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Aspartame and headache

Aspartame as a dietary trigger [1]
Randomised aspartame challenge

Aspartame is a dipeptide sweetener of phenylalanine and aspartic acid. It is widely used in the food industry, especially in diet products to reduce sugar content. Many substances that are sugar free contain aspartame, and individuals who consume large amounts of such products will consume large amounts of aspartame. Since the 1980s when aspartame started to be used, there have been sporadic reports linking it with headache. Bandolier readers asked whether any link had been established, hence this brief review.

Aspartame as a dietary trigger [1]

A survey of 190 consecutive patients at a specialist headache unit asked questions about dietary factors and headache. Of the 171 replies, most (77%) were from women, and headache diagnoses were mixed and included migraine, muscle contraction headache, mixed causes, and cluster headaches.

In the sample, 50% reported alcohol as a dietary trigger, 8% aspartame, and 2% carbohydrates. People with migraine more frequently mentioned aspartame (16%) than those with other headache causes.

Randomised aspartame challenge

There have been a number of randomised studies looking at aspartame and biochemistry and adverse events in volunteers, none of which has shown any difference between aspartame and placebo. Typically [2], the studies are well done but small, consisting of a few tens of patients. Though properly randomised and blind, and with a dose of aspartame (15 mg/kg) equivalent to two litres of aspartame sweetened drink, the power of a study with 10 patients is unlikely to uncover a minority of people who were particularly sensitive to aspartame. For comparison purposes, there is about 40 mg aspartame in a packet of sweetener.

What is needed is studies in patients who have already declared a sensitivity to aspartame to randomised, blind, challenges of aspartame and placebo under controlled conditions. There are three such trials [3-5], and details of the trial designs and main results are in Table 1.

Table 1: Three main RCTs of aspartame challenge

Van Den Eeden
Type of patient History of headache and neurological symptoms associated with aspartame Migraine patients not previously associated with aspartame Headaches after ingesting products containing aspartame
Crossover period Two one-day challenges with one day washout 30 days, with one week washout between 4 one week periods, two each of aspartame and placebo
Aspartame dose 30 mg/kg in divided doses between 8 am and noon 1,200 mg/day 30 mg/kg/day
Outcome assessment Patient and observer during the day Daily headache diary
Initially randomised 40 25 32
Full completers 40 11 18
Withdrawal none 12 (equal between aspartame and placebo periods)
Main results No difference in between aspartame or placebo in incidence of headaches or other symptoms. No difference in headache intensity, onset time, or duration Mean of 3.6 headaches on aspartame, 1.5 on placebo 33% of days with headache on aspartame, 24% on placebo, with more pronounced difference in those very sure that headaches were associated with aspartame. No difference in intensity or duration of headache

Although there is some consistency in design and dose of aspartame used, there are a number of possible confounding factors that make interpretation difficult. The main ones are the type of headache and the duration of exposure. It may be that migraine headaches are more likely to be associated with aspartame ingestion, and it might be that longer exposure is more likely to be a trigger.

The problem is that the two longer duration studies have high withdrawal rates, but not obviously more on aspartame than placebo. High withdrawal rates (here only 44 and 56% of patients completed the trials) make interpretation of the results from completers problematical.

In the one trial with no withdrawals [3], meticulously done, there was no acute triggering of headache with aspartame (Figure 1). Neither were any other symptoms more associated with aspartame individually, or collectively.

Figure 1: Results of single-dose aspartame challenge in aspartame sensitive headache


The answer seems to be that there is no completely satisfactory answer. On the basis of what we have, it is probably fair to say that if aspartame is a triggering factor for headache, it probably affects migraine, rather than other forms of headache. In addition, it is unlikely that it precipitates acute attacks, but perhaps prolonged exposure might cause more frequent headaches.

The lesson is probably to consider aspartame a trigger in some people with migraine who consume lots of diet drinks or other diet products. For those with a limited exposure to aspartame, it is unlikely to be a problem.


For those people who do have aspartame-triggered migraines, some treatments can be a bit problematical. Two such patients had migraines shown by exclusion diets to be associated with aspartame [6]. Their migraines were well controlled with standard therapies including triptans, but a wafer melt formulation of one triptan consistently made headaches worse, not better. It turns out that these melt formulations contain 4 mg aspartame - about a tenth of that in a packet of sweetener. An example of the importance of case reports in contributing important information.


  1. RB Lipton et al. Aspartame as a dietary trigger of headache. Headache 1988 29: 90-92.
  2. KA Lapierre et al. The neuropsychiatric effects of aspartame in normal volunteers. Journal of Clinical Pharmacology 1990 30: 454-460.
  3. SS Schiffman et al. Aspartame and susceptibility to headache. New England Journal of Medicine 1987 317: 1181-1185.
  4. SM Koehler, A Garos. The effect of aspartame on migraine headache. Headache 1988 28: 10-13.
  5. SK Van Den Eeden et al. Aspartame ingestion and headaches: a randomized crossover trial. Neurology 1994 44: 1787-1793.
  6. LC Newman, RB Lipton. Migraine MLT-down: an unusual presentation of migraine in patients with aspartame-triggered headaches. Headache 2001 41: 899-901.

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