Even seemingly harmless, over-the-counter medicines can cause serious side effects in rare cases. In recent years, there have been repeated reports of previously healthy, often young people suffering heart attacks, strokes or other acute serious events after taking cold remedies containing pseudoephedrine. However, epidemiological studies had not previously revealed any worrying effects of pseudoephedrine on the cardiovascular system. Research led by Prof. Dr. Thomas Eschenhagen, Director of the Institute for Experimental Pharmacology and Toxicology at the University Medical Centre Hamburg-Eppendorf (UKE), now aims to clarify this contradiction. The study is supported by the German Heart Foundation, among others.
‘A thorough risk assessment is essential, especially for widely available, over-the-counter cold remedies containing pseudoephedrine,’ emphasises heart specialist Prof. Dr. Heribert Schunkert, Deputy Chairman of the German Heart Foundation. According to Schunkert, the research project entitled ‘Association between the use of cold remedies containing pseudoephedrine and heart attacks’, which is funded with €77,500, makes an important contribution to better understanding side effects that have not yet been sufficiently investigated. ‘We want to understand exactly for whom and under what conditions these medicines could be dangerous, so that we can better protect patients if necessary.’
The tragic death from a heart attack of a previously healthy 42-year-old man
Prof. Eschenhagen became aware of the issue when, as an expert for the German Medical Association's Drug Commission, he examined the tragic case of a 42-year-old man. Just 30 minutes after taking a single sachet of the cold remedy Aspirin Complex, the man suffered a severe heart attack, from which he died a few days later. The man had no previous cardiovascular problems. However, the angiogram (X-ray) taken after the heart attack showed diffuse spasms (cramps) in the coronary arteries.
‘This case prompted me to take a closer look at the subject,’ reports Prof. Eschenhagen. ‘Similar case reports have been appearing in the literature for years, often involving previously completely unremarkable, frequently young people.’ As a pharmacologist, he finds the connection between coronary spasms and pseudoephedrine intake entirely plausible: ‘Pseudoephedrine is an indirect sympathomimetic that – similar to amphetamines such as ecstasy or cocaine – leads to the release of the neurotransmitter noradrenaline,’ he explains.
Contained in at least 15 over-the-counter cold remedies
Noradrenaline constricts blood vessels, thereby reducing swelling in the nose and sinuses when suffering from a cold. However, it also has a stimulating effect, similar to the aforementioned intoxicants. ‘This additional stimulating effect in people who are already feeling unwell and lethargic due to a flu-like infection is another reason for the popularity of these preparations,’ says Prof. Eschenhagen.
Pseudoephedrine is contained in at least 15 over-the-counter cold remedies, such as Aspirin Complex, Boxagrippal, Grippostad Complex, Grippal Complex Doppelherz, RatioGrippal, Wick Duogrippal and Rhinopront Kombi. Exact sales figures are not known. However, it can be assumed that these preparations are taken hundreds of thousands of times during a cold season in Germany alone. Prof. Eschenhagen views this popularity with some concern.
Search for the underlying gene constellation
Since epidemiological studies have not demonstrated any statistically significant adverse effects of pseudoephedrine on the cardiovascular system, one thing is clear: ‘These serious side effects must be very rare! An obvious explanation is that there is a specific – rare – gene constellation that makes certain individuals particularly susceptible to them,’ the pharmacologist speculates. ‘We now want to search for precisely this genetic constellation.’
To do this, cases in which such serious side effects have occurred must first be identified. This is not so easy, because the use of over-the-counter cold remedies has not been routinely recorded in medication histories following heart attacks. This has now been changed at the UKE. For several months now, patients admitted with a heart attack have been routinely asked about their use of over-the-counter cold remedies. A short, one-page questionnaire (with pictures of the relevant combination preparations) has been developed for this purpose. Prof. Eschenhagen would also like to encourage other doctors and clinics to use the questionnaire in order to obtain even more data.
Would a genetic test be the solution?
In addition, the University Heart and Vascular Centre Hamburg at the UKE has begun testing stored blood from heart attack patients from recent years for pseudoephedrine. This will then be compared with a group of patients who were admitted for other reasons. Is there a difference in the frequency of pseudoephedrine detection in the two groups? Perhaps there are also heart attack patients with pseudoephedrine detection who had coronary spasms and who could now be genetically tested retrospectively?
The aim of the study is to find at least 20 patients who suffered dangerous vascular spasms after taking cold remedies. But even with fewer cases – perhaps only three to five – it would be possible to draw conclusions about genetic risk, says Prof. Eschenhagen. He and his colleagues already have ideas about which genetic mutations could be responsible. ‘These could be gene variants that lead to overactivity of the vasoconstrictive signalling pathways or a malfunction of the vasodilatory signals,’ says the pharmacologist.
If such gene variants could be identified, people might in future be able to take a genetic test before resorting to over-the-counter combination cold remedies. This could help prevent dangerous side effects.
Expert tip: Treatment is also possible without pseudoephedrine
However, Prof. Eschenhagen has another simple tip for anyone who wants to play it safe: ‘Even ASA, ibuprofen or paracetamol alone can reduce fever and relieve aching limbs in cases of flu-like infections. And nasal sprays containing the active ingredients oxymetazoline or xylometazoline can clear the nose.’
He is critical of the additional stimulating effect of pseudoephedrine in combination preparations anyway: ‘The question is whether it is conducive to recovery if, thanks to the medication, you continue your daily activities unabated and then perhaps even risk heart muscle inflammation.’
Additional information: Who else could be at risk?
The Medicines Commission warns patients with severe uncontrolled high blood pressure and people with severe kidney damage against taking pseudoephedrine (1).
People with autonomic dysfunction, such as those with diabetes, Parkinson's disease or autoimmune disorders, should also be cautious. A study conducted in 1987 found that some of these individuals experienced extreme increases in blood pressure after taking pseudoephedrine.
And one more note: Since pseudoephedrine has an amphetamine-like effect, it is not unlikely that people who are particularly sensitive to the active ingredient will also show dangerous excessive reactions to illegal drugs such as cocaine, ecstasy or crystal meth. This could also apply to other prescription drugs with a similar mechanism of action, such as some migraine medications that contain ergotamine or a triptan, says pharmacologist Prof. Eschenhagen.
Not only heart attacks are a threat
In very rare cases, vascular spasms after taking pseudoephedrine can cause serious side effects not only in the heart, but also in other organs:
- In the digestive tract: As early as February 2019, there was a Europe-wide warning about ischaemic colitis (insufficient blood supply to the colon). (2)
- In the brain: In February 2024, the European Medicines Agency (EMA) warned of ‘thunderclap headaches’ and vascular damage in the brain such as ‘PRES’ (posterior reversible encephalopathy syndrome). (see 1) There are also case reports of strokes following pseudoephedrine use.
Following the fatal heart attack in a 42-year-old man described above, the German Medical Association's Drug Commission issued a Drug Safety Mail in December 2024. (3) Unlike in France, however, there are currently no restrictions on the approval of pseudoephedrine as an OTC (over-the-counter) medicine in Germany.
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