Synephrine

1.1. Sources

P-Synephrine (P-hydroxy-α-{methylaminomethyl}benzylalcohol) is a protoalkaloid compound and trace amine that can be endogenously produced in the human body, or can be found in high levels in the bitter orange (citrus aurantium) traditional chinese medicine and supplement.^[1][2] The bitter orange (sometimes also called Seville or Sour orange^[3]) is not a common fruit consumed except perhaps in Iran due to its bitter and sour taste;^[3] the common orange is citrus sinensis.

It can be found in:

• Citrus aurantium fruit (8848.8mg/kg dry weight; 96% total protoalkaloids^[4])

• Standard Citrus aurantium extract (71.5g/kg or 7.1% dry weight; 92.2% total protoalkaloids^[4]), although methanolic extracts may be more balanced between octopamine and synephrine (0.253 and 0.142%, respectively^[5])

1.2. Structure

The term synephrine tends to exclusively refer to parasynephrine or p-synephrine (insofar that the two are mostly synonymous in common usage^[1]) although two other variants, specifically metasynephrine (m-synephrine) and orthosynephrine (o-synephrine); they are thought to have similar properties,^[6] although p-synephrine is the particular variant found in the traditional medicine citrus aurantium (alongside the molecule it is made from, octopamine^[7][2]).

2.1. Metabolism

Synephrine is known to be an endogenous metabolite of octopamine metabolism, specifically its N-methylated derivative; its synthesis has been detected in the rat brain^[8] and it has been detected in human urine independent of supplementation or oral ingestion.^[9][10]

Synephrine appears to be an endogenously produced end product of tyramine metabolism, as tyramine is metabolized into octopamine (another trace amino acid) which is then oxidized into synephrine

Synephrine is a substrate for the monoamine oxidase (MAO) enzymes (K_m of 250µM and a V_max of 32.6nM/mg protein/30 minutes), seeming to be metabolized more by MAO-A than MAO-B^[11] (similar to its parent molecule octopamine,^[12] and the lack of difference in the metabolism of monoamines and their N-methylated derivatives has been noted previously with noradrenaline and normetanephrine^[13]).

The oxidation of octopamine into synephrine, as well as the oxidation of synephrine itself, is conducted via the MAO enzymes and mostly by MAO-A

2.2. Elimination

Oral supplementation of synephrine up to 150mg, at no time point, increases urinary octopamine above the LOQ when assessed after the 24 hours following a single dose;^[14] this is relevant as octopamine is banned by WADA whereas synephrine is not, and octopamine itself can be detected following oral ingestion of octopamine supplements.

3.1. Headache and Migraine

Synephrine is known to be endogenously produced as a metabolite in tyramine metabolism as it can be decarboxylated in plants from tyramine to produce synephrine (to give off carbon dioxide^[15]) and synephrine, as well as other trace amines (tyramine, octopamine) can be detected in plasma^[16] at levels much higher in persons with cluster headaches^[17] and in migraines with aurae.^[18] Synephrine specifically is also higher in persons with migraines with aurea (0.72+/-0.44ng/10⁸ platelets) although not in migraines without aurae (0.37+/-0.29ng/10⁸ platelets) which were similar to normal controls (0.33+/-0.25ng/10⁸ platelets).^[18]

Trace amine metabolism (tyramine based) appears to be perturbed in the pathology of migraines, and due to this platelet concentrations of synephrine may be higher than in persons without migraines or those with migraines but no aurae associated with the migraine. Significance to oral supplementation not known

4.1. Blood Pressure

A single dose of 50mg p-synephrine, when taken by healthy subjects in a rested state over the course of 75 minutes, does not appear to significantly influence blood pressure nor heart rate.^[19]

5.1. Metabolic Rate

A single dose of 50mg p-synephrine, when measured over the next 75 minutes in otherwise healthy subjects in a rested state, has been noted to increase by 65kcal ^[19] and this was without any influence on blood pressure or cognition.^[19]

5.2. Mechanisms

P-synephrine is a beta-agonist compound similar to ephedrine^[20][21]. It can increase the metabolic rate via increasing lipolysis and basal metabolic rate.^[1] These effects are independent of diet for the most part, and can exert a passive increase in basal metabolic rate to produce weight loss over an extended period of time.

Synephrine also has alpha-adrenergic antagonist capabilities. Affecting both the A1 and A2 receptors, albeit with a different potency.^[22] In both the cases of alpha and beta agonism, the effects of both forms of synephrine are much less than that of noradrenaline.

5.3. Human studies

It has been implicated in increasing the thermic effect of food, but one study noted this effect only in women.^[23]

##Citrus Flavonoids (Naringenin and Hesperidin)##

50mg p-synephrine can increase metabolic rate by 65kcal relative to placebo (which noted a 30kcal decrease; measurements taken in the fasted state over 75 minutes), and the addition of 600mg naringenin increases this increase in metabolic rate to 129kcal and a further increase of 100mg hesperidin to both the aforementioned ingredients can again increase the metabolic rate to 183kcal;^[19] consuming a higher total level of hesperidin (1,000mg) with the aforementioned doses of p-synephrine and naringenin resulted in a lesser increase of the metabolic rate by 79kcal relative to control.^[19]

6.1. Caffeine

Like ephedrine, P-synephrine also shows synergism with caffeine and is more pronounced in naive caffeine users.^[24]

7.1. General

P-synephrine does not seem to be a causative agent in increasing blood pressure^[25][26][23]

The Bitter Orange itself (the parent plant) has been linked to increased systolic and diastolic blood pressure.^[27] While a common patented blend of P-synephrine known as Xenadrine EFX (containing just 5.5 mg synephrine) has been linked to an increase in blood pressure, another patented blend, Advantra-Z (which contains a significantly higher dose of synephrine at 46.9 mg along with active bioflavonoids such as naringen and hesperidin) has not. Both appear to increase heart rate from baseline though (16.7 BPM and 11.7 BPM, respectively).^[25]

Overall, usage of P-synephrine appears to be quite safe and free of most adverse side effects.^[28]

7.2. Drug Testing

P-synephrine has failed to cause a false positive for drug testing (via a CEDIA amphetamines assay) following ingestion of 54mg p-synephrine via 900mg citrus aurantium extract.^[29]