One of the world’s leading cannabis scientists has shared his latest findings – the discovery of several new compounds which could play a role in managing a wide range of global health issues.
Professor Raphael Mechoulam, is widely regarded as the ‘father of cannabis’ following his discovery of the endocannabinoid system (ECS) in the early 90s.
In a one-off event at the Royal Society of Medicine in London on Monday 11 October, the professor discussed his latest work, including the discovery of new compounds that could play a role in treating brain injury, nicotine addiction and in preventing antibiotic resistance.
The event, which was organised by Integro Clinics, saw medical professionals, scientists and industry experts share their insights on the emerging field of cannabis medicine at the well-established institution.
Prof Mechoulam, shared his findings to a captive audience, attending virtually from his office at the Hebrew University of Jerusalem, in Israel.
His research offers promising potential for the treatment of a wide range of conditions and health issues.
Depression and pain
Cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA) are found in the cannabis plant before being synthesised to produce CBD and THC and are thought to be more potent.
Prof Mechoulam and his team of researchers recently stabilised CBDA, developing the compound cannabidiolic acid methyl ester (EPM301). According to a study carried out with researchers in Canada, this was found to reduce depression and lower pain in animal models.
Prof Mechoulam explained: “The plant actually doesn’t synthesise either THC or CBD. It synthesises their precursors which are acids.
“These compounds have not been investigated very thoroughly, because they are not stable, but we were able recently to stabilise CBDA by making a methyl ester and with this we have been able to look at the activity of this acid derivative.
“This particular compound, which is present in quite large amounts in the cannabis plant, is of considerable interest.”
Along with anandamide, 2-Arachidonoylglycerol (2-Ag) is one of two primary endocannabinoids which bind with both the CB1 and CB2 receptors.
Researchers have now found that 2-Ag is effective in reducing head trauma following traumatic brain injury, as well as reducing vasoconstriction – the narrowing (constriction) of blood vessels in the brain.
“We saw that 2-Ag when administered to mice lowers the damage [to the brain]… the damage in the control group was 50 percent higher than those that received 2-Ag,” said Prof Mechoulam, who hopes a drug will be developed using 2-Ag as a compound against brain damage.
His team was then able to identify and isolate another “more active” compound, arachidonoyl serine (AraS).
According to Prof Mechoulam, AraS acts similarly to anandamide, but does not bind to the cannabinoid receptors and is “much more potent” in reducing the effects of vessel constriction.
Prof Mechoulam also revealed that AraS can encourage the activity of antibiotics, potentially providing a solution to the major impending health crisis that is increased antibiotic resistance.
“One of the major problems we have in medicine today is that many of the microbes have antibiotic resistance and if we cannot overcome this major problem, we will be back as we were in the 1930s, with microbes that we cannot attack by antibiotics,” he said.
“When microbes are attacked by an antibiotic, one of the ways they resist is by producing a biofilm. Millions of microbes get together and they form a biofilm, which is not attacked by the antibiotic.
“We found that AraS can overcome the microbial resistance of these particular microbes… AraS prevents the biofilm formation by altering the surface of the cell without actually killing the bacteria.
“This may be a very promising way of overcoming microbial resistance.”
Another newly-discovered compound known as oleoyl serine (OS), an endogenous fatty acid produced in the bones, is thought to improve bone formation, reducing and even reversing the effects of osteoporosis.
Prof Mechoulam explained: “The bones we have do not stay the way they are throughout our life, they are broken down all the time by osteoclasts, and at the same time are being rebuilt by osteoblasts. In certain diseases, for example osteoporosis, the osteoclasts work overtime and the osteoblasts cannot promote enough bone formation.”
In a study, mice with osteoporosis symptoms were given OS for 40 days, with results showing that the bones stopped breaking down and began to recover.
Prof Mechoulam and colleagues concluded that OS reduces the effects of osteoporosis, reducing the breakdown of the bone and promoting bone formation.
“We can see now that bones do not continue breaking down and as a matter of fact recover,” he said.
“Most of the drugs that we have for osteoporosis usually just [work to] stop the disease or stop the disease to a certain extent. Very few of the drugs, if any at all, cause the formation of the bone again.”
Earlier this year, a stabilised derivative of OS, H2671 was also shown to exhibit “high efficacy” in reversing the effects of osteoporosis in Prader-Willi syndrome.
Mechoulam’s colleagues in Italy have discovered another endogenous compound, again closely related to anandamide, known as oleoyl glycine (OS).
Using a conditional place preference model [where mice or rats are given the option to go to food with or without nicotine] fellow researchers in Canada found that when mice were given OG, they did not become addicted to the nicotine in their food.
Prof Mechoulam revealed he was “disappointed” that the same model didn’t work with opioid addiction, but OG did prove effective in reducing both nicotine and opioid withdrawal symptoms.
“It turns out that withdrawal and addiction are two different types of response,” he explained.
“Today we know that OG works on nicotine addiction and does not work on opiate addiction, but it does work on nicotine and opiate withdrawal symptoms.”
The authors of the study concluded that morphine withdrawal reactions were accompanied by “suppressed endogenous levels of OG in different parts of the brain.”
Mechoulam and colleagues then stabilised this compound to develop oleoyl alanine which turned out to be “more active” for a “longer period” of time than OG.
He added: “We found that oleoyl alanine is not only more stable, but also a more potent anti-withdrawal molecule than OG, and I am under the impression that this compound should [be developed] to become a drug.”
CBN discovery could lead to new treatments for Alzheimer’s, say researchers
A new study suggests CBN has the potential for treating age-related neurodegenerative diseases.
More findings on the cannabinoid CBN could lead to the development of new treatments for neurodegenerative diseases such as Alzheimer’s and Parkinson’s, say researchers.
Derived from the cannabis plant, CBN is similar to THC, but is not psychoactive and is less heavily regulated by bodies such as the FDA.
Previous research by senior author Pamela Maher, a research professor and head of Salk’s Cellular Neurobiology Laboratory, found that CBN had neuroprotective properties, but it wasn’t clear how it worked.
Now, these new findings, published in the journal Free Radical Biology and Medicine, explain the mechanism through which CBN protects brain cells from damage and death.
“We’ve found that cannabinol protects neurons from oxidative stress and cell death, two of the major contributors to Alzheimer’s,” says Maher.
“This discovery could one day lead to the development of new therapeutics for treating this disease and other neurodegenerative disorders, like Parkinson’s disease.”
Maher’s team looked at the process of oxytosis, which is thought to occur in the ageing brain, and which growing evidence suggests may be a cause of Alzheimer’s disease.
In the study, the scientists treated nerve cells with CBN, and then introduced an agent to stimulate oxidative damage.
They found that the CBN worked by protecting mitochondria, the cell’s powerhouses, within the neurons. In damaged cells, oxidation causes the mitochondria to curl up like donuts—a change that’s also been seen in ageing cells taken from the brains of people with Alzheimer’s disease.
However, treating cells with CBN prevented the mitochondria from curling up and kept them functioning well.
To confirm the interaction between CBN and mitochondria, researchers then replicated the experiment in nerve cells that had the mitochondria removed. In these cells, CBN no longer demonstrated its protective effect.
“We were able to directly show that maintenance of mitochondrial function was specifically required for the protective effects of the compound,” Maher said.
Potential for other diseases
In another key finding, researchers showed that CBN did not activate cannabinoid receptors, which are required for cannabinoids to produce a psychoactive response. Thus, CBN therapeutics would work without causing the individual to become “high.”
First author Zhibin Liang, a postdoctoral fellow in the Maher lab, said: “CBN is not a controlled substance like THC, the psychotropic compound in cannabis, and evidence has shown that CBN is safe in animals and humans. And because CBN works independently of cannabinoid receptors, CBN could also work in a wide variety of cells with ample therapeutic potential.”
In addition to Alzheimer’s, the findings have implications for other neurodegenerative diseases, such as Parkinson’s, which is also linked to glutathione loss.
“Mitochondrial dysfunction is implicated in changes in various tissues, not just in the brain and ageing, so the fact that this compound is able to maintain mitochondrial function suggests it could have more benefits beyond the context of Alzheimer’s disease,” Maher said.
She added that the study shows the need for further research into CBN and other lesser-studied cannabinoids.
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New studies examine effects of THC and CBD on stroke
New data suggests both positive and negative effects of cannabis in stroke patients
A new study has shown that pre-treatment CBD may have a neuroprotective effect in stroke patients.
The study aimed to investigate the effect of CBD on oxidative stress and cell death which occurs in ischemic stroke patients.
It revealed that the cannabinoid may reduce the destructive effects of cell damage associated with stroke.
Ischemic strokes are the most common type of stroke. They occur when a blood clot blocks a flow of oxygen or blood to the brain. This takes place in arteries that have been narrowed or blocked over time by fatty deposits (plaques). The most common symptoms of a stroke include facial drooping on one side, not being able to lift your arms and slurred speech.
If this occurs, it is vital that a person be taken to the emergency room immediately.
The National Institute of Health Care and Excellence (NICE) estimate that there are around 100,000 strokes every year in the UK. It is also thought that 1.3 million people live with the effects of a stroke.
Stroke recovery and CBD results
The Study showed that CBD reduced the amount of infarction in those samples which had been given the cannabinoid. Infarction refers to the death of tissue as a result of a lack of blood supply and is commonly due to a blood vessel being obstructed or narrowed.
There were also differences in malondialdehyde level (MDA) – a common marker of oxidative stress – between the brains of the CBD group and the vehicle group.
It also revealed that CBD may help to protect tissue by preventing further damage.
THC and stroke risk
According to findings, cannabis consumers who experience a stroke known as an aneurysmal subarachnoid haemorrhage (aSAH), are twice as likely to develop further complications.
An aSAH occurs when a weakened blood vessel bursts on the surface of the brain leading to bleeding between the brain and tissue that covers it. It can result in neurological disabilities, long-term slurred speech or even death. It is estimated that aSAH affects around eight people per 100,000 of the population each year, accounting for six per cent of first strokes.
The study by the American Stroke Association suggested there is twice the risk of developing delayed cerebral ischemia for cannabis consumers. The researchers analysed data from 1,000 patients who had received treatment for bleeding over a 12 year period. In the group of participants, 36 per cent developed cerebral ischemia and 50 per cent had moderate to severe disabilities.
When comparing the results of patients who tested positive for THC with those who did not, they found cannabis consumers were 2.7 times more likely to develop cerebral ischemia. They were also 2.8 times more likely to develop long-term moderate to severe physical disabilities.
However, compared to those who tested negative for THC, the cannabis group did not have larger aneurysms, higher blood pressures or worse stroke symptoms when admitted to the hospital. They did not have any higher cardiovascular risk factors than the negative group.
Researchers are now conducting further studies in which they hope to better understand if THC can impact aneurysm formation and rupture.
New study shows CBD may prevent Covid-19 infection
Researchers are calling for more trials to determine if CBD could be a preventative or early treatment for the virus.
Researchers are recommending clinical trials to examine if CBD could help to prevent Covid infection after more positive findings have been published.
Researchers from the University of Chicago have reported that CBD may stop the infection of Covid-19 by blocking its ability to replicate in the lungs.
A number of cannabinoids including CBD and THC were tested along with 7-Hydroxycannabidiol (7-OH-CBD) which is thought to be produced when cannabidiol is processed by the body.
The study found that CBD showed a significant negative association with SARS-CoV-2 positive tests in a national sample of patients who were taking high doses of CBD, prescribed for epilepsy.
As a result of their findings, researchers are calling for more clinical trials to determine whether CBD could eventually be used as a preventative or early treatment for the virus.
Covid and CBD study
Researchers treated human lung cells with a non-toxic dose of CBD for two hours before exposing the cells to SARS-CoV-2 and monitoring them for the virus and the viral spike protein.
They found that, above a certain threshold concentration, CBD inhibited the virus’ ability to replicate.
Further investigation found that CBD had the same effect in two other types of cells and for three variants of SARS-CoV-2 in addition to the original strain.
CBD did not affect the ability of SARS-CoV-2 to enter the cell. Instead, CBD was effective at blocking replication early in the infection cycle and six hours after the virus had already infected the cell.
Like all viruses, SARS-CoV-2 affects the host cell by hijacking its gene expression machinery to produce more copies of itself and its viral proteins. This effect can be observed by tracking virus-induced changes in cellular RNAs. High concentrations of CBD almost completely eradicated the expression of viral RNAs.
When it came to the other cannabinoids, CBD was found to be the only potentially potent agent. There was no or limited antiviral activity noted by the similar cannabinoids including THC, CBDA, CBDV, CBC or even CBG.
Marsha Rosner, PhD, professor and senior author of the study said it was a completely unexpected result, she commented: “CBD has anti-inflammatory effects, so we thought that maybe it would stop the second phase of COVID infection involving the immune system, the so-called ‘cytokine storm.’ Surprisingly, it directly inhibited viral replication in lung cells.
She added: “We just wanted to know if CBD would affect the immune system. No one in their right mind would have ever thought that it blocked viral replication, but that’s what it did.”
The researchers do caution that this is not possible with commercially available CBD. The CBD tested was high-purity and also medical grade.
However, Rosner cautioned: “Going to your corner bakery and buying some CBD muffins or gummy bears probably won’t do anything. The commercially available CBD powder we looked at, which was off the shelf and something you could order online, was sometimes surprisingly of high purity but also of inconsistent quality. It is also hard to get into an oral solution that can be absorbed without the special, FDA-approved formulation.”
CBD and Covid studies
This is the second study to be released showing the potential for cannabinoids in Covid management and prevention.
A study by Oregon State University has revealed that the compounds cannabigerolic acid (CBGA) and cannabidiolic acid (CBDA), may have the ability to prevent the virus that causes Covid-19 from entering human cells.
Researchers and scientists, led by Richard van Breedan, found that a pair of cannabinoid acids bind to the SARS-CoV-2 spike protein, blocking a step in the process the virus takes for infection.
Targeting compounds that block the virus-receptor interaction has been helpful for patients with other viral infections such as HIV-1 and hepatitis.
The researchers and scientists identified the two cannabinoid acids through a screening technique, developed previously in van Breeman’s laboratory. The team also screened different botanicals such as red clover, hops, wild yam and three types of liquorice.
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