Saturday, July 9, 2011

Higenamine: PES Introduces New "Fat Burner" to the Market. Potent Thermogenic or Dangerous Stimulant?

Image 1: The reformulated PES Alpha T2
contains higenamine, alpha yohimbine
and 3.3-diiodo-l-thyronine
I just received an advertisement email containing some information about the reformulation of PES popular fatburner Alpha T2 (make sure to read "T2 a Fat Burner for Bulking?" for some details on the thyroid stimulating properties of 3.5-diiodo-l-tyronine the metabolically more active "brother" of the 3.3.-diiodo-l-tyronine in PES Alpha T2) mentioning a compound that is advertised as "an all new beta-agonist", that would have been found to be "more effective" than synephrine. While this claim did not impress me at all, I took the time and dug up some information about "higenamine"...

The adrenergic effects of higenamine (Hig. demethylcoclaurine) have been well established since the 1980s (Park. 1984). In fact, the cardioactive benzylisoquinoline alkaloid isolated from Aconiti tuber has long been used as a cardiotonic in traditional Chinese medicine (Zhou. 2003). Its inotropic effects, i.e. its effect on the contractivity of the heart muscle have been studied in various models and range, dependend on dose, from mild stimulation and a minor but significant increase in the effective refractory period (which would be beneficial for patients with bradyarrhythmias, i.e. slow heart beat, to tachycardia, the medical definition of which is an elevated heart rate that remains >100 beats per minute, even in the rested state (Yu. 1985).

In ancient Rome, high doses of Aconit powder were commonly used to poison unwanted enemies, who then died of a 'sudden and unexpected heart attack'. In that, it should be mentioned that the Romans used the whole plant, which, higenamine aside, contains other Aconites which potentially modified it's effects; interestingly, though Kimura et al. (Kimura. 1995) report that aconitine, another compound derived from aconite extract, does the exact opposite, i.e. it induces bradycardia (slow heart) beat and - if administered together (which is how nature meant it to be ;-) - higenamine and aconitine more or less neutralize each other.Enough of TCM and homeopathy... let's get back on the subject at hand.

Will this stuff burn away your love handles or will it literally break your heart? 
 
In order to answer these questions, we would, first of all,need to know how much higenamine actually is in the product - according to the original PES-writeup the reformulated ALPHA T2 contains 40mg higenamine per serving (2 caps).

Q: Is 40mg of higenamine a dangerous dose?  

A: 40mg taken orally appear to be perfectly save.

Details: According to a 1997 rodent-study on the acute toxicity of higenamine by Lo and Chen (Lo. 1997), orally administered even 2.0g/kg higenamine did no harm in the mouse model. For an adult human being this would translate to 160mg/kg or roughly 13g for someone who weighs 80kg. I would nevertheless refrain from consuming all 90 caps one bottle contains, at once - after all, you are no 160pound mouse, are you?

Image 2: Seeds of Aconitum nepellus.
The whole plant contains Aconites,
their concentration is yet particularly
high in the roots of the plant.
If we take into account the results of a 1996 study of the same authors (Lo. 1996), which found that oral bioavailability of higenamine in rabbits, is somewhere between 2.84% and 5.5%, and assume similar bioavailability in humans (rabbits are certainly not the most adequate model for human metabolism), one serving of alpha T2 would effectively deliver no more than 1.14mg-2.2mg of higenamine to your blood stream. This does not sound particularly potent, especially, if you consider the short terminal half-life of 22min (the short half-life does not contradict PES' claim that subjects in their tests felt effects of higenamine for 60 minutes; remember half-life != clearance). It took a dose of 50mg/kg, i.e. 4mg/kg to kill 50% of the mice in the aforementioned study by Lo (Lo. 1997). For our standard human being, weighing 80kg this would equal 320mg or 145x the maximally absorbed amount of higenamine in one serving of Alpha T2 - all that under the hypothetical assumption that we can translate absorption-kinetics observed in a rabbit model to human beings by using a standardized formula that is solely based on the ratio of body weight to surface area of man or rabbit respectively. Before we are trying to speculate about "effective dosages", however, we should initially establish that higenamine is in fact more than a inotopic agent in the arsenal of traditional Chinese medicine; or, in other words, that it does "burn" fat.
A note of caution! If you are taking blood thinning or antiplatelet medications, you should be aware that higenamine itself is a weak anticoagulant (Pyo. 2007; 2008). That being said anybody without respective health conditions should not be too worried and might even benefit from higenamine's anticoagulant effect, of which Yun-Choi et al. (Yun-Choi. 2002) found that it particularly antagonizes epinephrine induced aggregation. With epinephrine being elevated by the beta-adrenergic effects of higenamine, the latter effectively counters its own negative side effects (again, in healthy individuals).

Q: Will taking higenamine help me lose fat?

A: Higenamine is a beta-1 and beta-2 adrenergic agonist, meaning that it will raise your heart rate (beta-1) and help with lipolysis, i.e. the release of triglycerides from your fat cells, but you will still have to "burn" that fat on your own.

Figure 1: Chemical structure
of higenamine (Bai. 2008)
Details: The number of studies that are relevant to our fatloss question is relatively limited and studies from the late 1990s and early 2000s seem to suggest that, despite its stimulating effects on cardiomyocytes (heart muscle cells), higenamine would rather make you tired than spike you up: Shin et al. (Shin. 1999), for example, observed a decrease in tyrosine hydroxylase activity and consequently dopamine content of PC12 cell lines. This downregulation of the dopamine content in cells that, among various other functions, also synthesize, store and secrete catecholamines, would initially suggest the opposite, i.e. a calming and fat-sparing effect - after all, catecholamine induced beta-oxidation is what most of the fat burners out there are all about. More recently, however, Bai et al. (Bai. 2008) identified higenamine as the active, i.e. beta2-adrenergic ingredient, in Radix Aconiti Lateralis Preparata; results, which have since then been confirmed by Tsukiyama et al. (Tsukiyama. 2009) for higenamine isolated from Nandina domestica Thunberg. If you add to that the beta-1 agonistic effects observed in a study by Kimura et al. (Kimura. 1994) you have - just as PES promises - a synephrine analogue.

That being said, the aforementioned study on higenamine's effects on bronchoconstriction by Bai et al. (Bai. 2008) also provides useful information about the potential applicability of Aconti as a "fat burner". The scientists had used an in-vitro cell model, to elucidate the beta2-adrenergic activity of an extract from Aconiti Lateralis Preparata (RALP); and though the latter had not been specifically standardized for its hygenamine content, chromatographic and mass spectrometric analyses revealed that the active ingredient in the extract was in fact the same bioactive plant-alkaloid PES is now introducing to the supplement market. Other than Bai et al., who were interested in the ameliorative effects higenamine, as a beta2-agonists could exhibit on bronchoconstriction, our interest, however, is directed at its use as "fat burner". I assume, most of you will be familiar with the notion that commercially available pharmacological beta2-agonists, above all clenbuterol and its short acting relative albuterol, are widely (ab-)used by bodybuilders and fitness competitors as fat burners and/or ergogenics. Consequently, it stands out of question that higenamine will further liposlysis and may thus facilitate fat loss, the question is yet, to what extend?


Q: How effective is higenamine compared to prescription and over-the-counter beta-2 agonists?

A: It will work, and it is probably more potent than regular (and I guess even methyl-)synephrine. Data on its actual fat loss effects, is yet still not available.

Details: From the Bai study we know that the stimulating effects of higenamine on beta2-adrenoreceptors is dose dependent. We also know that the 40mg of higenamine each serving of the reformulated PES Alpha T2 will activate the beta2-receptors to some extent, what we do not know, yet is whether those 2.2mg that could potentially make it to your fat tissue would be enough to "increase your fat burning" (PES official write-up) significantly.
Figure 2: Dose [in mg/ml] response curves of the activity of albuterol, synephrine and higenamine in CHO-β2-AR-CRE-GFP cells.  Data are expressed as the mean percentage of the maximal response of the individual ligand (data adapted from Bai. 2008 and Bay. 2009).
If we now combine the data Gang Bai and his colleagues from the Nankai University  in Tianjin, China, collected for synephrine (Bay. 2009) and higenamine (Bai. 2008) a (I did that for you in figure 2), it seems that  higenamine is milligram by miligram less potent than regular synephrine, let alone its methylated version, which was used in the original formula and is specifically mentioned in the newsletter. But this does not necessarily mean that its absolute potency as a beta2-agonist falls behind, as well, since the values in figure 2 are expressed as percentage of the maximal activation of the individual ligand.

Since we have no data on lypolisis, we have to turn to the anti-astmatic effects of the compounds in order to judge the magnitude of the effect. At a dosis of 1ng/ml, albuterol was about 4x as potent in the ginea pig asthma model used in Bay. 2009, while higenamine at the same dosage exerted about 3/4 or 75% of the effect of salbutamol in the same model in Bai. 2008. Taken together this data suggest that
  • the dose response curve of higenamine inclines more steeply, than the one of synephrine or the presciption drug albuterol, thus finding the right dose could be a little more difficult
  • judged by its effects on bronchoconstriction in a ginea pig model, higenamine would be 75% as potent as albuterol and about 3x as potent as regular synephrine (I suppose methyl-synephrine would be somewhat more potent, but suspect that it would still fall short of higenamine)
Note that the above calculations are of hypothetical nature, as they are based on data from two different studies, despite using identical models and have been calculated on the relative magnitude of the bronchorelaxant effects measured in isolted guinea pig tracheal muscle. Definite conclusions with respect to the lipolytic effects of all three beta2-agonists discussed in this write-up are illegitimate. The above statements must thus be regarded as working hypothesis which still warrant validation by future research!

Concluding remarks

Whether and to what extend the 40mg of higenamine from PES reformulated Alpha T2 actually facilitate "fat burning" does yet remain to be seen, because the dosages from in-vitro data derived in an animal model cannot be translated into dosing regimens for human beings, as it would be the case in an in-vivo placebo controlled study, where rodents were actually supplemented with different amounts of higenamine or the full spectrum of ingredients present in PES' reformulated Alpha T2. Until such data is available all I can say is. The new Alpha T2 probably works just as well, if not better than the old one. I'll leave it up to you to decide whether that was "good" or "bad" ;-)

On a side note: You may have noticed that Performance Enhancing Supplement (PES) products in general and Alpha T2 in particular have been on "blow-out sale" for some time. While this may have been in preperation for the new product line to replace the old one, it is also probable that the PES guys are preparing for future legislative regulations. Synephrine has been way up on the list of substances scheduled to be added to the ban list ever since 2005 (cf. Position Statement of the Council for Responsible Nutrition. 2005). Thus, replacing the methyl-synephrine in the original formula may turn out to be a smart move regardless of whether or not the fat loss effects of higenamine are more or less pronounced than those of methyl-synephrine - at least they could still sell their products, when the FDA strikes again.