Research Update (Part 1):

Aspartame

by Mark D. Gold, Steven Wm. Fowkes and Ward Dean, M.D.

Aspartame is the generic name for the sweet-tasting chemical found in such brand-name products as NutraSweet, Equal, Spoonful, and Equal-Measure. The sweetness of aspartame was accidentally discovered in 1965 when chemist James Schlatter spilled some aspartame while synthesizing an anti-ulcer drug for G.D. Searle and Company (Searle). Later, he touched his thumb to his tongue while turning the pages of his lab notebook and noticed an intense sweetness.

Aspartame is actually composed of three parts: a molecule of aspartic acid (an amino acid), a molecule of phenylalanine (another amino acid), and a molecule of methanol (methyl alcohol, or wood alcohol). When aspartame is heated with water (or digested in the human body), it breaks down into these components. Because of this, aspartame actually delivers phenylalanine, aspartate and methanol into the tissues of the body differently than these components would be transported naturally. As we will see, this may result in a significant toxicity profile for aspartame.

The Food and Drug Administration (FDA) approved aspartame as a food additive for dry goods in 1981 and for carbonated beverages in 1983.[1] In 1985, Monsanto purchased Searle and made the NutraSweet Company a separate subsidiary. Over the years, aspartame has come to be one of the most heavily consumed food additives in US history. This transition has not been without incident. Over 75 percent of the adverse reactions to food additives reported to the FDA are for aspartame.[2] Some of these reactions are quite serious, possibly including seizures and death.[3] A recent Department of Health and Human Services report listed 90 different symptoms linked to aspartame ingestion, including headaches (and migraines), dizziness, seizures, nausea, numbness, muscle spasms, weight gain, rashes, depression, fatigue, irritability, tachycardia, insomnia, vision problems, hearing loss, heart palpitations, breathing difficulties, anxiety attacks, slurred speech, loss of taste, tinnitus, vertigo, memory loss and joint pain.[3]

According to researchers and physicians studying the adverse effects of aspartame, many chronic illnesses can be triggered or worsened by aspartame, including epilepsy, brain tumors, lymphoma, chronic fatigue syndrome, Alzheimer’s and Parkinson’s diseases, mental retardation, birth defects, fibromyalgia and diabetes.[4,5] Other conditions that may be worsened by long-term exposure to excitatory amino acids include: multiple sclerosis (MS), amylotrophic lateral sclerosis (ALS), memory and hearing loss, hypoglycemia, AIDS dementia, brain lesions and neuroendocrine disorders.

Aspartate as Excitotoxin

Dr. Russell L. Blaylock, a professor of neurosurgery at the University of Mississippi Medical Center, recently published Excitotoxins: The Taste That Kills, a book thoroughly detailing the damage caused by ingestion of aspartic acid (from aspartame) and glutamic acid (as MSG). Dr. Blaylock cites almost 500 scientific references to demonstrate why excess excitatory amino acids (free aspartate and glutamate) in our food supply are causing serious chronic neurological disorders and a myriad of other acute symptoms.[6]

Aspartate and glutamate serve as excitatory brain neurotransmitters. They stimulate NMDA (N-methyl-D-aspartate) receptors which excite the target neurons to higher states of activity. At normal concentrations, aspartate and glutamate provide moderate stimulation, which is necessary to healthy brain function. At high concentrations, aspartate or glutamate can overstimulate neurons to such an extent that resulting influx of calcium kills sensitive neurons. This influx also triggers excessive free radical production. This combined toxicity is referred to as excitotoxicity, and aspartate and glutamate are excitotoxins.

Protein-Bound and Free Amino Acids

Amino acids can exist in a free form (all by themselves) or bound into groups. Small groups of amino acids (two or more) are called peptides, and large groups (dozens to thousands) are called proteins. Normally, most aspartate and glutamate in food is bound into proteins. When these proteins are digested, they are slowly broken down into large peptides, which are in turn broken down into small peptides and free amino acids for absorption. This process is gradual and results in a long, slow and even absorption profile.

Small peptides (2-5 amino acids) are most efficiently absorbed. These are broken down into free amino acids in the lumen (intestinal cell lining). Because small peptides contain semi-random collections of different amino acids, the delivery of amino acids to the blood stream from peptide absorption and digestion is even and smooth. In other words, all of the amino acids found in the food are evenly released into the blood stream over the same period of time and in the same ratio they are found in the food.

Free amino acids can also be absorbed, but, unlike peptides, this process is active (requiring ATP energy). It is also selective. In other words, the free-amino-acid transport protein has higher affinity for some amino acids than others. This results in an uneven absorption profile; some amino acids peak early in the absorption period, and others peak later. Efficiency of amino acid utilization is correspondingly impaired. This is what doctors and scientists mean when they speak of a poor nitrogen-retention ratio (amino acids contain nitrogen).

The amount of free amino acids produced during normal digestion is relatively small. But when free amino acids are directly consumed, like when MSG or hydrolyzed (predigested) proteins are added to foods, their quick absorption can result in peak amino acid levels far beyond what is normal. In the case of glutamate and aspartate, higher-than-normal blood levels can lead to higher-than-normal levels in certain regions of the brain, causing hyperstimulation and excitotoxicity. Some people appear to be much more sensitive to excitatory neurotransmitters than others.

The Blood-Brain Barrier

The blood-brain barrier normally protects the brain from toxins and other large-molecular compounds that are found in the blood. However, it allows seepage of excess glutamate and aspartate, even when operating optimally. The blood-brain barrier doesn’t protect all areas of the central nervous system, and it can become damaged or compromised by numerous chronic and acute conditions. Such conditions can increase sensitivity of some individuals to glutamate and aspartate.

Infants and children are at special risk due to the fact that the blood-brain barrier is not fully developed in early life. Even the Federation of American Societies For Experimental Biology (FASEB), which usually conservatively understates problems (and supports the FDA party-line), recently stated in a review that “it is prudent to avoid the use of dietary supplements of L-glutamic acid by pregnant women, infants, and children.”[7] They went on to state, “The existence of evidence of potential endocrine responses, i.e., elevated cortisol and prolactin, and differential responses between males and females, would also suggest a neuroendocrine link and that supplemental L-glutamic acid should be avoided by women of childbearing age and individuals with affective disorders.” Aspartic acid (aspartate) from aspartame has the same excitatory effect on the body as glutamic acid and MSG.

The process by which excess glutamate and aspartate destroy neurons is gradual. In experimental animals, a majority of neural cells in particular areas of the brain can be killed before any obvious behavioral symptoms are noticed.

Phenylalanine from Aspartame

Phenylalanine is an essential amino acid that is used by the brain to make several neurotransmitters. Some individuals with a rare genetic disorder (phenylketonuria) cannot metabolize phenylalanine properly, which can lead to dangerously high levels of phenylalanine in the brain. This condition is the reason that all aspartame-containing beverages are required to list the warning: Phenylketonurics: Contains Phenylalanine.

Even in normal people, ingesting aspartame can lead to excess levels of phenylalanine in the blood and brain, especially when it is consumed along with carbohydrates. Excessive levels of phenylalanine can cause decreases in the levels of serotonin, a brain neurotransmitter involved in emotion and sleep. Low serotonin can lead to emotional disorders, depression, and poor sleep quality. In human testing, blood levels of phenylalanine were increased significantly in human subjects who chronically used aspartame.[8] Even a single dose of aspartame raised blood phenylalanine levels. In Congressional hearings, Dr. Louis J. Elsas testified that high blood phenylalanine can lead to high concentrations in parts of the brain, and that phenylalanine is especially dangerous for infants and fetuses.[9] The degree to which aspartame may alter the experience and behavior of people may not be sufficiently appreciated.

As Dr. Blaylock points out in his book, early studies measuring phenylalanine buildup in the brain were flawed.[6] These investigators measured average phenylalanine levels throughout the entire brain, which did not change much. Subsequent investigators have studied localized brain regions and have found large phenylalanine increases in the hypothalamus, medulla oblongata, and corpus striatum.

Methanol from Aspartame

Methanol (aka wood alcohol) is a deadly poison. Some people may remember that methanol was the poison in contaminated bootleg liquor that caused some “skid row” alcoholics to end up blind or dead. Methanol is gradually released in the small intestine as the methyl group of aspartame encounters the enzyme chymotrypsin. It is also released as aspartame is hydrolyzed by heat and water (as happens in hot beverages or improperly stored liquids) or metabolized by other tissues in the body.

Methanol is metabolized by the liver into formaldehyde and formic acid. Formaldehyde is a deadly neurotoxin and a major ingredient of embalming fluid. An EPA assessment states that methanol “is considered a cumulative poison due to the low rate of excretion once it is absorbed.” The recommended limit for methanol consumption is 7.8 mg per day. A one-liter or one-quart aspartame-sweetened beverage contains more than 50 mg of methanol. Heavy users of aspartame-containing products consume as much as 250 mg of methanol daily — 32 times the EPA limit.[10]

Symptoms from methanol poisoning include headaches, tinnitus (ear buzzing or ringing), vertigo (dizziness), nausea, gastrointestinal disturbances, weakness, memory lapses, chills, behavioral disturbances, neuralgias (shooting pains in the extremities) neuropathies (numbness) and neuritis (nerve inflammation). The most prominent symptoms are often related to eye sight: misty, blurred or obscured vision, progressive contraction of visual field, retinal damage and overt blindness. Formaldehyde is also carcinogenic (cancer causing), mutagenic (DNA damaging) and teratogenic (birth defect causing).[11]

Due to the lack of a couple of key enzymes, humans are many times more sensitive to the toxic effects of methanol than animals. Therefore, tests of aspartame toxicity or methanol poisoning on animals may not accurately reflect the degree of danger for humans. As pointed out by Dr. Woodrow C. Monte, Director of the Food Science and Nutrition Laboratory at Arizona State University, “There are no human or mammalian studies to evaluate the possible mutagenic, teratogenic, or carcinogenic effects of chronic administration of methyl alcohol.”[12]

Dr. Monte was so concerned about the unresolved safety issues that he filed suit with the FDA requesting a hearing to address these issues. He asked the FDA to “slow down on this soft drink issue long enough to answer some of the important questions. It’s not fair that you are leaving the full burden of proof on the few of us who are concerned and have such limited resources. You must remember that you are the American public’s last defense. Once you allow usage (of aspartame) there is literally nothing I or my colleagues can do to reverse the course. Aspartame will then join saccharin, the sulfiting agents, and God knows how many other questionable compounds enjoined to insult the human constitution with governmental approval.”[11] Shortly thereafter, the then-Commissioner of the FDA, Arthur Hull Hayes, Jr., approved the use of aspartame in carbonated beverages and then left the FDA for a position with Searle’s public relations firm.[12]

Although some fruit juices and alcoholic beverages contain small amounts of methanol, it is important to remember that this naturally occurring methanol is accompanied by much larger quantities of ethanol (ethyl alcohol), an antidote for methanol toxicity in humans.[10]

Methanol toxicity may also be mitigated by antioxidant sulfur compounds. Cysteine (an amino acid) and glutathione (a cysteine-containing tripeptide) dramatically mitigate the toxicity of acetaldehyde, a close chemical cousin to the formaldehyde produced by the metabolism of methanol. Cysteine is available over the counter in the US, and it should be taken with at least several times as much vitamin C to keep it in its “reduced” (active) state.

The troops of Desert Storm were “treated” to large amounts of aspartame-sweetened beverages which had been heated to over 86°F in the Saudi Arabian desert sun. Many of them returned home with numerous disorders (collectively referred to as “Gulf War Syndrome” with symptoms similar to formaldehyde poisoning. The free methanol in the beverages may have been a contributing factor in these illnesses.

Despite the known temperature sensitivity of aspartame, the FDA approved aspartame in 1993 for numerous food items to be heated above 86°F.

Diketopiperazine

Diketopiperazine (DKP) is a by-product of aspartame hydrolysis (see Figure 1). It is produced during long-term storage of aspartame-containing beverages and possibly during ingestion of aspartame.[13] DKP has been implicated in the occurrence of brain tumors.

Although Searle conducted animal experiments on the safety of DKP, the FDA found numerous experimental errors, including “clerical errors, mixed-up animals, animals not getting drugs they were supposed to get, pathological specimens lost because of improper handling,” and others.[14,15] These sloppy laboratory procedures may explain why both the test and control animals had sixteen times more brain tumors than would be expected in experiments of this length.[16]

In an ironic twist, shortly after these experimental errors were discovered, the FDA used guidelines recommended by Searle to develop the industry-wide standards for Good Laboratory Practices.[12]

DKP has also been implicated as a cause of uterine polyps and changes in blood cholesterol by FDA Toxicologist Dr. Jacqueline Verrett in her testimony before the US Senate.[15,17]

Possible Biological Effects of Aspartame

The components of aspartame (aspartate, phenylalanine and methanol) can lead to a wide variety of ailments. Some of these problems occur gradually, others are immediate, acute reactions. Those people that experience acute reactions are much more likely to recognize the association between aspartame consumption and symptoms and cease using it. While a substantial majority of aspartame users appear not to be suffering immediate reactions to aspartame, some of these individuals may be experiencing subclinical (subtle) toxicity which, over the long term, may result in significant damage from chronic exposure to excitotoxins, phenylalanine, methanol, and DKP.

Part II of this article will discuss 1) the possible special risks of aspartame in various conditions (birth, brain tumors, cancer, diabetes, depression and epilepsy) 2) the scientific impropriety and regulatory dishonesty perpetrated by Searle in getting aspartame approved, 3) the FDA’s complicity in defending that approval (and their failure to implement the Delaney Amendment), 4) the special effects of aspartame on pilots (private, commercial and military), 5) the co-option of professional organizations, educational institutions and scientific publications, and 6) the elimination of competitive alternatives to aspartame.

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References and Footnotes

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