Ephedra

Ephedra/Drug Interactions:

  • Acidifying agentsAcidifying agents: In laboratory research, ephedrine and pseudoephedrine were excreted more rapidly with urinary acidifiers, such as ammonium chloride (155).
  • AlcoholAlcohol: A brief episode of acute psychosis in a 32 year-old male followed the consumption of alcohol, caffeine, and Vigueur Fit? tablets containing ephedra alkaloids (151). However, it is unclear if ephedra caused this reaction.
  • Alkalinizing agentsAlkalinizing agents: In laboratory research, ephedrine and pseudoephedrine were excreted more slowly with urinary alkalinizers.
  • AnestheticsAnesthetics: In human research, ephedra demonstrated potential for decreasing the effectiveness of general anesthetics, such as halothane, cyclopropane, or propofol, and increasing the risk of arrhythmia (91; 92; 93; 15).
  • Antiadrenergic drugs (alpha-blockers)Antiadrenergic drugs (alpha-blockers): Theoretically, the sympathomimetic effects of ephedrine, such as mydriasis and hypertension, can be antagonized by antiadrenergic drugs, including clonidine, reserpine, or terazosin.
  • AntiandrogensAntiandrogens: Theoretically, ephedra can interact with antiandrogens.
  • Antiarrhythmic drugsAntiarrhythmic drugs: In human research, ephedra alone (e.g., ephedrine, ephedrine sulfate, pseudoephedrine, ephedra alkaloids) or in conjunction with caffeine (e.g., Metabolife 356?) has induced hypertension, chronotropic, and inotropic effects in humans (63; 57; 64; 65; 66; 67; 68; 69; 70; 71; 72). Metabolife 356?, a product containing ephedra and other ingredients, was associated with heart-rhythm abnormalities (arrhythmias, QT prolongation) (69).
  • Antiasthma drugsAntiasthma drugs: In a review, both ephedrine and pseudoephedrine caused bronchodilation (63). In human research, adjunct ephedrine sulfate to aminophylline increased forced expiratory volume in one second and peak flow rate vs. baseline (105). Increased forced vital capacity has also been observed in humans compared to placebo (14).
  • Antidepressants, monoamine oxidase inhibitors (MAOIsAntidepressants, monoamine oxidase inhibitors (MAOIs): When ephedra is administered in combination with MAOIs, increased sympathomimetic activity can increase the risk of hypertensive crisis. One case report noted a 28 year-old woman who developed encephalopathy, neuromuscular irritability, hypotension, tachycardia, rhabdomyolysis, and hyperthermia after taking a combination tablet containing ephedrine, caffeine, and theophylline (a "Do-Do") 24 hours after discontinuing phenelzine treatment (156).
  • Antidepressants, selective serotonin reuptake inhibitors (SSRIs)Antidepressants, selective serotonin reuptake inhibitors (SSRIs): Theoretically, ephedra can interact with SSRIs.
  • Antidepressants, tricyclics (TCAs)Antidepressants, tricyclics (TCAs): In one case report, concomitant use of amitriptyline and ephedrine was associated with hypotension in a 61 year-old woman undergoing ovarian cancer resection (90).
  • Antidiabetic agentsAntidiabetic agents: In human research, ephedrine alone or coadministered with caffeine has been associated with hyperglycemia (75; 73; 66). In contrast, crude extracts of Ephedra distachya have elicited hypoglycemia in normal and diabetic mice (74).
  • Antigout agentsAntigout agents: Theoretically, ephedra can interact with antigout agents.
  • AntihypertensivesAntihypertensives: In human research, ephedra has interacted with beta2-adrenergic receptor drugs (157). Ephedra alone (e.g., ephedrine, ephedrine sulfate, pseudoephedrine, ephedra alkaloids) or in conjunction with caffeine (e.g., Metabolife 356?) has induced hypertension, chronotropic, and inotropic effects in humans (63; 57; 64; 65; 66; 67; 68; 69; 70; 71; 72). Theoretically, ephedra can antagonize the activity of antihypertensive agents, such as beta-blockers, diuretics, angiotensin-converting enzyme inhibitors, or calcium-channel blockers. However, in several trials of ephedrine and caffeine combinations taken for weight loss, significant changes in mean heart rate or blood pressure were lacking vs. placebo or control (5; 4; 127).
  • Anti-inflammatory agentsAnti-inflammatory agents: In human research, coadministration of ma huang and various other agents as part of a modified Shegan Mahuang traditional Chinese medicine decoction normalized asthma-induced aberrations in the serum level of interleukin (IL)-10 (increased), IL-13 (decreased), and tumor necrosis factor (TNF)-alpha (decreased) (158).
  • Antilipemic agentsAntilipemic agents: In human research, coadministration of ephedra (e.g., ephedrine alkaloids) and caffeine (e.g., guarana, kola nut) decreased low-density lipoprotein (LDL) cholesterol and triglycerides, and increased high-density lipoprotein (HDL) cholesterol (73; 70).
  • Antiobesity agentsAntiobesity agents: Several human trials have shown that ephedrine alone or coadministered with caffeine facilitates weight loss (100; 159; 85; 86; 160; 161; 70; 162).
  • AspirinAspirin: In human research, aspirin potentiated the ephedrine's stimulatory effect on thermogenic response, as evidence by a larger increase in resting metabolic rate vs. ephedrine alone (101). However, this observed effect was limited to obese, not lean, individuals.
  • Cardiac glycosidesCardiac glycosides: In human research, ephedra alone (e.g., ephedrine, ephedrine sulfate, pseudoephedrine, ephedra alkaloids) or in conjunction with caffeine (e.g., Metabolife 356?) has induced hypertension, chronotropic, and inotropic effects in humans (63; 57; 64; 65; 66; 67; 68; 69; 70; 71; 72). However, in several trials of ephedrine-caffeine combinations taken for weight loss, significant changes in mean heart rate or blood pressure were lacking vs. placebo or control (5; 4; 127).
  • CNS stimulantsCNS stimulants: In a review of in vitro and in vivo research, ephedra (ephedrine and pseudoephedrine) stimulated the central nervous system (CNS) (63) and increased sympathomimetic activity (156). Also, 27 of 33 incidences of dietary supplement-associated seizures reported to the FDA over a seven-year period spanning 1993 to 1999 were deemed "probably" or "possibly" related to the use of ephedra (78).
  • Cytochrome P450-metabolized agentsCytochrome P450-metabolized agents: Shoseiryuto (TJ-19) contains eight herbal components, including Ephedra sinica. At the generally recommended dosage, TJ-19 is unlikely to cause a pharmacokinetic interaction with coadministered medications primarily dependent on the CYP1A2, CYP2D6, CYP3A, XO, and NAT2 pathways for elimination (163).
  • DiureticsDiuretics: The ephedra constituents ephedrine and pseudoephedrine possess diuretic properties (63; 57; 64; 65).
  • Drugs that may cause rhabdomyolysisDrugs that may cause rhabdomyolysis: Rare cases of severe rhabdomyolysis provoked by the ingestion of performance-enhancing herbal supplements containing ephedra or synephrine have been reported (122; 123). Rhabdomyolysis and myoglobinuric renal failure associated with ephedra use are very uncommon occurrences, but they are significant clinical events that should be closely monitored due to rampant use by young adults of ephedra-containing dietary supplements.
  • Drugs that may lower seizure thresholdDrugs that may lower seizure threshold: There have been case reports of seizures in patients taking ephedra (21; 22). Also, 27 of 33 incidences of dietary supplement-associated seizures reported to the FDA over a seven-year period spanning 1993 to 1999 were deemed "probably" or "possibly" related to the use of ephedra (78).
  • Ergot derivativesErgot derivatives: Ergot alkaloids exert alpha-adrenergic vasoconstrictive effects and when used in combination with ephedra can theoretically increase hypertensive effects.
  • Gastrointestinal agentsGastrointestinal agents: Anecdotal reports and clinical trials have noted various gastrointestinal adverse effects, including nausea, vomiting, dry mouth, anorexia, constipation, loose stools, heartburn, and abdominal discomfort (86; 1; 70; 87; 88; 89).
  • HepatotoxinsHepatotoxins: Increases in aminotransferase levels have been noted anecdotally. Case reports and human research have documented decreases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (73; 86), acute hepatitis possibly due to the presence of a contaminant (136), and fulminant exacerbation of autoimmune hepatitis from ephedrine (137).
  • Hormonal agentsHormonal agents: In human research, the ratio of serum T3 to T4 significantly increased after four weeks of treatment with ephedra, although after 12 weeks of treatment, the ratio decreased (85).
  • ImmunosuppressantsImmunosuppressants: In cellular research, human lymphocytes treated with ephedra extract increased immune cell proliferation of V2, V3, V8, V11, and V12 compared to lymphocytes treated with extracts of Acanthopanacis cortex, Rehmanniae radix, or white ginseng (164).
  • Methylxanthines (theophylline, caffeine)Methylxanthines (theophylline, caffeine): Use of ephedra with caffeine, theophylline, or other methylxanthines may result in additive neurologic, cardiovascular, and psychiatric adverse effects or toxicity. Fatalities have been associated with simultaneous caffeine and ephedrine use (80; 81; 82). A brief episode of acute psychosis in a 32 year-old male followed the consumption of alcohol, caffeine, and Vigueur Fit? tablets containing ephedra alkaloids (151). Notably, many commercial products contain both ephedra and caffeine. Theophylline combined with ephedrine can induce insomnia, anxiety, and adverse gastrointestinal effects, including vomiting (165).
  • OxytocicsOxytocics: Theoretically, concomitant use with ephedra may increase the risk of hypertension.
  • PhenothiazinesPhenothiazines: Theoretically, phenothiazines can block the alpha-adrenergic effects of ephedra.
  • Phenylpropanolamine (removed from the U.S. market)Phenylpropanolamine (removed from the U.S. market): Theoretically, concomitant use of ephedra and phenylpropanolamine can lead to additive effects (166).
  • Renally eliminated agentsRenally eliminated agents: Case reports of ephedra-induced nephrolithiasis (kidney stones) (83; 84) have been published. Other reported effects included diuresis, urinary retention, and dysuria. Rare cases of severe rhabdomyolysis provoked by the ingestion of performance-enhancing herbal supplements containing ephedra or synephrine have been reported (122; 123). Rhabdomyolysis and myoglobinuric renal failure associated with ephedra use are very uncommon occurrences, but they are significant clinical events that should be closely monitored due to rampant use by young adults of ephedra-containing dietary supplements. Ephedra's tannins have been proposed to possess some renal protective properties, based on experimental models of kidney failure in rats (167).
  • SteroidsSteroids: In human research, ephedrine has been reported to increase the clearance and reduce the effectiveness of dexamethasone (168; 10).
  • Thyroid hormonesThyroid hormones: In human research, the ratio of serum T3 to T4 significantly increased after four weeks of treatment with ephedra, although after 12 weeks of treatment, the ratio decreased (85).

    • Ephedra/Herb/Supplement Interactions:

  • AnestheticsAnesthetics: In human research, ephedra has demonstrated the potential to decrease the effectiveness of general anesthetics and increase the risk of arrhythmia (91; 92; 93; 15).
  • Antiadrenergic herbs and supplementsAntiadrenergic herbs and supplements: Theoretically, the sympathomimetic effects of ephedrine, such as mydriasis and hypertension, can be antagonized by antiadrenergic herbs and supplements.
  • AntiandrogensAntiandrogens: Theoretically, ephedra can interact with antiandrogens.
  • AntiarrhythmicsAntiarrhythmics: In human research, ephedra alone (e.g., ephedrine, ephedrine sulfate, pseudoephedrine, ephedra alkaloids) or in conjunction with caffeine (e.g., Metabolife 356?) has induced hypertension, chronotropic, and inotropic effects in humans (63; 57; 64; 65; 66; 67; 68; 69; 70; 71; 72).
  • Antiasthma herbs and supplementsAntiasthma herbs and supplements: In a review, both ephedrine and pseudoephedrine caused bronchodilation (63). In human research, adjunct ephedrine sulfate to aminophylline increased forced expiratory volume in one second and peak flow rate vs. baseline (105). Increased forced vital capacity has also been observed in humans compared to placebo (14).
  • Antidepressants, monoamine oxidase inhibitors (MAOIs)Antidepressants, monoamine oxidase inhibitors (MAOIs): Combining ephedra with herbs that have possible MAOI antidepressant activity, such as St. John's wort, may cause severe side effects, including dangerously high blood pressure, muscle breakdown, fever, and irregular heartbeats. When ephedra is administered in combination with agents possessing MAOI activity, increased sympathomimetic activity may increase the risk of hypertensive crisis. One case report noted a 28 year-old woman who developed encephalopathy, neuromuscular irritability, hypotension, tachycardia, rhabdomyolysis, and hyperthermia after taking a combination tablet containing ephedrine, caffeine, and theophylline (a "Do-Do") 24 hours after discontinuing phenelzine treatment (156).
  • Antidepressants, selective serotonin reuptake inhibitors (SSRIs)Antidepressants, selective serotonin reuptake inhibitors (SSRIs): Theoretically, ephedra can interact with herbs that have possible SSRI antidepressant activity.
  • Antigout herbs and supplementsAntigout herbs and supplements: Theoretically, ephedra can interact with antigout herbs and supplements.
  • Anti-inflammatory agentsAnti-inflammatory agents: In human research, coadministration of ma huang and various other agents as part of a modified Shegan Mahuang traditional Chinese medicine decoction normalized asthma-induced aberrations in the serum level of IL-10 (increased), IL-13 (decreased), and TNF-alpha (decreased) (158).
  • AntilipemicsAntilipemics: In human research, coadministration of ephedra (e.g., ephedrine alkaloids) and caffeine (e.g., guarana, kola nut) decreased LDL cholesterol and triglycerides, and increased HDL cholesterol (73; 70). Other agents with possible hypolipidemic properties include fish oil, garlic, guggul, and niacin.
  • Antiobesity herbs and supplementsAntiobesity herbs and supplements: Several human trials have shown that ephedrine alone or coadministered with caffeine facilitates weight loss (100; 159; 85; 86; 160; 161; 70; 162).
  • Appetite suppressantsAppetite suppressants: Several human trials have shown that ephedrine alone or coadministered with caffeine facilitates weight loss (100; 159; 85; 86; 160; 161; 70; 162).
  • Caffeine-containing herbsCaffeine-containing herbs: Theoretically, caffeine-containing herbs, such as cola nut, guarana, and yerba mate, can increase the risk of endocrine, cardiovascular, neurologic, or psychiatric adverse effects when taken concomitantly with ephedra (75; 73; 80; 81; 138; 151).
  • Cardiac glycosidesCardiac glycosides: In human research, ephedra alone (e.g., ephedrine, ephedrine sulfate, pseudoephedrine, ephedra alkaloids) or in conjunction with caffeine (e.g., Metabolife 356?) has induced hypertension, chronotropic, and inotropic effects in humans (63; 57; 64; 65; 66; 67; 68; 69; 70; 71; 72).
  • Chronotropic herbsChronotropic herbs: In human research, ephedra alone (e.g., ephedrine, ephedrine sulfate, pseudoephedrine, ephedra alkaloids) or in conjunction with caffeine (e.g., Metabolife 356?) has induced hypertension, chronotropic, and inotropic effects in humans (63; 57; 64; 65; 66; 67; 68; 69; 70; 71; 72).
  • Cytochrome P450-metabolized herbs and supplementsCytochrome P450-metabolized herbs and supplements: Shoseiryuto (TJ-19) contains eight herbal components, including Ephedra sinica. At the generally recommended dosage, TJ-19 is unlikely to cause a pharmacokinetic interaction with coadministered medications primarily dependent on the CYP1A2, CYP2D6, CYP3A, XO, and NAT2 pathways for elimination (163).
  • DiureticsDiuretics: The ephedra constituents ephedrine and pseudoephedrine possess diuretic properties (63; 57; 64; 65).
  • Gastrointestinal agentsGastrointestinal agents: Anecdotal reports and clinical trials have noted various gastrointestinal adverse effects, including nausea, vomiting, dry mouth, anorexia, constipation, loose stools, heartburn, and abdominal discomfort (86; 1; 70; 87; 88; 89).
  • HepatotoxinsHepatotoxins: Increases in aminotransferase levels have been noted anecdotally. Case reports and human research have documented decreases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (73; 86), acute hepatitis possibly due to the presence of a contaminant (136), and fulminant exacerbation of autoimmune hepatitis from ephedrine (137).
  • Herbs and supplements that cause rhabdomyolysisHerbs and supplements that cause rhabdomyolysis: Rare cases of severe rhabdomyolysis provoked by the ingestion of performance-enhancing herbal supplements containing ephedra or synephrine have been reported (122; 123). Rhabdomyolysis and myoglobinuric renal failure associated with ephedra use are very uncommon occurrences, but they are significant clinical events that should be closely monitored due to rampant use by young adults of ephedra-containing dietary supplements.
  • Herbs and supplements that lower seizure thresholdHerbs and supplements that lower seizure threshold: There have been case reports of seizures in patients who take ephedra (21; 22). Also, 27 of 33 incidences of dietary supplement-associated seizures reported to the FDA over a seven-year period spanning 1993-1999 were deemed "probably" or "possibly" related to the use of ephedra (78).
  • Hormonal herbs and supplementsHormonal herbs and supplements: In human research, the ratio of serum T3 to T4 significantly increased after four weeks of treatment with ephedra, although after 12 weeks of treatment, the ratio decreased (85).
  • Hyperglycemics and hypoglycemicsHyperglycemics and hypoglycemics: In human research, ephedrine alone or coadministered with caffeine has been associated with hyperglycemia (73; 75; 66). In contrast, crude extracts of Ephedra distachya have elicited hypoglycemia in normal and diabetic mice (74).
  • Hypertensives and hypotensivesHypertensives and hypotensives: In human research, ephedra alone (e.g., ephedrine, ephedrine sulfate, pseudoephedrine, ephedra alkaloids) or in conjunction with caffeine (e.g., Metabolife 356?) has induced hypertension, chronotropic, and inotropic effects in humans (63; 57; 64; 65; 66; 67; 68; 69; 70; 71; 72). However, in several trials of ephedrine-caffeine combinations taken for weight loss, significant changes in mean heart rate or blood pressure were lacking vs. placebo or control (5; 4; 127).
  • ImmunosuppressantsImmunosuppressants: In cellular research, human lymphocytes treated with ephedra extract increased immune cell proliferation of V2, V3, V8, V11, and V12 compared to lymphocytes treated with extracts of Acanthopanacis cortex, Rehmanniae radix, or white ginseng (164).
  • PotassiumPotassium: Theoretically, ephedra may lower serum potassium levels.
  • Renally eliminated agentsRenally eliminated agents: Case reports of ephedra-induced nephrolithiasis (kidney stones) (83; 84) have been published. Other reported effects include diuresis, urinary retention, and dysuria. Rare cases of severe rhabdomyolysis provoked by the ingestion of performance-enhancing herbal supplements containing ephedra or synephrine have been reported (122; 123). Rhabdomyolysis and myoglobinuric renal failure associated with ephedra use are very uncommon occurrences, but they are significant clinical events that should be closely monitored due to rampant use by young adults of ephedra-containing dietary supplements. Ephedra's tannins have been proposed to possess some renal protective properties, based on experimental models of kidney failure in rats (167).
  • SteroidsSteroids: In human research, ephedra reduced the effects of steroids (168; 10).
  • StimulantsStimulants: In a review of in vitro and in vivo research, ephedra (ephedrine and pseudoephedrine) stimulated the CNS (63) and increased sympathomimetic activity (156). Also, 27 of 33 incidences of dietary supplement-associated seizures reported to the FDA over a seven-year period spanning 1993-1999 were deemed "probably" or "possibly" related to the use of ephedra (78).
  • Urine-acidifying herbs and supplementsUrine-acidifying herbs and supplements: In laboratory research, ephedrine and pseudoephedrine were excreted more rapidly with urinary acidifiers (155).
  • Urinealkalinizing herbs and supplementsUrine-alkalinizing herbs and supplements: In laboratory research, ephedrine and pseudoephedrine were excreted more slowly with urinary alkalinizers.

    • Ephedra/Food Interactions:

  • AlcoholAlcohol: A brief episode of acute psychosis in a 32 year-old male followed the consumption of alcohol, caffeine, and Vigueur Fit? tablets containing ephedra alkaloids (151).
  • Coffee/teaCoffee/tea: Foods containing caffeine taken in combination with ephedra may increase the risk of endocrine, cardiovascular, neurologic, or psychiatric adverse effects. Fatalities have been associated with simultaneous caffeine and ephedrine use (80; 81; 82). A brief episode of acute psychosis in a 32 year-old male followed the consumption of alcohol, caffeine, and Vigueur Fit? tablets containing ephedra alkaloids (151).
  • Potassium-containing foodsPotassium-containing foods: Theoretically, ephedra may lower serum potassium levels.

    • Ephedra/Lab Interactions:

  • Blood pressureBlood pressure: In human research, ephedra alone (e.g., ephedrine, ephedrine sulfate, pseudoephedrine, ephedra alkaloids) or in conjunction with caffeine has induced hypertension, chronotropic, and inotropic effects in humans (63; 57; 64; 65; 66; 67; 68; 70; 71; 72). However, some combination ephedrine-caffeine studies have demonstrated contradictory results (5; 4; 127). In pregnant women undergoing spinal anesthesia for Cesarean delivery, intravenous ephedrine has also lowered the incidence of hypotension, increased systolic arterial pressure (SAP), and reduced the maximum decrease in SAP vs. saline control (89). Compared to metaraminol, a higher proportion of patients receiving intravenous ephedrine infusion demonstrated neonatal acidosis (umbilical arterial pH <7.2) and less control over arterial pressure (88).
  • DopamineDopamine: In human research, ephedrine increased dopamine levels (99).
  • LactateLactate: In human research, ephedrine increased lactate levels after exercise (99).
  • Lipid profileLipid profile: In human research, coadministration of ephedra (e.g., ephedrine alkaloids) and caffeine (e.g., guarana, kola nut) decreased LDL cholesterol and triglycerides, and increased HDL cholesterol (73; 70).
  • Liver function testsLiver function tests: Increases in aminotransferase levels have been noted anecdotally. Case reports and human research have documented decreases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (73; 86), acute hepatitis possibly due to the presence of a contaminant (136), and fulminant exacerbation of autoimmune hepatitis from ephedrine (137).
  • NorepinephrineNorepinephrine: In human research, the coadministration of ephedrine and caffeine increased postexercise levels of norepinephrine (99).
  • PotassiumPotassium: Theoretically, ephedra may lower serum potassium levels.
  • Pulmonary function tests (PFTs)Pulmonary function tests (PFTs): In a review, both ephedrine and pseudoephedrine caused bronchodilation (63). In human research, adjunct ephedrine sulfate to aminophylline increased forced expiratory volume in one second and peak flow rate vs. baseline (105). Increased forced vital capacity has also been observed in humans compared to placebo (14).
  • Serum glucoseSerum glucose: In human research, ephedrine alone or coadministered with caffeine has been associated with hyperglycemia (75; 73; 66). In other human research, ephedrine has also increased glucose levels both before and after exercise (99). In contrast, crude extracts of Ephedra distachya have elicited hypoglycemia in normal and diabetic mice (74).
  • Thyroid hormones (T3:T4 Ratio)Thyroid hormones (T3:T4 Ratio): In human research, the ratio of serum T3 to T4 significantly increased after four weeks of treatment with ephedra, although after 12 weeks of treatment, the ratio decreased (85).
  • Urine amphetamine/methamphetamineUrine amphetamine/methamphetamine: In laboratory analyses, ephedra has caused false-positive urine amphetamine or methamphetamine test results (169; 155; 170).