1. p-Synephrine

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

    BACKGROUND: The ingredients of numerous "ephedra-free" dietary supplements used for weight loss include bitter orange, which contains sympathomimetic alkaloids such as synephrine. Due to the similarity in chemical structure to ephedrine and the potential sympathomimetic effects of synephrine, it is hypothesized that bitter orange may increase blood pressure (BP) and heart rate (HR).

    OBJECTIVE: To determine the effects on BP and HR after a single dose of bitter orange in healthy adults.

    METHODS: In a prospective, randomized, double-blind, placebo-controlled, crossover study, 15 young, healthy, adult subjects received either a single dose of Nature's Way Bitter Orange--a 900 mg dietary supplement extract standardized to 6% synephrine--or matching placebo, with a one week washout period. Systolic BP (SBP), diastolic BP (DBP), and HR were measured at baseline and every hour for 6 hours after administration.

    RESULTS: SBP after bitter orange was significantly increased versus placebo at hours 1-5 (p < 0.0001); the peak difference was 7.3 +/- 4.6 mm Hg. Although the baseline DBP was higher than after administration of both placebo and bitter orange, DBP after bitter orange was significantly increased versus placebo at hours 4 and 5 (p < or = 0.02); the peak difference was 2.6 +/- 3.8 mm Hg. HR was significantly increased after bitter orange versus placebo for hours 2-5 (p < 0.01); the peak difference was 4.2 +/- 4.5 beats/min.

    CONCLUSIONS: SBP, DBP, and HR were higher for up to 5 hours after a single dose of bitter orange versus placebo in young, healthy adults.
    Blood pressure and heart rate effects

    Microbial metabolism of phenolic amines: degradation of dl-synephrine by an unidentified arthrobacter.

    Microorganismscapableofdegradi ngdl-synephrinewere isolatedfromsoilof Citrusgardensbyenrichmentcultu re,withdl-synephrineas thesolesource of carbonandnitrogen.Anorganismwh ichappears tobean arthrobacter,but whichcannotbeidentifiedwithany ofthepresentlyrecognizedspecie swas predominantintheseisolates.Itw as foundtometabolizesynephrinebya pathway involvingp-hydroxyphenylacetaldehyde, p-hydroxyphenylacetic acid, and3,4-dihydroxyphenylaceticacidas intermediates.Someoftheenzymes of thispathwaywere demonstratedincell-freeextracts.Anaromaticoxygena se, whichcouldalsobereadilyobtaine dina cell-freesystem,was foundtodegrade 3,4-dihydroxyphenylacetic acid by meta cleavage.

    Synephrine [l-p-hydroxy-a-(methylaminomethyl)benzyl alcohol] and octopamine [l-phydroxy-a-(aminomethyl)benzyl alcoholJ, which are well known sympathomimetic amines in animal metabolism and are structurally related to epinephrine and norepinehrine, are present in Citrus plants (17, 18). The proposed pathway for the biosynthesis of synephrine in Citrus (21) and the probable metabolic relationship of synephrine and few other phenolic compounds in animals (4, 13) are summarized in Fig. 1 and 2. Synephrine occurs at levels as high as 2 g/kg (fresh weight) in the leaves of Citrus reticulata (Tangerine and Cleopatra mandarin varieties) (22). Although the role of phenolic amines in animal metabolism and their mode of operation are far from completely understood, even less is known of their function in the plant world and no information is available on the mode of disposal of synephrine and related phenolic amines in nature. In Aerobacter aerogenes ATCC 9621, tyramine, however, is used as a source of carbon and nitrogen (11) and is probably degraded to p-hydroxyphenylacetaldehyde by a monoamine oxidase reaction followed by its subsequent conversion to p-hydroxyphenylacetic acid and then to 3,4-dihydroxyphenylacetic acid (2). The present communication describes the isolation from soil and partial characterization of an unidentified arthrobacter which metabolizes dl-synephrine.
    Full Text - http://jb.asm.org/content/122/3/866.full.pdf

    it has been said that p-Synephrine could be converted to epinephrine by the hydroxylase enzymes in the liver but it doesnt appear as so

    A Review of the Receptor-Binding Properties of p-Synephrine as Related to Its Pharmacological Effects

    Bitter orange (Citrus aurantium) extract and its primary protoalkaloid p-synephrine are used widely in weight loss/weight management and sports performance products. Because of structural similarities, the pharmacological effects of p-synephrine are widely assumed to be similar to those of ephedrine, m-synephrine (phenylephrine), and endogenous amine neurotransmitters as norepinephrine and epinephrine. However, small structural changes result in the receptor binding characteristics of these amines that are markedly different, providing a plausible explanation for the paucity of adverse effects associated with the wide-spread consumption of p-synephrine in the form of dietary supplements as well as in various Citrus foods and juices. This paper summarizes the adrenoreceptor binding characteristics of p-synephrine relative to m-synephrine, norepinephrine, and other amines as related to the observed pharmacological effects.
    Full Text - http://www.hindawi.com/journals/oximed/2011/482973/

    Oral dose of 46.9mg p-Synephrine will reach a blood concentration of 2 ng/mL and has a half life of 2-3 hours. Also p-Synephrine doesnt seem to agonize the alpha-1 receptor as much as m-Synephrine does

    Exactly which synephrine alkaloids does Citrus aurantium (bitter orange) contain?

    Following the withdrawal of ephedrine from the dietary supplement marketplace sales of products containing Citrus aurantium (CA) (bitter orange) for weight loss are believed to have increased dramatically. CA contains a number of constituents speculated to lead to weight loss, of which the most frequently cited constituent is synephrine. Concerns have been raised about the safety of products containing synephrine. To develop an adequate basis for clinical and public health recommendations, it is necessary to understand the nature of the synephrine alkaloids in CA. There are six possible isomers of synephrine (para, meta, ortho; and for each a d or l form). Some authors have stated that CA contains only p-synephrine, whereas other authors have stated that CA contains m-synephrine. This is an important distinction because the two molecules have different pharmacologic properties, which may differentially affect safety and efficacy. We are unable to identify published data that explicitly show whether CA contains p-synephrine, m-synephrine, or both. In this brief report, we show that at least one product purportedly containing synephrine alkaloids from CA contains both p-synephrine and m-synephrine. We believe this justifies further investigation into which synephrine alkaloids are present in CA and products purportedly containing synephrine alkaloids from CA and the relative quantities of each of the different isomers.
    A analysis on fat burner products containing synephrine has found both m-Synephrine and p-Synephrine in them.

    More on p-synephrine vs. m-synephrine - http://www.tampabayanalytical.com/Roman_ICSB2007.pdf
    "The only good is knowledge and the only evil is ignorance." - Socrates

  2. p-Synephrine and its effects on fat loss

    Safety and efficacy of citrus aurantium for weight loss.

    To examine the safety and efficacy of citrus aurantium, an herb now commonly used as a substitute for ephedra in dietary supplements marketed to promote weight loss, we conducted a systematic review. An extensive search of MEDLINE, EMBASE, BIOSIS, and the Cochrane Collaboration Database identified only 1 eligible randomized placebo controlled trial, which followed 20 patients for 6 weeks, demonstrated no statistically significant benefit for weight loss, and provided limited information about the safety of the herb.

    PMID 15541270
    Isopropylnorsynephrine is a stronger lipolytic agent in human adipocytes than synephrine and other amines present in Citrus aurantium.

    The weight loss observed in consumers of extracts of Citrus aurantium (bitter orange) has been tentatively attributed to the lipolytic and thermogenic effects of the alkaloids abundant in the unripe fruit. Synephrine, octopamine, tyramine, and other alkaloids have been repeatedly identified and quantified in Citrus members of the Rutaceae family or in their extracts incorporated in dietary supplements for weight management. However, there are only scarce reports on their lipolytic action. This study aimed at comparing the acute lipolytic activity of synephrine, octopamine, tyramine, and N-methyltyramine in rat and human adipocytes. Maximal response to the prototypical β-adrenergic agonist isoprenaline was taken as reference in both species. In rat, octopamine was slightly more active than synephrine while tyramine and N-methyl tyramine did not stimulate-and even inhibited-lipolysis. In human adipocytes, none of these amines stimulated lipolysis when tested up to 10 μg/ml. At higher doses (≥100 μg/ml), tyramine and N-methyl tyramine induced only 20% of the maximal lipolysis and exhibited antilipolytic properties. Synephrine and octopamine were partially stimulatory at high doses. Since synephrine is more abundant than octopamine in C. aurantium, it should be the main responsible for the putative lipolytic action of the extracts claimed to mitigate obesity. Noteworthy, their common isopropyl derivative, isopropylnorsynephrine (also named isopropyloctopamine or betaphrine), was clearly lipolytic: active at 1 μg/ml and reproducing more than 60% of isoprenaline maximal effect in human adipocytes. This compound, not detected in C. aurantium, and which has few reported adverse effects to date, might be useful for in vivo triglyceride breakdown.
    On RMR
    Effects of p-Synephrine alone and in Combination with Selected Bioflavonoids on Resting Metabolism, Blood Pressure, Heart Rate and Self-Reported Mood Changes

    Bitter orange (Citrus aurantium) extract is widely used in dietary supplements for weight management and sports performance. Its primary protoalkaloid is p-synephrine. Most studies involving bitter orange extract and p-synephrine have used products with multiple ingredients. The current study assessed the thermogenic effects of p-synephrine alone and in conjunction with the flavonoids naringin and hesperidin in a double-blinded, randomized, placebo-controlled protocol with 10 subjects per treatment group. Resting metabolic rates (RMR), blood pressure, heart rates and a self-reported rating scale were determined at baseline and 75 min after oral ingestion of the test products in V-8 juice. A decrease of 30 kcal occurred in the placebo control relative to baseline. The group receiving p-synephrine (50 mg) alone exhibited a 65 kcal increase in RMR as compared to the placebo group. The consumption of 600 mg naringin with 50 mg p-synephrine resulted in a 129 kcal increase in RMR relative to the placebo group. In the group receiving 100 mg hesperidin in addition to the 50 mg p-synephrine plus 600 mg naringin, the RMR increased by 183 kcal, an increase that was statistically significant with respect to the placebo control (p
    "The only good is knowledge and the only evil is ignorance." - Socrates

  3. Increasing the TEF of food

    Increase in the Thermic Effect of Food in Women by Adrenergic Amines Extracted from Citrus Aurantium**

    Objective: To compare the thermic response to a meal between men and women of varied body composition and to determine whether adrenergic amines extracted from citrus aurantium (CA) induce an increase in metabolic rate and enhance the thermic response to the meal.

    Research Methods and Procedures: In 30 healthy weight-stable subjects (17 women, 13 men; BMI: 20 to 42 kg/m2), body composition was determined by bioimpedance analysis followed by resting energy expenditure for 20 minutes, and the thermic effect of food (TEF) of a 1.7-MJ, 30-gram protein meal was determined intermittently for 300 minutes by indirect calorimetry. In a subset of 22 subjects, the TEFs of CA alone and when added to the same 1.7-MJ meal were determined. Blood pressure and pulse before and throughout the studies and catecholamine excretion were determined.

    Results: TEF was significantly lower in women than men (152 7 vs. 190 12 kJ and 8.8 0.4% vs. 11.0 0.7% of meal), independently of age and magnitude of adiposity. The thermic response to CA alone was higher in men, but, when added to the meal, CA increased TEF only in women and to values no longer different from men. CA had no effect on blood pressure and pulse rate but increased epinephrine excretion by 2.4-fold.

    Discussion: A 20% lower TEF in women suggests a diminished sympathetic nervous system response to meals, because with CA, TEF increased by 29% only in women. However, this acute response may not translate into a chronic effect or a clinically significant weight loss over time.
    (In women but not in men)
    "The only good is knowledge and the only evil is ignorance." - Socrates

  4. Has any company put out an adequately dosed fat burner with p-synephrine, hesperidin, and naringin per the doses used in that study?

    I'm pretty sure almost every synephrine product is using citrus aurantium, which has negligible levels of hesperidin in the first place, and are dosed too low to achieve the dose of naringin used in the study.

    This in reference to Int J Med Sci. 2011; 8(4): 295–301. that JudoJosh cited
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  5. Good question @De__eB
    "The only good is knowledge and the only evil is ignorance." - Socrates

  6. Interested as well, especially MS.

    I know Coop has recommended it as a weaker alternative to E and Neuron has written extensively on it.

    Personally, I have taken it for months now at 120mg with Caffeine 3x a day, it doesn't seem very effective; I am getting leaner, however my diet is on point and am taking other supps.

    **I use MS from Axenic.

  7. Quote Originally Posted by De__eB View Post
    Has any company put out an adequately dosed fat burner with p-synephrine, hesperidin, and naringin per the doses used in that study?

    I'm pretty sure almost every synephrine product is using citrus aurantium, which has negligible levels of hesperidin in the first place, and are dosed too low to achieve the dose of naringin used in the study.

    This in reference to Int J Med Sci. 2011; 8(4): 295–301. that JudoJosh cited
    It appears too much hesperidin blunts the RMR response to synephrine (probably secondary to adenosine agonism, or possibly central opioidergic activity -> decreased RMR). I'm unsure why using 100mg would increase RMR. As for naringin, it is classically used for its ability to block the CYP450 enzyme system in various regions of the body (gut, liver, etc), so that may play a role in potentiating synephrine's effects

  8. I'm surprised nutratech hasn't pushed the combination more, since the elevation in BMR was tripled with the two flavonoids tripled the BMR increase and they funded the study.
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