This famous quote by the evil sith Darth Maul in Star Wars may have well been the tactic used by the FDA when they banned the sale of ephedra in April of 2004. The FDA stated that the supplement presents an unreasonable risk to public safety, as it increases the chances of illness or injury. But one year later in April 2005, a federal judge in Utah overruled the ban. After examining the literature, the Court determined that it had not proved that a daily dosage of 10 milligrams or less of ephedra alkaloids present a significant risk of illness or injury.
In the journal of Archives of Toxicology this month 79: 330-340 (2005), listed was a research study entitled, “Short-term and long-term in vivo exposure to an ephedra and caffeine-containing metabolic nutrition system does not induce cardio toxicity in B6C3F1 mice.” Of course you won’t read about it in any of the major newspapers. The study looked at mice for one year, and its primary purpose was to compare normal and high dosages (dosages ranging from 1 to 10 times the human dose) of the supplement and examine the affect on the heart (1). The two groups were as follows: one group received a multi-nutrient system containing vitamins, minerals, omega-3 fatty acids, and phytochemical extracts of citrus, ephedrine, guarana, ginko, green tea, and octium. The control group received nothing. The animals given thermogenic stack consumed more food and were leaner and more active compared to control mice.
Results of the study concluded that after one year of using the caffeine/ephedrine supplement, neither the low dose (1X) nor high dose (10X) produced any adverse cardiovascular effects in the mice. In addition, at the end of the study (although there were fluctuations in cardio-sensitive enzyme activity), no major changes in CK (leakage enzyme present in high concentrations in the heart), LDH (enzyme found in heart, lungs, and blood), and AST (enzyme found in heart and liver) enzymes indicative of cardiovascular damage was observed.
The above study demonstrates that when used in moderation and for prolonged periods of time in healthy animals, ephedra is non-toxic even at high dosages. Another important consideration of the study was that as the dosage of caffeine and ephedrine were increased, so were all the other ingredients in the formula (i.e. vitamins, minerals, omega-3 fatty acids, and phytochemical extracts of ginko, green tea, and octium). This may have produced a cardio-protective affect. This is one of many studies reporting that ephedrine is a safe drug for healthy individuals.
For example, Greenway et al. (2) documented that caffeine and ephedrine has a long history of safe, non-prescription use. The adverse events accompanying acute dosing are mild and transient. Adverse events with caffeine and ephedrine reach and remain at placebo levels after 4–12 weeks of continuous treatment. Dr. Greenway an obesity expert also concluded that, “The benefits of caffeine and ephedrine in treating obesity appear to outweigh the small associated risks.” In addition, ephedrine and caffeine have been prescribed to almost 10 million people in Denmark as an aid to weight loss (4).
This is contrary to what the FDA has the general public believing, that a single dose of ephedrine and caffeine is going to cause a person to go into sudden cardiac arrest! This is a typical national news headline that appeared a short time ago, “Ephedrine and unheralded sudden cardiac death.” The study involved giving dogs a single dose of an over the counter ephedrine supplement. The dogs were separated into two groups: healthy dogs and dogs representing animal models of ischemic heart disease. In ischemic heart disease the blood supply to the heart becomes constricted causing damage to the heart muscle. The ischemic heart diseased dogs had surgical blockages placed in their arteries to their hearts to mimic cardiovascular disease. When ephedrine was given to healthy animals it did not raise their heart rates, either at rest or during exercise. Of the 15 dogs with a heart block given ephedrine, nine had increased ventricular arrhythmias (a dangerous and wild beating of the heart) and four had ventricular fibrillation (an extreme arrhythmia where the heart can no longer pump). One of the four animals with VF could not be resuscitated (3).
The author concluded that ephedrine overstimulates the sympathetic nervous systemic resulting in electrical instability in the heart, and provides evidence that the recent ban of ephedrine was fully justified. The study should have concluded that ephedrine is safe for healthy individuals but dangerous if you have an underlying heart or cardiovascular related disorder.
The conclusions are obvious: If you have a underlying heart condition or have a family history of heart disease, do not take caffeine/ephedrine or any thermogenic supplement without your doctor’s approval! So let’s take a brief look at the pharmacology and safety of ephedrine.
Ephedrine Alone and Ephedrine plus Caffeine
Ephedra contains several alkaloids including ephedrine, pseudoephedrine, norephedrine, methylephedrine, methylpseudoephedrine, and norpseudoephedrine. Ephedrine is rapidly absorbed from the GI tract; and peak serum levels vary between two and four hours. A common misconception about ephedrine is that it causes high blood pressure; this is only partially true, since ephedrine can temporarily increase blood pressure, before it rapidly returns to normal.
For example, one study monitored heart rate and blood pressure responses for eight hours in eight subjects receiving .25, .5, or 1.0 mg/kg of ephedrine sulfate. There was a dose dependent response with ephedrine dose and heart rate. This is due to ephedrine having a high binding affinity for ?1 receptors located on the heart. Interestingly, systolic blood pressure has a tolerance effect to ephedrine, basically blood pressure increases acutely by returns to normal fairly rapidly. This may be due to ephedrine binding to ?2 receptors that has an effect on vasodilation. The elevation in systolic blood pressure induced by ephedrine was nearly abolished by the acute compensatory mechanisms (i.e. body maintaining homeostasis), and suggests changes in systolic blood pressure in response to ephedrine is small (5). Similar findings have been reported as 25-50 milligrams of ephedrine produced only moderate effects on blood pressure (6).
In another study, ephedrine alone increased heart rate but did not affect systolic blood pressure, while caffeine increased systolic blood pressure but did not raise heart rate. Nevertheless, when caffeine and ephedrine are combined, the combination raises heart rate and blood pressure significantly (7).
Another interesting fact is that bitter orange (citrus aurantium) has similar pharmaceutical properties to ma huang. Bitter orange has been the replacement for ephedra in many thermogenic products. Bitter orange contains the adrenergic amines synephrine, octamine, hordenine, tyramine, and N-methyltyramine. The predominant constituents are synephrine and octapamine, which are structurally similar to norepinephrine. Synephrine is chemically similar to ephedrine though not as potent. Both ephedrine and synephrine affect alpha-adrenergic receptors and, to a lesser extent, beta-adrenergic receptors.
Other alkaloids, e.g., octopamine, in bitter orange have similar actions. Nevertheless, synephrine reportedly enters into, and is less active on the CNS than ephedrine (8). Therefore, synephrine is believed to have fewer adverse effects on the beta 1 and 2 receptors than ephedrine. Similar to ephedrine, bitter orange when ingested alone in modest dosages increased heart rate but has no effect on blood pressure. However, when combined with caffeine, it results in significant increases in both systolic and diastolic blood pressure responses (11).
Adverse Effects of Thermogenics
All thermogenic products clearly state that they are not recommended for those patients with high blood pressure, cardiovascular disease, diabetes, ect. Ephedrine causes increases in myocardial oxygen consumption by increasing heart rate, heart contraction, and vasoconstricts arteries, while potentially diminishing blood flow to the heart. Most thermogenics contain a combination of caffeine/ and or ephedrine or a substitute as synephrine.
It has been shown that both caffeine and ephedrine are weak thermogenics when administered separately but when administered together they have synergistic effects (18). In addition, caffeine is an adenosine antagonist, which constricts blood vessels and can increase blood pressure, especially in people prone to hypertension. In the Tex Heart Journal Inst . J 2005; 3:74-7, a case report was documented, where a 24- year old bodybuilder experiences an acute heart attack secondary to having a blood clot after taking a caffeine/ ephedrine based supplement continuously for one year. First off, the man had a genetic heart condition called ‘a right bundle branch block’. When a person has a right bundle branch block, electrical impulses are prevented from entering the right side of the heart’s conduction system. Many people have right bundle branch blocks and they commonly occur in normal, healthy individuals – it could have been the caffeine/ ephedrine stack that exacerbated his underlying cardiac condition.
What was also interesting is that the report did not mention anything about the use of anabolic steroids. It is well known that high dosages of anabolic steroids increase coagulation factors in the blood, increasing the susceptibility of blood clots, resulting in the hypercoaguability of blood. There appears to be an increased production of thromboxane A 2 and decreased production of prostaglandins with anabolic steroid use which promotes platelet production and aggregation (17).
It seems that people with a genetic susceptibility to cardiovascular disease are the one’s that are affected the most by themogenics. Kalman et al. (17) found no evidence of cardiovascular effects in overweight healthy subjects. In that study, overweight subjects were administered a caffeine and ephedra for 14 days. At the end of 14 days, there were no significant effects on any cardiovascular parameter measured which included: heart rate, systolic and diastolic blood pressure, heart chamber size, perceived sleep quality, ect. I think an important aspect of the study was that the dosage was gradually increased from one capsule twice a day for the first seven days, and then two capsules twice a day thereafter.
It could be speculated that many of the adverse cardiovascular effects of thermogenics could be minimized by using a gradual pyramiding of a low dose to a higher dose in people who have never taken thermogenics. Additionally, Dr. Greenway at Pennington Biomedical Research Center documented that herbal caffeine and ephedra caused no adverse effects noted from physical examination, electrocardiography, blood tests, or urinalysis of toxicology during a six month course of treatment (19).
As mentioned previously, ephedrine taken by itself will increase heart rate, whereas blood pressure responses are variable; mostly showing an acute increase in blood pressure but also a rapid return to normal levels. Ephedrine has been shown to delay heart rest between contractions or QTc. When you are hooked up to an electrocardiogram or ECG, it measures the electrical impulses produced by your heart. The QTc interval duration is a measure of the time intervals that occur during the electrical impulses that cause the heart to contract. Longer intervals can increase the risk of developing arrhythmia, or abnormal heart rhythms. When subjects took a single dose of ephedrine/caffeine containing products, 53 percent of participants had QTc intervals increases.
If a person had an underlying heart condition, this could potentially lead to a serious adverse event. When examining the study, I wondered whether it was caffeine causing the increase in QT interval or ephedrine? Adrenaline, which is a close cousin to ephedra, can also increase QTc interval (14). Caffeine on the other hand does not. For example, in one study participants were randomly designated to receive a placebo or 400 mg of caffeine on various days. Moderate caffeine consumption had no effect on changing QTc in healthy individuals (13). Interestingly, a 2005 study published in the journal of Pharmacotherapy reported that bitter orange; a close relative of ma huang had no effect on QTc interval or systolic blood pressure when administered by itself (9).
A possible way to alleviate these symptoms is to up potassium rich foods. Ephedrine based products have been shown to decrease serum potassium levels (20). Decreased potassium levels or hypokalemia has been known to prolong the relaxation phase of the heart, which has been shown to significantly induce arrhythmias in the heart. In addition, the people that are most likely to be potassium deficient are people who are on a strict diet or fasting, such as bodybuilders; if these people are also using ephedrine based products this could exacerbate the potassium deficiency. Generally, for healthy individuals this would not be much of a concern but for those patients with an underlying cardiovascular problem this could mean serious health consequences. Other drugs which have been associated with QTc prolongation include antimicrobials, histamine antagonists, diuretics, antidepressants, antipsychotics, cardiovascular drugs, and GI agents (15).
Ephedrine/caffeine at low dosages has mild affects on the cardiovascular system, but in high dosages can cause damage to the heart, especially as one ages (25). For example, rats that were considered young (seven weeks old) and old (14 weeks old) were given a small and large dosage of caffeine (30 mg/kg) and ephedrine (25 mg/kg) to examine cardiovascular effects. Remember a typical dose in most supplements is ~20 mg of ephedrine and 200 mg of caffeine; or .3mg/kg of body weight for ephedra and 3 mg/ kg for caffeine. The dosage studied would be roughly equivalent to 5 to -10 fold higher for caffeine and 10- 100 fold higher for ephedrine. No deaths were experienced in either the young or old rats when low dosages were administered. When large dosages were administered there were no deaths experienced in the young rats but in the older rats 57% keeled over and died! The researchers had no explanation as to why the younger rats survived compared to the older rats, but did document that a majority of the case studies in which adverse events for caffeine/ ephedrine were reported could be age related.
Psychotropic Stimulating Properties
Caffeine and ephedrine and their related compounds are lipophilic and cross the blood brain barrier. Its physical properties that account for their effects on the central nervous system, which include appetite suppression, anxiety, increased energy; and some people even experience mild euphoria. A recent study reported that both ephedrine and bitter orange both lacked having a significant effect on mood and emotional responses by themselves, however when combined with caffeine, subjects experience significant psychoactive effects such as ‘feelings of alertness’ and ‘euphoria’. (11).
It seems that caffeine may evoke more of a ‘buzz’ than ephedrine when administered alone. For example, Haller et al. (7) reported that ephedrine alone had no effect on any mood response; caffeine produced twice as many significant mood and physical responses as ephedrine; however caffeine and ephedrine was the only combination that made users feel ‘high’. All thermogenics recommend periodic discontinuation of their products to allow receptor upregulation, but this may prove difficult due to the pleasurable feeling produced by the caffeine and ephedrine. A 1998 study found that when competitive female weightlifters were surveyed, 19% displayed signs of ephedrine dependence (23). It could be due to caffeine/ ephedrine affecting the brain’s reward system, increasing dopamine, which causes sensations of euphoria. After a single combination of caffeine/ ephedrine when subjects were asked to describe their emotional feelings, “energetic” and “good drug effect” were common responses (24).
A huge point that needs to be stated is that to the author’s knowledge no clinical research trial has ever reported any major cardiovascular adverse events as stoke, myocardial infarction, ect. in association with the use of ephedra alkaloids for weight loss in healthy adults. The bulk of adverse reactions in hospital rooms have come from individual case reports!! Research has revealed that using higher than the recommended dosages of thermogenics can lead to undesirable cardiovascular effects, yet low dosages seems to be safe. One meta analysis concluded that the risk of having a major adverse event from ephedrine use is about 1 per thousand (26). The people that are most likely to suffer severe side effects of ephedrine/caffeine based products are those with a history of hypertension, atherosclerosis, insulin resistance, or conditions that are strongly associated with obesity.
A concluding remark reported in a research paper about ephedrine and caffeine interactions in the journal of Clinical Pharmacology and Therapeutics stated, “The consequences of caffeine and ephedrine are minimal in healthy people, however the increased sympathetic tone induced by ephedrine and caffeine could exacerbate hypertension and produce myocardial ischemia in induced cardiac arrhythmias in individuals with coronary heart disease.” To date there have been about 100 or more ephedrine related deaths to date. Thousands of people die each year in the United States from complications related to taking aspirin and other NSAIDs. In addition, nicotine, alcohol and painkillers kill many people, if not more. There is no ban on cigarettes, even though, according to the American Cancer Society, there are 440,000 deaths in the United States each year due to tobacco use.
As a precautionary measure, a routine ECG at a health clinic or doctors might be of benefit to any person considering the use of thermogenics or have used thermogenics for a long period of time. ECG’s are inexpensive and noninvasive and can detect if there are any cardiac abnormalities, and are a valuable assessment for any routine physical. In addition, taking fish oils might be of benefit to anyone taking thermogenics as they have been shown to reduce the risk of cardiac events as arrhythmias, stroke and thrombosis (27). It might not be in your best interest to use thermogenics year round without a taking a break and giving your receptors a chance to upregulate from long-term use. Any therapy that chronically stimulates the sympathetic nervous system and diminished parasympathetic activity will increase the risk of cardiovascular events. Diseases such as congestive heart failure and hypertension are often characterized by sympathetic over-stimulation; pharmacological treatment usually involves drugs that reduce sympathetic tone.
A useful approach may be to switch to a switch to an alternative thermogenic stack for a few weeks. A recent study in the European Journal of Clinical Nutrition reported that a combination of green tea, capsaicin, tyrosine, and calcium stimulated an increase in energy expenditure by ~48 kcal/day or 2%, without raising heart rate or blood pressure (21). It is not as thermogenic as caffeine/ephedrine based products which have been shown to elevate resting energy expenditure ~10% or 120 kcals/day (22), but hey that’s what the off-season is for.
1. Ray S, Phadke S, Patel C, Hackman RM, Stohs S. Short-term and long-term in vivo exposure to an ephedra- and caffeine-containing metabolic nutrition system does not induce cardiotoxicity in B6C3F1 mice. Arch Toxicol. 2005 Jun;79(6):330-40
2. Greenway FL. The safety and efficacy of pharmaceutical and herbal caffeine and ephedrine use as a weight loss agent. Obes Rev. 2001 Aug;2(3):199-211.
3. Adamson PB, Suarez J, Ellis E, Kanaly T, Vanoli E. Ephedrine increases ventricular arrhythmias in conscious dogs after myocardial infarction. J Am Coll Cardiol. 2004 Oct 19;44(8):1675-8.
4. Breum L, Pedersen JK, Ahlstrom F, Frimodt-Moller J. Comparison of an ephedrine/caffeine combination and dexfenfluramine in the treatment of obesity. A double-blind multi-centre trial in general practice.
Int J Obes Relat Metab Disord. 1994 Feb;18(2):99-103.
5. Persky AM, Berry NS, Pollack GM, Brouwer KL. Modelling the cardiovascular effects of ephedrine. Br J Clin Pharmacol. 2004 May;57(5):552-62.
6. White LM, Gardner SF, Gurley BJ, Marx MA, Wang PL, Estes M. Pharmacokinetics and cardiovascular effects of ma-huang (Ephedra sinica) in normotensive adults. J Clin Pharmacol. 1997 Feb;37(2):116-22.
7. Haller CA, Jacob P 3rd, Benowitz NL. Enhanced stimulant and metabolic effects of combined ephedrine and caffeine. Clin Pharmacol Ther. 2004 Apr;75(4):259-73.
8. HG, DiFernando D, Bagchi M, Bagchi D. Citrus aurantium as a thermogenic, weight-reduction replacement for ephedra: an overview. J Med 2002;33(1-4):247-64.
9. Min B, Cios D, Kluger J, White CM. Absence of QTc-Interval-Prolonging or Hemodynamic Effects of a Single Dose of Bitter-Orange Extract in Healthy Subjects.Pharmacotherapy. 2005 Winter;25(12):1719-24.
10. Bui LT, Nguyen DT, Ambrose PJ. Blood Pressure and Heart Rate Effects Following a Single Dose of Bitter Orange (January). Ann Pharmacother. 2005 Nov 29.
11. Haller CA, Benowitz NL, Jacob P 3rd. Hemodynamic effects of ephedra-free weight-loss supplements in humans. Am J Med. 2005 Sep;118(9):998-1003.
12. Grzesk G, Polak G, Grabczewska Z, Kubica J. Myocardial infarction with normal coronary arteriogram: the role of ephedrine-like alkaloids. Med Sci Monit. 2004 Apr;10(4):CS15-21.
13. Ammar R, Song JC, Kluger J, White CM. Evaluation of electrocardiographic and hemodynamic effects of caffeine with acute dosing in healthy volunteers. Pharmacotherapy. 2001 Apr;21(4):437-42.
14. Lee S, Harris ND, Robinson RT, Yeoh L, Macdonald IA, Heller SR. Effects of adrenaline and potassium on QTc interval and QT dispersion in man.
Eur J Clin Invest. 2003 Feb;33(2):93-8.
15. Viskin S. Long QT syndromes and torsade de pointes. Lancet 1999;354:1625-33.
16. Sullivan ML, Martinez CM, Gennis P, Gallagher EJ. The cardiac toxicity of anabolic steroids. Prog Cardiovasc Dis. 1998 Jul-Aug;41(1):1-15.
17. Kalman DS. An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra-caffeine weight loss product in healthy overweight adults. Int J Obes Relat Metab Disord. 2004 Oct;28(10):1355-6.
18. Astrup A, Breum L, Toubro S, Hein P, Quaade F. The effect and safety of an ephedrine/caffeine compound compared to ephedrine, caffeine and placebo in obese subjects on an energy restricted diet. A double blind trial.
Int J Obes Relat Metab Disord. 1992 Apr;16(4):269-77.
19. Greenway FL, De Jonge L, Blanchard D, Frisard M, Smith SR. Effect of a dietary herbal supplement containing caffeine and ephedra on weight, metabolic rate, and body composition. Obes Res. 2004 Jul;12(7):1152-7.
20. Haller CA, Jacob P, Benowitz NL. Short-term metabolic and hemodynamic effects of ephedra and guarana combinations. Clin Pharmacol Ther. 2005 Jun;77(6):560-71.
21. Belza A, Jessen AB. Bioactive food stimulants of sympathetic activity: effect on 24-h energy expenditure and fat oxidation. Eur J Clin Nutr. 2005 Jun;59(6):733-41.
22. Vukovich MD, Schoorman R, Heilman C, Jacob P 3rd, Benowitz NL. Caffeine-herbal ephedra combination increases resting energy expenditure, heart rate and blood pressure. Clin Exp Pharmacol Physiol. 2005 Jan-Feb;32(1-2):47-53.
23. Gruber AJ, Pope HG Jr. Ephedrine abuse among 36 female weightlifters. Am J Addict. 1998 Fall;7(4):256-61.
24. Haller CA, Jacob P 3rd, Benowitz NL. Pharmacology of ephedra alkaloids and caffeine after single-dose dietary supplement use. Clin Pharmacol Ther. 2002 Jun;71(6):421-32.
25. Howden R, Hanlon PR, Petranka JG, Kleeberger S, Bucher J, Dunnick J, Nyska A, Murphy E. Ephedrine plus caffeine causes age-dependent cardiovascular responses in Fischer 344 rats. Am J Physiol Heart Circ Physiol. 2005 May;288(5):H2219-24.
26. Shekelle PG, Hardy ML, Morton SC, Maglione M, Mojica WA, Suttorp MJ, Rhodes SL, Jungvig L, Gagne J. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA. 2003 Mar 26;289(12):1537-45.
27. Geelen A, Brouwer IA, Schouten EG, Maan AC, Katan MB, Zock PL. Effects of n-3 fatty acids from fish on premature ventricular complexes and heart rate in humans. Am J Clin Nutr. 2005 Feb;81(2):416-20.