Pain relief without the high

January 4, 2017

Science Daily/Leiden, Universiteit

Researchers at Leiden University led by Mario van der Stelt (Leiden Institute for Chemistry) have set ‘gold standards’ for developing new painkillers based on the medicinal effects of cannabis.

Medicinal marijuana

Medicinal marijuana is in frequent use as a painkiller, but its psycho-active side-effects are a major disadvantage. The pharmaceutical industry is desperately seeking a synthetic form of cannabis that inhibits inflammation and pain, but without the high. Leiden researchers have now brought the development of such drugs a step closer. In an article in Nature Communications they set out 'gold standards' for the use of reference substances, to improve trials with synthetic cannabis.

Many of the clinical trials carried out to date with with synthetic cannabis have failed, with no measurable effect being recorded in patients. One of the causes of these failures can be found in the pre-clinical lab, during testing with animals. Substances are often used in these tests whose biochemical and molecular-pharmaceutical effects have never been properly characterised. As a result, there have been a lot of contradictory publications on research findings, the results of which cannot be reproduced. This is having a major effect on the allocation of research funding, the use of animal testing and the exposure of patients to non-active substances.

International and public-private collaboration

Marjolein Soethoudt, a PhD candidate in Van der Stelt's research group, studied together with 12 international academic groups, the National Institute of Health (US) and pharmaceuticals concern Hoffman-LaRoche (Switzerland), the 18 most commonly used reference substances, including the psychoactive ingredient in marijuana, Δ9-THC. They carried out their studies under standardised conditions in 36 different tests, to analyse the molecular pharmacological characteristics of the substances. They hoped to be able to identify the most suitable reference sustances for the research on synthetic cannabis. The research led to three 'gold standards' that should make it possible to give an impetus to the development of new painkillers and anti-inflammatories.

Cannabinoid CB2 receptor

Δ9-THC binds to two types of proteins in the human body: the cannabinoid CB1 receptor in the brain and the cannabinoid CB2 receptor in the immune system. Activating the CB1 receptor in the brain makes you high, while activating the CB2 receptor has an anti-inflammatory effect. The three 'gold standards' are molecules that are highly selective in activating only the CB2 receptor and ignoring the CB1 receptor. These three gold standards also appeared to cause the fewest side-effects, nor did they give the mice a high. Earlier studies have shown that these substances do have an analgesic and anti-inflammatory effect. The researchers advise that these three gold standards should be used in future in research on new medicines that rely on the activation of the cannabinoid CB2 receptor for their effectiveness.

Drugs related to cannabis have pain-relieving potential for osteoarthritis

January 7, 2014

Science Daily/University of Nottingham

Chemical compounds synthesized in the laboratory, similar to those found in cannabis, could be developed as potential drugs to reduce the pain of osteoarthritis.

These compounds could also reduce joint inflammation, according to new research carried out at the Arthritis Research UK Pain Centre at The University of Nottingham.

Cannabis contains a number of natural chemicals called cannabinoids and the brain has the ability to respond to such compounds. Cannabis and synthetically manufactured cannabinoid compounds can relieve pain in animal models of arthritis, but their use has been limited because of undesirable psychological side-effects.

Now a team of researchers led by Professor Victoria Chapman at the Arthritis Research UK Pain Centre at The University of Nottingham have shown that selectively targeting one of the molecules involved in the body's natural pain-sensing pathways, called cannabinoid receptor2 (CB2) can also reduce pain in animal models of osteoarthritis. This works in part through the central nervous system (spinal cord and brain). The compound used in this study, called JWH133, is a synthetic cannabinoid molecule manufactured in a laboratory and is not derived from the cannabis plant.

When the research was extended to humans, studies of the human spinal cord tissue showed for the first time the presence of this receptor and, interestingly, that the amount of receptor was related to the severity of the osteoarthritis. This provides evidence from patients that this drug target may have clinical relevance to osteoarthritis pain.

Cannabinoids are known to have anti-inflammatory effects, and the team have demonstrated that JWH133 reduced the levels of inflammation in their studies of osteoarthritis. Thus, cannabinoid CB2 targeted drugs may have a dual beneficial effect for people with osteoarthritis by providing pain relief as well as reducing inflammation in the joint.

Their findings are published online in the journal PLOS One.

Victoria Chapman, Professor of Neuropharmacology, said: "This finding is significant, as spinal and brain pain signalling pathways are known to make a major contribution to pain associated with osteoarthritis. These new data support the further evaluation of the selective cannabinoid-based interventions for the treatment of osteoarthritis pain."

Professor Alan Silman, medical director of Arthritis Research UK, added: "Millions of people are living with the severe, debilitating pain caused by osteoarthritis, and better pain relief is urgently needed. This research does not support the use of recreational cannabis use. What it does suggest is that there is potential to develop a synthetic drug that mimics the behavior of cannabinoid receptors without causing serious side effects."

Osteoarthritis affects eight million people the UK and occurs when the cartilage at the ends of bones wears away, causing joint pain and stiffness, and is a major cause of pain and disability. Current treatment is limited to pain relief, exercise, physiotherapy weight-loss and joint replacement. There are currently no drugs that slow down its progression, and more effective treatment is urgently needed.

https://www.sciencedaily.com/releases/2014/01/140107092825.htm

Marijuana use may cause severe cyclic nausea, vomiting, a little-known, but costly effect

October 22, 2012

Science Daily/American College of Gastroenterology (ACG)

Marijuana use -- both natural and synthetic -- may cause cannabinoid hyperemesis (CH) a little-known but costly effect that researchers suggest is a serious burden to the health care system as it often leads to expensive diagnostic tests and ineffective treatments in an effort to find the cause of a patient's symptoms and provide relief, according to two separate case reports unveiled October 22 at the American College of Gastroenterology's (ACG) 77th Annual Scientific meeting in Las Vegas. Cannabinoid hyperemesis is characterized by a history of chronic cannabis use followed by a cyclic pattern of nausea, vomiting and colicky abdominal pain. Interestingly, compulsive hot baths or showers temporarily relieve symptoms, another characteristic which aids clinicians in diagnosis.

"Most healthcare providers are unaware of the link between marijuana use and these episodes of cyclic nausea and vomiting so they are not asking about natural or synthetic cannabinoid use when a patient comes to the emergency room or their doctor's office with these symptoms," said co-investigator Ana Maria Crissien-Martinez, M.D. of Scripps Green Hospital and Clinic in San Diego. She said CH was first described in a 2004 case series of 9 patients in Australia and since then, 14 case reports and 4 case series have been published, including a prospective series of 98 patients published by Mayo Clinic in February 2012.

"Patients who use cannabis whether natural or in synthetic form called 'Spice' also don't realize their unexplained episodes of cyclic nausea and vomiting may be a result of this use, with some increasing their cannabis use because they may think it will help alleviate their symptoms -- and it actually makes them worse," said Dr. Crissien-Martinez. "The only resolution is cannabis cessation."

Dr. Crissien-Martinez co-authored the case report, "Marijuana: Anti-Emetic or Pro-Emetic" which described a series of 9 patients with cannabinoid hyperemesis at Scripps Green Hospital with average age at diagnosis 30 years-old; 88 percent male; onset of cannabis use during teen years; 88 percent used cannabis daily; 56 percent compulsive bathing behavior; and 80 percent symptom resolution with cannabis cessation.

The other case report, "Spicing Up the Differential for Cyclic Vomiting: A Case of Synthetic-Cannabinoid Induced Hyperemesis Syndrome (CHS)," may be the first reported case of CH attributed to synthetic cannabinoid, according to Fong-Kuei Cheng, M.D. and his research team from Walter Reed Walter Reed National Military Medical Center/Uniformed Services University of the Health Sciences in Bethesda, MD.

"Legal synthetic cannabinoids became available in the United States by 2009 with widespread usage among military personnel due to its ability to elude standard drug testing. It is important to recognize that routine urine drug testing does not include JWH-018 and JWH 073, which are the primary components in synthetic cannabinoids," said Dr. Cheng.

The case report described a 22-year active duty military male who was admitted with a 10-month history of progressive, intermittent abdominal pain, nausea and vomiting, with episodes occurring every two months and lasting up to a week. He underwent several diagnostic tests before a urine synthetic cannabinoid test confirmed the diagnosis of cannabinoid hyperemesis syndrome (CHS). Since discontinuing these drugs, the patient has remained symptom-free, according to the case report.

"This case illustrates that CHS should be in the differential diagnosis of unexplained, episodic abdominal pain with nausea and vomiting, particularly if relieved with compulsive hot showers. Recognition of this syndrome is important to prevent unnecessary testing and to reduce health care expenditures," said Dr. Cheng. "We have also noted, particularly in the active duty population where drug testing for cannabis usage is done routinely, that there appears to be an increased usage instead of the synthetic cannabinoids, so we would advocate routine additional testing for them when the clinical suspicion is high."

Patients frequently have multiple hospital, clinic and emergency room visits with extensive negative work-up to include imaging studies, endoscopies, and laboratory testing before they are finally diagnosed with cannabinoid hyperemesis, according to the researchers of both case reports.

"We estimate $10,000 to be the minimum cost of one admission -- but on average our patients required admission to the hospital 2.8 times, a total of almost $30,000 for workup," said Dr. Crissien-Martinez, who added that that cost does not include the added costs of primary care physician and/or gastroenterologist and emergency room visits, which averaged 2.5 and 6 times respectively.

Dr. Crissien-Martinez said that 80 percent of the Scripps Green patients who stopped cannabis experienced symptom resolution; however, only one of them remained abstinent and consequently symptom-free.

"As health care providers, we must be aware of the potential side effects of chronic cannabis use and understand that cannabinoid hyperemesis is diagnosed clinically to avoid expensive diagnostic and therapeutic modalities," said Dr. Crissien-Martinez. "Instead the focus should be shifted towards counseling and resources allocated towards marijuana cessation."

https://www.sciencedaily.com/releases/2012/10/121022081353.htm

New Antidepressant Drug Increases 'Brain's Own Cannabis'

December 13, 2005

Science Daily/McGill University

Researchers have discovered a new drug that raises the level of endocannabinoids -- the 'brain's own cannabis' -- providing anti-depressant effects. The new research published in this week's Proceedings of the National Academy of Sciences (PNAS), suggests the new drug, called URB597, could represent a safer alternative to cannabis for the treatment of pain and depression, and open the door to new and improved treatments for clinical depression--a condition that affects around 20% of Canadians.

In preclinical laboratory tests researchers found that URB597 increased the production of endocannabinoids by blocking their degradation, resulting in measurable antidepressant effects. "This is the first time it has been shown that a drug that increases endocannabinoids in the brain can improve your mood," says the lead investigator Dr. Gabriella Gobbi, an MUHC and Université de Montréal researcher.

Endocannabinoids are chemicals released by the brain under certain conditions, like exercise; they stimulate specific brain receptors that can trigger feelings of well-being. The researchers, which included scientists from the University of California at Irvine, were able to measure serotonin and noradrenaline activity as a result of the increased endocannabinoids, and also conducted standard experiments to gauge the 'mood' of their subjects and confirm their findings.

"The results were similar to the effect we might expect from the use of commonly prescribed antidepressants, which are effective on only around 30% of the population," explains Dr. Gobbi. "Our discovery strengthens the case for URB597 as a safer, non-addictive, non-psychotropic alternative to cannabis for the treatment of pain and depression and provides hope for the development of an alternate line of antidepressants, with a wider range of effectiveness."

Cannabis has been known for its anti-depressant and pain-relief effects for many years, but the addictive nature and general health concerns of cannabis use make this drug far from ideal as a medical treatment. The active ingredient in cannabis--THC (Tetrahydrocannabinol)--stimulates cannabinoid receptors.

Funding for this study was provided by the Fonds de la Recherche en Santé du Québec (FRSQ), the Canadian Psychiatric Research Foundation (CPRF), the National Institute on Drug Abuse (NIDA) and an MUHC fellowship.

https://www.sciencedaily.com/releases/2005/12/051213172852.htm

Antidote to synthetic cannabis ‘Spice’ intoxication could be found in slimming drug

October 4, 2017

Science Daily/Queen Mary University of London

Early research from Queen Mary University of London has potentially found an antidote that can rapidly stop the intoxicating effects of cannabis and synthetic cannabinoids.

Synthetic cannabinoids, such as 'Spice' and 'Black Mamba', are becoming an increasing problem, especially with youths game to experiment and within the homeless and prison populations, due to their cheapness and odourless properties. Their super strength compared to cannabis is leading to an increasing number of severe adverse reactions and an increasing number of deaths.

The study, published in the British Journal of Pharmacology, looked at mice that were experiencing the effects of synthetic cannabinoid intoxication, to see the effects of treating them with a molecule known as AM251.

AM251 blocked the action of the synthetic cannabinoid on one of the brain receptors and led to a loss of the cannabinoid-related behavioural effects within a few minutes. This included a significant loss of sedation within 20 minutes, and a loss of the associated hypothermia within 40 minutes.

The researchers say that the most rapid way to develop an antidote would be to re-develop one of the slimming drugs, known as rimonabant, which also blocks the cannabinoid system on which marijuana acts.

https://www.sciencedaily.com/releases/2017/10/171004132517.htm