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Mosley, Mark MD, MPHEmergency Medicine News: August 2020 – Volume 42 – Issue 8 – p 2-3]

Marijuana is not a medical drug. It is a slang term for a plant of the Cannabis family that contains more than 60 different cannabinoid substances and more than 80 biologically active compounds. Using the term marijuana in place of THC would be like using willow tree in place of acetylsalicylic acid, the active ingredient in aspirin.

Even worse would be creating a multibillion-dollar industry using the term medical willow tree for a product that may not even contain acetylsalicylic acid. The consequences of peddling the term medical marijuana are far graver, however, than simply confusing a whole plant with one of its active ingredients.

The most commonly discussed compounds in the Cannabis plant are tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is lipid-soluble, highly bound to the brain, and interacts with endogenous cannabinoid receptors, making it psychoactive. CBD does not attach to the cannabinoid receptors in the brain, and is not psychoactive.

Only three Cannabis-related compounds are currently made for medical purposes, none of which has much scientific support. (JAMA. 2015;313[24]:2456; https://bit.ly/30BwkA5; Can Fam Physician. 2018;64[2]:e78; https://bit.ly/3hggTTU.) Delta-9-tetrahydrocannabinol is a synthetic cannabinoid called dronabinol (trade names: Marinol and Syndros). Its only FDA-approved indications are for weight gain in patients with HIV wasting syndrome and severe intractable nausea for chemotherapy patients.

Another THC isomer synthetically made is nabilone (trade name: Cesamet), an oral drug for severe chemotherapy nausea and spasticity for multiple sclerosis patients. Insurance does not cover them, and dronabinol costs upwards of $1000 per month and nabilone close to $2000 per month. These THC-containing compounds are the only FDA-approved drugs for rare circumstances that are predominantly end-stage (compassionate use) where the clinical science is mostly anecdotal. (JAMA. 2015;313[24]:2456; https://bit.ly/30BwkA5.)

The third compound is an oral cannabidiol compound with no THC in it, Epidiolex. It is only 13-19 percent bioavailable when taken orally. (Front Pharmacol. 2018;9:1365; https://bit.ly/2AudArL.) The FDA approved the drug for extremely rare intractable seizures in Dravet syndrome and Lennox-Gastaut syndrome. The drug’s benefits are debatable. It decreased the frequency of seizures in these devastating syndromes, but showed no overall improvement in quality of life, and was not included in the European National Institute for Health and Care Excellence recommendations. (BMJ. 2019;366:l5280.) Epidiolex is also a pharmacologically monitored CBD drug with a much higher concentration of CBD than what is sold over the counter as CBD oil.

These three compounds are the only medical Cannabis-related products, and all are synthetically made, FDA-approved, monitored for purity, safety, and consistency, and require a prescription. They are extremely expensive. Even under these conditions, there is poor science supporting their benefit. Perhaps future science will uncover more about the brain’s cannabinoid receptors that will change these negative conclusions, but it will require good clinical science instead of “I’ve talked with patients who used marijuana for cancer, and it really helped!” No science currently proves medical benefit. It is not just a lie but a dangerous one to suggest there is anything medical about marijuana.

The lie of medical marijuana is a classic example of availability bias. (JAMA. 2015;313[3]:241; https://bit.ly/2UEOVHR.) Five years ago, the idea that marijuana should be legal or that it might be medically beneficial to large segments of the population would have brought widespread laughter. Even those who were medical marijuana believers would have to admit that it was really an intentional misnomer to allow the legalization of recreational marijuana without feeling guilty.

It is now taken for granted that a large portion of high school kids are vaping weed and that grandmothers are buying CBD oil for arthritis. The more it is talked about and advertised as normal and even therapeutic, the more it is accepted as true. It is inconsistent that everyone seems to be embracing the widespread availability of marijuana when opioids and THC have similar neurobiological effects.

The brain has a natural cannabinoid system much like the intrinsic endogenous opioid receptors. Both increase dopamine, which registers as a reward and suppresses negative emotion and suffering. Exogenous opioids and exogenous cannabinoids also increase dopamine but to a much greater extent than endogenous pathways. When stimulated chronically, dopamine becomes down-regulated. Cannabinoids, completely separate from any pain-relieving properties, which initially decreased suffering, anxiety, and negative mood make one hypersensitive to suffering, anxiety, and negative mood.

THC is known for its acute immediate effects of slow thinking and difficulty with problem-solving, altered time and sense misperception, and memory difficulties can cause psychosis when used at higher doses. (N Engl J Med. 2014;370[23]:2219; https://bit.ly/3hmxTrM.) Marijuana used chronically is correlated with lower life satisfaction, poorer mental health, poorer relationships, decreased IQ, and low resilience. Mentally ill people in particular tend to self-medicate with marijuana, which paradoxically increases their anxiety and psychosis. It is reported that 20 percent of pregnant women under 24 use marijuana, though its effects on the fetal brain are unknown. (JAMA. 2017;318[24]:2490; https://bit.ly/3hnJoiE.)

Other associations include COPD, increased motor vehicular collisions, Cannabis hyperemesis syndrome, childhood overdoses from edibles, a gateway to harder drugs, and decreased school and work performance. Illicitly made marijuana can be laced with K2, fentanyl, and embalming fluid. (N Engl J Med. 2014;370[23]:2219; https://bit.ly/3hmxTrM.) It is true that overdosing on marijuana is rarely life-threatening, unlike opioids, but addiction and mental illness could actually be worse than opioids due to availability.

Now that a farm bill in December 2018 allowed hemp to be produced and marketed, many more of our farmers are growing marijuana for the billion-dollar CBD oil market, a basically worthless compound based on no science. Many people are marketing and using CBD products off-label, and some are selling and promoting them illegally in human and veterinary medicine. CBD will not contribute to addiction or mental illness, but it will continue to blur the line of what is meant by medical marijuana, and will dramatically increase demand and political will for legalizing medical and recreational marijuana, which for all pragmatic purposes become the same.

This political and medical schizophrenia is strange. If preventing addiction and helping the mentally ill is a moral and social imperative regarding opioids, why isn’t it for THC and marijuana? Medical marijuana is not an answer to chronic pain control, and any suggestion that using marijuana will help one use opioids less is an imaginary hope not based on good science.

We are already receiving reports of the possible cardiotoxicity of marijuana with high THC content. (Trends Cardiovasc Med. 2019;29[7]:403.) The opioid crisis will be followed by the Cannabis crisis because no matter the safeguards in place for the safer distribution of marijuana in any form, people who crave the dopamine from exogenous opioids or cannabinoids will fall into the same pattern of a brain reward system gone wrong. The difference between exogenous opioids and cannabinoids is that opioids have a proven scientific role in medicine and surgery; THC and marijuana do not.

Mark Mosley, MD10/15/2020 1:09 pm ETReally good and interesting comments. I am not pro or anti THC or CBD. I am pro science. Science exists because personal bias cannot be trusted. I completely agree that we need much better research on THC and CBD. The research we currently have would not qualify as good or strong science. This was exactly the point of my article; you can’t trust someone’s personal experience (even if it works). It is not closed-minded to desire good evidence before you start selling something. And I think it is deceitful to confuse marijuana with medical grade THC and medical grade CBD monitored and sold as a pharmaceutical.
salvicario8/25/2020 3:20 pm ETThank you for shedding light on this topic. Why has the FDA not prohibited sale of CBD oils and other substances and weighed in about the lies about its effect on anxiety, sleep, and other ailments? Pain physicians also have it for sale in their offices although it has never proven to have beneficial effect. Is it quackery or just lack of controlled trials that allows it to be sold OTC?
emermed8/25/2020 11:51 am ETThank you for that well written piece, one that I agree with and believe is long overdue. This is one of the first pieces I have read showing an appropriate level of alarm and clarity. I have been somewhat fascinated watching the degree to which the general public has fallen for the medical marijuana [marketing] campaign. But I have been a bit alarmed by the medical community’s apparent apathy to the matter. And no one mentions all the research on the toxic components of marijuana or all pulmonary histologic effects. Some of the early findings are still being reproduced and verified today, with some alarming statements. In “A comparison of mainstream and sidestream marijuana and tobacco cigarette smoke produced under two machine smoking conditions,” Moir, et al., reported that ammonia was found in mainstream marijuana smoke at levels up to 20-fold greater than that found in tobacco. Hydrogen cyanide, nitrogen monoxide (NO), nitrogen oxides (NOx), and some aromatic amines were found in marijuana smoke at concentrations three to five times those found in tobacco smoke. (Chem Res Toxicol. 2008:21[2]:494.) In 2014, Joshi, et al., stated, “Considering the unequivocal causal relationship that exists between tobacco smoking and lung cancer, there is a valid concern that smoking of marijuana may be a risk factor for lung and other cancers as well. Many earlier studies have shown that marijuana smoke contains qualitatively many of the similar chemicals (carcinogens and co-carcinogens) as tobacco smoke.” (Curr Opin Pulm Med. 2014;20[2]: 173.) In addition, they found that histopathologic and immunohistologic evidence in marijuana users, including bronchial squamous metaplasia and overexpression of molecular markers of pretumor progression, suggests biological plausibility of marijuana smoking as a risk factor for the development of lung cancer. The most striking observation of this study was the fact that marijuana users had rates of respiratory symptoms comparable with those of tobacco smokers who were 10 years older. (Curr Opin Pulm Med. 2014;20[2]: 173.) Respiratory symptoms in marijuana smokers are likely due to injurious effects of marijuana smoke on the bronchial mucosa. Fligiel, et al., demonstrated large airway inflammation on endobronchial biopsy specimens of habitual marijuana smokers. The histopathologic abnormalities reported were goblet cell hyperplasia, loss of ciliated epithelial cells, and intraepithelial and subepithelial inflammation. The authors concluded that smoking marijuana alone caused at least as extensive histopathologic abnormalities in the tracheobronchial mucosa as tobacco alone, including metaplastic changes and nuclear alterations that could be premalignant. (Chest. 1997;112[2]:319.) There is unequivocal evidence that habitual or regular marijuana smoking is not harmless and causes respiratory symptoms. (Curr Opin Pulm Med. 2014;20[2]: 173.) Smoking marijuana, regardless of tetrahydrocannabinol content, results in a substantially greater respiratory burden of carbon monoxide and tar than smoking a similar quantity of tobacco. Marijuana smoke contains about 50 percent more benzopyrene and nearly 75 percent more benzanthracene, both polycyclic aromatic hydrocarbon procarcinogens, than the smoke from a comparable quantity of an unfiltered Kentucky reference tobacco cigarette as well as other carcinogens and cocarcinogens found in tobacco smoke, including phenols, vinyl chlorides, nitrosamines, and reactive oxygen species. (N Engl J Med. 1988;318[6]:347.) Moreover, differences in the technique of smoking marijuana compared with tobacco, including deeper inhalation and much longer breath-holding time, in addition to the lower rod filtration offered by the more loosely packed marijuana in a joint, result in a fourfold increase in deposition of the tar from marijuana than from a comparable amount of tobacco, thus amplifying exposure of the lung to the carcinogens within the smoke. (Ann Am Thorac Soc. 2013;102013;[3]:239.) Endobronchial biopsies from habitual marijuana-only smokers reveal widespread histopathologic alterations, such as squamous cell metaplasia and cellular atypia comparable with those observed in biopsies from tobacco-only smokers (Chest. 1997;112[2]:319) and are recognized as precursors to the subsequent development of malignancy. (N Engl J Med. 1961;265:253.) In addition, immunohistology of bronchial tissue from the marijuana-only smokers revealed marked overexpression of the nuclear proliferation antigen Ki-67 and of epidermal growth factor receptor, both molecular markers of pretumor progression. (J Natl Cancer Inst. 1998;90[16]:1198.) And nonaddictive? Slippery slope. Search on YouTube for “trying to stop smoking pot/marijuana,” and you get a sense of how many people can’t or are having trouble stopping chronic abuse. Recently, I had a casual conversation with a primary care physician about marijuana legalization. And I asked and warned that he may see an increased number of patients with problems due to increased recreational use, increased public acceptance, increased potency, and all the unspoken negative health effects. He seemed dismissive of the negative pulmonary and health effects. I offered to share the literature, but he was not interested. I think that sets the global tone.
mjbonnin8/25/2020 11:44 am ETMy 35 years of practice as a residency-trained, board-certified emergency physician made me cynical about any benefits of marijuana. However, since my retirement due to significant orthopedic injury and living in a state where recreational Cannabis is legal, I have tried and used CBD for my chronic pain. Your diatribe against any medical benefit of CBD has no scientific basis. In fact, because it is still illegal at the federal level, little to no research has been done on CBD. While anecdotal, I can assure you that I use both topical and oral CBD for my joint pain which has been life-changing. It has no psychoactive effects like opiates and opioids, no constipation or respiratory depression, no GI bleed or renal ill effects, yet allows me to continue moving and enjoying life with much less pain. Rather than rail against the “grandmothers” using it for their arthritis, we should be encouraging and finding scientific research into the substances, which may be beneficial.
paul.pompa8/25/2020 10:49 am ETHonest. Evidence-based. Brave. Kudos.

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Medical Marijuana Is a Dangerous Lie

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