Ephedrine or Synephrine: What Is the Difference

When dietary supplements with ephedra alkaloids were banned in the United States in 2004, manufacturers of «fat burners» began looking for a replacement — and found it in bitter orange extract with synephrine. Since then synephrine has often been called a «legal analog of ephedrine». How similar these substances really are and how they differ is what the editors examine in this material.

Origin and Chemistry

Ephedrine is an alkaloid of plants of the ephedra genus, primarily Ephedra sinica, known in Chinese medicine as ma huang. It was isolated at the end of the 19th century, and later began to be synthesized. In medicine ephedrine is used as a means of raising blood pressure during anesthesia, and earlier — as a bronchodilator and decongestant.

Synephrine, or more precisely para-synephrine (p-synephrine), is the main protoalkaloid of the peel of bitter orange fruit (Citrus aurantium). In small amounts it is also present in the juices and fruits of other citruses, for example mandarins. It is p-synephrine that is the active substance of most supplements with bitter orange extract.

Both molecules belong to the phenylethylamines and structurally resemble adrenaline and noradrenaline. However, the details of their structure differ substantially. Ephedrine has no hydroxyl groups on the benzene ring, so it is quite lipophilic and easily crosses the blood-brain barrier. P-synephrine has a hydroxyl group in the para position of the ring, which makes the molecule more polar and significantly changes its pharmacology.

It is important not to confuse p-synephrine with meta-synephrine, known as phenylephrine. Phenylephrine is a medicine, a potent agonist of alpha-1 adrenergic receptors, used in nasal drops and to raise blood pressure. Frequent confusion between these isomers gives rise to erroneous conclusions about the safety of supplements.

How They Act on Adrenergic Receptors

Ephedrine is a mixed-action sympathomimetic. On the one hand, it directly stimulates alpha- and beta-adrenergic receptors; on the other, it promotes the release of noradrenaline from nerve endings. The result is an increase in heart rate and blood pressure, dilation of the bronchi, enhanced thermogenesis and marked stimulation of the central nervous system.

P-synephrine, according to the review by Stohs and colleagues (2011), has a significantly lower affinity for the alpha-1, alpha-2, beta-1 and beta-2 receptors than noradrenaline. Its metabolic effects are thought to be partly mediated by beta-3 adrenergic receptors, which are involved in lipolysis. These data were obtained mainly in experiments on animal tissues, so they should be transferred to humans with caution.

Because of its lower lipophilicity, p-synephrine penetrates the brain less well, so its stimulating effect on the central nervous system is weaker. Users usually describe it as a «milder» stimulant compared with ephedrine.

The practical consequence of this difference: ephedrine is a substance with a potent and predictable sympathomimetic action, while synephrine is a much weaker compound whose effects in humans are moderate and not always consistently reproduced in studies.

Effectiveness: What the Studies Have Shown

For ephedrine there is a meta-analysis prepared at the request of American health authorities — Shekelle et al. (2003) in the journal JAMA. The authors concluded that ephedrine and ephedra provide a modest short-term additional reduction in body weight compared with placebo — about 0.9 kg per month over several months. There were no data on long-term effectiveness.

Regarding athletic performance, the same analysis found no sufficient evidence of improved results with long-term use, although individual studies of combinations of ephedrine with caffeine showed a short-term increase in performance capacity.

For p-synephrine the evidence base is significantly weaker. Small studies showed a slight increase in resting metabolic rate or enhanced fat oxidation during physical activity, but most works had few participants, a short duration and often studied multi-component products, where the effect of synephrine cannot be separated from caffeine and other substances.

So ephedrine has a modest but documented effectiveness for weight loss in the short term, while synephrine has only preliminary and contradictory data.

Safety and Side Effects

The safety problems of ephedrine are well documented. The meta-analysis by Shekelle et al. showed that taking ephedrine or ephedra was associated with a 2-3-fold increase in the risk of psychiatric, autonomic and gastrointestinal symptoms and palpitations. An analysis of adverse event reports (Haller, Benowitz, 2000) described cases of strokes, heart attacks, seizures and sudden death in people who took ephedra supplements.

It was precisely these data that became the basis for the FDA's 2004 decision to ban dietary supplements containing ephedra alkaloids as posing an unreasonable risk to health.

Regarding p-synephrine, reviews by Stohs and colleagues conclude that at doses typical for studies, pure p-synephrine does not significantly increase heart rate and blood pressure. At the same time there are reports of cardiovascular events in people who took bitter orange supplements — mostly multi-component ones, with caffeine and other stimulants.

• Combining any of these stimulants with caffeine increases the load on the cardiovascular system.
• Special caution is needed for people with hypertension, arrhythmias, thyroid diseases and anxiety disorders.
• These substances should not be combined with MAO inhibitors and other drugs that affect the sympathetic system.

So the safety profile of synephrine looks more favorable than that of ephedrine, but this does not mean absolute safety, especially as part of «aggressive» fat burners.

Legal Status and Anti-Doping Rules

In the United States since 2004 dietary supplements with ephedrine alkaloids have been banned, although ephedrine as a medicine remains in circulation. In many countries, in particular in Ukraine, ephedrine is a controlled substance, since it serves as a precursor for the illegal production of methamphetamine.

In the WADA Prohibited List ephedrine belongs to the stimulants of section S6 and is prohibited in competition if its concentration in urine exceeds the established threshold — 10 micrograms per milliliter. This approach is due to the fact that ephedrine can enter the body from ordinary cold medicines.

P-synephrine is not among the prohibited substances, but WADA includes it in the Monitoring Program, that is, it tracks the prevalence of its use by athletes. The status may change, so athletes should check the current list every year.

One should also remember the risk of supplement contamination: products that declare only synephrine sometimes contain undeclared stimulants that may be prohibited.

Editorial Conclusions

Ephedrine and synephrine are similar only on the surface: both belong to the phenylethylamines and are used in the context of weight loss. Ephedrine is a potent sympathomimetic with a proven modest effect and equally proven serious risks. Synephrine is a much weaker substance with a milder safety profile, but also with modest evidence of effectiveness.

Calling synephrine «legal ephedrine» is incorrect: it reproduces neither the strength of action nor the risks of ephedrine, so one should not expect similar results from it.

For most people the main tools of weight control remain nutrition and physical activity, while stimulants can give only a small additional effect.

We also recommend reading our materials on caffeine as a fat burner, on combining stimulants, and on how to read the composition of pre-workout complexes.

References

1. Shekelle PG, Hardy ML, Morton SC, et al. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA. 2003;289(12):1537–1545.
2. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med. 2000;343(25):1833–1838.
3. Stohs SJ, Preuss HG, Shara M. A review of the receptor-binding properties of p-synephrine as related to its pharmacological effects. Oxid Med Cell Longev. 2011;2011:482973.
4. Stohs SJ, Preuss HG, Shara M. The safety of Citrus aurantium (bitter orange) and its primary protoalkaloid p-synephrine. Phytother Res. 2011;25(10):1421–1428.
5. U.S. Food and Drug Administration. Final rule declaring dietary supplements containing ephedrine alkaloids adulterated because they present an unreasonable risk. Fed Regist. 2004;69(28):6787–6854.
6. World Anti-Doping Agency. Prohibited List та Monitoring Program. Montreal: WADA; актуальні редакції.