ABSTRACT: Athletes may seek out cannabidiol (CBD) as an alternative pain-relief option due to inadequate relief associated with traditional therapies. Navigating the CBD issue is difficult due to the surrounding legal issues. Cannabinoids include marijuana, hemp, tetrahydrocannabinol (THC), and CBD. Cannabinoid (CB) receptors are found in the central nervous system. To date, relatively few drugs targeting them have been approved by the FDA. With CB2 receptors highly expressed in immune cells, reduction of inflammation and pain could be achieved with ligands that bind to these receptors. Research is inconclusive, and the effects of CBD products on the body are not completely known. Systematic reviews provide some information regarding what is known about benefits and harms. Several sports-governing agencies have weighed in on the cannabinoid discussion. Staying informed can help pharmacists advise athletes and others regarding the role of CBD in safe and effective pain management.
Cannabidiol (CBD) is everywhere, and seemingly being infused into everything, mostly because it can be and because people appear to be clamoring to buy it. CBD products may now be available in some form in the pharmacy where you work or pick up your own prescription medications.1,2 A 2019 survey estimates that 64 million Americans have tried CBD in some form since 2017.3 The majority of respondents indicated that they sought out CBD to reduce stress or anxiety, to help with joint pain, and to either replace or supplement a current OTC or prescription medication being taken for those conditions.3 Various CBD formulations abound (e.g., drops, oils, gummies, infusions, balms), and the therapeutic claims are grand, especially when it comes to pain relief.
For anyone with a physically demanding occupation that takes a toll on the body, pain can be a constant companion. Even routine exercise can result in some form of pain or discomfort, hence the expression “no pain, no gain.”4 The most common sports-related injuries include sprains and strains, knee injuries, swollen muscles, Achilles tendon injuries, pain along the shin bone, rotator cuff injuries, fractures, and dislocations.5 While initially these types of injuries are treated with immediate physical intervention—i.e., rest, ice, compression, and elevation—many athletes are subject to chronic injury and/or pain that develops over time from repetitive exercise or sport.6
Commonly recommended pain management includes OTC nonopioid medications such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin or ibuprofen.6 However, these options have their downside, especially with long-term use. NSAIDs can increase the risk of gastrointestinal bleeding and kidney injury when taken in high doses or for extended periods of time.7 Furthermore, NSAIDs are useful medications for mild pain but often cannot appropriately treat moderate-to-severe pain.
Opioids are commonly prescribed to athletes, particularly after painful surgeries due to injuries sustained during competition and the chronic pain that follows. The World Health Organization recommends that opioid medications, in combination or as monotherapy, be reserved for times when other options do not provide adequate pain relief.8,9 While these products are effective medications for moderate-to-severe pain, they come with additional risks. Acting directly on the central nervous system (CNS), opioids have side effects that impact cognitive function (e.g., sedation, drowsiness, dizziness, fatigue). Additionally, these medications are highly regulated due to their potential for abuse and the risk of fatal overdose. In light of the opioid crisis that the United States currently faces, this increased risk of addiction or diversion has led many athletes to search for alternatives, such as marijuana and, more recently, CBD.
To help pharmacists effectively counsel patient-athletes, this article reviews the reported claims for CBD—in particular, pain relief—its chemistry, the state of research on and regulation of CBD for pain, the attractiveness of this option to the patient-athlete and the weekend-warrior, and the rules of certain sports-regulating organizations pertaining to CBD use.
Although there are serious concerns regarding opioid use and abuse, marijuana and its derivatives are not a panacea. Derived from the dried flowers of the plant Cannabis sativa, marijuana contains a myriad of naturally occurring compounds know as cannabinoids, the most controversial being the psychoactive compound delta-9-tetrahydrocannabinol (THC).10,11 Marijuana has been listed in Schedule 1 of the Controlled Substances Act (CSA) since 1970.12 As such, its possession, distribution, and use are a criminal offense. This has frustrated those who would seek out its potential as a medication of last resort as well as those who would attempt to research it to validate its therapeutic claims. Like NSAIDs and opioids, marijuana can cause side effects from both short- and long-term use. Side effects may include altered senses, changes in mood, impaired body movement, impaired memory, difficulty thinking/problem solving, hallucinations, delusions, or psychosis. Long-term side effects may affect brain development and impair learning functions within the brain by altering connections.11 These types of physiologic responses are not conducive to elite athletic performance or the weekend athlete. Regardless, many in the athletic world would argue that using marijuana to alleviate chronic and/or severe pain is preferable to using opioids. One statistic used to advocate for lifting the ban on marijuana in the National Football League (NFL) indicates that former NFL players suffer opioid addiction at a rate of four times the general population.13 Also, the recent high-profile opioid-related overdose and death of a Major League Baseball player has further increased the outcry from players’ unions to remove the ban on, and stigma of, marijuana usage among its players.14,15
Navigating the CBD issue is difficult due to the legalities surrounding marijuana, hemp, and cannabinoids. First, marijuana and hemp are simply varieties of the Cannabis sativa plant. The plants are differentiated mainly by their inherent levels of THC: Hemp typically has less than 0.3% THC while marijuana has greater than 0.3% THC. The Agriculture Improvement Act of 2018 (i.e., 2018 Farm Bill, a further expansion of the 2014 Farm Bill) removed hemp from the CSA.16 As such, cannabis plants and derivatives that contain no more than 0.3% THC are no longer a controlled substance.
As of January 1, 2020, 11 states allow the legal sale of marijuana for recreational use among adults over the age of 21, and a total of 33 states have legalized the use of marijuana for medicinal purposes.17,18 In response, the acreage to grow hemp in the U.S. in 2019 experienced a 455% increase over 2018 levels.19 While hemp fiber has been historically valued to make ropes, paper, various building materials, and industrial lubricants,20 the farming boom is likely occurring in response to the demand for a source of CBD oil, which is readily extracted from low-THC hemp. It should be noted that the latest bill preserved the FDA’s authority to regulate these products under the Federal Food, Drug, and Cosmetic Act. This ability allows the FDA to protect the public by continuing to scrutinize CBD products that may pose a risk, and it is similar to the agency’s authority with dietary supplements. When a public risk is noted, the FDA has the ability to warn consumers and take enforcement action to remove harmful products, if necessary.21
Meanwhile, marijuana is still classified under federal law as a Schedule 1 drug. Legislation has also been proposed by the House Judiciary Committee to completely legalize marijuana at the federal level, but there is likely much debate still ahead.22 In the meantime, the layperson/amateur athlete governed by workplace policies banning illegal drug use and college-level student-athletes competing under the auspices of the National Collegiate Athletic Association (NCAA), which also bans illegal drug use, face a dilemma: Can CBD be used as an alternative to traditional pain management? Does CBD really work? Is it safe? Will its use result in a failed drug test leading to job termination or expulsion from a team? In a 2018 interview with Chemical and Engineering News, Dr. Melanie Kelly, professor of pharmacology at Dalhousie University in Halifax, Nova Scotia, summed up this dilemma: “We came out of this era of complete prohibition of cannabis, which was probably unwarranted, to this galloping ahead without appropriate research.”23
What Exactly Is CBD?
To understand why CBD can potentially be used for the treatment of pain, a brief review of cannabinoid receptors, endocannabinoids, and currently available cannabinoid drugs is necessary.24,25 There are two well-characterized cannabinoid (CB) receptors found in the CNS of the human body, CB1 and CB2. Both receptor types are G-protein coupled receptors (GCPR). While CB1 features more prominently and is found in higher levels within the brain, CB2 receptors are expressed to a greater extent in immune cells. Endocannabinoids are, as their name implies, cannabinoid chemical compounds endogenous to the human body. The endogenous cannabinoid receptor agonists, anandamide and 2-arachidonylglycerol, are shown in Figure 1 for structural comparison. They are derived from arachidonic acid, an eicosanoid (eicos indicating the 20 carbons in the backbone of the structure), which is a biochemical precursor to multiple endogenous chemicals (e.g., leukotrienes, prostaglandins). The endocannabinoids are lipophilic molecules thought to function as neuromodulators linked to pain, stress, anxiety, appetite, and motor learning. As such, structurally similar chemical molecules, if able to reach and bind to CB receptors or related molecular targets, may be effective in modulating the endocannabinoid system.
To date, relatively few drugs that target this system have been approved by the FDA. Marinol (dronabinol) is synthetically prepared THC.26 As a CB-receptor agonist, dronabinol was approved in 1985 to assist with weight loss in AIDS patients and nausea and vomiting from cancer chemotherapy. Acomplia (rimonabant), a CB1-inverse agonist used to treat obesity, had a short-lived run from 2006-2008 in several countries outside the U.S. but was ultimately withdrawn due to patients experiencing neurologic and psychiatric side effects. In 2018, after three clinical trials involving over 500 patients, Epidiolex (cannabidiol, 99% pure CBD oral solution)27 was approved for treatment of children and young adults with Lennox-Gastaut syndrome or Dravet syndrome. 23,28 Given in conjunction with other seizure medications, the number of seizures experienced was reduced significantly enough to obtain FDA approval.
Analysis of the chemical structure of CBD reveals significant structural homology to the endocannabinoids and THC. The difference is essentially a cyclic ether in THC that has been cleaved to yield the corresponding alcohol in CBD. This similarity may lend credence to the possibility that the compound is interacting with the endocannabinoid system, though the exact mechanism is unknown. Cesamet (nabilone), a synthetic analogue of THC, is also indicated for nausea associated with cancer chemotherapy.29 Lastly, Sativex (nabiximols, currently not approved in the U.S.) is an oromucosal spray that contains an extract of the Cannabis sativa plant containing THC and CBD in a 1:1 ratio, as well as specific minor cannabinoids and “other non-cannabinoid components.”30
Can CBD Treat Pain?
Although it is possible that CBD could effectively modulate pain, there is currently a lack of clinical data to definitively support this claim. With CB2 receptors highly expressed in immune cells, reduction of inflammation and pain could be achieved with ligands that bind to these receptors.31 Research is still inconclusive and the effects of CBD products on the body are not completely known. The classification of CBD as a Schedule 1 substance, although designed to prevent abuse, has hindered research. Studies completed to date have been deemed inconclusive or problematic.
The National Academies of Sciences, Engineering, and Medicine published an extensive literature database search in 2017 that considered over 10,000 scientific abstracts pertaining to cannabis.32 Nearly 100 different research conclusions pertaining to the health effects of cannabis and cannabinoid use were achieved and organized into five categories: conclusive, substantial, moderate, limited, and no/insufficient evidence.33 For example, the committee concluded that there was conclusive or substantial evidence that cannabis was effective for the treatment of chronic pain in adults but that there was only moderate evidence that cannabinoids or mixtures of THC and CBD (e.g., nabiximols) helped with improving short-term sleep outcomes in patients with sleep disturbances resulting from chronic pain (and other issues).33
Another systematic review on the benefits and harms of cannabis in chronic pain published by Department of Veterans Affairs (VA) in 2017 states that there is “low-strength evidence that cannabis preparations with precisely defined THC:CBD content (most in a 1:1 to 2:1 ratio) have the potential to improve neuropathic pain [in adults with chronic pain] but insufficient evidence in other patient populations. Most studies are small, many have methodologic flaws, and the long-term effects are unclear given the brief follow-up duration of most studies. The applicability of these findings to current practice may be low in part because the formulations studied may not be reflective of what most patients are using, and because the consistency and accuracy of labeled content in dispensaries are uncertain.”34
Can CBD Do Harm?
As with any OTC or prescription drugs, there is likely a particular amount of CBD that will cause harm. Exactly what that specific amount is and if chronic use over time can exacerbate the harm are still unknown. Liver injury has been observed as a result of CBD use. For Epidiolex, liver injury and elevated liver enzymes indicating liver injury were observed among patients during clinical trials.23,27 CBD can also affect the metabolism of other drugs, and if used with alcohol or other CNS depressants, it can cause sedation and drowsiness, leading to injuries. Additional side effects include diarrhea, changes in appetite and mood, fatigue, and nausea.
The FDA cautions that some CBD products are of unknown quality and feature unproven medical claims.35,36 In addition, CBD and THC in vaping devices have been found to be tainted with additives that resulted in significant patient harm.37 Advertisements for CBD products in particular aim to convince consumers that their product provides the purest, most potent form of CBD, while being careful to not say exactly what that potency is good for, since it is still illegal to market CBD by adding it to a food or labeling it as a dietary supplement.36
Will CBD Use Result in a Failed Drug Test for an Athlete?
Technically, the FDA does not allow the sale of CBD in any form, except for Epidiolex, and any company selling or marketing a CBD product could be the subject of scrutiny by the FDA. As monitoring of products occurs after they are marketed, full enforcement by the FDA is delayed. This situation is similar to that of other supplements attractive to athletes that persist on the market. For example, a company can claim a product is steroid-free (i.e., testosterone) and/or stimulant-free (i.e., amphetamine) and sell it as such until the FDA analyzes it and determines that it is adulterated. The company then removes it from market and replaces it with a repackaged and rebranded supplement, selling the product again until the FDA has time to evaluate. The cycle repeats endlessly. In the case of CBD, the FDA issued warning letters to at least 15 companies in late 2019.38 Infractions include the marketing or selling of an unapproved new drug, misbranded drugs, unapproved new animal drug, adulterated animal foods, and marketing an unapproved new drug for use in children.
An athlete, particularly a college athlete governed by the NCAA, may try a CBD oil or product to alleviate pain experienced from competition. However, the NCAA clearly lists nine banned drug classes: 1) stimulants; 2) anabolic agents; 3) alcohol and beta blockers (banned for rifle only); 4) diuretics and masking agents; 5) narcotics; 6) cannabinoids; 7) peptide hormones, growth factors, related substances and mimetics; 8) hormone and metabolic modulators (anti-estrogens); and 9) beta-2 agonists.39 Cannabinoids are further described as marijuana, THC, and synthetic cannabinoids (e.g., spice, K2, JWH-018, JWH-073). Although CBD is not explicitly listed as an example in this category, the NCAA policy draws the attention of the athlete and athletic staff to the chemical makeup of any compound in question by stating that “Any substance chemically/pharmacologically related to all classes listed above and with no current approval by any governmental regulatory health authority for human therapeutic use (e.g., drugs under pre-clinical or clinical development or discontinued, designer drugs, substances approved only for veterinary use) is also banned. The institution and the student-athlete shall be held accountable for all drugs within the banned-drug class regardless of whether they have been specifically identified. Examples of substances under each class can be found at www.ncaa.org/drugtesting. There is no complete list of banned substances.”39 CBD is chemically related, and nearly identical, to THC, which is explicitly banned by NCAA (Figure 2).
In response to the changing climate and legalization of marijuana in many states, NCAA has updated their drug testing policy to reflect an athlete’s potential exposure to second-hand marijuana smoke. The NCAA’s revised threshold for THC is now set at 35 nanograms per milliliter, a more than twofold increase.40 This is after a 2017 increase from 5 to 15 nanograms per milliliter, reflecting an overall sixfold increase. This move is said to mirror the standards and/or progressive acceptance of marijuana among major professional sports leagues. While not explicitly stated, this could also be an attempt to avoid positive test results from student-athletes ingesting CBD supplements that may not be completely “THC-free” as advertised.41 To this point, and with regard to the general population and their interest in passing workplace drug tests, in 2013 the U.S. Air Force banned airmen from consuming a particular yogurt product that included hemp seeds, stating that products made with hemp seed or hemp seed oil can contain varying levels of THC.42 Furthermore, a study published in JAMA tested a variety of CBD products and determined that 69% of the products tested contained amounts of CBD that differed from what was reported on the label, and 21% of these products had THC (some levels high enough to cause intoxication).41
Other sports-governing agencies have weighed in on the cannabinoid discussion. The World Anti-Doping Agency (WADA) has recently removed its prohibition on CBD and advises not to pursue positive THC levels below 150 nanograms per milliliter in a urine drug test.43,44 This is greater than four times the amount currently permitted by NCAA. The U.S. Anti-Doping Agency further cautions that despite CBD’s permitted status according to WADA, all other cannabinoids are still barred during competition.45 Both agencies emphasize, as does the FDA, that CBD products may still contain residual cannabinoid components such as THC. And for now, the weekend warrior is subject to drug policies set forth by their respective organizations, regardless of current state or federal law. Although medical marijuana has been legalized in some states, employers are not obligated to allow its use, and most states have not weighed in on the issue of employer accommodation.46
It appears that the public attitude towards marijuana, hemp, and all things related may be changing. Professional athletes are advocating for alternatives to traditional pain medication, and athletic governing organizations are relaxing their policies towards cannabinoids. Many who have used marijuana and/or CBD for chronic pain believe it is superior to other drugs like NSAIDs and opioids, although scientific evidence is unclear. As with any chemical, all should proceed with caution and realize that side effects, both short- and long-term, are possible. Although there may be benefits to the use of marijuana and CBD, they come with the responsibility of recognizing the potential for adverse drug effects and the possibility of misleading claims. With the current lack of regulation and standardization in the production of CBD extracts, there is no way to be certain of the contents of any CBD product. Pharmacists are accessible healthcare practitioners for athletes, athletic personnel, weekend athletes, and the general public inquiring about the benefits and risks of CBD for pain management. Staying informed can help pharmacists provide guidance when called upon to advise athletes with regard to the role of CBD in safe and effective pain management.
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