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Synephrine (p-Synephrine; Bitter Orange, Citrus aurantium)
A mild stimulant from bitter orange marketed for fat loss; it modestly raises fat oxidation but clinical weight-loss evidence is weak, and stacking it with caffeine or other stimulants adds sympathomimetic load.
What the evidence says
Synephrine doesn't have enough studies with structured effect-size data yet to pool a verdict. Browse the studies below for individual findings.
Most evidence is from high-quality meta-analyses and randomised trials published 2004–2026 with a typical study size of 13 participants.
Based on 31 studies · 1 meta-analysis · 14 RCTs · 23 total participants
Confidence
Moderate confidenceBy outcome
2 more outcomes with fewer studies not shown.
Acute trials consistently show a small rise in fat oxidation, but the meta-analysis found no weight-loss benefit and a blood-pressure rise, so clinical evidence stays weak.
16 randomised trials
94% were about Synephrine in an audit of 16 of them
Every randomised or controlled trial of Synephrine indexed in PubMed, not a hand-picked subset. Meta-analyses and systematic reviews are deliberately excluded from this count: most of them cover many compounds at once, so counting them would inflate it.
PubMed · as of Sep 2026
2 trials ongoing or recruiting · 8 completed on ClinicalTrials.gov
1 of the completed trials have posted results
Registered trials show research momentum for Synephrine, not proof of effect — a registration is a plan, and posted results are sponsor-reported, not peer-reviewed. They are never counted toward the evidence rating above.
Browse these trials on ClinicalTrials.govClinicalTrials.gov · as of Oct 2026
Synephrine (p-synephrine) is a protoalkaloid from bitter orange (Citrus aurantium), widely used in 'fat-burner' and pre-workout supplements after ephedra was banned. It is a mild sympathomimetic that can modestly increase metabolic rate and fat oxidation, especially around exercise.
However, randomized evidence for actual weight loss is weak, and most reported adverse events occur in multi-ingredient products that combine it with caffeine and other stimulants.
Those case reports did not establish p-synephrine as the cause, and no cited study measured how much the combination adds to cardiovascular risk, but additive stimulation (raised heart rate and blood pressure, palpitations) is plausible.
On its own at low doses it appears milder than ephedra, but it remains a use-with-caution stimulant, particularly for anyone with cardiovascular risk.
p-Synephrine weakly activates beta-3 (and to a lesser extent other) adrenergic receptors, nudging metabolic rate and lipolysis upward.
Increases energy expenditure and fat oxidation, most measurably around exercise.
Avoid — sympathomimetic effects raise cardiovascular load.
Avoid.
Avoid stacking with caffeine; use the lowest dose if at all.
Risk of dangerous blood-pressure elevation — do not combine.
Possible additive cardiovascular stimulation. French (ANSES 2014) and German (BfR 2012) risk assessments advise against combining synephrine with caffeine, as the cardiovascular effects may reinforce each other. Controlled trials point to caffeine driving most of the heart-rate and blood-pressure rise, and no cited study quantifies the combined risk. Avoid high-caffeine stacks.
May counteract or interact with cardiovascular drugs.
Bitter orange can inhibit CYP3A4, raising levels of some drugs (similar concern to grapefruit).
Tip: Use low isolated doses; avoid caffeine stacks
Tip: Reduce dose; avoid stimulant combinations
Tip: Reduce dose
Synephrine has an evidence score of 4.8/10 — emerging evidence based on 31 indexed studies, including 1 meta-analysis. A mild stimulant from bitter orange marketed for fat loss; it modestly raises fat oxidation but clinical weight-loss evidence is weak, and stacking it with caffeine or other stimulants adds sympathomimetic load. Representative study: PMID 36235672.
The commonly studied dose of Synephrine is 10-20mg p-synephrine 1-2x daily (≤50mg/day); avoid or minimize combining with caffeine/other stimulants (a typical label dose, not the dose used in the cited trials, which used 3 mg per kg of body weight). Individual needs vary — start at the lower end of the range and adjust based on how you respond.
The best time to take Synephrine is in the morning. It can be taken on an empty stomach. Taken earlier in the day for its stimulant/thermogenic effect (often pre-exercise); avoid late-day dosing and high-caffeine stacks.
Synephrine should be used with caution — talk to a healthcare provider before taking it. Reported side effects include increased heart rate / blood pressure, palpitations, jitteriness, anxiety, headache. How often they occur is not established for all of them. Use caution if any of these apply to you: Hypertension or cardiovascular disease; Arrhythmia or palpitations; Pregnancy and breastfeeding.
Caffeine
Probably helpsBlocks adenosine receptors to boost alertness, reaction time, and endurance — an umbrella review of 21 meta-analyses found it ergogenic for endurance, strength and power.
CoQ10
Likely helpsA lipid-soluble antioxidant central to mitochondrial energy production, with the strongest trial support for fertility/IVF outcomes and heart failure.
Urolithin A
Too few graded studiesPostbiotic that triggers mitophagy — the cleanup of damaged mitochondria — to support muscle health and cellular energy.
Berberine
Likely helpsActivates AMPK to regulate blood sugar, improve insulin sensitivity, and support lipid metabolism. Its only head-to-head trial with metformin cited here was a 36-person pilot, which does not show it can replace metformin.
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Reviewed by Dr. Baher Al Hakim · Last reviewed June 2026 · evidence from 31 studies · how we score · editorial policy
This information is for educational purposes only. It is not a substitute for professional medical advice. Always consult a qualified healthcare provider before starting, stopping, or changing any supplement or medication.