Introduction
Aegeline (N-[2-hydroxy-2(4-methoxyphenyl) ethyl]-3-phenyl-2-propenamide) is the latest attempt by the supplement industry to produce a natural "anabolic." This compound, extracted from Aegle marmelos Correa, is the para-methoxy derivative of N-Cinnamoyloctopamine, a common food additive.
As is the case with most other secondary amides, this compound will be metabolized in the liver into two different species: phenylacrylic acid, and para-methoxy-octopamine. The rate at which these two species are created is presently unknown.
In the murine model of diabetes, aegeline was shown to decrease blood sugar at a dose of 100 mg/kg. Converting this to HED based on BSA equals about 840 mg for a 70 kg adult human. At a human equivalent dose of about 420 mg, aegeline was demonstrated to decrease triglycerides, while improving cholesterol ratios in the murine model of dyslipdemia (1). The authors concluded, "The reasonable mapping of [aegeline] to validated pharmacophoric hypothesis and 3D QSAR model with an estimated activity (283 nM) suggest that [aegeline] might be a beta(3)-AR agonist." A follow-up study done in 2011 by the same researchers confirmed aegelines antihyperlipidemic & antihyperglycemic properties (2).
These results should not be surprising as octopamine has been known for years to possess these properties (3). In fact, octopamines beta(3)-agonism was clearly elucidated as far back as 1999 (4). Unfortunately, the beta(3)-adrenergic receptor is only weakly contributatory to lipolysis in humans, and octopamine was demonstrated to possess no capacity to induce lipolysis at all (4, 5). In beta(3) insensitive animals (humans), octopamine actually induces pro-adipogenic cascades through its production of hydrogen peroxide via intracellular deamination (3).
Summary
Aegeline may indeed possess inherent anabolism as a function of its ability to convert into an octopamine derivative. Indeed, para-methoxy-octopamine (Para-OMe-Octopamine) is one of octopamines metabolites via COMT in humans. Unfortunately, the anabolism that aegeline induces is likely restricted to adipocytes since humans are extremely insensitive to beta(3)-AR agonism.
In the studies in which aegeline demonstrated antihyperglycemic and antihyperlipidemic properties, the animals utilized were both murine which, as described above, are beta(3)-AR receptor sensitive. Furthermore, these animals were tested against specific disease pathologies to amplify their effects. It should go without saying that the results produced will probably not translate to humans.
References
(1) http://www.ncbi.nlm.nih.gov/pubmed/17197179
(2) http://www.ncbi.nlm.nih.gov/pubmed/21930379
(3) http://jpet.aspetjournals.org/content/299/1/96.long
(4) http://link.springer.com/article/10.1007%2FPL00005357?LI=true
(5) http://www.ncbi.nlm.nih.gov/pubmed/8121236
Why no discussion of beta-phenylacrylic acid, aka trans-cinnamic acid, a major active constituent of cinnamon? It's been shown to increase GLUT-4 in skeletal muscle, inhibit PTP1B and act as an insulin secretagogue. Surely some of those potential mechanisms could explain an anabolic effect, assuming these metabolites are present in significant quantities after ingestion.
ReplyDeletehttp://www.ncbi.nlm.nih.gov/pubmed/20929506
http://www.ncbi.nlm.nih.gov/pubmed/18651742
What is the oral bioavailability of aegeline?
Also, what is the mean elimination half-life of DMAA?
Any speculation as to negative pharmacological interactions with this compound and the liver? If your chemistry knowledge is as extensive as your physiology/pharmacology, what about toxic synth byproducts/impurities if they are using a synthesized version of the compound? Lots of supps using it are being pulled and the FDA thinks they have linked Aegeline to causing liver damage.
ReplyDeleteThere are a few ways this compound could be metabolized: oxidation, amide hydrolysis, or conjugation. Amide hydrolysis produces (non-energetically) a benzene compound with an extended conjugated hydrocarbon chain capable of "anti-oxidation" of radicals through resonance stabilization. Conjugation would produce more water soluble products capable of urinary/biliary excretion. Oxidation would (generally) produce non-amine containing carbon skeletons in addition to (some) free ammonia. If conjugation or hydrolysis are the preferred methods of metabolism, I would suspect there would be little, if any, potential hepatotoxicity. On the other hand, if oxidation is the preferred manner, then hepatotoxicity is possible. This is why pharmacokinetic studies are important prior to releasing a fairly unknown compound into the free market. Phase I clinical trials would also be nice.
ReplyDeleteIf I was to guess, I would surmise that oxidation would be the most likely primary & consistent method of metabolism. Conjugation is not as efficient with para-hydroxyl constituents, and amide hydrolysis is simply too slow and too variable.
ReplyDeleteInteresting, Thanks for the prompt and thorough response. Very true about phase 1s, but I guess that the companies argument is that it comes from whatever plant and has been consumed (although I believe that this shouldn't apply to pure compounds extracted from said plants.) for many years is the supplements version of human trials. Intriguingly, I was using 2 products that contained a lower and high dose of aegeline, OEPro thermo powder and versa-1 respectively, by USPlabs together and had to have blood levels taken around week 7 of an 8 week run I was planning. My liver enzymes were well within normal range and nothing in their ratios nor was there anything else to suggest something was amiss. Obviously I quit after I'd read about the potential link, and have noticed nothing since. This happened around the time they made the link, a month ago or so. Thanks for providing this blog, I love reading and learning from your work.
ReplyDeletePLEASE SEE THE "Aegeline and nonviral_hepatitis" SECTION OF THE WIKIPEDIA ARTICLE ON THE PLANT "Aegle marmelos" BEFORE USING THIS SUBSTANCE, WHICH CITES THE FDA AND DOJ INITIATIVES AGAINST ONE SUPPLIER WHOSE SUBSTITUTION OF SYNTHETIC AGENT FOR PLANT EXTRACT RESULTED IN A DEATH BY LIVER FAILURE, AND SEVERAL ADDITIONAL CASES REQUIRING CRITICAL MEDICAL ATTENTION (INCLUDING NEED FOR LIVER TRANSPLANT). OR, TRUST MR. O'BRIEN'S "If I was to guess…". M-E Duban, PhD
ReplyDeletehttps://en.wikipedia.org/wiki/Aegle_marmelos#Aegeline_and_nonviral_hepatitis