In this episode of the Curious About Cannabis Podcast, we take a look at CBD, the cannabinoid that has been all the rage lately. We are joined by neurologist and cannabinoid researcher, Dr. Ethan Russo, anesthesiologist and pain physician, Dr. James Taylor, and co-owner of Artemis, a premier CBD shop in New York City, Wendy Nguyen, to discuss the history of CBD, what people are experiencing with CBD, and how CBD affects the body.
Look for the associated behind-the-scenes (BTS) episodes for each of our guests to hear our full conversations!
Episode Transcript/Show Notes:
You’re listening to the Curious About Cannabis Podcast
Before we get started let me share a little disclaimer here. In this episode we are going to be discussing the medical uses of Cannabis. All of the information I present to you in this podcast is for education and entertainment purposes only and should not be considered medical advice. Never make decisions about your health based on anything you hear me or any other podcast host talk about. I’m simply sharing information that I’ve collected from talking with professionals with relevant experience or from research studies that are available. But I’m not a doctor, and you should always get your medical advice from a licensed health care professional. Now with that out of the way, let’s move on.
These days, CBD is all the hype.
The 2018 Farm Bill paved the way for legal hemp production in the United States, seeming to open up a multi-billion dollar hemp market that was now up for grabs. Of all the potential surrounding legal hemp, there was one section of the hemp market that had everyone’s attention – the CBD market. It is estimated that over 1000 CBD brands came onto the market in 2019, and it’s estimated that approximately a quarter of the US population has tried CBD.  Health claims have been boasted and promoted by CBD companies, doctors, entertainers, and social media influencers. So what’s the deal? Is CBD legit? Or it just another snake oil? And what does CBD actually do to your body?
In this episode we explore the history and science of the cannabinoid that’s all the craze – Cannabidiol, or CBD.
Hey everybody, this is Jason Wilson with the Curious About Cannabis Podcast. Thanks so much for tuning in once again! In this episode we are going to be taking a close look at one of the most popular cannabinoids produced by the Cannabis plant, Cannabidiol – or as it is better known, CBD.
And to guide our curious quest, we are going to explore several primary questions:
So let’s get started!
What is CBD?
[News Clip Compilation]
For the past few years, CBD has been big business. The price of a single one-ounce bottle of CBD tincture can range anywhere from $50 to $200 or more. Compare that to the average cost of a one-ounce bottle of a different herbal extract tincture like Echinacea or Elderberry that would typically cost somewhere between $10 and $20.
So, why is CBD getting tagged with such a high premium?
But what is CBD?
CBD, or Cannabidiol, is an oily compound produced in the resins of the Cannabis plant. Whether the Cannabis plant is considered hemp or marijuana – they both produce CBD, outside of some uncommon exceptions. In the United States, hemp is classified as Cannabis plants that contain less than 0.3% THC. In other countries the limit can be even lower, commonly 0.2%. Instead of THC, the primary cannabinoid that hemp varieties of Cannabis tend to produce is a cannabinoid called Cannabidiol, or CBD. Thanks to intentional breeding efforts, CBD can now be found in concentrations as high as 20 or 25% in hemp plants intended for CBD-rich resin production.
CBD is markedly different than THC. To start, CBD does not cause intoxicating or euphoric effects like THC does. This feature has gotten the attention of a lot of people, ranging from medical researchers looking to unlock the therapeutic potential of Cannabis without the risk of abuse to consumers interested in Cannabis but not looking to get high. Although CBD is not intoxicating, it is psychoactive, meaning that it elicits effects on neurons. This is a common misunderstanding about CBD.
A Brief History of CBD
The story of CBD goes back thousands of years – as cultures across time have used non-psychoactive varieties of Cannabis for different uses. But the most relevant part of our story really starts in 1940, when researchers Roger Adams, Madison Hunt and JH Clark published a report indicating the structure of a compound that they extracted and isolated from wild hemp in Minnesota. (Shout out to listeners in Minnesota! You’re a part of CBD history.) These researchers named this compound, Cannabidiol, or CBD as it would become commonly known. CBD was only the second cannabinoid found in Cannabis at the time, the first being Cannabinol, or CBN – a degradation product of THC.
In 1944 it was discovered that the effects of barbiturates could be extended if administered with CBD, but not with CBN or THC. There answer to why CBD had this effect would come almost 30 years later.
For a moment in 1963, scientists in Israel would shine light on CBD once again, before announcing their discovery of THC as the intoxicating components of Cannabis – a year later in 1964. CBD would become a bit more ignored once again until around the 1970s and 80s when research into CBD really began to pick up steam.
In 1972 it would be discovered that CBD inhibited certain enzymes in the body, which affects how the body metabolizes certain foods and drugs. This helped begin to complete the puzzle that stemmed from the barbiturate study three decades prior. In 1981 researchers were able to demonstrate anticonvulsant effects in humans – indicating that it might be an effective treatment for certain forms of epilepsy and spasticity. In 1982 CBD was found to exhibit anti-anxiety effects, which would later be reconfirmed in 1993.  In 1995 it was discovered that CBD improves symptoms of psychosis. In 1998 the United States government filed a patent on the antioxidant and neuroprotective effects of CBD, as well as THC.
The 2000s would become the decade of elucidating the activity of CBD. In 2001, researchers began to finally understand more about how CBD actually works in the body by revealing that CBD targets non-cannabinoid receptors in the body, stimulates the production of at least one endocannabinoid, Anandamide, and inhibits an enzyme responsible for breaking down Anandamide, effectively allowing it to linger in the body longer.
In 2002 researchers would confirm that CBD exhibits anti-nausea effects, which had already been reported as far back as the 1800s when systematic Cannabis research really began to take shape. In 2004 it was discovered that at certain dosages CBD can increase wakefulness and counteract THC induced sedation. So if you are feeling sleepy after using THC-rich Cannabis, a little bit of CBD might wake you back up! However, be careful, because CBD exhibits what is known as biphasic activity, meaning it acts differently in low doses versus high doses. At high doses, CBD can actually be sedating.
In 2005 it was discovered that CBD interacts with certain serotonin receptors in the body. In 2006 researchers would go on to discover that CBD also enhances adenosine receptor signaling, which is associated with heart health, blood pressure, and body temperature regulation. It was also in 2006 that researchers discovered that CBD can kill breast cancer cells – bringing significant attention to the compound as a potential anti-cancer drug.
In 2007 researchers began to understand why CBD reduced the effects of THC in some of their prior research. It turns out that CBD changes the shape and activity of CB1 receptors, even though it does not exhibit much affinity for them directly. In this way, it changes the way that THC binds to the CB1 receptor, modulating its activity. This kind of activity is called allosteric modulation, and CBD is considered an allosteric modulator of the CB1 receptor. This is why CBD is able to reduce the high associated with THC – it essentially deforms the CB1 receptor so that THC cannot stimulate the receptor as well as it normally would.
In 2008 it was discovered that CBD was a potent antibiotic against MRSA – a powerful infection that is commonly picked up in hospitals and often resists treatment. In 2012 researchers discovered that CBD may be as effective as standard antipsychotics. In 2014 it was discovered that CBD might be able to effectively treat acne in the skin by reducing inflammation, fighting bacteria on the skin, and changing the way that the skin produces oil.
The Modern CBD Industry
In 2018 in the United States, The Agricultural Improvement Act of 2018, also known as the 2018 Farm Bill, was passed, which effectively legalized hemp across the United States, including all of the cannabinoids and other chemical constituents of hemp varieties of Cannabis with THC concentrations below 0.3%, and CBD was removed from the Controlled Substances list, as long as the CBD was hemp derived.  Some may say that the CBD market began at this time, but CBD products had already been available in foods, cosmetics, and dietary supplements widely for years prior to the legalization of hemp, operating in somewhat of a regulatory grey area. In 2018, Epidiolex would officially become FDA approved for the treatment of certain forms of epilepsy in children.
The status of CBD as a pharmaceutical drug presents a problem for the CBD industry as a whole. The FDA does not allow drugs to be added to foods or supplements unless they have been marketed as foods or supplements previously. This is due to a set of laws in the Food Drugs and Cosmetics Act. Of course, the irony is that the CBD industry had been around for quite some time, not considering the exposure that humans have had to CBD throughout history. Cannabis in all its forms had been prohibited in the US for nearly 100 years, so of course Cannabis derived products were not openly marketed and sold. The Food Drug and Cosmetic Act was enacted in 1938, right around the same time that Cannabis prohibition began.
Considering that Cannabis was included in the United States pharmacopoeia for many years all the way up until prohibition began, it’s clear that Cannabis derived products had been a part of society well into the 1930s, and would have persisted had it not been for Cannabis prohibition. So, in the 1930s the opportunity for Cannabis to mature alongside the food and supplement industries was eliminated, and the only pathway to get federally legal Cannabis derived products to the public, was through pharmaceuticals. And now that hemp derived CBD and other cannabinoids are federally legal, 90 years later, the government argues that it can’t be put into food or supplements because it’s a drug. It just seems like an awkward argument when you take the full history into account.
Another argument that the FDA argues for resisting making any exceptions for CBD and hemp derived cannabinoids in foods or supplements is that there is not adequate data available to show that CBD is safe. They have argued that CBD could cause liver damage, and thus it should be researched longer before it is allowed to be widely available to be consumed. The study that they cite for this concern is a recent rodent study that looked at dosages that were orders of magnitude higher than the highest dosages used in comparable clinical trials for Epidiolex.
I spoke with Dr. Ethan Russo, about his thoughts on the idea of CBD causing liver damage.
I should point out that in the study, dosages of 15mg/kg or less were not found to exhibit these toxic effects. That’s approximately 930 milligrams of pure CBD for an average sized person.
It should also be noted that the World Health Organization issued a report on CBD very recently attesting to CBD’s remarkable safety profile.
At the time of this recording, the future of the CBD industry is very uncertain as hemp farmers, CBD product manufacturers, and legislators plead their case for changes to allow the CBD industry to continue operating as it has, with CBD foods, dietary supplements and cosmetics readily available to consumers. States are taking matters into their own hands, just as they have had to do with anything related to Cannabis and set their own laws for CBD.
The greater question lingering around the FDA’s involvement in the CBD industry is whether the FDA will take enforcement action against CBD companies. To date, they primarily seem concerned with going after companies making medical or health claims about CBD, but that’s not surprising. The FDA will always go after companies making unapproved medical claims, because that is in violation of the Dietary Supplement Health and Education Act of 1994 which made it illegal to make such claims without FDA approval. This is why you see an FDA statement on every dietary supplement label which says something to the effect of, “These claims have not been evaluated by the FDA and are not intended to diagnose, treat, cure, or prevent any disease.”
It seems as though the only pathway forward to a booming legal CBD industry, is through changes to federal law to allow an exception for CBD and other hemp derived natural products. Any law changes that are proposed should be carefully worded. Even if CBD is allowed in foods and supplements, if a law change does not also determine that CBD is Generally Recognized as Safe, or GRAS, then there could be another set of problems for the CBD industry to tackle.
Food additives like plant extracts and essential oils, have to have GRAS status to be freely added to foods or formulated into supplements. Until the FDA takes on the role of doing this research and granting GRAS status to CBD and other cannabinoids, it will be up to private companies to do their own expensive research to achieve what is called “self-affirmed” GRAS status, which only applies to their specific products, and not their competitors – essentially making a playing field where only the most well-funded CBD companies can survive long-term. To put this into perspective, gathering all the data needed to successfully achieve self-affirmed GRAS status can cost as much as a million dollars or more. At a time when the value of CBD as a commodity is rapidly shrinking, along with CBD product margins, this is a difficult task for small or medium sized hemp companies to pull off without coming together and pooling resources.
What are people experiencing with CBD?
Since the 2018 Farm Bill was passed, CBD shops have popped up across the country and even large retail chains like Kroger, Fred Meyer, CVS, and Walgreens are starting to carry CBD products.   Additionally, specialized hemp and CBD focused wellness stores have made their way into neighborhoods and cities across the US. I spoke with Wendy Nguyen, an owner of a premier CBD shop in New York City about her experience operating a CBD store.
I also had the chance to speak with a pain physician in North Carolina that has been working with patients that have chosen to try CBD as a potential solution to their chronic pain.
[James Taylor Clip]
One question that was on my mind when I was speaking with people about CBD was, what dosages are needed to get an effect? CBD products on the market have potencies of anywhere from 100 to 1000s of milligrams per 1oz bottle. When I reviewed the available scientific literature – I found that there was not a lot of information available. Epidiolex clinical trials utilized dosages of 5mg/kg to 20mg/kg, or 310mg to nearly 1500 mg for an average sized person. In a 2019 review of dosages utilized in published CBD studies, it was found that dosages below 2.5mg/kg of body weight were largely ineffective at treating most conditions measured, except for sleep disorders. That would be around 150mg of CBD for an average person. However, the research on CBD dosaging is complicated by the fact that CBD exhibits unique efficacy when it is administered in isolation versus when it is administered in the presence of other cannabinoids, terpenes, and other phytochemistry from the Cannabis plant. Many clinicians I spoke with commented that they were seeing better results at lower dosages with broad or full spectrum CBD versus isolate.
Some of the people I spoke with that used CBD regularly claimed that they saw relief at much lower dosages, as low as 10 or 15 mg of CBD per day, if taken regularly.
The frequency of dosing is very important because CBD, like THC, lingers in the body and can accumulate over time with repeated dosing. So it may be that low dosages of CBD might be effective when taken regularly, but when acute relief is required, higher dosages may be needed.
So clearly people are having profound experiences with CBD, but how does CBD actually affect the body?
How does CBD affect the body?
Like all other cannabinoids, CBD is not incredibly bioavailable in the body. Most of the CBD that anyone ingests is simply excreted either unmetabolized, or as a conjugated sugar – meaning that a glucose molecule adhered to the CBD molecule as it passed through the body. Some of the CBD that is ingested sticks to other lipophilic, or oil-loving, tissues in the body, which keeps it from circulating in the body and reaching sites of action. But for those molecules of CBD that do make it into the blood stream and get circulated throughout the body, and interesting series of events takes place.
First of all, it is important to know that CBD has very low affinity for either CB1 or CB2 receptors, which as you may remember from episode 6 of the podcast are two of the primary chemical receptors that make up the endocannabinoid system. Instead of directly affecting cannabinoid receptors, CBD stimulates these receptors indirectly by affecting the production and break down of endocannabinoids that the body produces on its own. As mentioned before, CBD stimulates the production of Anandamide, which is a partial agonist, or stimulator, of CB1 and CB2 receptors. Additionally, CBD inhibits an enzyme called Fatty Acid Amide Hydrolase, also known as FAAH, which would typically break down Anandamide, as well as a lot of other things in the body. This allows the Anandamide that the body produces to linger in the body longer, thus stimulating cannabinoid receptors for a longer time.
You could think of this as CBD nudging the endocannabinoid system to do its own thing, rather than completely hijacking the system altogether, like THC does. That’s not to say that the activity of THC is bad or undesirable – it’s just very different.
CBD also interacts with a putative cannabinoid receptor called GPR55. The GPR stands for G-protein coupled receptor, which is the type of chemical receptor that cannabinoid receptors are. GPR55 is thought to be responsible for some of CBD’s anti-epileptic activity, among other things.
In addition to these effects on endocannabinoids and cannabinoid receptors, CBD interacts with a lot of other chemical receptors including vanilloid receptors like TRPV1, which are also referred to as capsaicin receptors because capsaicin, the chemical responsible for the spiciness in peppers, also stimulates vanilloid receptors. CBD also interacts with serotonin receptors, commonly associated with mood, sleep and blood pressure. It also influences the activity of adenosine receptors, commonly associated with heart health, and PPAR-gamma receptors which are linked to insulin resistance and diabetes, among other things.
In addition to inhibiting enzymes that break down anandamide, CBD also has potent inhibitory effects on a group of liver enzymes called the cytochrome p450 enzymes, which are responsible for metabolizing many common drugs. This inhibitory effect is commonly referred to as “the grapefruit effect” because grapefruits are well known to also cause this same enzyme inhibition. In fact, you may have once been prescribed a medication that featured a label on the bottle that cautioned against taking with grapefruit. One of the most well-known drug interactions with CBD is with a blood thinning drug called Warfarin. CBD has also been demonstrated to exacerbate the negative side effects of some epilepsy drugs like Valproic Acid. Because of these kinds of interactions, it is important that anyone taking CBD with other medications do so under the supervision of a health care provider to stay safe.
One thing that should be mentioned here is that so far, we have been talking about how CBD, by itself, interacts with the body. When CBD is present in a complex mixture like a Cannabis extract with dozens or hundreds of other compounds, or when formulated in a food or topical product with other ingredients, effects can be different.  A hemp extract product should be judged by the total formulation, not just the quality of the hemp extract used as an ingredient in the product.
It’s also possible to manipulate the absorption and bioavailability of CBD using technologies like nano-emulsion, which is a process of breaking up a CBD extract into tiny droplets the size of a nanometer, which is one billionth of a meter, and then surrounding those droplets with a water friendly casing. This keeps the oil droplets from rejoining, maximizing their surface area and allowing the oil droplets to be suspended in water.
So far we’ve mostly been talking about how CBD affects the body when it’s ingested or inhaled, but what about the effects of CBD on the skin? There are all sorts of chemical receptors in the skin, just like you have in other parts of your body. In general, when CBD is applied to the skin, or topically, it only affects the area where it is applied. The exception is when CBD is applied transdermally, usually with a patch. These are like capsaicin patches or nicotine patches. They are specially formulated with ingredients that help carry things through the skin that normally would have a hard time penetrating. If CBD can soak through the outer layer of the skin, the epidermis, and reach the lower layer of the skin, the dermis, then it could end up reaching the blood where it could get distributed throughout the body.
So, does CBD help keep your skin healthy?
Safety of CBD
So you can see that CBD’s activity in the body is diverse and complex – and we still don’t understand the whole picture yet. Yet, despite our lack of knowledge about CBD, evidence seems to indicate that it is a pretty safe compound – even if some regulatory agencies disagree. The most common adverse effects associated with CBD are things like lethargy, appetite disruptions, and gastrointestinal distress. But everyone reacts to things differently, and in uncommon cases some people may react unfavorably to CBD. But, like THC, it is incredibly difficult, if not impossible, to overdose or die from using CBD.
At very high dosages of 15mg/kg of body weight or higher, it is possible to cause liver damage with CBD, but it is very uncommon for anyone to take dosages that high. That equates to a dose of around one gram of pure CBD for someone that weighs 140 pounds, or 62 kilograms. For someone like myself that weighs closer to 200 pounds, that dose would be closer to a gram and a half, or 1500 milligrams of CBD. To put this issue into better perspective, consider that most CBD products readily available on the market have serving sizes that feature doses of between 5 and 50 milligrams of CBD. According to the Safety Data Sheet for Epidiolex, CBD is tolerated well in humans orally at dosages up to 1500mg per day.
Based on the history of research that exists, it is clear that CBD has a lot of potential as a medicine. Research indicates it may be effective at treating things like anxiety, depression, sleep, various forms of spasticity, pain, bacterial infections, and inflammation. When it comes to skin treatment, it might be effective in battling acne and regulating inflammation of the skin. The fact that CBD is available as a pharmaceutical in various forms across the world, including the United States, is a testament to its medical value.
It is true that a lot more research is still needed to understand how to best unlock the therapeutic potential of CBD, but CBD is certainly not another snake oil.
But like many things, there is a lot of nuance around the topic. One of the big issues that needs to be understood is what dosages are needed to elicit therapeutic effects. While we have a pretty good understanding of what dosages not to exceed to stay safe, we don’t have a clear picture of what dosages to shoot for to achieve targeted therapeutic effects under different conditions. This is why many consumers of CBD are leaving it up to trial and error to find the dose that works best for them.
Let’s review what we’ve learned.
But for all of the promise of CBD, there is still a lot of unfounded hype for consumers to wade through. It is critical that consumers pay attention to the quality of CBD products as well as the dosages. Many CBD products feature incredibly low concentrations of CBD that are likely sub-therapeutic. In addition, CBD products can be quite expensive, leaving consumers paying out fortunes for low-potency sub-therapeutic products. And this trend isn’t likely to go away anytime soon. New hemp extract products featuring other lesser known cannabinoids like CBG, CBC, and CBN are already quickly gaining market buzz. It won’t be long before CBD passes the hype torch on to these other cannabinoids.
And with that, I’m your host, Jason Wilson. Thanks for listening. Stay curious and take it easy!
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