Synephrine (bitter orange): Evidence, Trial Doses & Interactions

About Synephrine (bitter orange)

An alkaloid structurally related to ephedrine, extracted from unripe bitter orange fruit. It became the standard stimulant in weight-loss and pre-workout products after ephedra was banned in the US.

Synephrine is best understood as the substance the supplement industry moved to when ephedra was prohibited in 2004, and its regulatory history has followed a similar arc more slowly. Its pharmacology is milder than ephedrine and defenders point out that p-synephrine has weak affinity for the receptors that drive cardiovascular effects. Against that sit case reports of ischaemic stroke, myocardial infarction, arrhythmia and angina in people using bitter orange products, almost always in combination with caffeine, which is how it is nearly always sold. Efficacy for weight loss is weak: meta-analyses report small increases in metabolic rate and minimal effects on body weight. Health Canada has restricted synephrine doses, and it appears on anti-doping monitoring lists.

Sold as

Capsule, Pre-workout powder, Weight-loss blends, Standardised bitter orange extract

Standardised to

Percentage synephrine in the extract, commonly 6–30%; blends routinely combine it with caffeine and other stimulants — a product without this marker may not resemble what was studied.

Also known as

p-Synephrine, Bitter orange extract, Zhi shi, Advantra Z

Regulation: Sold as a dietary supplement in the US with no pre-market efficacy review, having replaced ephedra after that was banned. Health Canada limits daily synephrine intake and prohibits combining it with high caffeine doses in licensed products. Synephrine is on the World Anti-Doping Agency monitoring programme rather than the prohibited list, and some military and sporting bodies restrict it.

What the research used

The amounts, forms and durations published trials of Synephrine (bitter orange) actually administered.

These are the amounts published trials administered — not a recommendation, and not a dose to copy. Trial participants were screened, supervised and given a characterised preparation. What is in a retail bottle is frequently not what was studied, and the amount that suits one person is not general advice.

Studied for Metabolic rate and weight studies
25–50 mg
Limited
p-Synephrine, usually with caffeine · Single dose to 12 weeks
Most trials gave it alongside caffeine and other ingredients, so effects cannot be attributed to synephrine. Effect sizes on body weight are small and short-lived.

This is general information about food, not medical advice. It cannot diagnose, treat or replace guidance from a clinician who knows your history.

When it was taken

Each window says whether a trial compared it against an alternative, or whether it is convention and pharmacology. Most timing advice is the second kind.

None of the timings below were directly compared in a trial. They reflect how the research happened to dose, or what the pharmacology implies — which is not the same as a timing being better.

Before exercise
Not enough
Taken before exercise or in the morning by convention in fat-loss products. No timing comparison has been published, and the cardiovascular effects are dose-related rather than timing-related.
Timing was not directly compared. This reflects convention or how the compound behaves in the body, not a trial showing this window works better.

Body composition

Weight Management

Limited evidence

Meta-analyses report small increases in resting metabolic rate and modest weight differences, almost always in products combining synephrine with caffeine and other stimulants. Attribution to synephrine itself is not possible from these trials.

What may be going on: p-Synephrine is an adrenergic agonist with relatively weak affinity for beta-1 and alpha-1 receptors, producing modest thermogenic effects.

Limited evidence. Early human work, or mostly lab and animal research.

View the 4 sources

Dietary herbal supplements with phenylephrine for weight loss.(opens in a new tab)
Randomised controlled trial · Journal of medicinal food · 2006 · PMID 17201647
p-Synephrine, the main protoalkaloid of Citrus aurantium, raises fat oxidation during exercise in elite cyclists.(opens in a new tab)
Randomised controlled trial · European journal of sport science · 2021 · PMID 32859142
Chinese herbal medicine for obesity: a randomized, double-blinded, multicenter, prospective trial.(opens in a new tab)
Randomised controlled trial · The American journal of Chinese medicine · 2014 · PMID 25406653
The Combined Effects of Exercise, Diet, and a Multi-Ingredient Dietary Supplement on Body Composition and Adipokine Changes in Overweight Adults.(opens in a new tab)
Randomised controlled trial · Journal of the American College of Nutrition · 2018 · PMID 29111889

Deep research mode adds each paper’s own conclusion and stated limitations.

Exercise performance

Muscle & Physical Performance

Not enough evidence

Small studies report improved repetitions to failure in resistance exercise. They are few, small, and typically involve stimulant blends rather than synephrine alone.

Not enough evidence. Not enough human research to say anything useful yet.

View the 4 sources

Acute consumption of p-synephrine does not enhance performance in sprint athletes.(opens in a new tab)
Randomised controlled trial · Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme · 2016 · PMID 26673246
The effects of supplementation with P-Synephrine alone and in combination with caffeine on resistance exercise performance.(opens in a new tab)
Randomised controlled trial · Journal of the International Society of Sports Nutrition · 2015 · PMID 26388707
The Effects of Supplementation with p-Synephrine Alone and in Combination with Caffeine on Metabolic, Lipolytic, and Cardiovascular Responses during Resistance Exercise.(opens in a new tab)
Randomised controlled trial · Journal of the American College of Nutrition · 2016 · PMID 27484437
Effects of ingesting a pre-workout dietary supplement with and without synephrine for 8 weeks on training adaptations in resistance-trained males.(opens in a new tab)
Randomised controlled trial · Journal of the International Society of Sports Nutrition · 2017 · PMID 28096757

Deep research mode adds each paper’s own conclusion and stated limitations.

Things to know

Interactions, contraindications and dose limits, most serious first. Concentrated extracts interact with medication in ways the whole plant does not, so this section carries more weight here than it does on a food page.

Worth knowing
Cardiovascular events reported
Case reports and adverse event databases describe ischaemic stroke, myocardial infarction, arrhythmia, angina and severe hypertension associated with bitter orange products, generally in combination with caffeine. Anyone with cardiovascular disease, hypertension or an arrhythmia should avoid it, and healthy users should be aware that this is the compound that replaced ephedra rather than a benign botanical.
Interaction
Bitter orange strongly inhibits CYP3A4
Interacts withCYP3A4 substrates, MAO inhibitors, decongestants, other stimulants
Bitter orange contains furanocoumarins and inhibits CYP3A4 much as grapefruit juice does, raising blood levels of a long list of medicines. It should not be combined with MAO inhibitors, and combining it with other stimulants or decongestants compounds the cardiovascular risk.
Worth knowing
Sport and military restrictions
Synephrine sits on the World Anti-Doping Agency monitoring programme, and some sporting and military organisations restrict it outright. Stimulant pre-workout products are also among the categories most often found contaminated with prohibited substances in independent testing.
Avoid
Not in pregnancy, breastfeeding or with heart conditions
There is no safety data in pregnancy, and an adrenergic stimulant is inappropriate for anyone with heart disease, hypertension, hyperthyroidism, glaucoma or anxiety disorders.

Synephrine (bitter orange)

What synephrine (bitter orange) may help with

About Synephrine (bitter orange)

What the research used

When it was taken

Before exercise

The evidence in depth

Body composition

Exercise performance

Things to know

Cardiovascular events reported

Bitter orange strongly inhibits CYP3A4

Sport and military restrictions

Not in pregnancy, breastfeeding or with heart conditions

What synephrine (bitter orange) may help with

About Synephrine (bitter orange)

What the research used

When it was taken

🏃Before exercise

The evidence in depth

Body composition

Exercise performance

Things to know

Cardiovascular events reported

Bitter orange strongly inhibits CYP3A4

Sport and military restrictions

Not in pregnancy, breastfeeding or with heart conditions

Before exercise