The world's oldest known habitual drug use can be traced to an island in Indonesia, where ice age hunter-gatherers sucked on betel nuts — palm seeds that contain a neuroactive substance, a new study finds.

Scientists made the discovery after studying strange grooves in the teeth of two prehistoric hunter-gatherers. The deep grooves were caused by regularly sucking on betel nuts (Areca catechu), likely for relief from the pain of toothache, according to the study, which was published Wednesday (Sept. 9) in the journal Science Advances.

The partial skeletons of the two people were found on the island of Sulawesi, but their lives were separated in time by thousands of years. One of them, a man who died between about the ages of 40 and 50, lived between 25,000 and 16,000 years ago. This period roughly corresponds to the Last Glacial Maximum, the coldest part of the last ice age — although Sulawesi was not covered with ice at that time. The second person, who was around the same age when they died, lived on Sulawesi between 7,600 and 6,300 years ago, according to the study. The sex of this individual could not be determined.

Betel nuts contain a neuroactive compound called arecoline, which has a powerful stimulant effect when chewed with slaked lime, or calcium hydroxide. This early method of directly sucking betel nuts, however, would have only made the mouth numb.

These hunter-gatherers had so much dental damage, the new analysis found that they must have sucked on betel nuts almost continuously throughout their lives. But it seems these numbing nuts didn't have the desired effect in the long run. Instead, it may have made their dental conditions worse by eventually exacerbating any painful holes in their teeth.

"The more they sucked on the nut to relieve toothache, the worse that the damage to their teeth became," study first author Adam Brumm, an archaeologist at Griffith University in Australia, told Live Science. The grooves progressively became deeper, and in one individual they exposed the tooth's inner pulp cavity. "It would have been excruciatingly painful," Brumm said.

Although a 2017 study showed that Neanderthals used the bark of plants like poplar (genus Populus) for its pain-killing properties (poplars contain salicylic acid, a form of the active ingredient in aspirin), this is the earliest evidence of a drug from plants being used habitually, Brumm said.

Plant-based drugs have been used in many other prehistoric societies: 10,000-year-old traces of the pollen of a psychedelic cactus have been found in Peru, and 13,000-year-old residues of alcoholic beer have been found in Israel.

Addictive nut

After determining the likely cause of the grooves, the researchers tested whether sucking on betel nuts — a behavior not seen before — resulted in a neuroactive effect. Their test subjects, genetically-engineered frog eggs with human neuroreceptors, revealed there was a neuroactive effect. Then, they examined samples from the teeth, which revealed traces of betel nut use.

Betel nut, also known as areca nut, is still widely used today in parts of South Asia and Oceania. Today, however, betel nut users mix it with slaked lime to make a chewable wad that has a stimulant effect. This chewable wad, also called a quid, is strongly addictive, and is used by an estimated 600 million people worldwide. But arecoline is also carcinogenic, and betel nut quids are often mixed with tobacco, so users are often diagnosed with mouth cancer.

The researchers speculate that the use of slaked lime with betel nuts originated much later, during the Neolithic, or "New Stone" Age, about 4,000 years ago on Sulawesi, when slaked lime was added to pottery to prevent it from shrinking and cracking during firing.

"It now seems probable that betel chewing as we know it evolved from a much simpler, older practice of just sucking on the intact nut," the researchers wrote in the new study.

It's likely that people of all ages used this remedy for toothache in prehistoric times, but the grooves only became apparent in mature people who had become addicted to the practice, Brumm said.

Drug use started before farming

The earlier betel-sucking man predated the Neolithic period not only in Sulawesi but also in the Fertile Crescent, where people began practicing agriculture around 12,500 years ago, Brumm said. Archaeologists have long debated whether people began using neuroactive plants as drugs before or after the introduction of farming, but the new finding shows that psychoactive drug use happened thousands of years earlier, Brumm said.

The new study is a "fantastic piece of research," Elisa Guerra Doce, a prehistoric archaeologist at the University of Valladolid in Spain who was not involved, told Live Science in an email.

The new study gives "particularly compelling and direct evidence for the antiquity of drug use," she said.

Guerra Doce is an expert on the prehistoric use of plants as neuroactive drugs. "In the specific case of betel nuts, the findings are especially significant because they also reveal the prehistoric roots of a deeply established cultural practice in Southeast Asia and the Pacific," she said.

The study also highlights how the prehistoric people of Sulawesi explored their natural world and figured out that it not only provided subsistence and medicinal resources but also had "substances that became integrated into social and cultural traditions over thousands of years," Guerra Doce said.