Long-term quinine use for idiopathic leg cramps or restless leg syndrome is associated with an increased mortality risk.

The UK findings, published in a JAMA Research Letter, support previous warnings about the off-label use of quinine.

The US Food and Drug Administration (FDA) has repeatedly warned about the risks of quinine including life-threatening hypersensitivity reactions, QT prolongation and serious cardiac arrhythmias.

The UK study compared all-cause deaths in almost 45,000 people exposed to quinine for more than one year and about 130,000 people who were not exposed.

They found a significant risk of death (Hazard ratio 1.24) in quinine users that was more pronounced in those under the age of 50 years.

Most people received a dose of about 203 mg/day and there was a strong correlation between dose and risk, with HR rising to 2.24 at 400mg/day.

The researchers said people would need to be drinking more than 1 litre per day of bitter lemon or tonic water to be exposed to even half the average daily dose of quinine taken by the study group.