Allosteric Modulation: The Versatility of Cannabinoid Receptors

These are exciting times for a cannabinoid researcher; new information must constantly be integrated with the growing body of knowledge surrounding the endocannabinoid system. At times, that new information can even flip our understanding of the system on its head. One great example of that is embodied in the research surrounding allosteric modulation. In our traditional understanding of the endocannabinoid system, there are two types of receptors: CB1 receptors, which are located primarily in the brain, and CB2 receptors, which are located throughout the central nervous system and immune system. CB1 receptors are known to be the primary cause of psychedelic effects from cannabis, so readers should not be surprised that THC bonds to those. In this model, receptors can either be activated or de-activated at varying degrees. For instance, a cannabinoid that barely activates a CB1 receptor would be a “weak/partial CB1 agonist”, while one that deactivates all CB2 receptors would be a “strong CB2 antagonist”. The first cannabinoids that were studied, such as THC, could adequately be described in such terms. However, as time went on, researchers began to suspect that cannabinoids could bond to our cannabinoid receptors at alternate sites, based on the knowledge that similar properties have been observed in other types of receptors. What’s the difference? Everything. Consider the process of inhibition: normal (orthosteric) inhibitors can either trap the agonist to keep it from activating the receptor or can compete with the agonist for a bonding site (effectively reducing the number of receptors that can…

Seeing is Believing: ICRS

Greetings readers, we’ve just returned from the 2015 International Cannabinoid Research Society (ICRS) conference. ICRS describes itself as “a non-political, non-religious organization dedicated to scientific research in all fields of the cannabinoids, ranging from biochemical, chemical, and physiological studies of the endogenous cannabinoid system to studies of the abuse potential of recreational Cannabis.” Many one-off or repeating conferences regarding cannabis and cannabinoid science have been held since the 70’s, after Raphael Mechoulam’s structural identification and synthesis of THC. However, ICRS represents one of the first and longest-running to focus on research stemming from Mechoulam’s later discovery of the endocannabinoid system, the system of receptors, enzymes, and neuromodulatory lipids that plays a role in a host of physiological and neurological activities. After attending almost every talk, we have a fresh stockpile of new information to report to you, straight from the frontlines of research. We will begin to unfold this information in the next few articles, but some of the most exciting new pieces involve new types of cannabinoid receptors and ways that cannabinoids can signal biological changes without receptors at all. Other new innovations in the field were highlighted by a terrific closing speech by Mechoulam, who spoke of endocannabinoid signaling that might occur through sources as unexpected as bacterial films, as well as the need for more testing to determine the actual harm cannabis might have on children. One perhaps unavoidable theme of the conference was the harmony and clash between research focusing on phytocannabinoids and synthetic cannabinoids. Although…

Medical Marijuana Laws and Adolescent Marijuana Use

One of the biggest hurdles with medical cannabis legislation is convincing the public that new laws will do more good than harm. In California, the rate of adults who have used medical cannabis is reportedly one in 20, which leaves 19 in 20 uninterested (or dishonest on surveys). Assuming the proportion of adults is roughly equal in other states, this means a large majority of voters are not voting with the mindset, “this enables me to use medical cannabis,” but instead voting with the mindset, “this enables others to use medical cannabis.” While those voters may realize the societal benefits of medical cannabis (such as decriminalization and reducing healthcare costs), their primary concerns will still be, “will this negatively affect me or my loved ones?”.  At the forefront of this discussion is the impact of medical cannabis laws on the opinions of teenagers toward cannabis. As reported in a recent study by Columbia University, almost 20% of high school seniors reported they’d be more likely to use cannabis if it were legalized for medical use, with 55% of adolescents believing cannabis would be easier to acquire. As a lawmaker, this is cause for alarm. To determine the best course for society, we must weigh the advantages of medical cannabis against possible disadvantages. However, just because teens believe themselves more likely to use cannabis because of medical cannabis laws does not necessarily make that true. Thus, researchers at Columbia set out to conduct a survey to establish the rate of adolescent…

Cannabinoids in Pain Management, A Review

Pain management is one of our most revisited topics here on the Cornerstone blog. Our commitment to reporting studies related to pain management should come as no surprise to readers; pain relief accounts for a substantial portion of all medical cannabis use. Usually we update you on new findings within the field; however, today we are going to take a step back for a more general review, courtesy of Ethan Russo and Andrea Hohmann. Medicine, as Russo points out, really began with plants. Our early ancestors would have noticed the effects of consuming plants within their environments and then learned to use those effects. Though we like to think of mankind as superior creators when compared to plants, humans are comparatively inefficient at producing pharmaceuticals. Plants have the surprising ability to produce complex chemicals like THC from sun, water, and dirt, whereas we have to build labs with precision machinery, electrical power, and contamination control! As a result, the first functional medicines were not human synthesized and instead came from plants. From coca leaves to morphine, these chemicals wove themselves into the history of human civilization. However, in modern times, plant-based chemicals are not generally accepted as medicine. This isn’t necessarily due to a bias against plants, but more importantly because plant-produced compounds are naturally inconsistent. In the case of cannabis, the way the plant is grown can greatly affect the profile of chemicals produced, not to mention the potency. Different buds on the same plant might even have significantly…

The US Race to Catch Up on Cannabis Research

You may have already seen this month’s issue of Time Magazine; it features a lab rat smoking a joint. Ten years ago, if someone had told me that this would be the cover of a fairly conservative magazine aimed at middle-age readers, I would have laughed. However, the feature article is actually a very fair and unbiased look at the global state of cannabis research. This is thanks in part to Bruce Barcott, the article’s principal co-writer and author of the book, “Weed the People: The Future of Legal Marijuana in America”. As a journalist Barcott has an incredible degree of familiarity with cannabis and seems to take a mostly positive stance. The TIME article echoed this sentiment by suggesting that cannabis does indeed help, and has the potential to help many but is also not harmless and may cause serious damage if used during pregnancy or by adolescents. This is not far from Cornerstone’s stance. To be fair, lately TIME seems to be trading legitimacy for readers in the race to stay relevant against newer media. For instance, making Kanye West the cover of TIME’s “100 Most Influential People” – I’m a Yeezy fan, but if he’s really the most influential person in the world (or even top 100), then we’re all in serious trouble. However, other well-respected publications have published similar articles, such as this month’s National Geographic article, “Science Seeks to Unlock Marijuana’s Secrets”, and CNN’s 2013 Chief Medical Correspondent feature “Why I Changed My Mind on…

Can Cannabis Lower Blood Pressure?

Cannabis has historically been thought of as a relaxant and a depressant of the physical body. As a result it’s no surprise that the idea of using cannabis to help manage blood pressure has gained some traction recently. While generally confirming the idea that cannabis can lower blood pressure, recent experiments have also shown some disagreement depending on the manner in which experiments are conducted. A review from the University of Nottingham encapsulates some of the discussion around the effect of cannabinoids on blood pressure, but for readers wanting a digested answer, the clearest part of the conversation is that cannabis use almost certainly does not contribute to high blood pressure, especially when vaporized. High blood pressure or hypertension is a condition in which the force of a person’s blood against their artery walls is higher than normal and therefore likely to lead to a host of other problems. Although high blood pressure that occurs without symptoms often goes unnoticed, the body can only compensate for unhealthy blood pressure for a limited amount of time. Left uncontrolled, high blood pressure can lead to heart attack, stroke, heart failure, vision loss, and poor kidney functioning, all without much warning. The general research pipeline for investigating a new area of medicine tends to flow from test tube, to rodents, and lastly to humans. Genetically modified rodents are expensive to create and time-consuming to maintain, so preliminary assays are usually first performed on the cells in question outside normal living conditions (such as…

THCV. Forget What You’ve Heard

One of the biggest obstacles to responsible proponents of medical cannabis is the amount of misinformation we have to contend with from both sides. On one side there are  government-sponsored publications that directly misconstrue the science behind cannabis. On the other, there are well-meaning citizens of the cannabis community that get carried away. To their credit, cannabis *is* a magical Swiss Army Knife of a plant. The amount of uses for cannabis from medical to industrial is mind-boggling; humanity has always had a special relationship to the plant, which is evident in some of the oldest Chinese characters. However, in the tide of wanting to support positive change and wanting modern society to see the truth about such a useful plant, some sources are too lenient on fact checking. For instance, someone who reads a study stating cannabis components kill cancer cells in a rat tumor, concludes that smoking cannabis cures cancer, and proceeds to distribute that viewpoint throughout the community. The truth is cannabis does hold answers to new chemotherapy drugs which may be used in conjunction with other treatments, but that’s obviously not the same as saying it is a cure for cancer. Overly-hopeful supporters of cannabis need to be carful not to unintentionally harm the integrity of the movement. This “hype” effect is especially pronounced in the case of tetrahydrocannabivarin (THCV). Just like the name sounds, this is a chemical cousin of THC, the principal psychoactive component of cannabis. However, there are a few key functional differences.…

Whole Plant CBD More Effective Than Pure CBD?

At Cornerstone, we talk frequently about dosing, not just because it’s important to members, but also because it’s important to us. The end goal is for every patient to experience the maximum benefit of medical cannabis. Although it seems tempting to think that more medicine always means more healing, that’s just not the reality of how cannabinoids are processed in the body. In truth the body’s response is much more complex. Exhibit A: This is a graph that illustrates anti-inflammatory properties of cannabidiol (CBD) at various doses.   You’ll notice that the shape is a bell curve, meaning that in many cases, more CBD could actually equate to less anti-inflammatory help. This is not a graph mistake; it’s a common observation of the effects of CBD. In other words, dose matters. As seen, the greatest effect of CBD will occur at the middle of the curve. Because dosage depends on body fat, tolerance, and a host of other individual factors it is very difficult to advise users on “the most effective dose” for them. Cornerstone can offer you suggestions, but ultimately, individual patients are going to have to discover what amounts and what dosing schedules work for them. What is clear to us though, is that patients may get more out of their medicines by showing restraint. All that aside, wouldn’t it be great if CBD could be given in a preparation that was not dose-dependent? Shouldn’t there be a way to beat the dose curve? This is exactly the question Israeli…

Does Long Term Cannabis Use Make You Dumb?

I vape cannabis several times a day and have no intentions of stopping anytime soon. It’s never slowed my work ethic or turned me into a zombie. Instead, I feel more creative and at peace. I don’t have any life threatening health conditions or chronic pain, and I’ve never been one to take a lot of pharmaceuticals. However, since I’m not a “hippy” by any means, I tend to have a lot of non-cannabis-using friends who occasionally ask me about my frequent cannabis use. Invariably, the question that always comes up is, “…do you think that stuff rots your brain over time? I heard it makes people dumb if they use it too much…” If you’re open about cannabis use, you’ll probably encounter this conversation at least once. Culturally, we’re used to the image of a stoner-burnout, a guy stuck in the 70’s that handles life like Jeff Bridges’ character in The Big Lebowski. We look at these people and we secretly wonder to ourselves, “did smoking cannabis all day every day make them this way? Will I be like that if I continue to use cannabis?” When we talk about the safety of cannabis, we’re really talking about quite a few things. First, there are the things that we know as facts. Fact: It’s damn near impossible to overdose on cannabis. The amount of THC that would be needed to cause an overdose is such a large quantity that the volume alone makes it difficult to do. For instance,…

Does Cannabis help Neuropsychiatric Disorders?

For most states with medical cannabis laws, patients are required to go through a screening process once a year to allow access to cannabis. On the one hand, this screening process is not designed to be severe, and realistically, few people are turned away from help with cannabis. On the other hand, this process is intended to serve as a boiler-plate to keep cannabis out of the hands of individuals for whom it might not be appropriate. Seeing that cannabis does not have harmful side-effects and is physically very safe, the real concern is whether patients who are already in an altered state of mind should be taking a psychoactive substance. Studies have linked early cannabis use to hastening the onset of serious psychiatric illnesses such as schizophrenia. This is not unique to cannabis and also true of any psychoactive substance. If someone is having a hard time navigating reality, taking a medicine or recreational drug that alters his/her mind-state even further may push him/her over the edge. Despite this well-established fact, there are also many psychiatric patients that receive relief from cannabis and tend to do worse without it. The medical field has also shown increased interest in treating psychiatric illness with cannabis. So what’s the deal? Does cannabis contribute to or relieve schizophrenia? Or is there no effect? The difficulty in answering this lies partly in the fact that schizophrenia is not well understood and could actually be multiple illnesses that have been lumped into one category due…