Cannabis is still tainted by the stigma of reefer madness, the racially-charged, anti-marihuana propaganda campaign that portrayed cannabis as a mortal threat to vulnerable women and children. How ironic that the erstwhile “Assassin of Youth” should become the savior for children with catastrophic seizure disorders and other life-threatening conditions. In June 2018, the FDA approved Epidiolex, a CBD oil extract from cannabis, as a treatment for two refractory pediatric seizure disorders.
“Protecting the children,” including the fetus, continues to be a key PR theme of the federal government’s war on drugs. Concerns surrounding cannabis in pregnancy, however, have far outpaced scientific data showing ill effects.
Question 2: Pregnant Women
In human research, when confounding variables like alcohol and tobacco use are accounted for, reviews fail to find evidence that CBD or cannabis alone cause harm to the fetus, as Project CBD documented in a recent report to California’s Office of Environmental Health Hazard Assessment (See Appendix B). 18 Among the key findings:
- There is insufficient evidence to conclude that maternal cannabis use causes low birth weight or long-term adverse developmental outcomes. 19
- Labeling cannabis, cannabis extracts, cannabis smoke, CBD or THC as reproductive toxins is not justifiable from high-quality scientific evidence and would misdirect public health and harm reduction efforts away from known teratogens, like alcohol and tobacco.
- Although cannabinoids are not intrinsically toxic, they may amplify the toxic effects of alcohol, nicotine, and other teratogens. Thus, public health messages should be tailored towards pregnant women using multiple substances.
Question 1: Liver Toxicity
Bogus science and inept reporting have promulgated misinformation about CBD and liver toxicity. Although there are real risks involved in some patient populations consuming large quantities of CBD, that risk is minimal for the vast majority of CBD consumers. In the real world, CBD consumers are not ingesting 0.25% of their body weight, the dose of CBD administered to mice in a flawed 2019 study purporting to demonstrate that CBD causes liver damage. In that study, scientists force-fed mice up 2460 mg/kg of CBD. These ridiculously large dosages were 100 times higher than the amount of CBD administered to epileptic children in clinical trials of Epidiolex. Project CBD has published an in-depth critique of preclinical research that correlates liver damage in humans to that observed in mice when they are administered massive doses (See Appendix C). 20 This type of research undermines serious efforts to understand the real risks of CBD and the problems it might actually cause.
When consumed in large amounts, CBD can inhibit drug-metabolizing enzymes. The Epidiolex data showed that around 25-50 mg/kg/day of CBD isolate sometimes caused issues with the liver, but there are important caveats. Of particular concern is the reported elevation in the liver enzymes ALT and AST. This occurs in roughly 5-15% of children in Epidiolex trials. However, nearly every report involves the concurrent use of valproate, a powerful anti-epileptic drug that can cause problems in and of itself. 21 The resulting elevation in the levels of these liver enzymes could be understood as the result of a severe drug-drug interaction. Regardless, many neurologists maintain that the combination of CBD and valproate can be an effective epilepsy treatment. 2223 Thus, doctors find it can be helpful to add CBD to a treatment regime that includes valproate, with the understanding that a patients’ liver function will need to be monitored. The co- administration of CBD and clobazam, which also has a high likelihood of drug interactions, is another combination that pediatric neurologists find works well – at least anecdotally.
The elevation of liver enzymes is indicative of stress on the liver, which could cause damage if it continues unabated. This can be safely managed when monitored by a doctor willing to adjust medications as needed. Additionally, these issues resolve when people stop taking CBD or reduce their dose. Thus far, there have been no reports of lasting harm when CBD treatment was ceased.
Question 3: Drug Interactions
CBD and THC can alter the metabolism of many commonly consumed pharmaceuticals. Project CBD has published an extensive report on cannabinoid-drug interactions to help health professionals and patients anticipate and avoid problematic outcomes, but also to take advantage of situations where cannabis and pharmaceuticals can act synergistically in a positive way (See Appendix D). 24 Key findings:
- Based on observations regarding the widespread use of raw cannabis flower and full- spectrum cannabis oil, it does not appear that there have been many contraindications due to interactions with other drugs. The clinical use of Sativex (a 1:1 CBD:THC sublingual tincture) and Marinol (a pure, synthetic THC pill) have resulted in few, if any, reported adverse events attributable specifically to interactions with pharmaceuticals.
- To the extent that there have been problematic drug interactions with cannabinoids, these have involved high doses of nearly pure CBD isolates, not cannabis in general. Even though THC is an intoxicant and CBD is not, the fact that people tend to use much higher doses of pure CBD makes it a much riskier player in metabolic drug interactions.
- CBD is intrinsically safe, but when extracted from the plant and concentrated as an isolate, high doses are necessary for therapeutic efficacy. Whole plant CBD-rich extracts have a broader therapeutic window and are effective at lower doses than single- molecule CBD. Problems can arise when a patient combines a high dose of an otherwise benign CBD isolate with a pharmaceutical that has a very narrow window between its therapeutic and toxic levels. The FDA might consider requiring a warning label for high- dose CBD isolate products.
- Ten milligrams of THC in a cannabis product is a generous dose for a naïve patient and sufficiently psychoactive for the occasional recreational user. (THC has its own built-in dysphoric guard rails – consume too much and you’ll know you’ve hit your limit.) Ten mgs of THC combined with an equal amount of CBD in a Sativex tincture hit the analgesic sweet spot in clinical trials. These are moderate doses compared to the amount of single molecule CBD (Epidiolex) administered to epileptic children in clinical trials – up to 50 mg per kilogram. CBD doses as high as 2000 mg are not uncommon among patients who obtain CBD isolates from internet storefronts and other unregulated sources.
- Limited preclinical research indicates that administering CBD and/or THC in conjunction with first-line chemotherapy drugs could potentiate the latter. 252627 The clinical translation would imply a reduction in the dosage of highly toxic chemo necessary to treat the cancer. This is an example of a potentially beneficial cannabinoid-drug interaction. If this translates to human experience, it would be a huge benefit. But if pure CBD delays chemo metabolism, dangerously high levels of a toxic drug could accumulate unless the dose of chemotherapy is reduced and properly managed. The fact that cannabinoids make radiation and chemotherapy both more tolerable and seemingly more effective is an area worth studying.
Question 1: Addiction
The abuse potential of cannabis is limited - along the lines of overeating or caffeine addiction - and the symptoms of withdrawal in people with chronic cannabis use disorder are mild compared to more dangerous drugs of abuse (opioids, amphetamines, alcohol). CBD actually shows anti-addictive properties in animal model experiments. 2829 Given the magnitude of the current opioid crisis, medical cannabis should be investigated as a harm reduction treatment for opioid addiction, as Project CBD urged in a special report on cannabis and opioids (See Appendix E). 30 Here are some key findings:
- Randomized controlled trials have shown that CBD-rich and THC-rich cannabis oil can be an effective treatment for chronic neuropathic pain and can improve the pain relief that opioids provide. Administering opioids and cannabis together results in a greater-than-additive analgesic effect, a synergistic reduction of pain. Chronic pain patients who use medical cannabis report they experience a decrease in opioid use, a decreased number of medications and side effects, and an improved quality of life.
- Supplementing an opioid-based pain-management regimen with cannabis could result in lower doses of opioids required for adequate analgesia. Lower doses of opioids will reduce the number of overdose deaths. This is an example of a potentially beneficial cannabinoid-drug interaction. Cannabis can prevent opioid tolerance building and the need for dose escalation. Cannabis can also decrease the symptoms of opioid withdrawal — nausea, vomiting, spasms, cramping, insomnia.
- Preclinical research suggests that CBD is protective against neurodegeneration caused by binge- drinking and may have therapeutic properties for alcohol, tobacco, opioid, cocaine, and psychostimulant addiction. 31 There’s also evidence that CBD can aid in addiction recovery by preventing relapse due to its effects on cue-induced memory.32
Question 2: Mental Illness
The claim that cannabis causes or precipitates psychosis has long been invoked as a reason for prohibiting cannabis. With hundreds of millions of dollars invested and over a century of dedicated research, the psychosis argument remains weak. Epidemiological research indicates there is little correlation between rates of cannabis use and schizophrenia in Western societies. But there is consistently an association between cannabis use and the development of psychosis. This could mean that cannabis might precipitate schizophrenia in vulnerable populations. Or it could mean that people use cannabis to self-medicate even before a diagnosis of schizophrenia. Some research suggests that schizophrenia predicts cannabis use, rather than the other way around. 33
Question 4: Responsible Use
Learning how to optimize one’s therapeutic use of CBD and cannabis may involve some trial and error. CBD can be effective at a wide range of dosages: lower doses are sometimes more effective therapeutically than higher doses. Project CBD has published a detailed guide to cannabis dosing based on data aggregated from physicians, patients, and medical scientists who are exploring the therapeutic attributes of CBD and other cannabis components (See Appendix F). 34
Cannabis prohibition is a fragile edifice built on a mountain of falsehoods. The most egregious falsehood of all is that herbal cannabis with more than 0.3 percent THC is a dangerous substance with no medical value. Lost amidst the steady drumbeat of anti-cannabis distortions over the years is an awareness of some of the real but subtle risks associated with chronic cannabis consumption – such as dehydration, drug interactions, and dysphoria. Cannabis, a hypotensive herb, might not be the best medicine for someone with low blood pressure. And dehydration could be an issue for any astringent botanical that is consumed on a regular basis. Contraindications and drug interactions are easily manageable. If THC-rich products induce dysphoria, one can try non-intoxicating CBD-rich options.
- Devitt-Lee, Adrian. “Pregnancy Complications: Can Cannabis Harm Your Fetus?” Project CBD, 23 Apr. 2019, www.projectcbd.org/politics/cannabis-and-pregnancy-safety.
- Goler N, Conway A, Young-Wolff KC. Data Are Needed on the Potential Adverse Effects of Marijuana Use in Pregnancy. Ann Intern Med. [Epub ahead of print 21 August 2018]169:492–493. doi: 10.7326/M18-1141
- Devitt-Lee, Adrian. “Is CBD Toxic to the Liver?” Project CBD, 11 July 2019, www.projectcbd.org/science/cbd-toxic-liver.
- Ghodke-Puranik, Yogita et al. “Valproic acid pathway: pharmacokinetics and pharmacodynamics.” Pharmacogenetics and genomics vol. 23,4 (2013): 236-41. doi:10.1097/FPC.0b013e32835ea0b2
- Szaflarski, Jerzy P. et al.”Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study.” Epilepsy & Behavior, Volume 87, Oct 2018, 131 - 136
- Sekar, Krithiga, and Alison Pack. “Epidiolex as adjunct therapy for treatment of refractory epilepsy: a comprehensive review with a focus on adverse effects.” F1000Research vol. 8 F1000 Faculty Rev-234. 28 Feb. 2019, doi:10.12688/f1000research.16515.1
- Devitt-Lee, Adrian. “A Primer on Cannabinoid-Drug Interactions.” Project CBD, 25 Sept. 2018, www.projectcbd.org/sites/projectcbd/files/downloads/cannabinoid-drug-int….
- Sandra Blasco-Benito, et al. “Appraising the “entourage effect”: Antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer,” Biochemical Pharmacology, Vol 157(2018) p 285- 293, https://doi.org/10.1016/j.bcp.2018.06.025.
- Torres, Sofía, et al. “A Combined Preclinical Therapy of Cannabinoids and Temozolomide against Glioma.” Mol Cancer Ther January 1 2011 (10) (1) 90-103; DOI: 10.1158/1535-7163.MCT-10-0688
- McAllister, S.D., Soroceanu, L. & Desprez, PY. J Neuroimmune Pharmacol (2015) 10: 255. https://doi.org/10.1007/s11481-015-9608-y
- Prud’homme, Mélissa et al. “Cannabidiol as an Intervention for Addictive Behaviors: A Systematic Review of the Evidence.” Substance abuse: research and treatment vol. 9 33-8. 21 May. 2015, doi:10.4137/SART.S25081
- Gonzalez-Cuevas, Gustavo et al. “Unique treatment potential of cannabidiol for the prevention of relapse to drug use: preclinical proof of principle.” Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology vol. 43,10 (2018): 2036-2045. doi:10.1038/s41386-018-0050-8
- Sulak, Dustin. “America’s Opiate Addiction Crisis and How Medical Cannabis Can Help.” Project CBD, Aug. 2016, www.projectcbd.org/sites/projectcbd/files/downloads/handout_sulak_1.pdf.
- Hamelink, Carol et al. “Comparison of cannabidiol, antioxidants, and diuretics in reversing binge ethanol-induced neurotoxicity.” The Journal of pharmacology and experimental therapeutics vol. 314,2 (2005): 780-8. doi:10.1124/jpet.105.085779
- Devitt-Lee, Adrian. “Drug Memories: CBD & Addiction.” Project CBD, 13 Apr. 2018, www.projectcbd.org/medicine/drug-memories-cbd-addiction.
- Gage, S H et al. “Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study.” Psychological medicine vol. 47,5 (2017): 971-980. doi:10.1017/S0033291716003172
- Lee, Martin A. “CBD & Cannabis Dosage Guide.” Project CBD, 1 Apr. 2019, www.projectcbd.org/how-to/cbd-dosage.