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Cannabinoids may help limit secondary damage of TBIs

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In the hours and days after a traumatic brain injury, inflammation inside the brain can accelerate to the point that more brain damage occurs, says a scientist working to better understand the acceleration and whether interventions like cannabinoids can improve patient outcomes.

While some TBI patients do well, most would benefit from therapy to create a better balance between the vigorous inflammation needed in the immediate injury aftermath to clean up the site and the deceleration needed to complete healing and avoid more brain damage, says Dr. Kumar Vaibhav, translational neuroscientist in the Department of Neurosurgery at the Medical College of Georgia.

“You cannot suppress the entire pro-inflammatory process otherwise it would be difficult to recover from your injury,” Vaibhav says. But in this case, there is too much inflammation, a major factor in the reality that one-third of hospitalized patients with a TBI die from damage that continues after their acute injury.

The aftermath of concussions, essentially a closed-head injury, in football players is another case. Immediate problems might include a headache, dizziness and fogginess but ongoing memory and sleep problems, depression, as well as epilepsy, Alzheimer’s and Parkinson’s also can later occur.

Neither surgical nor medical intervention typically enable control of inflammation to limit the secondary destruction, and better understanding inflammation in the brain is a major barrier to successful treatment, the scientist says.

Vaibhav is principal investigator on a new US$1.8 million grant from the National Institute of Neurological Disorders and Stroke further exploring the role of the body’s endocannabinoid system — identified by researchers studying the mind-altering effects of THC, and now known to play a role in immunity, sleep, memory and even reproduction. Its involvement appears to start with the physical injury that happens to our brains.

With a TBI, the injured brain cells’ plasma membrane, which helps contain the cell’s contents, ruptures, releasing lipids, or fats, a major component of the membrane, throughout the body. Two key endocannabinoids, 2-AG and AEA, which are also lipid molecules, also get released from the damaged membrane where they are made. These molecules are supposed to bind with endocannabinoid receptors and activate the endocannabinoid system to help regulate the immune response. The two main endocannabinoid receptors are CB1 and CB2, and in this case, the 2-AG’s target appears to be CB2 receptors, which are found on immune cells and known to reduce inflammation and related problems like swelling and blood vessel dysfunction.

“Within 24 hours after an injury, we see CB2 receptor activation and expression go up with 2-AG secreted in the blood,” Vaibhav says. “It’s a very quick response.” Trouble is, the injured cells also release an enzyme called MAGL and the now-free-floating lipids further activate it.

MAGL, or endocannabinoid-metabolizing enzyme monoacylglycerol lipase, as its long name implies is an enzyme whose job includes degrading 2-AG once it has done its job. Activation of MAGL is known to worsen TBI outcomes but exactly what it does after TBI is not well understood, Vaibhav says.

Vaibhav and his colleagues think the problem is that high MAGL appears to degrade 2-AG before it can play out its important anti-inflammatory role. He theorizes that high MAGL levels become instead a switch that turns up inflammation after TBI. He also has some evidence that reducing MAGL levels can help restore a healthy synergy between MAGL, 2-AG and the cannabinoid receptor CB2, making it a key point for intervention.

His research team is using both a research drug that inhibits MAGL and the cannabinoid CBD, which they have early evidence also inhibits MAGL, to see if they are correct.

His team has found reduced 2-AG in the cerebrospinal fluid of people with TBIs, but exactly why it was happening was unclear. In their laboratory model of a TBI, they have also found that MAGL levels are high while 2-AG levels are low, suggesting a link. And, that when they selectively activate the CB2 receptor early after a TBI, immune cells like macrophages are less inclined to promote inflammation, that swelling and blood flow are improved, and so are outcomes. Conversely, immune cells that are very inflammatory have high levels of MAGL inside, more evidence for their reasoning that when MAGL is high, it’s degrading too much 2-AG before it can go bind with the CB2 receptor and calm inflammation.

When they have reduced MAGL levels with the research drug, 2-AG concentrations went up, so did its binding to CB2 receptors, and immune cells began to favor reducing inflammation, findings which they published in 2018 in the journal Brain, Behavior and Immunity. “It’s actually polarizing macrophages into anti-inflammatory,” he says.

A major focus of the new grant is to look at what early inhibition of MAGL in immune cells — with the research drug, cannabinoids as well as commercially produced versions of the endocannabinoids 2-AG and AEA — does to the enzyme’s apparent natural predisposition to accelerate inflammation following a TBI.

“If we inhibit MAGL or over activate it, what happens?” Vaibhav says, of answers he is pursuing to better define MAGL’s role. He and his team are looking again to see if reduced activation of the CB2 receptor by 2-AG in the face of high MAGL is key to injury progression. And, whether progression includes affecting the white matter — brain tissue full of nerve fibers that enable connections between different parts of the brain and the spinal cord — and worsening problems like dementia.

He is inhibiting MAGL to also see how that plays out, and wants to learn more about why MAGL levels don’t just return to normal on their own. He also wants to connect the dots with yet another lipid, prostaglandins, which are made at the site of an injury, and whose many roles include promoting inflammation, because when MAGL degrades 2-AG, it enables more prostaglandin production.

Vaibhav also wants to know if MAGL and/or 2-AG levels right after an injury are biomarkers of whether a patient will have destructive secondary damage.

In addition to honing in on the best place to intervene and whether the research drug or CBD can do it, they also have to find the optimal time for intervention, so they don’t interfere with the initial aggressive immune response needed to clean up the injury.

“We need to find the optimal dose and time to intervene,” Vaibhav says. “You have to know how many immune cells are activated, how long they are activated and when they are going down or suppressed to help determine the optimal time for treatment, and that is one of the things we are trying to do.”

Macrophages are a type of immune cell that are early arrivers to an injury site to digest debris and stimulate tissue repair, and can both promote or deter inflammation. Vaibhav’s lab and others have shown that more than a month after a TBI, macrophages have shifted from an early role in suppressing inflammation to chronically promoting inflammation in a vicious, destructive cycle where inflammation damages neurons, which produces debris, which increases inflammation.

In fact, an accumulation of inflammation-promoting macrophages has been seen in the corpus callosum, which connects the two hemispheres of the brain and enables their communication, in more than 25% of people with TBIs, an accumulation that correlates with brain damage two decades after their injury.

Once immune cells get activated, their instinct and function is to scavenge cell debris, which is a good thing essential to healing. But when they stay activated, the cells also start digesting healthy brain tissue and the size of the damage increases, Vaibhav says. Once an enzyme like MAGL gets activated, its major focus becomes staying activated and it will for weeks, he says.

During normal times, MAGL and 2-AG levels are both relatively low inside a cell, including immune cells. MAGL degrades 2-AG if too much gets made for some reason, and 2-AG helps keep inflammation at bay.

The hydrolase FAAH metabolizes AEA, like MAGL does 2-AG. There is not substantial proof to date of the impact of high levels of MAGL on the other major endocannabinoid AEA, but it could be a similar scenario, Vaibhav says.

Vaibhav’s collaborators on the new grant and related studies include MCG neuroscientist Dr. Krishnan Dhandapani, who also studies TBI, and Dental College of Georgia immunologist Dr. Babak Baban, who also studies the endocannabinoid system and the impact of CBD, including on the deadly cytokine storms that occur in COVID-19.

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Why are women more likely to use medical cannabis than men?

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Women are more likely to swap their prescription medication for medical cannabis, a study has found.

Researchers in the US have found that women are more likely to use medical cannabis than men – and to reduce using prescription drugs as a result.

The study, which was carried out by a team at DePaul University in Chicago, examined the behaviours of medical cannabis patients with a range of chronic health conditions in Illinois.

In the state, patients do not need a prescription, but must have one of a number of conditions to qualify for a medical cannabis card.

Researchers concluded that women ‘appear to be more likely than men’ to use medical cannabis for a range of symptoms, including pain, anxiety, inflammation and nausea.

Although previous population studies have shown that men are more likely to use cannabis recreationally, women were found to increase their consumption since qualifying for medical cannabis and as a result have ’reduced or completely discontinued’ any prescribed medications they were taking.

The study came about following interviews with medical cannabis patients about how they use cannabis, either as a complementary or alternative treatment or to reduce prescription medication altogether.

“This was a correlational, cross-sectional study, in which we were looking at potential correlates of the discontinuation of prescription medication and female gender appeared to be one of them,” lead author and associate professor in health sciences at DePaul University Dr Douglas Bruce told Cannabis Health.

“We didn’t go into the study thinking that men and women were using cannabis differently, but women seem to be adopting medical cannabis in a way that parallels with how women are more likely to access alternative and complementary treatments, such as yoga, guided meditation or acupuncture.

The women in the study also reported ‘marginally lower levels’ of support from their primary care provider, and ‘significantly less support’ from specialist physicians than the men, which researchers believe could point to why women are more likely to look for other options.

“The study suggests interesting patterns and maps onto findings of other studies which weren’t looking at medical cannabis specifically, but alternative complementary therapy trends,” continued Dr Bruce.

“I’ve worked in public health for many years and there are feminist theories which would argue that men are less likely to seek out healthcare than women, and that women may be more likely to seek out alternatives due to less satisfaction with the medical care they receive.”

He added: “There are gendered patterns in terms of medical care utilisation and diagnoses that feed into women seeking out alternatives and being less bound by conventions regarding going to the doctor.”

The majority of women in the study reported fibromyalgia [a condition which is said to affect around seven times as many women as men] as their chief qualifying condition for medical cannabis, while in men the most common conditions were PTSD, spinal cord injury and cancer.

“We controlled for fibromyalgia, given that around 80 percent of those with fibromyalgia sufferers in the study were women, but the parameters of the final model remained the same, with the key differences being gender, the amount of support from a provider and whether the patient was treating multiple symptoms,” explained Dr Bruce.

A paper Dr Bruce and his team published earlier this year found that those with multiple symptoms were more likely to report experiencing some benefit from medical cannabis.

“Medical cannabis seems to infer the successful mitigation of a range of symptoms that may reinforce one another,” he said of the findings.

“Those who were treating multiple symptoms were more likely to rate cannabis as efficacious, which suggests some benefit in people using cannabis products instead of different classes of prescription medications to treat their individual symptoms, which is typically how they are prescribed.”

The report concludes that more ‘patient-centered studies’ on medical cannabis are needed to ‘understand differences in dosing, outcomes, beliefs, attitudes, formulations, pharmacology, and metabolism between men and women’.

“There’s a whole pharmacological universe that may be gendered, particularly in terms of how men and women metabolise these products,” added Dr Bruce.

“Medical cannabis is a real patient-driven phenomenon and one of my aims in conducting this kind of patient-centred research is that physicians will start to learn from their patients.

“More open communication within the medical practice will benefit both the patients and the provider.”

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Community extends support to cannabis icon Rick Simpson

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Medical cannabis legend Rick Simpson has appealed to his supporters for financial help after suffering a stroke in 2018.

Cannabis campaigners, advocates and patients, whose lives have been changed by Rick Simpson oil (RSO) are being urged to return the favour, as the man behind it has revealed he is facing huge medical bills.

Over the last 15 years Rick Simpson has become a household name for many of those who have experienced the benefits of medical cannabis.

A former engineer from Canada, Rick ‘rediscovered’ the benefits of the cannabis plant in 2004 and published his findings and recipe online.

He has since become one of the best-known and loudest cannabis activists in the world, hailed for growing the plant in his own garden and giving it away for free to those who could benefit from it.

It is thought that his work helped paved the way for regulation and legalisation of medical and recreational cannabis in several countries, including his home of Canada.

Now Rick has revealed that he suffered a stroke in May 2018 which left him paralysed, with doctors doubting that he would ever walk again.

He has spent the last two and a half years out of the limelight, focusing on his recovery with his wife Danijela, but now his family has admitted that the couple are facing ‘immense financial challenges’.

A Go Fund Me page has been launched with a target of $160,000 to help cover Rick’s medical expenses.

In a statement on the fundraising page, a family spokesperson said: “After years of advocating for people’s rights to heal themselves using natural remedies, more specifically cannabis oil today widely known as RSO – Rick Simpson Oil, which a great number of people around the world are using to either cure or help regulate many different health conditions, and after writing two books on the subject, giving countless interviews and lectures, Rick is now in need of some kindness from all of you who are willing and able to help.”

His supporters from across the world have urged people to help the man who has helped so many.

Prominent Irish campaigner Vera Twomey, whose daughter Ava uses cannabis oil to treat severe epilepsy, commented: “Our dear friend rick simpson has been a mainstay in the world of cannabis for decades the measure of his knowledge and willingness to help people all over the world about cannabis has resulted in saving lives on every continent.

“We are deeply indebted to this wonderful man and now we hope that we can support him in a small way in his recovery from illness. He deserves nothing but the best for his concern and actions for people worldwide.”

Meanwhile Canadian, Sheriann Baker, who claims RSO saved her life when she was diagnosed with terminal brain cancer in 2017, issued a moving message for him.

“Rick, I pray you return to full health soon,” she said.

“You have helped and inspired so many of us around the world and you gave us hope when some of us had none. You gave us the strength and the education to fight and I know I will forever be grateful to you for that.

“Please know the cannabis community around the world is praying for you.”

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CBD has no adverse effects on health – study

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A landmark study has shown that long-term exposure to CBD does not appear to have any adverse effects on health.

The study, which is the first of its kind to examine the toxicity and long-term effects of CBD, has found that it did not demonstrate ‘any degree of acute or life-long toxicity’.

Instead, CBD actually extended the average lifespan and increased activity in later life.

The research was conducted by Spectrum Therapeutics, the medical division of Ontario cannabis company, Canopy Growth Corporation, as part of a commitment to provide the data which is needed to support and influence public policy.

These findings could be instrumental in changing public attitudes and improving access to CBD for patients who use it to help manage a range of symptoms including anxiety and pain.

The study evaluated the solubility, stability, acute toxicity, thermotolerance, and effects on lifespan of CBD in what is thought to be the first long-term toxicity and lifespan research regarding the effects of chronic exposure to cannabidiol.

Acute and long-term exposure studies of CBD at physiologically relevant concentrations were studied in the worm model Caenorhabditis elegans (C. elegans), which is recognised as a valid model for this kind of research on the basis that 60-80 percent of their genes are shared with humans and their short lifespan of two-three weeks makes such studies feasible.

Researchers found that CBD did not demonstrate any degree of acute or life-long toxicity or related liabilities at physiological concentrations.

Instead, it extended the average lifespan up to 18 percent and increased late-stage life activity by up to 206 percent when compared to the untreated controls within the study.

While further research into the life-long use of CBD should be carried out in mammalian models, this study indicates a lack of long-term toxicity at physiologically relevant concentrations.

“Despite widespread use of CBD, no life-long toxicity studies had been conducted to date to determine the impact – or potential impact – of long-term exposure to CBD,” said Hunter Land, senior director of translational and discovery science at Canopy Growth, said:

“These results serve as the only CBD life-long exposure data in an in vivo model to date, and the absence of long-term toxicity gives us the evidence we need as an industry to continue researching the potential health benefits for the broader application of CBD.”

The study is published in Cannabis and Cannabinoid Research journal and available online.

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