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“The industry has shown that these cannabinoids are effective. However, synthetic cannabinoids have also come with great risk.”
Cannabis has been used for therapeutic purposes for thousands of years, and at one time or another, has been claimed to benefits hundreds of different ailments. Despite an overwhelming amount of anecdotal evidence in support of its use, the scientific medical community has been slow to adopt cannabis, and even slower to prescribe it to patients. This is in part due to the largely political prohibition and propaganda campaign which began around a hundred years ago, but there are also other reasons. Despite cannabis showing benefits for so man people, it has been difficult to develop safe and effective drugs due to high variability, contamination with molds, adverse side effects, and potential for dependency. Furthermore, the fact that the main cannabinoid in the plant, THC, is also psychoactive makes it very difficult to run a placebo-controlled trial, as the participants generally know whether they have been given the active compound or not.
So, most of the problems surrounding the medical use of cannabis are not necessarily due to efficacy, but other factors that are difficult to control. Over the years, several FDA approved drugs have emerged which have solved some of these issues. With patented synthetic cannabinoid drugs like Marinol® (dronabinol), Cesamet® (nabilone), Sativex® (CBD+THC), and, outside the US, Epidioloex® (CBD). The industry has shown that these cannabinoids are effective, and have eliminated the risk of mold contamination and variability in dosage. However, these synthetic cannabinoids have also come with great risk, are not well tolerated by patients, and still have many side effects. But what they have proven is the importance of the body’s endocannabinoid system to our physical and mental wellbeing.
As we have covered before, many cohorts of medical patients are already using cannabis to treat their problems or symptoms. This includes cancer patients using it for pain and appetite, MS suffers using it to reduce spacisity and pain, Alzheimer’s patients using it to protect neurons and bring relieve, and so many individuals using to self -treat depression, anxiety, and other mental issues. Now that we understand how vital the body’s endocannabinoid system is, researchers are starting to look at other ways to manipulate that system to bring about better health.
The Endocannabinoid System
The endocannabinoid system of the body was only discovered less than 50 years ago, and we are still trying to elucidate all its secrets. At the basic level, it contains two type of receptors, CB1 and CB2. These receptors are found throughout the body, however the greatest concentration of CB1 receptors is in the brain and central nervous system. These receptors influence many of our mental processes, mood, learning, and memory. THC, the most well-known cannabinoid in the cannabis plant triggers these receptors and is a partial antagonist, meaning that it causes them to slow down or shut off. The CB2 receptors are generally associated with the immune system and various organs, and is most well known for its interaction with a different cannabinoid, CBD, which is also a partial antagonist. But it is not only these exogenous cannabinoids that affect this system, we also have endogenous cannabinoids in our bodies. Scientists are only just starting to be able to identify and understand all these various endocannabinoids and other lipids which interact in complex ways to modulate our internal systems, termed the “endocannabinoidome.”
However, two endocannabinoids in particular seem to be the most prolific and important, the first is Anandamide (AEA), and the second to be discovered was 2-arachido noylglycerol (2-AG). Unlike the cannabinoids in the cannabis plant, these two seem to work in different ways on both CB1 and CB2 receptors. Now that we are aware of their importance, science is turning away from focusing on just the exogenous cannabinoids that were discovered in the 1960’s towards a new future of medicine that address ways to modulate the effects of these endogenous cannabinoids for therapeutic purposes without all of the issues that have kept most synthetic cannabinoids unable to get past Phase II trials. This new future was analyzed in great detail by a recent review published by Gregus and Buczynski this month in the journal Advances in Experimental Medicine and Biology. In their article, they detail the new directions medicines are moving in, with therapies directly targeting the endogenous cannabinoid supply in the body.
Reducing Endocannabinoid Breakdown
Our bodies work largely based on multiple systems of chemical transmitters sending signals within and between various operating systems. These signals are often sent through chemical transmitters, such as the serotonin or dopamine that most are familiar with, but what happens after these transmitters have done there job? Rather then let them roam around the blood stream and send signals where they are not wanted, we have enzymes that break them down. Many drugs work then to prevent the action of those enzymes. Take MDMA for example, this molecule prevents the breakdown of serotonin, so serotonin keeps being released into the synapses, and since its not being destroyed it keeps building up, flooding the user with feelings of euphoria, love, and joy. In the same way new drugs are being targeted to decrease the activity of enzymes which breakdown the body’s endocannabinoids, AEA and 2-AG.
As detailed in the study, researchers are now testing drugs which inhibit the action of these enzymes. New drugs are in development which selectively stop enzymes like FAAH, MGLL, and ABHD6, which in mice studies mimics some of the positive effects of giving THC or CBD. Because these enzymes not only affect AEA and 2-AG, it is still complicated, and many more trials will need to take place before a drug can go to market, but in rat studies it has been observed to result “in a battery of CB1-dependent and CB1-independent behavioral changes. . .These effects include, but are not limited to, decreased anxiety-like and depression-like behaviors, gastrointestinal function, altered expression of drug and alcohol withdrawal, as well as diminished inflammatory and neuropathic pain states.”
Even now, several drug companies are trialing FAAH inhibitor drugs, which mainly affects AEA levels, to treat a wider range of human conditions, including fear memory extinction, Tourette Syndrome, chronic pain associated with spinal cord injuries, osteoarthritis, and prostate issues. Other drugs are focused on the enzyme MGLL, which acts more on 2-AG. Already there are more than two hundred publications on MGLL inhibitors, many of them suggesting promise in the areas of “drug withdrawal , pain states, stress, immune function, cancer, gastrointestinal function, and neurodegeneration.” Giving the impression that 2-AG may work much like CBD, while AEA may be more analogous to THC.
Reducing the Production of Endocannabinoids
As discussed above, a new wave of drugs focused on increasing the bioavailability of endocannabinoids is on the way, but like the synthetic cannabinoids, they are not without their risks. Because current drugs are not entirely selective, they may inhibit enzymes from removing endocannabinoid-like lipids that could be deleterious for the patients. In many of the trails major side effects have been seen, including long-term psychological ones, that have temporarily halted testing or even sent researchers back to the drawing board. Another new class of drugs is being developed which would actually treat disorders where too much endocannabinoids are present, and focuses on preventing those endocannabinoids from being synthesized in the first place. This was first found in an FDA approved drug for treatment of obesity, Orlistat or Alli®, which was found to decrease the presence of two lipases known as DAGLα and DAGLβ, and thus lead to an 80% decrease in blood serum 2-AG levels.
Interestingly, in mice studies, knocking out the gene for DAGLα has almost the same effect as knocking out the gene for CB1 receptors, including enhanced metabolic function, lower body weight, decreased body fat, and reduced fasting insulin/lipid levels. It also brought psychological issues and increased mortality rates. These observations, coupled with other studies, led to the understanding that DAGLα is important in the development for the central nervous system, promoting neurogenesis and the dendritic connections between neurons. This has led to a race for new drugs utilizing the DAGLα pathways to cannabinoid synthesis in the treatment of diseases such as alcoholic fatty liver disease, Alzheimer’s disease, and neuropathic pain. Again, time will be needed to work out the side-effects, as DAGLα and β are also precursors for other compounds in the body, including many parts of the immune system such as the prostaglandins which act to initiate the body’s healing processes.
Change the Conditions Where Cannabinoids are Built
The last new frontier of treatment covered in the review looked more at how these endocannabinoids were being created from the precursors such as DAGLα and β, or the ‘substrate.’ This may end up being a more selective area for research than the previous two, potentially with less side effects. Already one drug, Lumigan® has been approved by the FDA to reduce ocular pressure associated with glaucoma, and it has the side effect of making eyelashes longer, so the drug is also marketed under another name, Lastisse®. But, the expectation of the authors was that this new class of drugs could replace many of the non-steroidal antiinfallmmatory drugs currently on the market (such as ibuprofen) which have many series side effects for the liver, kidneys, and GI tract.
What is the future of cannabis-based medicine?
Over the last hundred or so years, many researchers in the field of medicine have been very optimistic about the use of cannabis, based largely on anecdotal reports. However, many of these benefits cannot be scientifically replicated or proven, with cannabis often coming up short of its promise. But, it may be that cannabis has now ushered in a whole new revolution of drugs and therapeutics, from which cannabis is absent. The discovery of THC in the 1960’s led to the discovery of the body’s endocannabinoid system in the 1980’s, and today may be leading to a much better understanding of the interworking of our bodies, the mind-body connection, and so much more.
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