Neotame (Bulky aspartame)

About a year ago, I covered aspartame, the sometimes-maligned intense artificial sweetener. There is still a camp of substantial size insisting aspartame is deadly. Of course, it's widely sold, and still FDA-approved, etc. There is one group of people for whom aspartame is undisputedly dangerous, however: phenylketonurics.

Aspartame is metabolized via esterases and peptidases - esterases remove the methyl ester as methanol (tiny, tiny quantities, but this is a big part of why some people insist this is a dangerous sweetener). This yields a dipeptide of aspartic acid and phenylalanine. Peptidases cleave the molecule into separate aspartic acid and phenylalanine molecules. The phenylalanine is what's dangerous to phenylketonurics, who can't metabolize it and must eat a phenylalanine-limited diet (some suggest that free aspartic acid is a dangerous metabolite of the molecule, but that's another story). So here's how aspartame metabolism goes:


Enter neotame, the exact same molecule with a bulky side chain on the terminal nitrogen of the aspartic acid.


The bulky carbon tail doesn't impair the removal of the methyl ester, but it does keep it from being metabolized past the dipeptide! No phenylalanine metabolite:



More like this

By Myra L. Karstadt, Ph.D   Did you enjoy your acesulfame today?  How much did you eat?  Do you know whether acesulfame is safe to eat?  Those are not trick questions.  Acesulfame is currently one of the best-selling artificial sweeteners in America, but itâs likely that very few people even…
I only know about Phenylketonuria (PKU) because it is an elementary example of an autosomal recessive disease. Newborns are routinely tested, because those with PKU may develop mental retardation on a normal diet. That's about all I knew, but this from Wikipedia: If PKU is diagnosed early enough…
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This is just unbelievable. At a day care center in Arkansas, 10 kids were accidentally given windshield wiper fluid instead of Kool-Aid: Child welfare investigators plan to talk to the owner of an Arkansas daycare center where 10 children were sickened after they were given windshield wiper fluid…

And this is why the warning is on soda cans. Thanks.

more from The Independent,UK, Martin Hickman, re ASDA (unit of Wal-Mart Stores) and Marks & Spencer ban of aspartame, MSG, artificial chemical additives and dyes to prevent ADHD in kids: Murray 2007.05.16

See also:
ASDA (unit of Wal-Mart Stores WMT.N) and Marks & Spencer
will join Tesco and also Sainsbury to ban and limit aspartame,
MSG, artificial flavors dyes preservatives additives, trans fats,
salt "nasties" to protect kids from ADHD: leading UK media:
Murray 2007.05.15
combining aspartame and quinoline yellow, or MSG and
brilliant blue, harms nerve cells, eminent C. Vyvyan
Howard et al, 2005,
Felicity Lawrence: Murray 2005.12.21
50% UK baby food is now organic -- aspartame or MSG
with food dyes harm nerve cells, CV Howard 3 year study
funded by Lizzy Vann, CEO, Organix Brands,
Children's Food Advisory Service: Murray 2006.01.13

Health Medical

Asda and M&S to phase out food additives by end of year
By Martin Hickman, Consumer Affairs Correspondent
Published: 16 May 2007

Two of Britain's biggest food retailers have announced they will phase
out artificial colours and flavourings amid concern about the
substances' impact on children's behaviour.

Asda said its new guarantee meant that E-numbers would be removed from
all its own-brand products by the end of the year, while Marks &
Spencer promised to do the same for 99 per cent of its food in the
same time.

The sweetener Aspartame is also being removed

Some additives have been linked to temper tantrums, poor
concentration, hyperactivity, and allergic reactions in children.

A team from the University of Southampton has been researching the
effect of seven additives on three-year-olds and eight-to-nine year
olds in a study for the Food Standards Agency, which is expected to be
published later this year.
It is expected to raise concern about the combined chemical impact of
six colours studied --
tartrazine (E102),
ponceau 4R (E124),
sunset yellow (E110),
carmoisine (E122),
quinoline yellow (E104) and
allura red AC (E129) and
the preservative sodium benzoate (E211).

Announcing its move, Asda, Britain's third biggest supermarket, said
it will cost �30m to remove artificial colours, flavours, hydrogenated
fat or flavour enhancers, such as monosodium glutamate from its 9,000
own label food and soft drinks.

Artificial colours such as carmine (E120), erythrosine (E127),
quinoline (E104) and sulphite ammonia caramel (E150d) will be either
dropped outright or replaced with natural colours and fruit and

Artificial flavours will be replaced with natural flavours, such as

Aspartame is being replaced with Sucralose, a sweetener made from

Acknowledging that parental concern on additives is rising, Darren
Blackhurst, Asda's food trading director, said: "We know our
customers, particularly the mums and dads, are becoming more and more
concerned about what's in the food that they buy."

M&S said that 4,455 food products and soft drinks would be free of
artificial colours and flavours by the end of 2007.
The chain, which is still working on ways of reformulating 45 items of
confectionery and cola drinks, has already dropped monosodium
glutamate and tartrazine from its products.

Additives particularly associated with concerns about food intolerance
and children's diets such as Ponceau 4R and Sunset Yellow are often
used in cakes and bakery.
"Removing artificial colourings and flavourings from our cakes was
really important for us, as our birthday cakes are enjoyed by parents
and children alike," said a spokesman. The artificial colours
quinoline, brilliant blue, allura red, and carmosine once used in
birthday cakes had been replaced with beetroot and paprika natural
colours, the store said.

M&S's director of technology, David Gregory, said 95 per cent of its
foods would be free from artificial colourings and flavourings by

Nick Giovannelli, the project director of the Hyperactive Children's
Support Group, welcomed the news and said the retailer's step was "a
significant undertaking and a big commitment."

A brief guide to E-numbers

Although all E-numbers have been tested and approved for use within
the EU, concerns about them persist.

Researchers have associated problems with the following:

Tartrazine (E102)
Colouring found in sweets, drinks and other food. Potential effects
include headaches

Ponceau 4R (E124)
Colouring found in cake mixes and dessert toppings. Potential effects
include hives, hay fever and hyperactivity

Sunset Yellow (E110)
Colouring found in fruit juice, cereal and confectionery. Potential
effects include hay fever, eczema and hyperactivity

Carmoisine (E122)
Colouring found in sweets and marzipan. Potential effects include

Quinoline Yellow (E104)
Colouring found in processed foods, lipsticks, soap and toothpaste.
Potential effects include asthma, hives and skin rash

Allura Red AC (E129)
Colouring found in cereals and biscuits. Potential effects include
allergic reactions, asthma and hyperactivity

� 2007 Independent News and Media Limited

David Gregory Head of Technology, Food, Marks and Spencer [ photo ]

David Gregory David has worked with Marks & Spencer for 23 years and
is responsible for ensuring Marks & Spencer's foods are technically
innovative, safe and consistently meet high quality standards.

He is responsible for a team of over 70 technical specialists in
fields as diverse as animal welfare, pesticides, fish sourcing,
nutrition and material science and ensuring that they are fully
integrated into the commercial direction of the business.

He chairs the Marks & Spencer Corporate Social Responsibility (CSR)
Forum which facilities the management and integration of CSR into day-
to-day decision making and business systems.

David is a Chartered Scientist, a Chartered Environmental Health
Practitioner and a Fellow of the Institute of Food Science and

David has served on a number of Government bodies including DEFRA's
Research Priorities Group, The Chemistry Leadership Council and is
currently Chairman of DEFRA's Quality and Innovation Link Programme.

David is also a Governor of the Institute of Food Research at

Institute of Food Research
Norwich Research Park, Colney, Norwich NR4 7UA, UK
Tel: +44(0)1603 255000 Fax: +44(0)1603 507723

formaldehyde as a potent unexamined cofactor in cancer research --
sources include methanol, dark wines and liquors, aspartame, wood and
tobacco smoke: IARC Monographs on the Evaluation of Carcinogenic Risks
to Humans implicate formaldehyde in #88 and alcohol drinks in #96:
some related abstracts: Murray 2007.05.15

aspartame (methanol, formaldehyde) toxicity research summary: Rich
Murray 2007.05.15

One liter aspartame diet soda, about 3 12-oz cans,
gives 61.5 mg methanol,
so if 30% is turned into formaldehyde, the formaldehyde
dose of 18.5 mg is 37 times the recent EPA limit of
0.5 mg per liter daily drinking water for a 10-kg child:
2007.01.05 [ does not discuss formaldehyde from methanol
or aspartame ] comments

"Of course, everyone chooses, as a natural priority,
to actively find, quickly share, and positively act upon
the facts about healthy and safe food, drink, and

Rich Murray, MA Room For All
505-501-2298 1943 Otowi Road, Santa Fe, New Mexico 87505
group with 74 members, 1,429 posts in a public, searchable archive
aspartame groups and books: updated research review of
2004.07.16: Murray 2006.05.11
Aspartame Controversy, in Wikipedia democratic
encyclopedia, 72 references (including AspartameNM # 864
and 1173 by Murray), brief fair summary of much more
research: Murray 2007.01.01

Dark wines and liquors, as well as aspartame, provide
similar levels of methanol, above 120 mg daily, for
long-term heavy users, 2 L daily, about 6 cans.

Within hours, methanol is inevitably largely turned into
formaldehyde, and thence largely into formic acid -- the
major causes of the dreaded symptoms of "next morning"

Fully 11% of aspartame is methanol -- 1,120 mg aspartame
in 2 L diet soda, almost six 12-oz cans, gives 123 mg
methanol (wood alcohol). If 30% of the methanol is turned
into formaldehyde, the amount of formaldehyde, 37 mg,
is 18.5 times the USA EPA limit for daily formaldehyde in
drinking water, 2.0 mg in 2 L average daily drinking water.
methanol products (formaldehyde and formic acid) are main
cause of alcohol hangover symptoms [same as from similar
amounts of methanol, the 11% part of aspartame]:
YS Woo et al, 2005 Dec: Murray 2006.01.20
methanol (formaldehyde, formic acid) disposition:
Bouchard M et al, full plain text, 2001: substantial
sources are degradation of fruit pectins, liquors,
aspartame, smoke: Murray 2005.04.02

"According to model predictions, congruent with the data in the
literature [Dorman et al., 1994; Horton et al., 1992], a certain
fraction of formaldehyde is readily oxidized to formate,
a major fraction of which is rapidly converted to CO2 and exhaled,
whereas a small fraction is excreted as formic acid in urine.

However, fits to the available data in rats and monkeys of Horton et
al. [1992] and Dorman et al. [1994] show that, once formed, a
substantial fraction of formaldehyde is converted to unobserved forms.

This pathway contributes to a long-term unobserved compartment.

The latter, most plausibly, represents either the formaldehyde that
[directly or after oxidation to formate] binds to various endogenous
molecules [Heck et al., 1983; R�e, 1982] or is incorporated in the
tetrahydrofolic-acid-dependent one-carbon pathway to become the
building block of a number of synthetic pathways
[R�e, 1982; Tephly and McMartin, 1984].

That substantial amounts of methanol metabolites or by-products are
retained for a long time is verified by Horton et al. [1992] who
estimated that 18 h following an iv injection of 100 mg/kg of
14C-methanol in male Fischer-344 rats,
only 57% of the dose was eliminated from the body.

>From the data of Dorman et al. [1994] and Medinsky et al. [1997],
it can further be calculated that 48 h following the start
of a 2-h inhalation exposure to 900 ppm of 14C-methanol vapors
in female cynomolgus monkeys,
only 23% of the absorbed 14C-methanol was eliminated from the body.

These findings are corroborated by the data of Heck et al. [1983]
showing that 40% of a 14C-formaldehyde inhalation dose remained
in the body 70 h postexposure.

In the present study, the model proposed rests on acute exposure
data, where the time profiles of methanol and its metabolites were
determined only over short time periods
[a maximum of 6 h of exposure and a maximum of 48 h postexposure].

This does not allow observation of the slow release from the long-term

It is to be noted that most of the published studies on the detailed
disposition kinetics of methanol regard controlled short-term
[iv injection or continuous inhalation exposure over a few hours]
methanol exposures in rats, primates, and humans
[Batterman et al., 1998; Damian and Raabe, 1996;
Dorman et al., 1994; Ferry et al., 1980; Fisher et al., 2000;
Franzblau et al., 1995; Horton et al., 1992; Jacobsen et al., 1988;
Osterloh et al., 1996; Pollack et al., 1993; Sedivec et al., 1981;
Ward et al., 1995; Ward and Pollack, 1996].

Experimental studies on the detailed time profiles following
controlled repeated exposures to methanol are lacking."
brain cell tangles and neuron death similar to Alzheimers
via low dose formaldehyde from methanol,
Chunlai Nie, Rongqiao He et al, China, 2007.01.23 BMC
Neuroscience 28 pages, 63 references: Murray 2007.01.24
Coca-Cola carcinogenicity in rats, Ramazzini Foundation,
F Belpoggi, M Soffritti, Annals NY Academy Sciences
2006 Sept, parts of 17 pages: Murray 2006.12.02
Fiorella Belpoggi & Morando Soffritti of Ramazzini
Foundation prove lifetime carcinogenicity of Coca-Cola,
aspartame, and arsenic, Annals of the NY Academy of
Sciences: Murray 2006.11.28
Bristol, Connecticut, schools join state program to limit
artificial sweeteners, sugar, fats for 8800 students,
Johnny J Burnham, The Bristol Press: Murray 2006.09.22
Connecticut bans artificial sweeteners in schools,
Nancy Barnes, New Milford Times: Murray 2006.05.25
soft drinks and adolescent hyperactivity, mental distress,
conduct problems, Lars Lien, Nanna Lien, Sonja Heyerdahl,
Mayne Thoresen, Espen Bjertness 2006 Oct., A J Pub Health:
Murray 2006.10.21
healthy diet, vitamins, and fish oil help reduce
depression and violence, studies by Joseph Hibbeln,
Bernard Gesch, and Stephen Schoenthaler, articles by
Felicity Lawrence in UK Guardian Unlimited and Pat
Thomas in The Ecologist: Murray 2006.10.21
carcinogenic effect of inhaled formaldehyde, Federal
Institute of Risk Assessment, Germany -- same safe level
as for Canada: Murray 2006.06.02
Home sickness -- indoor air often worse, as our homes
seal in pollutants [one is formaldehyde, also from the 11%
methanol part of aspartame],
Megan Gillis, Murray 2006.06.01
effect of aspartame on oncogene and suppressor gene expressions in
mice, Katalin Gambos, Istvan Ember, et al, University of Pecs,
Hungary, In Vivo 2007 Jan; scores of their relevant past studies since
1977: Murray 2007.04.14
toxicity in rat brains from aspartame, Vences-Mejia A,
Espinosa-Aguirre JJ et al 2006 Aug: Murray 2006.09.06
aspartame rat brain toxicity re cytochrome P450 enzymes,
especially CYP2E1, Vences-Mejia A, Espinosa-Aguirre JJ
et al, 2006 Aug, Hum Exp Toxicol: relevant abstracts re
formaldehyde from methanol in alcohol drinks:
Murray 2006.09.29
combining aspartame and quinoline yellow, or MSG and
brilliant blue, harms nerve cells, eminent C. Vyvyan
Howard et al, 2005,
Felicity Lawrence: Murray 2005.12.21
50% UK baby food is now organic -- aspartame or MSG
with food dyes harm nerve cells, CV Howard 3 year study
funded by Lizzy Vann, CEO, Organix Brands,
Children's Food Advisory Service: Murray 2006.01.13
all three aspartame metabolites harm human erythrocyte
[red blood cell] membrane enzyme activity, KH Schulpis
et al, two studies in 2005, Athens, Greece, 2005.12.14:
2004 research review, RL Blaylock: Murray 2006.01.14
NIH NLM ToxNet HSDB Hazardous Substances Data Bank
inadequate re aspartame (methanol, formaldehyde,
formic acid): Murray 2006.08.19
HSDB Hazardous Substances Data Bank: Aspartame

DMDC: Dimethyl dicarbonate 200mg/L in drinks adds methanol
98 mg/L ( becomes formaldehyde in body ): EU Scientific
Committee on Foods 2001.07.12: Murray 2004.01.22
Aspartame Toxicity Information Center Mark D. Gold
12 East Side Drive #2-18 Concord, NH 03301 603-225-2100
"Scientific Abuse in Aspartame Research"
safety of aspartame Part 1/2 12.4.2: EC HCPD-G SCF:
Murray 2003.01.12 EU Scientific Committee on Food,
a whitewash
Mark Gold exhaustively critiques European Commission
Scientific Committee on Food re aspartame ( 2002.12.04 ):
59 pages, 230 references
RTM: Smith, Terpening, Schmidt, Gums:
full text: aspartame, MSG, fibromyalgia 2002.01.17
Jerry D Smith, Chris M Terpening,
Siegfried OF Schmidt, and John G Gums
Relief of Fibromyalgia Symptoms Following
Discontinuation of Dietary Excitotoxins.
The Annals of Pharmacotherapy 2001; 35(6): 702-706.
Malcolm Randall Veterans Affairs Medical Center,
Gainesville, FL, USA.
BACKGROUND: Fibromyalgia is a common rheumatologic
disorder that is often difficult to treat effectively.
CASE SUMMARY: Four patients diagnosed with fibromyalgia
syndrome for two to 17 years are described.
All had undergone multiple treatment modalities with
limited success.
All had complete, or nearly complete,
resolution of their symptoms within months after
eliminating monosodium glutamate (MSG)
or MSG plus aspartame from their diet.
All patients were women with multiple comorbidities
prior to elimination of MSG.
All have had recurrence of symptoms whenever MSG
is ingested.

Siegfried O. Schmidt, MD Asst. Clinical Prof.
Community Health and Family Medicine, U. Florida,
Gainesville, FL Shands Hospital West Oak Clinic
Gainesville, FL 32608-3629 352-376-5071
formaldehyde toxicity: Thrasher & Kilburn: Shaham: EPA:
Gold: Wilson: CIIN: Murray 2002.12.12

Thrasher (2001): "The major difference is that the
Japanese demonstrated the incorporation of FA and its
metabolites into the placenta and fetus.
The quantity of radioactivity remaining in maternal and
fetal tissues at 48 hours was 26.9% of the administered
dose." [ Ref. 14-16 ]

Arch Environ Health 2001 Jul-Aug; 56(4): 300-11.
Embryo toxicity and teratogenicity of formaldehyde.
[100 references]
Thrasher JD, Kilburn KH.
Sam-1 Trust, Alto, New Mexico, USA. full text full text
Jack Dwayne Thrasher, Alan Broughton, Roberta Madison.
Immune activation and autoantibodies in humans with
long-term inhalation exposure to formaldehyde.
Archives of Environmental Health. 1990; 45: 217-223.
PMID: 2400243

In molecular chemistry it would be one molecule of aspartic acid to one molecule of methanol to one molecule of phenylalanine. That's a lot of free methyl alcohol. By weight its 10%. The Trocho Study showed that the formaldehyde, converted from this free methyl alcohol embalms living tissue. Most of the toxicity is in the liver but there is substantial toxicity in the brain, retina, adipoise tissue (fat cells) and kidneys.

The propaganda used by the manufacturers is that there is just a small amount of methanol in aspartame, and there is more in tomato juice. Of course, this is ludicrous thinking because in fruits and vegetables there is always ethanol which is the classic antidote for methanol toxicity. There is no ethanol in aspartame. Further, methanol binds to pectin.

There is a 1000 page medical text called Aspartame Disease: An Ignored Epidemic, by H. J. Roberts, M.D. that goes into the free methyl alcohol issue, and the many neurodegenerative diseases and tumors triggered by aspartame. It's also discussed in "Excitotoxins: The Taste That Kills" by neurosurgeon Russell Blaylock, M.D.,

In the aspartame documentary, Sweet Misery: A Poisoned World, they go to a prison to interview Diane Fleming. Her athletic husband died with methanol poisoning. Even though she called the police at the urging of her physician and passed 3 lie detector tests, she has been imprisoned for 4 years.

Some people are now using Splenda, but this is a chlorocarbon poison. We call it DDT-Lite. The Splenda manufacturers have just lost two fights, in France and Philadelphia, and must relabel.

There is a safe sweetener, Just Like Sugar, made from chicory and orange peel you can get at Whole Foods or Wild Oats.

Dr. Betty Martini, D.Hum, Founder
Mission Possible International
9270 River Club Parkway
Duluth, Georgiua 30097
770 242-2599,
Aspartame Toxicity Center,

By Dr. Betty Mart… (not verified) on 19 May 2007 #permalink

"The propaganda used by the manufacturers is that there is just a small amount of methanol in aspartame, and there is more in tomato juice. Of course, this is ludicrous thinking because in fruits and vegetables there is always ethanol which is the classic antidote for methanol toxicity."

The above tells me that you have no clue what you are talking about. Scratch that the Dr honorific tells me that you are supposedly smart and educated thus could know what you are talking about, so you are lying.

In the liver methanol is oxidized by an enzyme to formic acid. The same enzyme oxidizes ethanol (booze) to acetic acid. It is the toxic effects formic acid which causes harm. The problem is that in humans (and all other monkeys) the metabolic pathway that breaks down formic acid is defective and we can only process a very limited quantity per hour. In acute methanol poisoning, formic acid builds up in the blood which is toxic to the cells in the optic nerve and thus makes you go blind. In more extreme cases death is caused by acidosis.

Ethanol (booze) is used in cases of acute methanol poisoning because it hogs the metabolic pathway that converts methanol to formic acid thus reducing the rate that the methanol is converted. The idea being as long as the amount of formic acid produced is small the body can deal with it safely. So the idea that the small amounts of ethanol in tomato soup protect against the small amounts of methanol in tomato soup based on it's use in treating acute methanol poising is silly, because the reason you use ethanol is simply to slow down the rate at which methanol is processed. It isn't an antidote in the normal sense of the word and therefor your use of the word that context is disingenuous.

Your body's own demethylation processes naturally create on the order of a handful of migs of formaldehyde a day. This far outweighs anything that you might get from aspartame; and anyways most of the mass of nutrasweet is a dextrin anyway.

Don't take any advice from a D.Hum who poses as a scientist. How many times have you had 10~20ccs of exposure to methanol on the bench with no effect? Or, heavens me, chloroform (which gets catabolized to carbon monoxide in your body)

If there's anything you should worry about in aspartame, it's DKP. But even this, has no established effect.

wow this has brought out the spammers... to the above poster saying its the methanol from the ester at fault - lets not be silly about it. for starters, orange juice is anywhere up to 3% v/v methanol. so a glass of orange juice contains 3000 mg of methanol, yet we don't see many protests about that (compare a can of aspartame containing drink, with 20 mg, 1/150th of the amount). so replacing asparatame with orange based sweetners is a little dim if your stated aim is to reduce methanol exposure. not that i think it is anything to worry about anyway

fear sells. the quantity of aspartame sweetener needed to cause damage solely due to the methanol it metabolizes is not something any sane human would want to put on their food/drink. in fact, the amount they put in pop is low enough [less than a gram] that the sugar probably causes far more harm than any methnaol does. for that matter, methyl esters can be found in fruits but it doesnt stop people from thinking they are good- they just are not aware of it. im not saying there isnt a reason to limit what you drink/eat for health reasons, im just saying dont be ignorant on the subject- go a little farther than "someone said it was bad" ask why and how...

Orange juice is up to 3% methanol? Whats the ethanol percentage in an American beer? Considering the amount of ethanol necessary for intoxication, how much high-MeOH orange juice does it take to make you fail a drunk driving test? "No, Officer, Ive been drinking OJ all night"

Yah that orange juice statistic seems fishy to me. I would imagine that one could both smell and taste 3% methanol. I read that the lethal dose of MeOH is 1-2 mL/kg. So in a 150lb adult (68.2kg) that means the lethal dose is between 68 and 136mL (and an order of magnitude less for blindness, etc).

That means one could expect to die from between 2.2 and 4.4 L of orange juice. Now I know that isn't the average human dosage, but I am quite certain that my brother consumed at least 2 liters/day when he was in high school. He's not dead or blind.

By Vince Noir (not verified) on 22 May 2007 #permalink

To me, aspartame, acesulfame-K, and every other phenylalanine-based sweetener do not taste sweet, beyond about the first half-second or so; the taste "morphs" almost as fast as it hits my tongue, to become something intensely bitter/sour and horrible, which seems to cling to my tongue for hours no matter what I do. What the heck is the chemistry behind that?

By Luna_the_cat (not verified) on 22 May 2007 #permalink

Aspartame is awful! Sugar is very bad but at least it doesn't cause all those cancers and tumors. And no one ever sues these companies? I know two diet coke drinkers that went through chemotherapy and pain.