Seniors increasingly are using cannabidiol, or CBD, to help manage a variety of chronic disease symptoms. A new paper from the Gerontological Society of America tackles key questions about safety and side effects. Cannabidiol Use in Older Adults ABSTRACT: Cannabidiol (CBD) is a nonpsychoactive component of the Cannabis sativa plant. CBD products, which have become popular in the United States, are
‘Not necessarily benign’: Geriatricians address safety as seniors turn to CBD for chronic conditions
Seniors increasingly are using cannabidiol, or CBD, to help manage a variety of chronic disease symptoms — despite a lack of high-quality clinical research on the drug, according to the Gerontological Society of America. A new paper presents key questions about CBD safety and side effects in older adults, and what information clinicians will need to answer patients’ questions about the drug.
The GSA paper, “Medical Use of Cannabidiol (CBD) in Older Adults: A Focused Discussion on Safety,” summarizes a 2020 meeting of experts in pharmacy, clinical medicine and research, law and policy.
CBD is an active ingredient of cannabis, or marijuana, and an essential component of medical marijuana. There is a perception that the growing variety of health products containing CBD are low-risk for side effects, and a need exists for more clinical guidance, panelists said.
“Despite the scarcity of evidence, older adults are interested in using, or are already using, CBD products to alleviate symptoms from numerous diseases, undeterred by the risks. Thus, it is urgent to address current gaps in knowledge about the safety of CBD products in older adults through scientifically rigorous research,” the authors wrote.
Clinicians now face questions such as what ingredients are contained in CBD products, what effects can be expected, and whether CBD products interact with prescription or over-the-counter medications.
“It remains unclear what evidence supports their use for common chronic conditions such as pain, insomnia, loss of appetite, depression, anxiety, and weight loss,” the authors wrote. There is also the overarching question of what role healthcare providers should play in counseling patients who may perceive CBD to be outside of the clinician’s realm.
Those concerns become more pronounced in the context of the human aging process, they added.
One sign of possible safety concerns related to non-Food and Drug Administration-approved CBD products has been a sharp rise in calls to poison control centers between 2014 and 2020, according to William J. Lynch Jr., BPharm, RPh, of Jefferson Health and Rowan University School of Osteopathic Medicine, in New Jersey.
Seniors not immune to adverse effects
It is known that CBD consumed as an ingredient in a non-FDA-approved medical product can produce acute impairment of attention, memory, verbal learning, executive function and psychomotor function, the GSA said. But exactly how aging-related changes in physiology affect the responses of older adults is yet unknown, it added.
Adverse reactions seniors may face when using non-FDA-approved CBD products include insomnia, diarrhea, fatigue, malaise, rash, vomiting, elevations in the liver enzymes, and infections, Lynch said.
“It’s important to know these effects because as pharmacists and physicians, we might modify a person’s medications if we found elevated liver function tests, for example — especially for older adults,” he said. “There also are many drug interactions with CBD that could cause increased clotting or bleeding, hepatotoxicity, or changes in metabolism that would require doses of other medications to be changed. CBD is not necessarily benign.”
Experts are concerned about a lack of oversight by the FDA and a lack of documentation on potential drug interactions. Inert or nonactive ingredients in non-FDA-approved CBD products (such as sesame seed oil and alcohol) also have the potential to trigger side effects, the GSA authors wrote.
The clinicians’ role
Clinicians have limited data to share with patients about the safety and efficacy of unapproved CBD products for difficult-to-manage conditions, including anxiety or agitation, depression, as well as behavioral symptoms of Alzheimer’s disease, said Brent Forester, M.D., MSc, chief of the Division of Geriatric Psychiatry at McLean Hospital in Massachusetts and co-president of the American Association for Geriatric Psychiatry.
The current regulatory environment, in which cannabis and most derivative products are treated as Schedule I controlled substances, is a barrier to needed research in these areas, Forester said.
The FDA is seeking to address several topics of interest to the public, according to April Inyard Alexandrow, Ph.D., lead for the agency’s Cannabidiol Policy Working Group. These include:
- What happens if people use CBD daily for sustained periods of time?
- What level of intake triggers the known risks associated with CBD?
- How do different methods of exposure affect intake (for example, oral consumption, topical use, smoking, vaping)?
Most of the GSA meeting participants agreed that CBD science trails well behind policy and product marketing. More data should be collected on the clinical reasons older patients are motivated to use CBD and impediments to proper research should be lifted, they agreed.
“Participants felt that there was a need to build out evidence about the safety profile and efficacy of CBD as it relates to pain, anxiety, insomnia, Parkinson’s disease, dementia, and other conditions for which CBD is considered a potential therapeutic for unmet needs,” they wrote.
Despite limited clinical training on CBD, it is important to support care teams in counseling older patients through the development of new educational opportunities and clinical tools for delivering reliable information, the authors concluded.
Cannabidiol Use in Older Adults
ABSTRACT: Cannabidiol (CBD) is a nonpsychoactive component of the Cannabis sativa plant. CBD products, which have become popular in the United States, are frequently used to treat pain, anxiety, and sleep disorders—conditions that affect older adults. Evidence is insufficient to recommend the use of CBD for these disease states. OTC CBD products are widely available, and there are significant concerns regarding their safety, including mislabeling, standardization issues, and drug interactions. The informed pharmacist will be a valuable resource for discussing the use and safety of CBD with older adults.
Cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) are among the many cannabinoids, or components, of the Cannabis sativa plant. CBD is nonpsychoactive, whereas THC has psychoactive properties such as euphoria and psychosis. Two common strains of Cannabis sativa are marijuana and hemp. 1 CBD may be derived from either marijuana (which often contains more than 15% THC) or hemp (having a THC concentration of no more than 0.3%). 2 In addition, CBD may be extracted from Cannabis indica and hybrid plants, which may have higher concentrations of CBD than THC. A recent survey revealed that one in seven Americans uses CBD products, with the most common reasons for its use being pain, anxiety, poor sleep, and arthritis. 3
Endogenous cannabinoids and phytocannabinoids such as CBD and THC modulate the endocannabinoid system (ECS). THC is a partial agonist on the cannabinoid (CB) 1 receptor that results in central nervous system (CNS) effects, such as the “high” associated with marijuana; it also has limited CB2 agonist activity in the immune system. CBD has minimal activity on CB receptors, but it affects the ECS and the non-ECS. 4 Some of the proposed mechanisms of CBD include agonist activity at serotonin 1A, transient receptor potential vanilloid 1, G protein–coupled receptor 55, and adenosine A2A receptors, which may explain some of the possible analgesic, anti-inflammatory, anxiolytic, and antiepileptic effects of CBD. 1,5
In the United States, about two-thirds of states have legislation approving cannabis for recreational use (11 states) and/or medicinal purposes (21 additional states). Seven states mandate pharmacist involvement, such as dispensing activities or consulting to dispensaries. 6 The only FDA-approved (in 2018) CBD product is Epidiolex, which is indicated for treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome. 7 The law prohibits the sale of foods or dietary supplements to which CBD has been added; however, a wide variety of products containing CBD are available at retail stores. 8
CBD formulations used in clinical trials include oral capsules, sublingual spray, oil-based solution, and topical gel. OTC CBD products are available in numerous other formulations, including topical balms and creams, e-liquid for inhalation, and infused foods and drinks. 1,9 Given the many formulations and manufacturers, nearly all CBD products lack standardization. The exception is Epidiolex, which is available as an oil-based oral solution formulated with sesame oil and standardized to contain 100 mg/mL of pure CBD extract. 7
CBD levels in commercially available products vary widely. The FDA has issued warning letters every year since 2015 to companies marketing unapproved new drugs that allegedly contain CBD. 8,10-13 As part of these warnings, the FDA tests the chemical content of CBD compounds, and it has found that many products do not contain the claimed level of CBD. Commercially available products have been assessed in laboratories, whose findings support the FDA’s concerns about product inconsistency and mislabeling. A laboratory assessment of OTC CBD products sold in the U.S. demonstrated that only 26 of 84 (31%) products tested were accurately labeled. 14 Not only was the amount of CBD in products overlabeled or underlabeled, but 21% of products contained THC even though it was not listed in the product information. In addition, the FDA has cited concerns regarding reports of contaminants such as pesticides and heavy metals. 8
The mislabeling of CBD products results in dosing uncertainty in the use of any commercially available OTC product. This is an important caveat in the extrapolation of dosages used in clinical research. In such research, a range of dosages have been used for different indications and routes of administration. For example, Epidiolex oral solution is approved for weight-based dosing from 5 mg/kg/day to a maximum of 20 mg/kg/day. 7 CBD has been given orally at dosages of 100 mg to 800 mg. 15,16 CBD topical gel has been used for fragile X syndrome at a dosage of 50 mg to 250 mg daily. 17 For smoking cessation, a CBD metered-dose inhaler has been administered at a dosage of 400 mcg as needed. 18
Administration and Absorption
CBD absorption depends on the product formulation. In animal and human studies, CBD administered orally has been shown to be poorly absorbed, with bioavailability of 13% to 19%. 19,20 CBD’s bioavailability is believed to be reduced by first-pass metabolism. Poor bioavailability can be avoided with the use of alternative formulations. There is an emerging market for novel delivery methods to increase CBD’s oral bioavailability. 21
Absorption of CBD may also be altered by food intake. In clinical trials, coadministration of Epidiolex with a high-fat, high-calorie meal increased plasma levels of CBD fourfold to fivefold compared with administration on an empty stomach. 7 In one study using a purified (99%) CBD capsule, coadministration with food resulted in a maximum concentration and AUC of 14-fold and fourfold higher, respectively, compared with administration on an empty stomach. 22 CBD inhalation in humans has an average bioavailability of approximately 31%, with the use of one type of metered-dose inhaler demonstrating bioavailability of more than 65%. 18,23 Transdermal absorption of CBD is variable in animal studies and has yet to be fully elucidated in humans. 4
CBD is FDA-approved for certain types of seizure disorders; for more information, see the manufacturer’s website for Epidiolex (www.epidiolex.com). The following section will focus on the common reasons for off-label CBD use, including pain, sleep disorders, and anxiety, all of which affect older adults.
Pain: An estimated 50 million American adults (20.4%) experience chronic pain, with persons aged 65 years and older constituting 61.2% of those affected. 24 Much of the data on chronic pain (e.g., neuropathic pain, cancer pain, diabetic peripheral neuropathy, fibromyalgia, HIV-associated sensory neuropathy, spasticity associated with multiple sclerosis [MS], and rheumatoid arthritis) involve the use of marijuana and cannabinoids (often THC, combination THC-CBD, or nabiximols [a specific mixture of THC, CBD, other minor cannabinoids, flavonoids, and terpenes]). Formulations used in pain studies range from smoked, oral, or oromucosal spray of THC; synthetic cannabis (nabilone); synthetic THC (dronabinol); and vaporized cannabis, with results suggesting modest reductions in pain and spasticity. 25
Sativex (nabiximols), an oromucosal THC-CBD spray, is approved in several European countries for treating symptoms of moderate-to-severe spasticity associated with MS, and a phase II/III clinical trial is currently under way in the U.S. to evaluate nabiximols for advanced cancer pain with inadequate analgesia from chronic opioids. 26 There is a paucity of data on CBD used for pain; most studies are in preclinical stages. 5,25,27
Sleep Disorders: Sleep disorders are disproportionately more prevalent in older adults. 28 Patients have commonly reported that cannabis is helpful for sleep. 29 CBD is used for alleviation of insomnia, but little is known about its effectiveness. One study that compared CBD with placebo for insomnia in 15 patients suggested that 160 mg of CBD may improve sleep duration without next-day sedation. 30 Somnolence was reported in nearly one-third of patients taking Epidiolex in clinical trials, which provides additional support for CBD’s benefits for sleep in some patients. 7 However, more research is needed to determine whether CBD is useful for individual components of insomnia, such as sleep latency, wakefulness after sleep onset, sleep duration, and overall sleep quality.
Anxiety: Evidence is not strong for the use of CBD for anxiety disorders. CBD has demonstrated some benefit for social anxiety disorder and social phobia when patients undergo a simulated public-speaking test. 31,32 However, these trials had small sample sizes and study biases. It is theorized that CBD could be beneficial for anxiety based on its mechanism of action at the serotonin receptor. 31
Other Disease States: Data on the use of CBD for various other conditions are mixed, and evidence is insufficient to recommend this practice. The efficacy of CBD has been studied in bipolar disorder, Crohn’s disease, diabetes, dystonia, fragile X syndrome, graft-versus-host disease, Huntington’s disease, opioid withdrawal, Parkinson’s disease, schizophrenia, and smoking cessation. 33 In addition, CBD has been reported to be useful for addiction, possibly by modulating dopamine and serotonin. 1
Adverse Effects and Safety
The use of CBD is considered “possibly safe” when used appropriately, based on some clinical evidence. 33 However, insufficient high-quality data exist to recommend CBD for most older adults. The most common adverse effects associated with CBD, reported in clinical trials of Epidiolex, are somnolence (~32%), decreased appetite (16%-22%), diarrhea (9%-20%), and increased liver-function tests (13%). 7 Other side effects are orthostatic hypotension, lightheadedness, and dry mouth. Adverse effects appear to be dose-related. The safety of CBD in the geriatric population has not been fully clarified, and Epidiolex clinical trials did not include patients older than 55 years. 7
There are practical concerns regarding CBD use in older adults. The geriatric population may be more susceptible to adverse effects of CBD commonly seen in younger adults, including sedation. CBD is hepatically metabolized, predominantly via CYP2C19 and CYP3A4. 4 Older adults with reduced hepatic function may be more susceptible to adverse effects of CBD.
Commercially available CBD products may not contain the CBD concentrations claimed on the label, and the FDA warns consumers to be aware of this inconsistency when using such products. 13 Of particular concern is the THC component in mislabeled CBD products. Older adults may be predisposed to adverse effects caused by the psychoactive properties of THC. The use of marijuana in older adults has been associated with increased risk of injury and adverse events. 34
CBD has been shown to inhibit hepatic enzymes. 4 In human studies, coadministration of CBD with antiepileptic drugs resulted in increased concentrations of drugs that are substrates of CYP2C9, CYP2C19, and CYP3A4. 35 Given CBD’s known sedative effect, there is also a theoretical concern for additive hypnotic reactions in combination with CNS depressants. TABLE 1 lists potential interactions with CBD.
The Pharmacist’s Role
A recent survey by the Arthritis Foundation revealed significant use of and interest in CBD for arthritis. The Foundation acknowledges the possible efficacy of CBD for treating pain, insomnia, and anxiety while also recognizing the lack of rigorous clinical studies. 36 Despite a scarcity of evidence for CBD use in the geriatric population, education on known and potential benefits and risks is vital to a patient’s decision-making process. The pervasive direct-to-consumer advertising and ubiquity of CBD products may foster misinformation or misinterpretation of actual evidence. The pharmacist should be prepared to give an unbiased assessment of CBD, including concerns about product mislabeling, underlabeling and overlabeling of CBD, and lack of THC labeling in a product containing it.
The pharmacist should consider patient-specific factors when discussing CBD use. A review of potential drug-drug interactions is warranted prior to using CBD. Counseling on pharmacokinetic variables, such as oral administration with or without food, may be relevant. Comorbidities may also be pertinent to the discussion, and safety concerns should be reinforced. For example, a patient with preexisting respiratory disease should avoid inhalation as the route of CBD administration. An honest and impartial discussion will facilitate a stronger patient–healthcare provider relationship.
If a patient has decided to use CBD, the pharmacist can direct the patient toward a top-quality CBD product. TABLE 2 provides questions to consider when recommending a CBD product. Given the increasing number of states and U.S. territories legalizing marijuana for medicinal or recreational use, the informed pharmacist will be a valuable resource for discussing the use and safety of CBD with older adults. 6