[2] In 1941, the research group of Samuel M. McElvain was the first to determine the structures of nepetalactones and several related compounds.

The terms cis and trans are used to refer to the relative stereochemistry at the ring fusion, and also to the methyl group as compared to the lactone on the cyclopentane.

[9] Nepetalactone is a bicyclic monoterpene produced through the terpenoid pathway in the genus Nepeta using its starting compound, geranyl pyrophosphate (GPP).

Through a Diels–Alder reaction with a group of cyclases known as nepetalactone-related short-chain dehydrogenase enzymes (NEPS), the different stereoisomers of nepetalactone are biosynthesized.

[7] Geraniol-8-hydroxylase is further oxidized by 8-hydroxygeraniol oxidoreductase (8OG) to produce 8-oxo-geranial which is reduced by iridoid synthase (ISY) and NADPH to form the intermediate 8-oxocitronellyl enol (scheme 2).

Species exhibiting overall lesser to no sensitivity include tigers (Panthera tigris), bobcats (Lynx rufus),[8] cougars (Puma concolor)[11] or oncillas (Leopardus tigrinus).

[12] Two thirds of adult domestic cats begin to lick, sniff, eat, scratch or roll over the nepetalactone source after being exposed to it.

[2] Felidae olfactory receptor exposure to nepetalactones or nepetalactols induces β-endorphin secretion in the blood; this endorphin release in turn activates μ-opioid receptors as an agonist, thus working in a similar manner as morphine or other opioids.

[5] Naloxone, a μ-opioid receptor antagonist, is known to block the effects of nepetalactones and nepetalactols in domestic cats, which supports this endorphin related mechanism of action.

[2][5] Repeated exposure to nepetalactones or nepetalactols does not induce opioid withdrawals in Felidae, probably because endogenous β-endorphin secretion is controlled.

This would make evolutionary pressure select for the behavior of rubbing of natural insect repellent.

This was proposed to be the reason for this widely preserved behavioral trait in Felidae in a paper published in 2021.