Bittersweet: Aspartame, and its consequences for our brain

The link between headaches and artificial sweeteners such as aspartame deserves more attention, as these are added to numerous foods, drinks and even medicines.

How does aspartame affect neurotransmitters?

Studies and case reports have described a correlation between migraines and headaches and the consumption of sweeteners for many years, with aspartame and sucralose being the most studied in this context.1–5 According to current understanding, this can be explained neurophysiologically as follows: Aspartame increases cerebral excitability and affects the balance of neurotransmitters, particularly serotonin and dopamine.2 These levels are often altered in migraine sufferers.6

It is important to remember that aspartame is derived from aspartic acid and phenylalanine. During metabolism, it is broken down into methanol, aspartic acid, and phenylalanine. Aspartame intake therefore increases the levels of these two amino acids in the brain, which can inhibit the synthesis and release of neurotransmitters such as dopamine, norepinephrine, and serotonin, which regulate neurophysiological activity.7,8

Certain breakdown products have neurotoxic effects: Methanol, albeit in small quantities, is further broken down into formaldehyde, a known cytotoxicant.6 A byproduct of the breakdown of aspartic acid is glutamate, which, as an excitatory neurotransmitter, can lead to overstimulation (excitotoxicity).7 In addition, elevated phenylalanine levels competitively inhibit tryptophan influx. Since tryptophan is a serotonin precursor, serotonin levels decrease, and lower serotonin concentrations trigger vasodilation in the brain, also a known pathophysiological characteristic of migraines.9

Aspartame also acts as a pro-inflammatory or chemical stressor. It can increase cortisol levels, which is associated with increased free radical formation. This increases the brain's susceptibility to oxidative stress, which can have adverse effects on neurological health.8

Other neuropsychiatric abnormalities associated with sweeteners

There are also indications of an association between sweeteners such as aspartame and other neurological and psychiatric disorders. Adverse effects on cognitive function, learning difficulties, seizures, irritability, anxiety, depression, and insomnia have been described.7,8 For example, according to prospective data from 31,700 women in the 2023 "Nurses Health Study II", consuming nine servings of artificially sweetened, highly processed foods and beverages per day increases the risk of depression by up to 50%.10,11

Migraine triggers vary from person to person, and a thorough medical history and headache diary can help identify them. However, dietary triggers are frequently reported by patients with a variety of different headache types, especially migraines.5 Some sufferers report that consuming products containing aspartame can trigger the onset of a migraine attack within a few hours, as one of the leading headache specialists in the US, Dr. Fred Cohen.2 Reducing or eliminating sweeteners can help reduce the frequency and severity of migraine attacks in these people.

Unfortunately, drug manufacturers also sometimes use such sweeteners. In case reports, taking an acute medication containing aspartame (Maxalt-MLT, active ingredient rizatriptan) worsened ongoing migraine attacks.4

Key take-aways

If a product is labeled "sugar-free," it often contains sweeteners. The latter have already been linked to weight gain, disturbances in lipid metabolism and the gut microbiome, as well as an increased risk of type 2 diabetes and cancer.10,12,13

An article by T. H. Chan of Harvard Medical School emphasizes that children, in particular, should not consume sweetened beverages long-term, as the effects are unknown.12 "Pregnant and breastfeeding women, children, diabetics, and those with migraine and epilepsy are particularly vulnerable to the adverse effects of sweetened products and should consume these products with extreme caution," concludes a review on their safety and toxicity.1

However, since many people are sensitive to food additives and these are often detrimental to health in several ways, choosing whole foods would be a sensible step (i.e., avoiding highly processed products and choosing foods that contain as few additives as possible).6

Sources
  1. Sharma, A., Amarnath, S., Thulasimani, M. & Ramaswamy, S. Artificial sweeteners as a sugar substitute: Are they really safe? Indian J Pharmacol 48, 237–240 (2016).
  2. Artificial sweeteners and migraine — Fred Cohen, MD Headache Specialist. Fred Cohen, MD https://www.headache123.com/blog/artificial-sweeteners-and-migraine.
  3. Patel, R. M., Sarma, R. & Grimsley, E. Popular sweetner sucralose as a migraine trigger. Headache 46, 1303–1304 (2006).
  4. Newman, L. C. & Lipton, R. B. Migraine MLT-down: an unusual presentation of migraine in patients with aspartame-triggered headaches. Headache 41, 899–901 (2001).
  5. Zaeem, Z., Zhou, L. & Dilli, E. Headaches: a Review of the Role of Dietary Factors. Curr Neurol Neurosci Rep 16, 101 (2016).
  6. Aspartame, a Potential Trigger for Migraines. Migraine.com https://migraine.com/blog/aspartame-a-potential-trigger-for-migraines.
  7. Dar, W. Aspartame-induced cognitive dysfunction: Unveiling role of microglia-mediated neuroinflammation and molecular remediation. International Immunopharmacology 135, 112295 (2024).
  8. Choudhary, A. K. & and Lee, Y. Y. Neurophysiological symptoms and aspartame: What is the connection? Nutritional Neuroscience 21, 306–316 (2018).
  9. Review, I. J. of R. and. Various Trigger Factors of Migraine: A Review of Pathophysiology and Mechanism. International Journal of Research and Review 11, (2024).
  10. Joshua, A., MS, & RDN. Are Artificial Sweeteners Bad for You? Verywell Health https://www.verywellhealth.com/artificial-sweeteners-5184450.
  11. Samuthpongtorn, C. et al. Consumption of Ultraprocessed Food and Risk of Depression. JAMA Network Open 6, e2334770 (2023).