K. Paul Stoller, M.D., FAAP
ABSTRACT
The artificial sweetener aspartame (6-methyl-1,2,3-oathiazine-4[3H]—one-2,2-dioxide salt of Lphenlalanyl-
2-methl-L-alpha-aspartic acid), is consumed, primarily in beverages, by a very large number
of Americans, causing significant elevations in plasma and brain phenylalanine levels. It is very likely that
aspartame, which was once considered a new chemical warfare agent by the US military has resulted in
an enormous toll in illness, disability, and death. The failure of the medical profession and many
governmental and other public health agencies to concern themselves with this ignored epidemic
parallels what has taken place with the use of Thimerosal in vaccines.
As with Thimerosal, the most grievous offense of the illegal approval and continued use of
aspartame pertain to the damage that this chemical can induce in infants and children. Moreover,
aspartame could affect subsequent generations born to mothers who were misled about the safety of this
and related chemicals. This paper will discuss the role of both aspartame and Thimersol in the pathology
of neurodegenerative disease.
INTRODUCTION
The chemicals we ingest may affect more than our own health.
They affect the health and vitality of future generations.
The danger is that many of these chemicals may not harm us
but will do silent violence to our children.
Senator Abraham S. Ribicoff (l971)
The artificial sweetener aspartame (6-methyl-1,2,3-oathiazine-4[3H]—one-2,2-dioxide salt of Lphenlalanyl-
2-methl-L-alpha-aspartic acid), is consumed, primarily in beverages, by a very large number
of Americans, causing significant elevations in plasma and brain phenylalanine levels. It is very likely that
aspartame, which was once considered a new chemical warfare agent by the US military has resulted in
an enormous toll in illness, disability, and death. The failure of the medical profession and many
governmental and other public health agencies to concern themselves with this ignored epidemic
parallels what has taken place with the use of Thimerosal in vaccines.As with Thimerosal, the most grievous offense of
the illegal approval and continued use of aspartame pertain to the damage that this chemical can induce in infants and
children. Moreover, aspartame could affect subsequent generations born to mothers who were misled about the safety of
this and related chemicals.
THE HISTORY OF ASPARTAME
In October 1980 the Public Board of Inquiry (PBOI) impaneled by the FDA to evaluate aspartame
safety found that the chemical caused an unacceptable level of brain tumors in animal testing. Based on
this fact, the PBOI ruled that aspartame should not be added to the food supply.
This ruling culminated 15 years of regulatory ineptitude, chicanery, and deception by the FDA and
the Searle drug company, aspartame’s discoverer and manufacturer (acquired by Monsanto in 1985), and
then started the ball rolling on two additional decades of maneuvering, manipulating, and dissembling by
the FDA, Searle, and Monsanto.
In 1965, a Searle scientist licked some of a new ulcer drug from his fingers and discovered the
sweet taste of aspartame. Searle’s early tests showed that aspartame produced microscopic holes and
tumors in the brains of experimental mice, epileptic seizures in monkeys, and was converted into
formaldehyde.
Despite of the information in its files, in 1974 the FDA approved aspartame as a dry-foods
additive. The renowned brain researcher, John Olney from Washington University in St. Louis reviewed
the available data and discovered two studies showing brain tumors in rats and petitioned the FDA for a
public hearing. Dr. Olney had already shown that aspartic acid (part of the aspartame molecule) caused
holes in the brains of rats. Aspartame also is one part phenylalanine, and one part methyl (or wood)
alcohol.
The FDA prevailed on Searle to refrain from marketing aspartame until after completion of the
hearing. In 1975, an FDA Special Commissioner’s Task Force reported serious problems with Searle’s
research that was conducted in a manner so flawed as to raise doubts about aspartame safety and create
the possibility of serious criminal intent. The FDA asked the US Attorney for Chicago to seek a grand jury
review of the monkey seizure study, but he let the statute of limitations run out, then (along with two
aides) proceeded to join Searle’s law firm.
In October 1980, the PBOI blocked aspartame marketing until the tumor studies could be
explained, and unless the commissioner overruled the board, the matter was closed. In November 1980,
Ronald Reagan was elected President and Donald Rumsfeld, president of Searle, joined the Reagan
White House. In January 1981, Rumsfeld told a sales meeting that he would call in his chips and get
aspartame approved – Dr. Arthur Hull Hayes, Jr. a pharmacologist and Defense Department contract
researcher became FDA commissioner and his first decision was to defy FDA advisors and approve
aspartame for dry foods. His last decision, before leaving his post because of improprieties (taking gifts
from Pharmaceutical companies) was to approve aspartame for soft drinks in 1983. He immediately
became senior medical advisor to Searle’s public relations firm for $1000/day. Rumsfeld received a $12
million bonus.
As soon as soft drinks with Nutrasweet began to be consumed, complaints began to arrive at the
FDA – dizziness, blurred vision, headaches, and seizures. The complaints were more serious than the
FDA has ever received on any food additive. In 1985, the FDA asked the Centers for Disease Control
(CDC) to review the first 650 complaints (there are now tens-of-thousands). The CDC found that the
symptoms in approximately 25% of cases stopped and then restarted with discontinuing the use of
aspartame and then restarting its use. The day the FDA released the CDC report, which they discounted,
Pepsi Cola announced its switch to aspartame with a worldwide media blitz.
At the same time, human brain tumors rose 10% and previously benign tumors turned virulent. An
FDA deputy commissioner said the data posed no problem; he then became Vice President of clinical
research for Searle.
Four hundred aspartame studies were done between 1985 and 1995. All of the studies Searle
paid for found no problem, but 100% of the studies paid for by non-industry sources raised questions.
NEUROTOXINS AS A FOOD ADDITIVE
The manifestations of aspartame disease in young children are myriad. They include severe
headache, convulsions, unexplained visual loss, rashes, asthma, gastrointestinal problems, obesity,
marked weight loss, hypoglycemia, diabetes, addiction (probably largely due to the methyl alcohol),
hyperthyroidism, and a host of neuropsychiatric features. The latter include extreme fatigue, irritability,
hyperactivity, depression, antisocial behavior (including suicide), poor school performance, the
deterioration of intelligence, and brain tumors.
An average aspartame-sweetened beverage would have a conservative aspartame content of
about 555 mg/liter, and therefore, a methanol equivalent of 56 mg/liter (56 ppm). For example, if a 25 kg
child consumed on a warm day, after exercising, two-thirds of a two-liter bottle of soft drink sweetened
with aspartame, that child would be consuming over 732 mg of aspartame (29 mg/kg). This alone
exceeds what the FDA considers the 99+-percentile daily consumption level of aspartame. The child
would also absorb over 70mg of methanol from that soft drink. This is almost ten times the Environmental
Protection Agency's recommended daily limit of consumption for methanol.
To look at the issue from another perspective, the literature reveals death from consumption of
the equivalent of 6 gm of methanol. It would take 200 12 oz. cans of soda to yield the lethal equivalent of
6 gm of methanol. According to FDA regulations, compounds added to foods that are found to cause
some adverse health effect at a particular usage level are actually permitted in foods only at much lower
levels. The FDA has established these requirements so that an adequate margin of safety exists to
protect particularly sensitive people and heavy consumers of the chemical. Section 170.22 of Title 21 of
the Code of Federal Regulations mandates that this margin of safety is 100-fold below the "highest noeffect"
level. If death has been caused by the methanol equivalent of 200 12 oz. cans of aspartame
sweetened soda, one hundredth of that level would be two cans of soda. The relationship of the lethal
dose to the "highest no effect" level has tragically not been determined for methanol but assuming very
conservatively that the level is one hundredth of the lethal dose, the FDA regulations should have limited
consumption to approximately 24 ounces of aspartame-sweetened soft drink per day.
The high ethanol/methanol ratio of alcoholic beverages must have a very significant protective
effect given that ethanol antidotes methanol, so ignore the argument that methanol already exists in
alcoholic beverages without untoward effects. This is absurd given that alcoholics have a much higher
incidence of cancer and other degenerative diseases, none of which can be attributed to ethanol alone. In
aspartame, the methanol is released, once in the body, unfettered by ethanol to be a pure poison.
The FDA allows a lower safety margin only when "evidence is submitted which justifies use of a
different safety factor." (21.C.F.R.170.22) No such evidence has been submitted to the FDA for methanol.
Thus, not only have the FDA's requirements for acute toxicity not been met, but also, no demonstration of
chronic safety has been made. The fact that methyl alcohol appears in other natural food products does
not exonerate its presence in aspartame, but increases greatly the danger of chronic toxicity developing
by adding another unnatural source of this dangerous cumulative toxin to the food system.
Since the amino acid phenylalanine can be neurotoxic, and can affect the synthesis of inhibitory
monoamine neurotransmitters, the phenylalanine in aspartame can mediate neurologic effects.
Chemicals and compounds that affect physiological systems are classified as drugs by the Food
and Drug Administration (FDA), and are subject to considerably more demanding regulatory procedures
than food constituents. Moreover, because food additives must be shown to be physiologically inert in
order to win initial FDA approval, once they have obtained this approval they are exempt from the
requirement, imposed on all drugs, that their safety be continuously monitored. Companies that
manufacture and use approved food additives are not obligated to monitor adverse reactions associated
with consumption of their product, nor to submit to the FDA reports of such adverse reactions; they are
also not required to carry out further government-mandated research programs to affirm their product's
safety.
However, the consumption of a number of food additives can cause physiological effects, which
include, for some, modification of the chemical composition and functional activities of the nervous
system.
1, 2 Moreover, in the case of aspartame these neural effects were largely unexplored prior to the
compound's addition to the food supply, and were not a factor in calculating the quantities that individuals
can safely consume (the ADI, or acceptable daily intake, currently set for aspartame at 50 mg/kg).
3 The effects of aspartame, and of certain other food additives, like caffeine, involve subtler biochemical
changes, as well as functional consequences that are demonstrable only in specially treated animals
4 (and possibly, by extrapolation, only in especially vulnerable people).
Although these physiological effects are unrelated to the reason that aspartame was placed in
food, they have important health implications given the very large number of people who consume
aspartame. If only 1% of the 100,000,000 Americans thought to consume aspartame ever exceed the
sweetener's ADI, and if only 1% of this group happen coincidentally to have an underlying disease that
makes their brains vulnerable to the effects of an aspartame-induced rise in brain phenylalanine levels,
then the number of people who might manifest adverse brain reactions attributable to aspartame would
still be about 10,000, a number on the same order as the number of neurologically related consumer
complaints already registered with the FDA and other federal agencies.
5, 6
Doses of aspartame, which are within the range actually consumed by some people can affect
the chemical composition of the brain, and thereby contribute to particular CNS sidle effects, including
headaches,
7 inappropriate behavior responses,8, 9 and seizures.10, 11
The major bio-chemical effect of aspartame, in humans, is to raise blood and, presumably, brain
phenylalanine levels
12; in contrast, its main effect in rodents is to raise blood (and brain) tyrosine levels,13,
14
and tyrosine is often the antidote to phenylalanine's effects on the brain. This species difference makes
questionable the extrapolation of much of the rodent literature to humans.
The existence of this major metabolic difference between rodents and people underscores the
point that only large-scale human studies could determine whether or not aspartame is risk-free. But
aspartame cannot be shown to be risk-free, and its regulatory classification should be changed, for
example, to that of a drug.
The Effect of Aspartame on Brain Phenylalanine Levels
The consumption of an aspartame-laden food or beverage contributes to the plasma the three
natural compounds contained within the aspartame molecule: the amino acids phenylalanine and aspartic
acid, and the alcohol methanol,
15 as well as various peptides (like B-aspartame or the aspartylphenylalanine
diketopoperazine that are formed from it spontaneously, on the shelf, or enzymatically,
after its consumption).
Plasma phenylalanine levels are not regulated by any known homeostatic mechanism. At any
particular time plasma levels simply reflect the amounts of phenylalanine being absorbed from the foods
most recently eaten.
16, 17 Consumption of the ADI aspartame dose is thus able to elevate plasma
phenylalanine levels about threefold.
18
Consumption of dietary phenylalanine in the usual way, as a constituent of protein, does not
elevate brain phenylalanine levels.
19 This is because the protein elevates plasma levels of the other large
neutral amino acids (LNAA) (valine, leucine, isoleucine, tryptophan, tyrosine) more than those of
phenylalanine. These other amino acids are considerably more abundant than phenylalanine in the
protein, and the branched-chain amino acids, unlike phenylalanine, are largely unmetabolized when they
pass through the portal circulation.
20
In contrast, consumption of phenylalanine in the form of aspartame, with the other LNAA, that are
always present in proteins, elevates plasma phenylalanine levels without elevating those of the other
LNAA, this causes marked elevations in the plasma phenylalanine ratio (the ratio of the plasma
phenylalanine concentration to the summed concentrations of the other LNAA).
13 Aspartame is the only known phenylalanine-containing food that elevates this ratio.
An elevation in the plasma phenylalanine ratio causes a parallel rise in brain phenylalanine levels,
since a single transport macromolecule within the endothelial cells lining the brain's capillaries mediates
the uptake of all of the LNAA; this macromolecule is unsaturated at normal plasma LNAA levels; and
each of the LNAA's compete for attachment to it, their success depending on their relative affinities for it
and their plasma concentration relative to those of its competitor.
4, 21 The elevation in the plasma phenylalanine ratio also tends to reduce the corresponding ratios for the LNAA, thus decreasing their brain uptakes and tending to lower their brain levels.
13 [Aspartame fails to lower brain tyrosine levels in the rat because the rat's liver hydroxylates dietary phenylalanine so rapidly that plasma tyrosine levels rise even more than those of plasma phenylalanine.
13, 14 However, in humans dietary aspartame probably reduces brain tyrosine uptake.]
If an aspartame-containing beverage is consumed along with, for example, a carbohydrate-rich,
protein-poor dessert food, its effect on brain phenylalanine is doubled.
13 This is because the insulin secretion elicited by the carbohydrate selectively lowers plasma levels of the branched-chain amino acids (by facilitating their uptake into skeletal muscle), without having much of an effect on plasma phenylalanine; this increases the effect of the aspartame on the plasma phenylalanine ratio.
17 A similar doubling may occur if the eater happens to be one of the perhaps 10 million Americans who are, without
knowing it, heterozygous for the phenylketonuria (PKU) gene.
22
Once within brain, neurons producing certain neurotransmitters, such as dopaminergic
nigrostriatal cells, the excess phenylalanine can inhibit enzymes (like tyrosine hydroxylase) needed to
synthesize the neurotransmitters. Excess circulating phenylalanine can also diminish the production of
brain catecholamines and serotonin by competing with their precursor amino acids for transport across
the blood-brain barrier. Hence, physiological processes that depend on the sustained release of
adequate quantities of these transmitters can be affected. One such process creates greater sensitivity to seizures.
23 In humans, aspartame, regardless of dose, causes greater increases in plasma (and brain) phenylalanine than tyrosine. (As shown below,sufficiently high aspartame doses, which transiently exceed the liver's capacity to hydroxylate
phenylalanine, can also potentiate seizures in rodents, whether these seizures are generated by drugs, electroshock, or inhalation of fluorothyl.)All of these relationships have now been demonstrated; most recently, the ability of phenylalanine to suppress dopamine release.
24
Aspartame and Seizure Susceptibility
To determine whether aspartame intake could modify seizure susceptibility, perhaps by
increasing plasma and brain phenylalanine levels, one of our group has examined its effects on the
incidence of seizures, their speed of onset, and the amount of convulsant required to produce the
seizures among mice given treatments known to be epileptogenic.25 In general, animals received various
aspartame doses 1 hr before a CD50 dose of the seizure-inducing treatment, or a fixed aspartame dose 1
hr before various doses of the treatment. The number of animals in each treatment group exhibiting
seizures in the next 60 minutes were counted (when the treatment was pentylenetetrazole), or the time
passing until a given animal had a seizure (when the treatment was inhaled fluorothyl or electroshock).
The aspartame doses used were those shown, in the mice, to cause blood phenylalanine levels to rise
by at least as much as blood tyrosine, i.e., doses of 1000 mg/kg or greater.
Aspartame administration produced a dose-dependent increase in seizure frequency among
animals subsequently receiving the CD50 dose of pentylenetetrazole (PTZ) (65 mg/kg) (Fig. 2). At the
1000 and 2000 mg/kg aspartame doses, 78 and 100% of the animals experienced seizures, compared
with 50% in the water-pretreated group. Other mice pretreated with a fixed dose (1000 mg/kg) of
aspartame, or with water, and given various doses (50-75 mg/kg) of PTZ an hour later exhibited a
significant leftward shift of the PTZ dose response curve (Fig. 3). Enhanced susceptibility to PTZ-induced
seizures was also observed among mice pretreated with phenylalanine (in doses equimolar to effective
aspartame doses), but not among animals pre-treated with aspartic acid or methanol. Co-administration
with aspartame of the LNAA valine, which competes with phenylalanine for passage across the bloodbrain
barrier,4, 21 protected mice from the seizure-promoting effects of the sweetener; in contrast,
alanine, an amino acid which does not compete with phenylalanine for brain uptake, failed to attenuate
aspartame's effect on PTZ-induced seizures.
The evidence does not indicate that aspartame itself causes seizures; but rather that it promotes
seizures in animals that are already at risk (that is, animals treated with PTZ, fluorothyl, or electroshock).
In a similar manner, it is possible that doses of the sweetener that cause a sufficient increase in brain
phenylalanine might increase seizure frequency among susceptible humans, or might allow seizures to
occur in people who are vulnerable but without prior episodes.
It is unfortunate but perhaps not surprising that questions about aspartame's phenylalaninemediated
neurological effects arose after the sweetener was added to the food supply. New clinical data
and the development of new hypotheses, based on laboratory research, can raise questions about any
relatively new compound, even after that compound has passed all of the safety tests required at the time
of its approval. What was and continues to be lacking is a process, free of political influence, for
monitoring possible adverse reactions after food and drug additives are placed in the market.
Government-mandated safety research does not exist for politically protected chemicals and
compounds, such as Thimerosal and aspartame.
REFERENCES
1. Hattan DG, Henry SH, Montgomery SB, Bleiberg MJ, Rulis AM, Bolger PM. Role of the Food and
Drug Administration in regulation of neuroeffective food additives. In: Wurtman RJ, Wurtman JJ, eds.
Nutrition and the Brain.
Vol. 6. New York, NY: Raven Press; 1983: 31-99.
2. Anonymous. Food additives permitted for direct addition to food for human consumption; aspartame;
denial of requests for hearing. Final rule, Federal Register 49, 6672-6682 (1984).
3. Pardridge WM. Potential effects of the dipeptide sweetener aspartame on the brain. In: Wurtman RJ,
Wurtman JJ, eds.
Nutrition and the Brain. Vol. 7. New York, NY: Raven Press; 1996: 199-241.
4. Bradstock MK, Serdular MK, Marks JS, Barmard RJ, Crane NT, Remmington PL, Trowbridge FL.
Evaluation of reactions to food additives: The aspartame experience.
Am J Clin Nutr. 1986;43:464-
469.
5. Department of Health and Human Services.
Quarterly Report on Adverse Reactions Associated with
Aspartame Ingestion
. DHHS, Washington, DC, Oct. 1, 1986.
6. Johns DR. Migraine provoked by aspartame.
N Engl J Med. 1986;315-456.
7. Ferguson JM. Interaction of aspartame and carbohydrates in an eating-disorder patient.
Am J
Psychiatry
. 1985;142:271.
8. Drake ME. Panic attacks and excessive aspartame ingestion. Lancetii: 631 (1986)
9. Wurtman RJ. Aspartame: Possible effect on seizure susceptibility. Lancet ii: 1060 (1985).
10. Watson RG. Seizure and mania after high intake of aspartame.
Psychosomatics. 1986;27:218-220.
11. Stegink L.D, Filer LJ Jr., Baker GL. Effect of aspartame and aspartame loading upon plasma and
erythrocyte free amino acid levels in normal adult volunteers.
J Nutr. 1977;107:1837-1845.
12. Yokogoshi H, Roberts CH, Caballero B, Wurtman RJ. Effects of aspartame and glucose
administration on brain and plasma levels of large neutral amino acids and brain 5-hydroxyindoles.
Am J Clin Nutr.
1984;40:1-7.
13. Fernstrom JD, Fernstrom MH, Gillis MA. Acute effects of aspartame on large neutral amino acids and
monoamines in rat brain.
Life Sci. 1983;32:1651-1658.
14. Ranney RE, Opperrnann JA, Muldoon E, McMahon FG. Comparative metabolism of aspartame in
experimental animals and humans.
J Toxicol Environ Health. 1976;2:441-451.
15. Fernstrom JD, Wurtman RJ, Hammarstrom-Wilkund B, Rand WM, Munro HN, Davidson CS. Diurnal
variation in plasma concentrations of tryptophan, tyrosine, and other neutral amino acids: Effect of
dietary protein intake.
Am J Clin Nutr. 1979;32:1912-1922.
16. Maher TJ, Glaeser BS, Wurtman RJ. Diurnal variations in plasma concentrations of basic and neutral
amino acids and in red cell concentrations of aspartate and glutamate: Effects of dietary protein.
Am J
Clin Nutr.
1984;39:722-729.
17. Stegink LD, Filer LJ Jr., Baker GL., McDonnell JE. Effect of an abuse dose of aspartame upon
plasma and erythrocyte levels of amino acids in phenylketonuric heterozygous and normal adults.
J
Nutr
. 1980;110: 2216-2224.
364
18. Fernstrom JD, Faller DV. Neutral amino acids in the brain: Changes in response to food ingestion.
J
Neurochem
. 1978;30:1531-1538.
19. Elwyn DH, Parikh HC, Shoemaker WC. Amino acid movements between gut, liver and periphery in
unanesthetized dogs. Am J Physiol. 1968;215:1260-1275.
20. Oldendorf WH. Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection.
Am J Physiol
. 1971;221:1629-1639.
21. Levy HL, Waisbren SE. Effects of untreated maternal phenylketonuria and hyperphenylalanemia on
the fetus.
N Engl J Med. 1983;309:1269-1274.
22. Jobe PC, Dailey JW, Reigel CE. Noradrenergic and serotonergic determinants of seizure
susceptibility and severity in genetically epilepsy-prone rates.
Life Sci. 1986;39:775-782.
23. Milner JD, Irie K, Wurtman RJ. Effects of phenylalanine on the release of endogenous dopamine from
rat striatal slices.
J Neurochem. 1986;47:1444-1448.
24. Reinhard JF, Reinhard JF Jr. Experimental evaluation of anticonvulsants. In: Vida JA, ed.
Anticonvulsants
. New York, NY: Academic Press; 1972: 58-110.
25. Olney JW, Farber NB, Spitznagel E, Robins LN. Increasing brain tumor rates: is there a link to
aspartame?
Journal of Neuropathology and Experimental Neurology. 1996;55: 1115-1123.
ABOUT THE AUTHOR
Dr. K. Paul Stoller is Medical Director of the Hyperbaric Medical Center of New Mexico, President
of the International Hyperbaric Medical Association, a Fellow of the American Academy of Pediatrics, a
Diplomat of the American Board of Pediatrics, a Diplomat of the American Board of Hyperbaric Medicine,
and a member of the American College for Hyperbaric Medicine. He was University of California
President's Undergraduate Fellow in the UCLA Medical Center's Department of Anesthesiology, and a
former Clinical Assistant Professor of Pediatrics, UNM School of Medicine. Dr. Stoller is also part of the
Divers Alert Network Physician Referral Network. Dr. Stoller is a founding board member of the
International Hyperbaric Medical Association, and its current President. He was also a founding board
member of the
Humane Farming Association, Science Editor of the Animals' Voice Magazine where he
was nominated for a
Maggie. His Op-Ed pieces have appeared in several newspapers and periodicals
from
The Atlanta Constitution, Los Angeles Times, Abq Tribune to The Scientist. He has served on both
the Injury Prevention Committee and the Environmental Hazards Committee of the American Academy of
Pediatrics.
No comments:
Post a Comment