A review published this week in the Canadian Medical Association Journal (CMAJ) warns that while the number of prescription drugs that have adverse effects from interactions with grapefruit are increasing, many doctors may be unaware of the effects. The review was performed by the same researchers who discovered the adverse interactions over 20 years ago.

“Many of the drugs that interact with grapefruit are highly prescribed and are essential for the treatment of important or common medical conditions,” said Dr. David Bailey, lead author of the study. “Recently, however, a disturbing trend has been seen. Between 2008 and 2012, the number of medications with the potential to interact with grapefruit and cause serious adverse effects…has increased from 17 to 43, representing an average rate of increase exceeding 6 drugs per year. This increase is a result of the introduction of new chemical entities and formulations.”

Many of the drugs that interact with grapefruit are also commonly abused, including benzodiazepines, oxycodone, and erectile dysfunction drugs. The side effects of drug interactions with grapefruit can include acute kidney failure, respiratory failure, gastointestinal bleeding, bone marrow suppression in people with compromised immune systems, renal toxicity, and sudden death.

Grapefruit, seville oranges, limes, and pomelos contain organic compounds called furanocoumarins, which inhibits the CYP3A4 enzyme. CYP3A4 normally metabolizes drugs, inactivating the effects of around 50% of all medication. For drugs in which very little of the actual drug is absorbed in to the bloodstream, the effect is essentially a mega-dose of the medication, which can lead to overdose. Interactions can occur even hours after grapefruit is consumed.

“Unless health care professionals are aware of the possibility that the adverse event they are seeing might have an origin in the recent addition of grapefruit to the patient’s diet, it is very unlikely that they will investigate it,” said the study’s authors. “In addition, the patient may not volunteer this information. Thus, we contend that there remains a lack of knowledge about this interaction in the general healthcare community.”

According to the review, people over 45 years old are the prime purchasers of grapefruit, and also the people who receive the most prescriptions for drugs. As a result, older people are most vulnerable to adverse grapefruit interactions.

“The current trend of increasing numbers of newly marketed grapefruit-affected drugs possessing substantial adverse clinical effects necessitates an understanding of this interaction and the application of this knowledge for the safe and effective use of drugs in general practice,” said the study’s authors.