CRx MAGAZINE

Winter 2020

Cannabis-Drug Interactions — A Special Risk for Older Adults

Cannabis-drug interactions are a concern for all patients, but older adults who take multiple medications are at greatest risk.

Older adults increasingly are turning to cannabis and cannabis-derived products to address unmet medical needs. One study showed the use of cannabis to have increased three-fold (2.9% to 9%) in persons aged 50 to 64 years from 2002 to 2014, while use by persons aged 65 or older increased by nearly 10-fold (0.2% to 2.1%).1 Furthermore, the market for CBD consumer products is expected to grow from an estimated $600 million to $2 billion in 2018 to $16 billion by 2025.2

This staggering growth is fueling the need for greater awareness and recognition by consumers, patients, and health care providers about potentially dangerous cannabis drug-drug interactions (DDIs), with increased concern for older adults who often take multiple medications for multiple comorbid conditions.

Considerations in Older Adults
In general, older adults are particularly vulnerable to negative consequences from adverse drug events (ADEs), including DDIs, regardless of medication. This is due to polypharmacy (use of multiple medications), comorbid conditions, and age-related changes such as altered absorption, altered drug distribution, reduced hepatic metabolism, reduced renal excretion, and altered neurophysiology, all of which affect pharmacokinetics and pharmacodynamics.3,4

Common uses of cannabis include those for cancer, chronic pain, epilepsy/seizures, nausea and vomiting, muscle spasms, inflammatory conditions, and Alzheimer’s and Parkinson’s diseases. Since many of these conditions overlap with conditions commonly occurring in older adults and treated with other medications, there’s a great likelihood of potential drug-related concerns.

Types of DDIs
DDIs can be divided into two categories of interactions: pharmacodynamic (what a drug does to the body) and pharmacokinetic (what the body does to a drug).

Pharmacodynamic interactions result when two drugs that exhibit similar effects on the body are given together. These interactions may result in additive (1+1=2) effects, synergistic (1+1>2) effects, or antagonist effects. Pharmacokinetic interactions result when one drug (perpetrator) affects the concentration of another drug (victim) by altering the victim drug’s bioavailability (changes in absorption or first-pass metabolism), clearance (changes in metabolism or excretion), or distribution (changes in cell membrane transport to the site of action).

Predicting cannabis-related DDIs can be challenging due to a number of variables, including genetic differences, age-related changes, dose-dependent factors (increased interaction risk with increased doses), variations in concentrations of THC and CBD, and possible inaccurate labeling of CBD products. It’s important to note that due to frequent polypharmacy in older adults, the potential for interactions is rarely as simple as looking at how one drug interacts with another.

Although clinical data evaluating cannabis DDIs is limited, it’s possible to make predictions for DDIs of concern by extrapolating what’s known from case reports in the literature and package inserts from commercially available products. Sativex is a combination of THC and CBD (1:1 ratio THC to CBD) marketed in the European Union countries as an adjunctive treatment for the symptomatic relief of spasticity and neuropathic pain in multiple sclerosis in adults.5 Epidiolex is an FDA-approved CBD product indicated for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome.6

Pharmacodynamic Interactions
Pharmacodynamic DDIs resulting in increased ADEs are possible when cannabis or CBD is used with a number of other drugs.

Central Nervous System Depression
The effects of THC on the central nervous system (CNS) include sedation, somnolence, ataxia, slowing of reaction time, motor incoordination, defects in short-term memory, and difficulty in concentration. These effects can be additive if cannabis is used together with other medications possessing CNS depressant effects such as benzodiazepines, antipsychotics, opiates, barbiturates, sedating antihistamines, and others. If possible, recommend avoidance of the concurrent use of cannabis and other CNS depressants.

CBD can cause sedation, somnolence, lethargy, fatigue, and asthenia. These effects appear to be moderately dose related. In Epidiolex studies, somnolence occurred in 23% and 25% of patients treated with CBD (10 and 20 mg/kg/day, respectively), followed by fatigue (11% and 12%), lethargy (4% and 8%), and sedation (3% and 6%).6 Clinicians should recommend avoidance of coadministration of CBD with CNS depressants when possible. Inform patients about the risk of excessive sedation and advise them to avoid operating vehicles and/or recommend they use CBD at bedtime. Tolerance may develop with prolonged therapy. Using lower doses and slow titration may be helpful until tolerance is achieved.

Cardiovascular Effects
Dose-related tachycardia and possible acute hypertension can occur when cannabis (due to THC) is used with drugs with sympathomimetic activity (eg, cocaine, epinephrine, beta-agonists). Tachycardia of up to 160 beats/minute or more could occur and is of significant concern in persons with cardiovascular conditions. Tachycardia can also result from interactions with anticholinergic medications (eg, first-generation antihistamines, tricyclic antidepressants).5,6

Because of the cardiovascular effects, cannabis isn’t recommended for patients with preexisting cardiovascular disease, such as ischemic heart disease, arrhythmias, poorly controlled hypertension, and severe heart failure.5

While tolerance can develop to tachycardia and acute hypertension concerns with chronic use, widespread vasodilation and postural hypotension still can occur. CBD use may reduce blood pressure. Interactions with medications known to lower blood pressure, including antihypertensives (eg, diuretics, beta-blockers, alpha-blockers) and other drugs known to cause hypotension (eg, nitrates, levodopa, tricyclic antidepressants, antipsychotics), could result in postural hypotension, syncope, falls, and increased fracture risk.7

Transaminase Elevation/Hepatic Injury
According to studies with Epidiolex, the most common reason for discontinuation was transaminase elevation. This increase appears to be dose related with an incidence of 8% at doses of 10 mg/kg/day, 16% at 20 mg/kg/day, and 3% with placebo. In controlled clinical trials, 2.7% vs 11.8% patients discontinued CBD treatment between the 10 mg/kg/day and 20 mg/kg/day treatment arms vs 1.3% for placebo.

In patients with epilepsy receiving the anticonvulsant valproate and Epidiolex, 21% had elevated transaminase levels, which is more than three times the upper limit of normal. Recommendations from prescribing information for Epidiolex suggest discontinuing or adjusting the dose and/or valproate if liver enzyme elevations occur.6

Caution should be taken when CBD is used with medications that have the potential to cause hepatic injury (eg, antiepileptics, antipsychotics, acetaminophen, some antibiotics, antifungals, and verapamil).

Pharmacokinetic DDIs
Due to alterations in drug metabolism (eg, interactions with hepatic enzymes), drug excretion (eg, phase II metabolic pathways), or distribution (eg, changes in drug transport), pharmacokinetic DDIs between cannabis products and a number of other medications can occur.

Cytochrome P450 Metabolic Pathway
Isoenzymes that make up the hepatic cytochrome P450 (CYP450) metabolic pathway are responsible for the metabolism of most drugs. The effect a drug has on these isoenzymes or how these isoenzymes affect a particular drug varies significantly.

Substrates, Inhibitors, and Inducers
Drugs that slow enzyme activity are referred to as “inhibitors,” while drugs that increase enzyme activity are referred to as “inducers.” Some drugs—those referred to as “substrates”—neither inhibit nor induce any enzymes but require an isoenzyme to be metabolized.

As would be expected, inducer drugs given together with substrate drugs (both involving the same isoenzyme) will lead to a decreased effect and amount of the substrate drug in the body, whereas inhibitor drugs given together with a substrate drug involving the same isoenzyme will lead to an increased effect of the substrate drug as it builds up and is not being metabolized as it normally would be.7

Genetic differences can exist and in part explain why one person may have significant risks for possible DDI-related adverse events while another person has no issues or concerns. Some individuals may be “poor” metabolizers due to dysfunctional or inactive enzymes, while others may be “extensive” metabolizers who have enzymes showing normal activity. The variation in metabolic activity may result in a 10- to 100-fold difference between poor and extensive metabolizers.7

CYP450 Isoenzymes
The CYP450 pathway can be grouped into classes of isoenzymes (eg, CYP3A, CYP2C). THC and CBD are metabolized by a number of different CYP450 isoenzymes. However, the most important appear to be CYP3A4 and CYP2C9 (for both THC and CBD), with CBD also being metabolized by CYP2C19. Recognizing which isoenzymes are involved with THC and CBD metabolism can help in predicting and possibly preventing DDIs.

CYP3A4
CYP3A4 not only is the most prevalent CYP enzyme in the liver but also is used by more than 50% of medications on the market for their metabolism and elimination from the body.8

CYP3A4 substrates include many immunosuppressants, chemotherapeutic agents, antidepressants, opioids, benzodiazepines, z-hypnotics, statins, and calcium channel blockers. When CBD is given with CYP3A4 substrates, there’s an increased risk of side effects related to the substrate. If possible, recommend avoidance of coadministration of CBD with CYP3A4 substrates. If it’s necessary to coadminister, reduce the dose of the substrate medication and monitor patients closely for ADEs and possible toxicity.9

CYP3A4 inhibitors may increase the bioavailability of CBD and increase the potential for side effects. Use with mild inhibitors is likely of no concern; however, when CBD is used with moderate and strong CYP3A4 inhibitors, a reduction in dose of CBD may be appropriate.9

Strong CYP3A4 inhibitors include clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, and loperamide.9,10

Moderate CYP3A4 inhibitors include amiodarone, erythromycin, fluconazole, miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, and conivaptan.10 Other moderate inhibitors of importance include grapefruit juice, cat’s claw, echinacea, wild cherry, chamomile, and licorice.

A study involving Sativex (four sprays) coadministered with the strong CYP3A4 inhibitor ketoconazole (400 mg; five days) resulted in an increased bioavailability of CBD by 89%. However, there was significant increase in healthy adult participants experiencing CNS-related adverse events—but this was possibly related to THC rather than CBD.9

CYP3A4 inducers may decrease CBD bioavailability and effectiveness. There may be a need to increase the dose of CBD when it’s used with strong and moderate CYP3A4 inducers. Strong inducers include enzalutamide and phenytoin. Moderate inducers include carbamazepine, topiramate, phenobarbital, rifampicin, efavirenz, and pioglitazone.9

CBD’s effects on CYP3A4 don’t appear to be a class effect, which may allow for one drug from a medication class to be changed to another medication should there be concern for a significant interaction. For example, azithromycin doesn’t inhibit CYP3A4, while all other macrolide antibiotics are known inhibitors of the isoenzyme.

For the medication class of calcium channel blockers, nondihydropyridine calcium channel blockers are known inhibitors of CYP3A4, while amlodipine and nifedipine aren’t. Lastly, among the nonnucleoside reverse transcriptase inhibitors (NNRTIs) used in the management of HIV, only delavirdine is an inhibitor of CYP3A4, whereas the other NNRTIs in the class are considered to be inducers of CYP3A4.10

CYP2C19
CYP2C19 substrates include antidepressants, antiepileptics, proton pump inhibitors, clopidogrel, propranolol, carisoprodol, cyclophosphamide, and warfarin.9

When CBD is used with CYP3A4 substrates, there’s an increased risk of side effects related to the substrate. When possible, caution against CBD use with CYP3A4 substrates. If necessary, reduce the dose of the substrate medication and monitor patients closely for ADEs and toxicity.9

CYP2C19 inhibitors may in increase CBD bioavailability and side effect risks. The dose of CBD may need to be reduced.9

Strong inhibitors include fluvoxamine and fluoxetine. Other inhibitors include proton pump inhibitors, cimetidine, ketoconazole, clopidogrel, fluconazole, and efavirenz.9

CYP2C19 inducers include rifampin, carbamazepine, phenobarbital, phenytoin, and St. John’s wort. Coadministration may result in decreased CBD bioavailability and possible decrease in CBD effectiveness. An increase in CBD dose may be necessary.9

When administered with rifampicin (600 mg; 10 days), a strong CYP3A4 and CYP2C19 inducer, CBD Cmax (the maximum drug concentration obtained following administration) decreased by 52%.9

CYP2C9
CYP2C9 substrates include rosiglitazone, buprenorphine, montelukast, celecoxib, sulfonylureas, losartan, naproxen, phenobarbital, phenytoin, rosuvastatin, valsartan, and warfarin.9

When CBD is used with CYP2C9 substrates, there’s an increased risk of side effects related to the substrate. When possible, avoid using CBD with CYP2C9 substrates. If necessary, reduce the dose of the substrate medication and monitor patients closely for ADEs and toxicity.9

Phase II Metabolic Pathways/Drug Transporters
Pharmacokinetic drug interactions can also occur as a result of interactions with phase II metabolic pathways and drug transport involving drug excretion.

UGT1A9/2B7
CBD can inhibit phase II metabolic pathways involving uridine 5’-diphospho-glucuronosyltransferase (UGT) enzymes, which are involved in the excretion of some medications due to inhibition of UGT1A9 and UGT2B7. Commonly used medications such as acetaminophen, ibuprofen, and naproxen are substrates of these enzymes. Interactions with over-the-counter naproxen and ibuprofen could lead to significant side effects (eg, bleeding).9

UGT1A9 substrates include regorafenib, acetaminophen, canagliflozin, sorafenib, irinotecan, propofol, mycophenolate, valproic acid, haloperidol, ibuprofen, dabigatran, and dapaglifozin.9

UGT2B7 substrates include hydromorphone, losartan, ibuprofen, naproxen, ezetimibe, lovastatin, simvastatin, carbamazepine, and valproate.9

The significance of this interaction was demonstrated using ethanol as a substrate. CBD reduced UGT1A9 activity by 49% and UGT2B7 by 70%.9 The Epidiolex product label suggests dosing changes of UGT1A9/2B7 substrates in the presence of CBD.6

Drug Transporters
The drug transporter enzymes breast cancer resistance protein (BCRP) and the bile salt export pump (BSEP) play a role in the efflux of xenobiotics from tissues and transport into excretion pathways. An inactive metabolite of CBD, 7-COOH-CBD is a substrate for P-glycoprotein and an inhibitor of BCRP and BSEP.9

When CBD is given with medications that interact with BCRP or BSEP, an increase in substrate side effects is possible. Recommend avoidance of coadministration. If that’s not possible, consider reducing the substrate dose and monitoring for side effects and toxicity.9

BSEP substrates include paclitaxel, digoxin, statins, telmisartan, glyburide, ketoconazole, rosiglitazone, and celecoxib.9

BCRP substrates include glyburide, imatinib, methotrexate, mitoxantrone, nitrofurantoin, prazosin, statins, and dipyridamole.9

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

General Recommendations

Consider the following suggestions when working with older adult patients who use cannabis:

• Increase patient awareness about the potential for cannabis and CBD drug-drug interactions (DDIs).

• Encourage patients to be open about any use of cannabis (medical or recreational) and CBD products.

• Health care providers should recognize that older adults are likely at a higher risk of DDIs.

• Educate patients to contact their prescribers or pharmacists with questions about possible DDIs.

• A risk-to-benefit assessment should be completed before using cannabis in patients receiving high-risk medications (eg, those with a narrow therapeutic window).

• In some cases, one medication in a drug class may be substituted for another medication in the class to help mitigate the risk.

• Counsel patients about the potential for excessive sedation and steps to mitigate risk to themselves and others, such as not operating vehicles or reserving use of CBD for nighttime.

• Some side effects may diminish with prolonged therapy, so recommend starting with lower doses and titrating up slowly.

• Many of the cannabis DDIs appear to be dose related, so dosage reductions of the substrate dose may allow for continuation of current therapy while minimizing risks.

• Monitor patients closely for possible side effects and DDIs and, as with any medication, consider adverse drug events to be medication related until proven otherwise.

— MDC

References

1. Bobitt J, Qualls SH, Schuchman M, et al. Qualitative analysis of cannabis use among older adults in Colorado. Drugs Aging. 2019;36(7):655-666.

2. Azer V, Blackledge J, Charles AM, et al. Cowen’s collective view of CBD. Cowen website. https://www.cowen.com/reports/cowen-collective-view-of-cbd/. Published February 25, 2019.

3. Zubenko GS, Sunderland T. Geriatric psychopharmacology: why does age matter? Harv Rev Psychiatry. 2000;7(6):311-333.

4. Jacobson SA, Pies RW, Katz IR. Clinical Manual of Geriatric Psychopharmacology. 1st ed. Washington, D.C.: American Psychiatric Publishing; 2007.

5. GW Pharma Ltd. Product monograph: Sativex. https://www.bayer.ca/omr/online/sativex-pm-en.pdf. Published March 31, 2015.

6. Greenwich Biosciences, Inc. Highlights of prescribing information: EPIDIOLEX (cannabidiol) oral solution, CV. https://www.epidiolex.com/sites/default/files/EPIDIOLEX_Full_Prescribing_Information.pdf. Updated December 2018.

7. Low A. Drug interactions: a matter for enzymes. GI Society website. https://badgut.org/information-centre/a-z-digestive-topics/drug-interactions-a-matter-for-enzymes/

8. Rendic S, Di Carlo FJ. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev. 1997;29(1-2):413-580.

9. Brown JD, Winterstein AG. Potential adverse drug events and drug-drug interactions with medical and consumer cannabidiol (CBD) use. J Clin Med. 2019;8(7):E989.

10. Common medications classified as weak, moderate and strong inhibitors of CYP3A4. Evidence-Based Medicine Consult website. https://www.ebmconsult.com/articles/medications-inhibitors-CYP3A4-enzyme. Updated October 2015.

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