Cannabis and Cannabinoid Research

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. You can find these show notes at CACPodcast.com

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

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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:

• • How toxic is Cannabis? And as an aside, what the heck is in Cannabis anyway?

• • What are the known health risks of Cannabis use?

• • How can anyone that chooses to use Cannabis or Cannabis products minimize those risks?

Now, this is a really big topic that we could spend hours upon hours exploring. And in effect this topic will end up being woven throughout the podcast. As such, there are several aspects of Cannabis safety that we won’t be getting into in this initial series of episodes. So if there is a topic we don’t end up covering immediately – don’t worry. We’ll get there.

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?

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How toxic are cannabinoids?

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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!

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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.

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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]

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By that measure, the carbon monoxide and tar exposure would end up causing problems before the cannabinoids in the Cannabis would.

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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?

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[ETHAN RUSSO SEGMENT]

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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.

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[ETHAN RUSSO SEGMENT]

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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.

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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]

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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?

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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]

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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].

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What are the health risks of Cannabis?

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So, okay, it is unlikely that anyone is going to experience a lethal overdose of Cannabis, but what about other health risks?

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[REEFER MADNESS SEGMENT]

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All reefer madness and propaganda aside,

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There are a variety of research papers out there that have summarized the common health risks of Cannabis use.

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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]

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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.

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Additionally, if you are smoking Cannabis, you also run a greater risk of experiencing chronic bronchitis and emphysema.[33]

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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.

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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.

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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]

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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]

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[CHS NEWS REEL]

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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.

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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.

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How might Cannabis interact with other medications?

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The next topic I wanted to explore is drug interactions with Cannabis.

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[NURSE JANNA INTERVIEW SEGMENT]

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That’s Janna Champagne, a registered nurse who over the past several years has focused her attention almost exclusively on Cannabis.

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[CONTINUE NURSE JANNA SEGMENT]

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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.

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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.

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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]

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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.

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[CONTINUE NURSE JANNA SEGMENT]

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Let’s review what we’ve learned so far:

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• • The primary constituents of Cannabis resins, THC and CBD, are not toxic and it is virtually impossible to lethally overdose on Cannabis or Cannabis products.

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• • There are other health risks associated with Cannabis use, however, like risks to lung health, mouth health, mental health, and heart health. Many of these risks can be minimized by avoiding smoking and using low doses.

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• • Cannabis can interact with medications and anyone taking drugs with narrow safety windows or a grapefruit warning on them should work with a health care professional to stay safe.

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So far everything we have explored about the health risks of Cannabis have ignored a critical element – contaminants.

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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.

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[OUTRO MUSIC]

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CITATIONS

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[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

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[2] Han et al. Demographic trends among older cannabis users in the United States, 2006-13. Addiction. 2017. 112(3): 516-525

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[3] ElSohly MA. Chemical Constituents of Cannabis. Cannabis and Cannabinoids: Pharmacology, Toxicology and Therapeutic Potential. 2002. Chapter 3.

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[4] ElSohly MA, Gul W. Constituents of Cannabis Sativa. Handbook of Cannabis. Oxford University Press. 2014. First Edition.

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[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

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[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.

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[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.

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[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.

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[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.

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[10] Ewing LE et al. Hepatotoxicity of a Cannabidiol-Rich Cannabis Extract in the Mouse Model. 2019. Molecules. 24(9): 1694.

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[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/

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[12] Rosenkrantz H et al. Toxicity of short-term administration of cannabinoids to rhesus monkeys. 1981. Toxicol Appl Pharmacol. 58(1):118-31.

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[13] Cannabidiol. ChemIDplus Database. https://chem.nlm.nih.gov/chemidplus/rn/13956-29-1

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[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

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[15] Huestis MA. Human Cannabinoid Pharmacokinetics. 2007. Chem Biodivers. 4(8): 1770-1804.

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[16] Caffeine. Toxnet Toxicology Data Network. https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+36

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[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.

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[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.

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[19] Benowitz NL, Henningfield JE. Reducing the nicotine content to make cigarettes less addictive. 2013. Tobacco Control. 22:i14-i17.

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[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.

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[21] Hartung B et al. Sudden unexpected death under acute influence of cannabis. 2014. Forensic Science International. 237: e11-e13

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[22] Sattout AH, Nicol MF. Cardiac arrest following cannabis use: a case report. 2009. Cases Journal. 2(208)

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[23] Cappelli F et al. Cannabis: a trigger for acute myocardial infarction? A case report. 2008. Journal of Cardiovascular Medicine. 9(7):725-728.

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[24] MacInnes DC, Miller KM. Fatal coronary artery thrombosis associated with cannabis smoking. 1984. J R Coll Gen Pract. 34(267): 575-576.

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[25] Ruchlemer R et al. Inhaled medicinal cannabis and the immunocompromised patient. 2015. Supportive Care in Cancer. 23(3): 819-822.

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[26] Gargani Y et al. Too Many Mouldy Joints – Marijuana and Chronic Pulmonary Aspergillosis. 2011. Mediterr J Hematol Infect Dis. 3(1): e2011005

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[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

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[28] Traffic Safety Facts 2017: A Compilation of Motor Vehicle Crash Data. 2017. National Highway Traffic Safety Administration. US Department of Transportation.

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[29] Lightning Safety Tips and Resources. National Weather Service. National Oceanic and Atmospheric Administration. https://www.weather.gov/safety/lightning

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[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.

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[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.

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[32] Pacher P et al. Cardiovascular Pharmacology of Cannabinoids. 2008. Handb Exp Pharmacol. 168: 599-625.

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[33] Volkow ND et al. Adverse health effects of marijuana use. 2014. N Engl J Med. 370(23): 2219-2227.

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[34] Crippa JA et al. Cannabis and anxiety: a critical review of the evidence. 2009. Hum Psychopharmacol. 24(7): 515-523.

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[35] Szaflarski JP, Bebin EM. Cannabis, cannabidiol, and epilepsy – from receptors to clinical response. 2014. Epilepsy Behav. 41: 277-282.

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[36] Simonetto DA et al. Cannabinoid hyperemesis: a case series of 98 patients. 2012. Mayo Clinic Proceedings. 87(2): 114-119

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[37] Grapefruit Juice and Some Drugs Don’t Mix. https://www.fda.gov/consumers/consumer-updates/grapefruit-juice-and-some-drugs-dont-mix

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[38] Bornheim LM et al. Characterization of cannabidiol-mediated cytochrome p450 inactivation. 1993. 45(6): 1323-1331.

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[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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