if they have chronic pain caused by cancer or a terminal illness.

Department of Health spokesman Mike Schommer said symptoms of sickle cell disease could potentially be added to the list of medical conditions in the future.

The main symptoms of sickle cell disease are fatigue and pain, and according to the state’s law, the commissioner of health may eventually add intractable pain to the list of qualifying medical conditions, making patients of sickle cell disease included.

Sickle cell patients have crescent-shaped blood cells instead of healthy, disc-shaped ones. Sickle cells block blood flow and cause pain and organ damage, according to the National Heart, Lung and Blood Institute.

Former University student Brianna Wilson has sickle cell anemia that gives her bone and muscle pain.

“Some people describe it as nails poking you, but for me, it’s pressure in my veins and upper body,” she said.

Physicians usually prescribe opiates, like morphine, to treat the pain, but researchers and patients agree that there are better ways to treat the disease. Wilson said the drugs are addictive and usually don’t offer good results.

School of Dentistry professor and pain expert Donald Simone, who is also working on the research project, said opiates sometimes have “problematic” side effects, such as respiratory depression. And Gupta said patients sometimes receive incorrect dosages of the drugs because their exact amount of pain is unknown.

Developing a means to measure the severe pain could be useful for doctors while making prescriptions, said biomedical engineering professor Bin He, another researcher who is involved in the project.

Medical marijuana is promising for sickle cell patients because it has a pain-relieving effect without as many severe side effects as morphine, Simone said.

The National Institutes of Health awarded the researchers $9.5 million in January to pursue studies on mice and patients. With that money, the research is expanding to California to test the effects of vaporized cannabis on 35 sickle cell disease patients beginning in July.

So far, the researchers’ study has found that mice with sickle cell disease are more sensitive to pain, especially when experiencing pressure, heat or cold, Simone said. By examining how neurons in the peripheral nerves and the spinal cord become overactive, the researchers are able to identify new ways to reduce pain, he said.

University of California-San Francisco professor Donald Abrams, who will lead the clinical trials in partnership with the Minnesota researchers, said there were many “hoops to jump through” in going forward with the study, like gaining approval from numerous government agencies.

Currently, 22 states and the District of Columbia allow medical marijuana programs, all varying in levels of strictness.

Minnesota’s law is among the nation’s strictest, and it prohibits patients from smoking or growing their own marijuana plants. The law mandates that two manufacturers operate four distribution centers each and that medical marijuana identification cards be available beginning July 2015 through a state-monitored registry.

“I can see [medical marijuana] helping,” Wilson said. “It’s chronic pain, so it should help, especially if it’s relaxing the muscles and things like that.””

http://www.mndaily.com/news/campus/2014/06/10/medical-marijuana-could-treat-pain-caused-sickle-cell-disease

“Medical Marijuana Policies Complicate Research Treating Chronic Sickle Cell Pain. A study by University of Minnesota researchers that was testing the effects of medical marijuana in treating chronic pain experienced by sickle cell patients has been forced out of the state due to a combination of restrictive state and federal policies stalling the project.”  http://www.huffingtonpost.com/2014/06/11/minnesota-medical-marijuana_n_5485383.html

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