Over a century since ephedrine discovery: an updated revisit to its pharmacological aspects, functionality and toxicity in comparison to its herbal extracts.

Ephedrine, a sympathomimetic amine that exhibits several adrenaline actions, is a plant alkaloid that is a common ingredient in several cold, asthma and narcolepsy treatment preparations, and in obesity management and sport medicine. Its principal action mechanism relies on its direct adrenergic actions as well as indirect role that involves the release of epinephrine and norepinephrine, thus increasing the activity of epinephrine and norepinephrine at the postsynaptic α and ß receptors. Nevertheless, its serious side effects, including stroke, heart attack, drug abuse and interactions, have never been comprehensively reviewed. We conducted a systematic review of data on ephedrine, including its occurrence in functional foods, pharmacological aspects, metabolism, pharmaco/toxicokinetics and clinical features. Furthermore, a review of ephedrine natural structural analogues with regards to their differential adrenergic receptor binding affinities, food interaction, and their impact on the pharmacokinetics and effects relative to ephedrine are presented for the first time, and in comparison to its action when present in herbs.

In search of an ideal drug for safer treatment of obesity: The false promise of pseudoephedrine.

Obesity is a major public health problem worldwide. Only relatively few treatment options are, at present, available for the management of obese patients. Furthermore, treatment of obesity is affected by the widespread misuse of drugs and food supplements. Ephedra sinica is an old medicinal herb, commonly used in the treatment of respiratory tract diseases. Ephedra species contain several alkaloids, including pseudoephedrine, notably endowed with indirect sympathomimetic pharmacodynamic properties. The anorexigenic effect of pseudoephedrine is attributable primarily to the inhibition of neurons located in the hypothalamic paraventricular nucleus (PVN), mediating satiety stimuli. Pseudoephedrine influences lipolysis and thermogenesis through interaction with ß3 adrenergic receptors and reduces fat accumulation through down-regulation of transcription factors related to lipogenesis. However, its use is associated with adverse events that involve to a large extent the cardiovascular and the central nervous system. Adverse events of pseudoephedrine also affect the eye, the intestine, and the skin, and, of relevance, sudden cardiovascular death related to dietary supplements containing Ephedra alkaloids has also been reported. In light of the limited availability of clinical data on pseudoephedrine in obesity, along with its significantly unbalanced risk/benefit profile, as well as of the psychophysical susceptibility of obese patients, it appears reasonable to preclude the prescription of pseudoephedrine in obese patients of any order and degree.

[The Adverse Effects of Ephedra Herb and the Safety of Ephedrine Alkaloids-free Ephedra Herb Extract (EFE)].

Ephedra Herb is defined in the 17th edition of the Japanese Pharmacopoeia (JP) as the terrestrial stem of Ephedra sinica Stapf., Ephedra intermedia Schrenk et C.A. Meyer, or Ephedra equisetina Bunge (Ephedraceae). The stems of Ephedra Herb contain greater than 0.7% ephedrine alkaloids (ephedrine and pseudoephedrine). Despite its high effectiveness, Ephedra Herb exert several adverse effects, including palpitation, excitation, insomnia, and dysuria. Both the primary and adverse effects of Ephedra Herb have been traditionally believed to be mediated by these ephedrine alkaloids. However, our study found that several pharmacological actions of Ephedra Herb were not associated with ephedrine alkaloids. We prepared an ephedrine alkaloid-free Ephedra Herb extract (EFE) by eliminating ephedrine alkaloids from Ephedra Herb extract (EHE) using ion-exchange column chromatography. EFE exerted analgesic, anti-influenza, and anticancer activities in the same manner as EHE. Moreover, EFE did not induce adverse effects due to ephedrine alkaloids, such as excitation, insomnia, and arrhythmias, and showed no toxicity. Furthermore, we evaluated the safety of EFE in healthy volunteers. The number of adverse event cases was higher in the EHE-treated group than in the EFE-treated group, although the difference was not significant. Our evidence suggested that EFE was safer than EHE.

Ephedrine Alkaloids-Free Ephedra Herb Extract, EFE, Has No Adverse Effects Such as Excitation, Insomnia, and Arrhythmias.

Ephedrine alkaloids-free Ephedra Herb extract (EFE) has been developed to eliminate the adverse effects caused by ephedrine alkaloid-induced sympathetic hyperactivation. Previously, we reported that EFE possesses analgesic, anti-influenza, and cancer metastatic inhibitory effects at comparable levels to that of Ephedra Herb extract (EHE). However, it has not yet been demonstrated that EFE is free from the known side effects of EHE, such as excitation, insomnia, and arrhythmias. In this study, the incidence of these adverse effects was compared between mice administered EHE and those administered EFE. Increased locomotor activity in an open-field test, reduced immobility times in a forced swim test, and reduced sleep times in a pentobarbital-induced sleep test were observed in EHE-treated mice, when compared to the corresponding values in vehicle-treated mice. In contrast, EFE had no obvious effects in these tests. In electrocardiograms, atrial fibrillation (i.e., irregular heart rhythm, absence of P waves, and appearance of f waves) was observed in the EHE-treated mice. It was suggested that this atrial fibrillation was induced by stimulation of adrenaline ß1 receptors, but not by hypokalemia. However, EFE did not affect cardiac electrophysiology. These results suggest that the abovementioned side effects are caused by ephedrine alkaloids in EHE, and that EFE is free from these adverse effects, such as excitation, insomnia, and arrhythmias. Thus, EFE is a promising new botanical drug with few adverse effects.

Efficient Preparation of Ephedrine Alkaloids-free Ephedra Herb Extract and Its Antitumor Effect and Putative Marker Compound.

Ephedra Herb is a crude drug for the treatment of headache, bronchial asthma, nasal inflammation, and the common cold. Although it has been considered that ephedrine alkaloids (EAs) are the principal active ingredients of Ephedra Herb, EAs are known to induce palpitations, hypertension, insomnia, and dysuria as major side effects. Therefore, the administration of EAs-containing drugs to patients with cardiovascular-related diseases is strongly contraindicated. Previously, we isolated herbacetin 7-O-neohesperidoside from Ephedra Herb. In addition, we found that herbacetin, a flavonoid aglycone in Ephedra Herb, had antiproliferative and analgesic effects. Therefore, the prospect of preparing safer natural medicines without the adverse effects associated with EAs was appealing. In this symposium review, to achieve the aim of producting a clinically useful Ephedra Herb extract with none of the adverse effects associated with EAs, I present an efficient preparation method of EAs-free Ephedra Herb extract, together with its chemical composition, antiproliferative effects, and a putative marker for quality control.

The Pharmacological Actions of Ephedrine Alkaloids-free Ephreda Herb Extract and Preparation for Clinical Application.

Ephedra Herb is defined in the 17th edition of the Japanese Pharmacopoeia as the terrestrial stem of Ephedra sinica STAPF., Ephedra intermedia SCHRENK et C.A. MEYER, or Ephedra equisetina BUNGE (Ephedraceae) which contains more than 0.7% ephedrine alkaloids (ephedrine and pseudoephedrine). The primary effects and adverse effects of Ephedra Herb are traditionally believed to be mediated by ephedrine alkaloids. We recently reported that Ephedra Herb extract (EHE) exhibits antimetastatic and antitumor effects by suppressing the hepatocyte growth factor-c-Met signaling pathway through the inhibition of c-Met tyrosine kinase activity. We confirmed that the non-alkaloidal fraction of EHE had c-Met-inhibitory activity. Moreover, we discovered herbacetin glycosides in EHE and demonstrated that herbacetin, the aglycone of the glycosides, shows c-Met-inhibitory activity and analgesic action. These findings suggest that some pharmacological actions of EHE may be produced by its non-alkaloidal fraction, which does not cause the adverse effects of ephedrine alkaloids. Therefore, we prepared ephedrine alkaloids-free EHE (EFE) by removing ephedrine alkaloids from EHE using ion-exchange column chromatography. EFE had c-Met-inhibitory action, analgesic effects, and antiinfluenza activity similar to EHE but had no toxicity. Now, we are evaluating the safety of EFE in healthy volunteers and its efficacy in patients to obtain licensing approval for its therapeutic use in the future.

Analgesic Effects and Side Effects of Ephedra Herb Extract and Ephedrine Alkaloids-free Ephedra Herb Extract.

Ephedra Herb is classified "pungent, slightly bitter, and warm" in tastes and natures, and is used to provide warmth to the body, dispel coldness, remove dampness, and reduce pain. Similar herbs are "pungent and hot" chili peppers, "pungent and hot" evodia fruit," "pungent and warm" ginger, "pungent and hot" processed ginger, "pungent and hot" Zanthoxylum fruit, etc. These herbs are prescribed to provide heat to the outer or inner body. Some pungent components such as capsaicin, evodiamine, gingerol, and shogaol are known to be activators of transient receptor potential vanilloid 1 (TRPV1). TRPV1, a pain receptor, is activated in response to irritant chemicals such as capsaicin and high heat (>43℃) and strongly acidic conditions (pH<6). The typical TRPV1 activator capsaicin has various effects such as improvement of peripheral circulation, enhancement of thermogenesis, and pain relief. These effects are commonly observed for the "pungent and hot/warm" herbs, suggesting that TRPV1 stimulation plays an important part in their pharmacological action. In this study, we demonstrated that Ephedra Herb extract (EHE) shows strong TRPV1 activation, although ephedrine didn't show such effects. Both EHE and ephedrine alkaloids-free EHE (EFE) expressed similar analgesic action following oral administration, suggesting the presence of active components other than ephedrine alkaloids. Furthermore, EFE did not show side effects such as loss of sleep and irregular heartbeat in mice. Caution needs to be exercised while prescribing Ephedra Herb because it contains ephedrine. The application of EFE in Kampo medicine might be a better alternative in some cases.

Ventricular arrhythmias induced by long-term use of ephedrine in two competitive athletes.

Ephedrine is a sympathomimetic substance used by sportsmen as a doping substance because of its stimulating and slimming effects. We report two cases of ventricular arrhythmias induced by abuse of ephedrine in two competitive athletes. Endomyocardial biopsies guided by electroanatomic mapping revealed contraction-band necrosis, a myocardial injury frequently observed in cases of catecholamine excess. Our cases suggest that long-term abuse of ephedrine may result in myocardial damage, and that these structural alterations may promote areas of slow conduction favoring re-entrant ventricular tachyarrhythmias and a long-lasting risk of ventricular arrhythmias.

How ephedrine escaped regulation in the United States: a historical review of misuse and associated policy.

OBJECTIVE: Ephedrine is not only efficacious in the treatment of numerous ailments, but also has a long history of misuse. Research was needed to examine ephedrine policy over time in order to determine potential regulatory flaws that allowed misuse to continue. METHODS: This review is based on primary literature derived from systematic searches of historical and scientific archives, as well as grey literature. RESULTS: Ephedrine managed to pass through numerous regulatory loopholes within seventy years. Despite warnings of misuse over the latter half of the century, ephedrine, and its herbal source, ephedra, were regulated in a piecemeal fashion and remained easily available to the public. Health authorities have struggled to control ephedrine, as an amphetamine "look-alike," as a methamphetamine precursor, as a dietary supplement, and as a medication. Despite being a potentially dangerous stimulant, under-regulation was perhaps more problematic than the substance itself. CONCLUSIONS: Tighter control of all ephedrine products, drugs and dietary supplements alike, might have prevented adverse outcomes and allowed this substance to remain available in a safer manner. Stringent regulation of all ephedrine products is necessary to prevent misuse and to protect the public's health.

Ischemic stroke associated with cough and cold preparation containing methylephedrine and supplement containing Chinese herbal drugs.

Methylephedrine is generally harmless and is contained in many cough and cold preparations. Likewise, Chinese herbal drugs are considered to be effective and to have few side effects. A 32-year-old woman experienced ischemic stroke attributed to concomitant administration of a cough and cold preparation containing methylephedrine and a supplement containing Chinese herbal drugs. Computed tomography and magnetic resonance imaging of the brain showed acute infarctions bilaterally in the cerebellum. Conventional angiography and magnetic resonance angiography showed transient stenosis of the left vertebral artery. These findings suggested vasospasm or dissection, presumably related to hypertension and/or angiitis or vasoconstriction of large cerebral arteries leading to local thrombosis as a result of stasis and sympathomimetic-induced platelet activation. Combining methylephedrine and Chinese herbal drugs might carry a risk of stroke.

Infarto do miocárdio em atleta jovem associado ao uso de suplemento dietético rico em efedrina / Myocardial infarction associated with the use of a dietary supplement rich in ephedrine in a young athlete

Suplementos dietéticos que contêm efedrina e outros alcalóides relacionados à efedrina são largamente consumidos em vários países, com propósito de estímulo energético e perda de peso. Mesmo sendo proibida a sua comercialização no Brasil, esses produtos podem ser comprados ilegalmente pela Internet ou em academias. Relatamos a seguir o caso de um jovem atleta, sem fatores de risco para doença cardiovascular, que apresentou infarto do miocárdio no período em que fez uso de suplemento rico em efedrina.

Dietary supplements containing ephedrine and other alkaloids related to ephedrine are largely consumed in various countries, with the purpose of energetic stimulation and weight loss. Despite the fact that it is not approved for marketing in Brazil, these products may be freely purchased over the Internet or at gyms/fitness centers. We report the case of a young athlete with no risk factors for cardiovascular disease who experienced a myocardial infarction during the period in which he used an ephedrine-rich supplement.

Popular ergogenic drugs and supplements in young athletes.

Ergogenic drugs are substances that are used to enhance athletic performance. These drugs include illicit substances as well as compounds that are marketed as nutritional supplements. Many such drugs have been used widely by professional and elite athletes for several decades. However, in recent years, research indicates that younger athletes are increasingly experimenting with these drugs to improve both appearance and athletic abilities. Ergogenic drugs that are commonly used by youths today include anabolic-androgenic steroids, steroid precursors (androstenedione and dehydroepiandrosterone), growth hormone, creatine, and ephedra alkaloids. Reviewing the literature to date, it is clear that children are exposed to these substances at younger ages than in years past, with use starting as early as middle school. Anabolic steroids and creatine do offer potential gains in body mass and strength but risk adverse effects to multiple organ systems. Steroid precursors, growth hormone, and ephedra alkaloids have not been proven to enhance any athletic measures, whereas they do impart many risks to their users. To combat this drug abuse, there have been recent changes in the legal status of several substances, changes in the rules of youth athletics including drug testing of high school students, and educational initiatives designed for the young athlete. This article summarizes the current literature regarding these ergogenic substances and details their use, effects, risks, and legal standing.

Myocardial infarction associated with the use of a dietary supplement rich in ephedrine in a young athlete.

Dietary supplements containing ephedrine and other alkaloids related to ephedrine are largely consumed in various countries, with the purpose of energetic stimulation and weight loss. Despite the fact that it is not approved for marketing in Brazil, these products may be freely purchased over the Internet or at gyms/fitness centers. We report the case of a young athlete with no risk factors for cardiovascular disease who experienced a myocardial infarction during the period in which he used an ephedrine-rich supplement.