Aspartame

Abstract

Objectives. Clinical insights concerning a remediable cause of pseudotumor cerebri (benign intracranial hypertension) due to aspartame disease.

Materials and Methods. Observations of six women with pseudotumor cerebri who consumed considerable aspartame products, especially "diet" sodas.

Results. The ocular and other manifestations of aspartame disease disappeared or dramatically improved in all subjects after avoiding aspartame products, even obviating surgery.

Conclusions. Aspartame disease should be considered in patients presenting with pseudotumor cerebri, especially weight-conscious young women. The associated clinical features and underlying mechanisms are reviewed, with emphasis on chronic methanol toxicity.

Aspartame disease caused by the use of products containing this chemical sweetener is a frequent but usually overlooked disorder. (1-7) In the author's data base of persons so afflicted, six women developed pseudotumor cerebri (benign intracranial hypertension). This appears to be the first report of such an association.

The clinical and public health implications are significant. An estimated 70% of the United States adult population currently consumes aspartame products. The more common neurologic problems caused or aggravated by aspartame are noted in the discussion.

Patients

All six women were in their 20s and 30s. Preoccupied with their weight, they used considerable aspartame, chiefly as "diet" sodas. The representative case reports illustrate the extensive studies and treatments undertaken -- ranging from repeated lumbar puncture for reducing cerebrospina] pressure to ventricular shunt procedures - prior to awareness of aspartame disease.

Representative Case Reports

Case 1

A registered nurse with an extensive background in neurology and psychiatry was diagnosed as having pseudotumor cerebri in February 1997. Intent upon losing weight, she began consuming considerable amounts of aspartame products. One month later, she suffered "fullness in my head, dizziness that wouldn't go away, impaired vision, panic attacks, and a squishy feeling in my head." Several neurologic consultations and multiple studies ensued when severe headache developed.

The patient realized that the only significant change in her habits had been the use of aspartame products. She avoided them in April 1997, with a progressive disappearance of symptoms. The repeat lumbar punctures being done in an attempt to decrease cerebrospinal fluid pressure were discontinued. Her "headache and strange feelings" would recur, however, if she drank an aspartame soda.

Case 2

The mother of two young children stated, "I used to drink aspartame by the hour." She was diagnosed as having pseudotumor cerebri by five neurologists.

This patient had experienced "floaters" and a large blind spot in the left eye. A neuro-ophthalmologist told her that she would become blind if a ventricular shunt was not performed to drain the excess cerebrospinal fluid causing pressure on the optic nerve. This was done in March 1998. Most of her symptoms persisted, however, especially severe headache, numbness of the feet and fingers, nausea, and extreme fatigne.

Several persons, including her father-in-law, supplied information about aspartame disease. She ignored it initially, but then decided to stop aspartame products on a trial basis. "I saw major results. The headaches were not as bad, and the other symptoms did not bother me as much."

Discussion

Each of these patients had been formally diagnosed by neurologists as having pseudotumor cerebri. Fortuitously, aspartame disease was considered thereafter by relatives or friends who had heard about aspartame disease, leading to aspartame abstinence.

Discussing pseudotumor cerebri in a previous text, (8) the author noted "the greatest frequency of this disease among women under the age of thirty." Wilson and Gardner (9) similarly emphasized the association of obesity and pseudotumor cerebri. Forty-eight of their 61 cases were characterized as "fat young women."

The importance of considering aspartame disease under these circumstances is obvious. The patients usually have a good prognosis, and can be spared much anxiety and formidable medical or surgical interventions if this condition is recognized.

The diagnosis of pseudotumor cerebri was based on evidence for increased intracranial pressure, and the absence of infection, a mass lesion (brain tumor), obstruction of the ventricular system, and focal neurologic signs. The most prominent features were headache, papilledema and other ocular abnormalities (decreased vision; visual field loss; extraocular palsies).

The following considerations are germane:

* No patient had taken corticosteroids, excessive vitamin A, or other possible contributory drugs (tetracycline; nalidixic acid).

* One patient developed concomitant diabetes insipidus, which also improved dramatically after aspartame avoidance.

* A female third-year medical student was excluded from this series because definitive tests were not done to exclude an inferred "membrane blockage between the third and fourth ventricle." She refused to quit aspartame products despite pleas from her parents (nationally known writers.) She developed blurred vision, severe headache, and problems with speech while consuming considerable diet sodas and aspartame-sweetened coffee prior to her. final exams. A shunt procedure was being considered.

* Attending physicians confirmed the striking improvement after aspartame abstinence. For example, the visual changes and headache improved markedly in a patient after avoiding aspartame for several weeks. Her physician was impressed that there were now only three or four blind spots in the visual fields, whereas "the whole outer circle had been grayish for almost halfway in."

* A 31-year-old woman with diagnosed pseudotumor cerebri wrote: "I used aspartame in my tea in the morning, diet cola during the day, and aspartame sodas all evening. Nothing touched my lips unless it was aspartame. When someone told me about reactions to it, I stopped using aspartame, and am doing much better. They may not even do the brain surgery now to relieve the pressure!"

Other Neurologic Aspects of Aspartame Disease

Aspartame and its metabolites are neurotoxic, based on extensive observations and coporate-neural research over 15 years. (1-7) Women are afflicted with clinical aspartame disease three times more often than men in the data bases of both the author and the FDA. The diagnostic criteria appear in previous reports. (14)

The following neurologic manifestations occurred among the initial 1200 aspartame reactors in the author's series. (7) They included patients personally attended and persons providing detailed reports in a 9-page questionnaire. (3)

The foregoing complaints usually improved following aspartame avoidance, and promptly recurred after resuming aspartame products, knowingly or inadvertently. Some examples:

* The aggravation or simulation of diabetic neuropathy by aspartame has been emphasized. (3,4,10)

* More than 40 aspartame reactors were given the diagnosis of "probable multiple sclerosis" prior to an impressive remission after aspartante abstinence. (3,4)

* A female aspartame reactor experienced Bell's palsy, paresthesias, blurred vision, dizziness, tinnitus, insomnia, depression and a dermatitis. She improved when diet colas were avoided, but then evidenced recurrence of the Bell's palsy and other symptoms after resuming aspartame sodas.

The suspected causative or aggravating role of aspartame in human brain cancer (11) also warrants mention in this context.

Mechanisms of Aspartame Neurotoxicity

Each of the components of aspartame - phenylalanine (50%); aspartic acid (40%); and the methyl ester (10%) that promptly becomes free methyl alcohol (methanol) after ingestion -- and their multiple breakdown products after exposure to heat or during storage are potentially neurotoxic. The mechanisms may variously involve dopamine (derived from phenylalanine), cerebral cholecystokinin (CCK), serotonin, endorphins, other important neurotransmitters, neuroglucopenia, the unique permeability of the blood-brain barrier to phenylalanine, and the "aging" effect of the stereoisomer D-aspartic acid. (1,3-5) Others include methanol-induced cerebral edema and fluid disturbances, noted in humans and experimentally. (12-15)

The severe neurotoxic effects from chronic intake of free methanol are pertinent. Dr. Herbert S. Posner (16) (National Institute of Environmental Health Sciences) wrote a review titled, "Biohazards of Methanol in Proposed New Uses," six years before FDA approval of aspartame. He emphasized failure to recognize the "delayed and irreversible effects on the nervous system of methanol...at widely varying levels of exposure and at rather low levels."

The intake of methyl alcohol from natural sources is less than 10mg daily. (17) Aspartame beverages average 55 mg methanol per liter, but nearly twice as much in some sodas. Accordingly, individuals who drink five liters a day could ingest over 400 mg methanol!

Several aspects of chronic methanol intake are listed:

* Methyl alcohol, the first component of aspartame released within the small intestine, is rapidly absorbed.

* Blood and methanol concentrations correlate with the amount of aspartame taken. The elevated blood methanol concentrations in normal subjects who ingest "abuse doses" may be detectable for eight or more hours.

* Humans are more vulnerable to methanol toxicity than animals because several of the enzymes required for its metabolism have been lost in evolution.

* One-fourth of aspartame reactors experience eye problem," (1,3,4) presumably in large measure due to methanol and its breakdown products.

* Methanol toxicity is enhanced by its slow rate of oxidation. Although the half life is about three hours in human volunteers who ingest small amounts (1-5 ml), complete oxidation to carbon dioxide usually requires several days.

* Methyl alcohol is detoxified through its oxidation to formaldehyde, and within minutes to formate or formic acid. The latter contribute to nervous system and immune dysfunction. One mechanism involves the conjugation of formaldehyde with human serum albumin (F-HSA) to form a new antigenic determinant. Persons chronically exposed to formaldehyde develop anti F-HSA antibodies and elevated Tal cells (antigen memory cells), consistent with sustained antigenic stimulation of the immune system. (19)

Other studies clarify the chronic toxicity of aspartame-derived formaldehyde. The highly reactive formaldehyde molecule becomes bound to proteins and nucleic acids. The adducts formed are difficult to eliminate through usual metabolic pathways. Using adult male rats given oral aspartame (14) C-labeled in the methanol carbon, Trocho et al. (20) convincingly demonstrated that formaldehyde derived from dietary aspartame binds to tissue components in vivo. Most of the radioactivity was bound to protein in plasma and liver, and had a long half life. It also was detected in brain, cornea and retina. Furthermore, progressive accumulation of more label could be demonstrated when non-labeled aspartame was given over ten days, suggesting that aspartame-derived formaldehyde adducts are cumulative in tissue proteins and nucleic acids. These investigators commented, "The cumulative effects derived from the incorporation of label in the chronic administration model suggest that regular intake of aspartame may result in th e progressive accumulation of formaldehyde adducts. It may be further speculated that the formation of adducts can help to explain the chronic effects of aspartame consumption on sensitive tissues such as brain."

Addendum: Case histories of two additional women in their thirties with aspartame disease and pseudotumor cerebri have been received.

References

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(8.) Roberts HJ. Difficult Diagnosis: A Guide to the Interpretation of Obscure Illness Philadelphia, W. B. Saunders Co, 1958.

(9.) Wilson, DH, Gardner, WJ. Benign intracranial hypertension with particular reference to its occurrence in fat young women. Caned M A J 1966; 95:102-105.

(10.) Roberts HJ. Complications associated with aspartame (NutraSweet[R]) in diabetics. Clin Res 1998; 3:489A.

(11.) Roberts HJ. Does aspartame cause human brain cancer? J Advanc M 1991;4 (Winter):23 1-241.

(12.) Menne FR. Acute methyl alcohol poisoning: a report of 22 incidences with postmortem examination Arch Path 1938; 26:77.

(13.) Bennet IL Jr, Carey HI, Mitchell GL Jr, Cooper MN. Acute methyl alcohol poisoning. A review based on experiences in an outbreak of 323 cases. Medicine 1953; 32:431.

(14.) Erlanson P, at al. Severe methanol intoxication. Acta Med Scand 1965; 177:393.

(15.) Rao KR, Aurora AL, Mithaiyan S, Ramakrishnan S. Biochemical changes in brain in methanol poisoning - an experimental study. Indian J M Res 1977; 65:285-292.

(16.) Posner HS. Biohazards of methanol in proposed new uses. J Toxicol Environ Health 1975; 1:153-171.,

(17.) Monte WC. Aspartame: Methyl alcohol and the public health. J Appl Nutr 1984; 36:42-54.

(18.) Stegink HD, Filer IJ Jr. Aspartame: Physiology and Biochemistry. New York, Marcel Dekker, Inc. 1984.

(19.) Thrasher JF, Broughton A, Micevich P. Antibodies and immune profiles of individuals occupationally exposed to formaldehyde. Six case reports. Am J Indust M 1988; 14:479-488.

(20.) Trocho C, Pardo R, Rafecas T, et al. Formaldehyde derived from dietary aspartame binds to tissue components in vivo. Life Sci 1998; 63:337-349.

Correspondence: H.J. Roberts, MD, FACP, 6708 Pamela Lane, West Palm Beach, Florida 33405 USA, 561-588-7628, Fax 561-547-8008

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