Posted: 11 January 2008
Possible neurologic effects of aspartame, TJ Maher, RJ Wurtman, Environ. Health Persp. 1987 Nov, full text: other seizure reports reaspartame, methanol, formaldehyde, formic acid: Murray 2008.01.10
Thursday, January 10, 2008
Seizures and hyponatremia after excessive intake of diet coke, LJ Mortelmans, M Van Loo, HG De Cauwer, K Merlevede, Klina General Hospital, Brasschaat, Belgium, EJEM 2008 Feb: Mark D. Gold critique: Murray 2008.01.10
Thursday, January 10, 2008
Eur J Emerg Med. 2008 Feb; 15(1): 51.
Seizures and hyponatremia after excessive intake of diet coke.
Mortelmans LJ, Luc.email@example.com,
Van Loo M,
De Cauwer HG, firstname.lastname@example.org,
Merlevede K. Karen.Merlevede@klina.be,
a Emergency Medicine
Klina General Hospital, Brasschaat, Belgium.
We describe a case of epileptic seizures after a massive intake of diet coke.
Apart from the hyponatremia due to water intoxication the convulsions can be potentiated by the high dose of caffeine and aspartame from the diet coke.
To our knowledge this is the first report of seizures due to excessive diet coke intake. PMID: 18180668
Aspartame & seizures, 3 cases, RJ Wurtman, Lancet 1985.11.09: Murray 1999.10.30
Aspartame: possible effect on seizure susceptibility.
Lancet 1985 Nov 9; 2(8463): 1060.
Richard J. Wurtman, Ph.D. email@example.com 617-253-3091
Professor of Neuroscience
Director of the Clinical Research Center,
Prof. of Health Sciences and Technology
Massachusetts Institute of Technlogy Cambridge, Mass. 02139
Richard J. Wurtman letter to the editor of The Lancet, November 9, 1985.
Aspartame: possible effect on seizure susceptibility
Aspartame, a sweetener in many diet beverages, contains phenylalanine but, unlike dietary proteins, lacks other neutral amino acids that compete with phenylalanine for uptake into the brain. (1-3)
Hence, its consumption causes unique modifications in the plasma amino acid pattern (3) which, in man, might be expected to increase brain phenylalanine levels (especially when carbohydrates are eaten concurrently) (2,3) and thereby affect catecholamine or serotonin synthesis. (4,5)
Since diminished brain monoamine levels have been related to depressed seizure thresholds in animal preparations, (6) very high aspartame doses might also affect the likelihood of seizures in symptomless but susceptible people.
Brief descriptions follow of three previously healthy adults who had grand mal seizures during periods when they were consuming such doses.
A 42-year-old secretary who drank four quarts (3-3/4 litres), of "Diet Coke" and almost the same amount of "LiteLine" lemonade daily became "moody" with weekly episodes of headache and nausea, visual hallucinations, feelings of deja-vu, and, ultimately, a grand mal seizure.
There was "no evidence for an underlying structural abnormality to account for her temporal lobe epilepsy."
During her 9 days in hospital she took no diet drinks and, for the first time in months, had no headaches; they recurred when she resumed the diet drinks at home and disappeared when she again discontinued the diet drinks.
A 27-year-old programmer with no neurological history had nocturnal episodes of twitching movements and abnormal breathing, and, ultimately, a severe headache followed by a grand mal seizure.
Phenytoin suppressed further seizures, but the other symptoms persisted until he discontinued his daily intake of four or five glasses of "Crystal Light"; its subsequent resumption was followed by the return of nocturnal "twitching, trembling, jerking, and hyperventilating."
All laboratory tests were normal except the electroencephalogram, which showed a grade one arrhythmia.
A 36-year-old professor who drank 900 ml or more of aspartame-sweetened iced tea daily had a grand mal seizure in bed.
Angiography demonstrated a left posterior frontal venous angioma, adjudged an "incidental finding."
Such case-reports can only suggest an association between aspartame and seizures, since the size and the seizure incidence (without aspartame) of the population at risk (young adults who sometimes consume large amounts of aspartame) are unknown.
However,the reports are compatible with evidence (3,5) that high aspartame doses may produce neurochemical changes that, in laboratory animals, are associated with depressed seizure thresholds. (6)
It thus seems prudent for physicians to inquire about aspartame consumption and other aspects of dietary history in evaluating patients with unexplained seizures.
Interpreting their responses will require that the labels on food products indicate not only the presence of the sweetener but also the actual amounts that the foods or beverages contain.
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139, USA
Richard J. Wurtman
1. Pardridge WM.
Regulation of amino acid availability to the brain.
In: Wurtman RJ, Wurtman JJ, eds. Nutrition and the brain: Vol 1.
New York: Raven Press, 1977: 141-204.
2. Wurtman RJ.
Neurochemical changes following high-dose aspartame with dietary carbohydrates.
New Engl J Med 1983; 309: 429-30.
3. Yokogoshi H, Roberts C, 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 1978; 40: 1-7.
4. Fernstrom JD, Faller DT.
Neutral amino acids in the brain: changes in response to food ingestion.
Am J Neurochem 1978; 30: 1531-38.
5. Pardridge WM.
Potential effects of the dipeptide sweetener aspartame on the brain.
In: Wurtman RJ, Wurtman JJ, eds.
Nutrition and the brain: Vol VII.
New York: Raven Press (in press).
6. Jobe PC, Ko KH, Dailey JW.
Abnormalities in norepinephrine turnover rate in the central nervous system of the genetically epilepsy-prone rat.
Brain Res 1984; 290: 357-60.
Letters to the Editor
September 13, 1986
Panic attacks and excessive aspartame ingestion
The artificial sweetener aspartame has been alleged to cause seizures(1) and neuropsychiatric symptoms(2) in large doses.
I have observed the precipitation by aspartame abuse of panic attacks in a previously symptomless patient with mitral valve prolapse, the association of which with anxiety disorder and panic attacks is controversial.(3)
The effects of aspartame on brain amines(4, 5) support the role of catecholamines in panic attacks and suggest that persons with mitral valve prolapse may have an exaggerated sensitivity to aspartame excess.
A 33-year-old cook had been found incidentally to have a mid-systolic click and murmur.
She had smoked two packs of cigarettes per day for several years, and daily consumed one or two cups of coffee and six to twelve cans of diet cola sweetened with aspartame.
When she was transferred to a different and very hot kitchen her consumption of diet cola went up to about twenty cans per day.
Within a week she began to feel persistently "shaky" at home and at work, and then had paroxysms of dizziness, diaphoresis, chest tightness, dyspnoea, claustrophobia, and the intense feeling that "something was about to happen" to her or that she "would die any minute."
Physical examination was normal except for click and murmur, and neurological examination was intact.
Laboratory studies, including thyroid function tests, electrocardiogram, and electroencephalogram, were normal.
A two-dimensional echocardiogram confirmed mitral valve prolapse.
She decreased her smoking by half and stopped drinking coffee, but the attacks continued daily until she reduced her intake of diet cola to two or three cans per day, at which time they subsided.
She could not maintain this moderate consumption, however, and after one week rapidly returned to her former level of intake, whereupon the daily attacks returned.
She changed to several brands of diet soft drink which contained no caffeine but the symptoms persisted.
With the aid of a behaviour modification programme she was able to reduce her daily consumption of such beverages to two or three cans, and has subsequently had relief from her symptoms. This patient had asymptomatic mitral valve prolapse but experienced typical panic attacks when consuming excessive amounts of aspartame-sweetened soft drinks, the attacks subsiding when she reduced her aspartame consumption.
She also smoked and drank coffee, so nicotine and caffeine may have played a part, but moderation of these was not effective while attacks subsided with reduction of cola intake.
Her panic attacks may well have been predisposed by mitral valve prolapse and precipitated by aspartame excess, which suggests that people with mitral valve prolapse may have an exaggerated susceptibility to aspartame and possibly to other stimulants as well.
Wurtman reported three patients, consuming more than a gallon of aspartame-sweetened tea daily, who experienced generalized seizures, although at least one patient was significantly hyponatraemic and may have had seizures on that basis.
A seizure followed by mania was described in a patient with bipolar affective disorder who consumed a gallon of aspartame-sweetened tea per week; the role of the patient's underlying affective disorder, as well as psychotropic medications, is not clear.
Administration of aspartame and carbohydrate increases brain tyramine content and suppresses the postprandial increase of tryptophan; this might have a catecholamine-augmenting and stimulant effect, as could the large increase in phenylalanine shown in rat brain after an aspartame load.
It is unclear how this might cause seizures, but the precipitation of cardiovascular and psychological features of anxiety is consistent with evidence that catecholamines play a part in pathogenesis of panic attacks and that adrenergic blockade is useful in their treatment.
Mitral valve prolapse and panic symptoms are both common and may overlap, but patients with mitral valve prolapse may be predisposed to panic symptoms under the influence of stimulants and adrenergic agonists and so may be unusually susceptible to the effects of excessive aspartame.
There is no evidence that aspartame is harmful in usual amounts, but perhaps patients with mitral valve prolapse should be cautioned against immoderate use.
Simultaneous consumption of large amounts of carbohydrates and aspartame, a common practice in snack eating today, should also be avoided.
Department of Neurology
Ohio State University College of Medicine
Columbus, Ohio 43210, USA
Miles E. Drake
(1) Wurtman, R.J.
Aspartame: possible effect on seizure susceptibility.
Lancet, 1985; iii: 1060.
(2) Walton, R.G.
Seizure and mania after high intake of aspartame.
Psychosomatics, 1986; 27: 218-20.
(3) Boudoulas, H., King, B.D., Wooley, C.F.
MVP: a marker for anxiety or overlapping phenomenon?
Psychopathology, 1984; 17(suppl 1): 98-106.
(4) Stegink, L.D. , Filer, L.J., Baker, G.L.
Effect of aspartame loading upon plasma and erythrocyte amino acid levels in PKU heterozygotes and normal adult subjects.
J Nutr, 1979; 109: 708-17.
(5) Wurtman, R.J.
Neurochemical changes following high-dose aspartame with dietary carbohydrates.
N Engl J Med, 1983: 309: 429-30.
Clin Toxicol (Phila). 2006; 44(1): 89-90
Drexel University College of Medicine, Emergency Medicine Control
Philadelphia, PA, USA. firstname.lastname@example.org
J Toxicol Clin Toxicol. 1998; 36(3): 175-81
Prognostic factors in patients with methanol poisoning.
Liu JJ, Daya MR, Carrasquillo O, Kales SN.
Department of Internal Medicine, Mayo Clinic Rochester, MN 55906, USA
To identify prognostic factors in methanol poisoning and determine the effect of medical interventions on clinical outcome.
Retrospective review of all patients treated for methanol poisoning from 1982 through 1992 at The Toronto Hospital.
Presenting history, physical examination, results of laboratory tests, medical interventions, and final outcomes after hemodialysis were abstracted.
Of 50 patients treated for methanol poisoning, 18 (36%) died, 32 (64%) survived.
Seven of the 32 survivors sustained visual sequelae (22%), the remaining 25 (78%) recovered completely.
Patients presenting with coma or seizure had 84% (16/19) mortality compared to 6% (2/31) in those without (p < 0.001).
Initial arterial pH < 7 was also associated with significantly higher mortality (17/19, 89% vs 1/31, 3%, p < 0.001).
There were no differences in time from presentation to dialysis between survivors and fatalities (8.4 +/- 3.6 vs 7.6 +/- 3.5 hours, p = 0.47).
The deceased patients had higher mean methanol concentration than the survivors (83 +/- 53 vs 41 +/- 25 mmol/L, p = 0.004).
Subgroup analysis of 19 patients presenting with visual symptoms who survived showed prolonged acidosis (5.4 +/- 2.3 vs 3.0 +/- 2.1 hours, p = 0.06) in those with persistent visual sequelae.
Coma or seizure on presentation and severe metabolic acidosis, in particular initial arterial pH < 7, are poor prognostic indicators in methanol poisoning.
Survivors presented with lower methanol concentrations.
Patients with residual visual sequelae had more prolonged acidosis than those with complete recovery.
Future studies will be needed to confirm the effect of correction of acidosis on final clinical outcome. PMID: 9656972
Heart Lung. 1992 May; 21(3): 260-4
Acute methanol poisoning: a case study.
School of Nursing, University of California, Los Angeles.
Acute methanol poisoning produces severe anion gap metabolic acidosis caused by the toxic accumulation of metabolites, primarily formic acid.
Formic acid produces serious neurologic sequelae.
Therefore, an understanding of the mechanism of toxicity, treatment, and clinical course is essential in preventing permanent neurologic dysfunction.
Prompt recognition and treatment are the keys to successful patient outcomes.
This article presents a case report of a patient with severe methanol poisoning with clinical course, treatment, and outcome. PMID: 1592617
Can J Neurol Sci. 1989 Nov; 16(4): 432-5.
Methanol poisoning: factors associated with neurologic complications.
Anderson TJ, Shuaib A, Becker WJ. Department of Internal Medicine
University of Calgary, Alberta, Canada
Hospital records of thirty patients with methanol poisoning were studied.
Neurologic manifestations at presentation including coma, seizures and decreased visual acuity were seen in nineteen patients.
The mean blood pH at presentation was significantly lower in the patients with these neurologic signs and symptoms than in the eleven patients without them (p less than 0.05).
Methanol levels at presentation tended to be higher in patients with neurologic manifestations at presentation and these patients tended to present later after methanol ingestion than those patients without neurologic manifestations.
Fifteen patients with methanol poisoning developed serious neurologic sequelae or died.
The mean blood pH was significantly lower in this patient group than in those who survived without neurologic sequelae (p less than 0.05).
Methanol levels at presentation were not different in the patients who developed neurologic sequelae or died as compared to those who did not.
The time from ingestion of methanol to presentation at the hospital was however significantly longer in those patients who developed neurologic sequelae or died (p less than 0.05).
Initiation of treatment within eight hours of ingestion of methanol was associated with a better clinical outcome. PMID: 2804806
Clin Chem. 1986 Feb; 32(2): 395-7
Formic and lactic acidosis in a fatal case of methanol intoxication.
Shahangian S, Ash KO.
A 33-year-old white man was admitted to the University of Utah Hospital after about 30 h of various symptoms, including blurred vision and (eventually) severe left flank and back pain.
Upon admission, his serum pH was 6.80 and serum bicarbonate concentration (calculated from pCO2 and pH) was 3.9 mmol/L.
The etiology for the acidosis became apparent 10 h after admission, when assay of the serum prepared from a blood specimen obtained at admission revealed a methanol concentration of 74 mmol/L (2.4 g/L).
At this time the patient was placed on hemodialysis and intravenously infused with sodium bicarbonate.
The methanol concentration in serum had decreased to 21 mmol/L 2 h later.
Formate and lactate concentrations were, respectively, 10 and 23 mmol/L in serum sampled 4.5 h after hospitalization, at which time serum pH was 6.91 and bicarbonate concentration 7 mmol/L.
The patient eventually died with extensive neuropathy. PMID: 3943215
http://www.clinchem.org/cgi/reprint/32/2/395 free full text
"The patient was a 33-year-old white man who had been complaining over a 30-h period of various symptoms of methanol poisoning, including abdominal pain, nausea, weakness, dizziness, blurred vision, and eventually severe pain in his left flank and back.
Enroute to the University of Utah Hospital, he became unresponsive and was in seizure upon arrival.
By arrival he was flaccid with no tonic-clonic movements and no incontinence, having been intubated by the paramedics.
Respiratory arrest also occurred enroute to the hospital, but he was adequately compensated for oxygen by immediate use of a respirator.
Blood pressure was normal, and the patient maintained adequate peripheral perfusion and urinary output throughout his hospitalization until shortly before his irreversible cardiorespiratory arrest.
At admission, the patient was severely acidotio-serum pH 6.80, calculated bicarbonate concentration 3.9 mmol/L, the etiology of which was not known until 10 h after admission, when a methanol concentration of 74 mmol/L (2.4 g/L; toxic concentration, >0.2 g/L) was measured in serum from a specimen collected 0.5 h after admission."
Vet Hum Toxicol. 1990 Apr; 32(2): 135-7.
Formate levels following a formalin ingestion.
Rocky Mountain Poison and Drug Center, University of Colorado, Health Sciences Center, Denver 80204-4507.
Although formalin ingestions have previously been reported in the literature, technology has only recently been developed to measure both formaldehyde and formate levels in plasma.
Methanol, formaldehyde, and formate levels were followed in the case reported here until the patient's death approximately 13 h after the ingestion.
The clinical course was marked by an initial profound CNS depression followed by an apparent clinically quiescent period.
Severe abdominal pain and retching preceded the development of seizures, DIC, severe hypotension, and cardiac arrest.
Methanol levels rose throughout this 13-h course.
Formate and formaldehyde levels increased until bicarbonate and ethanol therapy were instituted.
The "fixing" of the stomach by formaldehyde may have produced delayed absorption following formalin ingestion.
Therapeutic implications are discussed. PMID: 2327060
Department of Pharmacology and Therapeutics
Louisiana State University Health Sciences Center
1501 Kings Highway, Shreveport, Louisiana 71130-3932, USA
Arch Clin Neuropsychol. 2001 Jan; 16(1): 33-44.
A case of claimed persistent neuropsychological sequelae of chronic formaldehyde exposure: clinical, psychometric, and functional findings.
Comprehensive Neuropsychological Services of the Southern Tier, Vestal, NY 13850, USA. email@example.com, firstname.lastname@example.org
Many anecdotal cases and some clinical studies have demonstrated that formaldehyde exposure can cause multiple health-related problems and cerebral dysfunction.
The U.S. Consumer Product Safety Commission has documented multiple hazards related to formaldehyde exposure.
Some of this research has suggested that low levels of exposure can be very hazardous to one's health and can potentially result in heightened chemical sensitivities, seizures, and cognitive decline.
Some research suggests that exposure results in long-term immunological changes, cell neurofilament protein changes, and demyelination.
Symptomatically, exposure has been associated with respiratory problems, excessive fatigue, headaches, mood changes, and impaired attention, concentration, and memory functioning.
This article outlines the case of a biology teacher whose chronic formaldehyde exposure resulted in heightened sensitivity to formaldehyde, three tonic-clonic seizures, and dramatic amnesia as well as other cognitive dysfunction. PMID: 14590191
Arch Environ Health. 1994 Jan-Feb; 49(1):37-44.
Neurobehavioral impairment and seizures from formaldehyde.
Environmental Sciences Laboratory, University of Southern California, School of Medicine, Los Angeles.
Three patients were evaluated for effects of formaldehyde on central nervous system function.
Three patients had used formalin, formaldehyde with or without phenol, to fix whole animals for 14-30 y, and a fourth patient was covered several times by formaldehyde and phenol rainout from manufacturing spills.
All were disabled, and two had developed seizures.
They had elevated mood state scores (82 to 162) and elevated symptom frequency scores (111 to 138), compared with referent subjects.
There was excessive fatigue, somnolence, headache, difficulty remembering, irritability, and instability of mood.
Compared with referents, choice reaction time was prolonged in four of four (4/4) subjects, blink latency was delayed in 2/2, balance was abnormal in 3/4, and visual fields were constricted in 2/3.
Cognitive functions, measured by Culture Fair, block design, and digit symbol tests, were impaired in all.
Delayed verbal recall and visual reproduction were impaired in 3/4.
Perceptual motor speed on slotted pegboard and trail making A and B tests was reduced in 4/4.
Errors on fingertip number writing were abnormal in all.
Long-term memory was decreased in only one.
Extensive use of formaldehyde at work or repeated airborne exposure to formaldehyde and phenol appears to have impaired central nervous system function. PMID: 8117145
"The existence of this major metabolic difference between rodents and people underscores the necessity that large-scale human studies be carried out, preferably on selected populations whose members might be especially vulnerable to phenylalanine and to aspartame's other breakdown products, before conclusions be drawn about whether or not aspartame really is risk-free."
"The aspartic acid is unlikely to cross the blood-brain barrier (4), and very few data are available showing that the amounts of methanol or peptides generated by ADI doses of aspartame have significant neural effects."
Environ Health Perspect. 1987 Nov; 75: 53-7.
Possible neurologic effects of aspartame, a widely used food additive.
Maher TJ, Wurtman RJ. email@example.com
Department of Pharmacology, Massachusetts College of Pharmacy
Boston, MA 02115.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=3319565 free full text
The artificial sweetener aspartame (L-aspartyl-L-phenylalanyl-methyl ester), is consumed, primarily in beverages, by a very large number of Americans, causing significant elevations in plasma and, probably, brain phenylalanine levels.
Anecdotal reports suggest that some people suffer neurologic or behavioral reactions in association with aspartame consumption.
Since phenylalanine can be neurotoxic and can affect the synthesis of inhibitory monoamine neurotransmitters, the phenylalanine in aspartame could conceivably mediate neurologic effects.
If mice are given aspartame in doses that elevate plasma phenylalanine levels more than those of tyrosine (which probably occurs after any aspartame dose in humans), the frequency of seizures following the administration of an epileptogenic drug, pentylenetetrazole, is enhanced.
This effect is simulated by equimolar phenylalanine and blocked by concurrent administration of valine, which blocks phenylalanine's entry into the brain.
Aspartame also potentiates the induction of seizures by inhaled fluorothyl or by electroconvulsive shock.
Perhaps regulations concerning the sale of food additives should be modified to require the reporting of adverse reactions and the continuing conduct of mandated safety research. PMID: 3319565
Possible Neurologic Effects of Aspartame, a Widely Used Food Additive
-- by Timothy J. Maher (Department of Pharmacology, Massachusetts College of Pharmacy, 179 Longwood Avenue, Boston, MA 02115) and Richard J. Wurtman (Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139).
Food Additives as Neuroactive Environmental Constituents
For the very great majority of Americans, i.e., those who elect to eat processed foods, food additives are a ubiquitous constituent of the environment, and one with potentially important health effects.
The laws governing the sale of these compounds require that their addition to foods fulfill a specific purpose, such as improving flavor, retarding spoilage, or enhancing nutritional quality, and that such use be risk-free.
Implicit in this latter requirement is the expectation that the food additive not be found to affect physiological processes other than the nutritional or sensory ones underlying its use:
Compounds that do 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 exempted 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 also are 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).
These effects may generate health risks for some people.
Moreover, in the case of one such compound, the artificial sweetener aspartame (L-aspartyl-L-phenylalanyl-methyl ester), 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, on the nervous system are sometimes not of such a nature as to allow their detection by the standard neurotoxicological tests used to assess the safety of food additives, inasmuch as these effects need not be associated with cell death, nor with other visible manifestations of neuronal damage.
Rather, they involve more subtle 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 the additive was placed in the food, they may have important health implications just the same, given the very large number of Americans who are routinely exposed to environmental constituents added to the food supply.
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 neurally related consumer complaints already registered with the FDA and other federal agencies (5,6).
This report describes some of the available evidence, almost all of which has been accumulated in the past 2 years, that doses of aspartame, which are within the range actually consumed by some people, can affect the chemical composition of the brain, and may thereby contribute to particular CNS side effects, including headaches (7), inappropriate behavior responses (8,9), and seizures (10,11).
As will be noted, progress in anticipating aspartame's effects on the human brain has been hampered by a particular experimental problem related to differences in the speeds at which the rodent and human livers metabolize phenylalanine, the lone neutral amino acid in aspartame, to tyrosine.
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 (which makes questionable the extrapolation of much of the rodent literature to humans) then can be circumvented by using the rats or mice only as a source of tissues for in vitro studies, or by administering the aspartame in doses that transiently overwhelm the animals' capacity to metabolize it so that, as happens when people consume any dose, the sweetener causes brain phenylalanine to rise proportionately more than brain tyrosine.
The existence of this major metabolic difference between rodents and people underscores the necessity that large-scale human studies be carried out, preferably on selected populations whose members might be especially vulnerable to phenylalanine and to aspartame's other breakdown products, before conclusions be drawn about whether or not aspartame really is risk-free.
If aspartame cannot be shown to be risk-free, perhaps its regulatory classification could be changed; for example, to that of over-the-counter drug.
Or perhaps the federal regulation of novel food additives should be modified to require that adverse reactions be monitored and reported, and that continuing research on their safety be carried out as mandated by the FDA.
Effects of Dietary Aspartame on Brain Phenylalanine Levels: Possible Consequences for Neurotransmission.
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), possibly as well as various peptides (like B-aspartame or the aspartyl-phenylalanine diketopoperazine that are formed from it spontaneously, on the shelf, or enzymatically, after its consumption.
Our present concern is about the CNS effects of the phenylalanine.
The aspartic acid is unlikely to cross the blood-brain barrier (4), and very few data are available showing that the amounts of methanol or peptides generated by ADI doses of aspartame have significant neural effects.
Underlying our concern about the possible brain effects of the phenylalanine in ADI aspartame doses (approximately 2 g in a 175 lb man) are the following relationships:
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).
Thus, phenylalanine levels can normally vary between 30 and 90 uM, depending upon whether the subject has most recently eaten no-protein (i.e., phenylalanine-free) or high-protein meals.
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).
It should be noted that aspartame is probably the only phenylalanine-containing food that man has ever eaten which 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 LN AA 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, depending on the dose consumed.]
If an aspartame-containing beverage is consumed along with, for example, a carbohydrate-rich, protein-poor dessert food, its effects on brain phenylalanine are 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 (22) who are, without knowing it, heterozygous for the phenylketonuria (PKU) gene.
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, in rodents, is the suppression of seizure activity.
It has been recognized for years that animals given drugs [such as reserpine or Ro 4-1284 (23)] that deplete the brain of particular monoamine neurotransmitters, or that block the receptor-mediated effects of these transmitters, exhibit greater sensitivity to seizures (23).
In contrast, drugs [such as L-Dopa plus an MAO inhibitor, or L-Dops (23)] thought to enhance monoaminergic neurotransmission apparently protect rodents against the development of seizures.
Low doses of aspartame, which raise plasma tyrosine levels more than those of phenylalanine, might be expected to have no effect on seizure thresholds, or even to protect animals against the epileptogenic effects of drugs like pentylenetetrazole; in contrast, comparable doses, given to humans could enhance seizure susceptibility, since, in humans, all aspartame doses apparently cause greater increases in plasma (and brain) phenylalanine than in 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 from the rat's brain has been demonstrated.
Slices of caudate nucleus were superfused with a solution containing sufficient tyrosine (50 uM) to sustain dopamine's release, and were stimulated electrically [360 pulses; 12 Hz; 2 msec (24)] on two occasions, separated by an interval of about 60 min.
The addition of phenylalanine to the medium caused a dose-related suppression of subsequent dopamine release (shown as a reduction in the S2/Sl ratio).
The lowest phenylalanine concentration capable of impairing dopamine release (200 uM) was about three times that present in plasmas from fasting rats.
An aspartame dose that causes a proportionate threefold rise in the human phenylalanine content of plasma is the ADI dose (50 mg/ kg).
As explained above, this dose probably falls to 25 mg/kg if the aspartame is consumed along with a dietary carbohydrate (13), or to 12.5 mg/kg if the person consuming it in this manner also happens to be heterozygous for PKU.
Effects of Aspartame on Seizure Susceptibility in the Mouse
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 min were counted (when the treatment was entylenetetrazole), or the time passing until a given animal had a seizure (when the treatment was inhaled fluorothyl or electroshock).
See figure one at: http://www.dorway.com/graphics/wurtfig1.jpg
Figure 1. Effect of aspartame pretreatment on the percentage of mice convulsing following the administration of the CD50 dose of pentylenetetrazole. Groups of male CD-1 mice (average n = 24) received 0-2000 mg/kg aspartame via oral intubation followed by an SC injection of pentylenetetrazole 1 hr later. The number of mice convulsing with the various aspartame doses was determined. p < 0.05, significantly different from 0 mg/kg as determined by the chi-square test.
See figure two at: http://www.dorway.com/graphics/wurtfig2.jpg
Figure 2. Effect of aspartame (1000 mg/kg) on the percentage of mice convulsing at various doses of pentylenetatrazole. Groups (average n = 24) or male CD-1 mice received water or 1000 mg/kg aspartame via oral intubation followed by various doses of pentylenetetrazole, 1 hr later. The number of animals convulsing was determined. Aspartame pretreatment significantly (p < 0.05) shifted the dose-response curve as determined by the method of Litchfield and Wilcoxon.
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. 1).
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 (26).
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. 2).
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 blood-brain 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.
A seizure-promoting effect of aspartame was also observed in mice developing seizures in response to fluorothyl or to electroshock.
Animals were pretreated 60 min before exposure to 10% fluorothyl (delivered in a sealed chamber at a rate of 0.05 mL/min), and the time each took to develop clonus was measured.
Water-pre-treated control animals experienced clonus at 462 + or - 18 sec, while those receiving aspartame (1000 mg/kg) experienced clonus 35% sooner (298 + or - 10 sec) (p < 0.001) (26).
This enhancement of seizure susceptibility was also mimicked by equimolar phenylalanine (but not aspartic acid) and blocked by valine, which, given alone, failed to alter the time to clonus.
Aspartame (1000 mg/kg administered for 7 consecutive days) also accelerated the onset of hind limb flexion among mice given electroshock (50 mA, 60 Hz, 0.2 sec), a response that was mimicked by equimolar phenylalanine (Pinto and Maher, unpublished observations).
The above data indicate that APM has seizure-promoting activity in animal models that are widely used to identify compounds affecting (ie: usually protecting against) seizure incidence.
That its mechanism of action involves increased brain phenylalanine is indicated by the ability of equimolar phenylalanine to simulate the epileptogenic effect and by the ability of concurrently administered valine to protect against this effect.
The evidence does not indicate that aspartame itself causes seizures; rather 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.
Whether or not aspartame actually does promote seizures in susceptible humans will have to be explored in controlled clinical trials.
It is unfortunate but perhaps not surprising that questions about aspartame's phenylalanine-mediated neurologic 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 seems most important is that processes be developed for monitoring possible adverse reactions after food additives are placed in the food supply, and for continuing the conduct of government-mandated safety research.
Perhaps experience with aspartame will catalyze the development of such processes.
These studies were supported part by a grant from the National Institute of Neurological, Communicative Diseases and Stroke (NS21231).
An association has recently been proposed between the incidence of seizures and prolonged consumption of the phenylalanine-containing artificial sweetener, aspartame.
Since consumption of aspartame, unlike dietary protein, can elevate phenylalanine in brain, and thereby inhibit the synthesis and release of neurotransmitters known to protect against seizure activity, the effect of oral doses of aspartame on the sensitivity of mice to the proconvulsant agents, pentylenetetrazole and fluorothyl was studied.
Doses of aspartame were used which increased phenylalanine more than tyrosine in brain, as occurs in humans after the consumption of any dose of aspartame.
Pretreatment with aspartame significantly increased the percentage of animals convulsing after administration of pentylenetetrazole and significantly lowered the CD50 for this convulsant.
The average time to onset of seizures induced by fluorothyl in control mice was 510 sec; pretreatment with oral doses of 1000, 1500 and 2000 mg/kg of aspartame 1 hr earlier significantly reduced the time required to elicit seizures (394, 381 and 339 sec, respectively).
The seizure-promoting effect of aspartame could be demonstrated 30, 60 or 120 min after the 1000 mg/kg dose.
The seizures induced by either convulsant were potentiated by equimolar amounts of phenylalanine, a major endogenous metabolite of aspartame, while the other metabolites, aspartic acid and methanol, were without effect.
Administration together with aspartame of the large neutral amino acid valine, which competes with phenylalanine for entry into the brain, completely abolished the seizure-promoting effect of aspartame. (ABSTRACT TRUNCATED AT 250 WORDS) PMID: 3352866
Clin Allergy Immunol. 2007; 20:25-49.
Environmental and allergic factors in chronic rhinosinusitis.
Pinto JM, Naclerio RM.
Section of Otolaryngology-Head and Neck Surgery, Department of Surgery, The Pritzker School of Medicine, University of Chicago, Chicago, Illinois, 60637 USA. PMID: 17534044
Pinto, Jayant M Pinto, MD
Pinto Jayant Asst Prof, Otolaryngology- Head & Neck Surgery, Dept. Surgery, AMB E103G (MC 1035) (Sec'y, Jamie Phillips, 2-6727) Pgr.: 188-5255, Fax: 2-6809 2-6727 firstname.lastname@example.org
Environ Health Perspect. 1997 Mar; 105 Suppl 2:417-36.
Profile of patients with chemical injury and sensitivity.
Ziem G, McTamney J. Grace Ziem, James McTamney
Occupational and Environmental Medicine, Baltimore, Maryland, USA.
Patients reporting sensitivity to multiple chemicals at levels usually tolerated by the healthy population were administered standardized questionnaires to evaluate their symptoms and the exposures that aggravated these symptoms.
Many patients were referred for medical tests.
It is thought that patients with chemical sensitivity have organ abnormalities involving the liver, nervous system (brain, including limbic, peripheral, autonomic), immune system, and porphyrin metabolism, probably reflecting chemical injury to these systems.
Laboratory results are not consistent with a psychologic origin of chemical sensitivity.
Substantial overlap between chemical sensitivity, fibromyalgia, and chronic fatigue syndrome exists: the latter two conditions often involve chemical sensitivity and may even be the same disorder.
Other disorders commonly seen in chemical sensitivity patients include headache (often migraine), chronic fatigue, musculoskeletal aching, chronic respiratory inflammation (rhinitis, sinusitis, laryngitis, asthma), attention deficit, and hyperactivity (affected younger children).
Less common disorders include tremor, seizures, and mitral valve prolapse.
Patients with these overlapping disorders should be evaluated for chemical sensitivity and excluded from control groups in future research.
Agents whose exposures are associated with symptoms and suspected of causing onset of chemical sensitivity with chronic illness include gasoline, kerosene, natural gas, pesticides (especially chlordane and chlorpyrifos), solvents, new carpet and other renovation materials, adhesives/glues, fiberglass, carbonless copy paper, fabric softener, formaldehyde and glutaraldehyde, carpet shampoos (lauryl sulfate) and other cleaning agents, isocyanates, combustion products (poorly vented gas heaters, overheated batteries), and medications (dinitrochlorobenzene for warts, intranasally packed neosynephrine, prolonged antibiotics, and general anesthesia with petrochemicals).
Multiple mechanisms of chemical injury that magnify response to exposures in chemically sensitive patients can include neurogenic inflammation (respiratory, gastrointestinal, genitourinary), kindling and time-dependent sensitization (neurologic), impaired porphyrin metabolism (multiple organs), and immune activation. PMID: 9167975
http://www.dorway.com/92symptomsfotocopy.html FDA 1995.04.20
Recent aspartame (methanol, formaldehyde, formic acid) toxicity research: Rich Murray 2008.01.10
Methyl alcohol ingestion as a model etiologic agent in multiple sclerosis, WC Monte, D Glanzman, C Johnston; Methanol induced neuropathology in the mammalian central nervous system, Woodrow C. Monte, Renee Ann Zeising, both reports 1989.12.04: Murray 2007.12.28
Friday, December 28 2007
[ These seminal 1989 studies by Prof. Woodrow C. Monte are also given in this previous post, along his two recent comprehensive reviews:
Role of formaldehyde, made by body from methanol from foods and aspartame, in steep increases in fetal alcohol syndrome, autism, multiple sclerosis, lupus, teen suicide, breast cancer, Nutrition Prof. Woodrow C. Monte, retired, Arizona State U., two reviews, 190 references supplied, Fitness Life, New Zealand 2007 Nov, Dec: Murray 2007.12.26
Wednesday, December 26 2007
Folic acid prevents neurotoxicity from formic acid, made by body from methanol impurity in alcohol drinks [ also 11 % of aspartame ], BM Kapur, PL Carlen, DC Lehotay, AC Vandenbroucke, Y Adamchik, U. of Toronto, 2007 Dec., Alcoholism Cl. Exp. Res.: Murray 2007.11.27
Wednesday, November 27, 2007
"Of course, everyone chooses, as a natural priority, to enjoy peace, joy, and love by helping to find, quickly share, and positively act upon evidence about healthy and safe food, drink, and environment."
Rich Murray, MA Room For All email@example.com
1943 Otowi Road, Santa Fe, New Mexico 87505
http://RMForAll.blogspot.com New primary archive
Group with 115 members, 1,502 posts in a public archive
Details on 6 epidemiological studies since 2004 on diet soda (mainly aspartame) correlations, as well as 14 other mainstream studies on aspartame toxicity since summer 2005: Murray 2007.11.27
Wednesday, November 14, 2007
Souring on fake sugar (aspartame), Jennifer Couzin
Science 2007.07.06: 4 page letter to FDA from 12 eminent USA toxicologists re two Ramazzini Foundation cancer studies 2007.06.25: Murray 2007.07.18
Artificial sweeteners (aspartame, sucralose) and coloring agents will be banned from use in newly-born and baby foods, the European Parliament decided: Latvia ban in schools 2006: Murray 2007.07.12
Sainsbury's supermarket chain in UK details its bans of aspartame, sodium benzoate, and artificial flavourings and colours: Carol Key, Customer Manager: Murray 2007.11.09
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
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
Received 25 October 2006; revised 26 April 2007; accepted 27 April 2007
Correspondence: Professor E Pretorius, Department of Anatomy, University of Pretoria, BMW Building, Dr Savage Street, PO Box 2034, Pretoria 0001, Gauteng, South Africa.
European Journal of Clinical Nutrition (2007), 1-12 & 2007 Nature Publishing Group All rights reserved 0954-3007/07
Direct and indirect cellular effects of aspartame on the brain P Humphries 1,2, E Pretorius 1 and H Naude4 1 1 Department of Anatomy, University of Pretoria, Pretoria, Gauteng, South Africa and 2 Department of Anatomy, University of the Limpopo, South Africa
The use of the artificial sweetener, aspartame, has long been contemplated and studied by various researchers, and people are concerned about its negative effects.
Aspartame is composed of phenylalanine (50%), aspartic acid (40%) and methanol (10%).
Phenylalanine plays an important role in neurotransmitter regulation, whereas aspartic acid is also thought to play a role as an excitatory neurotransmitter in the central nervous system.
Glutamate, asparagines and glutamine are formed from their precursor, aspartic acid.
Methanol, which forms 10% of the broken down product, is converted in the body to formate, which can either be excreted or can give rise to formaldehyde, diketopiperazine (a carcinogen) and a number of other highly toxic derivatives.
Previously, it has been reported that consumption of aspartame could cause neurological and behavioural disturbances in sensitive individuals.
Headaches, insomnia and seizures are also some of the neurological effects that have been encountered, and these may be accredited to changes in regional brain concentrations of catecholamines, which include norepinephrine, epinephrine and dopamine.
The aim of this study was to discuss the direct and indirect cellular effects of aspartame on the brain, and we propose that excessive aspartame ingestion might be involved in the pathogenesis of certain mental disorders (DSM-IV-TR 2000) and also in compromised learning and emotional functioning.
European Journal of Clinical Nutrition advance online publication
8 August 2007; doi:10.1038/sj.ejcn.1602866
Keywords: astrocytes; aspartame; neurotransmitters; glutamate; GABA; serotonin; dopamine; acetylcholine
The artificial dipeptide sweetener, aspartame (APM; Laspartyl-L-phenylalanine methyl ester), is present in many products in the market, especially in unsweetened or sugar free products.
People trying to lose weight or patients with diabetes, including children, frequently use these products.
A recent observation indicated that aspartame is slowly making its way into ordinary products used every day, which do not carry any indication of being for people on diets or diabetics.
Thus, aspartame is used not only by the above mentioned group of people, but also by unsuspecting individuals.
Although there is concern and research evidence suggesting possible adverse neurological and behavioural effects due to aspartames metabolic components (phenylalanine, aspartic acid (aspartate), diketopiperazine and methanol), which are produced during its breakdown, research suggests that aspartame is not cytotoxic.
This debate still continues 20 years after the FDA had approved the use of aspartame.
As seen later in the literature study, phenylalanine may cross the blood-brain barrier and cause severe changes in the production of very important neurotransmitters.
Methanol breaks down into formate, which in turn is very cytotoxic and can even cause blindness.
The effects of aspartame have been studied on various species, including humans, rats, mice and rabbits.
Most studies described in the literature have a macroscopic approach.
If no adverse effects are visible after a single large administered dose of aspartame, it is believed that aspartame has no effect.
Further studies are not carried out microscopically to demonstrate possible adverse effects on the cellular basis.
Thus, results obtained from different studies vary from severe adverse effects to none observed.
The aim of this study was to investigate the direct and indirect cellular effects of aspartame on the brain, and we propose that excessive aspartame ingestion might be involved in the pathogenesis of certain mental disorders (DSM-IV-TR 2000) and also in compromised learning and emotional functioning.
Most diet beverages and food products currently in the market contain aspartame as an artificial sweetener.
However, controversy surrounds the effects of this non-nutritive artificial sweetener, as it is made up of three components that may have adverse effects on neural functioning, particularly on neurotransmitters (Figure 1), neurons and astrocytes.
In light of the possible adverse effects of aspartame, the research questions directing this study are formulated as follows:
What are the direct and indirect cellular effects of aspartame on the brain? How might excessive aspartame ingestion contribute to the pathogenesis of certain mental disorders? What are the implications for early brain development, emotional status and learning following high ingestion of aspartame?
Aspartame is composed of phenylalanine (50%), aspartic acid (40%) and methanol (10%).
The first two are known as amino acid isolates.
It has been reported that consumption of aspartame could cause neurological and behavioural disturbances in sensitive individuals (Anonymous, 1984; Johns, 1986).
Headaches, insomnia and seizures are some of the neurological disturbances that have been encountered, and this may be accredited to changes in regional brain concentrations of catecholamines, which include norepinephrine, epinephrine and dopamine (Coulombe and Sharma, 1986), all important neurotransmitters regulating life-sustaining functions.
The effects of phenylalanine, aspartic acid and methanol are first reviewed, followed by a discussion of altered neurotransmitter functioning, that is dopamine, serotonin, glutamate, g-aminobutyric acid (GABA), and acetylcholine.
The discussion is concluded with implications for early brain development, emotional status and learning following high ingestion of aspartame......
It was seen that aspartame disturbs amino acid metabolism, protein structure and metabolism, integrity of nucleic acids, neuronal function, endocrine balances and changes in the brain concentrations of catecholamines.
It was also reported that aspartame and its breakdown products cause nerves to fire excessively, which indirectly causes a very high rate of neuron depolarization.
The energy systems for certain required enzyme reactions become compromised, thus indirectly leading to the inability of enzymes to function optimally.
The ATP stores in the cells are depleted, indicating that low concentrations of glucose are present in the cells, and this in turn will indirectly decrease the synthesis of acetylcholine, glutamate and GABA.
The intracellular calcium uptake has been altered, thus the functioning of glutamate as an excitatory neurotransmitter is inhibited.
Mitochondria are damaged, which could lead to apoptosis of cells and infertility in men and also a lowered rate of oxidative metabolism are present, thus lowering concentrations of the transmitters glutamate and production of GABA.
The cellular walls are destroyed; thus, the cells (endothelium of the capillaries) are more permeable, leading to a compromised BBB.
Thus, overall oxidative stress and neurodegeneration are present.
From all the adverse effects caused by this product, it is suggested that serious further testing and research be undertaken to eliminate any and all controversies surrounding this product.
Phenylalanine and aspartic acid from low dose aspartame in rabbits interfere with blood coagulation, Pretorius E and Humphries P, U. of Pretoria, Ultrastruct Pathol 2007 March: Murray 2007.07.14
"The authors conclude by suggesting that aspartame usage may interfere with the coagulation process and might cause delayed fibrin breakup after clot formation.
They suggest this, as the fibrin networks from aspartame-exposed rabbits are more complex and dense, due to the netlike appearance of the minor, thin fibers.
Aspartame usage should possibly be limited by people on anti-clotting medicine or those with prone to clot formation."
Ultrastruct Pathol. 2007 Mar-Apr; 31(2): 77-83.
Ultrastructural changes to rabbit fibrin and platelets due to aspartame.
Department of Anatomy, Faculty of Medicine
University of Pretoria, South Africa.
[ Humphries P also at Department of Anatomy, University of Limpopo. Medunsa Campus, Garankuwa. South Africa ]
email: E. Pretorius firstname.lastname@example.org
*Correspondence to E. Pretorius
BMW Building, PO Box 2034
Faculty of Health Sciences
University of Pretoria, Pretoria 0001, South Africa
The coagulation process, including thrombin, fibrin, as well as platelets, plays an important role in hemostasis, contributing to the general well-being of humans.
Fibrin formation and platelet activation are delicate processes that are under the control of many small physiological events.
Any one of these many processes may be influenced or changed by external factors, including pharmaceutical or nutritional products, e.g., the sweetener aspartame (L-aspartyl-L-phenylalanine methyl ester).
It is known that phenylalanine is present at position P(9) and aspartate at position P(10) of the alpha-chain of human fibrinogen, and plays an important role in the conversion of fibrinogen to fibrin by the catalyst alpha-thrombin.
The authors investigate the effect of aspartame on platelet and fibrin ultrastructure, by using the rabbit animal model and the scanning electron microscope.
Animals were exposed to 34 mg/kg of aspartame 26x during a 2-month period.
Aspartame-exposed fibrin networks appeared denser, with a thick matted fine fiber network covering thick major fibers.
Also, the platelet aggregates appeared more granular than the globular control platelet aggregates.
The authors conclude by suggesting that aspartame usage may interfere with the coagulation process and might cause delayed fibrin breakup after clot formation.
They suggest this, as the fibrin networks from aspartame-exposed rabbits are more complex and dense, due to the netlike appearance of the minor, thin fibers.
Aspartame usage should possibly be limited by people on anti-clotting medicine or those with prone to clot formation. PMID: 17613990
http://www.alwayson.co.za/resia/ Resia Pretorius
Associate Professor in the Department of Anatomy
University of Pretoria, South Africa.
Research Focus Areas: