Here is a great article that I got on Ephedrine. It is long but has some good info in it. Great since summer is coming and I have seen an increase in the ECA questions.
Pain
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Effectiveness and associated health risks of herbal sources of ephedrine alkaloids when used as an aid in weight reduction
BY JAY MCCOMBS ([email protected]. Private forum - sorry no link.)
Department of Biology, Texas Christian University, Fort Worth, Texas
ABSTRACT
The purpose of this paper is to evaluate current research of the effectiveness of herbal products containing ephedrine alkaloids, examine possible health hazards associated with the use of these products, and assess the appropriateness of Food and Drug Administration (FDA) intervention in the sale and marketing of such supplements. Current legislation prevents the sale of synthetic ephedrine, so manufactures must seek forms they can market as herbal sources of ephedrine alkaloids. Most commonly, supplements contain the Chinese herb Ma Huang which is obtained from the dried stem of either Ephedra sinica, Ephedra equisetina, or Ephedra intermedia (White et al., 1997). The goal of this paper is to determine if herbal forms carry the same potency as a thermogenic antiobesity agent as does the synthetically obtained ephedrine. This paper also examines the claims of increased effectiveness of ephedrine when combined with caffeine and acetylsalicylic acid (ASA) as the ephedrine-caffeine-aspirin (ECA) stack. Often the two are present in their herbal forms guarana (Paullinia cupana) and white willow bark, as is the case in popular weight loss supplements such as Xenadrine and Hydroxycut. The paper also seeks to determine if increased risk of health hazards occur with the combination of other stimulants and drugs.
Key words: ephedrine; ephedra; ephedrine alkaloids; Ma Huang; weight loss; ECA stack.
CONTENTS
I.Introduction
II.Synthetic ephedrine versus herbal sources
(1)Pharmacokinetic aspects
(2)Pharmacological aspects
III.Ephedrine and weight reduction
(1)Ephedrine alone as a thermogenic
(2)The ephedrine-caffeine-aspirin stack
(a)Pharmacological aspects
(b)Evidence of increased efficacy for weight control
IV.Associated health risks
(1)Cardiovascular complications
(a)Cardiac complications
(b)Ischemic and hemorrhagic stroke
(2)CNS and behavioral effects
V.Conclusion
(1)Efficacy
(2)Safety
(3)FDA intervention
VI.References
I. INTRODUCTION
Ephedrine has been used for more than 5,000 years by the Chinese as an herbal remedy for hey fever and asthma; however, in recent years the herb has been embraced by Western circles as a thermogenic antiobesity agent and a recreational stimulant used for increased alertness or increased athletic performance. Ephedrine has established a rather notorious reputation for itself due to its intimate connection with several highly publicized instances of sudden death (Samenuk et al., 2002). Since Ma Huang (an herbal source of ephedrine alkaloids) is considered a supplement, it has not undergone rigorous Food and Drug Administration (FDA) testing to verify its effectiveness or safety. Fortunately, the substance has sparked considerable interest in the scientific and medical communities. Studies examining the effectiveness of synthetic ephedrine, herbal ephedrine, and combinations of herbal ephedrine and other herbs have all been well documented. The rise in the use of ephedrine products for weight control may be attributed to several factors including an increased trend of obesity in the population, the definitive linking of obesity to higher incidence of long term morbidity and increased rates of mortality, and the limited effectiveness of other conventional methods of weight reduction such as low calorie diet (Boozer et al., 2001).
Today, ephedrine-containing products marketed as weight control agents frequently contain an accompanying large dose of caffeine, frequently in the herbal form guarana (Paullinia cupana), and acetylsalicylic acid (ASA), generally found on the label as white willow bark. This combination is known in body building circles as the ephedrine-caffeine-aspirin (ECA) stack. The biochemical actions of these substances individually are all well understood (Battig, 1993) and the efficacy of this combination as a thermogenic agent has been thoroughly studied and the assessment of potential adverse reactions and side effects has been evaluated for over a decade (Astrup et al., 1992).
Ephedrine has been frequently maligned in press reports as a cause of acute cardiovascular complications, as having detrimental effects on the central nervous system, and as the acting agent in unexplained cases of sudden death. Most recently, these claims have surfaced in a study examining reports to the Adverse Reaction Monitoring System (ARMS) of the FDA (Samenuk et al., 2002). Other research on the efficacy of the herb also monitored participants’ perceptions of side effects both physically and emotionally and this information has been taken into account in this paper as well (Haller, Jacob & Benowitz, 2002).
II. Synthetic ephedrine versus herbal sources
Synthetic ephedrine hydrochloride is controlled by the FDA as an over the counter (OTC) drug and is allowed only for the treatment of congestion and as a bronchodilator. This means that synthetic ephedrine is unavailable for sale as a supplemental dietary aid. Consequently, supplement manufactures use the herb Ma Huang, which consists of extracts of the above ground plant parts of plants from the Ephedra family (Ephedra sinica, Ephedra equisetina, or Ephedra intermedia) as their source of ephedrine(White et al., 1997). The ephedrine alkaloids are (-)ephedrine, (+)psuedoephedrine,
(-)methylephedrine, (-)norephedrine, and (+)norspuedoephedrine (Gurley, 2000). Most frequently E. sinica is used due to its increased concentration of ephedrine and psuedoephedrine and lower levels of other potentially more dangerous ephedra alkaloids. The total alkaloid content of E.sinica is approximately 2% with ephedrine and psuedoephedrine accounting for 80% of total (Haller, Jacob & Benowitz, 2002). The analysis of products that listed Ma Huang as an active ingredient were found to contain on average 23.7 mg of alkaloids with 17.3 mg being ephedrine, 5.3 psuedoephedrine, and no significant concentration of other alkaloids. (Haller, Jacob & Benowitz, 2002). This is consistent with doses of pharmaceutical ephedrine used in previous weight loss studies (Astrup et al., 1992).
(1) Pharmacokinetic aspects
Before the pharmacological effects of ephedrine HCl and herbal forms may be examined, the pharmacokinetic profile of each must be investigated. Pharmacokinetics control the onset and intensity of pharmacological effects associated with ephedrine; therefore, the effects of herbal and synthetic forms may not be compared without first establishing and comparing the rates at which they enter the blood.
Herbal ephedrine may be taken in two forms: as a powdered herb or as a concentrated herbal extract. To test the rate at which a significant concentration of ephedrine reached the blood, serum concentration-time profiles were established by computer from serum samples taken at time 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, and 9 hours after ingestion of a powdered ma huang supplement. The absorption rate constant and tmax values were 0.49 h-1 and 3.9 hours respectively (White et al., 1997).
In a similar experiment performed by Gurley et al. (1998), the concentrated extract form of ma huang was administered to test participants. This experiment yielded an absorption rate constant of 1.36 h-1 and a tmax of 2.8 hours. This showed herbal ephedrine is absorbed more rapidly as a concentrated extract than as a powdered herb. This is significant for several reasons. First, the most common form of ma huang found in weight control supplements is from concentrated extracts. Second, when compared to pharmacokinetic profiles of pharmaceutical ephedrine, no appreciable differences were noted (Gurley et al., 1998).
(2) Pharmacological aspects
Pharmaceutical ephedrine is a sympathomimetic alkaloid drug with á-1, â-1, and â-2 adrenergic receptor agonist properties (White et al., 1997). Its effects are similar to those of epinephrine but less intense and having a longer duration. Its structure and central effects are similar to those of amphetamines but less pronounced (Battig, 1993; Wooltorton, 2002). As far as measurable cardiovascular affects, the most prevalent was on heart rate with an average increase of 11 beats per minute (bpm) (White et al., 1997). Other researchers examining the effects over a longer period of time reported no significant increase in heart rate (Pasquali & Casimirri, 1993). As expected, herbal ma huang has been shown to also cause increases in heart rate comparable to those of pharmaceutical-grade ephedrine ( Boozer et al., 2001). The reports of effects on blood pressure are variable, ranging from no change, to reduction(9 mmHg systolic and 7 mmHg diastolic), to elevation (7 mmHg systolic and 5 mmHg diastolic) in both systolic and diastolic blood pressure—even within the same study (Pasquali & Casimirri, 1993; White et al., 1997).
III. Ephedrine and weight reduction
Multiple studies on both animals and humans have demonstrated that â-adrenergic receptor agonist can aid in the reduction of body fat and in vitro studies in rat brown adipocytes have shown that ephedrine can also enhance tissue respiration (Pasquali & Casimirri, 1993). The chemical is termed a thermogenic because it can cause weight reduction by increasing energy expenditures rather than reducing food consumption as demonstrated in three double-blind cross over studies by Pasquali and Casimirri (1993). Subjects in the first study were selected based only on obesity (high body mass index (BMI)) and were then divided into three groups: a control given a placebo, one group given a dose of 75 mg of ephedrine per day, and another group given 150 mg of ephedrine per day. All groups were put on a diet of 4180-5016 Kj/day. All three groups showed reductions in body mass index; however, a significant difference was detected in groups given ephedrine. In the second study, subjects who had repeatedly shown an evident resistance to weight loss with conventional reduced-calorie dieting were selected. The experiment was repeated and weight loss was shown to be on average 2.41 kilograms while treated with ephedrine and 0.64 kilograms while using the placebo. The third experiment investigated a theory that â-adrenergic receptor agonist are capable of stimulating protein synthesis and increasing lean body mass. Subjects were selected only on the criteria of obesity (average BMI of 42.2). Subjects ate a very low calorie diet (VLCD) consisting of only 1965 kj/day for six weeks. During weeks 2-5 of the VLCD subjects were either given 50 mg of ephedrine three times daily or a placebo. While no difference in body weight loss was noticed, ephedrine treated groups demonstrated significantly lower levels of daily urinary nitrogen excretion and saw significantly improved nitrogen balance over untreated individuals.
(1) The ephedrine-caffeine-aspirin stack
Today, most supplements sold as thermogenic antiobesity agents contain ingredients to potentiate and enhance the effects of ephedrine. Most commonly, caffeine and aspirin are added. Together, this supplement is often called the ephedrine-caffeine-aspirin (ECA) stack. Obviously, the addition of other ingredients to a ma huang supplement will likely change its action. Research on the safety and efficacy of the ECA stack on humans started a decade ago and continues actively today (Astrup et al., 1992; Haller, Jacob & Benowitz, 2002).
(a) Pharmacological aspects
Caffeine is a well-studied CNS stimulant with known effects as a pressor agent through peripheral vasoconstriction through an á-adrenergic stimulation pathway. Evidence presented by Battig (1993) shows these effects are seen in doses starting at 200-300 milligrams daily (roughly the amount of caffeine in a cup of coffee) and may engender increases in blood pressure from 10-15 mmHg. Battig points out an interesting characteristic of the pressor effect. The effects of a mid-morning cup of coffee are at least two times less than the effects of the morning’s first cup. In fact, replacement of caffeinated coffee with decaffeinated showed no increase or decrease amongst frequent coffee drinkers. Also, as the reported number of cups per day increases so does the tolerance to the pressor effect. Caffeine has also been shown to cause gastric stimulation.
Aspirin has been used for centuries as an analgesic. It is a nonsteroidal anti-inflammatory agent that works extensively on the COX receptor pathways inhibiting prostaglandin synthesis. It has little effect on the heart in low doses; however, in high doses, it may cause increase plasma volume and increased cardiac output (Battig, 1993).
Effects of the ECA stack on heart rate were comparable to those of ephedrine alone. The greatest increase noted was 15 bpm seen 6 hours after initial ingestion (Daly et al., 1993; Boozer et al., 2000; Haller, Jacob & Benowitz, 2002). The effects on blood pressure were again mixed: two studies reported no significant change between placebo and actively treated groups (Daly et al., 1993; Boozer et al., 2000), while a more recent study reported somewhat elevated blood pressures (Haller, Jacob & Benowitz, 2002).
(b) Evidence for increased efficacy in weight control
The first of several studies on the efficacy of the ECA stack was published by Astrup et al. in 1992. The double-blind study used 16 independently selected obese but otherwise healthy females with a mean BMI of 37.0 who were then subdivided into two groups. The study lasted 8 weeks during which the women consumed a restricted 4200 kilojoule per day diet and were given either a placebo (P) or a supplement containing ephedrine and caffeine (EC). At the conclusion of the study the EC group lost an average 10.1 kg of body weight while the P group lost 8.4 kg. Of important note is the composition of the weight lost from each group. 4.5 kg more body fat was lost in the EC group than in the P group and only 1.1 kg of lean body mass was lost by the EC group compared to 3.9 kg by the P group. Also evaluated by this program was the adaptive reduction in energy expenditure (EE) by the body in response to low calorie dieting greatly hindering the effects of reduced calorie dieting. The EE was measured on two different occasions: the first day of treatment and after the end of the 8 week study. In the P group on the first day of treatment 24-hour EE decreased by an average of 19.4 kilojoules per kilogram lean mass compared to a reduction of only 12.5 kilojoules per kilogram lean mass in the EC group. At the end of the study the P group’s EE had decreased on average by 26.5 kilojoules per kilogram lean body mass. The EC group’s EE had decreased to only 15.6 kilojoules per kilogram lean body mass, still less than that of the P group on the first day of the trial.
Another noteworthy aspect of this study was the effect of the ephedrine-caffeine stack on carbohydrate and lipid oxidation versus the placebo group as measured before treatment started, at day 1, and at day 56. While carbohydrate oxidation was similar in both groups, as was lipid oxidation before treatment, the EC group showed increased lipid oxidation on day 1 and day 56.
A study by Daly et al. (1993) was conducted in the similar manner but continued the research over a longer duration to allow a cross-over portion and explore long term effectiveness and possible complications as well as adding aspirin to the stack. Also of note is that participants were free to eat as much or as little as the desired. In the first 8 weeks, individuals using the ECA stack lost an average 2.2 kg versus 0.7 kg in the placebo group. When the amount of weight lost per week was plotted on a graph the slope of the ECA group was greater (-0.265) when compared to the placebo group (-0.086).
In the next phase of the study eight subjects of the placebo group agreed to return five months later and take the ECA stack for 8 weeks in an unblinded study. After the end of the eight weeks the average weight loss was on average 3.5 kg versus an average 1.3 kg for the same group in the previous eight weeks when they were part of the placebo group without the ECA stack.
In the third phase of the experiment, six of the participants from phase two agreed to continue to use the ECA stack for at least five months so that their progress could be compared to the five months that lapsed between the two eight-week studies. At the end of five months the average weight loss for the five subjects was 5.2 kg versus 0.03 kilograms gained in the 5 months without ECA use.
A sixth, and yet unmentioned participant in the study followed a self-prescribed exercise and low calorie dieting routine. This participant lost 31.7 kg over the five months of ECA use compared to a gain of 1.6 kg over the five months without ECA use. All totaled, in sixty weeks this participant lost a total of 66.3 kilograms. Also of note, when the ECA dose was slowly decreased and diet and exercise routine maintained, the subject began to see a pattern of weight gain re-developing.
In a third study by Boozer et al. (2000) participants were again given either a supplement containing ephedrine and caffeine or a placebo. This study was another eight week, double-blind placebo-controlled study; however, the study was much larger than the previous two consisting of 60 participants. The study not only measured reduction in weight but body fat levels, anthropometric dimensions, and cardiovascular changes. Also, more attention was paid to possible adverse effects, both those measured by the researchers and those reported by the participants.
Effects on body weight concurred with the findings of previous researchers. The group using the EC stack showed an average decrease of 4.0 kg or 3.5% of baseline while the placebo group only decreased 0.8 kg or 0.09% of baseline. As before, when the weight changes were plotted, the slope of the EC group was much steeper.
When body fat levels were examined, once again the EC-treated group showed a greater decrease than the placebo group. On average the EC-treated group showed a reduction of 3.5 kg body fat while the placebo group saw a reduction of only 0.7 kg.
Anthropometric dimension analysis revealed similar results. Evaluation of hip and waist circumference in the EC-treated group showed a reduction of 3.4 cm in the waist and 4.7 cm in the hips. The placebo group showed reduction of only 0.8 cm in the waist and 0.4 cm in the hips.
Several cardiovascular factors were followed including serum lipids, serum glucose levels, mean systolic and diastolic blood pressure, heart rate, and ECG intervals and amplitudes. Serum lipid evaluation determined that the EC group had decreased serum triglyceride levels. There was a slight increase in serum glucose levels in the EC group while the P group decreased slightly. Comparison of the mean systolic pressure showed a difference only at week six when the EC group showed elevation by an average 4.1 mmHg increase from baseline while the P group showed a 2.6 mmHg decrease. At all other weeks there was no difference in the mean pressure or the deviation from baseline between the two groups. There was never any significant difference in mean diastolic blood pressure or change from baseline at any point between the two groups. Heart rate increased 6.9 bpm in the EC group while it decreased by 1.7 bpm in the P group.
IV. Associate health risks
Ephedrine’s notorious reputation began in 1983 when the FDA banned the combination of caffeine and phenylpropanolamine, also known as norephedrine, due to numerous reports of adverse reactions. Norephedrine was again the target of an FDA banning when over the counter (OTC) weight loss aids and nasal decongestants containing the chemical were banned due to the increased risk of stroke. Of important note is that the phenylpropanolamine sold in these products existed as a racemic mixture while the form found in Ephedra is only the (-)-isomer (Haller, Jacob & Benowitz). It is becoming increasingly clear that herbal supplements do, in fact, act as drugs and have serious interactions and profound clinical significance (Stein, 2002). As far as supplements containing ma huang, the only alkaloid present in great enough concentration to possibly cause any health problems is ephedrine. And since most supplements containing ma huang also contain caffeine and ASA, the safety of both ephedrine and the ECA stack will be evaluated.
(1) Cardiovascular complications
A number of cardiovascular complications have been credited to ephedrine and the use of the herb ma huang including ischemic and hemorrhagic stroke, myocardial infarction, clinical hypertension, tachycardia or palpitation, arrhythmia, and cardiac arrest (Halter & Benowitz, 2000).
(a) Cardiac complications
In the study by Pasquali & Casimirri (1993) a total of 88 individuals were studied for 2-4 months while using ephedrine in doses up to 150 mg a day. Palpitations were one cardiac- related side effect and were reportedly well tolerated and diminished with time. The other noted cardiac related side effect was an increased heart rate when compared to the placebo groups.
The study by Astrup et al. (1992) examined 16 individuals taking ephedrine and caffeine for 8 weeks. There was only one report of palpitations and it was described as well tolerated and transient in nature. The palpitations were no longer reported after 6-14 days.
The study by Daly et al. (1993) studied 24 individuals from 8 weeks to thirteen months. This study reported no significant difference in reported side effects between placebo and herbally treated groups.
The study by Boozer et al. (2001) studied 67 individuals. Of these individuals in the group taking ephedrine and caffeine there were four reports of palpitations, one report of palpitations and chest pain, and two reports of elevated blood pressure. ECG’s performed on all these individuals showed no abnormalities and the side effects were not characterized as serious or lasting.
A study by White et al. (1997) evaluated 12 individuals who ingested ma huang and looked specifically for cardiac type complications by use of ambulatory blood pressure devices. Their research showed that only 50% of the individuals showed increased heart rate, increasing on average by 9 bpm. Four participants showed slight increases in systolic blood pressure and two showed slight decreases. No other adverse effects were reported by participants.
The study conducted by Haller, Jacob & Benowitz (2002) evaluated 8 individuals given a single dose of 20 mg ephedrine and 200 mg caffeine for increases in heart rate and blood pressure. They received only two complaints of palpitations. An increase in heart rate was still seen 11 hours after ingestion. An increase in systolic blood pressure was also noted with one individual increasing by 14 mmHg above baseline 90 minutes after ingestion.
Two other studies approached the assessment of possible adverse reactions to ma huang containing supplements in a different way. Haller & Benowitz (2000) examined 140 reports of adverse effects to the FDA MedWatch system and ranked the symptoms as definitely, probably, possibly, or unrelated to ephedrine use based on symptoms resurfacing upon renewed ephedrine use, pharmacological probability of symptoms, or an improbable relation. 31% of the cases were definitely linked to ephedra, 31% possibly related, 17% unrelated, and 21% undetermined due to insufficient data. Of the 87 cases found to be feasibly related to ephedrine, the most common complication was hypertension. In 10 cases death was reported and 13 cases reported permanent impairment. The second study conducted by Samenuk et al. (2002) studied 926 reports made to the FDA’s Adverse Reaction Monitoring System (ARMS) from 1995 to 1997. Of these reports ma huang was temporarily related to myocardial infarction in 10 and “sudden or unwitnessed death” in 11.
(b) Ischemic an hemorrhagic stroke
Despite increases in systolic blood pressure in several of the clinical trials, none of the systolic blood pressures obtained ever exceeded 143 mmHg and none of the diastolic ever exceeded 90 mmHg.
Analysis of reports to the FDA’s ARMS determined 16 cases of stroke out of 926 cases reported could be related to ephedrine use (Samenuk et al., 2002). A similar study evaluating reports to the FDA’s MedWatch from June 1, 1997 to March 31, 1999 reveal 15 cases of stroke or transient ischemic attack (TIA) (Haller & Benowitz, 2000).
(2) CNS and behavioral effects
Effects on the CNS and behavior related to ephedrine use have been as serious as acute psychosis to mild effects such as headache and tremors.
Participants in the study by Astrup et al. (1992) linked ephedrine use to three instances of insomnia and one instance of tremors. Both of the reported were mild, transient and vanished completely after 6-14 days never to resurface during the eight week study.
A study by Pasquali & Casimirri (1993) had reports of agitation, insomnia, headache, weakness, giddiness, and tremor among its 88 participants. The adverse effects were reported as transient and well tolerated. Similarly, another study conducted by Daly et al. (1993) showed no significant differences between herbally supplemented groups and placebo controlled groups.
A fourth study by Boozer et al. (2001) showed symptoms of irritability in both placebo and herbal supplemented groups. The major side effects seen only in the herbal supplemented group were dry mouth, insomnia, and headache.
An analysis of the FDA MedWatch reports found 10 instances of seizures at least possibly related to ephedrine use (Haller & Benowitz, 2000). One report of a 22 year old male who was hospitalized for unexplained seizures and unresponsiveness was intimately linked to use of a popular ECA stack known as Hydroxycut. Toxicological urinary analysis as well as MRI-MRA scans both came back negative. The patient was found to be atraumatic and otherwise normal based on emergency department reports (Kockler, McCarthy & Lawson, 2001).
An instance of acute psychosis was also reported in a male who mixed an ECA type (Vigueur Fit) with alcohol. The man became agitated and violent and was eventually arrested and charged with criminal conduct (Tormey & Bruzzi, 2001).
