Aspartame

The food additive aspartame is a low-calorie, artificial sweetener - approximately 200

times sweeter than sugar. It is authorised world-wide, including in the European Union.
Aspartame is used in drinks, desserts, sweets, dairy products, chewing gums, energy-reduced and
weight control products, and as a table-top sweetener.1
Aspartame is composed of phenylalanine (50%), aspartic acid (40%) and methanol (10%)
which are also components of proteins in our body and in food. 1,2 The first two are known as
amino acid isolates. The phenylalanine in aspartame has been slightly modified by adding a
methyl group which gives aspartame its sweet taste.1 It has been reported that consumption of
aspartame could cause neurological and behavioural disturbances in sensitive individuals
Aspartame is fully broken down in our gut to aspartic acid and phenylalanine, which are
absorbed and enter our body. In addition, the methyl group from the modified phenylalanine is
released in the gut to form methanol. Methanol is also absorbed by the body and most of it used
to produce energy.
Phenylalanine may cross the bloodbrain 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.2
All the scientific studies to date in animals and human volunteers have shown that the
breakdown of aspartame in the gut is very rapid and complete. No aspartame has ever been
found in the blood or any organ after ingestion.1

Astrocytes influence on the transportation of phenylalanine

One of the major metabolite of aspartame is phenylalanine (Phe), the sweeteners
breakdown product.3 Phenylalanine can follow one of the two pathways of uptake in the body. A
part is converted into tyrosine (a nonessential amino acid) in the liver by the enzyme
phenylalanine hydroxylase. The remaining portion of phenylalanine (not converted in the liver)
will bind to a large neutral amino acid transporter (NAAT) to be carried over the bloodbrain
barrier (BBB).2

It is partly transformed into tyrosine by phenylalanine hydroxylase and then to L-3,4

dihydroxyphenylalanine (DOPA), dopamine (DA), noradrenaline (NA) and adrenaline (A) in the
liver. Phenylalanine may be used in protein synthesis and also to convert into phenylpyruvic acid
present in high concentration in patients with phenylketonuria (PKU).3
The remaining pool of phenylalanine crosses to the brain by neutral amino acid
transporters (NAAT) mainly situated in capillary vessels, a part of blood brain barrier (BBB). 3
These transporters are used to transport various amino acids: glutamine, histidine, methionine,
serine, threonine, tyrosine and tryptophan,which are important for neurotransmitters synthesis. 3
Astrocytes are involved in the modulation of the blood-brain barrier and thus influence
the transport of amino acids by the endothelium. 3 Presumably, astrocytes are directly involved in
the transport of phenylalanine and in the increase of its concentration in the brain after
consumption of aspartame.3
One of the essential amino acids delivered to the CNS by the BBB is tyrosine (Tyr)
required for the synthesis of dopamine (DA) and nonessential amino acid tryptophan (Trp)
involved in the formation of serotonin (5-HT). As a result of lack of neutral amino acid
transporters after binding phenylalanine to them, there is a deficiency of other amino acids
resulting in decreased production of these two neurotransmitters.3
A large number of compounds, including phenylalanine and tyrosine, compete with each
other for a binding site on the NAAT, because it is the only manner in which they can cross the
BBB. Importantly, tyrosine cannot be synthesized in the brain and has have to enter the BBB via
NAAT for production.2
Low dopamine levels in neurons of the substantia nigra in the midbrain forming neural
pathways reaching the striatum (globus pallidus, putamen and nucleus caudatus) and brain
cortex, lead to a reduction in mobility, balance and walking. These alterations are the first
symptoms of Parkinsons disease.3
Lower levels of serotonin in the hippocampus, raphe nucleus of the brain stem and
substantia nigra in the midbrain affect sleep, memory, sensory perception, control of mood,
temperature regulation disorders, depression and anxiety in adults.3

In summary, phenylalanine can directly influence the reduction of other important amino
acids penetration into the CNS by its competition for NAAT transporters. Consequently, it affects
indirectly the deficiency of certain neurotransmitters leading to functional disorders.3

Excitotoxicity of aspartate and glutamate in the CNS

Aspartic acid is thought to play a role as an excitatory neurotransmitter in the central
nervous system responsible for transmission of impulses between neurons.2,3 Glutamate,
asparagines and glutamine are formed from their precursor, aspartic acid.
Aspartate is the precursor for such amino acids as asparagine, glutamate and glutamine.
The excess of them, particularly glutamate, leads to hyperexcitability of neurons and is one of
the factors that induce death of neurons and astrocytes.3
Glutamate (Glu), a neurotransmitter is present in glutamatergic synapses of all neurons
in the mammalian brain. Astrocytes play a significant role in maintaining proper homeostasis of
these amino acids. Glutamate and aspartate released from neurons in excess are collected by the
astrocytic excitatory amino acid transporters.3
In addition, Mehl-Madrona (2005) observed that when the temperature of aspartame
exceeds 861F, the wood alcohol in aspartame is converted into formaldehyde and then to formic
acid, which in turn causes metabolic acidosis. The methanol toxicity is thought to mimic the
symptoms of multiple sclerosis. According to them, symptoms of fibromyalgia, spasms, shooting
pains, numbness in the legs, cramps, vertigo, dizziness, headaches, tinnitus, joint pain,
depression, anxiety, slurred speech, blurred vision or memory loss have been attributed to
aspartame.2
In summary, a metabolite of aspartame aspartate affects the excess of glutamate in the
CNS and both of these amino acids are excitotoxins for neurons and astrocytes. alterations in
neurons and astrocytes are similar to those occurring in neuro degenerative diseases such as
Alzheimers disease, epilepsy, Huntington's disease and multiple sclerosis.3

Methanols slight influence on brain structures

Another product produced by the metabolism of aspartame is methanol which constitutes
10% of the breakdown products of the sweetener.3
After consumption of aspartame methanol is converted to formaldehyde and then to
formic acid. Initially, methyl alcohol, which is weaker than ethanol, affects the depression of the
central nervous system.3
This is the latency period after which blurred vision and even blindness occur under the
influence of the transformation of methanol to formaldehyde in the retina. As a result of the
accumulation of formate, metabolic acidosis occurs and this may eventually cause CNS
depression, coma and death from respiratory system paralysis.3
Diketopiperazine aspartame metabolite formed as a result of prolonged storage of food
products
It has been suggested recently that the derivative of aspartame: diketopiperazine (DKP) is
a major carcinogenic factor. It arises as a result of prolonged storage of products containing the
sweetener in high temperature and pH above 6. Studies on aspartame sweetened beverages in the
Polish market showed the highest concentrations of phenylalanine and diketopiperazine in
energy drinks and cola.1,3
One major cause of perennial speculation about the safety of aspartame was its
carcinogenic effect on the brain. The debate on carcinogenicity of the sweetener started in the
1980s after approval of aspartame by the Food and Drug Administration (FDA) as an acceptable
food product.3
On the strength of studies conducted by the FDA, Onley et al. concluded that aspartame
may be a carcinogen. Researches on Sprague-Dawleys rats revealed the presence of minor
amounts of brain tumours originating mainly from the glial tissue, including the astrocytes. They
were gliomas: astrocytomas, oligodendrogliomas and also medulloblastomas and meningiomas.3
Their assertion was based on the data from the U.S. Surveillance, Epidemiology and End
Results (SEER) Program, supported by the National Cancer Institute (NCI). They noticed that
the incidence of brain tumours has increased with the appearance of aspartame on the market.
Moreover, based on the findings of Shepard et al., they assumed that the cause of the brain
tumours is the nitrosated aspartame.3

Dopamine involvement in emotional status and learning

In the preceding sections it was noted that when phenylalanine, one of the main
component of aspartame, competes with tyrosine for NAAT, a compromised dopamine
production will result, because phenylalanine will bind more frequently and freely than tyrosine
owing to its higher concentration. This will thus lead to lower concentrations of dopamine in the
brain.2
Dopamine receptors are numbered D1, D2, D3, D4 and D5 receptors, all playing an
important role in the dopaminergic system. The dopaminergic system is active in maintaining
normal motor behaviour, and loss of dopamine is related to Parkinsons disease, in which the
muscles are rigid and movement is difficult.2
Disturbances of the development of the dopaminergic system may lead to dyskinesia,
dystonia, tics, obsessivecompulsive disorders and abnormal eye movements.2

Implications of aspartame consumption for early brain development and everyday living.
Ingestion of aspartame results in a craving for carbohydrates, which will eventually result
in weight gain, especially because the formaldehyde stores in the fat cells, particularly in the hips
and thighs; therefore, aspartame is believed to cause problem in diabetic control.2
In addition, prenatal consumption of aspartame might result in mental retardation,
impaired vision, birth defects and is thought to play a role in the pathogenesis of Alzheimers
disease; furthermore, it is implicated in disruption of learning and emotional functioning due to
its involvement in alteration of certain neurotransmitters.2,3
The earlier research findings show that aspartame consumption might affect early brain
development and neurotransmitter systems, which might result in specific emotional, behavioural
and learning difficulties.3

Conclusion
These glial cells modulate BBB by functional changes in endothelial neutral amino acid
transporters. As a result of consuming aspartame, phenylalanine shows a significant affinity for
the NAAT transporters in the BBB blocking access for the essential amino acids necessary to the
synthesis of dopamine and serotonin in the CNS. Astrocytes may play an indirect role in this
process.3
Aspartate present in excess as a metabolite of aspartame is neurotoxic and it is a substrate
for glutamate. The methanol, contained in aspartame, is insufficient to bring about alterations in
the CNS. Astrocytes are the source of cancers such as astrocytoma caused by the carcinogenic
effect of diketopiperazine.2,3

Reference
1.

EFSA

Explains

The

Safety

of

Aspartame,

Availabe

at

http://www.efsa.europa.eu/sites/default/files/corporate_publications/files/factsheetasparta
me.pdf
2. Humpries.P, Pretorius.E, Naude.H,(2008), Direct and Indirect Cellular Effects of
Aspartame on the Brain, European Journal of Clinical Nutrition.
3. Rycerz Karol, Jaworska-Adamu Jadwiga Elzbieta,(2013), Effects of Aspartame
Metabolites on Astrocytes and Neuron, Department of Animal Anatomy and Histology,
Faculty of Veterinary Medicine, University of Life Sciences, Lublin, Poland