The National Collegiate Athletic Association (NCAA) <a href="https://www.ncaa.org/sports/2015/6/10/ncaa-banned-substances.aspx">lists synephrine</a> (bitter orange) as a banned stimulant. One small study found that taking 100 mg of synephrine slightly enhanced muscle endurance during resistance exercise compared to control.<a href="#ref-13" id="ref-link-13" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Ratamess NA, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/26388707" target="\_blank" rel="noopener noreferrer"&gt;The effects of supplementation with P-Synephrine alone and in combination with caffeine on resistance exercise performance.
&lt;/a&gt;&lt;/p&gt;J Int Soc Sports Nutr (2015)&lt;/div&gt;'>[13]</a> 
A longer-duration study found that 4 weeks of daily administration of a supplement containing 20 mg synephrine improved some areas of exercise performance, but after 8 weeks no clear differences compared to the supplement without synephrine were noted.<a href="#ref-4" id="ref-link-4" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Jung YP, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/28096757" target="\_blank" rel="noopener noreferrer"&gt;Effects of ingesting a pre-workout dietary supplement with and without synephrine for 8 weeks on training adaptations in resistance-trained males.
&lt;/a&gt;&lt;/p&gt;J Int Soc Sports Nutr (2017)&lt;/div&gt;'>[4]</a>

Is bitter orange considered a performance-enhancing supplement for athletes?

Bitter orange, also known as Citrus aurantium, is a citrus fruit originally used in Traditional Chinese medicine for stomach ailments, such as constipation, diarrhea, and indigestion.<a href="#ref-1" id="ref-link-1" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;&lt;a href="https://www.nccih.nih.gov/health/bitter-orange" target="\_blank" rel="noopener noreferrer"&gt;Bitter Orange: National Center for Complementary and Integrative Health
&lt;/a&gt;&lt;/p&gt;(May 2020)&lt;/div&gt;'>[1]</a> Today, bitter orange extract, standardized to p-synephrine content, commonly occurs in multi-ingredient formulations labeled as ephedra-free supplements for weight loss: p-synephrine is an alkaloid compound structurally similar to adrenaline and the banned dietary supplement ephedrine.<a href="#ref-2" id="ref-link-2" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Haaz S, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/16436104" target="\_blank" rel="noopener noreferrer"&gt;Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: an update.
&lt;/a&gt;&lt;/p&gt;Obes Rev (2006-Feb)&lt;/div&gt;'>[2]</a> The pharmacologic and pharmacokinetic properties of p-synephrine vary from its structural analogues enough to mitigate the risks previously seen with ephedrine-containing supplements. <a href="#ref-1" id="ref-link-1" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;&lt;a href="https://www.nccih.nih.gov/health/bitter-orange" target="\_blank" rel="noopener noreferrer"&gt;Bitter Orange: National Center for Complementary and Integrative Health
&lt;/a&gt;&lt;/p&gt;(May 2020)&lt;/div&gt;'>[1]</a>. p-synephrine should also not be confused with m-synephrine, a synthetic amine derivative of synephrine. m-synephrine does not meet the FDA dietary supplement definition and is a prohibited ingredient.

What is bitter orange?

Limited research did not find a benefit. An analysis of 3 small studies found that taking 10–54 mg of synephrine daily for 6–8 weeks had no significant effects on weight loss or fat mass.<a href="#ref-3" id="ref-link-3" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Koncz D, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/36235672" target="\_blank" rel="noopener noreferrer"&gt;The Safety and Efficacy of (Bitter Orange) Extracts and -Synephrine: A Systematic Review and Meta-Analysis.
&lt;/a&gt;&lt;/p&gt;Nutrients (2022-Sep-28)&lt;/div&gt;'>[3]</a> 
Limited research suggests that bitter orange supplements may increase fat oxidation during exercise and affect resting metabolic rate. One small study of 14 healthy adults found that taking a single dose of p-synephrine prior to one hour of cycling exercise, at a dosage of 3 mg of synephrine per kg of body weight (3 mg/kg), increased the amount of fat burned and decreased the amount of carbohydrates utilized, but did not affect total energy expenditure compared to placebo.<a href="#ref-14" id="ref-link-14" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Gutiérrez-Hellín J, Ruiz-Moreno C, Del Coso J. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/31691018" target="\_blank" rel="noopener noreferrer"&gt;Acute p-synephrine ingestion increases whole-body fat oxidation during 1-h of cycling at Fatmax.
&lt;/a&gt;&lt;/p&gt;Eur J Nutr (2020-Oct)&lt;/div&gt;'>[14]</a>. Another small study found that 10 individuals given 50 mg of synephrine had a 65 kcal increase in their resting metabolic rate compared to placebo, but this result was not significant.<a href="#ref-15" id="ref-link-15" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Stohs SJ, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/21537493" target="\_blank" rel="noopener noreferrer"&gt;Effects of p-synephrine alone and in combination with selected bioflavonoids on resting metabolism, blood pressure, heart rate and self-reported mood changes
&lt;/a&gt;&lt;/p&gt;Int J Med Sci (2011 Apr 28)&lt;/div&gt;'>[15]</a>

Does bitter orange help with weight loss?

There is interest in using bitter orange for weight loss and improvement in body composition (fat loss). However, this is not supported by clinical data.<a href="#ref-3" id="ref-link-3" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Koncz D, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/36235672" target="\_blank" rel="noopener noreferrer"&gt;The Safety and Efficacy of (Bitter Orange) Extracts and -Synephrine: A Systematic Review and Meta-Analysis.
&lt;/a&gt;&lt;/p&gt;Nutrients (2022-Sep-28)&lt;/div&gt;'>[3]</a> Bitter orange is also used for athletic performance, but its benefit is not clear.<a href="#ref-4" id="ref-link-4" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Jung YP, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/28096757" target="\_blank" rel="noopener noreferrer"&gt;Effects of ingesting a pre-workout dietary supplement with and without synephrine for 8 weeks on training adaptations in resistance-trained males.
&lt;/a&gt;&lt;/p&gt;J Int Soc Sports Nutr (2017)&lt;/div&gt;'>[4]</a>
One study found that applying bitter orange oil 20–25% to affected skin for 1 to 3 weeks was associated with cure of fungal infections like ringworm, jock itch, or athlete’s foot.<a href="#ref-5" id="ref-link-5" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Ramadan W, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/8737885" target="\_blank" rel="noopener noreferrer"&gt;Oil of bitter orange: new topical antifungal agent.
&lt;/a&gt;&lt;/p&gt;Int J Dermatol (1996-Jun)&lt;/div&gt;'>[5]</a> However, that study was limited by a lack of control group.

What are bitter orange’s main benefits?

Some limited research suggests that bitter orange supplements may increase blood pressure, while other research found no effect. A meta-analysis of small randomized controlled studies suggests that taking bitter orange extract alone or with other ingredients for 56–60 days increases systolic blood pressure by up to 6.4 mmHg compared to control; however, there was no significant effect on diastolic blood pressure. Acute administration of bitter orange extract tended to increase blood pressure over 3 hours, but this result was not statistically significant.<a href="#ref-3" id="ref-link-3" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Koncz D, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/36235672" target="\_blank" rel="noopener noreferrer"&gt;The Safety and Efficacy of (Bitter Orange) Extracts and -Synephrine: A Systematic Review and Meta-Analysis.
&lt;/a&gt;&lt;/p&gt;Nutrients (2022-Sep-28)&lt;/div&gt;'>[3]</a> One randomized crossover trial of 15 healthy, young adults given a single dose of bitter orange supplement containing 108 mg of synephrine, which was included in the above meta-analysis, reported that the participants given synephrine experienced modestly increased blood pressure and heart rate for up to 5 hours compared to placebo.<a href="#ref-16" id="ref-link-16" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Bui LT, Nguyen DT, Ambrose PJ. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/16317106" target="\_blank" rel="noopener noreferrer"&gt;Blood pressure and heart rate effects following a single dose of bitter orange
&lt;/a&gt;&lt;/p&gt;Ann Pharmacother (2006 Jan)&lt;/div&gt;'>[16]</a> In another small study, in which participants were given a single, smaller dose of 27 mg of synephrine and monitored for 8 hours, no significant difference from placebo was seen on t blood pressure or electrocardiogram (QT interval).<a href="#ref-17" id="ref-link-17" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Min B, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/16305290" target="\_blank" rel="noopener noreferrer"&gt;Absence of QTc-interval-prolonging or hemodynamic effects of a single dose of bitter-orange extract in healthy subjects
&lt;/a&gt;&lt;/p&gt;Pharmacotherapy (2005 Dec)&lt;/div&gt;'>[17]</a> In a small study of healthy young adults sitting quietly for 3 hours after taking a single dose of 103 mg p-synephrine, alone or with 240 mg caffeine, blood pressure and heart rate were not affected compared to placebo.<a href="#ref-18" id="ref-link-18" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Ratamess NA, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/29047215" target="\_blank" rel="noopener noreferrer"&gt;Acute cardiovascular effects of bitter orange extract (p-synephrine) consumed alone and in combination with caffeine in human subjects: A placebo-controlled, double-blind study.
&lt;/a&gt;&lt;/p&gt;Phytother Res (2018-Jan)&lt;/div&gt;'>[18]</a> These results suggest that caffeine and synephrine may not always have synergistic effects in the short term.
A small study of 10 healthy adults considered 2 different dietary supplements containing synephrine and compared heart rate and blood pressure results with placebo after a single dose (Advantra Z, containing 46.9 mg synephrine, and Xenadrine EFX, containing 5.5 mg
synephrine). Interestingly, the Xenadrine EFX group experienced more blood pressure and heart rate elevations than the Advantra group, possibly due to other ingredients in the supplement.<a href="#ref-19" id="ref-link-19" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Haller CA, Benowitz NL, Jacob P. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/16164886" target="\_blank" rel="noopener noreferrer"&gt;Hemodynamic effects of ephedra-free weight-loss supplements in humans.
&lt;/a&gt;&lt;/p&gt;Am J Med (2005-Sep)&lt;/div&gt;'>[19]</a>
The longer-term effects of a 20 mg daily dose of synephrine were examined in an 8 week study of healthy, young, resistance-trained males; researchers found no changes in blood pressure or heart rate compared to control.<a href="#ref-4" id="ref-link-4" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Jung YP, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/28096757" target="\_blank" rel="noopener noreferrer"&gt;Effects of ingesting a pre-workout dietary supplement with and without synephrine for 8 weeks on training adaptations in resistance-trained males.
&lt;/a&gt;&lt;/p&gt;J Int Soc Sports Nutr (2017)&lt;/div&gt;'>[4]</a>.

Does bitter orange increase blood pressure?

Bitter orange supplements, typically standardized to synephrine content, seem to have cardiovascular stimulant effects resulting in increased blood pressure and heart rate.<a href="#ref-3" id="ref-link-3" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Koncz D, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/36235672" target="\_blank" rel="noopener noreferrer"&gt;The Safety and Efficacy of (Bitter Orange) Extracts and -Synephrine: A Systematic Review and Meta-Analysis.
&lt;/a&gt;&lt;/p&gt;Nutrients (2022-Sep-28)&lt;/div&gt;'>[3]</a> There have been reports of adverse reactions in at least 35 people (most commonly palpitations, fainting and dizziness) after taking a synephrine-containing supplement. The specific supplement was not recorded in all cases, but for those cases where it was, the majority of the adverse events occurred with supplements in which synephrine was combined with other active ingredients, including <a href="/supplements/caffeine/" class="popover" data-tooltip="&lt;div&gt;&lt;h6&gt;Caffeine&lt;/h6&gt;&lt;p&gt;Caffeine is a central nervous system stimulant that can improve sports performance and aspects of cognitive function. Caffeine or caffeine-containing beverages are often taken to help restore alertness and wakefulness or to reduce drowsiness. Despite its side effects, caffeine is safe for most people, and caffeine-containing beverages like tea and coffee are socially acceptable and widely used.&lt;/p&gt;&lt;/div&gt;">caffeine</a>, deterenol (a synthetic stimulant), theophylline (a bronchodilator), <a href="/supplements/phenylethylamine/" class="popover" data-tooltip="&lt;div&gt;&lt;h6&gt;Phenylethylamine&lt;/h6&gt;&lt;p&gt;A trace amine and influencer of many of the 'happy hormones' such as dopamine and serotonin, β-phenylethylamine is an important molecule in the brain with limited supplemental usage due to being rapidly broken down into inactive components.&lt;/p&gt;&lt;/div&gt;">beta-phenylethylamine</a>, and <a href="/supplements/yohimbine/" class="popover" data-tooltip="&lt;div&gt;&lt;h6&gt;Yohimbine&lt;/h6&gt;&lt;p&gt;Yohimbine is promoted for its fat-burning properties and benefits for male sexual dysfunction. Though yohimbine is effective, side effects may include anxiety, nervousness, and an elevated heart rate, and the reported dose of yohimbine in many supplement formulas doesn’t match the actual dose.&lt;/p&gt;&lt;/div&gt;">yohimbine</a>. A supplement containing synephrine with caffeine was reported in most cases of cardiovascular adverse events.<a href="#ref-6" id="ref-link-6" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;de Jonge MLL, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/36639595" target="\_blank" rel="noopener noreferrer"&gt;Review of Case Reports on Adverse Events Related to Pre-workout Supplements Containing Synephrine.
&lt;/a&gt;&lt;/p&gt;Cardiovasc Toxicol (2023-Jan)&lt;/div&gt;'>[6]</a>. Examples of these events included heart rhythm issues,<a href="#ref-7" id="ref-link-7" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Nasir JM, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/15301335" target="\_blank" rel="noopener noreferrer"&gt;Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine.
&lt;/a&gt;&lt;/p&gt;Mayo Clin Proc (2004-Aug)&lt;/div&gt;'>[7]</a> stroke,<a href="#ref-8" id="ref-link-8" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Bouchard NC, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/15819293" target="\_blank" rel="noopener noreferrer"&gt;Ischemic stroke associated with use of an ephedra-free dietary supplement containing synephrine.
&lt;/a&gt;&lt;/p&gt;Mayo Clin Proc (2005-Apr)&lt;/div&gt;'>[8]</a> chest pain,<a href="#ref-9" id="ref-link-9" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Gange CA, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/16610576" target="\_blank" rel="noopener noreferrer"&gt;Variant angina associated with bitter orange in a dietary supplement.
&lt;/a&gt;&lt;/p&gt;Mayo Clin Proc (2006-Apr)&lt;/div&gt;'>[9]</a> and heart attack.<a href="#ref-10" id="ref-link-10" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Thomas JE, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/20069086" target="\_blank" rel="noopener noreferrer"&gt;STEMI in a 24-year-old man after use of a synephrine-containing dietary supplement: a case report and review of the literature.
&lt;/a&gt;&lt;/p&gt;Tex Heart Inst J (2009)&lt;/div&gt;'>[10]</a> 
Topical bitter orange products may cause irritation and increased sensitivity to the sun, increasing the risk for sunburns.<a href="#ref-11" id="ref-link-11" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Ulbricht C, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/24237193" target="\_blank" rel="noopener noreferrer"&gt;An evidence-based systematic review of bitter orange (Citrus aurantium) by the Natural Standard Research Collaboration.
&lt;/a&gt;&lt;/p&gt;J Diet Suppl (2013-Dec)&lt;/div&gt;'>[11]</a> 
Bitter orange might cause drug interactions. Some studies show that bitter orange juice increases blood levels of medications broken down by the liver enzyme called cytochrome P450 (CYP) 3A4. This seems to be due to the furanocoumarin constituents contained in certain citrus fruits.<a href="#ref-12" id="ref-link-12" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Costache II, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/32089733" target="\_blank" rel="noopener noreferrer"&gt;Pharmacokinetic Interactions between Cardiovascular Medicines and Plant Products.
&lt;/a&gt;&lt;/p&gt;Cardiovasc Ther (2019)&lt;/div&gt;'>[12]</a> Theoretically, bitter orange supplements that contain furanocoumarins can affect medications that need to be processed by the CYP3A4 enzyme in the liver.

What are bitter orange’s main drawbacks?

The synephrine in bitter oranges is thought to work as a sympathetic adrenergic agonist, stimulating receptors involved in the “fight or flight” response. These effects stimulate the cardiovascular system resulting in increased heart rate and blood pressure. Also, these effects may stimulate metabolism, resting metabolic rate and lipolysis (breakdown of fat). Appetite may also be suppressed via slowed movement of food through the gastrointestinal tract.<a href="#ref-2" id="ref-link-2" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;Haaz S, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/16436104" target="\_blank" rel="noopener noreferrer"&gt;Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: an update.
&lt;/a&gt;&lt;/p&gt;Obes Rev (2006-Feb)&lt;/div&gt;'>[2]</a> <a href="#ref-6" id="ref-link-6" class="ref-link popover" data-tooltip='&lt;div&gt;&lt;p class="mb-3"&gt;de Jonge MLL, et al. &lt;a href="https://pubmed.ncbi.nlm.nih.gov/36639595" target="\_blank" rel="noopener noreferrer"&gt;Review of Case Reports on Adverse Events Related to Pre-workout Supplements Containing Synephrine.
&lt;/a&gt;&lt;/p&gt;Cardiovasc Toxicol (2023-Jan)&lt;/div&gt;'>[6]</a>

How does bitter orange work?

Bitter orange

Fat Loss

Bitter Orange: National Center for Complementary and Integrative Health

Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: an update.

The Safety and Efficacy of  (Bitter Orange) Extracts and -Synephrine: A Systematic Review and Meta-Analysis.

Effects of ingesting a pre-workout dietary supplement with and without synephrine for 8 weeks on training adaptations in resistance-trained males.

Oil of bitter orange: new topical antifungal agent.

Review of Case Reports on Adverse Events Related to Pre-workout Supplements Containing Synephrine.

Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine.

Ischemic stroke associated with use of an ephedra-free dietary supplement containing synephrine.

Variant angina associated with bitter orange in a dietary supplement.

STEMI in a 24-year-old man after use of a synephrine-containing dietary supplement: a case report and review of the literature.

An evidence-based systematic review of bitter orange (Citrus aurantium) by the Natural Standard Research Collaboration.

Pharmacokinetic Interactions between Cardiovascular Medicines and Plant Products.

The effects of supplementation with P-Synephrine alone and in combination with caffeine on resistance exercise performance.

Acute p-synephrine ingestion increases whole-body fat oxidation during 1-h of cycling at Fatmax.

Effects of p-synephrine alone and in combination with selected bioflavonoids on resting metabolism, blood pressure, heart rate and self-reported mood changes

Blood pressure and heart rate effects following a single dose of bitter orange

Absence of QTc-interval-prolonging or hemodynamic effects of a single dose of bitter-orange extract in healthy subjects

Acute cardiovascular effects of bitter orange extract (p-synephrine) consumed alone and in combination with caffeine in human subjects: A placebo-controlled, double-blind study.

Hemodynamic effects of ephedra-free weight-loss supplements in humans.

Marina Shkayeva

Gregory Lopez

Natalka Roshak

Sara Gardy

Sarah Schriewer

Cardiovascular Health

General Cardiovascular Health

Metabolic Rate

Alertness

Anxiety Symptoms

Appetite

Blood Pressure

Blood glucose

Headaches

Heart Rate

QTc Intervals

Sedation

Aerobic Exercise Performance

Carbohydrate Oxidation

Healthy Aging

Diabetes & Blood Sugar

Liver Health

Metabolic Health

Hematocrit

Weight

Cycling Performance

Weight Loss & Maintenance

Exercise Recovery

Anaerobic Exercise Performance

Insomnia Signs and Symptoms

Sprint Performance Metrics

Mood & Depression

Mood Improvement

Muscle Size & Strength

Seville (sour) orange juice: synephrine content and cardiovascular effects in normotensive adults.

Safety evaluation of p-synephrine following 15 days of oral administration to healthy subjects: A clinical study.

Cardiovascular Safety of Oral p-Synephrine (Bitter Orange) in Healthy Subjects: A Randomized Placebo-Controlled Cross-over Clinical Trial.

A 60day double-blind, placebo-controlled safety study involving Citrus aurantium (bitter orange) extract.

Acute hematological and mood perception effects of bitter orange extract (p-synephrine) consumed alone and in combination with caffeine: A placebo-controlled, double-blind study.

Dietary herbal supplements with phenylephrine for weight loss.

Effects of p-Synephrine and Caffeine Ingestion on Substrate Oxidation during Exercise.

Acute p-synephrine ingestion increases fat oxidation rate during exercise

Effect of -Synephrine on Fat Oxidation Rate during Exercise of Increasing Intensity in Healthy Active Women.

Does the Time of Day Play a Role in the Acute Effect of -Synephrine on Fat Oxidation Rate during Exercise in Women? A Randomized, Crossover and Double-Blind Study.

Acute consumption of p-synephrine does not enhance performance in sprint athletes.

Bitter Orange  Intake Before Submaximal Aerobic Exercise Is Safe for Cardiovascular and Autonomic Systems in Healthy Males: A Randomized Trial.

The Effects of Supplementation with p-Synephrine Alone and in Combination with Caffeine on Metabolic, Lipolytic, and Cardiovascular Responses during Resistance Exercise.

The National Collegiate Athletic Association (NCAA) <a href="https://www.ncaa.org/sports/2015/6/10/ncaa-banned-substances.aspx">lists synephrine</a> (bitter orange) as a banned stimulant. One small study found that taking 100 mg of synephrine slightly enhanced muscle endurance during resistance exercise compared to control.[reference|url=https://pubmed.ncbi.nlm.nih.gov/26388707|title=The effects of supplementation with P-Synephrine alone and in combination with caffeine on resistance exercise performance.|published=2015|authors=Ratamess NA, Bush JA, Kang J, Kraemer WJ, Stohs SJ, Nocera VG, Leise MD, Diamond KB, Faigenbaum AD|journal=J Int Soc Sports Nutr|] 
A longer-duration study found that 4 weeks of daily administration of a supplement containing 20 mg synephrine improved some areas of exercise performance, but after 8 weeks no clear differences compared to the supplement without synephrine were noted.[reference|url=https://pubmed.ncbi.nlm.nih.gov/28096757|title=Effects of ingesting a pre-workout dietary supplement with and without synephrine for 8 weeks on training adaptations in resistance-trained males.|published=2017|authors=Jung YP, Earnest CP, Koozehchian M, Cho M, Barringer N, Walker D, Rasmussen C, Greenwood M, Murano PS, Kreider RB|journal=J Int Soc Sports Nutr|]

Bitter orange, also known as Citrus aurantium, is a citrus fruit originally used in Traditional Chinese medicine for stomach ailments, such as constipation, diarrhea, and indigestion.[reference|url=https://www.nccih.nih.gov/health/bitter-orange|title=Bitter Orange: National Center for Complementary and Integrative Health|authors=|published=May 2020] Today, bitter orange extract, standardized to p-synephrine content, commonly occurs in multi-ingredient formulations labeled as ephedra-free supplements for weight loss: p-synephrine is an alkaloid compound structurally similar to adrenaline and the banned dietary supplement ephedrine.[reference|url=https://pubmed.ncbi.nlm.nih.gov/16436104|title=Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: an update.|published=2006-Feb|authors=Haaz S, Fontaine KR, Cutter G, Limdi N, Perumean-Chaney S, Allison DB|journal=Obes Rev|] The pharmacologic and pharmacokinetic properties of p-synephrine vary from its structural analogues enough to mitigate the risks previously seen with ephedrine-containing supplements. [reference|url=https://www.nccih.nih.gov/health/bitter-orange|title=Bitter Orange|published=National Center for Complementary and Integrative Health]. p-synephrine should also not be confused with m-synephrine, a synthetic amine derivative of synephrine. m-synephrine does not meet the FDA dietary supplement definition and is a prohibited ingredient.

Limited research did not find a benefit. An analysis of 3 small studies found that taking 10–54 mg of synephrine daily for 6–8 weeks had no significant effects on weight loss or fat mass.[reference|url=https://pubmed.ncbi.nlm.nih.gov/36235672|title=The Safety and Efficacy of (Bitter Orange) Extracts and -Synephrine: A Systematic Review and Meta-Analysis.|published=2022-Sep-28|authors=Koncz D, Tóth B, Bahar MA, Roza O, Csupor D|journal=Nutrients|] 
Limited research suggests that bitter orange supplements may increase fat oxidation during exercise and affect resting metabolic rate. One small study of 14 healthy adults found that taking a single dose of p-synephrine prior to one hour of cycling exercise, at a dosage of 3 mg of synephrine per kg of body weight (3 mg/kg), increased the amount of fat burned and decreased the amount of carbohydrates utilized, but did not affect total energy expenditure compared to placebo.[reference|url=https://pubmed.ncbi.nlm.nih.gov/31691018|title=Acute p-synephrine ingestion increases whole-body fat oxidation during 1-h of cycling at Fatmax.|published=2020-Oct|authors=Gutiérrez-Hellín J, Ruiz-Moreno C, Del Coso J|journal=Eur J Nutr|]. Another small study found that 10 individuals given 50 mg of synephrine had a 65 kcal increase in their resting metabolic rate compared to placebo, but this result was not significant.[reference|url=https://pubmed.ncbi.nlm.nih.gov/21537493|title=Effects of p-synephrine alone and in combination with selected bioflavonoids on resting metabolism, blood pressure, heart rate and self-reported mood changes|published=2011 Apr 28|authors=Stohs SJ, Preuss HG, Keith SC, Keith PL, Miller H, Kaats GR|journal=Int J Med Sci|]

There is interest in using bitter orange for weight loss and improvement in body composition (fat loss). However, this is not supported by clinical data.[reference|url=https://pubmed.ncbi.nlm.nih.gov/36235672|title=The Safety and Efficacy of (Bitter Orange) Extracts and -Synephrine: A Systematic Review and Meta-Analysis.|published=2022-Sep-28|authors=Koncz D, Tóth B, Bahar MA, Roza O, Csupor D|journal=Nutrients|] Bitter orange is also used for athletic performance, but its benefit is not clear.[reference|url=https://pubmed.ncbi.nlm.nih.gov/28096757|title=Effects of ingesting a pre-workout dietary supplement with and without synephrine for 8 weeks on training adaptations in resistance-trained males.|published=2017|authors=Jung YP, Earnest CP, Koozehchian M, Cho M, Barringer N, Walker D, Rasmussen C, Greenwood M, Murano PS, Kreider RB|journal=J Int Soc Sports Nutr|]
One study found that applying bitter orange oil 20–25% to affected skin for 1 to 3 weeks was associated with cure of fungal infections like ringworm, jock itch, or athlete’s foot.[reference|url=https://pubmed.ncbi.nlm.nih.gov/8737885|title=Oil of bitter orange: new topical antifungal agent.|published=1996-Jun|authors=Ramadan W, Mourad B, Ibrahim S, Sonbol F|journal=Int J Dermatol|] However, that study was limited by a lack of control group.

Some limited research suggests that bitter orange supplements may increase blood pressure, while other research found no effect. A meta-analysis of small randomized controlled studies suggests that taking bitter orange extract alone or with other ingredients for 56–60 days increases systolic blood pressure by up to 6.4 mmHg compared to control; however, there was no significant effect on diastolic blood pressure. Acute administration of bitter orange extract tended to increase blood pressure over 3 hours, but this result was not statistically significant.[reference|url=https://pubmed.ncbi.nlm.nih.gov/36235672|title=The Safety and Efficacy of (Bitter Orange) Extracts and -Synephrine: A Systematic Review and Meta-Analysis.|published=2022-Sep-28|authors=Koncz D, Tóth B, Bahar MA, Roza O, Csupor D|journal=Nutrients|] One randomized crossover trial of 15 healthy, young adults given a single dose of bitter orange supplement containing 108 mg of synephrine, which was included in the above meta-analysis, reported that the participants given synephrine experienced modestly increased blood pressure and heart rate for up to 5 hours compared to placebo.[reference|url=https://pubmed.ncbi.nlm.nih.gov/16317106|title=Blood pressure and heart rate effects following a single dose of bitter orange|published=2006 Jan|authors=Bui LT, Nguyen DT, Ambrose PJ|journal=Ann Pharmacother|] In another small study, in which participants were given a single, smaller dose of 27 mg of synephrine and monitored for 8 hours, no significant difference from placebo was seen on t blood pressure or electrocardiogram (QT interval).[reference|url=https://pubmed.ncbi.nlm.nih.gov/16305290|title=Absence of QTc-interval-prolonging or hemodynamic effects of a single dose of bitter-orange extract in healthy subjects|published=2005 Dec|authors=Min B, Cios D, Kluger J, White CM|journal=Pharmacotherapy|] In a small study of healthy young adults sitting quietly for 3 hours after taking a single dose of 103 mg p-synephrine, alone or with 240 mg caffeine, blood pressure and heart rate were not affected compared to placebo.[reference|url=https://pubmed.ncbi.nlm.nih.gov/29047215|title=Acute cardiovascular effects of bitter orange extract (p-synephrine) consumed alone and in combination with caffeine in human subjects: A placebo-controlled, double-blind study.|published=2018-Jan|authors=Ratamess NA, Bush JA, Stohs SJ, Ellis NL, Vought IT, O'Grady EA, Kuper JD, Hasan SB, Kang J, Faigenbaum AD|journal=Phytother Res|] These results suggest that caffeine and synephrine may not always have synergistic effects in the short term.
A small study of 10 healthy adults considered 2 different dietary supplements containing synephrine and compared heart rate and blood pressure results with placebo after a single dose (Advantra Z, containing 46.9 mg synephrine, and Xenadrine EFX, containing 5.5 mg
synephrine). Interestingly, the Xenadrine EFX group experienced more blood pressure and heart rate elevations than the Advantra group, possibly due to other ingredients in the supplement.[reference|url=https://pubmed.ncbi.nlm.nih.gov/16164886|title=Hemodynamic effects of ephedra-free weight-loss supplements in humans.|published=2005-Sep|authors=Haller CA, Benowitz NL, Jacob P|journal=Am J Med|]
The longer-term effects of a 20 mg daily dose of synephrine were examined in an 8 week study of healthy, young, resistance-trained males; researchers found no changes in blood pressure or heart rate compared to control.[reference|url=https://pubmed.ncbi.nlm.nih.gov/28096757|title=Effects of ingesting a pre-workout dietary supplement with and without synephrine for 8 weeks on training adaptations in resistance-trained males.|published=2017|authors=Jung YP, Earnest CP, Koozehchian M, Cho M, Barringer N, Walker D, Rasmussen C, Greenwood M, Murano PS, Kreider RB|journal=J Int Soc Sports Nutr|].

Bitter orange supplements, typically standardized to synephrine content, seem to have cardiovascular stimulant effects resulting in increased blood pressure and heart rate.[reference|url=https://pubmed.ncbi.nlm.nih.gov/36235672|title=The Safety and Efficacy of (Bitter Orange) Extracts and -Synephrine: A Systematic Review and Meta-Analysis.|published=2022-Sep-28|authors=Koncz D, Tóth B, Bahar MA, Roza O, Csupor D|journal=Nutrients|] There have been reports of adverse reactions in at least 35 people (most commonly palpitations, fainting and dizziness) after taking a synephrine-containing supplement. The specific supplement was not recorded in all cases, but for those cases where it was, the majority of the adverse events occurred with supplements in which synephrine was combined with other active ingredients, including <a href="/supplements/caffeine/" class="popover" data-tooltip="&lt;div&gt;&lt;h6&gt;Caffeine&lt;/h6&gt;&lt;p&gt;Caffeine is a central nervous system stimulant that can improve sports performance and aspects of cognitive function. Caffeine or caffeine-containing beverages are often taken to help restore alertness and wakefulness or to reduce drowsiness. Despite its side effects, caffeine is safe for most people, and caffeine-containing beverages like tea and coffee are socially acceptable and widely used.&lt;/p&gt;&lt;/div&gt;">caffeine</a>, deterenol (a synthetic stimulant), theophylline (a bronchodilator), <a href="/supplements/phenylethylamine/" class="popover" data-tooltip="&lt;div&gt;&lt;h6&gt;Phenylethylamine&lt;/h6&gt;&lt;p&gt;A trace amine and influencer of many of the 'happy hormones' such as dopamine and serotonin, β-phenylethylamine is an important molecule in the brain with limited supplemental usage due to being rapidly broken down into inactive components.&lt;/p&gt;&lt;/div&gt;">beta-phenylethylamine</a>, and <a href="/supplements/yohimbine/" class="popover" data-tooltip="&lt;div&gt;&lt;h6&gt;Yohimbine&lt;/h6&gt;&lt;p&gt;Yohimbine is promoted for its fat-burning properties and benefits for male sexual dysfunction. Though yohimbine is effective, side effects may include anxiety, nervousness, and an elevated heart rate, and the reported dose of yohimbine in many supplement formulas doesn’t match the actual dose.&lt;/p&gt;&lt;/div&gt;">yohimbine</a>. A supplement containing synephrine with caffeine was reported in most cases of cardiovascular adverse events.[reference|url=https://pubmed.ncbi.nlm.nih.gov/36639595|title=Review of Case Reports on Adverse Events Related to Pre-workout Supplements Containing Synephrine.|published=2023-Jan|authors=de Jonge MLL, Kieviet LC, Sierts M, Egberink LB, van der Heyden MAG|journal=Cardiovasc Toxicol|]. Examples of these events included heart rhythm issues,[reference|url=https://pubmed.ncbi.nlm.nih.gov/15301335|title=Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine.|published=2004-Aug|authors=Nasir JM, Durning SJ, Ferguson M, Barold HS, Haigney MC|journal=Mayo Clin Proc|] stroke,[reference|url=https://pubmed.ncbi.nlm.nih.gov/15819293|title=Ischemic stroke associated with use of an ephedra-free dietary supplement containing synephrine.|published=2005-Apr|authors=Bouchard NC, Howland MA, Greller HA, Hoffman RS, Nelson LS|journal=Mayo Clin Proc|] chest pain,[reference|url=https://pubmed.ncbi.nlm.nih.gov/16610576|title=Variant angina associated with bitter orange in a dietary supplement.|published=2006-Apr|authors=Gange CA, Madias C, Felix-Getzik EM, Weintraub AR, Estes NA|journal=Mayo Clin Proc|] and heart attack.[reference|url=https://pubmed.ncbi.nlm.nih.gov/20069086|title=STEMI in a 24-year-old man after use of a synephrine-containing dietary supplement: a case report and review of the literature.|published=2009|authors=Thomas JE, Munir JA, McIntyre PZ, Ferguson MA|journal=Tex Heart Inst J|] 
Topical bitter orange products may cause irritation and increased sensitivity to the sun, increasing the risk for sunburns.[reference|url=https://pubmed.ncbi.nlm.nih.gov/24237193|title=An evidence-based systematic review of bitter orange (Citrus aurantium) by the Natural Standard Research Collaboration.|published=2013-Dec|authors=Ulbricht C, Costa D, Giese N, Isaac R, Liu A, Liu Y, Osho O, Poon L, Rusie E, Stock T, Weissner W, Windsor RC|journal=J Diet Suppl|] 
Bitter orange might cause drug interactions. Some studies show that bitter orange juice increases blood levels of medications broken down by the liver enzyme called cytochrome P450 (CYP) 3A4. This seems to be due to the furanocoumarin constituents contained in certain citrus fruits.[reference|url=https://pubmed.ncbi.nlm.nih.gov/32089733|title=Pharmacokinetic Interactions between Cardiovascular Medicines and Plant Products.|published=2019|authors=Costache II, Miron A, Hăncianu M, Aursulesei V, Costache AD, Aprotosoaie AC|journal=Cardiovasc Ther|] Theoretically, bitter orange supplements that contain furanocoumarins can affect medications that need to be processed by the CYP3A4 enzyme in the liver.

The synephrine in bitter oranges is thought to work as a sympathetic adrenergic agonist, stimulating receptors involved in the “fight or flight” response. These effects stimulate the cardiovascular system resulting in increased heart rate and blood pressure. Also, these effects may stimulate metabolism, resting metabolic rate and lipolysis (breakdown of fat). Appetite may also be suppressed via slowed movement of food through the gastrointestinal tract.[reference|url=https://pubmed.ncbi.nlm.nih.gov/16436104|title=Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: an update.|published=2006-Feb|authors=Haaz S, Fontaine KR, Cutter G, Limdi N, Perumean-Chaney S, Allison DB|journal=Obes Rev|] [reference|url=https://pubmed.ncbi.nlm.nih.gov/36639595|title=Review of Case Reports on Adverse Events Related to Pre-workout Supplements Containing Synephrine.|published=2023-Jan|authors=de Jonge MLL, Kieviet LC, Sierts M, Egberink LB, van der Heyden MAG|journal=Cardiovasc Toxicol|]

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