Long-term exposure to quinine – a compound found in tonic water and bitter lemon – may increase a person’s risk of death.

That’s the conclusion of a new study published today in the Journal of the American Medical Association (JAMA).

Quinine is a medication approved by the United States Food and Drug Administration (FDA) for the treatment of malaria.

However, the drug is often prescribed “off-label” for the prevention or treatment of leg cramps, despite an FDA warning about its adverse effects.

These include blood-related disorders such as thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome, which can be life-threatening and cause kidney damage.

“Furthermore,” note Dr. Laurence Fardet, of the Universite Paris-Est Creteil in France, and colleagues, “many drinks such as bitter lemon or tonic waters contain quinine, and hence, many may be exposed to quinine daily.”

For their study, Dr. Fardet and his team set out to investigate how long-term exposure to quinine might influence patients’ risk of death.

Read more: Why some countries can get rid of malaria and others can’t »

Younger adults at greatest risk

The researchers used data from The Health Improvement Network (THIN) to reach their findings.

THIN is a primary care database that holds information on more than 12 million nationally representative adults from the United Kingdom.

The study included 175,195 adults. Of these, 44,669 were prescribed at least 100 milligrams of quinine daily for the treatment of muscular cramps or restless leg syndrome.

More than 100 milligrams of quinine per day is the equivalent to consuming at least 1 liter of tonic water or bitter lemon daily.

Over a median follow-up duration of 5.7 years, there were 11,598 deaths (4.2 per 100 person-years) among individuals exposed to quinine, compared with 26,753 deaths (3.2 per 100 person-years) among the 130,496 individuals who were not exposed to quinine.

The researchers found that the greater the exposure to quinine, the greater the risk of death.

For example, adults who had a daily quinine dose of 300-399 milligrams had an 83 percent greater risk of death, compared with a 25 percent greater death risk for those exposed to 200-299 milligrams of quinine daily.

The association between long-term quinine exposure and increased risk of death was strongest for adults under the age of 50, the team reports.

Read more: Treatments for restless leg syndrome »

Study limitations

The researchers caution that there are some limitations to their study, such as the inability to control for certain factors that might predispose quinine-exposed patients to higher mortality.

Furthermore, the researchers did not collect data on participants’ beverage intake, so it is possible that their quinine intake was higher than reported.

While further research is clearly required on how exposure to quinine affects mortality, Fardet and the research team believe that their current findings indicate that healthcare professionals should be cautious when prescribing the drug to patients off-label.

“The benefits of quinine in reducing cramps should be balanced against the risks,” the team concluded.