Prototype Nutrition Ketoforce

Jun

21

More reasons why NMT won’t work

By Patrick Arnold

Let me preface this post by apologizing for my lack of objectivity in my last post on N-methyltyramine (NMT).  Many have dismissed the science I presented in my original post on this subject on the basis that I show bias against Mr. Klein.  And it is true, I do not like the man and I have personal reasons to completely distrust him on many levels.  I understand how my expression of such personal animosity can distract one from the facts.  So in this post I will keep all personalities out of the discussion and merely focus on the science.  Furthermore, I ask that you also refer to my original post and critique the facts I presented there if you may.  I always keep my comments option open on my blogs and invite any rebuttals, so dont be shy if you take issue with my statements.

So here is some more evidence.

1)  NMT has been shown to have no lipolytic activity and in fact may be anti-lipolytic.  What that means is that it not only has been shown to not have fat burning qualities but it may actually interfere with fat burning.

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

Source

Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Toulouse, France.

Abstract

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

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2) Its elimination half life is extremely short (5.6 minutes).  If you recall in my original post I told you that its structural characteristics are such that it will be rapidly destroyed by monoamine oxidases, and this is precisely why it’s half life is so short.  Knowing this you must consider any “in-vitro” data on how NMT functions is in large part irrelevant because after ingestion the compound wont  last long enough in the body to be of practical significance.  Well, unless you take a dose every half hour throughout the day or something.

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Disposition of N-methyl-[ring-3,5-3H]tyramine in rabbits and mice.

Hai H, Guo ZG, Wang JM.

Abstract

After iv bolus injection of N-methyl-[ring-3,5-3H] tyramine ([3H]MT) [editors note:  this is an radioisotopically labelled version of NMT] 14.8 MBq/kg in rabbits, the plasma concentration-time data was found to be in accordance with the 2-compartment model. The pharmacokinetic parameters were: T1/2 alpha = 0.3 min, T1/2 beta = 5.6 min, K12 = 0.69/min, K21 = 0.21/min, K10 = 1.6/min, VC = 0.4 L/kg, Cl = 0.62 L/kg.min-1. [3H]MT was taken up by organs rapidly and extensively. Two min after administration, a large amount of radioactivity was detected in every organ sampled. The highest amounts were in the kidney and liver, followed by lung, small intestine, heart, skeletal muscle, spleen, brain and fat. The drug was metabolized extremely fast in vivo. The metabolites were found in the plasma chromatogram just 0.5 min after dosing, while over 80% were found in the urine within 1 h. After a 1 h collecting period, the radioactivity recovered in the urine amounted to 79% of the injected dose. By the end of a 6 h collection, almost no drug was detected in the body.

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3)  NMT will increase your appetite.  I am not kidding you – in fact it was even patented in Japan for this specific purpose.  Articles were published showing it is the major constituent in beer that causes increased gastric secretions and hence those cravings you get for bratwursts or potato chips after a few budweisers.  Obviously, appetite stimulation is not a property amenable to  a diet related supplement product.  It may on the other hand be an ingredient useful in a bulking up supplement.

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Abstract:

PROBLEM TO BE SOLVED: To provide an aperitive additive for beverages and foods that can be readily and simply taken to safely and effectively increase the appetites and provide aperitive beverages and foods containing the same.

SOLUTION: This invention provides the beverages and foods to which at least one of N-methyltyramine and N,N-dimethyl-tyramine and a gastrin secretion-promoting fraction as a fermentation product are added as a gastrin secretion-promoting component, or provides an aperitive additive, an additive for domestic animals and an appetite-increasing agent containing the same. In addition, this invention provides the use of the gastrin secretion-promoting component for producing these additives and the production process for the gastrin secretion-promoting fraction.

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Stimulatory effect of N-methyltyramine, a congener of beer, on pancreatic secretion in conscious rats.

Tsutsumi E, Kanai S, Ohta M, Suwa Y, Miyasaka K.

Alcohol Clin Exp Res. 2010 Feb;34 Suppl 1:S14-7. Epub 2009 Mar 6.

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Yokoo Y, Kohda H, Kusumoto A, Naoki H, Matsumoto N, Amachi T, Suwa Y, Fukazawa H, Ishida H, Tsuji K, Nukaya H.

Alcohol Alcohol. 1999 Mar-Apr;34(2):161-8.

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So there you have it.  A blog with some intriguing and relevant science about a nutritional supplement ingredient.  No personal attacks and a real intent to avoid bias on my behalf. 
Once again, I remind you that my comment section is open.  I invite anyone that disagrees with my conclusions on the posted science, or who has valid scientific arguments of their own, to post them there (instead of on some web forum where I am banned  and unable to stand up for myself)

11 Responses so far

Well seems I continue to be debated from behind the protective walls of the bb.com fortress – where cowards like this guy synapsin can throw stones with no fear of counterattack.

I decided to post a rebuttal to him here anyway, with the hopes that maybe it will be relayed to where he and his buddies can read it.

my rebuttal is too long to post as a comment. i suppose i will just see if it cant be put on bb.com another way

Would be willing to post your reply on BB.com if you need, Patrick.

yet you delete my posts on the subject? pussy?

PA obviously personal attacks does not strengthen your (well thought out btw) comments on NMT but I find that more often than not, the quality of a company and the quality of their products is in directly corelation to the person who heads or represents them.
Ha I would like to see the bb.com argument but I hate to waste my time on drivel, maybe for entertainment purposes on a Friday night LoL

PS didn’t mean your comments are drivel, the other person obviously just to be clear

@hightowerpharm Don’t get your panties in a wad, the admin that approves comments from first time users was on vacation.

Patrick, is there any specific textual evidence to pair that EP -> DOPGAL schema? It’s definitely antiquated because MAO is barely involved in EP metabolism in humans. Since oral tyramine has a half life of about a half hour, it’s likely that NMT hangs around for longer despite the IV references. For example, rabbits express an enzyme called epinephrine dehydrogenase which has not been discovered in human plasma. Human studies have thoroughly refuted the role of MAO in peripheral catecholamine metabolism in favor of o-methylation; but that’s not really the point considering NMT. The n-methyl group is a steric hinderance and human pharmacokinetic date must be collected to determine its half life (try 50mg fasted). This is an interesting debate nonetheless and it’s a shame it got heated and personal so fast.

Interesting information Pinch. I assume that MAO is still very important in the CNS metabolism of catecholamines. And for sympathomimetics that have unsubstituted benzene rings it must still be of primary importance i assume

For tyramime, indeed. Here’s somewhat of an elaboration to clarify my point:

http://img529.imageshack.us/img529/6505/picture1rmn.png
(4)
Fig. 1. Certain chemical additions to both non-catecholamine and catecholamine sympathomimetics can impact the way in which it interacts with certain proteins. One such example is monoamine oxidase B, which catalyzes the deamination (removal of the nitrogen, and subsequent inactivation) of PEA, dopamine, and tyramine. The other form of this enzyme, MAO-A, deaminates catecholamines like EP and NE, although they do share substrates for which each enzyme has respective preferential affinity (8)

Just copy pasta that excerpt into google if you’d like my references

You can see there how a methyl group influences substrate binding/overlap of the alpha carbon and that free p orbital. As seen in literature comparing monoamines with an n terminus vs. an alkyl terminus, there are marked kinetic differences.

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