Ephedra , ephedrine, and pseudoephedrine

General information

Ephedra consists of a mixture of different members of the Ephedraceae family ( E. sinica , E. equisetina , and E. gerardiana ). Its actions are due to the presence of ephedrine and pseudoephedrine.

Both ephedrine and pseudoephedrine are worryingly popular [ ] and are widely available without prescription. Oral doses of ephedrine 25–30 mg are often prescribed, for example for orthostatic hypotension. Lower oral doses, present in some “cold remedies” in tablet form, are unlikely to be efficacious, although they are risky where the drug is contraindicated, for example in patients with cardiac disease. Ephedrine used in nasal sprays and drops can have systemic effects in the doses normally used. Such products are widely available over the counter in many countries. In Texas some 500 cases of adverse reactions were reported between 1993 and 1995 [ ]. Three of these cases have been highlighted because of their serious nature: one patient died from myocardial infarction, one had a series of generalized absence seizures, and a third had a fatal subarachnoid hemorrhage as the result of taking an unsuitable dose.

Ephedrine

Ephedrine is a sympathomimetic drug prepared from members of the Ephedra family, such as Ephedra vulgaris, also called the sea grape. It is available as ordinary pharmaceutical formulations of ephedrine, but also in herbal formulations of Ephedra, including a Chinese herbal medicine called Ma huang, which has been used since ancient times as a stimulant and in the treatment of asthma, and in formulations combined with caffeine. It is used to treat asthma, nasal congestion, fever, obesity, and anhidrosis. It is also abused as a recreational drug. Of 140 reports of adverse events related to Ephedra supplements submitted to the FDA between June 1997 and March 1999, 31% were definitely or probably causally related to Ephedra [ ]. In 47% of the cases, there were cardiovascular symptoms and in 18% central nervous system effects; 10 patients died.

Ephedrine is longer-acting than adrenaline and can exert any type of adrenergic effect, including metabolic changes and dysuria. It has a somewhat smaller effect on the cardiovascular system than adrenaline but a relatively larger effect on the central nervous system; even low doses can, in sensitive patients, cause tremor, insomnia, and anxiety, and such problems are much more marked if ephedrine is given together with caffeine, as it sometimes is for appetite control [ ]. In children, ephedrine sometimes paradoxically induces sedation. Psychosis has resulted from excessive self-medication [ ].

Pseudoephedrine

Pseudoephedrine is a stereoisomer of ephedrine, in which two of three chiral centers are different.

“Herbal ecstasy”

“Herbal ecstasy” is a term used for many different herbal formulations, none of which contains ecstasy. Some of the names for these herbs (which can be sold in stores) include “The Bomb,” “Reds,” and “Sublime.” In New Zealand analysis of “The Bomb” showed substantial amounts of ephedrine and the Ministry of Health removed it from the market. Some symptoms associated with herbal ecstasy include headache, dizziness, palpitation, tachycardia, and raised blood pressure. Thus, in countries where the term “herbal ecstasy” is commonly used, it is important that those who see patients who have taken a formulation with that name should not confuse it with ecstasy, as toxicity and medical management may be quite different [ ].

General adverse effects and adverse reactions

Because they are thermogenic in experimental animals Ephedra alkaloids have been used to aid weight loss [ ]. However, they are associated with too many cardiovascular and nervous system adverse effects to be of use [ ]. For example, in one short-term study consumption of two doses 5 hours apart of an Ephedra + caffeine mixture (325 + 90 mg) in 16 healthy adults, associated with peak plasma ephedrine concentrations of 130–140 ng/ml, caused increased heart rate, blood pressure, and glucose concentrations, and reduced potassium concentrations [ ], and a meta-analysis showed that ephedrine and Ephedra are associated with increased risks of psychiatric symptoms, autonomic symptoms, upper gastrointestinal symptoms, and palpitation [ ]. In 2004 formulations containing Ephedra alkaloids were banned by the FDA [ , ], although the ban was overturned in Utah by a federal judge in the following year [ ].

Organs and systems

Cardiovascular

Cardiologists and pharmacologists from Boston have reviewed cases of possible cardiovascular toxicity associated with the use of Ma huang. Among over 900 cases of possible toxicity reported to the Food and Drug Administration, they identified 37 patients (23 women) in whom stroke (n = 16), myocardial infarction (n = 10), and sudden death (n = 11) appeared to be temporally related to consumption of Ma huang. The authors noted that in all but one of these cases the doses used were within the range recommended by the manufacturers. In the seven patients on whom autopsies were performed, coronary artery disease was found in three and cardiomyopathy in another three, with features suggesting sympathomimetic toxicity. The authors emphasized the toxicity of Ma huang in relatively young individuals (the mean age of the 37 patients was about 43 years), even though the relevant pathogenic mechanisms remain to be fully defined.

Hypertension

The cardiovascular effects, subjective effects, and abuse potential of single intranasal doses of ephedrine 5 and 10 mg have been compared with oral doses of (−)ephedrine 50 mg in 16 healthy Caucasian men with no drug/alcohol/nicotine abuse or dependence [ ]. Intranasal ephedrine caused an increase in blood pressure but associated orthostatic hypotension.

In subjects with impaired baroreflex function, oral pseudoephedrine 30 mg or phenylpropanolamine 12.5 and 25 mg produced significant increases in blood pressure. When they were taken with water the increase in blood pressure was greater. The maximal increase in systolic blood pressure occurred after 60 minutes and the pressure returned to baseline by 2 hours [ ].

Pseudoephedrine is a component of some non-prescription basal decongestants given by mouth; even quite ordinary doses of such products (for example 120 mg) can cause hypertension in sensitive subjects, such as those with a pheochromocytoma and those with at least a family history of hypertension [ ].

A 21-year-old man presented with hypertension (blood pressure 220/110 mmHg) and ventricular dysrhythmias after taking four capsules of herbal ecstasy [ ]. He was treated with lidocaine and sodium nitroprusside and his symptoms resolved within 9 hours.

Severe hypertension has also been attributed to pseudoephedrine abuse [ ].

In a meta-analysis of 24 studies involving 1285 subjects the authors concluded that in healthy individuals pseudoephedrine significantly increased heart rate (2.83/minute; CI = 2.0, 3.6) and increased systolic blood pressure (0.99 mmHg; 95% CI = 0.08, 1.9), with no effect on diastolic pressure [ ]. In patients with controlled hypertension there was an increase of similar magnitude in systolic blood pressure (1.2 mmHg; CI = 0.56, 1.84). Higher doses and immediate-release formulations were associated with greater increases in blood pressure, although it was difficult to be certain what the average dose was in these studies; from the data presented it was usually 60 mg once or twice daily. The authors reported isolated cases of much greater rises in blood pressure (up to 20 mmHg systolic) but again it was difficult to determine the doses used. They concluded that immediate-release formulations had a greater effect than modified-release formulations, and that a dose-response relation could be discerned. Evidently many cases of pseudoephedrine-related cardiovascular effects involved higher doses than have been used in formal studies or are recommended by manufacturers. There appeared to be a smaller effect in women than in men. Shorter duration of use was associated with greater increases in systolic and diastolic blood pressures. There were no clinically significant adverse outcomes. However, a rare adverse event may not be seen with such a small sample size.

Hypertensive encephalopathy with generalized tonic-clonic seizures has been attributed to abuse of over-the-counter formulations containing a mixture of ephedrine and caffeine alkaloids [ ].

Cardiac dysrhythmias

Cardiac dysrhythmias have been attributed to ephedrine both in therapeutic doses [ ] and when used as a drug of abuse [ ].

A 25-year-old woman became hypotensive after the administration of epidural anesthesia for an elective cesarean section. She was given intravenous ephedrine 9 mg, after which she complained of nausea. For an unexplained reason this was taken as an indication to give a further 9 mg of ephedrine. She immediately developed sinus tachycardia with atrial and multifocal ventricular extra beats, followed by short runs of ventricular tachycardia. She remained asymptomatic and recovered after about 5 minutes.

One must have some concerns about the high dose used here for a relatively modest level of hypotension with a systolic blood pressure of 100 mmHg.

A 21-year-old Canadian man presented with severe head ache, nausea and vomiting, hypertension (220/120 mmHg), and a sinus tachycardia of about 120/minute with frequent multifocal ventricular extra beats. He was treated with intravenous sodium nitroprusside and lidocaine and recovered fully within 24 hours.

The authors concluded that ephedrine was very largely responsible for the cardiovascular toxicity.

Ventricular tachycardia has been attributed to ephedrine [ ].

A 19-year-old woman took ephedrine to enhance her sports performance and after 10 days developed hemodynamically unstable ventricular tachycardia resistant to cardioversion and amiodarone. She converted to sinus rhythm 60 hours later, presumably when the plasma ephedrine concentration had fallen sufficiently.

The authors thought that ephedrine had not been the sole cause of tachycardia in this case, but that it had triggered the dysrhythmia in association with an underlying propensity to idiopathic left ventricular tachycardia, which they reproduced electrophysiologically during catheterization.

In a double-blind, randomized, placebo-controlled, crossover study, 13 healthy volunteers took TrimSpa, which contains more than 30 ingredients, including Ephedra 15 mg and caffeine 60 mg, or matching placebo tds for 7 days with a 7-day washout period between treatments [ ]. There were no differences in QT _c interval or systolic blood pressure between the two groups. However, in one subject taking TrimSpa the QT _c interval increased by 96 msec from baseline, more than double the largest increase in the placebo group.

In an earlier study Metabolife 356, which contains Ephedra and caffeine, prolonged the average QT _c interval from 396 to 419 milliseconds and increased the mean systolic blood pressure from 119 to 124 mmHg in 15 young healthy volunteers compared with placebo, although the extent to which this was due to Ephedra or other components of Metabolife 356 is not clear [ ].

Some individuals may be at particular risk of dysrhythmogenic effects of Ephedra alkaloids, but if so the susceptibility factors, particularly the role of caffeine, are not understood.

Myocardial ischemia

About 5% of patients with a myocardial infarction have normal coronary arteries at angiography. In many cases there is coronary artery spasm and/or thrombosis, perhaps with underlying endothelial dysfunction of the epicardial arteries. It is important in such cases to obtain a complete history of the use of drugs, including over-the-counter drugs.

There have been reports of myocardial ischemia due to ephedrine and pseudoephedrine. The EIDOS and DoTS descriptions of this reaction are shown in Figure 1 .

Acute myocardial infarction in a young athlete who had used ephedrine over the previous 5 years to improve physical performance was associated with an intracoronary thrombus in the left anterior descending coronary artery; after removal of the thrombus, only an intact non-obstructive atherosclerotic plaque was found [ ].

Figure 1, The EIDOS and DoTS descriptions of myocardial ischemia due to Ephedra drugs.

The authors suggested that in this case there was a pathogenetic link between non-obstructive coronary atherosclerosis, focal vasoconstriction, and obstructive thrombosis.

A previously healthy 19-year-old man took tablets containing a total of 24 mg of Ephedra alkaloids and 100 mg of caffeine, and 15 minutes later developed severe chest pain radiating down the left arm [ ]. An electrocardiogram showed an inferolateral myocardial infarct, confirmed by creatine kinase and troponin I measurements. He made a full recovery, and coronary angiography showed only minimal atherosclerotic disease of the left anterior descending artery.

The authors emphasized the dangers of Ephedra- containing over-the-counter formulations, even in fit young people.

A 28-year-old mixed martial arts fighter took Therma-Pro™, a dietary supplement, to lose weight before fights [ ]. Besides weight loss, he suffered palpitation, tremors, and insomnia. After taking four tablets a day for 3 days he developed intense tight chest pain at rest, which worsened with effort and improved with rest. Simple analgesia was ineffective. Six days later he developed syncope and a right-sided hemiparesis. After 30 days the hemiparesis had resolved but he had congestive heart failure NYHA class II. An electrocardiogram showed an extensive anterior electrical inactivity and echocardiography showed a left ventricle with dimensions at the upper limit of normal and a 45% ejection fraction with anteroseptal, apical, and anterior akinesia and thrombus in the left ventricle. Coronary angiography showed an occluded anterior descending artery.

Therma-Pro contains Ma huang extract 250 mg, equivalent to ephedrine 20 mg.

A 16-year-old boy with a sore throat took cefazolin 2 g/day, paracetamol 1500 mg/day, and three doses of pseudoephedrine 60 mg, and 1 day later developed chest pain lasting 4 hours [ ]. An electrocardiogram showed ST segment elevation in the inferolateral leads and his troponin T concentration creatine kinase and creatine kinase-MB activities were raised. Echocardiography showed a low ejection fraction (40%) and hypokinetic anterior, apical, lateral, and inferior wall segments of the left ventricle. Coronary angiography showed normal coronary arteries.

The authors suggested that he had had a myocardial infarction triggered by pseudoephedrine and acute streptococcal infection.

A previously healthy 32-year-old man from Nigeria developed substernal chest pain at rest associated with nausea and sweating 45 minutes after taking two tablets of an over-the-counter cold remedy containing pseudoephedrine 30 mg and paracetamol 500 mg per tablet [ ].. He recalled a similar but less severe episode 1 week earlier after taking the same medication. There was no relevant past medical history or family history of coronary artery disease. An electrocardiogram showed ST elevation in the inferolateral leads and the plasma creatine kinase activity and troponin I concentration were both raised. Coronary angiography showed normal arteries.

The authors concluded that this episode had been caused by coronary vasospasm initiated by pseudoephedrine and warned of the dangers of this type of medication, even in otherwise healthy individuals. The temporal association between ingestion of pseudoephedrine and the myocardial infarction suggested a causal relation. The absence of coronary artery disease at catheterization combined with the cardiac magnetic resonance imaging findings were consistent with an acute myocardial infarction caused by vasospasm due to pseudoephedrine.

A 19-year-old male cigarette smoker with normal coronary arteriography had an upper respiratory infection, for which he brought Gripex®, each tablet of which contains paracetamol 325 mg, pseudoephedrine HCl 30 mg, and dextromethorphan HBr 10 mg [ ]. He took four tablets twice, about 3 hours apart, a total of 240 mg of pseudoephedrine within 3 hours. He had an acute myocardial infarction 12 hours later. Other drugs, such as cocaine and amphetamines, were excluded. Subsequent coronary angiography and echocardiography showed a non-Q-wave myocardial infarction with normal coronary arteries.

In a meta-analysis of the effects of Ephedra or ephedrine-containing products compared with control, the odds ratio of palpitation was 2.29 (95% CI = 1.27, 4.32) [ ].

Two competitive athletes experienced ventricular dysrhythmias after using ephedrine; endomyocardial biopsies showed contraction-band necrosis, a myocardial injury that is often observed in cases of catecholamine excess [ ].

Ephedrine is sometimes used to treat vasovagal episodes and has been reported to cause coronary artery spasm and myocardial infarction in these circumstances [ ].

Two apparently healthy women, aged 26 and 34 years, who were given spinal anesthesia for pelvic or hip surgery, both developed hypotension and bradycardia and were given intravenous ephedrine in divided doses, in one case a total of 20 mg and in the other 30 mg. In both cases this resulted in ventricular tachycardia and raised troponin I concentrations and creatine kinase activity, but Q waves did not follow. Coronary angiography showed normal arteries in both cases and the women recovered, apparently fully.

The authors rightly pointed out that atropine is a safer and more appropriate intervention in circumstances such as these.

Arteritis

Arteritis has been attributed to ephedrine [ ].

A 44-year-old French woman was given intravenous ephedrine during anesthesia and developed hypertension (systolic pressure 180 mmHg) with nausea, vomiting, and progressive drowsiness. She had a history of migraine, antiphospholipid antibodies, mitral valve prolapse, and atrial fibrillation treated with propranolol. Immediately after anesthesia she developed headache, vomiting, and drowsiness. CT scanning showed frontal and parietal hemorrhagic infarcts, and cerebral angiography showed multiple segments of constriction and dilatation consistent with arteritis. She was left with residual visual and memory deficits.

This is the first case of this kind associated with ephedrine, and it seems plausible that the patient’s previous history indicated a genetic predisposition to vascular disease.

Nervous system

The hazard associated with use of over-the-counter nutritional supplements containing ephedrine by athletes has been illustrated [ ].

A 24-year-old, previously healthy, male university athlete developed a severe right-sided headache and collapsed with left-sided weakness while sprinting [ ]. Earlier that morning he had taken at least five tablets of Xenadrine, each of which contained ephedrine 34 mg, pseudoephedrine 24 mg, methylephedrine 6 mg, and caffeine 363 mg. He was not taking any other medications and had no history of trauma. His blood pressure was 137/87 mmHg and his heart rate 58/minute. Imaging showed moderate vasospasm in the right middle cerebral artery. He was treated with milrinone and heparin, and after 6 days was discharged to a rehabilitation center taking prophylactic aspirin.

In a consecutive stroke registry since 1988, 22 patients (10 men and 12 women) had strokes associated with over-the-counter sympathomimetic drugs [ ]. There was intracerebral hemorrhage in 17, subarachnoid hemorrhage in four, and ischemic stroke in one. Stroke was associated with the use of pseudoephedrine (60–300 mg) in four cases.

The largest manufacturer of Ephedra- containing supplements is Metabolife. The firm has repeatedly insisted that it was not aware of adverse events associated with its products, and claimed that they were “absolutely safe” [ ]. An investigation by the US Justice Department into the truth of these statements showed that between 1997 and 2002 the company had received over 13 000 reports of suspected adverse drug reactions; they included nearly 2000 reports of significant adverse reactions.

Stroke has been attributed to pseudoephedrine [ ].

A 4-year-old girl with a nasopharyngeal rhabdomyosarcoma had a stroke after taking pseudoephedrine for 3 days, without hematological abnormalities. She was given intravenous diazepam and phenytoin. An MRI scan showed occlusion of the left middle cerebral artery and a narrowed internal carotid artery. There was significant recovery in 2 months.
A 33-year-old man had a stroke while taking a herbal remedy (Thermadrene) containing Ephedra alkaloids and guaraná for “boosting his energy” [ ]. He was immediately treated with alteplase and was referred for rehabilitation 9 days later. At follow-up 5 months later he still had a minor neurological deficit.

Sensory systems

Transient cortical blindness has been attributed to an Ephedra -based supplement [ ].

A 29-year-old man took the Ephedra -containing supplements, Stacker 3 and Ripped Fuel Extreme, and had a severe headache and a generalized tonic–clonic seizure. He became stuporose and combative, with a systolic blood pressure of 220 mmHg, a sinus tachycardia, and a temperature of 39.6 °C. Electrocardiography and cardiac enzymes confirmed an acute myocardial infarction and he had fulminant hepatic failure, acute renal failure, and rhabdomyolysis. He recovered, but 1 week later developed complete bilateral visual loss without nystagmus, consistent with cortical blindness. His blood pressure was again markedly raised. He stopped using Ephedra and recovered.

The authors suggested that Ephedra had caused a reversible posterior leukoencephalopathy.

Psychiatric

Ma huang can cause psychiatric complications, which can last several weeks. These have been reviewed in the context of two cases of psychotic reactions [ ].

A 27-year-old US Marine presented with depressed affect, irritability, and poor concentration and eventually admitted 2 years self-medication with Ma huang to improve workout performance.
A 27-year-old US Marine developed a frank psychosis with ideas of reference and some paranoid ideation. He had been taking two preparations containing Ma huang, although the duration of use was unclear.

After discontinuing the drug both made a full recovery. The authors emphasized the importance of recognizing possible abuse of such “natural” medications, widely perceived to be harmless despite warnings and attempted restrictions by regulatory authorities. Treatment is supportive while awaiting spontaneous recovery after drug withdrawal.

Ephedrine-induced mania occurred over a 3-month period in a patient who took the “recommended” dose of a dietary supplement [ ].

A 40-year-old woman without a prior psychiatric history took the Ephedra -containing weight loss pill Xenadrine®, 4 pills /day, for 6 weeks and developed manic symptoms. Within days her family noted confusion, difficulty in falling asleep, and rapid tangential speech. She continued to take the supplement and became more erratic and severely disinhibited. She under-went in-patient psychiatric hospitalization and was stabilized over 20 days on risperidone, divalproex, and temazepam. Two months later, despite medication compliance, her manic and depressive symptoms re-emerged. Sertraline was added to divalproex and she remained symptom-free for 5 months. She stopped taking her medications, and in 2 weeks developed severe depression. She was treated with citalopram, divalproex, risperidone, and temazepam and remained stable.

This case was unusual, because most cases of ephedrine-induced mania involve a pre-existing mood disorder, suggesting that ephedrine can exacerbate pre-existing mood disorders. Also, in her first described manic episode the symptoms persisted for several months after ephedrine withdrawal. The authors speculated that ephedrine may “unmask” mood disorders in susceptible individuals.

Pseudoephedrine is often used by scuba divers to avoid ear barotrauma. The psychometric and cardiac effects of pseudoephedrine have been evaluated at 1 atmosphere (100 kPa, sea level) and 3 atmospheres (30 kPa, 20 m) in a double-blind, placebo-controlled, crossover study in 30 active divers in a hyperbaric chamber [ ]. Pseudoephedrine did not cause significant alterations in psychometric performance at 3 atmospheres.

A young child suffered from visual hallucinations caused by high doses of pseudoephedrine [ ].

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