Sports Medicine, Toxicology

Performance Enhancing Drugs - A Review of Non-Steroidal Drugs of Abuse

Performance enhancing drugs (PEDs) are commonly used by competitive, professional, and Olympic athletes. It has been estimated that there are at least 3 million PED users in America, which puts PED use on a scale similar to commonly encountered diseases such as Type 1 Diabetes and HIV.1 There are several broad categories of PEDs, including steroidal and non-steroidal. In a patient presenting to the emergency department with PED abuse, the history and physical exam are critical in identifying the etiology of the patient's illness because most PED test results will not be available to guide emergency department management. Although uncommon, the emergency department provider must be prepared to identify and manage these unusual toxidromes. Patient history may be especially challenging in this population as they may be reluctant to acknowledge their PED use. This review covers some of the non-steroid options which are commonly used by athletes and weightlifters of both amateur and professional status.

STIMULANTS
Athletes use stimulants due to perceived benefits such as increased energy, stamina, muscle strength, and fat loss. One stimulant, ephedrine, acts on the central nervous system by increasing the release of noradrenaline as well as stimulating alpha and beta receptors. Through these effects, it increases peripheral vasoconstriction which leads to increased blood pressure. It also increases heart rate and cardiac output. Ephedrine can improve cognitive and physical performance,2 as well as cause people to feel anxious, high, or stimulated.3 Ephedrine has been used medically for asthma and allergies due to its decongestant properties and effect as a bronchial smooth muscle relaxer. Other stimulants of abuse include synephrine and caffeine.

Presentation. Ephedrine is similar in structure to methamphetamine and can present acutely with a sympathomimetic toxidrome. However, the effects of ephedrine are much less potent and longer acting than amphetamines. Side effects of ephedrine include anxiety, tremors, psychosis, irritability, headache, and dizziness. Overdose can also cause confusion, hallucinations, convulsions, and difficulty with respiration. The most serious potential signs and symptoms of overdose include rapid, irregular heartbeat and significantly elevated blood pressure. There is at least one documented case of acute myocardial infarction in a young patient with no cardiac risk factors who was taking an ephedrine product.4 Another study reported a patient who used ephedrine chronically and developed pulmonary edema, congestive heart failure, and myocardial necrosis. Five years after stopping ephedrine, the patient was symptom free with improvement in previously reduced left ventricular ejection fraction.5 Adverse reactions have been documented when ephedra is taken in doses greater than 32 mg/day.6

Synephrine increases metabolism and energy expenditure,7 but does not lead to weight loss.8 A study of adverse effects in humans revealed that synephrine did not significantly change serum chemistries, urinalysis, blood cell counts, blood pressure, heart rate, or EKG data.7 There is one study that reported a patient taking an herbal supplement which consisted of synephrine, caffeine, and guarana who presented to the emergency department with headaches and a blood pressure of 234/130. The authors utilized the Naranjo Adverse Drug Reaction Probability Scale to suggest that an adverse drug reaction was the probable cause.9

Caffeine is a methylxanthine, which is a pharmaceutical class with mild stimulant and bronchodilator effects and guarana is an herb which contains caffeine. One important distinction related to caffeine is that it is not an adrenergic stimulant, but rather it acts on adenosine receptors which inhibits drowsiness. From the perspective of the emergency department provider, caffeine still presents similar to other stimulants and is managed similarly.

Diagnosis. The diagnosis is primarily clinical. Both ephedrine and synephrine may cause a positive amphetamine result on a urine drug screen because of their similar chemical structures.10 Testing for ephedrine and synephrine specifically is not routinely available in the ED.

Treatment.  In general, patients presenting with a stimulant or sympathomimetic toxidrome should be treated with benzodiazepines. In patients presenting with seizures, benzodiazepines remain the drug of choice. In general, benzodiazepine administration should be titrated to stabilize vital signs and mental status. In rare, critical cases, phentolamine sulfate 5 mg IV or 100 mg po should be considered and dexamethasone can be administered for life threatening hyperpyrexia. Early consultation with a medical toxicologist and/or poison center (1-800-222-1222) is recommended when managing these patients.

BETA 2 AGONISTS
While beta 2 agonists have well documented utility in the treatment of asthma and COPD, there is also potential for abuse of these agents. Beta agonists have shown benefits for athletes such as increased protein turnover in skeletal muscle after resistance training11 and increase in lean body mass.12

Presentation. Side effects of beta 2 agonists include tremors, anxiety, and palpitations. Tremor has been correlated with hypokalemia, so evaluating and correcting potassium is recommended.13

Diagnosis. The diagnosis is primarily clinical. These substances are detected in the urine via ELISA, although testing for beta agonists is not readily available in most emergency departments.

Treatment. Benzodiazepines and beta blockers may be used to treat overdose symptoms in the acute setting if heart rate and blood pressure can tolerate it. Early consultation with a medical toxicologist and/or poison center (1-800-222-1222) is recommended when managing these patients.

MELDONIUM
Meldonium is a substance used by athletes because it has been proven to improve exercise tolerance14 and rehabilitation after exercise.15 Meldonium acts by interfering with L-carnitine metabolism via inhibiting GBB hydroxylase. This results in increased ATP generation, increased glucose consumption, and protects the mitochondria from free fatty acid overload. Meldonium also has beneficial effects on memory and neuroinflammation. In rat studies it has been shown to reduce glycated hemoglobin, increase glucose tolerance, and protect against cardiac ischemia. Meldonium is approved for use in some European countries for stable angina and in others for bronchitis or asthma.

Presentation. Side effects of meldonium are not well described and there is no clear clinical toxidrome. Two side effects listed on the drug label include tachycardia and reduction in blood glucose.16

Diagnosis. The diagnosis is based primarily on history of present illness as there are no clear clinical or laboratory indicators. Testing for meldonium is not readily available in most emergency departments.

Treatment. There is no known antidote for meldonium. Tachycardia can be treated with benzodiazepines and rate controlling agents, while blood glucose can be managed with glucagon or carbohydrate rich food and drink. Early consultation with a medical toxicologist and/or poison center (1-800-222-1222) is recommended when managing these patients.

CREATINE
Creatine has long been used by athletes and weightlifters because it increases strength and power in high intensity exercises over a short duration of time and it also increases lean body mass.17 Creatine is available over the counter and is a legal substance, but it is abused by athletes who take amounts greater than the recommended dose or for prolonged periods of time. Short term creatine supplementation increases blood levels of phosphocreatine, which is used to increase ATP production by cells with high energy requirements.18

Presentation. Some side effects of creatine are due to its osmotic effect, which decreases urinary volume and causes urinary retention. This can lead to increased risk for muscle cramps, heat-related illness, and dehydration.19 One of the more serious side effects include an increased risk for compartment syndrome due to its osmotic effects. There has also been a case report of acute hepatotoxicity in a patient who took creatine above the recommended dose. There is no standard dose of creatine, but 0.07 g/kg of body weight has been suggested in the literature.20

Diagnosis. The diagnosis is primarily clinical. The physician should be particularly attentive to renal function, liver function, and electrolyte disturbances and should perform a thorough musculoskeletal exam. Testing for creatine is not commonly available in the ED.    

Treatment. There is no antidote for creatine overdose. Adverse effects of the substance can be treated symptomatically. If there is concern for urinary retention, a bladder scan and straight catheterization should be performed as indicated. Electrolytes and liver profile should be monitored in patients suspected of creatine overdose. If there is hepatotoxicity, the main treatment is to stop the use of creatine. Caution should also be utilized when using medications which are metabolized via the liver. Early consultation with a medical toxicologist and/or poison center (1-800-222-1222) is recommended when managing these patients.

GAMMA HYDROXYBUTYRATE (GHB)
GHB may be used for performance enhancing reasons because it is believed to improve exercise performance and muscle mass. There is evidence to support that GHB increases growth hormone concentration without onset of sleep.21 GHB acts by binding to the GABA-B receptor to cause CNS depression.22

Presentation. Patients with GHB overdose or abuse will typically present to the emergency department with CNS and respiratory depression. Other side effects of GHB can include seizures, hypotension, amnesia, aggressiveness, hypotonia, hallucinations, and dizziness.

Diagnosis. GHB can be detected in the hair for months after use, but for emergency department purposes, it can be detected in the urine within 12 hours of ingestion.23

Treatment. There is no reversal agent available for GHB. Patients with GHB toxicity should be watched closely and treated symptomatically. Some GHB intoxicated patients may require mechanical ventilation or vasopressors depending on severity of respiratory and cardiovascular depression. Patients might recover within 4-6 hours while still in the emergency department. Early consultation with a medical toxicologist and/or poison center (1-800-222-1222) is recommended when managing these patients.    

CALCIUM CHANNEL BLOCKERS and BETA BLOCKERS
Calcium Channel Blockers (CCBs) and Beta Blockers (BBs) may be abused by athletes who participate in sports where a slow heart rate is beneficial, such as archery.

Presentation. Both CCBs and BBs can cause EKG changes such as QT prolongation, first degree AV block, and bundle branch block. Mild side effects of CCBs include peripheral edema and elevated blood sugar. Overdose can lead to shock, acute kidney injury, and there have been rare case reports of death due to CCB overdose.24,25 Common side effects of BBs include bronchospasm, dyspnea, diarrhea, nausea, bradycardia, hypotension, sexual dysfunction, hypoglycemia, and hypokalemia. Seizures are another, more serious, adverse effect of beta blocker toxicity.        

Diagnosis. The diagnosis is primarily clinical. Testing for CCBs and BBs is not commonly available in the ED.

Treatment. Treatment is guided by the suspected degree of toxicity. If CCB or BB toxicity is suspected, then point-of-care blood glucose, serum electrolytes, and serial EKGs should be monitored. If the patient presents to the ED within 1 hour of overdose ingestion, activated charcoal is recommended for both CCBs and BBs if no concern for aspiration exists.26 Multi-dose activated charcoal is a reasonable option in patients ingesting sustained release preparations if the airway is stable or protected and their gastrointestinal tract is intact. In cases of extended release formulations, delayed administration of activated charcoal and/or whole-bowel irrigation may be of benefit if no contraindications are present. Orogastric lavage may be considered in patients with significant toxicity with a protected airway. For both CCBs and BBs, it is recommended to start with atropine (if needed) and then proceed to IV glucagon (ideally should be given with an antiemetic), IV calcium gluconate, IV high-dose insulin therapy with glucose (hyperinsulinemia-euglycemia therapy), and isotonic fluids. Catecholamine vasopressors and phosphodiesterase inhibitors may also be utilized if initial treatments fail. In severe refractory cases, lipid emulsion therapy may be an option. Other management considerations for BBs include sodium bicarbonate if the patient has QRS widening or magnesium sulfate if there is QTc prolongation. Unless mild, most patients with BB or CCB overdose will require admission to the hospital. Early consultation with a medical toxicologist and/or poison center (1-800-222-1222) is recommended when managing these patients.

CANNABINOIDS

Cannabis has well-documented recreational use, but athletes may also use the substance as a performance enhancer to reduce pain and anxiety. Additionally, cannabis increases focus and propensity to take risks, which can be of benefit in certain sports. However, one review of 15 studies found that it does not  improve strength or aerobic exercise tolerance.27 Cannabinoids work as CB1 and CB2 receptor agonists, which are found in the brain and peripheral tissue, respectively.28

Presentation. Side effects of cannabinoids include cardiac and respiratory depression as well as impaired attention, anxiety, panic, and impaired memory. One common presentation is cyclic vomiting syndrome or cannabis hyperemesis syndrome. Patients with this condition have acute episodes of vomiting for less than 1 week. Another side effect of cannabis is acute psychosis. Other serious side effects may be seen when marijuana is mixed or laced with other more dangerous drugs.

Diagnosis. The diagnosis is often clinical and laboratory testing is unnecessary. THC, the active ingredient in cannabinoids, can be detected in several different ways--it can be measured in sweat, urine, blood, hair, and oral fluid. In the emergency department, cannabis can be tested in the urine. It is important that the emergency physician consider synthetic cannabinoids or cannabinoids laced with other drugs of abuse.

Treatment. Treatment of cannabis intoxication is supportive. If patients have been vomiting, they can be treated with IV fluids, electrolyte replacement as indicated, and antiemetics. For patients experiencing cannabis hyperemesis syndrome, hot baths have shown therapeutic benefit and have more supporting evidence than pharmaceutical antiemetics. There is no antidote for cannabis intoxication.

DIURETICS (MASKING AGENTS)
Masking agents may be used by athletes in an attempt to avoid detection of PED use. The most common masking agent is a diuretic. There are varying mechanisms depending on the type of diuretic, but all diuretics dilute the urine by increasing water loss in the urine. This is beneficial to athletes using PEDs because diluted urine leads to lower concentration of the banned substance. Ideally for the athlete, the concentration of the illegal substance will not be detected or will be under the legal limit as a result of the dilution. In some sports, diuresis may be beneficial for weight loss such as in wrestling or mixed martial arts.

Presentation. Abuse of diuretics can lead to hypotension and electrolyte imbalances such as hypomagnesemia, hypokalemia, hyperglycemia, and hyperuricemia, which may lead to gout.

Most severely, diuretic abuse can lead to severe hyponatremia, central pontine myelinolysis, and renal injury.29

Diagnosis. The diagnosis is primarily clinical. Diuretics can be tested via the urine, although this test is not commonly available in the ED.

Treatment. There is no antidote available and diuretic toxicity should be treated symptomatically. If patients present with concern for diuretic toxicity, then blood pressure, serum electrolytes, and EKG should be monitored closely. If sodium is abnormal, it should be corrected slowly with a goal change in sodium of no more than 6-8 mEq in 24 hours.

Conclusion
There are a wide variety of PED options for athletes beyond the classically considered androgenic hormones. The incidence of these patients presenting to the emergency department is not well studied, but is likely rare. However, patients may not volunteer their drugs of abuse and the clinical toxidromes can be challenging to diagnose and manage in the uncooperative patient. In many cases, the emergency medicine physician may not know the drugs of abuse at the time of presentation. This review serves to describe some of the non-steroidal performance enhancing drugs of abuse that may present to the emergency department setting and potential challenges in diagnosis and management. In general, early consultation with a medical toxicologist and/or poison center (1-800-222-1222) is recommended when treating these patients.

References
1. Pope HG, Wood RI, Rogol A, Nyberg F, Bowers L, Bhasin S. Adverse Health Consequences of Performance-Enhancing Drugs: An Endocrine Society Scientific Statement. Endocr Rev. 2014;35(3):341-375.
2. Williams AD, Cribb PJ, Cooke MB, Hayes A. The effect of ephedra and caffeine on maximal strength and power in resistance-trained athletes. J Strength Cond Res. 2008;22(2):464-470.
3. Chait LD. Factors influencing the reinforcing and subjective effects of ephedrine in humans. Psychopharmacology (Berl). 1994;113(3-4):381-387.
4. Forte RY, Precoma-Neto D, Chiminacio Neto N, Maia F, Faria-Neto JR. Myocardial infarction associated with the use of a dietary supplement rich in ephedrine in a young athlete. Arq Brassileiro Cardiol. 2006;87(5):e179-e181.
5. Martinez-Quintana E, Rodriguez-Gonzalez F, Cuba-Herrera J. Myocardial necrosis and severe biventricular dysfunction in the context of chronic ephedrine abuse. [Article in Spanish.] Adicciones. 2010;22(1):25-28.
6. Andraws R, Chawla P, Brown DL. Cardiovascular effects of Ephedra alkaloids: A comprehensive review. Prog Cardiovasc Dis. 2005;47(4):217-225.
7. Stohs SJ, Preuss HG, Shara M. A review of the human clinical studies involving Citrus aurantium (bitter orange) extract and its primary protoalkaloid p-synephrine. Int J Med Sci. 2012;9(7):527-538.
8. Manore MM. Dietary supplements for improving body composition and reducing body weight: where is the evidence? Int J Sport Nutr Exerc Metab. 2012;22(2):139-154.
9. Moaddeb J, Tofade TS, Bevins MB. Hypertensive Urgency Associated with Xenadrine EFX Use. J Pharm Pract. 2011. [Epub ahead of print.]
10. Levisky JA, Karch SB, Bowerman DL, Jenkins WW, Johnson DG, Davies D. False-positive RIA for methamphetamine following ingestion of an Ephedra-derived herbal product. J Anal Toxicol. 2003;27(2):123-124.
11. Hostrup M, Reitelseder S, Jessen S, et al. Beta2-adrenoceptor agonist salbutamol increases protein turnover rates and alters signaling in skeletal muscle after resistance exercise in young men. J Physiol. 2018;596(17):4121-4139.
12. Jessen S, Onslev J, Lemminger A, Backer V, Bangsbo J, Hostrup M. Hypertrophic effect of inhaled beta2-agonist with and without concurrent exercise training: A randomized controlled trial. Scand J Med Sci Sport. 2018;28(10):2114-2122.
13. Cazzola M, Matera MG. Tremor and β(2)-adrenergic agents: Is it a real clinical problem? Pulm Pharmacol Ther. 2012;25(1):4-10.
14. Ivanova S, Ivanov K, Ivanov V, Peteva G. Meldonium, the ‘novel’ doping in professional sport. Oxid Commun. 2017;40(2):986-992.
15. Kakhabrishvili Z, Chabashvili N, Akhalkatsi V, Skhirtladze T, Chutkerashvili T. Mildronate effect on physical working capacity among highly qualified judokas. Ann Biomed Res Edu. 2002, 2, 551.
16. Knych HK, Stanley SD, McKemie DS, et al. Pharmacokinetics and pharmacodynamics of meldonium in exercised thoroughbred horses. Drug Test Anal. 2017;9(9):1392-1399.
17. Greydanus DE, Patel DR. Sports Doping in the Adolescent: The Faustian Conundrum of Hors De Combat. Pediatr Clin North Am. 2010;57(3):729-750.
18. Havenetidis K. The use of creatine supplements in the military. J R Army Med Corps. 2016;162(4):242-248.
19. Kim J, Lee J, Kim S, Yoon D, Kim J, Sung DJ. Role of creatine supplementation in exercise-induced muscle damage: A mini review. J Exerc Rehabil. 2015;11(5):244-250.
20. Butts J, Jacobs B, Silvis M. Creatine Use in Sports. Sports Health. 2018;10(1):31-34.
21. Brailsford AD, Bartlett C, Kicman AT, Cowan DA. Increases in Serum Growth Hormone Concentrations Associated with GHB Administration. J Anal Toxicol. 2017;41(1):54-59.
22. Busardo FP, Jones AW. GHB Pharmacology and toxicology: acute intoxication, concentrations in blood and urine in forensic cases and treatment of the withdrawal syndrome. Curr Neuropharmacol. 2015;13(1):47-70.
23. Kapoor P, Deshmukh R, Kukreja I. GHB acid: A rage or reprive. J Adv Pharm Technol Res. 2013;4(4):173-178.
24. Kumar S, Thakur D, Gupta RK, Sharma A. Unresponsive shock due to amlodipine overdose: An unexpected cause. J Cardiovasc Thorac Res. 2018;10(4):246-247.
25. Sklerov JH, Levine B, Ingwersen KM, Aronica-Pollack PA, Fowler D. Two cases of fatal amlodipine overdose. J Anal Toxicol. 2006;30(5):346-351.
26. Palatnick W, Jelic T. Emergency department management of calcium-channel blocker, b
27. Kennedy MC. Cannabis: Exercise performa
28. Cabral GA, Griffin-Thomas L. Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation. Expert Rev Mol Med. 2009;11:e3.
29. Copeland PM. Diuretic abuse and central pontine myelinolysis. In: Psychotherapy Psychosomatics. 1989;52(103)101-105.

Related Articles

Do Sports Have an Effect on Gang Violence?

Can participation in sports programs reduce the chances of delinquent behavior in school-age children? A sports medicine fellow weighs in.

GHB: A Forgotten Foe Rises

The classic story of GHB intoxication you may see in your ED — “you are about to intubate a comatose patient and they wake up suddenly.” What next?
CHAT NOW
CHAT OFFLINE