Metilsinefrina

Methylsynephrine (Oxilofrine): A Comprehensive Reference

1. Identity: Names, Chemical Structure, and Relationship to Related Compounds

Methylsynephrine is the colloquial and supplement-label name most frequently encountered in the consumer marketplace for the pharmaceutical compound formally known as oxilofrine. Methylsynephrine is also known as oxilofrine and p-hydroxyephedrine. Oxilofrine is the generic name of the drug and its International Nonproprietary Name (INN). It is also known by synonyms including methylsynephrine, oxyphedrine, and hydroxyephedrine.

The compound belongs to the phenethylamine class of alkaloids. Its molecular structure is based on a phenethylamine skeleton and is related to those of many other drugs and to the major neurotransmitters epinephrine and norepinephrine. Its precise structural relationship to synephrine is defined by a single chemical modification: addition of a methyl group to the α-position in the side-chain of synephrine gives oxilofrine (methylsynephrine). Four stereoisomers (two pairs of enantiomers) are possible for this substance.

The N-methyl group is a pharmacologically critical structural feature. The presence of a methyl group on the amine nitrogen (the N-methyl group) is a key structural feature of methylsynephrine. In the broader class of phenethylamines, the size of the substituent on the amino group influences receptor selectivity. While smaller substituents tend to favor alpha-adrenergic activity, larger groups generally confer greater beta-receptor selectivity. The N-methyl group in methylsynephrine contributes to its activity at both α- and β-adrenergic receptors.

Methylsynephrine/oxilofrine is the racemic 4-hydroxylated analogue of ephedrine. It is also related to pholedrine (4-hydroxy-N-methylamphetamine). Chemical derivatives of oxilofrine have been developed as distinct pharmaceutical agents: several other sympathomimetics and vasodilators were developed as chemical derivatives of oxilofrine, such as the β2-adrenergic receptor agonists buphenine and isoxsuprine.

The compound's molecular formula as the hydrochloride salt is C₁₀H₁₆ClNO₂, and it is registered in PubChem under CID 2723805. Its formal IUPAC designation is 4-[1-hydroxy-2-(methylamino)propyl]phenol. Oxilofrine (4-[1-hydroxy-2-(methylamino)propyl]phenol), also known as methylsynephrine, p-hydroxyephedrine, oxyephedrine, 4-HMP and suprifen, is a pharmaceutical drug developed in Europe in the 1930s to stimulate the heart, increase blood pressure and improve oxygen exchange.

2. Natural Source and Botanical Claims: A Critical Examination

A central point of scientific and regulatory controversy surrounding the use of the name "methylsynephrine" on supplement labels is whether this compound is naturally occurring. The name implies a relationship to synephrine, which is a naturally occurring alkaloid. Synephrine, a constituent of bitter orange and other citrus species, is a legal supplement ingredient. However, the two compounds are distinct chemical entities with different structures and regulatory statuses.

U.S. law does not permit dietary supplements to contain unapproved pharmaceutical drugs such as oxilofrine. Dietary supplements may contain certain extracts of botanical ingredients, but, to our knowledge, oxilofrine has never been identified in, or extracted from, any plant. However, a synonym for oxilofrine, 'methylsynephrine', may mislead consumers and regulators.

One supplement brand explicitly claimed a plant source: one supplement brand (Phenadrine, APS) listed methylsynephrine as an extract of a shrub, Acacia rigidula. Acacia rigidula has been previously listed on supplement labels as the source of another synthetic stimulant, β-methylphenylethylamine (BMPEA). Researchers assessed this claim and found it unsupported: they were not aware of a single study in which oxilofrine or BMPEA had been detected in the Acacia rigidula plant.

Thus, all credible evidence from peer-reviewed literature and regulatory bodies indicates that methylsynephrine/oxilofrine is a purely synthetic compound with no verified natural plant source. Its inclusion in supplements under the label "methylsynephrine" is widely considered a strategy for regulatory circumvention exploiting consumer and regulator confusion with the botanically derived compound synephrine.

3. Pharmaceutical History and Development

Since it was first synthesized in the early 1930s, oxilofrine has been studied in animals and humans. It is a pharmaceutical drug developed in Europe in the 1930s to stimulate the heart, increase blood pressure and improve oxygen exchange.

In Germany, where the drug was developed in the 1930s as a sympathomimetic agent to stimulate cardiac function and elevate blood pressure, it has been approved and marketed under brand names such as Carnigen for this indication from approximately 1950 until 2010, with typical dosages ranging from 16 mg to 40 mg per administration. The approval reflects its historical use as an antihypotensive medication in cases of low blood pressure, though production and availability have since declined.

Oxilofrine was originally developed in the 1930s as a cardiac stimulant. Trade names included Suprifen (Bayer) and, combined with an adenosine-containing standardized organ extract, Carnigen (Hoechst AG). In combination with normethadone, it was marketed as a cough suppressant under the trade name Ticarda. As of 2021, this formulation was still manufactured in Canada by Valeant and sold as Cophylac.

The pharmaceutical history of oxilofrine is thus entirely European in origin. Oxilofrine is a pharmaceutical stimulant prescribed in dosages of 16 to 40 mg to stimulate the heart and increase blood pressure. It has never been approved for use in the USA as a prescription drug or as a dietary supplement.

There is no verified history of oxilofrine or methylsynephrine as a constituent of traditional herbal medicine. Any claims to this effect rest on confusion with synephrine itself, the distinct alkaloid from Citrus aurantium (bitter orange). Synephrine, not oxilofrine/methylsynephrine, was the historically used constituent of bitter orange preparations employed in Chinese and Mediterranean folk medicine. The two compounds should not be conflated in historical accounts.

4. Key Constituents, Active Compounds, and Mechanisms of Action

Methylsynephrine/oxilofrine acts as an indirectly acting sympathomimetic amine. Its primary pharmacological mechanism involves the release of the endogenous neurotransmitter norepinephrine from presynaptic stores, thereby activating adrenergic receptors throughout the body: oxilofrine is described as an ephedrine-like indirectly acting sympathomimetic and antihypotensive agent. It acts as a norepinephrine releasing agent and indirectly activates the α- and β-adrenergic receptors.

Evidence from in vitro studies of cardiac tissue supports this norepinephrine-releasing mechanism: experiments in vitro have shown oxilofrine (4-HMP) to release noradrenaline from cardiac ventricular sections. This effect sets in at a concentration of 10⁻⁵ mol/l and reaches the 30% level at 5×10⁻⁵ mol/l. The inhibition of noradrenaline storage is still more pronounced. At 5×10⁻⁵ mol/l the inhibition is 60%.

In terms of direct receptor interactions, oxilofrine has both alpha- and beta-adrenergic agonist properties: the drug has positive inotropic effects (increases myocardial contractility). As an α-adrenergic receptor agonist, oxilofrine activates the Alpha-1 adrenergic receptor. Activation of said receptor causes vasoconstriction, which is likely how it treats cough. By that mechanism, secretion of mucus into the airway would be dampened, thus reducing the urge to cough.

The compound's cardiac actions have been characterized in pharmacological terms by the U.S. National Center for Advancing Translational Sciences (NCATS): oxilofrine has been found (1) to act predominantly as a beta1 agonist increasing the speed and force of heart muscle contraction (inotropic effects), specifically, increasing left ventricular ejection fraction and stroke volume; (2) to increase blood pressure; (3) to have variable effects on heart rate; and (4) to potentially increase oxygen uptake by the lungs.

A possible additional mechanism involves sigma-1 receptors: it has been postulated that oxilofrine acts as a sigma-1 receptor agonist, since it shares structural similarities to dextromethorphan and methamphetamine, two other sigma-1 receptor agonists. This hypothesis is not yet supported by direct clinical evidence and remains speculative.

Dozens of studies in a variety of animal models including dogs, cats, rabbits, rats, and guinea pigs have been consistent in demonstrating sympathomimetic properties of oxilofrine similar to ephedrine.

5. Scientific Evidence by Area of Use

5.1 Orthostatic Hypotension and Cardiovascular Support

The primary pharmaceutical use for which oxilofrine/methylsynephrine has been formally evaluated is the treatment of orthostatic hypotension. This is also the only area with controlled human clinical trial data.

Double-blind placebo-controlled trial (orthostatic hypotension): In a double-blind study, the antihypotensive agent oxilofrine was compared with placebo in patients suffering from orthostatic circulatory regulation disorders of the sympathicotonic type. After a washout period of one week, 30 patients were treated for two weeks with oxilofrine and 30 with placebo. The area of the blood pressure amplitude determined with the Schellong test between the 8th minute prone and the 15th minute erect increased during treatment with oxilofrine from 126 ± 21 mmHg × min to 187 ± 39 mmHg × min (increase: 48%). The increase under placebo was only 20.8%. The difference in the primary variable was significant. The systolic pressure at the end of treatment with oxilofrine in the Schellong test was virtually constant; under placebo, the systolic pressure decreased.

This is the most robust clinical evidence available. The study supported the use of oxilofrine in orthostatic hypotension but was conducted in a specific patient population under supervised pharmaceutical dosing and cannot be extrapolated to healthy individuals using unregulated supplement doses.

5.2 Cardiovascular Pharmacokinetics in Healthy Volunteers

Combined pharmacokinetic and clinical study (single dose, healthy volunteers): In a combined pharmacokinetic and clinical trial, the correlation was investigated between plasma levels of oxilofrine and the haemodynamic effects on eight healthy volunteers after an oral dose of 120 mg oxilofrine. Plasma levels of free oxilofrine were measured by capillary gas chromatography mass fragmentography. Cardiovascular as well as echocardiographic parameters (left ventricular extent and velocity of fractional shortening) have been measured. The results pharmacokinetically showed a marked enterohepatic reabsorption profile with a second oxilofrine plasma peak occurring in between the second and third hours.

The cardiovascular findings from this study were as follows: the heart rate and mean arterial blood pressure remained unchanged. The total peripheral resistance decreased on average. Systolic blood pressure increased by a maximum of 13.8%, the diastolic decreased by 8.8%. Increasing of the extent of left ventricular fractional shortening by 20.9% and the velocity by 29.5% indicated a positive inotropic effect, which was long lasting.

These findings demonstrate a measurable positive inotropic effect at 120 mg (a dose substantially above the 16–40 mg pharmaceutical range), with complex effects on different blood pressure components. The study was small (n=8) and did not examine exercise or combined stimulant exposure, which is the context in which supplement users are typically exposed.

5.3 Weight Loss and Metabolic Effects

Methylsynephrine is commonly used for weight loss, athletic performance, lung problems, and other uses, but there is no good scientific evidence to support these uses. No peer-reviewed human clinical trials have specifically evaluated methylsynephrine/oxilofrine as a weight-loss or fat-burning agent, either as a standalone intervention or as part of a supplement combination. Claims of thermogenic or lipolytic effects in this context are extrapolations from its adrenergic receptor activity, not from direct human clinical evidence.

5.4 Athletic Performance Enhancement

Oxilofrine appears on the WADA Prohibited List due to its cardiovascular stimulant properties. Oxilofrine is currently a World Anti-Doping Agency (WADA) prohibited substance when used in competition. More specifically, the WADA prohibited list explicitly names "Oxilofrine (methylsynephrine)" as a prohibited stimulant. Its prohibition was added to the WADA list in 2006. The World Anti-Doping Agency (WADA), an international independent agency combating doping in sporting events, added oxilofrine to its list of prohibited substances in 2006.

No controlled human clinical trials have demonstrated verified ergogenic benefits (improved athletic performance outcomes) from oxilofrine in healthy athletes, meaning its performance-enhancing potential in the sports context rests on its pharmacological profile (increased cardiac output, elevated blood pressure) rather than on any direct sports performance trial evidence. There is no good scientific evidence to support these uses.

5.5 Angiogenesis Inhibition (Preclinical Only)

A distinct isomeric variant, R-(−)-β-O-methylsynephrine (OMe-Syn), has been investigated in preclinical research for antiangiogenic properties. A natural product, R-(−)-β-O-methylsynephrine (OMe-Syn) isolated from plants from the Rutaceae family, was identified in a previous screen as an inhibitor of angiogenesis. In this study, researchers conducted two animal model experiments to investigate the in vivo antiangiogenic activity of OMe-Syn. OMe-Syn significantly inhibited angiogenesis in a transgenic zebrafish model as well as in a mouse retinopathy model.

To elucidate the underlying mechanisms responsible for the antiangiogenic activity of OMe-Syn, researchers used phage display cloning to isolate potential OMe-Syn binding proteins from human cDNA libraries and identified nucleoporin 153 kDa (NUP153) as a primary binding partner of OMe-Syn. OMe-Syn competitively inhibited mRNA binding to the RNA-binding domain of NUP153. Furthermore, depletion of NUP153 in human cells or zebrafish embryos led to an inhibition of angiogenesis, in a manner similar to that seen in response to OMe-Syn treatment.

This research is preclinical only (animal models and cell studies). It involves a structurally specific isomeric form and has no established clinical relevance in humans. It should not be conflated with the supplement use context.

6. Body Systems Associated with Methylsynephrine/Oxilofrine

• Cardiovascular system: The primary target system. Oxilofrine acts on cardiac muscle and vascular smooth muscle via adrenergic receptors, producing positive inotropy, changes in blood pressure, and effects on peripheral vascular resistance.
• Sympathetic nervous system: Stimulates sympathetic outflow via norepinephrine release and direct adrenergic receptor activation.
• Respiratory system: Has been used as a component in antitussive (cough-suppressant) formulations, with α-adrenergic-mediated vasoconstriction in the airway mucosa proposed as the mechanism.
• Metabolic/adipose: Claimed (but unproven in clinical trials) to promote lipolysis through beta-adrenergic stimulation, consistent with the general mechanism of sympathomimetic amines.

7. Dosage Forms and Dosages Reported in Sources

In countries where oxilofrine has been used to treat medical conditions, it has been formulated in 16 mg, 20 mg, 32 mg, and 40 mg dosages.

Oxilofrine is a pharmaceutical stimulant prescribed in dosages of 16 to 40 mg to stimulate the heart and increase blood pressure.

In the pediatric pharmaceutical context: in countries where oxilofrine is prescribed by doctors, the usual amount of the drug for adolescents is 24 mg or less.

The pharmacokinetic study in healthy volunteers employed a dose of 120 mg of oxilofrine in a single oral dose.

In the supplement context, dosing has been highly variable and frequently inaccurate. Among 27 brands of supplements analysed, oxilofrine was present in 14 different brands (52%) at dosages ranging from 0.0003 to 75 mg per individual serving. Of the supplements containing oxilofrine, 43% (6/14) contained pharmaceutical or greater dosages of oxilofrine. Following instructions on the label, consumers could ingest as much as 250 mg of oxilofrine per day.

Label accuracy was also a significant problem: only 15% of the supplements (4/27) listed a specific quantity of methylsynephrine on the label, and 75% (3/4) of these brands were inaccurately labelled.

The appropriate dose of methylsynephrine depends on several factors such as the user's age, health, and several other conditions. At this time there is not enough scientific information to determine an appropriate range of doses for methylsynephrine as a dietary supplement.

8. Regulatory Status

United States (FDA): Methylsynephrine does not fit under any of these categories [of legally defined dietary ingredients], rendering misbranded any dietary supplement products that declare methylsynephrine as a dietary ingredient. Methylsynephrine is a substance that does not meet the statutory definition of a dietary ingredient.

On March 31, 2016, the FDA issued warning letters to 7 companies regarding a total of 8 products marketed as dietary supplements for which the product labeling lists methylsynephrine as a dietary ingredient. Despite this action, even after receiving warning letters from the FDA, some sports and weight loss supplement companies continue to use oxilofrine as an undeclared ingredient in their products despite it being prohibited.

WADA (World Anti-Doping Agency): The WADA Prohibited List explicitly names "Oxilofrine (methylsynephrine)" as a prohibited stimulant in competition. For comparison, synephrine (the botanically derived compound from bitter orange) is included in the 2025 Monitoring Program and is not considered a prohibited substance.

U.S. Department of Defense: According to the U.S. Food and Drug Administration (FDA), methylsynephrine does not meet the definition of a dietary supplement. Also, it is banned by the World Anti-Doping Agency (WADA) for use during competitive sports, and by the Department of Defense (DOD) for use by military personnel.

Pharmaceutical markets: Brand names of oxilofrine include Carnigen, Cophylac (with normethadone), Suprifen, and Ticarda (also with normethadone), among others. Oxilofrine has been marketed in Austria, Canada, and Germany. It is mostly no longer marketed today.

9. Doping Cases and Sports Violations

Multiple notable doping cases involving oxilofrine from contaminated supplements have been documented. The World Anti-Doping Agency considers oxilofrine a doping agent, and has banned it from sports. Since 2009, several athletes have been suspended after testing positive for the drug.

In 2009, Brazilian/American cyclist Flávia Oliveira was suspended for 2 years after taking a supplement known as "HyperDrive 3.0+" which contained methylsynephrine, a chemical equivalent of oxilofrine, among other substances. Her sentence was eventually reduced to 18 months after an appeal as there was enough evidence that she had unknowingly consumed said substance as the old label did not list methylsynephrine.

On 18 September 2010, Vietnamese weightlifter Hoàng Anh Tuấn, silver medalist at the 2008 Summer Olympics, was handed a four-year ban, later reduced to two years, for testing positive with the substance.

10. Safety Considerations and Adverse Events

10.1 Adverse Events Linked to Supplement Exposure

Consumption of supplements containing oxilofrine may pose serious health risks. One brand of supplements containing oxilofrine has been linked to serious adverse events including vomiting, agitation, and cardiac arrest.

According to the research, 26 adverse events have been reported in the Netherlands linked to supplements containing oxilofrine. These supplements led to nausea and vomiting, tachycardia, chest pain and cardiac arrest.

In the Netherlands investigation, the adverse event profile was reported in detail: oxilofrine was found at doses of 1 to 5 mg in combination with several other stimulants. It is not known which stimulant, or combination of stimulants, might have been responsible for the reported adverse events including tachycardia, chest pain and cardiac arrest.

As of March 30, 2016, FDA had received 47 adverse event reports associated with products containing methylsynephrine. However, the FDA cautioned that no causal link can be established between the ingredient and the adverse events.

10.2 Cardiovascular Risk Mechanism

Oxilofrine's cardiac effects are considered analogous to those of ephedrine, a compound the FDA banned from supplements in 2004: the dietary ingredient has been studied in animals and humans. It has been found to cause effects on the heart similar to ephedrine, which was banned by FDA in 2004 for its serious side effects.

Human studies of the compound at pharmaceutical doses raise concerns relevant to supplement consumers: human studies using lower dosages suggest that the increased demand on the heart muscles might lead to palpitations, arrhythmias, increased blood pressure, or other adverse effects.

10.3 Vulnerability of Younger Users

Of particular concern with respect to the safety of oxilofrine are the more than one million youth athletes who use sports supplements in the USA. Their relatively small developing bodies might be particularly vulnerable to adult dosages of oxilofrine.

In countries where oxilofrine is prescribed by doctors, the usual amount of the drug for adolescents is 24 mg or less. Research found oxilofrine in supplements at more than three times the usual pediatric dose. Combined with physical activity and other stimulants commonly found in supplements, the consequences could be catastrophic.

10.4 Unknown Risks in Healthy Individuals Using Supplements

No one knows what risks a healthy person could face from taking oxilofrine regularly. It is essentially a synthetic version of ephedra — which the FDA banned from dietary supplements because of serious risks including heart attack and stroke. "We know that at prescription doses, oxilofrine increases heart rate and blood pressure," noted researcher Cohen. "The question is, what will that do in a healthy person who's exercising?"

10.5 Supplement Adulteration Context

The appearance of oxilofrine in supplements occurred specifically as the supplement industry sought replacements for ephedra alkaloids following the FDA's 2004 ban. Since then, many synthetic drugs, such as oxilofrine, have been introduced into supplements in an effort to replace the stimulant effects of ephedra. Researchers from NSF, Harvard Medical School, the National Center for Natural Products Research at the University of Mississippi, and the Netherlands' RIVM identified oxilofrine across multiple supplement categories: in April 2016, researchers found the unapproved pharmaceutical stimulant oxilofrine in 14 over-the-counter dietary supplement products. The research, published in Drug Testing and Analysis, described the public health implications of this disguised ingredient.

Oxilofrine has also been identified alongside other prohibited stimulants in the same products. A 2021 study identified it as one of nine prohibited stimulants found in sports and weight loss supplements, alongside deterenol, phenpromethamine (Vonedrine), octodrine, BMPEA, 1,3-DMAA, 1,4-DMAA, 1,3-DMBA, and higenamine. The risks of consuming these combinations of stimulants is unknown.

11. Summary of Evidence Strength

• Orthostatic hypotension (pharmaceutical use): Supported by at least one double-blind placebo-controlled trial (n=60) and multiple human pharmacokinetic studies. Evidence is moderate for the specific pharmaceutical indication at controlled doses.
• Weight loss: No controlled human clinical evidence. Based solely on pharmacological inference from adrenergic receptor activity. Evidence strength: none/insufficient.
• Athletic performance enhancement: No controlled human trial evidence. WADA prohibition is based on pharmacological profile, not demonstrated performance trials. Evidence strength: none/insufficient.
• Angiogenesis inhibition: Preclinical only (animal models, cell studies). Involves a specific optical isomer. No human evidence. Evidence strength: preclinical only.

References

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