Epilepsia, 36(3):270-275, 1995 Raven Press, Ltd., New York Q International League Against Epilepsy
Aspartame and Seizure Susceptibility: Results of a Clinical Study in Reportedly Sensitive Individuals
A. James Rowan, *Bennett A. Shaywitz, Linda Tuchman, Jacqueline A. French, Daniel Luciano, and *Colleen M. Sullivan
Departments of Neurology, Department of Veterans Affairs Medical Center, Bronx; and Mount Sinai School of Medicine, New York, New York; and *Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, U.S.A.
Summary: The high intensity sweetener aspartame has been implicated anecdotally in seizure provocation. This possibility was investigated with a randomized, double- blind, placebo-controlled,cross-over study. After an ex- tensive search, 18 individuals (16 adults and 2 children) who had seizures allegedly related to aspartame con- sumption were admitted to adult or pediatric epilepsy monitoring units where their EEG was monitored contin- uously for 5 days. Aspartame (50 mg/kg) or identically enpackaged placebo was administered in divided doses at 0800, 10o0, and 1200 h on study days 2 and 4. All meals
Aspartame (L-aspartyl-L-phenylalanine methyl ester), a widely used artificial sweetener, has been alleged to be responsible for provoking epileptic sei- zures. These allegations are based both on anec- dotal reports (Wurtman, 1985; Walton, 1986, 1988; Eshel and Sarova-Pinhas, 1993) and on consumer complaints lodged with the U.S. Food and Drug Administration (Tollefson, 1988). The FDA re- quested a review of these complaints by the Centers for Disease Control (CDC, 1984). The CDC evalu- ation failed to support a relation between seizures and aspartame. Many accounts contained insuffi- cient detail either to diagnose the occurrence of a true seizure or to determine a cause-effect relation (CDC, 1984). The CDC report further stated that a causal relation between seizures and aspartame could be established only through "focused" clinical studies; i.e., by prospective evaluation with well-controlled study methods of the specific indi- viduals who complained of seizures related to aspartame.
Received December 1993; revision accepted June 1994.
Address correspondence and reprint requests to Dr. A. J. Rowan at Neurology Service, Bronx V A Medical Center, 130 W. Kingsbridge Rd., Bronx, NY 10468, U.S.A.
were uniformly standardized on treatment days. No clin- ical seizures or other adverse experiences were observed after aspartame ingestion. Mean plasma phenylalanine (Phe) concentrations increased significantly after aspar- tame ingestion (83.6 pIM) as compared with placebo (52.3 p m . Results suggest that aspartame, in acute dosage of -50 mg/kg, is no more likely than placebo to cause sei- zures in individuals who reported that their seizures were provoked by aspartame consumption. Key Words: Aspar- tame-Electroencephalography-Aminoacids- Seizures-Clinical trials.
partame consumption. Because of the widespread consumption of aspartame-containing products, de- termining whether certain "sensitive" individuals may have seizures induced by aspartame consump- tion clearly is an important public health issue. To investigate the validity of reports of seizures result- ing from aspartame consumption, we conducted a randomized, double-blind, placebo-controlled cross-over study in 18 individuals who had experi- enced seizures reportedly related to aspartame con- sumption.
METHODS
From 1986 to 1990, 159 recruitment letters were sent to individuals who had become known to the FDA, CDC, or the The NutraSweet Company and who claimed to have experienced seizures after consuming aspartame or who had come to our at- tention as a result of our canvassing of 8,760 adult and pediatric neurologists by letter. In addition, ad- vertisements were placed in two neurologicjournals (Neurology and Archives of Neurology) requesting neurologists' identification of such individuals. These exhaustive recruitment efforts resulted in
270
only 18 study subjects (16 adults and 2 children) who had seizures reportedly related to aspartame, considerably fewer than the 30 adults and 30 children provided for in the original protocols. Our dif- ficulty in locating subjects was unexpected in view of the numbers of aspartame-sensitive individuals suggested by the monitoring systems. Recruitment efforts continued for 5 years and were abandoned only after it became clear that few if any additional subjects would be found. Subjects eligible for study must have experienced an epileptic seizure report-
edly due to aspartame. The seizure must have oc- curred within 24 h after ingestion of an aspartame- containing product. The age range for children was 4-17 years; no age limit was set for adults. Those treated with antiepileptic drugs (AEDs) were required to have received a stable regimen for at least 30 days before study entry. Subjects with phenylke- tonuria (PKU) were excluded, as were those who had consumed aspartame-containing products or who had had clinical seizures S 7 days before the start of study. Those with serious medical or pro- gressive neurologic disease were excluded.
Initial screening for possible entry into the study was conducted by a pediatric neurologist or an adult neurologist specializing in epilepsy, neither of whom was directly involved in the study. Evalua- tion included a detailed neurologic and medical his- tory and a comprehensive neurologic examination. Participants signed informed consent that was ap- proved by the respective institutional review boards.
Preadmission and test procedures are shown in Table 1. Subjects were admitted either to the Epi- lepsy Unit of the Bronx VA Medical Center or the Pediatric Service of Yale-New Haven Hospital. Five days of continuous EEG recording were per- formed by a seven-channel ambulatory cassette EEG recording (Oxford 9000) using a previously de- scribed standard montage (Ebersole and LeRoy,
1983). AEDs and any other medications were ad- ministered according to the subject's usual schedule. During the day, hard-copy EEG writeout in addition to standard cassette recording was performed in adults. Subjects were allowed almost full mobility, limited only by the cable (50 feet) between the cassette recorder and the EEG machine. In a living-room setting, they conducted normal daytime activities, including reading, TV viewing, and con- versation. Continuous closed-circuit television (CCTV) monitoring of adult subjects was used dur- ing the day to record behavior. At night, cassette recording without CCTV was used. Subjects were required to remain in the monitoring room at all times except when permitted to make telephone
TABLE 1. Study protocol Study dayltest and procedure
Preadmission Medical history Physical examination Neurologic examination Adverse experience questionnaire Drug history Routine hematology Routine blood chemistries Urinalysis Plasma amino acids Standard EEG AED concentrations CT scana
Day 1: Admission Day 2: Baseline I
Plasma amino acids (0745 h) AED concentrations (0745 h) Continuous 24-h EEG telemetry
Day 3: Treatment I Plasma amino acids (0745 and 1145 h) AED concentrations (0745 h) Continuous 24 hour EEG telemetry Test article administration (0800, 1000, and 1200 h)
Day 4: Baseline I1 Same as day 2
Day 5: Treatment I1 Crossover with treatment, same schedule as day 3
Day 6: Baseline 111, same as day 2 plus Physical examination Neurologic examination Routine hematology
Routine blood chemistries Urinalysis
AED, antiepileptic drugs; CT, computed tomography. a If not done within 6 months of study.
calls or to take an evening walk if accompanied by study personnel.
On treatment days, subjects received either as- partame or identically packaged placebo (micro- crystalline cellulose) capsules according to a com- puter-generated random assignment schedule. As- partame was administered in capsules of 300 mg in a -5O-mg/kg dose. The total dose was divided into three equal doses administered at 0800, 1000, and
1200 h. The 0800- and 1200-h doses were administered with standard meals, and the 1000-h dose was administered with 8 ounces of water. Identical food intake was required on the 2 treatment days. In ad- dition, subjects were required to sip a small amount of sweet juice before taking the capsules to mask any residual sweetness that might adhere to the capsule surface.
AED levels were determined by homologous en- zyme immunoassay (EMIT). Amino acid profiles were determined from whole blood collected in so- dium heparin. Frozen plasma samples were for- warded to L.D. Stegink at the University of Iowa for analysis with a Beckman Amino Acid Analyzer (Stegink et al., 1985).
ASPARTAME AND SEIZURE SUSCEPTIBILITY 271
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272 A. J. ROWAN ET AL.
The five cassettes from each subject representing 5 days of continuous EEG monitoring were randomized by the study coordinator and identified by numbers 1-5. Cassettes were played through an Oxford playback unit in numerical sequence. EEGs were quantified for the presence of epileptiform discharges (ED) defined as spikes, sharp waves, and spike-wave or polyspike-wave complexes.
Discrete discharges were enumerated for each 16-s epoch, and totals were tabulated for each hour of recording. In the event of runs of epileptiform activity, the type of discharge and total number of seconds in each run were recorded. For purposes of analysis, all discrete epileptiform discharges, re- gardless of type, were summed for any 24-h period. We also made a separate analysis of discharges oc- curring during wakefulness and sleep. Occurrence of any electrographic seizure, along with its char- acteristics and duration, was also noted. Record- ings were also rated for sleep stage according to the criteria of Rechtschaffen and Kales (1968).
The plan for statistical analysis was developed before the blind was broken. Data from children and adults were pooled except for those of subject
17, who experienced occupational exposure to as- partame. Supplementary analyses including subject 17 were also performed to evaluate the impact of the exclusion. Codes disclosing treatment se- quences were not broken until a computer database including all response variables and adverse expe- riences was complete. The primary variable for sta- tistical analysis was seizure incidence. Ancillary variables were (a) incidence of subjects differing in the number of epileptiform discharges (defined as spike, sharp wave, spike-wave, and polyspike-wave discharges) between aspartame and placebo periods, and (b) incidence of subjects whose total count of ED differed between treatment days.
The statistical method used for incidence variables was the exact form of McNemar's test (Fleiss, 1981); a 5% two-sided level was considered statistically significant. No formal adjustments were made for multiplicity of response variables. Amino acid data were assessed by analysis of variance ap- propriate to a two-period cross-over study.
RESULTS
Thirty-sixindividualswere screenedto determine their eligibility for inclusion in the study. Twenty- nine of the 36 potential subjects were judged eligi- ble; 7 did not meet protocol criteria (3 did not have a verifiable seizure after aspartame consumption, 1 had a cerebral neoplasm, 1 had severe hyperten- sion, 1 was pregnant, and 1 had a psychiatric disturbance). Eighteen agreed to participate; the re- mainder declined for personal reasons. The study group consisted of 16 adults and 2 children. The 2 children were aged 10 and 15 years; the 16 adults were aged 20-70 years (mean 35 years). The 16 fe- males and two males resided in 15 states. No im- portant abnormalities were noted on computed to- mography scan or neurologic examinations. The screening EEG showed abnormalities in 13 sub- jects. Fourteen of the 18 subjects had experienced recurrent seizures; 4 had only single seizures. His- tory of 9 subjects showed only generalized convul- sions; 7 others had generalized convulsions to- gether with either absence seizures (4 subjects) or complex partial seizures (3 subjects) (CPS). One subject had only CPS, and 1 had loss of conscious- ness without motor activity. Sixteen were receiving AEDs at the time of study.
All subjects except subject 17 had a history of aspartame-containingsoft drink consumption of 12- 108 ouncedday (mean 49.3 ounces). Seven used other aspartame-containing products, including chewing gum, sugar substitute (Equal), cereal, tea, or lemonade. Subject 17 had only respiratory and dermal contact with aspartame through occupa- tional exposure.
Nine subjects received aspartame on treatment day 1 followed by placebo on day 2; the other 9 received placebo followed by aspartame. Aspar- tame dose ranged from 45.1 to 64.5 mg/kg (mean 50.4 mg/kg). The 64.5 mg/kg dose was administered to a child who weighed 27.9 kg. The maximum dose administered to adults was 54.5 mg/kg.
No clinical seizures were observed during the course of the study. Electrographic seizures during sleep, during which no CCTV monitoring was per- formed, occurred in 2 subjects. One of the 2 (sub-
ject 6) had two electrographic seizures; the first oc- curred 10 h 11 min after the last dose of placebo (day 3), and the second occurred on the following baseline day (day 4). The other subject (16) had a recorded electrographic seizure 18 h 17 min after the last dose of placebo (day 3). The recorded events were of focal onset and lasted 41-105 s. In both cases, placebo was the first treatment arm.
Seven subjects demonstrated no epileptiform ac- tivity during the 5 days of recording. In 9 subjects, comparison of total discharges for the 2 treatment days showed no important differences (Table 2). None of the McNemar's tests derived from contin- uous EEG recordings approached statistical signif- icance (all p 30.50). There were no statistically sig- nificant differences between the 2 treatment days for any of the sleep variables (i.e., total sleep time, total time awake, percentage of time awake, per-
Epilepsia, Vol.36, No. 3, 1995
TABLE 2. AED levels and EEG discharge rates AED level EEG discharges/
DISCUSSION
The concept that aspartame consumption might lead to seizures is based on the notion that aspar- tame may affect neurotransmitter mechanisms in brain (Fisher, 1989). Consumption of Phe as aspar- tame may increase plasma Phe without increasing other LNAA, leading to an increase in plasma Phe/ LNAA ratio, which in turn may increase transpor- tation of Phe across the blood-brain barrier (BBB) and concomitantly decrease transportation of the other LNAA. Excess Phe in brain may inhibit en- zymes needed to synthesize neurotransmitters (e.g., tyrosine hydroxylase). Production of brain catecholaminesand serotonin may also diminish be- cause excess plasma Phe competes with their pre- cursor LNAA (tyrosine, tryptophan) for transport across the BBB. Thus, physiologic processes that depend on sustained release of adequate quantities of-these neurotransmitters may be affected (Maher and Wurtman, 1987; Fisher, 1989). Animal studies have shown that these transmitters have the poten- tial to modulate seizure threshold, seizure severity, and other manifestations of seizure activity, and
similar mechanisms have been postulated to influ- ence seizure susceptibility in humans (Maher and Wurtman, 1987).
Numerous studies have been made of the influ- ence of aspartame on seizure precipitation in ani- mals. In a review of >40 animal studies in which different models of epilepsy were used, Jobe and Dailey (1993) concluded that aspartame, even when administered in doses 1,000 times greater than those currently consumed by humans, does not cause sei- zures. Of the animal studies, the study in baboons may be the most relevant since baboons and hu- mans metabolize aspartame similarly. Meldrum et al. (1989) examined the effect of aspartame or Phe on seizure susceptibility and severity in photosen- sitive baboons. Large oral bolus doses of aspartame or Phe had no effect on these measures despite large increases in plasma Phe concentrations and Phel LNAA ratio. The results of the amino acid analyses in this study indicate that plasma Phe concentra- tions and plasma Phe/LNAA ratios were signifi- cantly increased after aspartame as compared with placebo consumption. The magnitude of the Phe concentrations and Phe/LNAA ratios observed was in accord with that noted in other studies in which similar aspartame doses were used (Stegink, 1984, 1987; Burns et al., 1990).
We could not enroll the planned number of 30 adults and 30 children despite extensive recruitment efforts for 5 years. Nevertheless, if the focusing process was successful in identifying aspartame-
(I.Lg/ml) Subject AED APM Placebo APM
24 h
1None--U U 2 VPA 32 86 0 0
3 PHT 8.7 VPA 66.8
14.7 13.1 12.0 32.1
4.6 7.0 3.8 3.6
41.4 16.6 50.5
16.2 25 26 65.7 69 19 19
4 ESM 65
0 0 TNTC TNTC
13 151 131
04 10 19 29 28 13 13
0 0 33 13
-
5 PHT 6 PB 7 PHT 8 PHT
VPA 9 CBZ 10 CBZ 11 CBZ 12 CBZ 13 VPA
14 PB VPA
AED, antiepileptic drug; APM, aspartame; PLAC, placebo; TNTC, too numerous to count; PB, phenobarbital;PHT, phe- nytoin; CBZ, carbamazepine; VPA, valproate; ESM, ethosuxi- mide.
centage of time in sleep stages I-IV and REM). Ta- ble 2 shows AED concentrations and numbers of epileptiform discharges for the 2 treatment days. Overall, AED concentrations remained relatively stable. The ratio of AED concentration at day 6 to day 2 averaged 0.96 [95%confidence interval (CI) was 0.85-1.071.
Mean (kSD) plasma phenylalanine (Phe) concentrations before the 0800-h dosing were 50.1 ? 8.2 pM for aspartame and 50.6 k 8.0 pM for placebo. Neither this difference nor that for the 0800-h data for any of the other amino acids was statistically significant.Mean(*SD)Pheconcentrationsat 1200 h, after dosing at 0800 and 1000 h, were 83.6 k 21.2 p M for aspartame and 52.3 k 9.1 p M for placebo. The difference was statistically significant (p = 0.0001). Mean (+SD) plasma ratio of Phe to the sum of all other large neutral amino acids (LNAA: iso- leucine, leucine, valine, tyrosine, tryptophan, and methionine) at 1200 h was also significantly increased (p =O.OOOl) after aspartame (0.143 * 0.03) as compared with placebo (0.091 k 0.01). Normal subjects have a fasting plasma Phe/LNAA ratio of -0.100 kO.01 (Stegink et al., 1991). Data for Phe and Phe/LNAA were evaluated to determine if fasting values on the day after aspartame administration were increased, a condition that would suggest a possible carryover effect. There was no suggestion of such an effect for either Phe or its ratio to LNAA.
15 CBZ 16 PHT 17 None - - 18 CBZ 5.7 9.4 U U
5.2 15.4 13.2
8.9 28.6 5.0 7.1 3.2 4.2 48.5 16.8 71.5
ASPARTAME AND SEIZURE SUSCEPTIBILITY 273
4.2 3.9 0 0 14.6 15.3 22 9
0n A
Placebo
0
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274 A. J. ROWAN ET AL.
sensitive individuals, the study would have an excellent chance to detect a clinically important dif- ference. That only 18 individuals were identified to be studied suggests that the relation between aspartame consumption and seizures is rare. However, as with findings of any study involving a small number of study subjects ingesting acute doses, our findings may not be applicable to some as-yet- unidentified sensitive individuals consuming aspartame for longer times.
In our study group, 14 subjects had chronic re- current seizures; 4 experienced only single seizures. In such a population, seizure occurrence might be expected at any time regardless of aspartame exposure. The 2 subjects who experienced nocturnal electrographic seizures during the study had epilepsy and were receiving AED therapy, but past frequency of such events was unknown. In both cases, recorded electrographic seizures occurred on baseline or placebo days. The doses of aspartame used in this study represent a very large amount of the sweetener; e.g., a 12-ounce can of
diet soda contains 180 mg aspartame. For person weighing 70 kg (the average weight of subjects in this study), an aspartame dose of 50 mg/kg is the equivalent of 19 cans of diet soda, an amount greater than that which most individuals would consume in 4 h and far greater than the intake reported by our subjects. We therefore consider a 50-mg/kg dose of aspartame a significant acute challenge, especially in subjects who had reported aspartame sensitivity.
The question of an influence of AED levels on likelihood of seizure occurrence was addressed. Five of the 18 subjects were receiving AEDs at the times they reported seizures in association with as- partame, and 16 were receiving AEDs at the time of study. AEDs were continued at the patients' usual dosages and daily trough levels were obtained. The close mean ratio (0.96) of AED concentrations at day 6 to day 2 suggests that AED concentrations remained relatively stable during hospitalization; furthermore, these data indicate that AED concentrations were not low on admission (e.g., due to poor compliance) with subsequent increase during the course of the study. In addition, the mean ratio (0.91) of AED concentrations on the 2 treatment days (i.e., aspartame/placebo) was not significantly different from 1.0.
Camfield et al. (1992) reported apparent exacer- bation of generalized spike-wave complexes induced by aspartame in children with untreated absence attacks. To our knowledge, this is the only clinical study to suggest that aspartame may affect seizures. Camfield et al. (1992) used four-channel
ambulatory EEG recordings of -4-6h to compare the effects of a single dose of aspartame (40 mg/kg) with placebo (sucrose) in 10 children with untreated absence seizures. The results showed no significant difference in the number of spike-wave bursts or mean length of spike-wave discharges, and clinical seizures were not measured. The only statistically significant finding was greater total duration of spike-wave activity per hour with aspartame treat- ment as compared with sucrose treatment. Several factors may have confounded the results of the study. First, sucrose (1.6 g/kg) may not have constituted an inert placebo, since glucose has been reported to affect EEG activity (Gibbs et al., 1939). Second, according to Shaywitz and Novotony (1993):
Without a true placebo, a comparison of spike-wave discharges during treatment with a comparable un- treated period is required in order to reasonably con- clude that these changes were not within normal variability. Given the absence of a true placebo or an adequate baseline period, it is not possible to reliably determine if there was any effect on a spike-wave discharges, let alone whether such effects were due to aspartame.
Thus, use of a short baseline period (only 1 h) was inadequate for comparison purposes.
Another study failed to demonstrate any effects of aspartame in children with documented epilepsy. Shaywitz et al. (1994) evaluated 10 children with a variety of seizure disorders using a randomized, double-blind, cross-over design. Each child was treated with aspartame 34 mg/kg/day or placebo for 2 weeks. During each treatment phase, children were admitted to a research unit for a standard 21- lead EEG, continuous 24-h cassette EEG, and de- termination of biochemical variables in plasma and urine. Shaywitz et al. (1994) concluded that aspar- tame does not provoke seizures in a group of children with a variety of seizure types.
In addition to subjects with documented epilepsy, individuals heterozygous for PKU have been sug- gested as a possible population sensitive to aspartame. However, a randomized, double-blind, cross- over study in 48 PKU heterozygotes administered aspartame 15 or 45 mg/kg/day for 12 weeks showed no significant differences in either clinical and spectral analysis of the EEG during aspartame treatment as compared with placebo treatment (Benninger et al., 1993).
Our results show no evidence that aspartame, ad- ministered acutely and at a total dose of -50 mg/kg, results in clinical seizures in individuals who reported having seizures provoked by aspartame consumption. Furthermore, in the conditions of our Epilepsia, Vol.36, No. 3, 1995 study, no evidence indicated that EEG epileptiform activity is activated by aspartame.
Acknowledgment: This work was supported in part by a grant from The NutraSweet Company, Deerfield, Illinois. We thank the following individuals who made important contributions to this study: Drs. David Rosenbaum and Alan Aron who screened potential candidates; Jean Watkins, Jacqueline Roldan, Cloe Silva, Sarah West, and Cheryl1 Scott, EEG technologists and Jean Dispensa, clinical nutritionist.
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(Note: Mary Nash Stoddard met Dr. Richard Wurtman, Dr. Ralph Walton and many pilots, healthcare professionals and others who had tied their Seizures into Aspartame ingestion. Stoddard and Wurtman were both giving sworn Testimony in Washington at the Nov. 3, 1987 Senate Hearing on the Safety of Aspartame. Stoddard's Testimony included an FDA Official whose daughter, she thought, had seizures on Aspartame.)
