Home Ingredients Advantra Z® (Bitter Orange p-Synephrine — Nutratech)

Advantra Z® (Bitter Orange p-Synephrine — Nutratech)

Citrus aurantium
Evidence Level
Preliminary
7 Clinical Trials
4 Documented Benefits
1/5 Evidence Score

Advantra Z is a patented bitter orange (Citrus aurantium) extract standardized to p-synephrine, supplied by Nutratech and later Novel Ingredients, and sold as a thermogenic; a review by consultants to the maker says the same extract is also known as Kinetiq. Its own trials are small and mostly run or funded by people tied to the maker. A single 50 mg dose did not significantly raise resting metabolic rate unless naringin and hesperidin were added, no trial of the extract has measured weight loss, and pooled data from 18 placebo-controlled p-synephrine trials showed no significant weight loss. Safety trials of about 49 mg found no blood pressure change, but an independent single-dose trial saw heart rate rise. It is on the NCAA banned list, and France's ANSES advises against combining it with caffeine or using it during physical activity.

Studied Dose About 47 to 52 mg of p-synephrine per dose in trials of this extract, taken once, daily for 15 days, or twice daily for 30 to 60 days; one exercise trial used 100 mg. ANSES advises supplement intake below 20 mg/day; BfR, no more than 6.7 mg/day.
Active Compound p-Synephrine from an extract of bitter orange (Citrus aurantium) immature fruit; trial reports describe Advantra Z as standardized to about 50 to 60 percent p-synephrine, and a maker-linked analysis found total furanocoumarins below 20 micrograms per gram.

Benefits

Resting Metabolic Rate After a Single Dose

In one double-blind trial run by researchers tied to the maker, with 10 people per group and one reading 75 minutes after dosing, 50 mg of p-synephrine from this extract gave a resting metabolic rate 65 kcal above placebo, a difference not reported as significant. Only the arm that added 600 mg naringin and 100 mg hesperidin was significantly above placebo (183 kcal).

Supported by Trial 1

Body Weight and Body Composition

No published placebo-controlled trial of this extract has measured body weight or body fat; a 30-day study of chews made with it tracked only self-rated appetite and energy. For p-synephrine from any source, pooled data from 18 placebo-controlled trials showed no significant weight loss and no change in body composition, while blood pressure rose with prolonged use.

Supported by Trial 1, Trial 4

Squat Repetitions in Resistance Exercise

In a maker-funded crossover trial in 12 college-aged men, 100 mg of p-synephrine from this extract, about twice a 50 mg serving, taken for 3 days and before testing, gave 6 percent more squat repetitions than placebo and about 11 percent more volume load. No other trial of the extract has tested performance, and adding 20 mg of synephrine to a pre-workout for 8 weeks gave no extra strength gain.

Supported by Trial 3, Trial 4

Appetite Control and Energy Ratings

In a maker-funded 30-day study, 40 overweight adults who ate a chew with 51.5 mg of p-synephrine from this extract before their two largest meals rated their eating control and energy higher than with placebo chews, on a questionnaire the authors created. Body weight and food intake were not measured, and in a single-dose trial self-rated energy and hunger did not differ from placebo.

Supported by Trial 1, Trial 3

Mechanism of action

1

Adrenergic Amine Related to Ephedrine

The extract's main active compound, p-synephrine, is an adrenergic amine; Health Canada notes its structural resemblance to epinephrine and ephedrine. Reviews by consultants to the maker say it binds little to the alpha-1, alpha-2, beta-1 and beta-2 receptors and call it a non-stimulant thermogenic agent. The p-synephrine page covers the receptor studies, including those in human fat cells.

2

Fat Breakdown Markers Around Resistance Exercise

In 12 men given 100 mg of p-synephrine from this extract, blood glycerol, a marker of fat breakdown, rose at rest before exercise, and oxygen use and energy expenditure stayed higher than with placebo for 30 minutes after a squat session. Free fatty acids did not differ, and heart rate during exercise rose only when 100 mg of caffeine was added.

3

Blood Pressure and Heart Rate

In an independent crossover trial in 10 adults, one dose with 46.9 mg synephrine from this extract did not raise blood pressure, but compared with placebo, heart rate at 6 hours was increased from baseline, by 11.4 beats per minute. Maker-linked trials of about 49 mg once, daily for 15 days, or twice daily for 60 days found no significant pressure rise. Pooled p-synephrine trials show blood pressure rising with prolonged use.

Clinical trials

1
50 mg p-Synephrine and Resting Energy Use: Single-Dose RCT
PubMed

Double-blind, randomized, placebo-controlled trial of Advantra Z alone or with naringin and hesperidin, measured once 75 minutes after a dose in vegetable juice. One author is a Nutratech employee and two have consulted for Nutratech, which supplied the test materials. (Stohs et al. 2011, Int J Med Sci)

Healthy adults, 10 per treatment group.

50 mg p-synephrine alone gave a reading 65 kcal above placebo, not reported as significant. Only 50 mg p-synephrine plus 600 mg naringin and 100 mg hesperidin was significantly above placebo (183 kcal, p < 0.02). No group differed from placebo in heart rate, blood pressure or self-rated symptoms.

2
Single 46.9 mg Dose: Blood Pressure and Heart Rate Crossover
PubMed

Randomized, double-blind, placebo-controlled three-arm crossover from a university clinical pharmacology group comparing Advantra Z, a multi-ingredient product and placebo, one week apart; PubMed lists NIH support. (Haller et al. 2005, Am J Med)

10 healthy adult nonsmokers.

Advantra Z (46.9 mg synephrine) did not raise blood pressure, but compared with placebo, heart rate at 6 hours was increased from baseline (11.4 beats per minute, P = 0.031). The multi-ingredient product raised blood pressure.

3
100 mg p-Synephrine Before Squats: Resistance Exercise Crossover RCT
PubMed

Double-blind, randomized crossover trial of Advantra Z chews (100 mg p-synephrine), the same with 100 mg caffeine, or placebo, each taken for 3 days and on the test morning before 6 sets of squats at 80% of 1RM. Funded by a grant from Nutratech; one author has consulted for Nutratech. (Ratamess et al. 2015, J Int Soc Sports Nutr)

12 healthy, college-aged men.

p-Synephrine alone and with caffeine raised total repetitions over the control protocol (by 11.0%) and placebo (by 6.0%) and raised volume load by 10.6%; only the caffeine combination raised mean power and velocity. Blood lactate and perceived exertion did not change, and no adverse effects were reported.

4
100 mg p-Synephrine Around Squats: Blood Markers and Heart Rate
PubMed

Companion report from the Nutratech-funded squat crossover, with blood samples and gas exchange before, during and for 30 minutes after exercise; the brand is not named in the abstract; a later review by coauthor SJ Stohs, funded by the maker Novel Ingredients, lists it among Advantra Z trials. (Ratamess et al. 2016, J Am Coll Nutr)

12 healthy men.

Serum glycerol rose before exercise only with the synephrine treatments; free fatty acids did not differ; oxygen uptake and energy expenditure were higher through 30 minutes after exercise. Heart rate changed only when caffeine was added.

5
About 49 mg Once: ECG, Heart Rate and Blood Pressure Over 8 Hours
PubMed

Double-blind, placebo-controlled crossover safety trial; the brand is not named in the abstract; a later review by coauthor SJ Stohs, funded by the maker Novel Ingredients, identifies the extract as Advantra Z. (Shara et al. 2016, Phytother Res)

18 healthy adults (9 men, 9 women).

No significant changes in ECG, heart rate, systolic blood pressure, blood chemistry or blood cell counts; diastolic pressure fell 4.5 mmHg at 60 minutes. No adverse effects were reported.

6
About 49 mg Daily for 15 Days: Placebo-Controlled Safety Crossover
PubMed

Double-blind, placebo-controlled crossover with cardiologist assessment, ECG and blood tests at baseline and days 5, 10 and 15; the brand is not named in the abstract; a later review by coauthor SJ Stohs, funded by the maker Novel Ingredients, identifies the extract as Advantra Z. (Shara et al. 2018, Phytother Res)

16 healthy adults.

No significant changes in heart rate, ECG, blood pressure, blood cell counts or blood chemistry at any time point, and no adverse effects were reported.

7
About 49 mg Twice Daily for 60 Days: Placebo-Controlled Safety Trial
PubMed

Double-blind, placebo-controlled safety trial of bitter orange extract alone or with naringin and hesperidin; three coauthors disclosed Nutratech employment or consulting in their 2011 trial; the brand is not named in the abstract; a later review by coauthor SJ Stohs, funded by the maker Novel Ingredients, identifies the extract as Advantra Z. (Kaats et al. 2013, Food Chem Toxicol)

Healthy adults, 25 per group in three groups.

No significant changes in systolic or diastolic blood pressure, blood chemistries or blood cell counts; small heart rate differences between groups that the authors called clinically insignificant; no adverse effects reported.

Side effects and drug interactions

Common Potential side effects

Blood pressure rose in pooled placebo-controlled trials of p-synephrine from any source with prolonged use (systolic +6.4 mmHg, diastolic +4.3 mmHg), and in a single-dose trial of this extract, compared with placebo, heart rate at 6 hours was increased from baseline, by 11.4 beats per minute. Germany's BfR warns that synephrine and caffeine reinforce each other's effects on heart rate and blood pressure.
France's ANSES received 18 well-documented adverse-event reports linked to supplements with Citrus-derived p-synephrine; the 13 cases judged possibly, likely or very likely related included cardiovascular effects, liver injury, high blood phosphate and a neurological effect. All the products named in cardiovascular reports also contained caffeine.
NCCIH notes reports of abnormal heart rhythms, heart attacks and strokes in people taking bitter orange products, though most products contained several ingredients, so the role of p-synephrine is unclear. A review of 30 published case reports (35 people) after synephrine-containing pre-workout products found mostly chest pain, palpitations, fainting and dizziness, but could not rule out caffeine and other ingredients.
Maker-linked trials of this extract, at doses of up to 100 mg and about 98 mg a day for 60 days, reported no adverse effects; they enrolled healthy adults only.
ANSES strongly advises against use by people under treatment, in particular for high blood pressure, heart disease or depression, by pregnant or breastfeeding women, and by children and adolescents. NCCIH also says it may not be safe during pregnancy or breastfeeding.
On the NCAA banned stimulant list (2026-27); WADA's 2026 Monitoring Program tracks synephrine in competition but does not prohibit it.

Important Drug interactions

Health Canada's 2010 synephrine notice lists antihypertensives, thyroid hormones, MAO inhibitors and tricyclic antidepressants as prescription drugs to discuss with a health care practitioner before use.
Do not combine with caffeine: ANSES advises against combining p-synephrine with caffeine, caffeine-containing preparations or any substance with similar effects on the heart and circulation.
May work against blood pressure medication: pooled placebo-controlled trials show systolic and diastolic pressure rising with prolonged use.
Health Canada's 2010 notice says not to use synephrine products with phenylephrine or pseudoephedrine decongestants, ephedra or ephedrine products, or other drugs that raise blood pressure.
CYP3A4 drugs: bitter orange fruit contains furanocoumarins, the grapefruit-type compounds that block CYP3A4. A maker-linked analysis found less than 20 micrograms per gram in each of four standardized samples of this extract, judged too low to matter, but no human interaction study of the extract exists; if a medicine carries a grapefruit warning, ask a pharmacist.

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Frequently asked questions about Advantra Z® (Bitter Orange p-Synephrine — Nutratech)

Is Advantra Z the same extract as Kinetiq?

A review by two consultants to the maker states that the patented, p-synephrine-standardized bitter orange extract is known as Advantra Z or Kinetiq. The published trials that name a brand call it Advantra Z, and no PubMed-indexed trial uses the Kinetiq name, so the studies on this page are studies of Advantra Z.

Does Advantra Z help with weight loss?

No published placebo-controlled trial of this extract has measured weight or body fat. Its trials measured resting metabolic rate after one dose (not significant for p-synephrine alone), exercise performance, safety markers and self-rated appetite. For p-synephrine from any source, pooled data from 18 placebo-controlled trials showed no significant weight loss, while blood pressure rose with prolonged use.

Can competitive athletes use Advantra Z?

Synephrine (bitter orange) is on the NCAA banned stimulant list for 2026-27. WADA does not prohibit it but includes it in its 2026 Monitoring Program, in competition only, to track patterns of use in sport. France's ANSES advises against using p-synephrine during physical activity.

What is Advantra Z?

Advantra Z is a patented bitter orange (Citrus aurantium) extract standardized to p-synephrine, supplied by Nutratech and later Novel Ingredients, and sold as a thermogenic; a review by consultants to the maker says the same extract is also known as Kinetiq.

What is Advantra Z used for?

NutraSmarts does not list Advantra Z under a health category. What the research covers: In one double-blind trial run by researchers tied to the maker, with 10 people per group and one reading 75 minutes after dosing, 50 mg of p-synephrine from this extract gave a resting metabolic rate 65 kcal above placebo, a difference not…

What is the recommended dosage of Advantra Z?

The clinically studied dose is About 47 to 52 mg of p-synephrine per dose in trials of this extract, taken once, daily for 15 days, or twice daily for 30 to 60 days; one exercise trial used 100 mg. ANSES advises supplement intake below 20 mg/day; BfR, no more than 6.7 mg/day. Always follow the product label and check with a healthcare provider for personal advice.

Is Advantra Z safe, and does it have side effects?

Side effects and cautions reported for Advantra Z include: Blood pressure rose in pooled placebo-controlled trials of p-synephrine from any source with prolonged use (systolic +6.4 mmHg, diastolic +4.3 mmHg), and in a single-dose trial of this extract, compared with placebo, heart rate at 6 hours was increased from baseline, by 11. It may also interact with some medications. Advantra Z is not right for everyone, so check with a healthcare provider first if you are pregnant or breastfeeding, have a medical condition, or take prescription medication.

Does Advantra Z interact with any medications?

Possible interactions include: Health Canada's 2010 synephrine notice lists antihypertensives, thyroid hormones, MAO inhibitors and tricyclic antidepressants as prescription drugs to discuss with a health care practitioner before use. If you take prescription medication, check with a pharmacist or doctor before using it.

How strong is the scientific evidence for Advantra Z?

NutraSmarts rates the evidence for Advantra Z as Preliminary (1 out of 5). It is backed by 7 study summaries and 20 cited references summarized on this page. A higher rating reflects more, larger, and better-designed human studies.

References(20 citations)

Evidence ratings on NutraSmarts are based on the totality of human clinical research, with emphasis on randomized controlled trials, meta-analyses, and systematic reviews. The references below directly support claims made throughout this page.

  1. Stohs SJ, Preuss HG, Keith SC, Keith PL, Miller H, Kaats GR. Effects of p-synephrine alone and in combination with selected bioflavonoids on resting metabolism, blood pressure, heart rate and self-reported mood changes. Int J Med Sci. 2011;8(4):295-301. doi: 10.7150/ijms.8.295.PubMedUsed to support: Double-blind, randomized, placebo-controlled trial with 10 subjects per group, measured once 75 minutes after a single dose in vegetable juice. The p-synephrine was given as the patented bitter orange extract Advantra Z (described as 60 percent p-synephrine). 50 mg p-synephrine alone gave a resting metabolic rate 65 kcal above placebo; adding 600 mg naringin gave 129 kcal; adding 600 mg naringin and 100 mg hesperidin gave 183 kcal, the only increase reported as significant (p<0.02); adding 1000 mg hesperidin instead gave 79 kcal. No group differed from placebo in heart rate, blood pressure or self-rated symptoms, including energy and hunger. One author is a Nutratech employee and two have consulted for Nutratech, which supplied the test materials.
  2. Haller CA, Benowitz NL, Jacob P 3rd. Hemodynamic effects of ephedra-free weight-loss supplements in humans. Am J Med. 2005;118(9):998-1003. doi: 10.1016/j.amjmed.2005.02.034.PubMedUsed to support: Randomized, double-blind, placebo-controlled, three-arm crossover study in 10 healthy adult nonsmokers from a university clinical pharmacology group; PubMed lists NIH and US Public Health Service support. Single doses of Advantra Z (46.9 mg synephrine), a multi-ingredient product (Xenadrine EFX, 5.5 mg synephrine) and placebo were given a week apart. Advantra Z did not raise blood pressure, but compared with placebo, heart rate at 6 hours was increased from baseline (11.4 beats per minute, P = 0.031); the abstract does not say whether 11.4 is the raw or the placebo-adjusted change. A later review by SJ Stohs, a consultant to the maker, attributes the 6-hour rise to a meal given at 3 hours. The multi-ingredient product raised systolic and diastolic pressure, which the authors attribute to caffeine and other stimulants rather than bitter orange alone.
  3. Ratamess NA, Bush JA, Kang J, Kraemer WJ, Stohs SJ, Nocera VG, Leise MD, Diamond KB, Faigenbaum AD. The effects of supplementation with P-Synephrine alone and in combination with caffeine on resistance exercise performance. J Int Soc Sports Nutr. 2015;12:35. doi: 10.1186/s12970-015-0096-5.PubMedUsed to support: Double-blind, randomized crossover trial in 12 healthy college-aged men using chews made with Advantra Z: 100 mg p-synephrine, 100 mg p-synephrine plus 100 mg caffeine, or placebo, each taken for 3 days and on the test morning before 6 sets of squats at 80 percent of 1RM. Both synephrine treatments raised total repetitions over the control protocol (11.0 percent) and placebo (6.0 percent) and volume load (10.6 percent); only the caffeine combination raised mean power and velocity; blood lactate and perceived exertion did not change and no adverse effects were reported. Funded by a grant from Nutratech; SJ Stohs has served as a Nutratech consultant.
  4. Ratamess NA, Bush JA, Kang J, Kraemer WJ, Stohs SJ, Nocera VG, Leise MD, Diamond KB, Campbell SC, Miller HB, Faigenbaum AD. The Effects of Supplementation with p-Synephrine Alone and in Combination with Caffeine on Metabolic, Lipolytic, and Cardiovascular Responses during Resistance Exercise. J Am Coll Nutr. 2016;35(8):657-669. doi: 10.1080/07315724.2016.1150223.PubMedUsed to support: Companion report on the same 12 men and the same 100 mg p-synephrine, p-synephrine plus caffeine and placebo treatments, with blood samples and gas exchange around a squat protocol. Serum glycerol rose before exercise only with the two synephrine treatments, free fatty acids did not differ, oxygen uptake and energy expenditure were higher with both through 30 minutes after exercise, and fat oxidation favored them at 25 to 30 minutes after exercise. Mean heart rate during exercise was highest with the caffeine combination, and no heart rate changes were seen unless caffeine was added. A later review by coauthor SJ Stohs lists this study among trials of Advantra Z.
  5. Shara M, Stohs SJ, Mukattash TL. Cardiovascular Safety of Oral p-Synephrine (Bitter Orange) in Healthy Subjects: A Randomized Placebo-Controlled Cross-over Clinical Trial. Phytother Res. 2016;30(5):842-7. doi: 10.1002/ptr.5590.PubMedUsed to support: Double-blind, placebo-controlled crossover trial in 18 healthy adults (9 men, 9 women) given bitter orange extract with 49 mg p-synephrine; a later review by coauthor SJ Stohs, a consultant to Novel Ingredients, identifies the extract as Advantra Z. Over 8 hours there were no significant changes in ECG, heart rate, systolic blood pressure, blood chemistry or blood cell counts; diastolic pressure fell 4.5 mmHg at 60 minutes. No adverse effects were reported. Safety outcomes only, single dose, healthy adults.
  6. Shara M, Stohs SJ, Smadi MM. Safety evaluation of p-synephrine following 15 days of oral administration to healthy subjects: A clinical study. Phytother Res. 2018;32(1):125-131. doi: 10.1002/ptr.5956.PubMedUsed to support: Placebo-controlled, double-blind crossover study in 16 healthy adults given bitter orange extract with 49 mg p-synephrine daily for 15 days, with cardiologist assessment, ECG and blood tests at baseline and days 5, 10 and 15; a later review by coauthor SJ Stohs identifies the extract as Advantra Z. No significant changes occurred in heart rate, ECG, blood pressure, blood cell counts or blood chemistry, and no adverse effects were reported. Safety outcomes only, healthy adults, 15 days.
  7. Kaats GR, Miller H, Preuss HG, Stohs SJ. A 60day double-blind, placebo-controlled safety study involving Citrus aurantium (bitter orange) extract. Food Chem Toxicol. 2013;55:358-62. doi: 10.1016/j.fct.2013.01.013.PubMedUsed to support: Double-blind, placebo-controlled safety trial giving bitter orange extract (about 49 mg p-synephrine) twice daily, alone or with naringin and hesperidin, to 25 healthy subjects per group for 60 days; a later review by coauthor SJ Stohs identifies the extract as Advantra Z. No significant changes occurred in systolic or diastolic blood pressure, blood chemistries or blood cell counts; heart rate differences between groups were small and called clinically insignificant; no adverse effects were reported. Coauthors H Miller (a Nutratech employee) and SJ Stohs and HG Preuss (Nutratech consultants) disclosed those ties in their 2011 trial.
  8. Kaats GR, Leckie RB, Mrvichin N, Stohs SJ. Increased eating control and energy levels associated with consumption of bitter orange (p-synephrine) extract: a randomized placebo-controlled study. Nutrition and Dietary Supplements. 2017;9:29-35. doi: 10.2147/NDS.S136756.SourceUsed to support: Not PubMed-indexed; read in full from the publisher. Double-blind, placebo-controlled 30-day study in 40 overweight adults (four groups of 10, two switching between chew types at day 15) eating a chocolate chew with 51.5 mg p-synephrine from Advantra Z, or a placebo chew, before their two largest meals (103 mg a day). On a 13-item questionnaire created by the authors, the active chew scored better than placebo overall (p = 0.001) and on eating control and energy subscales (p < 0.001). One eating-control item favored placebo. Body weight and food intake were not reported, the authors note the results rest on perceptions only, and no adverse effects were reported. Funded by a grant from Novel Ingredients, which supplied the chews; SJ Stohs has consulted for Novel Ingredients.
  9. Stohs SJ, Miller H, Romano F. Absence of furanocoumarins in Advantra Z® (Citrus aurantium, bitter orange) extracts. J Diet Suppl. 2014;11(3):288-93. doi: 10.3109/19390211.2014.937047.PubMedUsed to support: Laboratory analysis of four standardized Advantra Z extracts by liquid chromatography and mass spectrometry. Total furanocoumarins (the grapefruit-type compounds, found in bitter orange fruit, that block CYP3A4) were below 20 micrograms per gram in each, which the authors judge insufficient to affect drug metabolism at commonly used doses. Coauthors H Miller (a Nutratech employee) and SJ Stohs (a Nutratech consultant) disclosed those ties in their 2011 trial. No human drug-interaction study of the extract was done.
  10. Stohs SJ, Badmaev V. A Review of Natural Stimulant and Non-stimulant Thermogenic Agents. Phytother Res. 2016;30(5):732-40. doi: 10.1002/ptr.5583.PubMedUsed to support: Review by two authors who have served as consultants for Novel Ingredients. It states that the patented, p-synephrine-standardized bitter orange extract is known as Advantra Z or Kinetiq, describes p-synephrine as binding little to alpha-1, alpha-2, beta-1 and beta-2 adrenergic receptors, and calls it a non-stimulant thermogenic agent. Cited here for product identity and the maker-side mechanism claim, not as independent evidence.
  11. Stohs SJ. Safety, Efficacy, and Mechanistic Studies Regarding Citrus aurantium (Bitter Orange) Extract and p-Synephrine. Phytother Res. 2017;31(10):1463-1474. doi: 10.1002/ptr.5879.PubMedUsed to support: Review whose acknowledgement cites a grant from Novel Ingredients; the author has served as a consultant to Novel Ingredients. It identifies the bitter orange extract used in the 60-day safety trial, the single-dose and 15-day cardiovascular trials and the squat trials as Advantra Z, and concludes that bitter orange extract and p-synephrine are safe at commonly used doses. Independent risk assessors (BfR, ANSES) reached more restrictive conclusions. It also argues that the heart rate rise 6 hours after 46.9 mg in the 10-subject study by Haller and colleagues reflected a meal given at 3 hours (citing it as Haller 2008). Cited here for product identity, not as independent evidence.
  12. Koncz D, Tóth B, Bahar MA, Roza O, Csupor D. The Safety and Efficacy of Citrus aurantium (Bitter Orange) Extracts and p-Synephrine: A Systematic Review and Meta-Analysis. Nutrients. 2022;14(19):4019. doi: 10.3390/nu14194019.PubMedUsed to support: Systematic review and meta-analysis of 18 placebo-controlled human trials of synephrine or bitter orange extract from any source (a class reference, not a trial of this brand). Weight loss in the synephrine groups was not significant after prolonged treatment and body-composition measures did not change, while systolic blood pressure rose 6.37 mmHg (95% CI 1.02 to 11.72, p = 0.02) and diastolic 4.33 mmHg (95% CI 0.48 to 8.18, p = 0.03). The authors declare no commercial or financial conflicts.
  13. Jung YP, Earnest CP, Koozehchian M, Cho M, Barringer N, Walker D, Rasmussen C, Greenwood M, Murano PS, Kreider RB. Effects of ingesting a pre-workout dietary supplement with and without synephrine for 8 weeks on training adaptations in resistance-trained males. J Int Soc Sports Nutr. 2017;14:1. doi: 10.1186/s12970-016-0158-3.PubMedUsed to support: Class reference: double-blind trial in 80 resistance-trained men over 8 weeks comparing placebo, a caffeinated multi-ingredient pre-workout, and the same pre-workout plus a Nutratech Citrus aurantium extract (30 percent synephrine, 20 mg synephrine) that the paper does not name as Advantra Z. There were no significant group interactions for body composition (DXA), resting heart rate and blood pressure, 1RM strength, anaerobic capacity or blood chemistry, and synephrine gave no additive benefit. Funded by an unrestricted grant from Nutrabolt, maker of the pre-workout base; two authors work for or advise Nutrabolt.
  14. de Jonge MLL, Kieviet LC, Sierts M, Egberink LB, van der Heyden MAG. Review of Case Reports on Adverse Events Related to Pre-workout Supplements Containing Synephrine. Cardiovasc Toxicol. 2023;23(1):1-9. doi: 10.1007/s12012-022-09777-z.PubMedUsed to support: Review of published case reports through August 2021 (a class reference covering synephrine from any source): 30 case reports describing 35 patients after use of synephrine-containing pre-workout supplements, most often presenting with chest pain, palpitations, syncope and dizziness; diagnoses raised included ischemic heart disease, cardiac arrhythmias and cerebrovascular disease, and 5 patients were left disabled or still on medication at last follow-up. The authors cannot exclude confounding by caffeine and other ingredients, and case reports cannot show how often such events occur. The authors declare no conflict of interest.
  15. ANSES (French Agency for Food, Environmental and Occupational Health and Safety). Compléments alimentaires minceurs à base de p-synéphrine : l’Anses publie aujourd’hui ses recommandations. ANSES. 2014;News release dated 5 May 2014 summarizing the ANSES opinion. Accessed 2026..SourceUsed to support: Not PubMed-indexed; French government risk assessment (in French). ANSES received 18 well-documented adverse-event reports linked to supplements with Citrus-derived p-synephrine; the 13 cases of possible to very likely causality included cardiovascular effects, liver injury, hyperphosphatemia and a neurological effect. Products named in cardiovascular reports supplied 1 to 72 mg/day and all contained caffeine. ANSES treats 20 mg/day, the intake of heavy citrus consumers, as a reference value that supplement intake should not exceed (not a strict safety limit), advises against combining p-synephrine with caffeine or substances with similar cardiovascular effects, strongly advises against use by people under treatment (in particular for hypertension, heart disease or depression), pregnant or breastfeeding women, children and adolescents, and advises against use during physical activity.
  16. Federal Institute for Risk Assessment (BfR). Health assessment of sports and weight loss products containing synephrine and caffeine. BfR Opinion No. 004/2013. Bundesinstitut für Risikobewertung. 2012;Opinion dated 16 November 2012 (English translation). Accessed 2026..SourceUsed to support: Not PubMed-indexed; German government risk assessment. States that synephrine and caffeine taken together can reinforce each other's effects on heart rate (possibly including arrhythmia) and blood pressure, and recommends that no more than 6.7 mg/day of synephrine be consumed from a food supplement, the intake from conventional foods for average consumers assuming maximum synephrine contents, so that total intake for frequent citrus consumers stays at or below 25.7 mg/day. Some high-dose combination products were judged unsafe.
  17. Health Canada, Natural Health Products Directorate. Notice: Guidelines for the Use of Synephrine in Natural Health Products (archived). Health Canada. 2010;Notice dated January 2010; archived and no longer updated. Accessed 2026..SourceUsed to support: Not PubMed-indexed; archived regulatory notice, later revised. Notes synephrine's structural resemblance to epinephrine and ephedrine, set 30 mg/day as the then maximum for total synephrine plus octopamine, did not permit caffeine in synephrine products without sufficient human clinical evidence, listed antihypertensives, thyroid hormones, MAO inhibitors and tricyclic antidepressants as prescription drugs warranting practitioner advice, and contraindicated use with phenylephrine or pseudoephedrine decongestants, ephedra or ephedrine products, or other drugs that raise blood pressure.
  18. National Collegiate Athletic Association. 2026-27 NCAA Banned Substances. National Collegiate Athletic Association. 2026;Banned drug class list for the 2026-27 academic year. Accessed 2026..SourceUsed to support: Not PubMed-indexed; official NCAA list. Under the Stimulants class, 'Synephrine (bitter orange)' is listed among the example banned substances, along with octopamine and hordenine.
  19. World Anti-Doping Agency. The 2026 Monitoring Program. World Anti-Doping Agency. 2025;Official WADA document, published September 2025. Accessed 2026..SourceUsed to support: Not PubMed-indexed; official WADA document. Lists synephrine under Stimulants, in-competition only. The Monitoring Program covers substances that are not on the Prohibited List but that WADA wishes to monitor in order to detect potential patterns of misuse in sport.
  20. National Center for Complementary and Integrative Health. Bitter Orange. National Center for Complementary and Integrative Health. 2024;Fact sheet, last updated November 2024. Accessed 2026..SourceUsed to support: Not PubMed-indexed; NIH fact sheet. Reports cases of abnormal heart rhythms, heart attacks and strokes in people who took bitter orange products, notes that most products contained multiple ingredients so the role of bitter orange or p-synephrine is unclear, says effects on body weight are unclear, and says it may not be safe during pregnancy or breastfeeding.