Identifying And Preventing Drug Interactions With Energy Drinks

Noting the increased popularity of energy drinks, this author looks at the potential dangers that may arise when these drinks interact with a patient’s prescription drugs.

The consumption of energy drinks has continued to gain popularity since the 1997 debut of Red Bull, the current leader in the energy drink market.¹ Energy drink marketing is targeted to the 18- to 35-year-old consumer. More than 500 new energy drinks launched worldwide in 2006 and beverage companies are realizing the financial rewards of the $5.7 billion energy drink industry.

Given this expanding energy drink market and the resulting consumption of these energy drinks, there has been a growing body of medical literature describing the significant adverse health events after the ingestion of these beverages.² Energy drink makers are required to tell the United States Food and Drug Administration (FDA) about any adverse events related to their products.

Researchers have linked energy drinks with multiple caffeine sources to a higher rate of side effects, which generally involve the nervous, digestive or cardiovascular systems.² To date, little published research has explored the relationship between energy drink consumption and prescription medication drug interactions. Podiatric physicians may be aware of the most relevant drug-drug interactions. However, they may be unaware that energy drink ingredients may interact with medications through pharmacokinetic or pharmacodynamic mechanisms resulting in harmful adverse effects. Recognizing the existence of drug interactions with energy drinks ingestion can empower a clinician with the knowledge to avoid dangerous interactions that may result in hazardous, negative patient outcomes.

A Closer Look At Energy Drink Ingredients

There are many energy drinks on the market (see photo) and they do not all contain the same ingredients. However, these are the most common ingredients:

• Caffeine
• Sugar
• Yerba mate
• Guarana
• Taurine
• L-carnitine
• 5-hydroxytryptophan
• Vinpocetine
• Yohimbine
• Ginseng
• Ginkgo biloba
• Glucuronolactone
• B vitamins

Further, the non-herbal or non-natural ingredients in energy drinks can often resemble chemical structures one would see in chemistry books.

Caffeine. Caffeine is one of the most abundant and ingested compounds on the earth. Moreover, caffeine is the most common ingredient in energy drinks and is the chemical that provides the energy boost. In the U.S., 80 percent of adults consume caffeine every day and the average adult has a daily intake of 400 mg.³ Caffeine is defined as a drug because it stimulates the central nervous system and causes increased alertness. Also, caffeine gives most people a temporary energy boost and elevates their mood. After consumption, caffeine usually reaches its peak level in blood within one hour and stays there for approximately four to six hours.

Recent research suggests that caffeine's antioxidant effects may help protect people from diseases such as Alzheimer's when they consume it in moderate amounts^.4 Caffeine increases the release of acid in the stomach, sometimes leading to an upset stomach or "heartburn." Caffeine is a diuretic. Therefore, the body loses water and the consumer craves more to quench the resulting thirst.

Energy drinks typically contain 80 to 141 mg of caffeine per 8 ounces, the equivalent of five ounces of coffee or two 12-ounce cans of caffeinated soft drinks.³ Caffeine pharmacokinetics are rapid (t-max 30 to 120 minutes and complete absorption occurs as the caffeine crosses freely through the blood-brain barrier, placental and testicular barriers. Caffeine has demonstrated no specific tissue accumulation with prolonged ingestion. The body almost completely metabolizes caffeine with 3 percent or less being excreted unchanged in urine. The main route of metabolism in humans (70 to 80 percent) is N-3 demethylation to paraxanthine (1,7-dimethylxanthine, 17X), which is catalyzed by cytochrome (CYP) 1A2 in the liver. Caffeine has a half-life of four to five hours, which may be prolonged in patients with hepatic diseases, infants and neonates (up to 100 hours), or during pregnancy. Further, smoking increases clearance of caffeine due to its actions on CYP1A2.⁵    

White and colleagues reported their observations centered on pharmacokinetic analysis and comparison of caffeine administered as coffee chilled or hot versus chilled energy drinks.⁶ Results from this study suggest that contrary to concerns about potential rapid absorption of caffeine from rapidly consumed cold energy drinks, caffeine absorption and exposure from instant coffee and sugar-free energy drinks are similar irrespective of drink temperature or rapid versus slow administration times.⁶

Chemically, caffeine is a methylxanthine or a phosphodiesterase inhibitor. We can describe the effects of caffeine predominantly through its antagonistic activity at adenosine receptors. Four adenosine receptors (A1, A2A, A2B and A3) are known in humans and their presence, distribution and effects vary among organs and tissues, even among vessel types. Caffeine acts, at least in part, by facilitating dopamine D2 receptor transmission.

Ciprofloxacin consumption with caffeine increases caffeine’s effects, which could cause headaches, high blood pressure, restlessness, insomnia and nervousness.⁷

Consuming caffeine concurrently with duloxetine (Cymbalta, Lilly) increases the risk for duloxetine side effects like nausea, dry mouth, insomnia, drowsiness and constipation.⁷ Lithium and caffeine consumption can lead to lithium toxicity symptoms such as nausea, vomiting, diarrhea, drowsiness, muscle weakness, tremor, lack of coordination, blurred vision or ringing in the ears.⁷ Ropinirole (Requip, GlaxoSmithKline) and caffeine consumption causes too much ropinirole to enter the bloodstream, leading to confusion, vomiting, weakness, fainting, agitation and drowsiness.⁷ Since caffeine’s and theophylline’s chemical structures are similar, the effects are additive, increasing the risk of side effects of theophylline such as convulsions, tremors, insomnia, vomiting and heart palpitations.⁷ Tizanidine and concurrent caffeine use can cause low blood pressure, dizziness, light-headedness and fainting.⁷

Yerba mate. Yerba mate is made from the naturally caffeinated and nourishing leaves of the celebrated South American rainforest holly tree (ilex paraguariensis). Prescription medication drug interactions with yerba mate include: quinolones, cimetidine and estrogens, causing jitteriness, increased heart rate and headaches.^7,8 Other drug interactions with yerba mate include combination effects with beta-adrenergic agonists and monoamine oxidase inhibitors that may include nervousness, high blood pressure and a fast heart rate.⁷ Also, anticoagulant-antiplatelet drugs as well as nonsteroidal anti-inflammatory drugs (NSAIDs) taken with Yerba mate slow blood clotting, which might increase the chances for bleeding.⁷ Alcohol increases the effect of Yerba mate and caffeine on the body. Finally, there is a pharmacokinetic drug interaction with Yerba mate and terbinafine (Lamisil, Novartis), which alters metabolism and may increase the chances for adverse effects.⁷

Guarana. A rainforest vine from the Amazon, guarana is another common ingredient in energy drinks. The people of the Amazon use guarana seeds for increased energy and alertness. The guarana seed has the highest caffeine content of any other plant and has the same benefits, risks and potential side effects as caffeine.^9,10 The concurrent use of guarana, caffeine and Yerba mate may reduce the sedative/anxiolytic effect of benzodiazepines and other hypnotics.⁷ Also, these ingredients will reduce the blood levels of medications such as aminoglutethimide, carbamazepine, phenobarbital or rifampin (Rifadin, Sanofi) when people consume these concurrently.⁷ Increased blood levels can occur when patients take guarana with fluvoxamine, ketoconazole, ciprofloxacin, norfloxacin or ofloxacin. β-adrenergic agonists, disulfiram (Antabuse) or aspirin.⁷

Taurine. Taurine is an amino acid that is a common ingredient in energy drinks, and also occurs naturally in some foods. Taurine is a derivative of cysteine, which contains a thiol group. It is one of the few known naturally occurring sulfonic acids. Taurine has essential functions in the body and most healthy people can make enough to meet their needs. However, adults with serious illnesses and infants must obtain taurine from consumed foods.¹¹

There is a lack of information about the long-term effects of ingesting large amounts of taurine. The amount of taurine in an 8-ounce serving of a typical energy drink is about 1,000 mg, which is considered safe.¹² Some energy drink manufacturers claim that taurine helps with exercise performance but this has not been proven.¹¹ Decreased blood pressure has been observed with the consumption of taurine. Therefore, patients should exercise caution when taking taurine with captopril, enalapril, losartan (Cozaar, Merck), valsartan (Diovan, Novartis Pharmaceuticals), diltiazem, amlodipine (Norvasc, Pfizer), hydrochlorothiazide (Microzide) and furosemide (Lasix, Sanofi).

Carnitine (L-carnitine). Carnitine is a natural compound, an amino acid made in the liver and kidneys, which is involved with energy metabolism. Research does not support the claim that carnitine increases exercise recovery. In amounts greater than 3 g per day, carnitine can cause nausea, vomiting and diarrhea.¹³ Most energy drink manufacturers don't list the amount of carnitine on the nutrition facts label so the prudent healthcare provider can take this opportunity to inform the patient of this fact to assist in avoiding a negative outcome from a deadly drug interaction. L-carnitine seems to decrease how well the thyroid hormone works in the body. L-carnitine might increase the effects of warfarin and increase the chances of bruising and bleeding.⁷

5-hydroxytryptophan. Oxitriptan, also known as 5-hydroxytryptophan (5-HTP), is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of the neurotransmitter serotonin. A total of 89 drugs are known to interact with 5-hydroxytryptophan with 68 major drug interactions and 21 moderate drug interactions.⁷ All these interactions affect the medications’ pharmacokinetics profile and one should consider the metabolism affecting a drug’s half-life, duration of action and onset.

Vinpocetine. A man-made chemical resembling a substance found in the periwinkle plant, in the broadest terms, vinpocetine is a powerful memory enhancer. It achieves this principally by facilitating cerebral metabolism and improving blood flow in the brain. Vinpocetine works by causing mild dilation of blood vessels, thereby allowing for an increase in cerebral blood flow, which results in increased oxygenation and glucose utilization. Authors have postulated that vinpocetine might slow blood clotting.7 Taking vinpocetine along with medications that also slow clotting might increase the chances of bruising and bleeding.⁷ Some medications that slow blood clotting include aspirin, clopidogrel (Plavix, Bristol-Myers Squibb), diclofenac, ibuprofen, naproxen, dalteparin (Fragmin, Pfizer), enoxaparin, heparin and warfarin.⁷

Yohimbine. Yohimbe is the name of an evergreen tree found in parts of central and western Africa. The bark of yohimbe contains a chemical called yohimbine, which is used to make medicine. Yohimbine is an alpha-blocker. It works by increasing certain chemicals in the body that dilate the pupils of the eye. It also dilates blood vessels and increases blood flow in the penis, which helps to improve erectile function. Yohimbine might affect the body in some of the same ways as some medications for depression called monoamine oxidase inhibitors. Clonidine is an agent to decrease blood pressure and yohimbine might increase blood pressure and cancel the pharmacological effects of both agents.⁷ Some medications are changed and broken down by the liver. Yohimbine might decrease how quickly the liver breaks down the following medications: amitriptyline, clozapine, codeine, desipramine (Norpramin, Astellas Pharma), dextromethorphan, donepezil (Aricept, Pfizer), fentanyl, flecainide, fluoxetine (Prozac, Lilly), meperidine (Demerol, Pfizer), methadone, metoprolol, olanzapine (Zyprexa, Lilly), ondansetron (Zofran, GlaxoSmithKline), tramadol and trazodone.⁷

Ginseng and ginkgo biloba. Ginseng and ginkgo biloba are known as G-herbs that people use as alternative medicines or natural supplements. Ginseng and ginkgo biloba may improve memory when people take them together. Consumers should be aware that both ginseng and ginkgo biloba can interfere with proper drug action of certain medications such as insulin, oral hypoglycemic agents, blood thinners and diuretics.^7,14 These medications are changed by the liver cytochrome P450 2D6 because they are classified as CYP2D6 substrates. Such interactions can cause severe health problems. Energy drink manufacturers claim that ginseng can help athletic performance but this claim also has not been proven. The amount of ginseng in most energy drinks is less than the amount traditionally considered beneficial.¹⁰

Glucuronolactone. Manufacturers add glucuronolactone to some energy drinks as part of the product's "energy blend." It occurs naturally in our bodies and in foods such as fruits. There is some evidence to suggest that glucuronolactone may decrease exercise fatigue but more research is needed to form a definite conclusion.¹⁵ Studies have not shown this compound to have any negative effects on health but the research is limited and there is also not enough evidence to set safe consumption levels.¹⁰

B vitamins. Manufacturers add B vitamins to most energy drinks with the claim that B vitamins boost mental and physical performance. Although a deficiency in certain B vitamins can lead to fatigue, getting more B vitamins than needed does not provide extra energy. Most people get plenty of B vitamins from their diets, especially from fortified foods. When patients consume more B vitamins than they need from energy drinks or other sources, these vitamins are lost in the urine.^16,17 Although most of the B vitamins in energy drinks are not toxic, too much vitamin B₆ (pyridoxine) can be dangerous. The highest level of vitamin B₆ intake considered to be safe is 100 mg per day.¹⁶ Most energy drinks contain 2–3 mg of vitamin B₆ per 8-ounce serving.¹⁰

Detailing Drug Interactions With Commonly Prescribed Medications

Guerra recently introduced the ClinCalc DrugStats Database and the 2017 Top 200 Drugs based on the most commonly prescribed medications in the U.S. on his ClinCalc.com website.¹⁶ The author says the list is based on Pareto’s Principle, namely that 80 percent of effects come from 20 percent of causes. In this case, the 20 percent represents the 80 percent of prescriptions that are actually filled. While the actual percentages deviate from that 80/20, the principle holds.

I used the top 200 medications for 2017 for this review, identifying drug interactions between energy drink ingredients and most frequently prescribed medications.¹⁶ The data were primarily qualitative and were based on reports in the current compendium, recent journal articles and drug monographs. I used current literature sources to resolve conflicting information presented in reference materials. I researched ten ingredients of energy drinks for potential drug interactions with the top 200 prescribed medications for 2017. The table “Drug Interactions With Energy Drink Ingredients” (see PDF) lists the 200 medications using generic names, followed by an “X” that indicates the possibility of a drug interaction.

During the review, I noted that some reviewed medications had no information available in the medical literature identifying any drug interaction with listed energy drink ingredients. Therefore, the actual number of medications with reported drug interactions was actually 43.5 percent (87) of the 200 reviewed medications. I combined caffeine, Yerba mate and guarana as one category because of their similarities. Therefore, I used eight ingredient columns as well as 87 generic drug names to construct the easily readable table.

I found a total of 164 drug-ingredient interactions in the literature.¹⁶ This research revealed that both warfarin and acetaminophen with hydrocodone (Vicodin, AbbVie) have drug interactions with five ingredients found in energy drinks. Aspirin, dabigatran (Pradaxa, Boehringer Ingelheim) and rivaroxaban (Xarelto, Janssen Pharmaceuticals) all have the potential for interactions with four ingredients found in energy drinks. The natural product ginkgo biloba was the ingredient that interacted with 60.9 percent (53) of the reviewed medications followed by caffeine (28) and ginseng (23). Distribution of the total number of reported drug interactions and energy drink ingredients are in the graphic at the right.

Emphasizing Open Communication With Patients About Energy Drinks

Patient-physician communication is of pivotal importance when it comes to energy drink consumption. Most physicians are either unfamiliar or unwilling to develop any level of expertise with the ingredients found in energy drinks. This topic is as important as determining prescription drug use, over-the-counter product use, tobacco and alcohol consumption and illicit drug usage, and clinicians need to consider this during the history and physical process.^14,17,18

Unfortunately, energy drinks are not regulated by the FDA. Also, energy drink ingredients include herbal products and there is still no protocol for standardization of herbal products. Given these issues, the risk of potential for deadly drug interactions is heightened.¹⁴ There are reports in the medical literature centered on energy drinks and adverse effects on patients.

The prudent podiatric physician will make sure to obtain correct information as to accurate energy drink consumption for each patient and encourage discontinuation or reduction of these products to avoid drug interactions that may have deadly implications. Given that the ingredients in energy drinks are herbal in nature, podiatric physicians should have a detailed knowledge and understanding of the potential risks, and purported benefits of herbal ingredients. They should thoroughly inquire about the patient's use of energy drinks and energy supplemental products.^14,19 Patients may be reluctant to disclose energy drink consumption as they may feel their physicians have little knowledge about herbal products, let alone ingredients in energy drinks. Other patients may not consider these ingredients as dietary supplements or even to be medications, or feel that herbals are not related to their current medical care.^14,20,21

Clinicians should remember that the American Society of Anesthesiologists (ASA) suggests that patients discontinue all herbal medications two to three weeks before an elective surgical procedure.^14,22,23 Empowered with this information, podiatric physicians may help their patients safely use pharmacologic treatment by avoiding reportedly harmful interactions with the ingredients found in energy drinks.

In Conclusion

This review offers the health-care provider information regarding potential prescription drug interactions. The table “Drug Interactions With Energy Drink Ingredients” serves as a ready reference for podiatric physicians and other healthcare professionals when monitoring and counseling patients regarding the potential of drug interactions with ingredients found in energy drinks. With increased recognition of the existence of drug interactions with energy drinks, clinicians can be more empowered to avoid dangerous drug interactions that may result in hazardous, negative patient outcomes.

Dr. Smith is in private practice at Shoe String Podiatry in Ormond Beach, Fla.

References

1. U.S. Energy Drinks Industry and Market - Statistics & Facts. Statista. Consumer Goods & FMCG Non-alcoholic beverages, energy drinks. Available at https://www.statista.com/topics/1687/energy-drinks/ . Accessed July 1, 2017.

2. Ali F, Rehman H, Babayan Z, et al. Energy drinks and their adverse health effects: A systematic review of the current evidence. Postgrad Med. 2015;127(3):308-22.

3. Food and Drug Administration. FDA to investigate caffeine intake. Available at https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm350570.htm accessed July 5, 2017.

4. León-Carmona, J.R., Galano, A. Is Caffeine a good scavenger of oxygenated free radicals? Journal of Physical Chemistry B 2011 115(15), 4538.

5. Thorn CF, Aklillu E, McDonagh EM, et al. PharmGKB summary: caffeine pathway. Pharmacogenetics and genomics (2012). Available at https://www.pharmgkb.org/literature/14988376 . Accessed August 21, 2017.

6. White JR, Padowskib JM, Yili Z, et al. Pharmacokinetic analysis and comparison of caffeine administered rapidly or slowly in coffee chilled or hot versus chilled energy drink in healthy young adults. Clinical Toxicology. 2016, 54(4):308-212.

7. Drug Interactions Checker - For Drugs, Food & Alcohol. Available at https://www.drugs.com/drug_interactions.html . Accessed July 2, 2017.

8. Yerba mate. WebMD. Available at https://www.webmd.com/vitamins-supplements/ingredientmono-828-yerba%20mate... . Accessed July 2, 2017.

9. Griffin RM, Leopold DC. Vitamins and supplements lifestyle guide: Guarana. WebMD. Available at https://www.webmd.com/diet/supplement-guide-guarana#1 .

9. Higgins JP, Tuttle TD, Higgins CL. Energy beverages: Content and safety. Mayo Clinic Proceedings. 2010; 86(9):1033–1041.

10. Clauson KA, Shields KM, McQueen CE, Persad N. Safety issues associated with commercially available energy drinks. J Am Pharm Assoc. 2008; 48(3):e55–e67.

11. Bub E, Shelnutt K.https://ufdcimages.uflib.ufl.edu/IR/00/00/08/62/00001/FY132400.pdf . Accessed August 22, 2017.

12. National Institutes of Health (NIH). Office of Dietary Supplements. Dietary supplement fact sheet: Carnitine. https://ods.od.nih.gov/factsheets/carnitine . Published 2006.

13. Smith RG. An appraisal of herbal and drug interactions: podiatric implications. Podiatry Manage. 2014; 33(4):173-181.

14. Tamura S, Tomizawa S, Tsutsumi S, Suguro N, Kizu K. Metabolism of glucuronic acid in fatigue due to physical exercise. Jpn J Pharmacol. 1966; 16(2):138–56.

15. National Institutes of Health (NIH). Office of Dietary Supplements. Dietary supplement fact sheet: Vitamin B. Available at https://ods.od.nih.gov/factsheets/vitaminb6/ . Published 2011.

16. Guerra T. The Top 200 Drugs of 2017? Pharmacy Times. Available at https://www.pharmacytimes.com/contributor/tony-guerra-pharmd/2017/03/the-top-200-drugs-of-2017 . Accessed August 2, 2017.

17. Hoyte CO, Albert D, heard KJ. The use of energy drinks, dietary supplements, and prescription medications by united states college students to enhance athletic performance. J Comm Health. 2013; 38(3):575-576.

18. Kaye AD, Clarke RC, Sabar R, et al. Herbal medicines: current trends in anesthesiololgy practice—a hospital survey. J Clin Anesth. 2000; 12(6):468-471.

19. Rowe DJ, Baker AC. Perioperative risks and benefits of herbal supplements in aesthetics surgery. Aesthetic Surg J. 2009; 29(2):150-157.

20. Blendon RJ, DesRoches CM, Benson JM, et al. Americans’ view on the use and regulation of dietary supplements. Arch Intern Med. 2001; 161(6):805-810.

21. Elder NC, Gilbert A, Minz R. Use of alternative health care by family practice patients. Arch Fam Med. 1997; 6(2):181-184.

22. Wong A, Townley SA. Herbal medicines and anaesthesia. Cont Ed Anesth Crit Care Pain. 2011; 11(1):14-17.

23. American Society of Anesthesiology. What you should know about herbal and dietary supplement use and anesthesia. Patient information leaflet, 2003.