safety of aspartame Part 2/2 12.4.2: EC HCPD-G SCF: Murray 1.12.3: FDA Docket 02P-0317 Recall Aspartame as a Neurotoxic Drug
safety of aspartame Part 2/2 12.4.2: EC HCPD-G SCF:
Murray 1.12.3 rmforall:
FDA Docket 02P-0317 Recall Aspartame as a Neurotoxic Drug
Please post this to the FDA Dockets website.
Rich Murray, MA Room For All rmforall@...
1943 Otowi Road, Santa Fe, New Mexico 87505 USA 505-986-9103
[ Continued from Part 1/2 ]
Headache was one of the more common symptoms that was reported to the
FDA and evaluated by the CDC (Janssen and Van der Heijden, 1988;
Several studies were carried out to test the potential association
between aspartame intake and the onset of headaches. Although the
results of a questionnaire-based study (Lipton et al., 1989) and two
double-blind out-patient investigations (Koehler and Glaros, 1988; Van
Den Eeden et al., 1994) employing daily doses of up to 30 mg/kg bw/day
indicated a potential association between aspartame intakes and [p12]
headache, it was not possible to deduce causality as the effect of diet
had not been adequately controlled for and the interpretation of the
data was complicated by a high drop out rate and a limited experimental
Another study employing a controlled environment, which was also a
randomised double-blind placebo-controlled cross-over trial, concluded
that aspartame was no more likely than placebo to trigger headaches
(Schiffman et al., 1987). This study consisted of 40 subjects who
complained of aspartame-related headaches. Subjects received aspartame
challenges on days three or five at a total dose of 30 mg/kg bw
(for a 70 kg person); subjects received placebo on the other days. While
35% of subjects developed headaches while on aspartame, 45% developed
headaches while on placebo. In addition, no treatment related effects
were detected in blood pressure, or plasma concentrations of cortisol,
insulin, glucagon, histamine, epinephrine or norepinephrine. The
subjects who had headaches had lower plasma concentrations of
norepinephrine and epinephrine just before the development of headache.
This study has been criticised for using tightly controlled experimental
conditions which did not mimic normal life (Edmeads, 1988), but
Schiffman et al. (1987) argued that the nature of the study and the
primary focus of the questions raised by CDC dictated that they
use carefully controlled conditions at a hospital setting.
The AFSSA (2002) report noted that Among the possible adverse effects
of aspartame, researchers have paid particular attention to seizures.
Several studies have suggested a relationship between the consumption of
large amounts of aspartame and the triggering of epileptic seizures. In
an old study (1972), on new-born monkeys (2-3 animals per group) treated
with doses of aspartame of 1, 3 and 4g/kg bw/day for 52 weeks, epileptic
seizures were recorded at the highest doses, after 218 days of
treatment. Thereafter, sporadic convulsions were observed during
handling of the animals. These symptoms were identical with those
observed in young monkeys treated with phenylalanine.
In contrast, in a similar study also conducted on young monkeys, no
effect was observed at doses of aspartame of 2 and 2.7 g/kg bw/day. The
different results observed in the two studies could be explained by
differences in the exposure conditions, the food and the state of health
of the animals (JECFA, 1980).
Walton et al. (1993) reported, in a study conducted on 13 patients
suffering from depression, that the administration of 30 mg/kg bw/day of
aspartame for 7 days caused severe side effects in these patients which
led the authors to conclude that the use of this sweetener in depressive
patients should be avoided.
The same author (Walton, 1986) reported a case of 7 epileptic [p13]
seizures and serious behavioural problems in a woman being treated with
antidepressants who ingested large quantities of tea containing
Wurtman (1985) indicated that the administration of aspartame, due to
an increase in phenylalanine absorption in the brain, could affect the
synthesis of catecholamines or serotonin and cause seizures. He based
his findings on three examples of heavy consumers of diet drinks and
on experimental studies on animals demonstrating that the consumption of
aspartame reduced the threshold of sensitivity to chemically induced
seizures (Maher et al., 1987; Guiso et al.,1988; Pinto et al., 1988).
Finally Camfield et al. (1992) demonstrated that aspartame could
increase the duration of certain types of epileptic seizure in
The ATIC on the Internet reported a large amount of evidence from
people who have identified aspartame as the cause of their health
problems and in particular of seizures. These statements should be taken
into account but with the reservation that they have not been examined
according to any academic standard. They may, however, in certain cases,
reflect the hypersensitivity of certain individuals to aspartame or its
Effects on seizures have been reported with phenylalanine, aspartic acid
and methanol but these were under specific conditions (high doses,
individual sensitivity, types of seizures, etc.) which are not
representative of the general population and of current use of this
sweetener in food (Anderson et al., 1996).
This causal relationship between aspartame and epileptic seizures has
been refuted by a large number of scientists who base their opinions on
numerous experimental studies conducted on laboratory animals or on
clinical or tolerance studies in humans (Anderson et al., 1996; Gaull,
1985; Rowan et al., 1995; Shaywitz et al., 1994; Tollefson et al., 1992;
1993; Dailey et al., 1991; Zhi et al., 1989; Sze, 1989; Tilson et al.,
The Epilepsy Institute in the USA has also concluded that aspartame is
not the cause of epileptic seizures (Congressional Record, June 20,
In the United States various consumer complaints about aspartame have
been collected by the Special Nutritionals Adverse Event Monitoring
System (SN/AEMS). The sources of these reports were the FDA, federal and
local health agencies, consumers and health professionals. Of 2621 side
effects reported, concerning 3451 products, some ten cases concerned
preparations concerning aspartame (mixtures also containing vitamins,
amino acids and various nutritional supplements). The effects reported
included seizures, death, nervous and cardiac symptoms, oedema and
Still in the United States, the Center for Disease Control assessed 517
complaints about aspartame (1983). The symptoms reported were headaches,
mood changes, insomnia, abdominal pain, nausea, convulsions, etc These
symptoms are observed frequently in the general population. Although it
might be possible that certain individuals are particularly sensitive to
aspartame, these data, which relate to a large number of people, have
not enabled any relationship to be demonstrated between the consumption
of aspartame and the occurrence of convulsive seizures.
Other effects [p14]
Idiosyncratic reactions described as allergic-like (hives, rashes) were
reported by some consumers to CDC in response to aspartame (Tollefson,
However, the results of a multi-centre, randomised, double-blind,
placebo-controlled, cross-over study in individuals who were convinced
they were allergic to aspartame indicated that aspartame and its
conversion products are no more likely than placebo to cause
urticaria and angio-oedema (Geha et al., 1993).
This finding was supported by the outcome of another study, which also
demonstrated that alleged allergic reactions to aspartame were not
reproducible under blinded conditions (Garriga et al., 1991).
However as with the Geha et al. (1993) study, the authors reported major
difficulties in enrolling subjects with a history of
allergy/hypersensitivity reactions to aspartame.
A number of other studies focused on the effects of aspartame on hunger
and food intake (Rolls and Shide, 1996) and in the control of body
weight (Kanders et al., 1996). Sensory and post-ingestion experience
with aspartame was reported by these reviewers not to be associated with
increased energy intake or increases in body weight.
Since the SCFs extensive reviews of aspartame were carried out in 1984
and 1988 (SCF, 1985, 1989), the objective of the present review was to
identify any more recent data suggesting there might be additional
endpoints requiring evaluation or effects at lower doses than those
previously considered. To this end, consideration has been given to
aspects of metabolism and toxicity as well as to clinical studies
conducted to address the reported adverse effects of aspartame in
healthy and potentially sensitive individuals.
Consideration has also been given to recent estimates of intake.
Aspartame is unique among the intense sweeteners in that the intake of
its component parts can be compared with intakes of the same substances
from natural foods. It is clear that the consumption of aspartame
represents only a minor source of aspartic acid, Phe or methanol in the
diet (Renwick, 1990). The available estimates of intake of aspartame by
mean and high level consumers are fairly consistent among European
countries, even though different approaches were used for the
assessment. They show that intakes in high level consumers, including
adults, children, and diabetics of all ages, range up to 10 mg/kg bw/day
and thus are unlikely to exceed the current ADI for aspartame of 40
mg/kg bw established by the SCF (1985, 1989).
Studies both in healthy subjects and in PKU heterozygotes confirm the
SCFs earlier conclusion (SCF, 1989) that despite the plasma variations
in Phe levels following single and repeated administrations of
aspartame, Phe levels generally remain within normal postprandial
In 1996, a report suggesting a connection between aspartame and an
increase in the incidence of brain tumours in the USA was published
(Olney et al., 1996).
The SCF considered this report and concluded that the data did not
support the proposed biphasic increase in the incidence of brain tumours
The issue had also been considered earlier by the FDA and by the UK
Committee on Carcinogenicity of Chemicals in Food, Consumer Products and
the Environment (COC). The FDA stated that analysis of the National
Cancer Institute database on cancer incidence in the USA did not support
an association between the use of aspartame and increased incidence of
brain tumours (FDA, 1996). The COC agreed that the findings provided no
evidence of the proposed biphasic increase in the incidence or either
all brain tumours or selected tumour types in the USA during the 1980s
and concluded that the data published by Olney et al. did not raise any
concerns with regard to the use of aspartame in the UK (COC, 1996).
The recent review by AFSSA (2002) covered all the original experimental
studies and concluded that aspartame and DKP are not genotoxic and that
none of the carcinogenicity tests on rodents indicate a relationship
between treatment with aspartame and the appearance of brain tumours.
The Committee agrees with this conclusion concerning the experimental
AFSSA also reviewed more recent publications on the human
epidemiological data and concluded that The epidemiological study by
Olney et al., which suggested a link between the placing on the market
of aspartame and a possible increase in the frequency of brain cancers
in humans, did not provide any scientific evidence to justify or
demonstrate a basis for this suggestion; to date it has not been
confirmed. (AFSSA, 2002).
The Committee agrees with this view and reaffirms its conclusion of
1997 (SCF, 1997).
The Committee has also reviewed the study by Trocho et al. (1998), who
reported the occurrence of stable DNA and protein adducts in the liver
of rats following aspartame administration. The Committee noted that the
study used aspartame radiolabelled on the methanol portion, and that
during metabolism of aspartame in the gut, radiolabelled methanol will
be split off and enter the bodys one-carbon pool, with the potential to
appear anywhere there is methylation. The Committee therefore agrees
with the analysis of Tephly (1999) that formation of DNA adducts has not
AFSSA (2002) has also evaluated the scientific literature on epilepsy
and EEG anomalies and concluded that there is a lack of evidence, based
on the current state of knowledge, which would enable a causal link to
be established between the consumption of aspartame and the occurrence
of epileptic seizures or anomalies on an electro-encephalogram. The
Committee agrees with this conclusion of AFSSA.
The present review also addressed the data on other neurological
endpoints including cognition, mood and behaviour. Although the data
varied in quality, evidence for a causal relationship between aspartame
consumption and these endpoints could not be [p16] established.
The Committee noted that despite targeted animal studies, no consistent
effects of aspartame on neurotransmitters or their precursors have been
Studies have also been specifically designed to follow up individuals
reporting that they were sensitive to aspartame during post-marketing
surveillance, together with studies on individuals, including children,
who, because of underlying medical conditions, might be considered
sensitive to aspartame. Aspartame administration did not induce changes
in behaviour, cognition, mood or learning.
The data on headaches received special consideration as this was a
commonly reported symptom during postmarketing surveillance. The data on
headaches vary in quality, but the one well, controlled double-blind,
cross-over trial showed that aspartame was no more likely than placebo
to be associated with headaches.
Studies on allergic-like reactions in individuals who themselves
reported such reactions to aspartame have not confirmed their occurrence
when later studied under controlled conditions.
The Committee concluded that on the basis of its review of all the data
in animals and humans available to date, there is no evidence to suggest
that there is a need to revise the outcome of the earlier risk
assessment or the ADI previously established for aspartame. [p17]
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aspartame: methanol, formaldehyde, formic acid toxicity:
brief review: Murray 1.10.3 rmforall
for 958 posts in a public searchable archive
formaldehyde & formic acid from methanol in aspartame:
Murray: 12.9.2 rmforall
It is certain that high levels of aspartame use, above 2 liters daily
for months and years, must lead to chronic formaldehyde-formic acid
toxicity, since 11% of aspartame (1,120 mg in 2L diet soda, 5.6 12-oz
cans) is 123 mg methanol (wood alcohol), immediately released into the
body after drinking (unlike the large levels of methanol locked up in
molecules inside many fruits), then quickly transformed into
formaldehyde, which in turn becomes formic acid, both of which in
time become carbon dioxide and water-- however, about 30% of the
methanol remains in the body as cumulative durable toxic metabolites of
formaldehyde and formic acid-- 37 mg daily, a gram every month.
If 10% of the methanol is retained as formaldehyde, that would give 12
mg daily formaldehyde accumulation, about 60 times more than the 0.2 mg
from 10% retention of the 2 mg EPA daily limit for formaldehyde in
Bear in mind that the EPA limit for formaldehyde in
drinking water is 1 ppm,
or 2 mg daily for a typical daily consumption of 2 L of water.
RTM: ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999
This long-term low-level chronic toxic exposure leads to typical
patterns of increasingly severe complex symptoms, starting with
headache, fatigue, joint pain, irritability, memory loss, and leading to
vision and eye problems and even seizures. In many cases there is
addiction. Probably there are immune system disorders, with a
hypersensitivity to these toxins and other chemicals.
Confirming evidence and a general theory are given by Pall (2002):
testable theory of MCS type diseases, vicious cycle of nitric oxide &
peroxynitrite: MSG: formaldehyde-methanol-aspartame:
Martin L. Pall: Murray: 12.9.2 rmforall
Functional Therapeutics in Neurodegenerative Disease Part 1/2:
Perlmutter 7.15.99: Murray 1.10.3 rmforall
formaldehyde toxicity: Thrasher & Kilburn: Shaham: EPA: Gold: Murray:
Wilson: CIIN: 12.12.2 rmforall