Aspartame is no more likely than placebo to cause urticaria/angioedema: results of a multicenter, randomized, double-blind, placebo-controlled, crossover study

J Allergy Clin Immunol. 1993 Oct;92(4):513-20. doi: 10.1016/0091-6749(93)90075-q.


Background: Anecdotes and single case reports have suggested that the high-intensity sweetener, aspartame, may be associated with allergic/hypersensitivity-type reactions.

Methods: We conducted a multicenter, placebo-controlled clinical study to evaluate individuals who had experienced urticaria and/or angioedema allegedly associated with ingestion of an aspartame-containing product. Despite extensive recruiting efforts over 4 years, only 21 subjects could be enrolled. After admission to clinical research units, subjects were given aspartame and placebo in a randomized, double-blind, crossover fashion. Subjects received, on different days, increasing doses (50, 300, 600 mg) of aspartame and placebo at 8:00 AM, 10:00 AM, and noon. Subjects who weighed less than 40 kg received one half of these doses. Conversion products of aspartame, aspartyl-phenylalanine diketopiperazine and beta-aspartame, were also included in the aspartame arm of the study. Positive reactions were defined as urticaria (hives with wheals 4 mm or more in diameter with a collective diameter of at least 15 mm or one or more hives with a wheal of 4 mm or greater with a flare of 8 mm or greater) or as angioedema.

Results: According to these criteria, four reactions were observed; two followed aspartame ingestion and two followed placebo ingestion (p = 1.00). The incidence of other adverse experiences was no different after aspartame versus placebo ingestion (p = 0.289).

Conclusion: These results indicate that aspartame and its conversion products are no more likely than placebo to cause urticaria and/or angioedema reactions in subjects with a history consistent with hypersensitivity to aspartame.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Angioedema / chemically induced*
  • Aspartame / administration & dosage
  • Aspartame / adverse effects*
  • Capsules
  • Child
  • Double-Blind Method
  • Drug Hypersensitivity / etiology*
  • Female
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Placebos
  • Urticaria / chemically induced*


  • Capsules
  • Placebos
  • Aspartame