Herb & supplement monograph

Bitter Orange Drug Interactions, Uses, Effectiveness, Safety & More

Medically reviewed by Dr. Brian Staiger, PharmD, BCPS ·Updated July 2026

What is this page for?

First and foremost: how Bitter Orange interacts with medications. The heart of this page is the interaction list — every drug Bitter Orange is known to interact with, and how serious each one is.

But these pages have grown well beyond that into a full monograph — what Bitter Orange is, what people use it for and how strong the evidence is, its safety and side effects, and answers to the questions we’re asked most — written and reviewed by the clinical staff at HelloPharmacist. It’s educational information from our licensed clinical databases, not medical advice, and we don’t sell or endorse products. Our editorial policy

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Interaction report

Drugs that interact with Bitter Orange

959 medications have a known interaction with Bitter Orange, graded by severity. Select any drug for the full evidence-based detail.

10 major interactions. These combinations can be clinically significant — best avoided, or used only with close professional supervision. Always check with your pharmacist before combining them with Bitter Orange.

Don’t want to scroll the list? Just ask.

Tell us the medications you take and we’ll check each one against Bitter Orange using our pharmacist-reviewed interaction data.

AI summaries are generated from our Bitter Orange interaction data for education only — always confirm with your pharmacist. How we use AI

2,830 drugs

Read The List Like a Pharmacist

What Severity, Likelihood & Evidence Mean

Severity — How Serious It Can Be

Major. Clinically significant; generally best avoided, or used only under direct professional supervision.
Moderate. May need monitoring, a dose adjustment, or separating the times you take each one.
Minor. Generally not clinically significant, but still worth noting and mentioning to your pharmacist.
No known interaction. Checked against our sources with nothing documented — not the same as proven safety.

Likelihood — How Well It’s Documented

Likely. Well-controlled human studies have demonstrated the likely existence of this interaction
Probable. Interaction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports.
Possible. Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists
Unlikely. Interaction has been demonstrated in animal or in lab research but has been shown not to occur in humans.

Where This Data Comes From

Interaction records are evidence-graded and sourced from the Natural Medicines database (TRC Healthcare), the same reference used by pharmacists and hospitals.
Each drug listed above links to the full report for that exact Bitter Orange combination — clinical detail, likelihood, evidence level, and citations.
Content is reviewed by licensed HelloPharmacist pharmacists — see our data sources and editorial standards.

The big picture

The kinds of drugs Bitter Orange affects

Every type of medication (drug category) Bitter Orange is known to interact with. Open any category for the detail — or search your exact drug in the checker above.

All 13 drug categories Bitter Orange interacts with

Midazolam (versed)Monoamine Oxidase Inhibitors (maois)Antidiabetes DrugsCaffeineColchicineCytochrome P450 3a4 (cyp3a4) SubstratesDextromethorphan (robitussin Dm, Others)Felodipine (plendil)Indinavir (crixivan)Qt Interval-prolonging DrugsSildenafil (viagra)Stimulant DrugsCytochrome P450 2d6 (cyp2d6) Substrates

Midazolam (Versed)

Bitter orange might increase blood levels of midazolam.
One small clinical study shows that bitter orange juice can increase midazolam levels, likely through inhibition of cytochrome P450 3A4 (CYP3A4). Theoretically, bitter orange might increase the risk of midazolam-related adverse effects.

Likelihood Probable Evidence B

Monoamine Oxidase Inhibitors (Maois)

Theoretically, taking MAOIs with synephrine-containing bitter orange preparations might increase the hypertensive effects of synephrine, potentially leading to hypertensive crisis.
Bitter orange contains tyramine, octopamine, and synephrine, which are MAO substrates.

Likelihood Probable Evidence D

Antidiabetes Drugs

Theoretically, bitter orange might increase the risk of hypoglycemia when taken with antidiabetes drugs.
Some clinical research shows that drinking a tea containing bitter orange and Indian snakeroot reduces fasting and postprandial glucose levels in patients with type 2 diabetes who are using antidiabetes drugs. However, it is unclear if these effects are due to bitter orange, Indian snakeroot, or the combination. An animal study also shows that p-synephrine in combination with gliclazide , a sulfonylurea, causes an additional 20% to 44% decrease in glucose levels when compared with gliclazide alone.

Likelihood Possible Evidence B

Caffeine

Bitter orange might increase blood pressure and heart rate when taken with caffeine.
Small clinical studies show that taking bitter orange in combination with caffeine can increase blood pressure and heart rate in otherwise healthy normotensive adults. Theoretically, this might increase the risk of serious cardiovascular adverse effects.

Likelihood Possible Evidence B

Colchicine

Bitter orange might affect colchicine levels.
Colchicine is a substrate of P-glycoprotein and cytochrome P450 3A4 (CYP3A4). Bitter orange has been reported to inhibit CYP3A4 and increase levels of CYP3A4 substrates. However, one small clinical study in healthy adults shows that drinking bitter orange juice 240 mL twice daily for 4 days and taking a single dose of colchicine 0.6 mg on the 4th day decreases colchicine peak serum levels by 24%, time to peak serum level by 1 hour, and overall exposure to colchicine by 20%. The clinical significance of this finding is unclear.

Likelihood Possible Evidence B

Cytochrome P450 3A4 (Cyp3A4) Substrates

Bitter orange might increase levels of drugs metabolized by CYP3A4.
Small clinical studies suggest that single or multiple doses of freshly squeezed bitter orange juice 200-240 mL can inhibit CYP3A4 metabolism of drugs, causing increased drug levels and potentially increasing the risk of adverse effects. However, the extent of the effect of bitter orange on CYP3A4-mediated drug interactions is unknown. Some evidence suggests that bitter orange selectively inhibits intestinal CYP3A4, but not hepatic CYP3A4. Its effect on P-glycoprotein, which strongly overlaps with CYP3A4 interactions, is unclear. One small clinical study shows that drinking 8 ounces of freshly squeezed bitter orange juice has no effect on cyclosporine, which seems to be more dependent on hepatic CYP3A4 and P-glycoprotein than intestinal CYP3A4.

Likelihood Possible Evidence B

Dextromethorphan (Robitussin Dm, Others)

Bitter orange might increase blood levels of dextromethorphan.
One small clinical study shows that bitter orange juice increases dextromethorphan levels, likely through cytochrome P450 3A4 (CYP3A4) inhibition. Theoretically, bitter orange might increase the risk for dextromethorphan-related adverse effects.

Likelihood Possible Evidence B

Felodipine (Plendil)

Bitter orange might increase blood levels of felodipine.
One small clinical study shows that bitter orange juice increases felodipine levels, likely through cytochrome P450 3A4 (CYP3A4) inhibition. Theoretically, bitter orange might increase the risk for felodipine-related adverse effects.

Likelihood Probable Evidence B

Indinavir (Crixivan)

Bitter orange might increase blood levels of indinavir.
One small clinical study shows that bitter orange juice slightly increases indinavir levels, but this effect is likely to be clinically insignificant. Bitter orange selectively inhibits intestinal cytochrome P450 3A4 (CYP3A4); however, the metabolism of indinavir seems to be more dependent on hepatic CYP3A4. The effect of bitter orange on other protease inhibitors has not been studied.

Likelihood Possible Evidence B

Qt Interval-Prolonging Drugs

Theoretically, bitter orange might have an additive effect when combined with drugs that prolong the QT interval, potentially increasing the risk of ventricular arrhythmias.
One case report suggests that taking bitter orange in combination with other stimulants such as caffeine might prolong the QT interval in some patients.

Likelihood Possible Evidence D

Sildenafil (Viagra)

Bitter orange juice might increase blood levels of sildenafil.
A small clinical study in healthy adult males shows that drinking freshly squeezed bitter orange juice 250 mL daily for 3 days and taking a single dose of sildenafil 50 mg on the 3rd day increases the peak plasma concentration of sildenafil by 18% and the overall exposure to sildenafil by 44%. Theoretically, this may be due to inhibition of cytochrome P450 3A4 by bitter orange.

Likelihood Probable Evidence B

Stimulant Drugs

Theoretically, bitter orange might increase the risk of hypertension and adverse cardiovascular effects when taken with stimulant drugs.
Bitter orange appears to have stimulant effects.

Likelihood Possible Evidence B

Cytochrome P450 2D6 (Cyp2D6) Substrates

Theoretically, bitter orange might increase levels of drug metabolized by CYP2D6.
In vitro research shows that octopamine, a constituent of bitter orange, weakly inhibits CYP2D6 enzymes. This effect has not been reported in humans.

Likelihood Possible Evidence D

Monograph

Bitter Orange: Uses, Safety & Side Effects

Medically reviewed by Dr. Brian Staiger, PharmD, BCPS · Reviewed July 2026 ·

The bottom line

Bitter orange is a citrus fruit whose extracts contain synephrine, a mild stimulant often added to weight-loss and energy supplements. Evidence that it works for weight loss or performance is limited, and because it can raise heart rate and blood pressure, people with heart problems, high blood pressure, or who are pregnant should avoid it. Talk to your pharmacist or doctor before using it, especially if you take other stimulants.

Scientific name: Citrus aurantium
Family: Rutaceae
Part used: Fruit (especially the dried immature fruit and peel), flowers, and essential oil (neroli)
Common forms: Capsules, tablets, extracts, dried peel, tea, and essential oil

People commonly use it for

Weight loss
Athletic performance and energy
Digestive upset
Appetite control
Aromatherapy for stress (neroli oil)

Popular and traditional uses — not proof it works. See “Uses & effectiveness” below for the evidence.

Safety at a glance

OverallUse caution

Generally limited use may be tolerated, but the synephrine it contains can affect heart rate and blood pressure.

PregnancyLikely Safe

When used orally in the amounts found in foods. Bitter orange has Generally Recognized as Safe (GRAS) status in the US.

Read the full pregnancy detail

BreastfeedingLikely Safe

When used orally in the amounts found in foods. Bitter orange has Generally Recognized as Safe (GRAS) status in the US.

Read the full breastfeeding detail

Pregnancy & breastfeeding ratings are from Natural Medicines (Therapeutic Research Center). Safety guidance is general; always confirm with your pharmacist or doctor for your situation.

Jump to a section

Overview

Bitter orange (Citrus aurantium) is a citrus fruit also called Seville orange or sour orange. It is native to Southeast Asia and is now grown in many warm regions around the world. The fruit is more sour and bitter than a regular sweet orange, which is why it is often used to make marmalade and flavorings rather than eaten fresh.

Different parts of the plant are used. The peel and dried unripe fruit are used in supplements and traditional medicine, while the flowers are distilled to make neroli oil, a popular ingredient in perfumes and aromatherapy.

Today, bitter orange is best known as an ingredient in weight-loss and energy supplements. After ephedra was banned in many countries, bitter orange extract (standardized to its synephrine content) became a common replacement.

How it works

The main active compound in bitter orange supplements is synephrine, a substance similar in structure to ephedrine and to the body's own adrenaline. Synephrine is a stimulant that can mildly increase heart rate, blood pressure, and the rate at which the body burns energy.

It is thought to work on adrenaline-type receptors in the body, which may slightly raise metabolism and suppress appetite. These effects are often stronger when bitter orange is combined with caffeine.

Much of what we know comes from laboratory studies, animal research, and small human trials. The fruit also contains vitamin C, flavonoids, and other antioxidants, but these are not the reason it is used in stimulant supplements.

Effectiveness

Does Bitter Orange work?

Here’s what the research actually shows for each use — graded by Natural Medicines and reviewed by Dr. Brian Staiger, PharmD.

Evidence overview · 30 uses evaluated

30 Insufficient evidence

How to read these evidence grades

Natural Medicines’ 7-point scale. We show each rating’s label word-for-word.

1EffectiveStrong, consistent evidence it works.

2Likely EffectiveGood evidence, though not yet conclusive.

3Possibly EffectiveSome evidence suggests a benefit.

4Possibly IneffectiveSome evidence it may not help.

5Likely IneffectiveFairly strong evidence it doesn’t help.

6IneffectiveStrong evidence it doesn’t work.

7Insufficient Reliable Evidence to RateToo little research to say either way.

For Bitter Orange, current evidence isn’t strong enough to rate any specific use. The conditions it has been studied for are listed below.

Also studied for 30 conditions — evidence insufficient to rate

Insufficient Reliable Evidence To Rate Allergic rhinitis (hay fever)