Rinsing with menthol-flavored mouthwash causes a tingly, cooling sensation because the compound triggers a cold-sensitive ion channel in sensory neurons. Now scientists have found a compound that is even more chilling. Isolated from nutmeg, the chemical is the most potent activator of the cooling channel yet found in nature (ACS Med. Chem. Lett. 2017, DOI: 10.1021/acsmedchemlett.7b00104).
l-Menthol, which comes from mint, is the king of naturally derived cooling compounds and is added to products such as cough drops and cosmetics. But menthol has some shortcomings: At low concentrations, its effect can be weak and short-lived, and bumping up its concentrations too high can cause irritation.
To find other cooling agents from natural sources, Tomohiro Shirai and colleagues at Kao Corp. screened extracts of various botanicals and spices for the ability to activate the cold-sensitive ion channel, called transient receptor potential melastatin 8 (TRPM8). After many years of searching, the researchers eventually isolated a compound in nutmeg that binds to and activates TRPM8.
The compound—part of a class of plant molecules known as neolignans—is about 30 times as potent as l-menthol and almost as potent as icilin, a synthetic cooling agent. The nutmeg compound binds TRPM8 at a different site than menthol does, meaning it could complement menthol’s effects if the two were combined in a product.
In a mouthwashing test, the researchers rinsed their mouths with a solution of the new compound for 30 seconds and rated its cooling effect over the course of half an hour. The nutmeg compound took five minutes to reach menthol’s initial level of cooling, but the cooling lasted for 30 minutes, compared with 10 minutes for menthol.
The compound has a long way to go before it could be considered marketable, however, says John C. Leffingwell, president of the flavor and fragrance consulting firm Leffingwell & Associates. Because of the small amounts found in nutmeg, this compound would need to be synthesized at a low enough cost to be mass-produced for the consumer market and pass tests for toxicity and taste.