What's in a name?
In our final episode for Season One, we explore the ways in which Cannabis is named and represented in the market place - by strain name and indica/sativa designation. How do strain names and indica/sativa designations relate to genetic lineage and chemical profiles? Where did the indica vs. sativa model come from? How should confused consumers navigate the strain game? Contributions from: Angus of The Real Seed Company; Steve Albarran and Brad Bogus of Confident Cannabis The Real Seed Company: www.therealseedcompany.com Confident Cannabis: www.confidentcannabis.com Connect by Confident Cannabis: connect.confidentcannabis.com Phylos Galaxy: https://phylos.bio/galaxy/ Kannapedia by Medicinal Genomics: http://www.kannapedia.net/ EPISODE TRANSCRIPT You’re listening to the Curious About Cannabis Podcast. Hey everybody, Before we get started, I have a short announcement. This is the last episode of our first season, and I want to just take a moment to say thank you so much for coming on this journey with me over the past several months. We will be taking a small break from episodes like these to get new content ready to share with you for season two, which will start this Summer. We will be restructuring the podcast a bit, based on your feedback. Going forward we will be releasing the behind-the-scenes interviews regularly throughout the entire year, but we will only be releasing seasons of our topical episodes, like this one, twice a year, with one season starting in late Fall, and one season starting in Summer. If you can’t wait for the next season, consider becoming a patron at patreon.com/curiousaboutcannabis where you will get access to a secret patron’s only podcast feed with content you won’t hear on our public feed as well as early access to Season Two content. You’ll also get access to other educational content, early releases of videos, exclusive videos, discounts for the Curious About Cannabis Book, and more. Check it out at patreon.com/CuriousAboutCannabis. Thanks again for your support and tuning in throughout this season. Now, without further ado, let’s get on to the episode. [Shutter] Gorilla Glue. Grape Krush. Blue Dream. Koala. Mr. Nice. OG Kush. Skywalker Haze. Moonshine Haze. AK-47. Trainwreck. Tangie. Hash Plant. Trinity. Vortex. What’s in a name? Go into any legal Cannabis dispensary in Oregon and your head is likely to spin trying to keep up with the seemingly limitless numbers of names of different varieties of Cannabis on the shelf. It’s enough to keep Cannabis connouisseurs on their toes, while the Cannabis curious are sometimes left confused and bewildered. And beyond these various strain names, we have other labels, like indica, sativa, and hybrid. Supposedly some make you sleepy. Some make you feel awake. Others are supposedly balanced for a productive lifestyle. But is there really anything to this system of naming and categorizing Cannabis varieties? What do all of these names mean? In this episode, we will be taking a look into the world of Cannabis names, The Strain Game. [INTRO MUSIC] Hey everybody this is Jason Wilson with the Curious About Cannabis Podcast. If you have been involved in the Cannabis industry for any amount of time or have visited a dispensary, you may be familiar with the company and website, Leafly.[1] Leafly was originally started as a way to collect information on Cannabis strains. Over time they have evolved, but their core focus on strains has certainly not gone away. Here is some copy from their website describing Cannabis strains: “Marijuana strains are organized into three primary types: sativa, indica, and hybrid. Each type of strain has unique effects on both the mind and body. For example, sativa strains are uplifting and pair well with activities like social gatherings and being physically active. On the opposite end of the strain spectrum, indica strains are relaxing and can help amplify a deep level of physical sedation - making indica great for those times when you need deep sleep. Lastly, there are hybrid strains which fall between indicas and sativas. Hybrid strains offer a combination of both energizing and relaxing effects. Hybrid strains are great for the times when it’s too late for an energizing sativa or too early for a sedating indica strain.” But is this legit? Or could this be a well-intentioned, but ill-fated effort that is ultimately misleading consumers and promoting bias and placebo in the consumer market? Many claims are often made surrounding the name of a Cannabis variety including information about the plant’s genetic lineage, it’s chemical profile, and the effect it will have on a consumer. In today’s episode we are going to be taking a critical look at the way Cannabis is commonly categorized – by strain name and indica/sativa designation. And to guide our curious quest we will be focusing on several key questions:
So, without further ado, let’s get started. What is a Cannabis Strain? If you ask different people in the Cannabis industry what they think of the concept of Cannabis strains, you are likely to get mixed reactions. Some people think that strains are completely useless, outdated ideas. Some think they are concepts reserved for the craft Cannabis cultivators that have an in-depth understanding of the source of the genetics that they cultivate. While others think that strain names are vitally important for understanding the effects that a product may have on them. So, what’s really going on here? First let’s talk about the word “strain”. In biology, the term “strain” is generally only used when talking about micro-organisms. There are various strains of E. coli, for instance. But in botany, the term “strain” is not typically used to describe different varieties of plants. Instead, the term “variety” is commonly used. More specifically, the term, “cultivar”, meaning “cultivated variety” is often used to refer to different plant types of the same species and subspecies. An additional taxonomical rank used in botany is “form” which is a level lower than variety and is often used to distinguish slightly different varieties of a variety. Let’s take the Cannabis strain Gorilla Glue, or GG, for example. There are different varieties of Gorilla Glue, like Gorilla Glue #4, and Gorilla Glue #12, etc. But Gorilla Glue itself is a variety of a subspecies of Cannabis. So, GG #4 and #12 would be considered forms of the Gorilla Glue variety. So, if we want to be botanically correct, we should replace the term “strain” altogether, with the term “cultivar”. And if there are variations of a particular cultivar, then those variations should be called “forms”. Indica vs Sativa But what about these terms Indica and Sativa? The old colloquial wisdom states that there are three species of Cannabis plants: sativa, indica and ruderalis. Indica Cannabis plants are short, bushy, and produce heavily sedating effects, whereas sativa plants are tall, airy, and produce stimulating effects.[2] And ruderalis plants are often either considered wild plants or perhaps wild and autoflowering plants. But where did this idea come from? Let me begin by saying that Cannabis researchers have long debated how to categorize Cannabis and how many species of Cannabis there are. The terms sativa, indica, and ruderalis are only a few of many terms that have been used throughout time to organize Cannabis. These terms have been used inconsistently by different researchers throughout time to describe different types of Cannabis plants. This basic idea of sativa plants being tall and wide branched and indica plants being short and densely branched comes from a researcher named Richard Schultes in the early 1970s. Schultes suggested that there are three species of Cannabis – sativa, indica and ruderalis.[3] Each of these species was associated with basic morphological characteristics – that the tall Cannabis plants were Cannabis sativa, the short bushier plants were Cannabis indica, and the very small, sometimes unbranching, forms of Cannabis plant often seen in the wild were considered Cannabis ruderalis. However, a few years later another taxonomical model for Cannabis would be presented that focused on the plant’s chemical profiles, rather than morphology. This taxonomic model, presented by Small and Cronquist, suggests that Cannabis is one single species, Cannabis sativa, with at least two subspecies, sativa and indica.[4] Under this model, the sativa subspecies consists of fiber-type and low THC varieties of Cannabis, while the indica subspecies consisted of high THC and 1:1 THC,CBD ratio plants. Genetic research performed by John McPartland and Geoffrey Guy confirmed that THC-rich varieties of Cannabis are all of the same species. So if we accept this model, which I should point out that not everyone believes this model is accurate, but we’ll save that for later, If we accept the Small and Cronquist model, then all THC-rich varieties of Cannabis should be Cannabis sativa subspecies indica. Some researchers felt it made little sense to organize a plant based on its intoxicating properties, and so later on in 1980, a researcher named Loran Anderson would refine Schulte’s taxonomical model, taking Schultes’ focus on the growth form of Cannabis varieties and adding details about leaf characteristics to the picture.[5] Anderson characterized Cannabis indica as short broad leaf plants, Cannabis sativa as tall narrow leaf plants, and Cannabis ruderalis as small, weedy plants. Anderson also pointed out that these distinctions between sativa, indica and ruderalis have little to do with chemical profiles. So this the work of Schultes and Anderson are largely why we refer to Cannabis plants as indica or sativa based on how they look. But why do we often use these terms to refer to chemical profile as well? Well, it’s a complicated story, and maybe too complicated to dive into too much in this episode. But basically, the term Cannabis sativa was originally used by Carl Linnaeus in the 1753 to describe a non-intoxicating form of Cannabis commonly cultivated in Europe, which we would today call hemp.[6] Cannabis indica was originally used by Jean-Baptiste Lamarck thirty years later to describe Cannabis from India that was intoxicating.[7] The plants he reviewed had narrow leaves, not wide leaves, and the primary difference was that the plants were a little shorter, more aromatic, and intoxicating. Later on, the term Cannabis sativa would be used by a Russian researcher to describe forms of Cannabis from Afghanistan that were used to make hash – a significant departure from Carl Linnaeus. Then later on the term Cannabis indica would be applied to forms of Cannabis from Afghanistan that were used to make hash. So these uses of the terms Cannabis sativa and indica would become confused throughout time, and blended in the minds of many with the taxonomical models that Small and Cronquist and Schultes and Anderson put together, separately, ultimately resulting in a totally confused vernacular that we have been stuck with to this day.[8] [ANGUS] This is Angus from The Real Seed Company. Angus has spent years travelling around the world collecting seeds of Cannabis varieties often referred to as “landrace strains”, which are varieties which have naturalized to the region in which they grow. Through his travels, Angus has had the opportunity to get to know people from cultures all over the world that have been growing Cannabis for millenia, and along the way he has studied the issue of Cannabis taxonomy in depth as he has become a de facto Cannabis historian. [ANGUS] But the story gets even more confusing. So far we’ve talked about two ways of categorizing Cannabis – one that categorizes Cannabis by morphology, and the other that categorizes Cannabis by chemotype. But there’s another way of categorizing Cannabis which we already hinted at. And that’s by the plant’s genes. The researcher Karl Hillig performed several different experiments looking at the genetic and chemical variation among Cannabis varieties. In his genetic research, he made a scatter plot representing the differences between samples, and then compared the data to different indica/sativa taxonomical models.[9] What he found was that of the major taxonomical models that he reviewed, including those by Schultes and Small and Cronquist, none of them fit his data. His data showed two distinct clusters, seemingly representative of a split in the Cannabis gene pool. In their book Cannabis Evolution and Ethnobotany, Robert Clarke and Mark Merlin present a revised taxonomical model that states that all THC-rich cultivars and broad-leafed hemp cultivars are Cannabis indica, and all narrow leaf hemp is Cannabis sativa.[10] This model also posits that all Cannabis varieties are ultimately derived from a single Putative Ancestor. In Clarke and Merlin’s model, THC-rich Cannabis varieties are separated on the subspecies level by their morphology and named after their presumed origins. So narrow leaf THC-rich varieties are Cannabis indica ssp. indica, representing their presumed origins of India, while broad leaf THC-rich varieties are Cannabis indica ssp. afghanica, referring to their presumed origin of Afghanistan. Broad leaf hemp varieties would be Cannabis indica ssp. chinensis, representing origins from China, and narrow leaf hemp varieties would be Cannabis sativa ssp. sativa. Upon careful review, it appears that the colloquial use of indica and sativa is really just a bastardized synthesis of taxonomical systems, and it doesn’t accurately represent any single system of organizing Cannabis. In short – it’s made up. It seems to take elements from each of these systems that we have covered but fails to accurately deliver on any of them. It’s really quite a mess that should be abandoned. When I was attending the University of Mississippi and spending time at the NIDA Cannabis lab there, I asked the researchers how many species of Cannabis they recognized, and I was given a firm answer that there was only one species of Cannabis. When reviewing the Integrated Taxonomical Information System, Cannabis is listed as a single species – Cannabis sativa.[11] Perhaps as genomic research into Cannabis progresses, the taxonomy of Cannabis will evolve. Based on trends in biology, this is likely to be the case. Genetic research is leading to many changes in how all of life is categorized, across the board, and Cannabis is not likely to escape this rearrangement. Taking a step back from all of these taxonomical models, let’s briefly discuss what terms like “sativa”, “indica”, “ruderalis” mean from a botanical perspective. The term “sativa” is typically used to refer to cultivated plants. For instance, the common oat is Avena sativa. The term “indica” technically means “from India.” And the term “ruderalis” is derived from the word “ruderal”, usually used to describe plants that grow easily in disturbed areas. Cannabis researcher John McPartland has argued that we should take the meanings of these terms seriously when deciding how to talk about Cannabis. For instance, as far as we can tell, only domesticated varieties of Cannabis still exist in the world. Sure, there are plants that have escaped cultivation and re-naturalized, but are there really any varieties of Cannabis in existence that are untouched by human domestication? It’s highly unlikely. So, does that mean that all Cannabis in existence today is technically “sativa”? And then what about the use of the term “indica”? McPartland has argued that we should actually split THC-rich Cannabis into two varieties based on their origins – one being indica, and one being called afghanica. So regardless of how we want to categorize Cannabis, if we want our vocabulary to be consistent, we should use these terms intentionally according to the manner in which these terms have been applied to other plants. In John McPartland’s 2018 review of Cannabis taxonomy and systematics, he provides a suggestion for fixing these labels in our cultural vernacular to make them more accurate. He states, “In summary, reconciling the vernacular and formal nomenclatures: “Sativa” is really Indica, “Indica” is actually Afghanica, and “Ruderalis” is usually Sativa. All three are varieties of one species, Cannabis sativa.”[12] But, leaving the taxonomy debate aside for a moment, just how reliable are indica/sativa designations or strain names in terms of genetic lineage and chemical profiles? Let’s start with genetic lineage. Do strain names and indica/sativa designations correlate with genetic lineage? The short answer is – not really.[13] First let’s look at some basic issues. First of all, strain names are often mislabeled. This happens intentionally and unintentionally. It’s common for Cannabis cultivators to cultivate multiple varieties – and it makes sense that in the hustle and bustle of harvesting and processing, some containers of plants may get mislabeled. However, on the more nefarious end of things, some cultivators will change the cultivar name of a batch of Cannabis in an attempt to make it more likely to sell. Second, strain names are often inappropriately applied to plants propagated from seed. These two issues alone have muddied the playing field so much, that the reliability of any strain name, just in terms of genetic lineage, is a real crap shoot. The same issues can be said for indica/sativa designations. Even if we were to accept the colloquial definitions of indica and sativa – the fact of the matter is that cultivators and product manufacturers often uses these labels to indicate an anticipated effect more so than the genetic lineage or even morphology of the plant. Additionally, there are several online tools that allow you to examine how genetically similar and dissimilar different Cannabis samples are. One is called the Galaxy by Phylos Bioscience[14], and the other is Kannapedia by Medicinal Genomics[15]. Using these tools, we can examine data related to samples that were labeled as “Blue Dream” for instance. On the Phylos Galaxy, right away we can see different unique genetic clusters, with some clusters being substantially unique. On Kannapedia you can search for all sorts of samples and see the hodge podge of “close relatives”, some that are labeled the same strain, and some that seemingly should be quite different based on colloquial wisdom. Now, this isn’t to say that there is absolutely no consistency behind strain names. I want to point out that there are in fact genetic patterns among Cannabis varieties. For instance, going back to the Phylos Galaxy you’ll find that there are distinct genetic clusters of close relatives among any one strain name, but which cluster is “the true OG?” The “true Blue Dream”? Is it the biggest cluster? If so, why? Who decides what “Blue Dream” or “OG Kush” actually is, genetically? In the Kannapedia database, while you will see a strain name listed, you also will see a unique identifier that is the true “label” associated with the genetics that were tested. From a genetic perspective, the strain name is largely irrelevant. However, if you focus on a sample that was labeled “Blue Dream”, for example, you will likely see that it has close relatives that are also labeled as “Blue Dream”. So there is some consistency. Just not enough consistency to trust the labels. So strain names and indica sativa designations don’t mean much in terms of genetic lineage. But what about chemical profiles?[16] To begin to tackle this issue, we need to review a lot of data. So I went to my friends at Confident Cannabis[17] to get their opinions on this issue. Confident Cannabis is a technology company that provides various software solutions to Cannabis testing labs, growers, producers, and dispensaries to bring transparency to the supply chain. Their platform captures a lot of data about products moving around in the Cannabis industry, and by analyzing that data, they have been able to glean some interesting insights. [STEVE ALBARRAN] This is Steve Albarran, the CEO of Confident Cannabis [STEVE ALBARRAN] I had Brad Bogus from Confident Cannabis go through the Connect platform[18] with me to explain how it works and what I was seeing. [BRAD BOGUS] But what about indica/sativa designation? [BRAD BOGUS] The ugly truth of the matter is that there are various plants labeled the same strain with distinctly different cannabinoid and terpenoid profiles. This can be for various reasons, like the mislabeling of strain names. But it can also be due to the fact that terpenes are highly influenced by environmental conditions and they can change rapidly when Cannabis is in storage. You could take a clone of a Cannabis variety and grow it in different conditions and get slightly different terpene concentrations. You could take plants grown in the same conditions and dry them or store them differently and end up with different terpene profiles. So these names don’t seem to be strongly correlated with genetic lineage. And they don’t seem to mean much in the way of chemical profiles. So what gives? Well, in short, we need a new system of a categorizing and talking about Cannabis. If we are interested in how something will affect somebody, we care about chemical profile, and we need a vocabulary for talking about patterns of chemical profiles. If we are interested in discussing plant morphology, we need a vocabulary to talk about that which is consistent, accurate, and separate from the vocabulary used to talk about chemical profiles. If we are interested in discussing genetic lineage, we need assistance from genetic mapping tools and some standardized names of Cannabis cultivars which are based on genetic data. Several researchers and companies, like Leafly, have proposed alternative methods to address these distinct problems, but none of these solutions have really taken a strong hold in the Cannabis industry yet. Going back to where we started, with Leafly, they have attempted to produce a visual guide to understanding a strain’s chemical profile, represented by a series of shapes and colors with unique meanings.[19] The attributes that are associated with each strain are based on numerous lab tests, which is certainly a step in the right direction. The website then goes on to associate each strain with effects like “sleepy”, “relaxing”, “uplifted”, “energetic” – but this is potentially flawed in a number of ways. First, it assumes that a strain name is represented by one particular chemical profile, which as we have talked about in this episode, is not consistent. Even when basing the findings on aggregates of terpene data, you are still left with an average chemical profile that does not necessarily represent what someone will find in a dispensary. And concerning the predicted effects, if you dive deeper into the data, you often find that even consumers don’t agree on the effects of a Cannabis variety. For many strains on Leafly’s website, close to 50% of people report the most commonly reported effects, meaning that nearly half of people that tried the strain did not feel those same effects. Another issue that we haven’t really gotten into at all in this episode is: even if you know the chemical profile of a Cannabis variety – can you really predict the effects it will have on somebody? We’ll save that question for another time. So as a consumer trying to find Cannabis products that work best for you, what do you do after you learn that all of these names are unreliable? My takeaway is this – stop relying on strain names. Stop relying on indica/sativa designations. Start journaling. Pay attention to the chemical profiles and the organoleptic characteristics of what you consume and keep track of how you respond. You may find that a single chemical profile affects you differently at different times of the day, or in different settings. You may find that that Cannabis that your budtender told you would put you to sleep actually makes your heart race and wakes you up. You may find that a small toke produces very different effects than consuming a larger dose. There are so many variables at play that will influence how a person will respond to Cannabis. To dilute all of those variables down into a simplified model of Cannabis strains or indica/sativa designations is a fool’s errand. There is also the hidden and impossible to quantify variable – which is you. The chemistry of the product is only part of the picture, and the biochemistry that your own body brings to the table is the other part of the picture. No one can tell you what will work for you, or how something will affect you. And there is no sure-fire way to predict it. It comes down to trial and error. If you are looking for a good journal designed for this purpose, check out Gold Leaf’s Patient Journal.[20] I’ll be doing a review of Goldleaf’s journals and other educational materials that will be posted on the Curious About Cannabis YouTube channel soon. So let’s review what we’ve learned:
And with that, I’m your host, Jason Wilson. Thanks again for tuning in for this episode and this season. It’s been a great pleasure to have you join me on this journey. Until next time, stay curious, and take it easy. [OUTRO MUSIC] CITATIONS [1] www.Leafly.com [2] www.leafly.com/strains [3] Schultes RE, Klein WM, Plowman T, Lockwood TE. 1974. Cannabis: An Example of Taxonomic Neglect. Botanical Museum Leaflets, Harvard University. 23(9): 337-367. [4] Small E and Cronquist A. 1976. A Practical and Natural Taxonomy for Cannabis. Taxon. 25(4): 405-435. [5] Anderson LC. 1980. Leaf Variation Among Cannabis Species From A Controlled Garden. Botanical Museum leaflets, Harvard University. 28(1): 61-69. [6] Linnaeus C. 1753. Species Plantarum. [7] Lamarck JB. 1788. Encyclopédie Méthodique, Botanique, Tome second, Part 2. Panckou>[8] McPartland JM. 2018. Cannabis Systematics at the Levels of Family, Genus, and Species. Cannabis and Cannabinoid Research. 3(1): 203-212. [9] Hillig KW. 2005. Genetic evidence for speciation in Cannabis (Cannabaceae). Genetic Resources and Crop Evolution. 52: 161-180. [10] Clarke RC and Merlin MD. 2013. Cannabis: Evolution and Ethnobotany. University of California Press. [11] http://www.itis.gov/ [12] McPartland JM. 2018. Cannabis Systematics at the Levels of Family, Genus, and Species. Cannabis and Cannabinoid Research. 3(1): 203-212. [13] Sawler J et al. 2015. The Genetic Structure of Marijuana and Hemp. PLoS One. https://doi.org/10.1371/journal.pone.0133292 [14] https://phylos.bio/galaxy/ [15] http://www.kannapedia.net/ [16] Piomelli D and Russo EB. 2016. The Cannabis sativa Versus Cannabis indica debate: An Interview with Ethan Russo, MD. Cannabis and Cannabinoid Research. 1(1): 44-46. [17] www.confidentcannabis.com [18] http://connect.confidentcannabis.com/ [19] https://www.leafly.com/strains [20] https://shopgoldleaf.com/products/patient-journal [21] Piomelli D and Russo EB. 2016. The Cannabis sativa Versus Cannabis indica debate: An Interview with Ethan Russo, MD. Cannabis and Cannabinoid Research. 1(1): 44-46.
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Episode Description:
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. [NEWS CLIP] 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.[1] 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.[2] [3] 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. [INTRO MUSIC] 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.[4] 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.[5] (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.[6] 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.[7] 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.[8] 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.[9] In 1982 CBD was found to exhibit anti-anxiety effects, which would later be reconfirmed in 1993.[10] [11] In 1995 it was discovered that CBD improves symptoms of psychosis.[12] In 1998 the United States government filed a patent on the antioxidant and neuroprotective effects of CBD, as well as THC.[13] 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.[14] 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.[15] In 2004 it was discovered that at certain dosages CBD can increase wakefulness and counteract THC induced sedation.[16] 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.[17] In 2005 it was discovered that CBD interacts with certain serotonin receptors in the body.[18] 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.[19] 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.[20] 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.[21] 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.[22] In 2012 researchers discovered that CBD may be as effective as standard antipsychotics.[23] 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.[24] 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.[25] [26] 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.[27] 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.[28] 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.[29] 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.[30] 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.[31] I spoke with Dr. Ethan Russo, about his thoughts on the idea of CBD causing liver damage. [ETHAN RUSSO] 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.[32] 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.[33] 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.[34] [35] [36] 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. [Wendy Clip] 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.[37] 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. [JAMES TAYLOR] 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. [WENDY NGUYEN] 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.[38] 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.[39] 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.[40] 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.[41] This inhibitory effect is commonly referred to as “the grapefruit effect” because grapefruits are well known to also cause this same enzyme inhibition.[42] 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.[43] CBD has also been demonstrated to exacerbate the negative side effects of some epilepsy drugs like Valproic Acid.[44] 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.[45] [46] 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.[47] 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? [WENDY NGUYEN] 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.[48] 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.[49] [Ethan Russo] 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! [Outro Music] Citations: [1] United States H.R.2 115 Agriculture Improvement Act of 2018 [2] Brightfield Group 2019 U.S. CBD Market Report: https://www.brightfieldgroup.com/library/us-cbd-market-report-2019 [3] BDS Analytics Press Release: https://bdsanalytics.com/u-s-cbd-market-anticipated-to-reach-20-billion-in-sales-by-2024/ [4] Russo E. 2011. Taming THC: potential cannabis synergy and phytocannabinoids-terpenoid entourage effects. Br J Pharmacol. 163(7): 1344-1364. [5] Adams R, Hunt M, Clark JH. 1940. Structure of cannabidiol, a product isolated form the marihuana extract of Minnesota wild hemp. I. J Am Chem Soc. 62(1): 196-200. [6] Loewe S. 1944. Studies on the pharmacology of marihuana The Marihuana Problems in the City of New Yorked. The Mayor's Committee on Marihuana. pp. 149–212.Lancaster, PA: The Jaques Cattell Press [7] Mechoulam R, Shvo Y. 1963. Hashish. I. The structure of cannabidiol. Tetrahedron. 19(12): 2073-2078. [8] Paton WDM, Pertwee RG. 1972. Effect of cannabis and certain of its constituents on pentobarbitone sleeping time and phenazone metabolism. Br J Pharmacol. 44: 250-261. [9] Carlini EA, Cunha JM. 1981. Hypnotic and antiepileptic effects of cannabidiol. J Clin Pharmacol. 21(S1): 417S-427S. [10] Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. 1982. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (Berl). 76(3): 245-250. [11] Zuardi AW, Cosme RA, Graeff FG, Guimaraes FS. 1993. Effects of ipsapirone an dcannabidiol on human experimental anxiety. J Psychopharmacol. 7(1 Suppl): 82-88. [12] Zuardi AW, Morais SL, Guimaraes FS, Mechoulam R. 1995. Antipsychotic effect of cannabidiol. 56(10): 485-486. [13] https://patents.google.com/patent/US6630507B1/en [14] Bisogno T et al. 2001. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 134(4): 845-852. [15] Parker LA, Mechoulam R, Schlievert C. 2002. Cannabidiol, a non-psychoactive component of cannabis and its synthetic dimethylheptyl homolog suppress nausea in an experimental model with rats. Neuroreport. 13(5): 567-570. [16] Nicholson AN, Turner C, Stone BM, Robson PJ. 2004. Effect of Delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults. J Clin Psychopharmacol. 24(3): 305-313. [17] Zuardi AW, Guimarães FS, Moreira AC. 1993. Effect of cannabidiol on plasma prolactin, growth hormone and cortisol in human volunteers. Braz J Med Biol Res. 26(2): 213-7. [18] Russo EB, Burnett A, Hall B, Parker KK. 2005. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 30(8): 1037-1043. [19] Carrier EJ, Auchampach JA, Hillard CJ. 2006. Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci U S A. 103(20): 7895 – 7900. [20] Ligresti A et al. 2006. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther. 318(3): 1375-1387. [21] Thomas et al. 2007. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol. 150(5): 613-623. [22] Appendino G et al. 2008. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod. 71(8): 1427-1430. [23] Leweke FM et al. 2012. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2(3): e94. [24] Olah A et al. 2014. Cannabidiol exerts sebostatic and anti-inflammatory effects on human sebocytes. J Clin Invest. 124(9): 3713-3724. [25] Corroon J, Kight R. Regulatory Status of Cannabidiol in the United States: A Perspective. Cannabis Cannabinoid Res. 2018. 3(1): 190-194. [26] United States H.R.2 115 Agriculture Improvement Act of 2018, Sec. 297A Definitions (1) [27] https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms [28] https://www.fda.gov/consumers/consumer-updates/what-you-need-know-and-what-were-working-find-out-about-products-containing-cannabis-or-cannabis [29] https://www.fda.gov/about-fda/histories-product-regulation/1938-food-drug-and-cosmetic-act [30] https://www.fda.gov/consumers/consumer-updates/what-you-need-know-and-what-were-working-find-out-about-products-containing-cannabis-or-cannabis [31] Ewing LE et al. 2019. Hepatotoxicity of a Cannabidiol-rich cannabis extract in the mouse model. Molecules. 24(9): 1694. [32] World Health Organization (WHO). Cannabidiol (CBD) Critical Review Report. Expert Committee on Drug Dependence Fortieth Meeting. June 2018. [33] Dietary Supplement Health and Education Act of 1994. Public Law 103-417. 103rd Congress. [34] https://www.supermarketnews.com/organic-natural/kroger-carry-cbd-products-945-stores [35] https://www.nbcnews.com/health/health-news/cvs-sell-cbd-products-800-stores-8-states-n986016 [36] https://www.cnbc.com/2019/03/27/walgreens-to-sell-cbd-products-in-some-stores.html [37] Millar SA, Stone NL, Bellman ZD, Yates AS, England TJ, O’Sullivan SE. A systematic review of cannabidiol dosing in clinical populations. Br J Clin Pharmacol. 2019. 1-13. Electronic publication. [38] Deutsch DG. 2016. A personal retrospective: elevating anandamide (AEA) by targeting fatty acid amide hydrolase (FAAH). Front Pharmacol. 7: 370. [39] Whalley BJ et al. 2018. A role of GPR55 in the antiepileptic properties of cannabidiol (CBD) (P2.277). Neurology. 90 (15 Supplement). [40] https://www.projectcbd.org/science/how-does-cbd-work [41] Yamaori S et al. 2011. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life Sci. 88(15-16): 730-736. [42] https://www.healthline.com/nutrition/grapefruit-and-medications [43] Grayson L et al. 2018. An interaction between warfarin and cannabidiol, a case report. Epilepsy Behav Case Rep. 9: 10-11. [44] Szaflarski JP et al. 2018. Long‐term safety and treatment effects of cannabidiol in children and adults with treatment‐resistant epilepsies: Expanded access program results. Epilepsia. 59(8): 1540-1548. [45] Gallily R, Yekhtin Z, Hanus LO. 2015. Overcoming the bell-shaped dose-response of cannabidiol by using cannabis extract enriched in cannabidiol. Pharmacology & Pharmacy. 6: 75-85. [46] Russo EB. 2018. The case for the entourage effect and conventional breeding of clinical cannabis: no “strain,” no gain. Front Plant Sci. 9: 1969. [47] Yen CC et al. 2018. Nanoemulsion as a strategy for improving the oral bioavailability and anti-inflammatory activity of andrographolide. Int J Nanomedicine. 13: 669-680. [48] Iffland K, Grotenhermen F. 2017. An update on safety and side effects of cannabidiol: a review of clinical data and relevant animal studies. Cannabis Cannabinoids Res. 2(1): 139-154. [49] https://www.greenwichbiosciences.com/sites/default/files/Epidiolex%20Material%20Safety%20Data%20Sheet%20(MSDS).pdf 
Episode Description: In this episode we begin to explore the ways in which Cannabis affects the body by exploring one of the primary physiological systems in our body's affected by Cannabis - the endocannabinoid system (ECS). Cannabis helped researchers discover it. Now medical science is trying to understand what to do with it. Discover the history of possibly one of the most significant medical discoveries of the past century, courtesy of Cannabis, in this episode of the Curious About Cannabis Podcast!
Interview contributions by endocannabinoid system researchers Dr. Kevin Spelman (BTS #04) and Dr. Ethan Russo (BTS #05). Transcript: COMING SOON 
#05 Cannabis as Medicine - Part Two
Episode Description: Continuing from our previous episode, we dive into exploring how medical claims are derived, what it takes to develop a drug in the United States, and what outcomes health care professionals are seeing in their patients that are using Cannabis as a medicine. TRANSCRIPT 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. [INTRO SEGMENT] In the previous episode of the podcast we began exploring the concept of Cannabis as medicine. We looked at many of the ways in which Cannabis has been used as a medicine in the past, and some ways in which Cannabis based pharmaceuticals are being used as medicines today. Picking up where we left off, I wanted to explore the ways in which medical claims are derived. How do we determine that something is a medicine? And what results are clinicians seeing in their patients that are using Cannabis? [INTRO MUSIC] Hey everybody, this is Jason Wilson with the Curious About Cannabis Podcast, thanks so much for tuning in once again. As we covered in the previous episode, there are a lot of medical claims swirling around Cannabis. If you go into just about any Cannabis dispensary, you are likely to see posters on the wall indicating the myriad of different chemicals in Cannabis and their supposed effects.[1] [2] However, many times these kinds of charts are built off of very simple, pre-clinical research data, that may not have any relevance in a real-life Cannabis use scenario. How are medical claims derived? So, how are medical claims derived? There are several forms of medical research of varying degrees of quality.[3] On one end of the spectrum are anecdotal reports – these are basically eye-witness testimonies from a single person or small group of people. Up from that you have case studies, usually written by a professional describing an incident in detail. Moving along, there are observational studies, where a health care professional watches a patient engage in an activity and records the outcomes. On the other far end of the spectrum is the gold standard of randomized controlled trials.[4] When a drug is being developed, typically the first way it is studied is through in vitro research.[5] In vitro studies are laboratory studies performed in test tubes or petri dishes. In vitro literally means, "in glass". [JUSTIN FISCHEDICK] This is Justin Fischedick. Justin is a natural products researcher that studies the activity of the chemical constituents of plants, including Cannabis. [JUSTIN FISCHEDICK] Then there are in vivo studies, which are in living animals.[6] [JUSTIN FISCHEDICK] But there are limitations to each of these types of studies, and the results of an in vitro study or an in vivo animal study cannot always be easily extrapolated to real-life human clinical situations.[7] [JUSTIN FISCHEDICK] I had a conversation with cellular and molecular biologist, Dr. Anthony Smith, about this issue regarding the limitations of animal studies.[8] [ANTHONY SMITH] A lot of Cannabis research has, up to a point, been primarily in vitro and in vivo rodent studies, but very few research projects with Cannabis have crossed into the world of placebo controlled double blind clinical trials with large patient populations, and many politicians and regulatory bodies continue to claim that because of this lack of clinical trial data, herbal Cannabis or Cannabis products cannot be deemed safe or a viable medicine for a condition. Let’s break this phrase down. “Placebo controlled” refers to the fact that a compound is given to some of the patients in a trial which is intended to have no effect. In general, it is expected that if something is a candidate to be considered a medicine, it needs to perform better than a placebo. It can be difficult to adequately utilize a placebo in a THC-rich Cannabis study. Because THC has such distinct effects, it is pretty difficult to fool people into thinking they got the drug when they actually did not. This is referred to as “incomplete blinding” because the patients are not truly blinded to whether they received the drug or not. The gold standard for clinical trials is for a study to be “double blind”. “Double blind” refers to the idea that both the clinician performing the study, and the patients participating in the study, are blind to whether they received the research drug, or the placebo. This is important because there are various biases that can enter a study if the physician knows who has had the placebo or not, and likewise, patients may react differently in a study if they know they are receiving a placebo – although some modern research is beginning to call this idea into question. Lastly, large sample sizes are required in order to understand whether the results of a clinical trial are representative of a larger population.[9] A study that only examines the response of a couple dozen or even a couple hundred people is really small, and can’t really represent the hundreds of millions of people living in the United States, much less the billions of people living in the world. There’s also the issue of repeatability that is worth mentioning. Even if a research study is placebo-controlled and double blinded with a good sample size – it is still important that the study be replicated by another set of researchers, in another location, with a different population of people. Research findings are much more robust when they have been repeated.[10] There is always the chance that there are some variables unaccounted for in a study that could explain the results differently than what the researchers were focused on. When trying to interpret medical research, there is also the issue of deciphering what the clinical studies are trying to measure, and whether the significant effects that are identified in a study are relevant in a real-life clinical setting. This is the issue of statistical significance vs clinical significance.[11] Statistical significance is a measure of the likelihood that a result is not due to pure chance. Whereas clinical significance is a measure of the practical significance of a treatment in a clinical setting. Basically, just because a research study determines that something exhibits an effect that is statistically significant, it doesn’t mean that the effect will end up being significant in any practical sense when someone consumes that thing. There is another similar issue also facing drug development and medical research, and that’s the battle between efficacy research and effectiveness research.[12] [JASON MILLER] So we’ve established that there are a lot of different ways to study medicine, and the results of some of these studies are not necessarily straightforward to interpret. [ETHAN RUSSO] All of these nuance details about research are important when it comes to the development of Cannabis based pharmaceuticals. To get a drug approved as a medicine in the United States, a company has to present lots of data that shows that the drug, and not a placebo, provide an intended therapeutic effect for a particular condition or set of conditions.[13] That takes a lot of time, a lot of energy, and a lot of money. [ETHAN RUSSO] Sativex, or Nabiximols as it is also known, is a particularly interesting drug to focus our attention on. Sativex is a mouth spray that consists of a standardized Cannabis extract with a 1:1 ratio of CBD to THC.[14] Unlike Epidiolex[15], which is often criticized for being an isolated cannabinoid drug like Marinol[16] – Sativex consists of a wide diversity of plant compounds extracted from Cannabis. This means that the clinical data on Sativex is likely to be more relevant when thinking about the therapeutic potential of herbal Cannabis or Cannabis extracts, than research on isolated THC, like Marinol, or CBD, like Epidiolex. [ETHAN RUSSO] Dr. Russo makes a great point here. Just because cannabinoid and Cannabis-based pharmaceuticals are being developed, it doesn’t mean that herbal Cannabis and the use of Cannabis extracts is going away anytime soon. And in fact, many people tend to prefer the use of herbal Cannabis or Cannabis extracts for a number of reasons. Sometimes it’s efficacy related, but sometimes it’s cost related. Pharmaceuticals can be extremely expensive.[17] When you can grow a plant at home and can easily make your own extract with as good or better efficacy than a pharmaceutical, it’s pretty hard to justify going the pharmaceutical route. However, pharmaceuticals are standardized and very consistent batch to batch. It’s possible that trying to treat a condition with homegrown Cannabis or black market (or even legal medical or recreational) Cannabis may not provide consistent outcomes because the products’ chemistry will be different batch to batch. Unfortunately, there is really not much research available regarding herbal Cannabis or Cannabis extracts. This is for multiple reasons. One reason is that research tends to happen with products that can be patented. So, there is not a huge financial incentive to do expensive research on herbal Cannabis or unstandardized Cannabis extracts. Another issue is that Cannabis flower and extracts are very diverse and inconsistent in their chemistry batch to batch. What are clinicians seeing in patients using Cannabis? However, despite all of these issues, clinicians around the US are noticing striking results in many patients. [JANNA CHAMPAGNE] [JAMES TAYLOR] All of this positive benefit that some of these health care professionals are seeing does not mean that Cannabis is without risks. For an in-depth review of the risks associated with Cannabis use, I recommend listening to the first three episodes of this season where we explored the question, “Is Cannabis Safe?”. Cannabis can interact with other medications and it’s not for every person or every condition. [JASON MILLER] So despite some of the miraculous claims about Cannabis – it’s not a cure-all, and some of the claims made by advocates are overhyped. However, other clinicians I spoke with shared additional stories of the successes of the medical use of Cannabis – which begs a question – just how much evidence is required before Cannabis, or any other natural product, can be accepted as an effective medicine? We’ve discussed that the gold standard of medical research is considered to be the randomized controlled trial – but it’s an extremely expensive process to get something through the drug approval process in the United States.[18] Because this process is so expensive, it is rare for a company to spend the millions, or sometimes billions, of dollars required to study a natural product alone that they cannot patent and capitalize on later. Additionally, natural products are challenging to standardize and control, which does not lend itself well to modern medical research schemes. [JAMES TAYLOR SEGMENT] We have also covered the fact that Cannabis has an extraordinarily long track record with humans, going back nearly 5000 years or more. Through that time, records of varying degrees of quality have been kept about the medical use and toxicity of Cannabis for thousands of years. The historical record indicates that Cannabis has been considered a potent medicine all the way up until the 1930s when Cannabis prohibition began. We haven’t even discussed the history of Cannabis prohibition here but let me just say – Cannabis prohibition was not backed by science, and many medical associations were unhappy when access to Cannabis was prohibited. Modern research has confirmed that, in fact, many of the traditional medical uses of Cannabis are well-founded and, compared to many foods and drugs, Cannabis is very safe. Where we lack clinical research, we have a host of anecdotal reports, case studies, and observational studies documenting the medical efficacy of Cannabis. And while these types of research may be considered lower quality, at a point these reports become overwhelming in their results. And yet, today in 2019 in the United States, people are still struggling to get legal access to medical Cannabis. While many of you may already be familiar with a little girl named Charlotte Figgi[19] that brought nationwide attention to the treatment of CBD-rich Cannabis for seizures in a famous CNN special with Dr. Sanjay Gupta called Weed[20], you may be less familiar with another little girl that is fighting the same fight in my home state of Mississippi, and her name is Harper Grace[21]. Harper Grace is a little girl that also suffers from seizures, similar to Charlotte. Her parents found that CBD-rich Cannabis was an effective treatment. In 2014, after a lot of advocacy from Harper Grace’s parents and friends, the state legalized CBD oil, in a limited capacity for limited conditions in a limited selection of patients. Since the law passed, which is actually named after Harper Grace, that little girl still has not been able to get access to CBD treatment, and now her parents are fighting for statewide medical marijuana legalization for 2020. [NEWS CLIP] This issue is especially poignant considering the countries only federally sanctioned Cannabis research and development laboratory is located at the University of Mississippi. Let’s review what we’ve learned.
So, how is Cannabis a medicine? Well, simply put, a lot of ways. There is still a lot we don’t know, but there is a lot we do know regarding the safety of Cannabis and the use of Cannabis traditionally as a medicine for thousands of years throughout human history. While, yes, some of the claims about cannabis as a medicine are over-hyped, a lot of them aren’t. A lot of people are finding relief from very serious conditions that they are having to live with every day through the help of Cannabis. Today it seems like the rationale for restricting access to Cannabis or Cannabis products often comes down to an argument around safety and a lack of research. Harper Grace is fighting for access to CBD oil because lawmakers in Mississippi feel that Cannabis needs to be studied more to understand its risks. The FDA has stated that they are unlikely to allow CBD in foods because they want to better understand the potential risks.[25] This issue with CBD safety is particularly interesting considering the World Health Organization already issued a report in 2018 claiming “CBD is generally well tolerated with a good safety profile…To date there is no evidence of any public health-related problems associated with the use of pure CBD.”[26] Despite this determination, the FDA backs their stance by citing a recent rodent study that claimed to have identified the liver damaging effects of CBD[27] – however as we covered in episode one of the podcast – this study was a rodent study that utilized massive, unrealistic, doses of CBD before uncovering damaging effects. At doses more typical of what anyone might encounter in real life – these liver damage effects were not observed. Very recently, democratic presidential candidate and former vice president Joe Biden stated that he believed that there needed to be more research into the risks of Cannabis, particularly as a gateway drug, before legalizing the plant federally.[28] Yet, as we also covered in episode one of the podcast, an administrative law judge in the US in 1988 made a formal statement attesting to the safety profile of Cannabis and the need to reschedule it to a more lenient drug schedule.[29] So, what do you think? Do we need more research into the safety of Cannabis before we legalize nationwide? How much evidence is enough before people are allowed open, legal access to Cannabis for medical purposes around the world? Personally, I was left with a couple of questions:
So far, we have been looking at the various ways Cannabis is used as a medicine. But what do cannabinoids and other chemicals in Cannabis actually do in the body to elicit these medicinal effects? Join me in our next episode as we take our fantastic voyage into the human body to understand how Cannabis works. In the next episode we begin to explore the question, “What is the endocannabinoid system?” Until next time, I’m your host, Jason Wilson. Thanks, and take it easy. [OUTRO MUSIC] CITATIONS [1] https://www.coloradopotguide.com/images/blog/Health-Effects-of-Marijuana-Reduced.png [2] https://miro.medium.com/max/1400/0*T-fJXuEjKW4qGUXM.jpg [3] Rohrig et al. Types of Study in Medical Research. Part 3 of a Series on Evaluation of Scientific Publications. Dtsch Artztebl Int. 2009. 106(15): 262-268. [4] Kabisch et al. Randomized Controlled Trials. Part 17 of a Series on Evaluation of Scientific Publications. Dtsch Artztebl Intl. 2011. 108(39): 663-668. [5] Devlin RB et al. In vitro studies: what is their role in toxicology? Exp Toxicol Pathol. 2005. 57 Supple 1:183-188. [6] Lorian V. Differences between in vitro and in vivo studies. Antimicrob Agents Chemother. 1988. 32(10): 1600-1601. [7] Ghallab A. In vitro test systems and their limitations. EXCLI J. 2013. 12: 1024-1026. [8] Geraghty RJ et al. Guidelines for the use of cell lines in biomedical research. 2014. Br J Cancer. 111(6):1021-1046. [9] Waterbor JW et al. Considerations of sample size in medical research. JAAPA. 2008. 21(4) [10] Mullane K et al. Chapter 1 – Reproducibility in Biomedical Research. Research in the Biomedical Sciences. Transparent and Reproducible. 2018. pp. 1-66. [11] LeFort SM. The Statistical versus Clinical Significance Debate. 1993. 25(1):57-62. [12] Singal AG et al. A Primer on Effectiveness and Efficacy Trials. Clin Transl Gastroenterol. 2014. 5(1): e45. [13] https://www.fda.gov/drugs/development-approval-process-drugs [14] https://www.gwpharm.com/healthcare-professionals/sativex [15] https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms [16] http://marinol.com/ [17] https://www.ama-assn.org/delivering-care/public-health/how-are-prescription-drug-prices-determined [18] Fassbender M. Clinical trial cost is a fraction of the drug development bill, with an average price tag of $19m. 2018. https://www.outsourcing-pharma.com/Article/2018/09/26/Clinical-trial-cost-is-a-fraction-of-the-drug-development-bill [19] https://www.cnn.com/2013/08/07/health/charlotte-child-medical-marijuana/index.html [20] https://www.cnn.com/2013/08/08/health/gupta-changed-mind-marijuana/index.html [21] Rowell N. Harper Grace’s Legacy. North Side Sun. 2019 Apr 11. https://www.northsidesun.com/news-breaking-news/harper-grace%E2%80%99s-legacy [22] Russo E. The Pharmacological History of Cannabis. Chapter 2. Handbook of Cannabis. Oxford University Press. 2014. p.23-29 [23] Whiting PF et al. Cannabinoids for Medical Use. A Systematic Review and Meta-Analysis. JAMA. 2015. 313(24): 2456-2473. [24] Hill KP. Medical Use of Cannabis in 2019. JAMA. 2019. 322(10): 974-975. [25] https://www.fda.gov/consumers/consumer-updates/what-you-need-know-and-what-were-working-find-out-about-products-containing-cannabis-or-cannabis [26] World Health Organization (WHO). Cannabidiol (CBD) Critical Review Report. Expert Committee on Drug Dependence. Fortieth Meeting. 2018. https://www.who.int/medicines/access/controlled-substances/CannabidiolCriticalReview.pdf [27] Ewing et al. Hepatotoxicity of a Cannabidiol-Rich Cannabis Extract in the Mouse Model. Molecules. 2019. 24(9): 1694. [28] https://www.washingtonpost.com/nation/2019/11/18/joe-biden-marijuana-gateway-drug-legalization/ [29] https://www.nytimes.com/1988/09/07/us/judge-urges-allowing-medicinal-use-of-marijauna.html 
Episode Description: In this episode, we begin exploring the idea of Cannabis as a medicine. How has Cannabis been used as a medicine in the past? How is Cannabis being used as a medicine today? What does modern medical research have to say regarding what Cannabis can and can't treat? Featured guests include Ethan Russo MD, Jason Miller DACM, James Taylor MD, and Kevin Spelman PhD.
Transcript: 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. [Shutter] [KEVIN SPELMAN CLIP] Here in the state of Oregon, medical Cannabis has been available since 1998 for registered patients with a doctor’s recommendation. There are a variety of conditions that can qualify someone to join the Oregon Medical Marijuana Program, such as cancer, glaucoma, PTSD, or HIV, but the most common condition being treated with medical Cannabis, by far, is pain. At the time of this recording, in 2019, 88% of the 27,000 qualifying patients in Oregon’s Medical Marijuana Program reported severe pain as a condition that they intended to treat with Cannabis.[1] The remaining conditions ranked from most common to least common are spasms, PTSD, nausea, cancer, neurological disease, seizures, glaucoma, wasting syndrome, HIV/AIDS.[2] Clearly people are trying to treat a wide variety of serious conditions with Cannabis. If Cannabis is an effective therapy for just some or all of these conditions, it could change the health and wellbeing for a massive amount of people currently suffering every day. So what do we really know about Cannabis? How is Cannabis a medicine? [INTRO] Hey everybody, I’m Jason Wilson and you’re listening to the Curious About Cannabis podcast. Thanks for tuning in once again. In this episode we’ll be exploring the idea of Cannabis as a medicine. And to guide our curious quest I wanted to explore several primary questions:
Let’s get started. In 2015 the Journal of the American Medical Association published a review, acknowledging a list of therapeutic applications of Cannabis, while also expressing skepticism over others.[3] The National Academy of the Sciences, Engineering and Medicine released a lengthy 400+ page review also identifying clear therapeutic applications of Cannabis and its constituents.[4] [NEWS CLIP][5] I have to point out here that when we talk about the medical use of Cannabis, we aren’t just talking about smoking Cannabis. There are lots of ways to consume Cannabis, and each consumption method affects the body differently. Sure, Cannabis can be smoked or vaporized, but it can also be eaten in the form of Cannabis infused foods or taken sublingually by taking drops of a Cannabis tincture under the tongue. Cannabis can also be administered on the skin, topically. Less commonly, Cannabis can also be taken as a suppository. Anything consumed orally will take longer to take effect because it has to pass through the digestive system and undergo a process called first-pass metabolism before the cannabinoids are passed into the bloodstream. During this metabolic process, cannabinoids are chemically altered. For instance, when THC is ingested orally, nearly half of the THC is metabolized to a compound called 11-OH-THC, which is considered nearly four times as strong as THC.[6] This is why the experience of eating Cannabis products can be so unique and sometimes more powerful than consuming Cannabis by other means. However, when smoking, vaping, using sublingual products, or suppositories, cannabinoids bypass the liver and pass straight into the blood, leading to a much faster onset and avoiding the chemical alteration that happens during metabolism. So it seems among the scientific and medical communities, there is no doubt that in some contexts, Cannabis can be a medicine. But to what extent? For what conditions? At what dosages? In what form? That is where much of the debate currently resides. According to the United States government, at the time of this recording in 2019, Cannabis and it’s cannabinoid constituents are classified as schedule I drugs, a classification reserved for drugs that are presumed to have no medical value and a high propensity for abuse.[7] Other drugs that are classified as schedule I include things like heroin and bath salts. To put this into perspective, drugs like cocaine and methamphetamine, which are schedule II drugs, are less controlled than Cannabis. Despite the US government’s determination that Cannabis should be a schedule I drug and as such has no medical value – the government actually held a patent on the antioxidant and neuroprotective properties of cannabinoids up until this year.[8] To many, this patent represented deep hypocrisy. Regardless of the legal status of Cannabis, there are many people across the US that have jumped on the Cannabis bandwagon, touting benefits so profound and diverse that it can’t help but sound like a pitch for the next snake oil. [JASON MILLER] That’s Dr. Jason Miller, a medicinal plant and Chinese medicine expert that has been noticing that more and more of his patients are talking about Cannabis. [JASON MILLER] So what’s the truth here? To start, let’s explore the ways Cannabis has been used as a medicine throughout history. Then we can look at some of the more modern Cannabis research and see how some of these traditional uses hold up against modern science. How has Cannabis been used as a medicine in the past? Cannabis has been used by humans for a long, long, long time. We’re talking thousands of years. We’re talking 5000 years. Half of a decamillenium. Decamillenium? Is that a word? It is now. [JASON MILLER] In Chapter 2 of the book the Handbook of Cannabis, Ethan Russo, a neurologist and cannabinoid researchers that has been studying Cannabis for over 25 years, summarizes some of the ways in which Cannabis was used therapeutically throughout the last several millenia.[9] Here’s an extremely condensed version. Oral traditions of Cannabis use for appetite stimulation and fighting the effects of old age date back to nearly 3000 years BCE.[10] That’s 5000 years ago! In 1500 BCE, the Atharva Veda indicates that Indians were using Cannabis for anxiety relief.[11] Cannabis is suspected to even be a component of the holy anointing oil of the Hebrews as far back as 750 BCE.[12] [13] The juice of the leaves was noted to be a remedy for earaches in the first century.[14] In the second century Chinese records indicate Cannabis was used in wine as an anesthetic.[15] In the early 10th century Persian records indicate it was even used to stimulate hair growth.[16] In 1542 it was noted that the Cannabis roots could be boiled and used to treat gout and burns.[17] Throughout the 16th century records indicate Cannabis was used for sore muscles, stiff joints, burns, wounds, jaundice, colic and even tumors.[18] In 1839 a researcher named O’Shaughnessy studied Indian use of Cannabis and performed experiments in dogs, and then later people, to determine if Cannabis was a suitable treatment for tetanus, rabies, epilepsy and rheumatoid disease.[19] Shortly after O’Shaughnessy published his findings, Cannabis began showing up in the European and United States Pharmacopoeias. O’Shaughnessy is a particularly interesting figure in the history of medical Cannabis. We are going to be learning more about his work in future episodes. As records become more easily obtainable, we can find records throughout the 18th and 19th centuries of Cannabis being used to treat migraines, pain, spasticity, anxiety, depression, and insomnia.[20] Cannabis was even featured in the US Pharmacopoeia as a medicine until the 12th edition released in 1942 after marijuana prohibition had begun in 1937.[21] You can still look up old issues of the USP and look for Extractum Cannabis or Tinctura Cannabis aka Extract of Hemp or Tincture of Hemp. Upon the initial publication of Cannabis in the USP in 1851, the 9th edition of the US Dispensatory had this to say about the medical use of Cannabis: “It has been found to cause sleep, to allay spasm, to compose nervous disquietude, and to relieve pain…The complaints in which it has been specially recommended are neuralgia, gout, rheumatism, tetanus, hydrophobia, epidemic cholera, convulsions, chorea, mental depression delirium tremens, insanity, and uterine hemorrhage.”[22] After Cannabis prohibition began, Cannabis became unavailable as a medicine, and research into the plant progressively slowed down into the late 1950s. Modern medical research into Cannabis really took off in the 1960s when THC was isolated and synthesized.[23] A little known fact – but CBD was actually isolated and characterized approximately 20 years prior to when THC was isolated.[24] But because CBD did not elicit an intoxicating effect, it was largely ignored at first. As THC research progressed throughout the 1960s and 1970s, research confirmed that THC could reduce nausea and vomiting associated with cancer chemotherapy[25], that THC had the same analgesic activity as codeine[26], and that THC performed as well as the anti-asthma drug salbutamol aka albuterol or Ventolin as a bronchodilator.[27] The 1980s ushered in renewed interest in CBD as well as continued research on THC. In 1981 CBD was identified as an anticonvulsant.[28] A year later it would be found that CBD could help relieve the anxiety brought on by THC.[29] In 1985, the unique flavonoid Cannflavin A was discovered, breaking Cannabis research away from the cannabinoid chemical class to encompass other types of plant compounds.[30] It was also in 1985 that the pharmaceutical drug Marinol was approved by the FDA for chemotherapy related nausea.[31] [ETHAN RUSSO] That’s Ethan Russo, and he knows a thing or two about cannabinoid pharmaceuticals. [ETHAN RUSSO] And then in 1988 scientists finally discovered a chemical receptor in the body that seemed to be responsible for most of THC’s effects – the cannabinoid type 1 receptor, or CB1 receptor.[32] This marks the beginning of piecing together a fascinating puzzle about a physiological system that had since been ignored – the endocannabinoid system, which wouldn’t be formally named for another 10 years.[33] But we’ll get into that story in another episode. In 1993 CBD’s anti-anxiety effects that had been previously noted in the 1980s was again confirmed.[34] In 1997 it was found that THC could help reduce agitation in patients with dementia.[35] In 2003 clinical trials of the Cannabis based pharmaceutical Sativex began, investigating whether it could be effective in treating multiple sclerosis symptoms.[36] In 2005 Sativex would go on to be approved in Canada for the treatment of MS related pain.[37] Over the years Sativex would later be approved for other types of pain such as neuropathic pain and cancer pain.[38] [39] Eventually Sativex would be approved in the UK and Spain for spasticity in MS patients.[40] In 2010 it would be discovered that Sativex can also treat nausea related to chemotherapy treatments.[41] [ETHAN RUSSO] Over and over, health care professionals I spoke with commented on the superior efficacy of broader spectrum Cannabis products over isolated cannabinoids.[42] [JAMES TAYLOR] This is Dr. James Taylor, a pain physician working in North Carolina. Ever since hemp became federally legal in the United States, he has been working with his patients to understand how hemp extracts, and CBD particularly, might be a tool to help treat chronic pain. [JAMES TAYLOR] This difference in therapeutic outcome between isolated compounds from Cannabis and the use of herbal Cannabis or broad-spectrum Cannabis extracts is attributed to something often called – the entourage effect.[43] [KEVIN SPELMAN] So far we have looked at the ways in which Cannabis has been used as a medicine in the past, and some ways in which Cannabis and cannabinoid drugs are being used as medicine today. Join us in part two of this series where we pick up on our quest to understand Cannabis as a medicine by examining the ways in which medical claims are derived. How do we determine that something is a medicine? And what results are clinicians seeing in their patients that are using Cannabis? Until next time, I’m your host, Jason Wilson, stay curious and take it easy! CITATIONS [1] Oregon Medical Marijuana Program Statistical Snapshot October 2019. https://www.oregon.gov/oha/PH/DISEASESCONDITIONS/CHRONICDISEASE/MEDICALMARIJUANAPROGRAM/Documents/OMMP_Statistical_Snapshot_10-2019.pdf [2] Oregon Medical Marijuana Program Statistical Snapshot October 2019. https://www.oregon.gov/oha/PH/DISEASESCONDITIONS/CHRONICDISEASE/MEDICALMARIJUANAPROGRAM/Documents/OMMP_Statistical_Snapshot_10-2019.pdf [3] Whiting PF, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015. 313(24): 2456-2473. [4] National Academies of Sciences, Engineering, and Medicine. 2017. The health effects of cannabis and cannabinoids: Current state of evidence and recommendations for research. Washington, DC: The National Academies Press. [5] CBS This Morning. New Report Finds Benefits and Risks of Marijuana. https://www.youtube.com/watch?v=Jx6ioVF5KhE&t=13s [6] Huestis MA. Human Cannabinoid Pharmacokinetics. Chem Biodivers. 2007. 4(8): 1770-1804. [7] Lists of Scheduling Actions Controlled Substances and Regulated Chemicals. United States Department of Justice. Drug Enforcement Administration. https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf [8] Hampson et al. Cannabinoids as antioxidants and neuroprotectants. Patent US6630507B1. https://patents.google.com/patent/US6630507B1/en [9] Russo E. The Pharmacological History of Cannabis. Chapter 2. Handbook of Cannabis. Oxford University Press. 2014. p.23-29 [10] Shou-Zhong, Y. The Divine Farmer’s Materia Medica: A Translation of the Shen Nong Ben Cao Jing. 1997. Boulder, CO: Blue Poppy Press. [11] Grierson, GA. The hemp plant in Sanskrit and Hindi literature. Indian Antiquary. 1894. 260-262. [12] Alter R. The Five Books of Moses: A Translation with Commentary. 2004. New York: W.W. Norton & Co. [13] Russo EB. History of Cannabis and its preparations in saga, science and sobriquet. Chemistry and Biodiversity. 2007. 4: 2624-2648. [14] Dioscorides P and Beck LY. De Materia Medica. 2011. Hildesheim: Olms-Weidmann. [15] Julien MS. Chirugie chinoise. Substance anesthétique employée en Chine, dans le commencement du III-ième siecle de notre ère, pour paralyser momentanement la sensibilité. Comptes Rendus Hebdomadaires de l’Académie des Sciences. 1849. 28:223–229. [16] Lozano I. The therapeutic use of Cannabis sativa L. in Arabic medicine. Journal of Cannabis Therapeutics. 2001. 1: 63-70. [17] Fuchs L. The great herbal of Leonhart Fuchs: De historia stirpium commentarii insignes, 1542 (notable commentaries on the history of plants). 1999. Stanford, CA: Stanford University Press. [18] Gerard J and Johnson T. The Herbal: or, General History of Plants. 1975. New York: Dover Publications [19] O’Shaughnessy WB. (1838–1840). On the preparations of the Indian hemp, or gunjah (Cannabis indica); their effects on the animal system in health, and their utility in the treatment of tetanus and other convulsive diseases. Transactions of the Medical and Physical Society of Bengal, 71–102, 421–461. [20] Russo E. The Pharmacological History of Cannabis. Chapter 2. Handbook of Cannabis. Oxford University Press. 2014. p.23-29 [21] United States Pharmacopoeia 12th Edition. 1942 [22] George B. Wood and Franklin Bache, eds., 1851, The Dispensatory of the United States of America, 9th ed. Philadelphia: Lippincott, Grambo, 1851, pp. 310-311. [23] Gaoni Y and Mechoulam R. Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. J. Am. Chem. Soc. 1964. 86(8): 1646-1647. [24] Adams R et al. Structure of Cannabidiol, a Product Isolated from the Marihuana Extract of Minnesota Wild Hemp. I. J. Am. Chem. Soc. 1940. 62(1): 196-200. [25] Sallan SE et al. Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. New England Journal of Medicine. 1975. 293: 795–797. [26] Noyes R Jr et al. The analgesic properties of delta-9- tetrahydrocannabinol and codeine. Clinical Pharmacology and Therapeutics. 1975. 18: 84–89. [27] Williams, SJ et al. Bronchodilator effect of delta1-tetrahydrocannabinol administered by aerosol of asthmatic patients. Thorax. 1976. 31: 720–723. [28] Carlini EA and Cunha JM. Hypnotic and antiepileptic effects of cannabidiol. Journal of Clinical Pharmacology. 1981. 21: 417S–427S. [29] Zuardi AW et al. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology. 1982. 76: 245–250. [30] Barrett ML et al. Isolation from Cannabis sativa L. of cannflavin – a novel inhibitor of prostaglandin production. Biochemical Pharmacology. 1985. 34: 2019–2024. [31] Russo E. The Pharmacological History of Cannabis. Chapter 2. Handbook of Cannabis. Oxford University Press. 2014. p.23-29 [32] Devane WA et al. Determination and characterization of a cannabinoid receptor in rat brain. Molecular Pharmacology. 1988. 34: 605–613. [33] Di Marzo V. ‘Endocannabinoids’ and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance. Biochimica et Biophysica Acta. 1998. 1392: 153–175 [34] Zuardi AW et al. Effects of ipsapirone and cannabidiol on human experimental anxiety. Journal of Psychopharmacology. 1993. 7: 82–88. [35] Volicer, L et al. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer’s disease. International Journal of Geriatric Psychiatry. 1997. 12: 913–919. [36] Wade, DT et al. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clinical Rehabilitation. 2003. 17: 18–26. [37] Rog DJ et al. Randomized controlled trial of cannabis based medicine in central neuropathic pain due to multiple sclerosis. Neurology. 2005. 65: 812–819. [38] Notcutt W et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 “N of 1” studies. Anaesthesia. 2004. 59: 440–452. [39] Berman JS et al. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain. 2004. 112: 299–306. [40] Novotna A et al. A randomized, double-blind, placebo-controlled, parallel group, enriched-design study of nabiximols (Sativex®), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. European Journal of Neurology. 2011. 18: 1122–1131. [41] Duran M et al. Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting. British Journal of Clinical Pharmacology. 2010. 70: 656–663. [42] Russo EB. The case for the entourage effect and conventional breeding of clinical cannabis: no “strain,” no gain. Front. Plant Sci. 09 January 2019. https://doi.org/10.3389/fpls.2018.01969 [43] Ben-Shabat S et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. European Journal of Pharmacology. 1998. 353: 23–31. 
#03 Is Cannabis Safe? Part Three: Adolescent Cannabis Use and Harm Reduction
Episode Description: In this episode of the Curious About Cannabis Podcast we wrap up our three-part series on Cannabis safety and harm reduction by exploring the question, "Is Cannabis Safe?". First we talk about adolescent Cannabis use before discussing ways in which Cannabis users can minimize or eliminate many of the risks associated with Cannabis. Make sure you listen to episodes 1 and 2 prior to listening to this episode! Episode Transcript: You’re listening to the Curious About Cannabis Podcast. [Reefer Madness Clip] [Shutter] Hey everybody, this is Jason Wilson with the Curious About Cannabis podcast, thanks so much for tuning in once again. Over the last two episodes we have been exploring the topic of Cannabis safety and harm reduction. We explored the toxicity of some of the major chemical constituents of Cannabis resins, how Cannabis can interact with medications, and contaminants that could be found in Cannabis products. Now, for this third and final part of this series, we are focusing on the topics of teen Cannabis use before diving into some of the ways that Cannabis users can minimize the potential risks associated with Cannabis use. So here we go, the third and final part of our series where we explore the question: “Is Cannabis Safe?” [INTRO MUSIC] What about adolescent Cannabis use? What are the risks of exposing children to Cannabis at an early age? As you might imagine, this is a very complicated question. For this episode we are going to ignore the topics of Cannabis use during pregnancy, while breastfeeding, or medical Cannabis use in children. We’ll explore those topics in other episodes. For this episode, we are going to focus on looking at the health risks of adolescent Cannabis use during the teenage years. The topic of adolescent Cannabis use is a complicated and sensitive topic. Kids today have become very wary of drug education of any kind, primarily because kids have been exposed to tales of exaggerated harms or outright lies about drug use for decades as part of prohibition and abstinence-based drug education programs.[1] [2] [MATT VOGEL SEGMENT] This is Matt Vogel. Matt is a health and wellness educator that works with high school and college students to teach about health, substance use, and harm reduction strategies. [MATT VOGEL SEGMENT] Regarding Cannabis, kids have been told that it will kill brain cells, lead to schizophrenia or other mental health issues, make them lazy or stupid, or cause them to move on to other drugs like cocaine or heroin. It should first be pointed out that there are big differences between acute or occasional Cannabis use and chronic Cannabis use. In general, acute Cannabis use is pretty safe, physiologically, with the biggest risks being risks of motor discoordination, which is why it is not a good idea to drive after using THC-rich Cannabis, memory disruption, and psychological distress.[3] However, most of the major risks that adolescents learn about Cannabis are associated with chronic, or repeated, Cannabis use. While chronic Cannabis use can alter the way the brain functions[4] [5] [6], and we need to understand the consequences of that more, to say that it kills brain cells is dishonest. Cannabis can make some parts of the brain less active while making other parts of the brain more active.[7] In fact, in some cases Cannabis can actually encourage new brain cells to grow in a process called neurogenesis[8] [9]. While Cannabis can exacerbate or reveal underlying mental health problems in adolescents, there is not strong evidence that it actually causes these problems.[10] [11] And the only time that Cannabis seems to act as a gateway to other drugs seems to be when users are exposed to those other drugs on the black market.[12] The issue of adolescent Cannabis use and IQ is a more complicated problem. Research has confirmed that there does not seem to be a link between Cannabis use and low IQ, but there does seem to be a link between early onset Cannabis use and poor cognitive performance.[13] [14] If you dig through the research, a common theme emerges. The issue is that THC in Cannabis can, in some people, interfere with the learning process, by disrupting attention and memory. Ultimately users that are affected in this way have to work harder to perform as well as they typically would without Cannabis. Depending on the situation, Cannabis use can also cause kids to avoid social interactions, which can cause problems with the development of emotional intelligence and social skills.[15] [16] [17] Chronic THC-rich Cannabis use can interfere with learning processes at a time when a person is going through critical developmental stages, resulting in poor development into adulthood. Although the brain is not actually a muscle, it acts like one in the sense that if you don’t exercise it, it won’t perform well. But a lot of these possible outcomes are difficult to assess[18] because there are a lot of variables that affect a person’s cognitive development including social factors, concurrent drug use, such as alcohol use, and underlying mental health disorders to name a few. In addition, everyone responds to Cannabis differently. There are also a wide variety of Cannabis products, with different risks associated with them. It has to be noted here, that the context of Cannabis use has a lot to do with outcomes. There are children, teens, and adults throughout the world with qualifying medical conditions that are using Cannabis medically and exhibiting very few adverse events.[19] [20] In addition, CBD rich Cannabis or Cannabis products that don’t have intoxicating effects do not present the same psychological health risks as THC rich Cannabis products. Dose is also an important factor to consider. Lower dosages of either THC or CBD present fewer risks than higher doses. So if Cannabis can be used responsibly, while minimizing adverse events, then what does that look like?[21] When does Cannabis use become Cannabis abuse? [MATT VOGEL SEGMENT] One thing I really appreciated about my conversation with Matt was his attention to how complicated this topic is, and that there is no one size fits all answer regarding teen Cannabis use and the potential risks involved. Even just finding reputable information about Cannabis can be challenging in the age of internet headlines and memes [MATT VOGEL SEGMENT] So, let’s assume an adolescent has decided that they want to experiment with Cannabis. How long should they wait in order to stay safe? [MATT VOGEL SEGMENT] How can people minimize the risks of using Cannabis? This all begs the next question, what can people do to reduce the risks associated with Cannabis use? From Matt’s perspective, that begins with cultivating a healthy amount of self-awareness regarding not only substance use, but health and wellness in general. [MATT VOGEL SEGMENT] And beyond all of that, Matt had a simple recommendation to reduce risk that was echoed by many of my other guests. [MATT VOGEL SEGMENT] I asked veteran Cannabis and cannabinoid researcher, Dr. Ethan Russo, about his thoughts on minimizing risks associated with Cannabis use. Right away he wanted to bring attention to the diverse and sometimes uncertain quality of Cannabis products on the market. [ETHAN RUSSO SEGMENT] So it’s clear that the first step of minimizing risk is to ensure you find clean, high quality products. But what comes next? Many people understand that it can be a very uncomfortable and unpleasant experience to take too much Cannabis, so what can people do to avoid this? I spoke with Dr. Jason Miller about this issue. Jason is a doctor of acupuncture and Chinese medicine that is an expert regarding the clinical use of medicinal plants. Recently he started having a lot of patients coming to him to ask about Cannabis, so he began taking note of what their experiences and outcomes were like in order to be prepared to counsel others on the potential pitfalls and promises of Cannabis use. The first goal, he noted, was to develop strategies to avoid taking too much in the first place… [JASON MILLER SEGMENT] Okay, so let’s say you’ve done your best to find your minimum effective dose, and you still went too far and are in the midst of an uncomfortable Cannabis experience. What can be done? [JASON MILLER SEGMENT] In case you don’t know, Acetylcholine is a neurotransmitter in our brains that among many things is responsible for influencing things like sleep, arousal, memory, and attention.[22] [23] [24] [25] [26] [JASON MILLER SEGMENT] And if you forget all of these suggestions, there are some products on the market now that claim to combat Cannabis intoxication. [PEGGY ANDERSON SEGMENT] That’s Peggy Anderson, the founder of a company called Canna Help You? Which is dedicated to providing seniors with education about Cannabis. In one recent study, it was found that the demographic of Cannabis users over the age of 65 is growing faster than any other demographic of older adults. Many of these users don’t want to be intoxicated and are particularly concerned about taking too much THC. Peggy shared some of her experience with this issue. [PEGGY ANDERSON SEGMENT] The feedback I got from some of my guests mirrors some of the suggestions found in literature dating back all the way to the 10th century. See Taming THC by Ethan Russo.[27] I asked some of my guests whether they thought that Cannabis products, overall were safe or not. The response was consistent. In places where Cannabis is legal and the quality of Cannabis products are regulated, Cannabis seems to be safer than it has ever been. [ANTHONY SMITH SEGMENT] [PEGGY ANDERSON SEGMENT] Alright, Let’s review what we’ve learned, across these past three episodes:
So, is Cannabis safe? In toxicology it is well known that nearly anything can be toxic when consumed in a particular way or in a particular dose. In the early 1500s, the swiss physician, alchemist, and astrologer Paracelsus said, “All things are poison, and nothing is without poison. It is the dose alone that makes a thinit so a thing is not a poison.”[31] Today this is often simplified to the saying, “The dose makes the poison.” This applies to everything, including the water we drink and the air we breathe. Nothing in life is without risk, but in general Cannabis is safer, physiologically, than many substances we engage everyday, like coffee. While there are some rare exceptions and contraindications to be aware of, Cannabis, as long as it is clean, seems to be pretty safe and well tolerated by most people, especially at low doses. Deaths attributed to Cannabis are extremely rare[32] [33], and most adverse events that could arise from Cannabis use, like hyperemesis syndrome[34], are usually reversible. To minimize risk, wait as long as you can to try Cannabis for the first time, avoid smoking, only use Cannabis of a known quality, start with low dosages, and slowly increase dosage to find a minimum effective dose. And remember, if you do take too much THC and are having an uncomfortable experience, there are a variety of things you can do to help ease that uncomfortable feeling, and, most importantly, the feeling will eventually pass and you will be fine. I know that some of you listening might be wondering about the issue of substance abuse and addiction as a risk, which I did not cover in these episodes. Don’t worry, there will be an episode dedicated to that issue, as well as issues like pediatric Cannabis use and Cannabis use while pregnant or breastfeeding. So stay tuned as we revisit the issue of Cannabis safety in other episodes. And with that, I’m your host, Jason Wilson. Until next time, stay curious. [OUTRO Music] Special thanks to our guests that were so gracious in spending time with me for interviews. To check out the citations for this episode, and there are plenty, you can check out the show notes by visiting CACPodcast.com. If you want to learn more about Cannabis, you can check out the Curious About Cannabis book, available on Amazon.com and other online book retailers. If you like what we are doing and want to support the show please consider supporting the podcast by liking and sharing this episode. You can also support us on Patreon at patreon.com/naturallearningenterprises where you can get access to the full-length guest interviews, behind-the-scenes content, and more! You can also connect with Curious About Cannabis on social media on Instagram, Facebook, Twitter, and YouTube. [OUTRO Music continues] Citations: [1] Rosenbaum DP, et al. Cops in the Classroom: A Longitudinal Evaluation of Drug Abuse Resistance Education (DARE). Journal of Research in Crime and Delinquency. 1994. 31(1): 3-31. [2] Birkeland S et al. Good reasons for ignoring good evaluation: the case of the drug abuse resistance education (D.A.R.E.) program. Evaluation and Program Planning. 28(3): 247-256. [3] Karilla L et al. Acute and long-term effects of cannabis use: a review. Curr Pharm Des. 2014. 20(25): 4112-4118 [4] Ashtari M et al. Medial temporal structures and memory functions in adolescents with heavy cannabis use. Journal of Psychiatric Research. 2011. 45(8): 1055-1066. [5] Demirakca T et al. Diminished gray matter in the hippocampus of cannabis users: possible protective effects of cannabidiol. Drug and Alcohol Dependence. 114(2-3): 242-245. [6] Steel R et al. Delta-9-tetrahydrocannabinol disrupts hippocampal neuroplasticity and neurogenesis in trained, but not untrained adolescent Sprague-Dawley rats. Brain Research. 2014. 1548: 12-19. [7] Jager G et al. Cannabis use and memory brain function in adolescent boys: a cross-sectional multicenter functional magnetic resonance imaging study. J Am Acad Child Adolesc Psychiatry. 2010. 49(6): 561-572. [8] Wolf SA et al. Cannabinoid receptor CB1 mediates baseline and activity-induced survival of new neurons in adult hippocampal neurogenesis. Cell Communication and Signaling. 2010. 8:12. [9] Jiang W et al. Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic and antidepressant like effects. Neuroscience. 2005. 115(11): 3104-3116. [10] Rubino T et al. Adolescent exposure to cannabis as a risk factor for psychiatric disorders. J Psychopharmacol. 2012. 26(1): 177-188. [11] Johns A. Psychiatric effects of cannabis. Br J Psychiatry. 2001. 178: 116-122. [12] Hall W and Lynskey M. Is cannabis a gateway drug? Testing hypotheses about the relationship between cannabis use and the use of other illicit drugs. Drug and Alcohol Review. 24(1): 39-48 [13] Jackson N et al. Impact of adolescent marijuana use on intelligence: Results from two longitudinal twin studies. PNAS. 113(5):E500-E508. [14] Harvey M et al. The relationship between non-acute adolescent cannabis use and cognition. Drug and Alcohol Review. 26(3): 309-319. [15] Nehra DK et al. Emotional intelligence and self esteem in cannabis abusers. Journal of the Indian Academy of Applied Psychology. 38(2): 385-393. [16] Nehra DK et al. Alexithymia and emotional intelligence among people with cannabis dependence and health control: a comparative study. Dysphrenia. 2013. 5(1): 49-55. [17] Limonero JT et al. Perceived emotional intelligence and its relation to tobacco and cannabis use among university students. Psicothema. 2006. 18: 95-100. [18] Pope HG et al. Early-onset cannabis use and cognitive deficits: what is the nature of the association? Drug and Alcohol Dependence. 2003. 69(3):303-310. [19] Sznitman SR and Zolotov Y. Cannabis for therapeutic purposes and public health and safety: a systematic and critical review. International Journal of Drug Policy. 2015. 26(1): 20-29 [20] Blake DR et al. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology. 2005. 45(1): 50-52. [21] Lau N et al. Responsible and controlled use: older cannabis users and harm reduction. International Journal of Drug Policy. 2015. 26(8): 709-718. [22] Acetylcholine. Neuroscience. 2nd Edition. https://www.ncbi.nlm.nih.gov/books/NBK11143/ [23] Miyazawa M and Yamafuji C. Inhibition of Acetylcholinesterase Activity by Bicyclic Monoterpenoids. J Agric Food Chem. 2005. 53(5): 1765-1768. [24] Ryan MF and Byrne O. Plant-insect coevolution and inhibition of acetylcholinesterase. Journal of Chemical Ecology. 1988. 14(10): 1965-1975. [25] Pattanaik J et al. Acorus calamus Linn.: A herbal tonic for central nervous system. Journal of Scientific and Innovative Research. 2013. 2(5): 950-954. [26] Mukherjee PK et al. In vitro Acetylcholinesterase inhibitory activity of the essential oil from Acorus calamus and its main constituents. Planta Med. 2007. 73(3): 283-285. [27] Russo EB. Taming THC: potential cannabis synergy and phytocannabinoids-terpenoid entourage effects. Br J Pharmacol. 2011. 163(7): 1344-1364. [28] Abrams D et al. Vaporization as a Smokeless Cannabis Delivery System: A Pilot Study. Clinical Pharmacology and Therapeutics. 82(5): 572-578. [29] Volkow ND et al. Adverse Health Effects of Marijuana Use. N Engl J Med. 2014. 370: 2219-2227. [30] Bornheim LM et al. Characterization of cannabidiol-mediated cytochrome P450 inactivation. Biochemical Pharmacology. 1993. 45(6): 1323-1331. [31] Paracelsus, dritte defensio, 1538. [32] Gargani Y et al. Too Many Mouldy Joints – Marijuana and Chronic Pulmonary Aspergillosis. Mediterr J Hematol Infect Dis. 2011. 3(1): e2011005. [33] Bachs L and Morland H. Acute cardiovascular fatalities following cannabis use. Forensic Science International. 2001. 124(2-3): 200-203. [34] Simonetto DA et al. Cannabinoid Hyperemesis: A Case Series of 98 Patients. Mayo Clinic Proceedings. 87(2): 114-119. 
Episode Description: Continuing from our previous episode, we continue exploring the basic question, "Is Cannabis Safe?", this time focusing on contaminants that could be found in Cannabis or Cannabis products. We speak with biochemist Dr. Anthony Smith about what contaminants labs are commonly finding in Cannabis. We also speak with herbal scientist, Travis Simpson, about his concerns regarding Cannabis processing operations and the potential contaminants that may be introduced to products through bad manufacturing practices. Finally we talk again with neurologist and cannabinoid researcher, Dr. Ethan Russo, to discuss the "vaping crisis" that has claimed the lives of as many as 37 people in the United States and affected nearly 2000 users. This is part two of a three part series exploring the question, "Is Cannabis Safe?"
Transcript: You’re listening to the Curious About Cannabis Podcast. [Intro Preview] [Shutter] Hey everybody, this is Jason Wilson with the Curious About Cannabis podcast. Thanks so much for tuning in once again. This episode is part two of a three-part series exploring Cannabis safety and harm reduction. If you haven’t listened to the first part of this series, I really recommend stopping this episode and going back to listen to this series from the beginning. Previously we explored some of the main chemicals in Cannabis, the adverse health risks associated with Cannabis, and how Cannabis can interact with medications.[1] Today we will be focusing on a critical topic that has a huge impact on the safety of Cannabis products – Cannabis contaminants. [INTRO MUSIC] What contaminants might be found in Cannabis products? Anthony Smith is a biochemist that has spent that last five years analyzing Cannabis products for potency and purity in labs all across the United States and Canada. [ANTHONY INTERVIEW SEGMENT] Before we continue, let’s talk a little more about pesticides. Many pesticides are designed to disrupt the nervous systems or hormone signaling in insects.[2] The problem is that this same effect can happen in humans, if someone is exposed to enough of a certain pesticide for long enough periods of time.[3] Additionally, some pesticides, like myclobutanil, a common fungicide[4], can degrade into toxic compounds like hydrogen cyanide when heated.[5] You might be thinking, what’s the big deal about pesticides in Cannabis? Aren’t we already exposed to pesticides through our food? Well, that’s true, but the problem relates to the way in which Cannabis is consumed. When you eat something, your body works hard to ensure that any toxins are captured, broken down, and excreted from the body before they have a chance to reach your blood stream.[6] But when you smoke something, you are bypassing those metabolic processes, and the compounds that enter the lung will pass directly into the blood stream.[7] So essentially when you smoke you are bypassing your body’s natural defense systems that might otherwise keep you safer. It’s also really important to point out that many pesticides, as well as mycotoxins, can become concentrated in Cannabis extracts. The process of making a Cannabis concentrate can elevate contaminants like pesticides as much as 5 to 10 times the concentration found in the Cannabis flower[8], meaning that if you are consuming a Cannabis concentrate, you are potentially being exposed to much greater doses of contaminants than if you were consuming the Cannabis flower used to produce that concentrate. I also want to point out that it’s not enough to simply test Cannabis flower for contaminants prior to making a concentrate. It is possible for there to be very trace amounts of pesticides or other contaminants present in the flower that won’t show up on a standard contaminant screening – but when concentrated they suddenly become present in dangerous levels. [BACK TO ANTHONY SMITH SEGMENT] The leaching of contaminants[9] [10] from cultivation, processing or packaging equipment is an issue that people working in the natural products industry have had to think about for quite some time. However some Cannabis companies are still learning about typical herbal processing and manufacturing best practices – putting consumers at risk. I spoke with Travis Simpson, an herbal scientist that has spent the past several years working with hemp in the Cannabis industry. He shared some of his concerns regarding contaminants from manufacturing and packaging equipment. [TRAVIS SIMPSON SEGMENT] One of the important things to note regarding most of these contaminants, including pesticides, metals, and mycotoxins, is that you won’t necessarily have an immediate reaction when you are exposed to these toxins. They can build up in the body over time, and you may not exhibit any symptoms for a long time before the body finally reaches a tipping point.[11] So just because you may have consumed a Cannabis product and didn’t notice any adverse effects, that does not mean that you are not being exposed to harmful contaminants. The takeaway from my discussions was clear – know the purity of your Cannabis before consuming. But this is easier said than done. There are still many places in the US and abroad that have not legalized Cannabis or established strict testing requirements for Cannabis.[12] For users getting their Cannabis from the black market, they are left at the mercy of their supplier’s quality. Unfortunately, this can sometimes lead to tragic consequences. [ETHAN RUSSO SEGMENT] Dr. Russo is referring to a recent string of fatalities linked to lung infections or lung damage associated with vape pens.[13] [“VAPE CRISIS” NEWS REEL] At the time of this recording, there have been 29 recorded deaths, and over 1300 reported cases of lung infections or damage linked to vape pens[14]. And these reports are growing at a rapid rate. While the exact culprit responsible for these illnesses and deaths has not yet been identified, investigators suspect it has to do with additives or contaminants. [CONTINUE ETHAN RUSSO SEGMENT] There is other evidence that contaminants in Cannabis have caused very serious problems for some people, which in rare cases has led to death. There are several case studies available of patients that contracted fatal lung infections, such as a condition called aspergillosis.[15] [16] Aspergillosis is a condition where the spores of certain species of Aspergillus fungi get nestled in small scrapes and crevices in the lungs where they begin to grow, forming a fungal mass called an aspergilloma[17]. This ultimately starts to break down lung function and can be fatal. In some fatal aspergillosis cases reported, contaminated Cannabis was deemed to be a contributing factor, and possibly the sole cause.[18] This is more common in immunocompromised users than regular healthy users, but that just highlights the tragedy here. Many people with serious health conditions are turning to Cannabis as a medicine – and those patients are the ones most vulnerable to the adverse health effects of consuming contaminated Cannabis. So let’s review what we’ve learned so far:
Find out in the third and final part of this series where we finish our curious quest to discover, “Is Cannabis Safe?” [OUTRO MUSIC] Citations and Resources [1] “#01 Is Cannabis Safe? Part One”. The Curious About Cannabis Podcast. Natural Learning Enterprises. 2019. https://cacpodcast.weebly.com/episodes/01-is-cannabis-safe-part-one [2] How Pesticides Work. Kentucky Pesticide Safety Education Program. http://www.uky.edu/Ag/Entomology/PSEP/12pesticides.html [3] Kim et al. Exposure to pesticides and the associated human health effects. Science of the Total Environment. 2017. 575(1): 525-535. [4] https://www.nbcnews.com/health/vaping/tests-show-bootleg-marijuana-vapes-tainted-hydrogen-cyanide-n1059356 [5] Product Safety Assessment: Myclobutanil. Dow Chemical. http://msdssearch.dow.com/PublishedLiteratureDOWCOM/dh_08d6/0901b803808d60fd.pdf?filepath=productsafety/pdfs/noreg/233-01023.pdf&fromPage=GetDoc [6] Pond SM, Tozer TN. First-pass elimination. Basic concepts and clinical consequences. Clin Pharmacokinet. 1984. 9(1): 1-25. [7] Huestis MA. Human Cannabinoid Pharmcokinetics. Chem Biodivers. 2009. 4(8): 1770-1804. [8] Voelker R, Holmes M. Pesticide Use on Cannabis. Cannabis Safety Institute. 2015. https://cannabissafetyinstitute.org/wp-content/uploads/2015/06/CSI-Pesticides-White-Paper.pdf [9] https://www.coleparmer.com/chemical-resistance [10] https://www.scilabware.com/en/chemicalcompatibility/ [11] Williams et al. Human aflatoxicosis in developing countries: a review of toxicology, exposure, potential health consequences, and interventions. The American Journal of Clinical Nutrition. 2004. 80(5):1106-1122. [12] https://norml.org/laws [13] https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html [14] https://www.sciencenews.org/article/vaping-tied-nearly-1300-lung-injuries-29-deaths-united-states [15] Gargani et al. Too Many Mouldy Joints – Marijuana and Chronic Pulmonary Aspergillosis. Mediterr J Hematol Infect Dis. 2011. 3(1): e2011005. [16] Ruchlemer et al. Inhaled medicinal cannabis and the immunocompromised patient. Support Care Cancer. 2015. 23(3):819-822. [17] https://www.mayoclinic.org/diseases-conditions/aspergillosis/symptoms-causes/syc-20369619 [18] Gargani et al. Too Many Mouldy Joints – Marijuana and Chronic Pulmonary Aspergillosis. Mediterr J Hematol Infect Dis. 2011. 3(1): e2011005. 
Episode One: Is Cannabis Safe? Part One
Welcome to the very first episode of the Curious About Cannabis podcast! Briefly I wanted to introduce the podcast and let you know what to expect. There are two different types of podcast episodes that we’ll be presenting this season. Each primary episode, like this one, is a 20 – 30 minute beginner to intermediate educational episodes exploring a critical Cannabis topic or question. Accompanying the primary episodes are behind-the-scenes episodes. A behind-the-scenes episode features a full-length interview or conversation between myself and a guest, typically running anywhere from 45 minutes to two and a half hours. These behind-the-scenes episodes are more for anyone wanting a deeper dive into some of the content covered in the primary episodes. Each primary episode has accompanying show notes that feature the show transcript and citations so you can explore any of the topics we present more deeply in your own time. I am really excited to finally be sharing this content with you. I hope you enjoy it and find it valuable. And with that, I present the first episode of the Curious About Cannabis podcast. - Jason Wilson =========================================================== You’re listening to the Curious About Cannabis Podcast [Shutter] [NURSE JANNA SEGMENT] The combined North American Cannabis market alone is expected to exceed 16 billion dollars in value in 2019.[1] People all over the world are taking notice and becoming more curious than ever about Cannabis. The momentum of Cannabis legalization across the world does not seem to be slowing down. And as more places legalize Cannabis, broader demographics of Cannabis users are emerging.[2] As more and more people are trying Cannabis without fear of legal repercussions, I wanted to understand just how safe Cannabis products are or aren’t. [INTRO MUSIC] How safe is Cannabis, really? Hey everybody, this is Jason Wilson with the Curious About Cannabis Podcast. Thanks for tuning in. Today we are going to be talking all about Cannabis safety and harm reduction in an effort to understand whether Cannabis is really as safe as many people claim. To start our curious quest, we’ll be focusing on three main questions:
Let’s get started. What’s in Cannabis? Cannabis contains a lot of different chemicals. Depending on what research paper you read, there are anywhere from 400 to over 500 compounds that have been characterized in Cannabis so far.[3] [4] [5] But some researchers think there are likely far more chemicals in Cannabis, as well as other plants generally, than have been identified so far. [KEVIN SPELMAN SEGMENT] That’s Kevin Spelman, a molecular biologist and phytochemist that has dedicated his professional career to understanding why plants affect the body the way they do. And lately, he has had his eyes on Cannabis. [KEVIN SPELMAN SEGMENT] So despite what the scientific literature says, there very well may be a thousand or more chemicals found in Cannabis. When Cannabis is burned, however…[6] [JUSTIN FISCHEDICK SEGMENT] That’s Justin Fischedick, a natural products researcher that once burned Cannabis joints to see what was in the smoke…for science.[7] [CONTINUE FISCHEDICK QUOTE] Cannabinoids, like THC or CBD, are by far the most abundant compounds found in the resins surrounding the female Cannabis flowers. To be accurate, these compounds actually start off in the plant as THCA and CBDA. When heated, THCA and CBDA change into their well-known counterparts, THC and CBD. So how toxic is THC and CBD? How toxic are cannabinoids? In one now famous study in 1973, dogs were given THC orally in escalating doses all the way up to 9 grams of THC per kilogram of body mass in an attempt to find a lethal dose.[8] To put that into perspective, it’s not uncommon for a lot of dogs to weigh somewhere between 20 and 30 lbs. In kilograms, that would be 9 – 14kg. For a 9kg dog, this study would have administered 81 grams of THC in a single dose. If we assume that a Cannabis cigarette, or joint, contains a gram of Cannabis containing 20% THC, that’s the equivalent of approximately 400 joints, or over 115 grams of concentrate…at once! Now, let’s jump forward from 1973 to 1988 – there was a petition to try to reclassify the legal status of Cannabis. Cannabis was and is currently at the time of this recording considered a schedule one drug by the Drug Enforcement Agency. This category of drugs is reserved for drugs with no accepted medical use and a high propensity for abuse. Other drugs in this category include things like heroin and bath salts. Well, in the 80s there was a push to reschedule Cannabis, and administrative law judge Francis young issued a report commenting on the issue. In his report, he stated: “…in order to induce death, a marijuana smoker would have to consume 20,000 to 40,000 times as much marijuana as is contained in one marijuana cigarette…A smoker would theoretically have to consume nearly 1500 pounds of marijuana within about fifteen minutes to induce a lethal response.”[9] By that measure, the carbon monoxide and tar exposure would end up causing problems before the cannabinoids in the Cannabis would. But that was THC. What about CBD? As recently as this year, in 2019, a report was issued claiming that CBD was identified as being toxic for the liver.[10] Publications like Forbes promoted headlines reading “CBD Causes Liver Damage”[11]. So is this something Cannabis consumers need to be concerned about? [ETHAN RUSSO SEGMENT] I had the chance to talk about the safety of CBD with Dr. Ethan Russo, a neurologist and cannabinoid researcher that worked as a medical advisor for the development of two cannabinoid pharmaceuticals, Sativex and Epidiolex. Epidiolex, specifically, is a pure CBD pharmaceutical. [ETHAN RUSSO SEGMENT] If you look up the LD50 for Cannabidiol, you’ll typically find data reporting intravenous doses of over 200mg/kg.[12] [13]It would be extremely difficult to get that much CBD in your bloodstream through typical consumption methods. For an average human that weighs 65kg, or around 144lbs, 200mg/kg equates to a dose of approximately 13,000mg, or 13 grams of pure CBD – in the bloodstream. Consider that CBD-rich Cannabis contains approximately 10-20% CBD, or 100 to 200 mg of CBD per gram of Cannabis flower. So if you consume a gram of CBD-rich Cannabis flower, you are getting exposed to maybe 200mg of CBD at best. Ignoring the fact that CBD is not very bioavailable and much of the CBD you consume is simply excreted[14] [15], 200mg is approximately 1.5% of 13 grams. To put this into better context, for caffeine, the LD50 is 200mg/kg of oral caffeine (that’s not to say that it is the same as the 200mg/kg LD50 that I mentioned for CBD. Keep in mind that the CBD LD50 is intravenous. this is actually a lot lower than the CBD LD50, because not all of the orally consumed caffeine will make it into the bloodstream), which would be like drinking somewhere between 75 and 100 cups of coffee back to back.[16] While for nicotine, the LD50 is around 8 – 13mg/kg, or over half a gram of nicotine.[17] That’s about 40 cigarettes.[18] [19] You may be saying, okay sure, it may be difficult to overdose on THC or CBD, but Cannabis contains a lot more chemicals than THC – and you’d be right! So just how many reported deaths are there associated with Cannabis use? While many advocates of Cannabis claim that there have been no deaths attributed to Cannabis – that is not exactly true, however the number is still very low. Like extremely low. We don’t know the exact numbers, but there have been a handful of case studies reported that have linked fatal heart attacks and lung infections with Cannabis use, but these reports have been difficult to confirm definitively.[20] [21] [22] [23] [24] [25] [26]And yet according to some estimates there are nearly 100 million people in the United States alone that admit to having at least tried Cannabis once, and over 30 million are classified as regular users – and that’s just based on how many people are willing to admit their own Cannabis use on a survey.[27] So, we are looking at a handful of possible fatalities linked to Cannabis use, compared to tens of millions of users in the United States alone. Let’s assume 1 out of 10 million users were to die from Cannabis use in some way, that would mean that you would have a 0.00001% chance of dying from Cannabis use, and even that’s an exaggerated number. You would have a much greater chance of dying by getting into a car crash[28] or getting struck by lightning[29]. What are the health risks of Cannabis? So, okay, it is unlikely that anyone is going to experience a lethal overdose of Cannabis, but what about other health risks? [REEFER MADNESS SEGMENT] All reefer madness and propaganda aside, there are a variety of research papers out there that have summarized the common health risks of Cannabis use. One common symptom of Cannabis use is dry mouth, also called xerostomia. Xerostomia can negatively affect mouth health if not managed properly and can lead to changes to the bacteria and fungi that live in our mouths, potentially leading to gum disease, tooth decay, bad breath, and even an altered sense of taste.[30] Now, many may assume that the dry mouth effect from Cannabis use is related to smoking, but this does not seem to be the case. The dry mouth effect is directly linked to the stimulation of cannabinoid receptors in the body, regardless of how you choose to use Cannabis.[31] Another thing Cannabis affects directly is blood pressure. Interestingly enough, Cannabis can lead to lower blood pressure with repeated use, but at high dosages, Cannabis can cause elevated blood pressure and heart rate[32], which can be particularly problematic for users that have a prior history of heart issues, such as high blood pressure or previous occurrence of heart attacks. This effect is made worse by smoking. Additionally, if you are smoking Cannabis, you also run a greater risk of experiencing chronic bronchitis and emphysema.[33] THC-rich Cannabis can cause motor coordination disruption, potentially increasing the risk of falls, home or workplace accidents, and car wrecks. However, this effect tends to be more mild in frequent users that have built up tolerance. THC-rich Cannabis can present several psychological health risks to users, including memory disruption, anxiety, fear, and paranoia. When it comes to the negative psychological effects of Cannabis, new or infrequent users are more likely to experience these effects compared to regular users.[34] Additionally Cannabis can act as a precipitating event for mental health problems to reveal themselves in younger users – but we will talk more about that later. Although Cannabis has gained popularity for being a potential treatment for seizure and tremor conditions like epilepsy and Parkinson’s, there has been some research that has revealed that Cannabis could actually exacerbate these conditions in as much as a third of the population.[35] In addition to these risks, there is also a condition that can develop in chronic users, usually in users that have been using high THC Cannabis regularly for two years or more, called Cannabinoid Hyperemesis Syndrome.[36] [CHS NEWS REEL] The good news is that for anyone that may experience this condition, it typically goes away if you simply stop consuming Cannabis for a while. However, there are some reported cases where users that stopped using Cannabis to recover, re-experienced the nausea and vomiting symptoms when they starting using Cannabis again. Cannabinoid hyperemesis syndrome is a somewhat controversial condition. Some people claim that it is likely caused by contaminants in Cannabis products, rather than the cannabinoids found in Cannabis. However, this has not been substantiated, as of yet. Also, in states that have legalized Cannabis use, reports of this condition are starting to become more prevalent as people become more comfortable talking about their Cannabis use with their health care providers. So, potentially this condition is actually more widespread than once thought. We just don’t really know, yet. How might Cannabis interact with other medications? The next topic I wanted to explore is drug interactions with Cannabis. [NURSE JANNA INTERVIEW SEGMENT] That’s Janna Champagne, a registered nurse who over the past several years has focused her attention almost exclusively on Cannabis. [CONTINUE NURSE JANNA SEGMENT] Other health care professionals I spoke with said that they are particularly concerned about interactions with things like blood thinning medications, chemotherapy drugs, epilepsy drugs, and immune system therapy drugs, like HIV treatments. Some of this concern regarding drug interactions relates to CBD more than THC. And this has everything to do with a thing called “the grapefruit effect”.[37] It’s been long known that certain foods and medications can change the way the body metabolizes things, like other foods and drugs. This effect is so well known with grapefruit that some drugs even have a grapefruit warning on them. If you ever see a grapefruit warning on a medication, it is referring to this potential interaction that could occur where compounds in the grapefruit can slow down the liver’s ability to metabolize a lot of different medications by inhibiting a group of enzymes called the P450 enzymes. This inhibition will cause the levels of medications in the blood to rise. For people taking drugs with narrow safety windows, this can be very problematic. Well, it turns out that CBD exhibits this same effect, the grapefruit effect. [38] Anyone using CBD, particularly high doses of CBD, along with other medications should be particularly cautious and work with a healthcare professional to stay safe.[39] So, while it seems like Cannabis is relatively safe compared to a lot of other things, like coffee, there are some serious drug interactions that can occur. [CONTINUE NURSE JANNA SEGMENT] Let’s review what we’ve learned so far:
Join me in part two of this series as we explore the health risks of contaminants and additives in Cannabis products. Until next time, thanks and take it easy. [OUTRO MUSIC] CITATIONS [1] Legal marijuana industry had banner year in 2018 with $10B worth of investments. https://www.nbcnews.com/news/us-news/legal-marijuana-industry-had-banner-year-2018-10b-worth-investments-n952256 [2] Han et al. Demographic trends among older cannabis users in the United States, 2006-13. Addiction. 2017. 112(3): 516-525 [3] ElSohly MA. Chemical Constituents of Cannabis. Cannabis and Cannabinoids: Pharmacology, Toxicology and Therapeutic Potential. 2002. Chapter 3. [4] ElSohly MA, Gul W. Constituents of Cannabis Sativa. Handbook of Cannabis. Oxford University Press. 2014. First Edition. [5] ElSohly M.A., Radwan M.M., Gul W., Chandra S., Galal A. (2017) Phytochemistry of Cannabis sativa L.. In: Kinghorn A., Falk H., Gibbons S., Kobayashi J. (eds) Phytocannabinoids. Progress in the Chemistry of Organic Natural Products, vol 103. Springer, Cham [6] O’Brien Fehr K, Kalant H. Analysis of Cannabis Smoke Obtained Under Different Combustion Conditions. 1972. Canadian Journal of Physiology and Pharmacology. 50(8): 761-767. [7] Fischedick J, Van Der Kooy F, Verpoorte R. Cannabinoid receptor 1 binding activity and quantitative analysis of Cannabis sativa L. smoke and vapor. 2010. Chem Pharm Bull (Tokyo). 58(2):201-7. [8] Thompson GR et al. Comparison of acute oral toxicity of cannabinoids in rats, dogs and monkeys. 1973. Toxicology and Applied Pharmacology. 25(3):363-372. [9] Young F. In the Matter of Marijuana Rescheduling Petition. Opinion and recommended Ruling, Findings, of Fact, Conclusions of Law and Decision of Administrative Law Judge. Sep 6 1988. Part VIII. [10] Ewing LE et al. Hepatotoxicity of a Cannabidiol-Rich Cannabis Extract in the Mouse Model. 2019. Molecules. 24(9): 1694. [11] Adams M. Marijuana Study Finds CBD Can Cause Liver Damage. Forbes. Jun 18 2019. https://www.forbes.com/sites/mikeadams/2019/06/18/marijuana-study-finds-cbd-can-cause-liver-damage/ [12] Rosenkrantz H et al. Toxicity of short-term administration of cannabinoids to rhesus monkeys. 1981. Toxicol Appl Pharmacol. 58(1):118-31. [13] Cannabidiol. ChemIDplus Database. https://chem.nlm.nih.gov/chemidplus/rn/13956-29-1 [14] Millar et al. A Systematic review on the pharmacokinetics of cannabidiol in humans. 2018. Pharmacol. https://www.frontiersin.org/articles/10.3389/fphar.2018.01365/full [15] Huestis MA. Human Cannabinoid Pharmacokinetics. 2007. Chem Biodivers. 4(8): 1770-1804. [16] Caffeine. Toxnet Toxicology Data Network. https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+36 [17] Mayer B. How much nicotine kills a man? Tracing back the generally accepted lethal dose to dubious self-experiments in the nineteenth century. 2014. Arch Toxicol. 88(1): 5-7. [18] Taghavi S et al. Nicotine content of domestic cigarettes, imported cigarettes and pipe tobacco in Iran. 2012. Addict Health. 4(1-2): 28-35. [19] Benowitz NL, Henningfield JE. Reducing the nicotine content to make cigarettes less addictive. 2013. Tobacco Control. 22:i14-i17. [20] Yurtdas M, Aydin MK. Acute myocardial infarction in a young man; fatal blow of the marijuana: a case report. 2012. Korean Circ J. 42(9): 641-645. [21] Hartung B et al. Sudden unexpected death under acute influence of cannabis. 2014. Forensic Science International. 237: e11-e13 [22] Sattout AH, Nicol MF. Cardiac arrest following cannabis use: a case report. 2009. Cases Journal. 2(208) [23] Cappelli F et al. Cannabis: a trigger for acute myocardial infarction? A case report. 2008. Journal of Cardiovascular Medicine. 9(7):725-728. [24] MacInnes DC, Miller KM. Fatal coronary artery thrombosis associated with cannabis smoking. 1984. J R Coll Gen Pract. 34(267): 575-576. [25] Ruchlemer R et al. Inhaled medicinal cannabis and the immunocompromised patient. 2015. Supportive Care in Cancer. 23(3): 819-822. [26] Gargani Y et al.Too Many Mouldy Joints – Marijuana and Chronic Pulmonary Aspergillosis. 2011. Mediterr J Hematol Infect Dis. 3(1): e2011005 [27] Yahoo News/Marist Poll: Weed and the American Family. April 17, 2017. Marist Poll. http://maristpoll.marist.edu/yahoo-newsmarist-poll/#sthash.VAK0GIiK.dpbs [28] Traffic Safety Facts 2017: A Compilation of Motor Vehicle Crash Data. 2017. National Highway Traffic Safety Administration. US Department of Transportation. [29] Lightning Safety Tips and Resources. National Weather Service. National Oceanic and Atmospheric Administration. https://www.weather.gov/safety/lightning [30] Versteeg PA et al. Effect of cannabis usage on the oral environment: a review. 2008. International Journal of Dental Hygiene. 6(4): 315-320. [31] Kopach et al. Cannabinoid receptors in submandibular acinar cells: Functional coupling between saliva fluid and electrolytes secretion and Ca2+ signaling. 2012. Journal of Cell Science. 125:1884-1895. [32] Pacher P et al. Cardiovascular Pharmacology of Cannabinoids. 2008. Handb Exp Pharmacol. 168: 599-625. [33] Volkow ND et al. Adverse health effects of marijuana use. 2014. N Engl J Med. 370(23): 2219-2227. [34] Crippa JA et al. Cannabis and anxiety: a critical review of the evidence. 2009. Hum Psychopharmacol. 24(7): 515-523. [35] Szaflarski JP, Bebin EM. Cannabis, cannabidiol, and epilepsy – from receptors to clinical response. 2014. Epilepsy Behav. 41: 277-282. [36] Simonetto DA et al. Cannabinoid hyperemesis: a case series of 98 patients. 2012. Mayo Clinic Proceedings. 87(2): 114-119 [37] Grapefruit Juice and Some Drugs Don’t Mix. https://www.fda.gov/consumers/consumer-updates/grapefruit-juice-and-some-drugs-dont-mix [38] Bornheim LM et al. Characterization of cannabidiol-mediated cytochrome p450 inactivation. 1993. 45(6): 1323-1331. [39] Grayson L et al. An interaction between warfarin and cannabidiol, a case report. 2018. Epilepsy Behav Case Rep. 9: 10-11. |
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