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Synephrine HCL

Updated · 33 sources · Editorial policy

Synephrine HCl is the hydrochloride salt of p-synephrine, the main alkaloid in the fruit and peel of bitter orange (Citrus aurantium). It is sold mainly in “fat burner” and pre-workout supplements, either as the isolated salt or as bitter orange extract standardized to synephrine. Its use grew after the FDA banned ephedrine alkaloids in dietary supplements in 2004, and it is often marketed as an ephedra alternative (NCCIH).

The single most important fact: synephrine is not an approved drug for any use, and controlled trials have not shown that it causes weight loss. A 2022 meta-analysis of 18 placebo-controlled trials found no significant effect on body weight or body composition, but a small rise in blood pressure with 8 weeks of use (Koncz et al., Nutrients 2022).

This page summarizes what clinical trials, reviews and regulators report. It is for education only and is not medical advice.

Property Detail
Class Phenethylamine protoalkaloid; adrenergic (sympathomimetic) amine
Other names p-Synephrine, oxedrine; historically sold as the tartrate salt Sympatol
Natural source Bitter orange (Citrus aurantium) fruit and peel
Approval status Not an FDA-approved drug; sold in the US as a dietary supplement ingredient
Route Oral
Doses in human trials 6–214 mg/day of synephrine in a 2022 meta-analysis; commonly used doses 25–100 mg/day
Half-life About 2 h (radiolabeled study); 3.0 h in a supplement study
Oral bioavailability About 22% as unchanged drug, because of heavy first-pass metabolism
WADA status (2026) Not prohibited; on the 2026 Monitoring Program
Other sport bodies Listed by the NCAA as a banned stimulant

What it is

Synephrine is 4-[1-hydroxy-2-(methylamino)ethyl]phenol, formula C₉H₁₃NO₂, molecular weight 167.2 g/mol (PubChem: synephrine). The hydrochloride salt has a molecular weight of 203.7 g/mol (PubChem: synephrine hydrochloride). Synephrine base therefore makes up about 82% of the salt’s weight, so 10 mg of synephrine HCl contains about 8.2 mg of synephrine.

Synephrine exists as three positional isomers. Only the para form (p-synephrine) is generally accepted to occur in bitter orange (Koncz et al., Nutrients 2022). The forms are easy to confuse:

Compound Relationship to p-synephrine Status
p-Synephrine The bitter orange alkaloid; the subject of this page Supplement ingredient; WADA Monitoring Program
m-Synephrine (phenylephrine) Same formula, hydroxyl group in the meta position Drug used as a nasal decongestant and vasoconstrictor (PubChem); the most potent isomer at α1-adrenergic receptors
Methylsynephrine (oxilofrine) Synthetic methylated derivative Not a permitted dietary ingredient in the US; WADA-prohibited stimulant
Ephedrine Structurally related; no phenolic hydroxyl group Banned from US supplements in 2004; WADA-prohibited above a urine threshold

Toxicologists have warned that “synephrine is not Neo-Synephrine”: Neo-Synephrine is a brand of phenylephrine, the meta isomer, and the two should not be treated as the same drug (Bouchard and Hoffman, Mayo Clin Proc 2004).

How it is thought to work

Synephrine is an adrenergic amine. It acts on several adrenergic and serotonergic receptors and possibly on trace amine-associated receptors, though how these effects add up in people is not settled (Rossato et al., Food Chem Toxicol 2011).

How strongly it acts on the cardiovascular system is disputed:

  • Industry-linked reviews argue that p-synephrine binds weakly to α1, α2, β1 and β2 receptors and therefore has little effect on heart rate or blood pressure at common doses (Stohs et al., Phytother Res 2020). The lead author has served as a consultant to a supplement ingredient company.
  • Independent laboratory work found that p-synephrine was the most potent of a set of supplement amines at activating human α1A, α1B and α2A receptors in cell assays. Kinetic modeling predicted that reported supplement intakes could reach concentrations that activate α1 receptors (Pinckaers et al., Arch Toxicol 2025). This is in-vitro and modeling data, not a human outcome study.

Pharmacokinetics

The main human data come from an older radiolabeled study and one supplement study:

Parameter Value Source
Absorption Essentially complete from the gut Tritium-labeled synephrine in 10 oral-dose patients (Hengstmann and Aulepp 1978)
Oral bioavailability (unchanged) About 22% Same study
Time to peak 1–2 h; 90 min in the supplement study Same study; Haller et al., Am J Med 2005
Half-life About 2 h; 3.0 h in the supplement study Same two studies
Main urinary metabolite p-Hydroxymandelic acid (about two-thirds of urinary activity after IV dosing) Hengstmann and Aulepp 1978
Unchanged in urine 2.5% of an oral dose; 10% of an IV dose Hengstmann and Aulepp 1978

The low bioavailability reflects fast breakdown in the liver. In an isolated perfused rat liver (an animal experiment), more than 90% of p-synephrine was removed in a single pass at low concentrations (da Silva-Pereira et al., Food Funct 2016). Synephrine is a substrate of monoamine oxidase (MAO), the enzyme that breaks down many amines (Pinckaers et al., Arch Toxicol 2025).

Regulatory status

  • United States. Synephrine and bitter orange are sold as dietary supplement ingredients, which are not reviewed by the FDA for safety or effectiveness before sale (NCCIH). Synthetic relatives such as methylsynephrine and isopropyloctopamine are not legal dietary ingredients (Pawar et al., Drug Test Anal 2020).
  • France. The food safety agency ANSES concluded that synephrine intake from food supplements should stay under 20 mg/day, and advised against combining it with caffeine or using it during exercise, as summarized by Koncz et al. 2022.
  • Germany. Scientists at the Federal Institute for Risk Assessment (BfR) considered up to 6.7 mg/day from supplements, equal to the median intake from ordinary foods in Germany, to be a safe intake. They cited cardiovascular effects at high doses, especially combined with caffeine and exercise (Bakhiya et al., Mol Nutr Food Res 2017).
  • Sport. WADA’s 2026 list states that synephrine is part of the 2026 Monitoring Program and is “not considered” a prohibited substance. Two close relatives, octopamine and methylsynephrine (oxilofrine), are prohibited in-competition as specified stimulants under S6.B (WADA 2026 Prohibited List). The NCAA lists “synephrine (bitter orange)” as a banned stimulant (NCCIH).

What the research shows

Most trials are small, short and used bitter orange extract or multi-ingredient products rather than synephrine alone. Many used caffeine as well, which makes it hard to separate the two. NCCIH concludes that bitter orange “has not been clearly shown to be helpful for any health-related purpose” (NCCIH).

Weight loss and body composition

A 2004 systematic review found only one eligible randomized trial: 20 patients over 6 weeks, with no significant weight-loss benefit (Bent et al., Am J Cardiol 2004).

The 2022 meta-analysis pooled the three trials that lasted 6–8 weeks. They used 10–54 mg/day of synephrine, all with an exercise program, and two also restricted diet (Koncz et al., Nutrients 2022):

Outcome vs placebo Mean difference (95% CI) p
Body weight 0.60 kg (−5.62 to 6.83) 0.85
Body fat −1.87% (−3.92 to 0.18) 0.07
Fat mass −0.32 kg (−3.76 to 3.11) 0.85
Fat-free mass 0.47 kg (−4.19 to 5.13) 0.84

None of these differences was statistically significant. An earlier industry-linked review described “modest increases in weight loss” with synephrine-containing products over 6–12 weeks, but most of those products also contained caffeine or other ingredients (Stohs et al., Int J Med Sci 2012).

Resting metabolic rate

In a randomized trial with 10 people per group, a single 50 mg dose of p-synephrine raised resting metabolic rate by 65 kcal relative to placebo, but this alone was not reported as statistically significant. Only one combination with naringin and hesperidin (two citrus flavonoids) reached significance, at 183 kcal (p under 0.02) (Stohs et al., Int J Med Sci 2011). One author was an employee of, and two were consultants to, a supplement ingredient company.

Fat oxidation during exercise

A series of double-blind crossover trials from one Spanish lab measured fat burning during cycling tests:

Trial n Synephrine dose Peak fat oxidation, placebo → synephrine
Gutiérrez-Hellín and Del Coso, Br J Clin Pharmacol 2016 18 3 mg/kg 0.29 → 0.40 g/min (p = 0.01)
Gutiérrez-Hellín and Del Coso, Phytother Res 2018 17 1, 2 or 3 mg/kg 0.35 → 0.47 (1 mg/kg); 0.55 g/min (2 and 3 mg/kg)
Gutiérrez-Hellín and Del Coso, Med Sci Sports Exerc 2018 13 3 mg/kg, with or without 3 mg/kg caffeine 0.30 → 0.43 g/min; 0.45 with caffeine (no added effect)

In these trials, synephrine shifted fuel use toward fat during low-to-moderate exercise without changing total energy expenditure; the two 2018 trials also found no change in heart rate. More fat burned during a single session does not by itself mean more fat lost over weeks, and the longer trials above did not show that.

Strength and exercise performance

  • Acute dosing. In 12 college-age men, 100 mg of p-synephrine, with or without 100 mg caffeine, taken for 3 days before testing and on the test morning, increased squat repetitions by about 6% vs placebo (Ratamess et al., JISSN 2015). A companion paper found higher oxygen use and energy expenditure in the 30 minutes after exercise, and higher heart rate only when caffeine was added (Ratamess et al., J Am Coll Nutr 2016).
  • Eight weeks of training. In 80 resistance-trained men, adding 20 mg/day of synephrine to a caffeine-containing pre-workout product gave no additional training benefit over the same product without synephrine (Jung et al., JISSN 2017).

NCCIH summarizes the performance studies as inconsistent, with most showing no benefit (NCCIH).

Side effects and risks

Blood pressure and heart rate

Single-dose trials give mixed results:

Trial Design Synephrine dose Result vs placebo
Bui et al., Ann Pharmacother 2006 Crossover, n = 15 ≈54 mg (900 mg extract, 6% synephrine) Systolic BP up to +7.3 mmHg; heart rate up to +4.2 beats/min; raised for up to 5 h
Haller et al., Am J Med 2005 Crossover, n = 10 46.9 mg (bitter orange extract) No BP change; heart rate +11.4 beats/min at 6 h
Shara et al., Phytother Res 2016 Crossover, n = 18 49 mg No change in heart rate, systolic BP or ECG
Kaats et al., Food Chem Toxicol 2013 Parallel, 25 per group, 60 days ≈49 mg twice daily No change in BP, blood chemistry or blood counts

In the Haller study, a multi-ingredient “ephedra-free” product with only 5.5 mg of synephrine raised blood pressure by about 9–10 mmHg. The authors attributed this mainly to caffeine and other stimulants in that product.

The 2022 meta-analysis found no significant acute change in blood pressure or heart rate. After about 8 weeks of 10–49 mg/day, however, pooled data from two trials (75 participants) showed higher systolic blood pressure by 6.37 mmHg (95% CI 1.02–11.72) and diastolic by 4.33 mmHg (95% CI 0.48–8.18) (Koncz et al., Nutrients 2022). The authors concluded that synephrine “may not be a safe alternative to ephedrine” for people with cardiovascular risk factors.

Case reports of serious events

Serious cardiovascular and neurological events have been reported in people using synephrine-containing supplements, including:

A 2023 review collected 30 case reports covering 35 patients who had used synephrine-containing pre-workout products. The most common complaints were chest pain, palpitations, fainting and dizziness. Five patients were left disabled or still on medication at last follow-up (de Jonge et al., Cardiovasc Toxicol 2023).

Case reports cannot prove cause. Most products contained caffeine or other stimulants, and none of the reviewed cases measured synephrine in the product itself (Stohs and Ray, J Diet Suppl 2020). NCCIH states that it is unclear whether bitter orange or synephrine caused these events (NCCIH).

Caffeine and other stimulants

Synephrine is rarely sold alone. The combination with caffeine is the main concern of European risk assessors (Bakhiya et al., Mol Nutr Food Res 2017). In the Ratamess trials, heart rate during exercise rose only when caffeine was added to 100 mg of synephrine. For related stimulants, see ephedrine, yohimbine and DMAA.

Who was advised to avoid it

  • Pregnancy and breastfeeding. NCCIH notes it may not be safe, and animal data suggest bitter orange substances might reduce milk production.
  • Medications. NCCIH advises talking to a clinician because of possible interactions. Investigators studying Seville orange juice advised that people with severe hypertension, tachyarrhythmias or narrow-angle glaucoma, and people taking MAO inhibitors, avoid it (Penzak et al., J Clin Pharmacol 2001).
  • Children, adolescents and other sensitive groups. ANSES discourages use in these groups (Koncz et al. 2022).

Quality and contamination

FDA scientists tested 59 US products labeled as containing bitter orange or its amines (Pawar et al., Drug Test Anal 2020):

  • Of the 23 products that stated a synephrine amount, only 5 (22%) contained 80–120% of the labeled amount.
  • Several products contained more amines than a typical bitter orange extract would supply.
  • Six products contained methylsynephrine, at up to 240 mg per daily serving, and one contained isopropyloctopamine, at up to 76 mg. Neither is permitted in US supplements, and their effects in people are not known.

This means the label dose of a synephrine product may not match what it contains, and products can contain stimulants that are banned in sport.

Key takeaways

  • A bitter orange alkaloid sold as a supplement. Synephrine HCl is a salt of p-synephrine (about 82% synephrine by weight). It is not an approved drug and is not the same compound as phenylephrine.
  • Short-acting and poorly bioavailable. Its half-life is about 2–3 hours, and only about 22% of an oral dose reaches the body unchanged.
  • No proven weight loss. A 2022 meta-analysis found no significant effect on weight or body composition. Increased fat burning during single exercise sessions has not translated into fat loss in longer trials.
  • Blood pressure is the main measured risk. Single doses have given mixed results, but 8 weeks of use raised blood pressure by about 6/4 mmHg in pooled data. Serious cardiac events have been reported, mostly with caffeine-containing products.
  • Labels are unreliable. In an FDA analysis, most products did not contain their labeled synephrine dose, and some contained banned synthetic stimulants.
  • Allowed by WADA but monitored. Synephrine is on WADA’s 2026 Monitoring Program, while the related octopamine and methylsynephrine are prohibited in-competition. The NCAA bans synephrine.

Sources

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  3. National Center for Biotechnology Information. PubChem Compound Summary: Synephrine (CID 7172); Synephrine hydrochloride (CID 42609626); Phenylephrine (CID 6041). PubChem; PubChem; PubChem.
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