I’m skeptical about … CBD (cannabidiol).

     With passage of the Farm Bill in 2018, CBD (cannabidiol) products became legal in all states under federal law, provided they are derived from hemp containing less than 0.3% THC. But just as multiple states have legalized cannabis in opposition to federal laws that prohibit physicians from prescribing it, there are still several states where cannabis products including CBD remain illegal irrespective of federal laws to the contrary.

 

 

The FDA defines a “drug” as a substance intended to diagnose, treat, or prevent disease. Compounds may be synthetic or naturally occurring; it’s the intent of use that defines whether or not a compound is a drug. In general, drugs are presumed to be unsafe until proven to be safe, meaning that manufacturers bear the burden of submitting safety data to the FDA prior to approval. There are multiple steps to the process:

  1. Preclinical phase. Before a drug company can test a drug on humans, it must first prove that the drug is safe in animals, and present the data to the FDA as part of an investigational new drug application.
  2. Phase one clinical trials. In the first round of clinical trials, manufacturers administer the drug to healthy individuals at varying doses while measuring bioavailability, duration of action, elimination, toxicity, and safety outcomes. Typically, the trials are small with just 20-80 participants. These trials are concerned with dosage and safety, not effectiveness.
  3. Phase two clinical trials. In the second round of clinical trials, researchers administer the drug to patients with the condition or disease the drug is intended to treat to assess efficacy. (Does the drug work?) Trials should be randomized, blinded, and comparative against existing drugs or a placebo. Typically, such trials involve 100 or more participants.
  4. Phase three clinical trials. In the third round, researchers work with the FDA to design a larger trial to determine the ideal drug dosage in targeted patient populations, monitor side effects, and determine effectiveness. Trials typically involve 1,000 patients or more.
  5. Approval. This phase includes data submission and analysis. The FDA reviews the data (often many thousands of pages) and issues an approval decision in six to ten months.
  6. Phase four, post-marketing surveillance. The FDA may require manufacturers to complete post-approval studies to generate additional information about a drug’s long-term safety, efficacy, and optimal use. The FDA also maintains a MedWatch website where consumers and physicians may voluntarily report concerns or adverse events surrounding a drug’s use.

 

[JACC – Basic to Translat Sci 2016; 1 (3): 170.]

The process is long, onerous, expensive, and usually unsuccessful, as only about 10% of drugs for which an investigational new drug application is submitted are ultimately approved. It’s far cheaper and quicker to bring a product to market as a dietary supplement. As opposed to drugs, dietary supplements are presumed safe until proven unsafe. They are not regulated by the FDA and cannot make claims regarding a capacity to “treat, diagnose, or prevent” disease. Supplements are regulated by the Center for Drug Evaluation and Research (CDER), subject to guidelines under the Dietary Supplement Health and Education Act of 1994. The rigorous testing required for drug approval does not apply to supplements, loosely defined as “products taken orally for supplementing the diet.” Such products run the gamut from minerals and vitamins to a wide array of naturally occurring herbs and botanicals.

 

 

(csnews.com)

And here’s the Catch-22: Although over-the-counter CBD products are legal under the federal Farm Bill, they are not FDA-approved as drugs, dietary supplements, or food additives, meaning that their sale under any of these guises is a violation of the law. But that hasn’t stopped thousands of companies, stores, and internet distributors from marketing and selling them in places where cannabis products are legal under state laws. A recent Google search for “CBD products” in March, 2020 yielded 205,000,000 results in just 0.68 seconds. When supplements are purposefully added to foods, like gummies, gels, brownies, and cookies, they are considered “food additives,” and fall under the regulatory guidelines of the Federal Food, Drug, and Cosmetic Act that requires FDA pre-market review and approval before retail sale. Additives that are Generally Recognized As Safe (GRAS) are exempt, but the FDA has expressly stated that CBD products do not meet criteria for inclusion on this list. CBD is not approved as a food additive.

CBD is FDA-approved for just one indication; the treatment of refractory seizures (Dravet’s and Lennox-Gastaut variant epilepsy), where it is available by prescription in liquid form at a concentration of 100 mg/ml (Etodiolox). Irrespective of legalities, the market remains flush with product. On this issue, the FDA is outnumbered and outgunned, although did manage to flex its muscles a bit in recently issuing a warning to 15 companies for sales violations that included the illegal marketing of unapproved human and animal drugs (CBD), making fraudulent health claims, and the unauthorized use of CBD additives in foods. This, coming on the heels of a June, 2019 warning to Curaleaf, a leading cannabis company, for clear marketing violations that included false health claims that CBD has been “shown to be effective in treating Parkinson’s disease,” is “a natural alternative to pharmaceutical-grade treatments for depression and anxiety,” and possesses “properties that counteract the growth and spread of cancer.” All unproven, but, even if true, still illegal to include in marketing materials because CBD is not FDA-approved for the treatment of any of these conditions.

 

 

The storm of controversy surrounding this compound lies with the fact that, although isolated from cannabis plants, CBD (cannabidiol) is devoid of euphoric effects. It does not cause people to get “high,” and has virtually no affinity for CB1 or CB2 receptors where THC (tetrahydrocannabinol) exerts its effects. CBD is not an inert compound as previously believed, but its effects are altogether different than THC-containing preparations. CBD is capable of binding to a number of non-cannabinoid receptors in the brain and throughout the body that are responsible for its therapeutic effects.

Receptors are small protein molecules, often embedded within membranes, that are capable of recognizing and responding to chemical signals. Affinity is the attraction a compound has for a specific receptor. CBD has almost no affinity for CB1 and CB2 receptors (the ones responsible for the psychotropic effects of marijuana). Some compounds act as antagonists, binding to a receptor without provoking a chemical response, while blocking the receptor to binding by other compounds. Other substances act as agonists, wherein binding provokes a chemical signal. Still others are capable of binding directly to enzymes, inhibiting or enhancing specific chemical reactions. CBD is capable of all three. It acts as a mild antagonist at CB1 receptors, but is an agonist when bound to vanilloid receptors (e.g. TRPV1 and TRPV2) and serotonin receptors (5-HT1A). CBD also inhibits the reuptake of specific endogenous endocannabinoids like anandamide. Because CBD is capable of binding to so many different receptors and affecting so many reactions, it has promise as a treatment for a host of medical conditions, and this goes a long way to explaining the Wild-West marketing of CBD as a cure-all for everything.

 

Although the structures of THC and CBD are almost identical, they exert very different effects.

 

The data is another matter. Animal studies support CBD’s antioxidant, anti-inflammatory, and neuroprotective effects. The strength of these effects and their applicability in humans is unproven and largely untested. Just because a compound is capable of eliciting a chemical response doesn’t mean that it will be useful to treat or prevent human diseases. For example, vitamin E has strong antioxidant properties but has been a bust at preventing heart disease. CBD’s anti-inflammatory effects are weaker than typical NSAIDs. Its neuroprotective effects have yet to be evaluated in human trials, so it’s impossible to say at this juncture just where and how CBD fits in as a treatment. Most data are anecdotal and fraught with bias. The largest study to date, published in 2016, was an open-label, non-placebo-controlled study of CBD’s effectiveness for treatment-resistant epilepsy, and involved just 162 patients. Because CBD is a cannabis product—a schedule 1 narcotic in the eyes of the DEA—this means a bureaucratic nightmare for those seeking to conduct clinical trials. This is an easy compound to buy, but a hard one to study.

The Lancet paper mentioned above and a randomized controlled trial that appeared in the New England Journal of Medicine the following year that demonstrated a 23% decline in seizure frequency with CBD relative to a placebo in children with a severe form of epilepsy, provided enough evidence for the FDA to approve CBD for this specific indication. But that’s it.

 

(J Clin Med 2019; 8: 989.)

 

CBD, combined with THC in a 1:1 ratio, is available in spray form (Sativex) to treat multiple sclerosis spasticity and neuropathic pain in the UK, Canada, and a host of European nations, but is not available here in the States. Otherwise, there are no approved CBD products for medicinal use, although that hasn’t stopped thousands of people from using CBD to self-medicate chronic pain, anxiety, depression, insomnia, and a host of other ailments. CBD comes in all manner of preparations. Take your pick from capsules, tablets, powders, tinctures, essential oils, suppositories, foods, candies (gummies), beverages, vaping products, topical gels and transdermal patches, candles (“aroma therapy”), skin and beauty products, even pet foods and chew toys. It is often packaged with other botanicals like cloves, hops, turmeric, and ashwagandha in herbal supplements to promote “health and wellness.” Remind yourself again that nonspecific health claims in the absence of actual evidence mean nothing.

 

(stevesgoods.com)

 

But it’s not a case of “all hype, no hope.” CBD does indeed possess chemical properties that make it an intriguing candidate as an adjunctive therapy for a host of conditions. There are both theoretical and pre-clinical data to suggest that CBD might be beneficial in treating chronic pain, Parkinson’s, multiple sclerosis, schizophrenia, addiction disorders, anxiety disorders, PTSD, autism, stroke and traumatic brain injury. Unfortunately, there is not yet nearly enough patient data to make treatment recommendations for any of these conditions. Testimonials are not science. Know that none of the epilepsy trials utilizing CBD have been able to replicate the success anecdotally reported by parents belonging to a Facebook group dedicated to sharing information about the use of CBD-enriched cannabis to treat their children’s seizures. In general, it’s a fool’s game to use yourself or a family member as a guinea pig based on internet endorsements or website testimonials. On the flip side, I am totally empathetic to those seeking solutions to problems for which the traditional medical community has no answers. But until the DEA reclassifies CBD as a schedule IV or V drug (those with little to no abuse potential), research trial data will be hard to come by, and CBD sales will remain an area rife with hucksterism.

 

[Mayo Clinic Proc 2019; 94 (9): 1840.]

In an online study of more than 2,400 CBD users, 62% of respondents reported that they use CBD to treat an underlying medical condition. The three most common reasons cited were: 1) pain; 2) anxiety; and 3) depression. More than a third of respondents reported that CBD worked “very well,” with just 4% reporting that it worked “not very well.” That’s better than just about any prescription drug on the market, but given that CBD is being used primarily to treat diseases, then, by definition, it falls under the categorization of a “drug,” not a “supplement.” As such, the sale of CBD products requires the submission of randomized controlled trial data to the FDA for approval—something these fly-by-night companies have no interest in doing. Although CBD is not addictive, that doesn’t mean that it is safe.

 

Reasons cited for CBD use. (Cannabis Cann Res 2018; 3 (1): 152.)

 

Unfortunately, there is little to no trial evidence that CBD relieves pain, reduces anxiety, or treats depression. A 2019 systematic review of cannabinoid products to treat pain in humans included just a single study looking at CBD for pain; a 2003 trial of just 12 patients with neuropathic pain, where CBD resulted in marginal pain relief versus a placebo. That’s it. While there is a plethora of data showing that THC, or THC in combination with CBD, relieves pain, there is no similar data for CBD alone. Nor is there much trial data that CBD relieves anxiety; a trial in 12 patients with social anxiety disorder whose anxiety before a simulated public speaking engagement was partially attenuated by pre-treatment with CBD, and another in 57 healthy volunteers, where 300 mg of CBD (but not 150 mg or 600 mg) achieved similar results. Unfortunately, these findings offer no evidence that CBD mitigates anxiety on a day-to-day basis in non-public speakers. Finally, there are no published randomized controlled trials on CBD for the treatment of depression, just a couple of desultory case reports. Note that while the absence of evidence is not the same as evidence of absence, there simply isn’t any data to justify the current craze surrounding CBD oil.

There is, however, evidence for potential harm. CBD is metabolized via the p450 cytochrome oxidase system, as are many other commonly prescribed drugs. Taking CBD enhances the effects of some drugs while weakening the effects of others. For example, the antifungal drug ketoconazole and cardiac drugs amiodarone and verapamil inhibit the p450 system, meaning that CBD metabolism is diminished when taken with these drugs. Other drugs compete with CBD for p450 binding, meaning that when taken together, the metabolism of these drugs is inhibited, leading to an increased risk of side effects. An example is warfarin (Coumadin), a commonly prescribed blood thinner. CBD enhances the blood thinning effects of warfarin, potentially leading to serious bleeding complications. The list of drugs with shared metabolism is long and unfamiliar to most physicians, which is why you should seek the advice of a pharmacist familiar with your medications and complementary supplements before starting any CBD product. In a supervised trial of healthy volunteers, 100% of patients taking the THC/CBD product Sativex experienced adverse reactions when taken concomitantly with ketoconazole.

Even when taken alone, CBD is not devoid of side effects. In a dose-dependent fashion, CBD results in sedation and fatigue in 41-51% of users, decreased appetite in 16-22%, and diarrhea in 9-20%. CBD is associated with an increased risk of suicidal thoughts, and an increased risk of developing upper respiratory infections and pneumonias. It also results in transient liver function abnormalities in 8-16% of users, which was the most common reason to stop the drug in studies on CBD for seizures. Nonetheless, over-the-counter use is generally well tolerated in doses of up to 1,500 mg per day. Unlike THC products, CBD is not addictive.

 

Note: CBD oils need to be distinguished from cannabis oils, the latter containing THC and other cannabinoids. [Mayo Clinc Proc 2019; 94 (9): 1840]

Unfortunately, the product you buy likely doesn’t contain the actual amount of CBD as listed on the label (if the label lists this information at all). In a study of CBD content of 84 commercially available online products, labels were accurate only about a quarter of the time, with 43% under-labeling the correct CBD content and 26% over-labeling. More than 20% of the products also contained THC that wasn’t listed on the label. In another study of 21 Dutch products, only four were correctly labeled. This is what happens when product sales go unsupervised and unregulated. The public gets ripped off. Consumers should be for more protections, not fewer.

Know also, that CBD absorption is poor when taken orally, and largely dependent on whether it is consumed with food. According to Dr. Orrin Devinsky, Director of the NYU Comprehensive Epilepsy Center and a leading expert on CBD, “bioavailability is in the range of 4–6%, which is terrible.” But, if taken after a fatty meal, “you can get that up to 16–20%.” There also appears to be a “sweet spot” for therapeutic use, meaning that the intended effect may not occur when the dose is either too high or too low. If you decide to take the plunge, a few precautions:

  • Look for products certified under the FDA’s Current Good Manufacturing Practices (CGMP), or those certified by the National Science Foundation (NSF).
  • Best products have independent adverse event reporting programs. Look for a phone number on the label.
  • Seek products certified as organic or eco-farmed to limit pesticide and heavy metal contamination.
  • Look for quality controls that include batch laboratory testing to confirm CBD levels and THC levels less than 0.3%

Chances are you’ll have difficulty locating any products conforming to all of the above. In the absence of such controls, however, consider yourself a lab animal.

 

(Credit: Don Bartletti, LA Times, Getty)

 

 

References:

  1. Peter Corr and David Williams, “The Pathway from Idea to Regulatory Approval: Examples for Drug Development,” Conflict of Interest in Medical Research, Education, and Practice, (Washington, DC: Nat’l Academies Press, 2009).
  2. Gail Norman, “Drugs, Devices, and the FDA: Part 1, An Overview of Approval Processes for Drugs,” JCCC: Basic to Translational Sci 2016; 1 (3): 170-79.
  3. “FDA Warns 15 Companies for Illegally Selling Various Products Containing Cannabidiol as Agency Details Safety Concerns,” US Food and Drug Administration, Press Release, Nov 25, 2019,
  4. Paula Krasny, “Proceed with Caution: Marketing Claims for Cannabis and CBD Products,” Cannabis Business Executive, Aug 5, 2019.
  5. Jamie Carroon and Jake Felice, “The Endocannabinoid System and its Modulation by Cannabidiol (CBD),” Altern Ther Health Med 2019; 25 (s2): 6-14.
  6. Emilio Perucca, “Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last?,” J Epilepsy Res 2017; 7: 61-76.
  7. Carmen Mannucci et al., “Neurological Aspects of Medical Use of Cannabidiol,” CNS & Neurol Disorders -Drug Targets 2017; 16: 541-53.
  8. Orrin Devinsky et al., “Cannabidiol in Patients with Treatment-Resistant Epilepsy: An Open-Label Interventional Trial,” Lancet 2016; 15: 270-78.
  9. Orrin Devinsky et al, “Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome,” NEJM 2017; 376 (21): 2011-20.
  10. Tom Freeman et al., “Medicinal Use of Cannabis Based Products and Cannabinoids,” BMJ 2019; 365: l1141.
  11. Joshua Brown and Almut Winterstein, “Potential Adverse Drug Events and Drug–Drug Interactions with Medical and Consumer Cannabidiol (CBD) Use,” J Clin Med 2019; 8: 989.
  12. Brenda Parker and Catherine Jacobson, “Report of a Parent Survey of Cannabidiol-Enriched Cannabis Use in Pediatric Treatment-Resistant Epilepsy,” Epilepsy Behav 2013; 29 (3): 574-77.
  13. Jamie Carroon and Joy Phillips, “A Cross-Sectional Study of Cannabidiol Users,” Cannabis and Cann Res 2018; 3 (1): 152-61.
  14. Julio Yanes et al., “Effects of Cannabinoid Administration for Pain: A Meta-Analysis and Meta-Regression,” Experimental Clin Psychopharm 2019; 27 (4): 370-82.
  15. Derick Wade et al., “A Preliminary Controlled Study to Determine Whether Whole-Plant Cannabis Extracts Can Improve Intractable Neurogenic Symptoms,” Clin Rehab 2003; 17: 21-29.
  16. Mateus Bergamaschi et al., “Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naive Social Phobia Patients,” Neuropsychopharm 2011; 36: 1219-26.
  17. Ilia Lineras et al., “Cannabidiol Presents an Inverted U-Shaped Dose-Response Curve in a Simulated Public Speaking Test,” Brazilian J Psych 2019; 41 (1): 9-14.
  18. C. Stott et al., “A Phase I, Open-Label, Randomized, Crossover Study in Three Parallel Groups to Evaluate the Effect of Rifampicin, Ketoconazole, and Omeprazole on the Pharmacokinetics of THC/CBD Oromucosal Spray in Healthy Volunteers,” Springerplus 2013; 2: 236.
  19. Marcel Bonn-Miller et al., “Labeling Accuracy of Cannabidiol Extracts Sold Online,” JAMA 2017; 318 (17): 1708-09.
  20. Arno Hazekamp, “The Trouble with CBD Oil,” Med Cannabis and Cann 2018; 1: 65-72.
  21. Michael Eisenstein, “The Reality Behind Cannabidiol’s Medical Hype,” Nature 2019; 572: s2-4.
  22. J. Harrison et al., “Clinicians’ Guide to Cannabidiol and Hemp Oils,” Mayo Clinic Proc 2019: 94 (9): 1840-51.

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