Quick Navigation

Ephedrine

Ephedrine is one of the four active components of the herb Ephedra. It is able to induce fat loss via increasing the amount of fat available for fuel as well as by increasing heat expenditure. It has been implicated in increasing the metabolic rate by up to 5% in humans. It has also been noted to cause serious side-effects in some instances, and its legal status varies by region.

Our evidence-based analysis on ephedrine features 98 unique references to scientific papers.

Kamal Patel
Research analysis led by Kamal Patel.
All content reviewed by the Examine.com Team. Published: Jan 4, 2013
Last Updated:

Summary of Ephedrine

Primary Information, Benefits, Effects, and Important Facts

Examine.com special safety warning on ephedrine and ephedra products:
While dietary supplements containing ephedrine alkaloids have been used with an acceptable margin of safety and efficacy by many individuals, they can be downright dangerous for those with certain underlying medical conditions. A number of case reports have implicated ephedrine alkaloids as the cause of serious adverse health effects in isolated individuals- including but not limited to heart attack, stroke, seizures, and even death.[9] It should also be noted that supplements ephedrine alkaloids are currently banned in the United States.[10] Any decision to use ephedrine or ephedra products should be made in close consultation with your personal physician.

Ephedrine (ih-fed-rin) is one of the four active components of the herb Ephedra. It is able to induce fat loss via increasing the amount of fat available for fuel as well as by increasing heat expenditure. It has been implicated in increasing the metabolic rate by up to 5% in humans.

Ephedrine also interacts with muscle cells, increasing heat expenditure in them as well as fat cells. It can also prevent the breakdown of muscle tissue to a small degree.

Ephedrine is highly synergistic with caffeine, and for this reason is commonly found in something called an ECA stack (Ephedrine, Caffeine, and Aspirin).

Side effects include an increase in blood pressure that goes away with cessation and increases in some blood parameters (glucose, insulin) that also go away with cessation of use. It has been reported to be a hyperstimulant when taken in doses above what is recommended.

Ephedrine is well studied and a fairly reliable compound for short- to medium-term weight loss (less than 6 months) and mild performance improvements, usually in trained individuals. However, it does not work under all situations; longer-term weight loss and effects in untrained individuals have not been studied much and sometimes produce negative results. While it has been implicated in weight reduction independent of exercise and diet changes, efficacy is maximized with minimal side-effects when ephedrine is combined with diet and exercise.

Learn which supplements work (and which don’t) to achieve your health goals

Enter your email to get our free mini-course on supplements.

100% backed by science, we take an independent and unbiased approach to figure out what works (and what's a waste of time and money). Arm yourself with the knowledge needed to make the right choices to improve your health.



Things To Know & Note

Is a Form Of

Other Functions:

Primary Function:

Also Known As

Ephedra Vulgaris, Ephedraceae, ma huang

Do Not Confuse With

Ephedrone, Epinephrine

Goes Well With

Methylxanthines such as caffeine and theophylline (a component of green tea)

Caution Notice

Examine.com Medical Disclaimer

  • Ephedrine is highly stimulatory, and the plant (Ephedra) more-so.

How to Take Ephedrine

Recommended dosage, active amounts, other details

All Doses Standardized to Ephedrine HCl

In an ECA stack, ephedrine is dosed at 20-24mg for three doses taken throughout the day.

Human studies have found success with ephedrine in isolation on fat metabolism with doses of 20-50mg thrice a day. The higher range (150mg) may be too stimulatory for some, and can induce headaches or light hand tremors.

Ephedrine tends to be consumed with xanthine compounds like caffeine and sometimes with Aspirin. The combination of Ephedrine and caffeine is shown repeatedly to be highly synergistic.

Frequently Asked Questions about Ephedrine

Do I need to cycle ephedrine?
Surprisingly, ephedrine does not appear to need cycling for the fat burning aspect of it (it may for neurological stimulation and appetite suppression). If using an ECA stack, however, the caffeine may need to be cycled
Read full answer to "Do I need to cycle ephedrine?"

Human Effect Matrix

The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects ephedrine has on your body, and how strong these effects are.
Grade Level of Evidence
Robust research conducted with repeated double-blind clinical trials
Multiple studies where at least two are double-blind and placebo controlled
Single double-blind study or multiple cohort studies
Uncontrolled or observational studies only
Level of Evidence
? The amount of high quality evidence. The more evidence, the more we can trust the results.
Outcome Magnitude of effect
? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.
Consistency of research results
? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.
Notes
grade-b
Fat Mass
Notable Very High See all 4 studies
It is thought that most weight lost with ephedrine administration is due to fat mass, due to a slight muscle preserving effect; studies that note reductions in fat mass support this hypothesis
grade-b
Metabolic Rate
Notable Very High See all 6 studies
Ephedrine, secondary to the stimulatory properties, appears to reliably increased metabolic rate
grade-b
Weight
Notable High See all 10 studies
Ephedrine tends to result in reliable weight loss over time relative to control (assuming calories are held equal), which is mostly due to a loss of body fat
grade-b
Blood Pressure
Minor Low See all 5 studies
There may be an acute increase in blood pressure seen with ephedrine intake, although this does not appear to be overly reliable; long-term usage of ephedrine does not seem to alter blood pressure, and may reduce it secondary to weight loss
grade-b
Heart Rate
Minor Moderate See all 5 studies
An increase in heart rate is present following ephedrine administration which correlates well with its psychostimulatory properties; this is not 100% reliable, and heart rate increases may not occur
grade-c
Nasal Congestion
Notable Very High See 2 studies
Ephedrine appears to result in notable nasal decongestion
grade-c
HDL-C
Minor Very High See 2 studies
An increase in HDL-C has been noted with ingestion of ephedrine, may be confounded with weight loss also seen in the trials
grade-c
LDL-C
Minor - See study
A decrease in LDL-C has been noted to be associated with ephedrine, although this may be confounded with weight loss (also seen in the trials)
grade-c
Skeletal Muscle Atrophy
Minor - See study
May decrease the rate of skeletal muscle breakdown over time
grade-c
Subjective Well-Being
Minor - See study
Appears to increase well being acutely following the first doses of ephedrine, secondary to the psychostimulatory effects
grade-c
Triglycerides
Minor Very High See 2 studies
There appears to be a decrease in triglycerides over time with ephedrine ingestion, which may be due to either the fat burning effects of ephedrine or the weight loss that tends to ensue
grade-c
Power Output
- - See study
No significant influence on power output with standard oral doses of ephedrine (higher doses may influence power output, but this is not well researched)
grade-d
Appetite
Minor - See study
A decrease in appetite following ephedrine intake is noted and thought to be secondary to its psychostimulatory effects
grade-d
Nausea
- See study
Ephedrine has been noted to reduce postoperative nausea, but is also linked to inducing nausea secondary to its psychostimulatory and appetite suppressing effects. The latter is more practical for supplementation

Studies Excluded from Consideration

Scientific Research on Ephedrine

Click on any below to expand the corresponding section. Click on to collapse it.

Click here to fully expand all sections or here to fully collapse them.

1Sources and Structure

1.1Composition (Ephedra)

Ephedrine is found in the Ephedra Sinica plant, also known as Ma Huang or Chinese Ephedrea. This distinction is important as there is an entire genus called Ephedrea in the family Ephedraceae, and the ephedrine alkaloids touted as fat burners are only present in Sinica.[11]

Ephedra in general contains more than 50 species, and is found world-wide. Many are adapted to semiarid and desert conditions, although some are found in humid or temperate climates in the Mediterrean and North America.[11][12]

Ma Huang (Ephedra Sinica), the one sold as a fat burner, contains:

  • Ephedrine alkaloids (main fat burning compounds, topic of article) mostly in Ephedra Sinica, distachya, equisetina, monosperma and gerardiana[11] 

  • Ephedrine precursor, cathinone (norpseudoephedrine)[13] and derivative ephedroxane.[14]

  • Cyclopropyl analogues of amino acids (glutamate) including (2S,3R,4S)-3,4-methanoproline in the stems and leaves of many plants, and in the seeds in high amounts.[11] Not in the stems or leaves of Ephedra altissima or Viridus.

  • (2S,3S,4S)-2-(carboxycyclopropyl)glycine, a cyclopropyl compound that is an agonist of some glutamate receptors (MGluR2, MGluR3) and found in high amounts in Ephedra antisyphilitica (0.5% by stem weight). The related compound (2S,3S,4R)-2-(carboxycyclopropyl)glycine may also be psychoactive, and is found in the berries of Ephedra foemina

  • Kynurenate compounds (6-hydroxykynurenate, 6-methoxykynurenate, 7-methoxykynurenate) in the stem, none in the root. Also contains the parent compound of kynurenate acid (4-hydroxyquinoline-2-carboxylic acid) at concentrations up to 1% dry mass in Ephedra fasciculata and funerea

  • Proanthocyanidin compounds, and the tannin compounds ellagitannins and gallotannins.[11]

New world ephedra plants (those found in North and South America, about half of the species by number) do not contain substantial amounts of ephedrine alkaloids,[11] although there are unconfirmed claims that there may be a pseudoephedrine content.[15][16] The one study to analyze various Ephedra species noted no ephedrine or pseudoephedrine in North American species.[11]

1.2Ephedrine (Ephedrine Alkaloids)

'Ephedrine', as a molecule, possesses two chiral centers. Due to this flexibility in its structure, it can exist in four states (or stereoisomers). They are:

  • 1R,2S (-)- Ephedrine

  • 1S,2S (+)- Pseudoephedrine

  • 1S,2R (+)- Ephedrine

  • 1R,2R (-)- Pseudoephedrine

Additionally, ephedrine and pseudorephedrine can lose a methyl group to become norephedrines, or be methylated to become N-methylephedrine. Norephedrine and Norpseudoephedrine are also known as Phenylpropinolamine, or PPA.

1.3Properties

Ephedrine appears to be stable in the urine for up to 9 months at temperatures ranging from -20°C to 37°C, and 15 hours at 60°C which simulated a weekend left in a car trunk or glovebox in a hot environment.[17][18] Ephedrine was also stable during 6 freeze-thaw cycles (-20°C to 22°C).[17]

2Pharmacology

2.1Digestion and Absorption

Ephedrine administration at 50mg is able to reduce gastric emptying rate in humans, and potentially reduce meal absorption speeds.[19][20]

2.2Systemic

All below pharmacology can be reviewed here.[21]

Ephedrine is able to act with the muscle cells directly and induce thermogenesis in myocytes. It has also been reported that urinary excretion of nitrogen is reduced during ephedrine supplementation, indicating that this interaction or a like interaction exerts a muscle sparing effect.

Ephedrine can also increase thermogenesis via its vasoconstrictory abilities and the phenomena of 'hot pipes', otherwise known as vascular thermogenesis[22] as well as acting on brown adipose tissue's beta-adrenergic receptors system.

Supplementation with ephedrine increases plasma insulin, glucose, and C-peptide in a dose dependent manner, possibly due to the state of transient insulin resistant classical stimulants induce.

Ephedrine seems to be synergistic with methylxanthine compounds (such as caffeine and theophylline), a dose of 22mg/30mg/50mg ephedrine/caffeine/theophylline has been shown to be twice as effective as ephedrine alone[23], and in comparisons between different combinations of ephedrine and caffeine a dose of 20mg/200mg has been shown to be the most synergistic.[24] This discovery led to the rise of the ECA stack, which is a stack of ephedrine/caffeine/aspirin which is dosed 20mg/200mg/91mg accordingly.

3Neurology

3.1Sensitivity

Ephedrine appears to be a more potent stimulant during periods of caloric restriction, relative to higher caloric intakes.[25] The neural stimulant effects are further increased when paired with caffeine.[26]

4Fat Mass and Obesity

4.1Mechanisms

Ephedrine is able to directly agonize all three subsets of β-adrenergic receptors of brown adipose tissue, leading to increased thermogenesis[27] without significantly activating the α-adrenergic receptor class[28] and possibly antagonizing activation from agonists of these receptors.[28] The β-class of adrenergic receptors are seen as the class that stimulate lipolysis, where the alpha class is inhibitory.[29]

The order of potency (EC50 followed by relative potency to the reference standard of isoproterenol) of the isomers of ephedrine on β1 subunits are 1R,2S(500uM, 68%) > 1S,2R(72mM, 66%) > 1S,2S(309mM, 53%) = 1R,2R(1122mM, 53%)[29] while the influence on the β2 subunits have a similar order of potency of 1R,2S(360uM, 78%) > 1R,2R(7mM, 50%) > 1S,2S(10mM, 47%) > 1S,2R(106mM, 22%).[29] β3-subunits only appear to be agonized in humans weakly by the 1R,2S isomer at an EC50 value of 45mM and 31% response relative to isoproterenol while other isomers are mostly inactive.[29]

This agonism may not appear to be seen in vivo at doses of 50mg taken thrice daily.[30]

It has been shown to increase only the beta-3 subunit in white adipose tissue in rats, but enhances glycerol release from brown adipose tissue and inhibits glucose uptake for both types of adipocyte.[31]

Ephedrine isomers are direct agonists at beta-adrenergic receptors and may directly stimulate lipolysis, but the EC50 values are fairly high and may not reflect serum levels following ingestion

4.2Metabolic Rate and Oxygen consumption

Human studies have found that oxygen consumption via an initial ephedrine dose (20mg) increases an expected amount 30-60 minutes after ingestion in all cases (with more potency in those not adapted to stimulants), although chronic ingestion of ephedrine alleviates the expected drop between 1-3 hours post ingestion. This suggests that ephedrine confers more benefits to fat burning with usage over a longer period (4-12 weeks) rather than intermittently, and the suspected mechanism is augmentation of beta-adrenergic sensitization.[32]

Ephedrine seems to, in and of itself, increase metabolic rate via REE independent of exercise; this is dissimilar to caffeine, which requires exercise to induce it's fat-burning effects to significant levels. Coincidentally, this may be the reason why the combination of Ephedrine and Caffeine shows synergism with exercise in increased oxygen consumption.[33] The combination of ephedrine and caffeine has been noted to be similarly effective (trending to be more effective) than 15mg dexfenfluramine over 12 weeks.[3]

It has been noted that caffeine ingestion does, however, increase ephedrine's effects on REE independent of exercse[34] and that this effect on potentiating was also noted with green tea, suggesting that the methylxanthine class of compounds (via increasing adrenaline) are causative of the potentiation.[23]

The previous animal studies have noted a 10% increase in REE with ephedrine supplementation, however human studies are more variable at 3.6%,[30] 10.7% (with caffeine),[7] and 7.1%.[35] Studies using indirect calorimetry note various increases, such as 30.1±5.4kcal/3hours at 20mg ephedrine + 200mg caffeine, and 22.7±7.7kcal/3hours at half the ephedrine dosage.[24] It has also been noted to reduce a 13% reduction in REE (from caloric restriction) into an 8% reduction, saving 5% of the metabolic rate.[6]

Metabolic rate, thermogenesis, and oxygen consumption are all reliably increased with ephedrine supplementation. The increase is greater with caffeine or other xanthine compounds, is greater in obese persons, and shows most practical significance during periods of caloric restriction. Estimates are around 5-12% increases in metabolic rate.

4.3Longterm Human Interventions on Fat Loss

Some case studies have supported the idea that ephedrine (paired with caffeine) can be of use to hypothalamic obesity with long-term success.[5]

Human studies in overweight females indicate that a 20mg x 3 dosage protocol is capable of reducing bodyweight independent of dietary and exercise changes by 2.5kg in 4 weeks and 5.5kg in 12 weeks, suggesting a reduced return-on-investment with ephedrine supplementation (independent of changes in oxygen consumption). In a sample of 5, 2 subjects reported slight hand tremors upon initial supplementation.[36]

Usage of the ECA stack has been investigated, and without intentional caloric restriction in obese persons showed 2.2kg weight loss over 8 weeks against 0.7kg for placebo.[37] When unblinded, the 2.2kg loss increased to 3.2kg.

With caloric restriction, EC shows 3.4kg greater weight loss relative to placebo over 16 weeks in obese persons[38] and 30-60mg (paired with 300-600mg caffeine) showed 5.9kg more fat loss in 20 weeks in adolescents.[1]

Additionally, long-term use of ephedrine (5 months) is associated with continued fat loss (5.2kg) relative to control (-0.03kg).[37] In some studies where fat loss between groups is not statistically significant, significant positive trends in body composition are seen.[6]

5Exercise Performance and Skeletal Muscle

5.1Skeletal Muscle Hypertrophy

Ephedrine, as a beta-adrenergic agonist, can preserve muscle mass by reducing nitrogen excretion (and titrating nitrogen balance towards a positive state). Human interventions note a decrease in urinary nitrogen with acute ephedrine usage[39] and at least one study that did not note weight loss was due to a loss of bodyfat concurrent with an increase in muscle gain, with 4.5kg more fat lost and 2.8kg less muscle mass lost over 8 weeks.[6] These numbers may be inflated due to the women being obese at baseline.

Skeletal muscle may contribute up to 50% of the fat burning potential of ephedrine, as it acts mostly in brown fat stores and skeletal muscle.[40]

5.2Power Output

In 9 otherwise healthy resistance trained men, ingestion of 300mg caffeine with 60mg ephedra sinicus (ephedrine content not disclosed) 60 and 150 minutes prior to muscular testing with a 1 rep max bench press and lat pulldown test noted that despite increased attitude towards and alertness during weight lifting that there was no significant differences in strength when compared to 300mg glucose placebo.[41] Another trial assessing muscular output with weight training with a higher dose of ephedrine (0.8mg/kg 90 minutes before leg press:bench press supersets to failure) noted 3 more reps on the leg press associated with ephedrine over placebo (16 over 13) and when combining with caffeine this was increased to 6 reps (19 versus 16) with less improvement (1 and 2 extra reps, respectively) with the bench press; the authors noted that fatigue during supersets may have played a role, and these results were only significant during the first superset test (with a 2 minute rest period, the subsequent two tests were not statistically significance).[42]

One study using a single acute dose of 24mg ephedrine in otherwise healthy untrained men failed to note any power output enhancement after acute dosing.[43]

Studies using ergometer assessments of power fail to find improvements in power output associated with 60mg ephedra sinicus (and 300mg caffeine)[41] and ephedrine in isolation has been associated with improving power output during a 30s wingate test (at time points of 5 and 10 seconds, insignificant at other time points) when measured 90 minutes after ingestion of 1mg/kg;[44] this latter study has been criticized for its conclusions, where the clinical significance was minor (less than 1% improvement when averaged over all 30 seconds) and may not be worth the risks associated with high dose ephdrine consumtption.[45]

Power output improvement with lower doses of ephedrine appears unreliable, whereas higher doses (0.8-1mg/kg) have been associated with enhanced power output when taken 90 minutes before exercise. The cost-benefit analysis of these high doses of ephedrine has been questioned, however, with some authors arguing it may not be the best intervention due to possible side-effects associated with stimulant usage

5.3Physical endurance

In a test on performing high intensity cycling until failure (where placebo managed to pedal for 12.6 minutes) the ingestion of 1mg/kg ephedrine is associated with a trend to reduce time to exhaustion (by 19%) that failed to reach statistical significance, but combining this dose with 5mg/kg caffeine improved the effects (to 39%) and was significant.[46] This improvement has been replicated elsewhere with similar dosing, and the increase in heart rate was replicated and a lower rate of percieved exertion was noted.[47]

One study assessing performance on a weighted (11kg) 10 kilometer run following ingestion of 0.8mg/kg ephedrine noted a 2.8% improvement in run time associated with ephedrine over placebo (similar effects in caffeine plus ephedrine) associated with improved pace during the last 5k and no significant influence on VO2 max; this was attributed to the increase in serum free fatty acids and modulation of catecholamines (less adrenaline and more dopamine).[48]

Limited evidence, but ephedrine appears to enhance endurance exercise performance which may merely be secondary to increased free fatty acid levels in serum and possibly a reduced rate of percieved exertion

6Interactions with Hormones

6.1Estrogen

Ephedrine, at 0.5mg/kg daily, exerts an anti-estrogenic effect in mice and was more potent than Ephedra Sinica and Synephrine at doing so.[49]

7Cardiovascular Interactions

7.1Blood Pressure

Many of the human studies (to be discussed) noted slight increases in blood pressure ranging from 5-23mmhg systolic with no influence on diastolic.[32][7] These effects were acute and causative of the ephedrine administration.

Over a long period of time (8-12 weeks) ephedrine is associated with reduced blood pressure, although this is due to weight loss.[50][3] Sometimes blood pressure is not significantly affected at all chronically, however.[51][52][53] In regards to persons with hypertension who may still experience the acute rise in blood pressure, treatment with ephedrine may be problematic acutely but has been argued, over time, to be beneficial secondary to reduction in weight.[50]

With a controlled dose of ephedrine, it does not seem to change heart rate in and of itself. Variations in HR are typically causative of excessive adrenaline levels when pairing ephedrine with an adrenaline increasing agent such as caffeine or from anxiety.

7.2Heart Rate and Cardiac Health

One human study noted decreases in serum potassium levels when ephedrine was being used (20mg x 3). The decreases were, on average, from 4.1mmol to 3.7mmol, although the decrease was blunted with chronic administration.[36]

Other human studies[39][54] have noted less drastic increases in adrenaline levels and no changes in urinary excretion of adrenaline markers but have noted less urinary nitrogen excretion, indicating a better nitrogen balance and thus muscle sparing potential of ephedrine supplementation (50mg thrice a day).

7.3Cardiotoxicity and Overdose

At high doses of 50mg/kg bodyweight (Ma Huang, or ephedra) or 25mg/kg bodyweight ephedrine, clinical and biological signs of toxicity are apparent.[55] Doses of 12.5mg/kg bodyweight Ma Huang (equivalent to 6.25mg/kg ephedrine) paired with caffeine show minimal toxic signs. An acute dose of 25mg/kg bodyweight (14x recommended human dose) is lethal to rats when fed by gavage.[56]

Cardiotoxicity, in rat models, appears to be more of a concern for older animals.[57]

7.4Lipoproteins and Triglycerides

Ephedrine (thus study using caffeine) has been noted to reduce the rate of HDL-C decreases seen with hypocaloric dieting without significantly affecting overall total cholesterol.[4]

8Nutrient-Nutrient Interactions

8.1ECA stack

The ECA stack was first proposed in 1989[58] and tested in 1990[59] as nutraceuticals that interacted with each other. It was already noted at this time that xanthine compounds (of which caffeine is included) can cause the efficacy of 22mg ephedrine in increasing the metabolic rate to approximately double[23] and in animals to more effectively suppress the appetite.[60][61][62]

Caffeine is able to increase metabolic rate on its own, but its combination with ephedrine appears to be synergistic (greater than the sum of its parts) rather than just additive. The pairing of the two results in an increased metabolic rate greater than the two added together mathematically.[24] The mechanism appears to be through adenosine antagonism, as the other theory (phosphodiesterase inhibtion) may not be relevant in vivo due to low cellular concentrations of caffeine relative to what is needed to cause large inhibition.[63]

Caffeine has been noted as a synergist with ephedrine in vivo[24] and used effectively in a wide variety of studies to induce weight loss in conjunction with a diet or diet with exercise program.[64] and some studies suggest that it is needed for the fat loss effects of ephedrine to differ from placebo.[38] This may be secondary to 'non-responders' to ephedrine, which seems to be negated by coingestion of a xanthine compound.[35] Basically, those who do not respond to ephedrine seem to respond to ephedrine with xanthines.

The synergism between ephedrine and xanthines has been roughly quantified as 64% more than the expected values of the added value of the two compounds in one study.[24] This is more of a pharmacodynamic synergism, as taking the combination of ingredients does not appear to alter the pharmacokinetic profile of either.[26]

One study noted the combination of caffeine and ephedrine did not influence diastolic blood pressure while either compound in isolation did, and that the combination did not influence systolic blood pressure to a greater degree than either compound in isolation.[24] This indicates that the combination is, at least, no worse than either in isolation in regards to acute blood pressure spikes.

Although aspirin has been shown to cause greater reductions in body fat when combined with ephedrine, it does not significantly affect body weight on its own.[65] In animals, ephedrine decreased body fat percentage by 18% while ephedrine combined with aspirin decreased body fat percentage by 27%.[65] works through prostaglandin inhibition, which increases ephedrine-induced adrenaline release.[66] Aspirin in combination with caffeine and ephedrine has failed to acutely increase the thermic effect of food.[8]

8.2Nicotine

Ephedrine and caffeine mixtures have been used in attempts to reduce the weight gain seen with smoking cessation, and although benefit has been noted ephedrine has failed to significantly modify quitting rates.[2]

9Safety and Toxicity

9.1Safety and Toxicity within Recommended Dosage Range

Ephedrine, paired with caffeine, appears to be a safe supplement for adolescents (16 years average, 14-17) given adequate supervision.[1]

Some reviews note that interventions are no different from placebo[67] (although said meta-analysis established CI's ranging from 2-3.5[68]) and that the benefits of fat loss outweigh the costs.[67]

No clinically significant withdrawal symptoms are seen from usage of 20mg/200mg ephedrine/caffeine three times daily for 24 weeks.[69][70]

9.2Case studies

As a foreward, a large registry based case-crossover study comparing naive and habitual ephedrine/caffeine users found no difference in adverse effects between groups, and found no overall relation with adverse cardiovascular outcomes.[71] Additionally, a meta-analysis of 50 studies and 284 case reports reported to the FDA (out of 18,000) noted that there was an association with ephedrine/ephedra and heart palpitations/autonomic side effects, but that case reports are the data are insufficient to draw conclusions about a rate less than 1 per thousand.[68] More dramatic side-effects are seen when reviewing FDA 'reports of adverse events'[72] but these tend to be associated with social panic; said meta-analysis[68] found only 284 out of 18,000 acceptable when controlling for temporal relations (ephedrine consumed 24 hours prior to report) and no other confounds were present. This suggests that 98.5% of non-medical cases were due to hypochondria, although by no means excludes possible harm.

Ephedrine has been associated with stroke in unknown dosages in persons with a history of drug abuse[73]

At least one case of human heart damage has been reported in a 44 year old male, but this was confounded with usage of a wide variety of compounds.[74] Another case study noted usage of Ephedrea, Xenadrine, and Hydroxycut for 2 years resulting in coronary artery aneurysm[75] which may be related to the Xenadrine formulation without Ephedrine.[76][77]

One study notes ephedrine associated with kidney stones, but takes an overly dramatic approach in the abstract.[78] Ephedrine alkaloids were found to comprise 95% of a kidney stone by weight in a person on 4 medications with a single kidney who suffered from kidney failure in the past. However, contacts of the author noted "over 200" other cases of kidney stones containing Ephedra Alkaloids. The supplement used by the case subject contained 170mg Ephedra (6% ephedrine).[78]

Ephedrine has, at least once, been used to commit suicide. The exact oral dose was unknown, but was well beyond the highest recommended therapeutic dosages.[78]

9.3Legality

Many countries place restrictions on the sale of bulk ephedrine in order to prevent mass methamphetamine production, as ephedrine is a substrate for meth.[79] 

In 2004 the United States Food and Drug Administration (FDA) issued a ruling prohibiting the sale of dietary supplements containing ephedra, citing an unreasonable risk of illness or injury.[80] In addition to the FDA ban on sales, laws governing the sale, use, and possession of ephedra products have been established at the state and local level. If you are considering the use of ephedra, be sure to check first whether doing so complies with all national/local laws in your region.

References

  1. ^ a b c Molnár D, et al. Safety and efficacy of treatment with an ephedrine/caffeine mixture. The first double-blind placebo-controlled pilot study in adolescents. Int J Obes Relat Metab Disord. (2000)
  2. ^ a b Nørregaard J, et al. The effect of ephedrine plus caffeine on smoking cessation and postcessation weight gain. Clin Pharmacol Ther. (1996)
  3. ^ a b c Breum L, et al. Comparison of an ephedrine/caffeine combination and dexfenfluramine in the treatment of obesity. A double-blind multi-centre trial in general practice. Int J Obes Relat Metab Disord. (1994)
  4. ^ a b Buemann B, et al. The effect of ephedrine plus caffeine on plasma lipids and lipoproteins during a 4.2 MJ/day diet. Int J Obes Relat Metab Disord. (1994)
  5. ^ a b Greenway FL, Bray GA. Treatment of hypothalamic obesity with caffeine and ephedrine. Endocr Pract. (2008)
  6. ^ a b c d Astrup A, et al. The effect of ephedrine/caffeine mixture on energy expenditure and body composition in obese women. Metabolism. (1992)
  7. ^ a b c Vukovich MD, et al. Caffeine-herbal ephedra combination increases resting energy expenditure, heart rate and blood pressure. Clin Exp Pharmacol Physiol. (2005)
  8. ^ a b Horton TJ, Geissler CA. Post-prandial thermogenesis with ephedrine, caffeine and aspirin in lean, pre-disposed obese and obese women. Int J Obes Relat Metab Disord. (1996)
  9. ^ NIH Office of Dietary Supplements: Ephedra facts.
  10. ^ a b c d e f g Caveney S, et al. New observations on the secondary chemistry of world Ephedra (Ephedraceae). Am J Bot. (2001)
  11. ^ Introduction to Biology and Evolution of the Gnetales.
  12. ^ Biosynthesis of the Ephedra alkaloids: evolution of the C6-C3 skeleton.
  13. ^ Ephedroxane, anti-inflammatory principle of Ephedra herbs.
  14. ^ Alkaloid-bearing plants and their contained alkaloids.
  15. ^ Max B. This and that: the ethnopharmacology of simple phenethylamines, and the question of cocaine and the human heart. Trends Pharmacol Sci. (1991)
  16. ^ a b Van Eenoo P, et al. Results of stability studies with doping agents in urine. J Anal Toxicol. (2007)
  17. ^ Jiménez C, et al. Stability studies of amphetamine and ephedrine derivatives in urine. J Chromatogr B Analyt Technol Biomed Life Sci. (2006)
  18. ^ Jonderko K, Kucio C. Effect of anti-obesity drugs promoting energy expenditure, yohimbine and ephedrine, on gastric emptying in obese patients. Aliment Pharmacol Ther. (1991)
  19. ^ Kucio C, Jonderko K, Adamczak D. Effect of ephedrine on gastric emptying in obese patients. Pol Arch Med Wewn. (1991)
  20. ^ Astrup A, et al. Pharmacology of thermogenic drugs. Am J Clin Nutr. (1992)
  21. ^ The apparent absence of serotonin-mediated vascular thermogenesis in perfused rat hindlimb may result from vascular shunting.
  22. ^ a b c Dulloo AG, Miller DS. The thermogenic properties of ephedrine/methylxanthine mixtures: human studies. Int J Obes. (1986)
  23. ^ a b c d e f Astrup A, et al. Thermogenic synergism between ephedrine and caffeine in healthy volunteers: a double-blind, placebo-controlled study. Metabolism. (1991)
  24. ^ Morgan JB, et al. A study of the thermic responses to a meal and to a sympathomimetic drug (ephedrine) in relation to energy balance in man. Br J Nutr. (1982)
  25. ^ a b Haller CA, Jacob P 3rd, Benowitz NL. Enhanced stimulant and metabolic effects of combined ephedrine and caffeine. Clin Pharmacol Ther. (2004)
  26. ^ Bukowiecki L, Jahjah L, Follea N. Ephedrine, a potential slimming drug, directly stimulates thermogenesis in brown adipocytes via beta-adrenoreceptors. Int J Obes. (1982)
  27. ^ a b Ma G, et al. Pharmacological effects of ephedrine alkaloids on human alpha(1)- and alpha(2)-adrenergic receptor subtypes. J Pharmacol Exp Ther. (2007)
  28. ^ a b c d Vansal SS, Feller DR. Direct effects of ephedrine isomers on human beta-adrenergic receptor subtypes. Biochem Pharmacol. (1999)
  29. ^ a b Shannon JR, et al. Acute effect of ephedrine on 24-h energy balance. Clin Sci {Lond}. (1999)
  30. ^ Cheng JT, et al. Stimulatory effect of D-ephedrine on beta3-adrenoceptors in adipose tissue of rats. Auton Neurosci. (2001)
  31. ^ a b Astrup A, et al. Enhanced thermogenic responsiveness during chronic ephedrine treatment in man. Am J Clin Nutr. (1985)
  32. ^ Nielsen B, et al. Effect of physical training on thermogenic responses to cold and ephedrine in obesity. Int J Obes Relat Metab Disord. (1993)
  33. ^ The thermogenic properties of ephedrine/methylxanthine mixtures: animal studies.
  34. ^ a b Molnár D. Effects of ephedrine and aminophylline on resting energy expenditure in obese adolescents. Int J Obes Relat Metab Disord. (1993)
  35. ^ a b Enhanced thermogenic responsiveness during chronic ephedrine treatment in man.
  36. ^ a b Daly PA, et al. Ephedrine, caffeine and aspirin: safety and efficacy for treatment of human obesity. Int J Obes Relat Metab Disord. (1993)
  37. ^ a b Astrup A, et al. The effect and safety of an ephedrine/caffeine compound compared to ephedrine, caffeine and placebo in obese subjects on an energy restricted diet. A double blind trial. Int J Obes Relat Metab Disord. (1992)
  38. ^ a b Pasquali R, et al. Effects of chronic administration of ephedrine during very-low-calorie diets on energy expenditure, protein metabolism and hormone levels in obese subjects. Clin Sci (Lond). (1992)
  39. ^ Astrup A, et al. Contribution of BAT and skeletal muscle to thermogenesis induced by ephedrine in man. Am J Physiol. (1985)
  40. ^ a b Williams AD, et al. The effect of ephedra and caffeine on maximal strength and power in resistance-trained athletes. J Strength Cond Res. (2008)
  41. ^ Jacobs I, Pasternak H, Bell DG. Effects of ephedrine, caffeine, and their combination on muscular endurance. Med Sci Sports Exerc. (2003)
  42. ^ Sidney KH, Lefcoe NM. The effects of ephedrine on the physiological and psychological responses to submaximal and maximal exercise in man. Med Sci Sports. (1977)
  43. ^ Bell DG, Jacobs I, Ellerington K. Effect of caffeine and ephedrine ingestion on anaerobic exercise performance. Med Sci Sports Exerc. (2001)
  44. ^ Goldberg L, Elliot D, Kuehl K. Re: Bell, DG, I Jacobs, and K Ellerington. Effect of caffeine and ephedrine ingestion on anaerobic exercise performance. Med Sci Sports Exerc.33:1399-1403, 2001. Med Sci Sports Exerc. (2002)
  45. ^ Bell DG, Jacobs I, Zamecnik J. Effects of caffeine, ephedrine and their combination on time to exhaustion during high-intensity exercise. Eur J Appl Physiol Occup Physiol. (1998)
  46. ^ Bell DG, et al. Reducing the dose of combined caffeine and ephedrine preserves the ergogenic effect. Aviat Space Environ Med. (2000)
  47. ^ Bell DG, McLellan TM, Sabiston CM. Effect of ingesting caffeine and ephedrine on 10-km run performance. Med Sci Sports Exerc. (2002)
  48. ^ Arbo MD, et al. Screening for in vivo (anti)estrogenic activity of ephedrine and p-synephrine and their natural sources Ephedra sinica Stapf. (Ephedraceae) and Citrus aurantium L. (Rutaceae) in rats. Arch Toxicol. (2009)
  49. ^ a b Ingerslev J, Svendsen TL, Mørk A. Is an ephedrine caffeine treatment contraindicated in hypertension. Int J Obes Relat Metab Disord. (1997)
  50. ^ Coffey CS, et al. A randomized double-blind placebo-controlled clinical trial of a product containing ephedrine, caffeine, and other ingredients from herbal sources for treatment of overweight and obesity in the absence of lifestyle treatment. Int J Obes Relat Metab Disord. (2004)
  51. ^ Hackman RM, et al. Multinutrient supplement containing ephedra and caffeine causes weight loss and improves metabolic risk factors in obese women: a randomized controlled trial. Int J Obes (Lond). (2006)
  52. ^ Boozer CN, et al. Herbal ephedra/caffeine for weight loss: a 6-month randomized safety and efficacy trial. Int J Obes Relat Metab Disord. (2002)
  53. ^ Does ephedrine promote weight-loss in low-calorie adapted obese women?.
  54. ^ Dunnick JK, et al. Cardiotoxicity of Ma Huang/caffeine or ephedrine/caffeine in a rodent model system. Toxicol Pathol. (2007)
  55. ^ Nyska A, et al. Acute hemorrhagic myocardial necrosis and sudden death of rats exposed to a combination of ephedrine and caffeine. Toxicol Sci. (2005)
  56. ^ Howden R, et al. Ephedrine plus caffeine causes age-dependent cardiovascular responses in Fischer 344 rats. Am J Physiol Heart Circ Physiol. (2005)
  57. ^ Dulloo AG, Miller DS. Ephedrine, caffeine and aspirin: "over-the-counter" drugs that interact to stimulate thermogenesis in the obese. Nutrition. (1989)
  58. ^ Krieger DR, et al. Ephedrine, caffeine and aspirin promote weight loss in obese subjects. Trans Assoc Am Physicians. (1990)
  59. ^ Dulloo AG, Miller DS. Reversal of obesity in the genetically obese fa/fa Zucker rat with an ephedrine/methylxanthines thermogenic mixture. J Nutr. (1987)
  60. ^ Dulloo AG, Miller DS. The thermogenic properties of ephedrine/methylxanthine mixtures: animal studies. Am J Clin Nutr. (1986)
  61. ^ Dulloo AG, Miller DS. Prevention of genetic fa/fa obesity with an ephedrine-methylxanthines thermogenic mixture. Am J Physiol. (1987)
  62. ^ Dulloo AG, Seydoux J, Girardier L. Potentiation of the thermogenic antiobesity effects of ephedrine by dietary methylxanthines: adenosine antagonism or phosphodiesterase inhibition. Metabolism. (1992)
  63. ^ Effects of a weight-loss aid in healthy overweight adults: double-blind, placebo-controlled clinical trial.
  64. ^ a b Dulloo AG, Miller DS. Aspirin as a promoter of ephedrine-induced thermogenesis: potential use in the treatment of obesity. Am J Clin Nutr. (1987)
  65. ^ Dulloo AG. Ephedrine, xanthines and prostaglandin-inhibitors: actions and interactions in the stimulation of thermogenesis. Int J Obes Relat Metab Disord. (1993)
  66. ^ a b Greenway FL. The safety and efficacy of pharmaceutical and herbal caffeine and ephedrine use as a weight loss agent. Obes Rev. (2001)
  67. ^ a b c Shekelle PG, et al. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA. (2003)
  68. ^ Toubro S, et al. The acute and chronic effects of ephedrine/caffeine mixtures on energy expenditure and glucose metabolism in humans. Int J Obes Relat Metab Disord. (1993)
  69. ^ Toubro S, et al. Safety and efficacy of long-term treatment with ephedrine, caffeine and an ephedrine/caffeine mixture. Int J Obes Relat Metab Disord. (1993)
  70. ^ Hallas J, et al. Use of a prescribed ephedrine/caffeine combination and the risk of serious cardiovascular events: a registry-based case-crossover study. Am J Epidemiol. (2008)
  71. ^ Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med. (2000)
  72. ^ Bruno A, Nolte KB, Chapin J. Stroke associated with ephedrine use. Neurology. (1993)
  73. ^ Martínez-Quintana E, Rodríguez-González F, Cuba-Herrera J. Myocardial necrosis and severe biventricular dysfunction in the context of chronic ephedrine abuse. Adicciones. (2010)
  74. ^ Flanagan CM, et al. Coronary artery aneurysm and thrombosis following chronic ephedra use. Int J Cardiol. (2010)
  75. ^ Holmes RO Jr, Tavee J. Vasospasm and stroke attributable to ephedra-free xenadrine: case report. Mil Med. (2008)
  76. ^ Sachdeva R, et al. Coronary thrombosis related to use of Xenadrine RFA. Tex Heart Inst J. (2005)
  77. ^ a b c Backer R, et al. Fatal ephedrine intoxication. J Forensic Sci. (1997)
  78. ^ Kurashima N, et al. Determination of origin of ephedrine used as precursor for illicit methamphetamine by carbon and nitrogen stable isotope ratio analysis. Anal Chem. (2004)
  79. ^ NIH Office of Dietary Supplements: Ephedra Health Information.
  80. Boozer CN, et al. An herbal supplement containing Ma Huang-Guarana for weight loss: a randomized, double-blind trial. Int J Obes Relat Metab Disord. (2001)
  81. Eccles R, et al. Efficacy and safety of single and multiple doses of pseudoephedrine in the treatment of nasal congestion associated with common cold. Am J Rhinol. (2005)
  82. Bogacka I, et al. The effect of beta-adrenergic and peroxisome proliferator-activated receptor-gamma stimulation on target genes related to lipid metabolism in human subcutaneous adipose tissue. Diabetes Care. (2007)
  83. Taverner D, Danz C, Economos D. The effects of oral pseudoephedrine on nasal patency in the common cold: a double-blind single-dose placebo-controlled trial. Clin Otolaryngol Allied Sci. (1999)
  84. Toubro S, Astrup A. Randomised comparison of diets for maintaining obese subjects' weight after major weight loss: ad lib, low fat, high carbohydrate diet v fixed energy intake. BMJ. (1997)
  85. Pasquali R, et al. Does ephedrine promote weight loss in low-energy-adapted obese women. Int J Obes. (1987)
  86. Kim HJ, et al. Effect of herbal Ephedra sinica and Evodia rutaecarpa on body composition and resting metabolic rate: a randomized, double-blind clinical trial in Korean premenopausal women. J Acupunct Meridian Stud. (2008)
  87. Wuhrman E, Clark M. Use of ephedrine for the short-term treatment of postoperative nausea and vomiting: a case report. J Perianesth Nurs. (2011)
  88. Pasquali R, et al. A controlled trial using ephedrine in the treatment of obesity. Int J Obes. (1985)
  89. Agonist-Directed Desensitization of the β2-Adrenergic Receptor.
  90. Kenakin TP. Cellular assays as portals to seven-transmembrane receptor-based drug discovery. Nat Rev Drug Discov. (2009)
  91. Fang Y. Label-Free Receptor Assays. Drug Discov Today Technol. (2011)
  92. Fang Y, Ferrie AM. Label-free optical biosensor for ligand-directed functional selectivity acting on beta(2) adrenoceptor in living cells. FEBS Lett. (2008)
  93. Receptor internalization and ERK1/2 phosphorylation are dependent on the agonist exposure time.
  94. The desensitization and resensitization patterns of quiescent A431 cells induced by epinephrine is sensitive to stimulation duration and several inhibitors.
  95. January B, et al. beta2-adrenergic receptor desensitization, internalization, and phosphorylation in response to full and partial agonists. J Biol Chem. (1997)
  96. Characterization of β2-Adrenergic Receptor Dephosphorylation: Comparison with the Rate of Resensitization.
  97. Sears MR. Adverse effects of beta-agonists. J Allergy Clin Immunol. (2002)
  98. Nelson HS. Is there a problem with inhaled long-acting beta-adrenergic agonists. J Allergy Clin Immunol. (2006)

This page is regularly updated, to include the most recently available clinical trial evidence.

Each member of our research team is required to have no conflicts of interest, including with supplement manufacturers, food companies, and industry funders. The team includes nutrition researchers, registered dietitians, physicians, and pharmacists. We have a strict editorial process.

This page features 98 references. All factual claims are followed by specifically-applicable references. Click here to see the full set of references for this page.

Examine.com is intended to be used for educational and information purposes only. Examine.com and its Editors do not advocate nutritional supplementation over proper medical advice or treatment and this sentiment will never be expressed through pages hosted under Examine.com. If using any pharmaceuticals or drugs given to you by a doctor or received with a prescription, you must consult with the doctor in question or an equally qualified Health Care Professional prior to using any nutritional supplementation. If undergoing medical therapies, then consult with your respective Therapist or Health Care Professional about possible interactions between your Treatment, any Pharmaceuticals or Drugs being given, and possible nutritional supplements or practices hosted on Examine.com.

Examine.com does not assume liability for any actions undertaken after visiting these pages, and does not assume liability if one misuses supplements. Examine.com and its Editors do not ensure that unforeseen side effects will not occur even at the proper dosages, and thereby does not assume liability for any side effects from supplements or practices hosted under the domain of Examine.com.

Popular Supplements

TOP NUTRITION ARTICLES

Never miss an update!

Your e-mail is safe with us. We don’t share personal data.
Tweet