From: "Carl V. Phillips" <carlp@sph.umich.edu>

Subject: Re: Sugar substitutes: aspartame & saccharin side effects?

> From: "Brent J. Waguespack" <sarge7@communique.net>

> Aspertame, there has been some recent discussions about soda pops that are

> made with this sweetner. Some people say it gives them headaches because

> the sweetner in the coke turns into an alcohol base type sugar.

The transition problems (partially converting to formaldehyde and methanol

at "high" temperatures -- in the 150F range) are only part of the story.

There is some reason to believe that aspartic acid (one of the two amino

acids that composes aspartame), which is very similar to glutamine, may

have negative neurological effects on some (many?) people. There are a

few natural experiments where people have eaten diets extremely high in

glutamine (compared to other aminos) and many people (up to half) have

suffered neurological symptoms. A few percent ended up with irreversible

Parkinson's-like conditions.

The problem is probably due to the fact that unprotected glutamine excites

neurons (in some people at least), sometimes to the point where they die

from the overexertion. A precursor of this -- or a symptom that it is

already happening -- is a headache. This is likely the problem with MSG

for many people. Based on biochemical similarities, it seems possible

that aspartic acid does the same thing. (Does anyone know of any studies

-- there wasn't much in the literature the last time I researched this a

few years ago?)

I am usually very conservative on my interpretation of data about

consumption and health, but this is one that really worries me. We are

performing a potentially very nasty experiment on tens of millions of

people (a lot more than are in Saudi Arabia ;-), because we don't know if

long term exposure might cause permanent neuron damage.

--Carl Phillips, PhD

University of Michigan School of Public Health

Dear All,

The debate about aspartame, aspartylphenylalanine-omethyl ester is

obviously gaining momentum and before getting down to the

nitty-gritty of neurotoxicity of aspartic acid, phenylalanine or

methanol you might like to consider a group of clinical scientists

who regularly feed patients intravenously with large amounts of

L-amino acids and small peptides. The literature is quite clear

about neurotoxicity of these infusion solutions. If, for example

plasma glutamic acid is raised by infusion of a parenteral solution

containing high levels of glutamic acid at a high infusion rate and

this leads to raised plasma glutamic acid concentrations then there

are documented cases of headaches, nausea and vomitting. The reason

for this is that the infusion rate exceeds the rate of conversion of

glutamic acid to glutamine. The moral is obvious, infuse at an

appropriate dose and rate (see 1. Stegink, L.D., Shepherd, J.A.,

Brummel, M.C., and Murray, L.M. Toxicity of protein hydrolysate

solutions: correlation of glutamate dose and neuronal necrosis to

plasma amino acid levels in young mice. Toxicology. 2:285-299, 1974,

1. Guzman, R.J., Irwin, R.G., Hansen, D.M., and Hidalgo, J. Influence

of dosage regimen on responses of the arcuate nucleus to subcutaneous

injection of a protein hydrolysate. Toxicology. 5:62-68, 1975., 1.

Grimble, G. Glutamine, glutamate and pyroglutamate - facts and

fantasies. Clin.Nutr. 12:66-69, 1993.).

The same considerations apply to possible neurotoxicty of intravenous

synthetic dipeptides. Now i.v. infusion is a really stiff test of

toxicity because it bypasses the gut and liver which modify plasma amino

acid composition. In addition, there is the possibility that these

peptides cross the blood brain barrier and exert all sorts of nasty

effect there. The reality is somewhat different as the following

paper suggests. The notes which follow are mine.

Himmelseher, S., Pfenninger, E., and Herrmann, P. Cerebrospinal and plasma amino acid concentrations after administration of iv glycyl-glutamine and glycyl-tyrosine containing amino acid solutions. J.Parent.Ent.Nutr. 20:281-286, 1996.

Intravenous synthetic dipeptides evoke a certain action potential amongst their exponents when it is discovered that glycylglutamine is an inhibitory neuropeptide derived from b-endorphin and that alanylglutamate is a potent inhibitor of arachidonic acid metabolism in vitro. If it were possible for small peptides to cross the blood-brain barrier then dipeptide-enriched TPN may cause damaging central neurological effects. This study investigated 30 elderly men who were undergoing prostate surgery. 15 received an infusion of standard amino acid solution, the other 15 received an isonitrogenous infusion containing additionally, glycylglutamine and gylcyltyrosine which accounted for 25% of the total amino acis. After 12 hours of infusion no dipeptide could be detected in CSF. Furthermore, despite infusion of a high load of glycyltyrosine, none could be detected in plasma. In contrast, glycylglutamine concentration was 308 +/- 111 umol/L at the end of the infusion. (cp. 705.4 +/- 114.5 umol/L glutamine, and 294.9 +/- 58.0 umol/L glycine). The only evidence that glycyltyrosine could have crossed the BBM was that CSF tyrosine was higher during peptide + amino acid infusion than amino acid infusion alone. However, the fact that the amino acid control solution contained no tyrosine may explain this. It can therefore be concluded that the BBM is extremely impermeable to these two synthetic dipeptides. It is probably impermeable to most small peptides because in order to deliver therapeutic peptides into the CSF, they require addition of a bulky lipohilic moiety or protection of the peptide bond from hydrolysis. There has been no evidence to date that the BBM contains the peptide transporters PEP-T1 or PEP-T2 which are capable of transporting dipeptides intact in the gut, kidney or placenta. It is for these reasons that synthetic dipeptides made entirely of L-amino acids have few safety implications for the brain, even when it is suggested that excessive consumption of low calorie Cola containing Aspartame (aspartylphenylalanine-Omethylester) causes brain cancer. The rapidity of hydrolysis of peptides to L-amino acids, makes them rather safe

Conclusion

Oral doses of aspartylphenylalanine-omethylester (50mg) are peanuts

in comparison with the huge doses of peptides which are presented to

the intestinal mucosa each day during protein digestion and

assimilation. I would defy anyone to detect the effects of these

doses on plasma phenylalanine and aspartic acid concentrations. If

these are not significantly changed then it is unlikely that these

individual amino acids will exert a neurotoxic effect on the brain or

other nervous tissue.

George Grimble PhD

Reader in Clinical Nutrition

Addictive Behaviour Centre

Roehampton Institute London