Citrus aurantium · PhytoNexus

01 Identity and provenance

Accepted binomial: Citrus aurantium
Common names: Bitter Orange
Family (APG IV): Rutaceae
Part used: Peel, Fruit
Verification tier: Tier 2 · Verified Clinical columns reviewed and a source is on record.
Reviewer note (2026 audit): Stohs SJ et al. Phytother Res 2017;31:1463-75 (NOTE declared COI) | Hansen DK et al. FDA cardiovascular animal study | VERIFIED 2026 (batch 3) - synthetic analogue, application, interactions, side effects and references populated from retrieved primary/regulatory sources. Interactions labelled CLINICAL vs THEORETICAL. Marketed-formulation column intentionally blank. | COMPOSITION

02 Constituent chemistry

Chemical class	Marker compound	Synthetic analogue in use
Protoalkaloids, volatile oil	Synephrine Peel, Fruit	Phenylephrine, Ephedrine (STRUCTURAL similarity - p-synephrine is a phenylethylamine protoalkaloid), though receptor binding differs.

The analogue column is what makes the interaction reasoning tractable: where a constituent has a marketed structural counterpart, the counterpart's interaction profile is the starting hypothesis for the plant.

Looking up structures and physicochemical properties from PubChem…

03 Stated application

Reported activity: Widely used in weight management and sports supplements, largely as an ephedra replacement after the 2004 US ban. Traditional Chinese use (zhi shi) for indigestion and abdominal pain.
Reported adverse effects: EVIDENCE IS GENUINELY CONTESTED - record both sides. NCCIH: cases of arrhythmia, myocardial infarction and stroke have been reported, but nearly all involved multi-ingredient products, so causal attribution to bitter orange is unclear; evidence on cardiovascular effects is inconclusive. FDA animal work found raised blood pressure and heart rate. Reviews concluding p-synephrine is safe are authored by consultants to a bitter-orange marketer (declared conflict of interest) - weight accordingly. Health Canada regards 1-50 mg/day as unlikely to cause harm.

04 Interaction matrix

Source column, verbatim: CLINICAL CONCERN: caffeine co-ingestion - most reported adverse events involve multi-ingredient stimulant products. NCAA bans synephrine as a stimulant. Caution with sympathomimetics, MAOIs and antihypertensives.
Normalised onto 2 canonical drug classes below.

Curated from the reviewed source

Drug class	Severity	Mechanism type	Provenance	Expected effect
Antihypertensives Cardiovascular	4Contraindicated	PD-additive	curated A	Orthostatic hypotension, dizziness, syncope and falls; or loss of blood-p…	why ▾
Chemistry of this pair. Phenethylamine and methylxanthine constituents release noradrenaline and block adenosine receptors, producing direct sympathomimetic drive. Class mechanism. Vasodilator, diuretic, ACE-inhibitory and calcium-antagonist activity in botanical extracts adds to prescribed blood-pressure lowering. A minority (ephedrine-, glycyrrhizin- and caffeine-bearing) act in the opposite direction and antagonise control. Expected Orthostatic hypotension, dizziness, syncope and falls; or loss of blood-pressure control with pressor botanicals. Management Home BP log for 2 weeks after any change. Warn about postural symptoms; review in the elderly and in those on multiple agents. Onset rapid Evidence A - human data with a cited source Matched on “antihypertensives” Find evidence for this pair Map this mechanism
CNS stimulants and sympathomimetics CNS	4Contraindicated	PD-additive	curated A	Tachycardia, hypertension, arrhythmia, insomnia, anxiety, stroke and myoc…	why ▾
Chemistry of this pair. Phenethylamine and methylxanthine constituents release noradrenaline and block adenosine receptors, producing direct sympathomimetic drive. Class mechanism. Ephedrine, pseudoephedrine, caffeine, synephrine and cathine-type constituents add to prescribed stimulant and decongestant sympathomimetic drive. Expected Tachycardia, hypertension, arrhythmia, insomnia, anxiety, stroke and myocardial infarction in susceptible people. Management Avoid in cardiovascular disease, hyperthyroidism and pregnancy. Ask about weight-loss and sports supplements by brand. Onset rapid Evidence A - human data with a cited source Matched on “sympathomimetics” Find evidence for this pair Map this mechanism

Predicted from constituent chemistry

These edges are not clinical findings. Each one is a rule inference: a constituent class in this plant is known to act on a target that the drug class also acts on. They are shown because a blank cell reads as “safe”, and for a Tier 1 entry a blank cell only means “not yet looked at”. Treat them as a literature-search agenda, not as a warning.

Drug class	Severity	Mechanism type	Provenance	Expected effect
Antiarrhythmics Cardiovascular	4Contraindicated	PD-additive + electrolyte-mediated	predicted D	Proarrhythmia, QT prolongation, torsade de pointes, ventricular arrhythmi…	why ▾
Chemistry of this pair. Phenethylamine and methylxanthine constituents release noradrenaline and block adenosine receptors, producing direct sympathomimetic drive. Class mechanism. Botanicals that shift potassium or magnesium, block sodium or potassium channels, or prolong repolarisation add to class I and class III antiarrhythmic effects on an already unstable myocardium. Expected Proarrhythmia, QT prolongation, torsade de pointes, ventricular arrhythmia. Management Avoid. If unavoidable, baseline and follow-up ECG with QTc measurement plus potassium and magnesium correction. Onset rapid Evidence D - in silico rule prediction only Find evidence for this pair Map this mechanism
Cardiotoxic drugs Organ toxicity	4Contraindicated	Organ-toxicity additive	predicted D	Arrhythmia, reduced ejection fraction, myocarditis-like presentation.	why ▾
Chemistry of this pair. Phenethylamine and methylxanthine constituents release noradrenaline and block adenosine receptors, producing direct sympathomimetic drive. Class mechanism. Aconitine-type alkaloids, cardenolides and high-dose ephedrine add to anthracycline, trastuzumab and antiarrhythmic myocardial toxicity. Expected Arrhythmia, reduced ejection fraction, myocarditis-like presentation. Management Avoid during cardiotoxic chemotherapy. Baseline and follow-up echocardiography where exposure has occurred. Onset unspecified Evidence D - in silico rule prediction only Find evidence for this pair Map this mechanism
Narrow-therapeutic-index CYP3A4 substrates Pharmacokinetic	4Contraindicated	PK-CYP3A4	predicted D	Toxic accumulation or subtherapeutic failure of the co-prescribed drug, s…	why ▾
Chemistry of this pair. Alkaloidal bases have pH-dependent absorption and commonly interact with hepatic CYP isoenzymes and efflux transporters. Class mechanism. Furanocoumarins, bergamottin, piperine, glabridin and berberine inhibit CYP3A4; hyperforin, andrographolide and several diterpenes induce it through PXR. Because CYP3A4 handles roughly half of marketed drugs, the affected list is broad and the direction is product-specific. Expected Toxic accumulation or subtherapeutic failure of the co-prescribed drug, sometimes fatal for antiarrhythmics, immunosuppressants and oncology agents. Management Screen the full regimen for 3A4 substrates. Where the substrate has a narrow index, avoid rather than monitor. Onset unspecified Evidence D - in silico rule prediction only Find evidence for this pair Map this mechanism
Antacids, PPIs and H2 blockers Gastrointestinal	2Moderate	PK-absorption	predicted D	Reduced or erratic absorption of alkaloids; heartburn and reflux from pre…	why ▾
Chemistry of this pair. Alkaloidal bases have pH-dependent absorption and commonly interact with hepatic CYP isoenzymes and efflux transporters. Class mechanism. Gastric pH elevation alters the dissolution and ionisation of alkaloidal and enteric-coated botanical products; menthol- and peppermint-oil products lose their enteric protection at high pH and can be released prematurely. Expected Reduced or erratic absorption of alkaloids; heartburn and reflux from premature release of volatile-oil preparations. Management Separate administration by 2 hours. Avoid non-enteric peppermint oil in reflux disease. Onset unspecified Evidence D - in silico rule prediction only Find evidence for this pair Map this mechanism
Topical antiseptics, keratolytics and irritants Dermatology	2Moderate	PD-additive local	predicted D	Contact dermatitis, chemical burn, photoirritation, unexpected systemic a…	why ▾
Chemistry of this pair. Volatile terpenes are lipophilic, cross membranes readily and induce or inhibit CYP2B6 and CYP3A4 depending on the constituent. Class mechanism. Essential-oil terpenes, capsaicinoids and phorbol-type diterpenes add to the barrier disruption caused by topical antiseptics, retinoids and keratolytics, and increase percutaneous absorption of anything applied with them. Expected Contact dermatitis, chemical burn, photoirritation, unexpected systemic absorption from broken skin. Management Patch test first. Never apply undiluted essential oils to broken or freshly shaved skin, or with occlusion. Onset rapid Evidence D - in silico rule prediction only Find evidence for this pair Map this mechanism

05 Hazard register

product variability - adverse events almost all involve multi-in

06 Confusable material

These entries could be mistaken for this one in trade, in the herbarium, or in a prescription. Powdered material is often indistinguishable, so the check is macroscopic, microscopic and chromatographic rather than nominal.

Citrus bergamia Bergamot	Rutaceae	Same genus (Citrus)
Citrus limon Lemon	Rutaceae	Same genus (Citrus)
Citrus sinensis Sweet Orange	Rutaceae	Same genus (Citrus)
Momordica charantia Karela (Bitter gourd)	Cucurbitaceae	Shares the common name "bitter"

07 Mechanism map

Chemistry sorts to the left, pharmacology to the right. Dashed edges are predicted. Drag nodes, scroll to zoom, export at 3× for a figure.

species

chemical class

marker compound

drug class

expected effect

hazard

08 Open literature

Abstract-scoped query built from this binomial, its common names and its marker compounds, run live against Europe PMC, PubMed and OpenAlex, then ranked locally against an evidence hierarchy.

Checking openFDA spontaneous reports…

09 Isomechanistic neighbours

Species whose interaction profile overlaps this one, ranked by shared severity weight rather than by count — a shared contraindication counts for more than a shared minor signal. Practical use: these are the plants you should not stack with this one, because the mechanisms summate.

Species	Family	Shared classes	Jaccard
Ephedra sinica Ephedra	Ephedraceae	6	0.67
Ephedra gerardiana Himalayan Ephedra	Ephedraceae	6	0.55
Camellia sinensis Green Tea	Theaceae	5	0.38
Aconitum napellus Monkshood	Ranunculaceae	5	0.63
Aconitum ferox Vatsanabha	Ranunculaceae	5	0.63
Carapichea ipecacuanha Ipecac	Rubiaceae	4	0.44

10 References and notes

Source column: NCCIH Bitter Orange fact sheet

NCCIH Bitter Orange fact sheet

manual

BibTeX for all 1 records

@article{anon,
  title = {NCCIH Bitter Orange fact sheet},
}

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