Ephedrine

Last Updated: December 19 2022

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.

Ephedrine is most often used for.



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1.

Sources and Structure

1.1

Composition (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.[1]

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.[1][2]

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[1]
  • Cathine (d-norpseudoephedrine)[3] and derivative ephedroxane.[4]
  • 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.[1] 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.[1]

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,[1] although there are unconfirmed claims that there may be a pseudoephedrine content.[5][6] The one study to analyze various Ephedra species noted no ephedrine or pseudoephedrine in North American species.[1]

1.2

Ephedrine (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 _nor_ephedrines, or be methylated to become N-methylephedrine. Norephedrine and Norpseudoephedrine are also known as Phenylpropinolamine, or PPA.

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1.3

Properties

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.[7][8] Ephedrine was also stable during 6 freeze-thaw cycles (-20°C to 22°C).[7]

2.

Pharmacology

2.1

Digestion and Absorption

Ephedrine administration at 50mg is able to reduce gastric emptying rate in humans, and potentially reduce meal absorption speeds.[9][10]

2.2

Systemic

All below pharmacology can be reviewed here.[11]

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[12] 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[13], and in comparisons between different combinations of ephedrine and caffeine a dose of 20mg/200mg has been shown to be the most synergistic.[14] 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.

3.

Neurology

3.1

Sensitivity

Ephedrine appears to be a more potent stimulant during periods of caloric restriction, relative to higher caloric intakes.[15] The neural stimulant effects are further increased when paired with caffeine.[16]

4.

Fat Mass and Obesity

4.1

Mechanisms

Ephedrine is able to directly agonize all three subsets of β-adrenergic receptors of brown adipose tissue, leading to increased thermogenesis[17] without significantly activating the α-adrenergic receptor class[18] and possibly antagonizing activation from agonists of these receptors.[18] The β-class of adrenergic receptors are seen as the class that stimulate lipolysis, where the alpha class is inhibitory.[19]

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%)[19] 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%).[19] 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.[19]

This agonism may not appear to be seen in vivo at doses of 50mg taken thrice daily.[20]

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.[21]

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

4.2

Metabolic 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.[22]

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.[23] The combination of ephedrine and caffeine has been noted to be similarly effective (trending to be more effective) than 15mg dexfenfluramine over 12 weeks.[24]

It has been noted that caffeine ingestion does, however, increase ephedrine's effects on REE independent of exercse[25] 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.[13]

The previous animal studies have noted a 10% increase in REE with ephedrine supplementation, however human studies are more variable at 3.6%,[20] 10.7% (with caffeine),[26] and 7.1%.[27] 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.[14] 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.[28]

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.

4.3

Longterm 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.[29]

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.[30]

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.[31] 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[32] and 30-60mg (paired with 300-600mg caffeine) showed 5.9kg more fat loss in 20 weeks in adolescents.[33]

Additionally, long-term use of ephedrine (5 months) is associated with continued fat loss (5.2kg) relative to control (-0.03kg).[31] In some studies where fat loss between groups is not statistically significant, significant positive trends in body composition are seen.[28]

5.

Exercise Performance and Skeletal Muscle

5.1

Skeletal 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[34] 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.[28] 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.[35]

5.2

Power 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.[36] 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).[37]

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.[38]

Studies using ergometer assessments of power fail to find improvements in power output associated with 60mg ephedra sinicus (and 300mg caffeine)[36] 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;[39] 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.[40]

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

5.3

Physical 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.[41] 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.[42]

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).[43]

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

6.

Interactions with Hormones

6.1

Estrogen

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.[44]

7.

Cardiovascular Interactions

7.1

Blood 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.[22][26] 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.[45][24] Sometimes blood pressure is not significantly affected at all chronically, however.[46][47][48] 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.[45]

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.

7.2

Heart 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.[30]

Other human studies[34][49] 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).

7.3

Cardiotoxicity 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.[50] 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.[51]

Cardiotoxicity, in rat models, appears to be more of a concern for older animals.[52]

7.4

Lipoproteins 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.[53]

8.

Nutrient-Nutrient Interactions

8.1

ECA stack

The ECA stack was first proposed in 1989[54] and tested in 1990[55] 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[13] and in animals to more effectively suppress the appetite.[56][57][58]

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.[14] 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.[59]

Caffeine has been noted as a synergist with ephedrine in vivo[14] and used effectively in a wide variety of studies to induce weight loss in conjunction with a diet or diet with exercise program.[60] and some studies suggest that it is needed for the fat loss effects of ephedrine to differ from placebo.[32] This may be secondary to 'non-responders' to ephedrine, which seems to be negated by coingestion of a xanthine compound.[27] 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.[14] This is more of a pharmacodynamic synergism, as taking the combination of ingredients does not appear to alter the pharmacokinetic profile of either.[16]

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.[14] 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.[61] In animals, ephedrine decreased body fat percentage by 18% while ephedrine combined with aspirin decreased body fat percentage by 27%.[61] works through prostaglandin inhibition, which increases ephedrine-induced adrenaline release.[62] Aspirin in combination with caffeine and ephedrine has failed to acutely increase the thermic effect of food.[63]

8.2

Nicotine

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.[64]

9.

Safety and Toxicity

9.2

Case 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.[69] 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.[66] More dramatic side-effects are seen when reviewing FDA 'reports of adverse events'[70] but these tend to be associated with social panic; said meta-analysis[66] 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[71]

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.[72] Another case study noted usage of Ephedrea, Xenadrine, and Hydroxycut for 2 years resulting in coronary artery aneurysm[73] which may be related to the Xenadrine formulation without Ephedrine.[74][75]

One study notes ephedrine associated with kidney stones, but takes an overly dramatic approach in the abstract.[76] 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).[76]

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.[76]

9.3

Legality

Many countries place restrictions on the sale of bulk ephedrine in order to prevent mass methamphetamine production, as ephedrine is a substrate for meth.[77]

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.[78] 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.

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