Can Ambroxide Differ in Pleasantness Without Differing in Intensity?

Two people may perceive a fragrance as similarly strong yet differ in how pleasant they find it. A study of the fragrance material ambroxide and a single olfactory receptor offers a clue to why.

A 2025 study identified OR7A17 as a receptor that responds to ambroxide and compared perception in people carrying genetic variants with different receptor functions. In a small Japanese study, participants without a functional variant rated purified ambroxide as less pleasant and less woody. In contrast, the groups did not differ significantly in detection threshold or perceived intensity.

Searching for a receptor that detects ambroxide

Ambroxide is one of the compounds that characterize the scent of ambergris, and synthetic versions are also used in perfumery. This study mainly concerns a specific molecule, (−)-ambroxide. It should be distinguished from an experiment comparing people’s responses to natural ambergris as a whole.

The researchers expressed 378 human olfactory receptors in cultured cells and tested their responses to ambroxide. OR7A17 emerged as a candidate, and its concentration-dependent response was subsequently confirmed.

They also compared ambroxide preparations from different suppliers with a purified sample from which trace impurities had been removed. Because the receptor still responded after purification, they concluded that ambroxide itself, rather than an impurity, activates OR7A17.

Not a receptor for every amber-scented material

The researchers compared a range of fragrance materials, thinking that OR7A17 might recognize amber-scented materials broadly. Its response range proved narrower than expected: although it responded weakly to materials such as Orbitone and Iso E Super, it did not respond to many other amber-scented materials.

They then synthesized and tested molecules with changes to parts of ambroxide’s ring structure. In some cases, even small structural changes greatly reduced the response, while other changes preserved it. The fragrance descriptor “amber” and the range of molecules recognized by a single receptor are not the same thing.

Two variants behaved differently in cells

Public genome data revealed major OR7A17 variants that differ at two amino acid positions. The paper calls the functional variant IA and the variant with impaired responsiveness TS.

In cultured cells, the TS variant did not respond to ambroxide or other compounds that activated the IA variant. Less receptor protein reached the cell surface, suggesting that receptor stability might be altered. The proposed molecular binding site was inferred from structural modeling and calculations, not from directly determining the receptor’s actual three-dimensional structure.

The frequency of people carrying two TS copies varied among regional populations in the public data and was relatively high in East Asian populations. However, this was not a survey measuring fragrance preferences under matched conditions across regions. The connection to historical uses of ambergris is a hypothesis discussed by the authors.

Measuring intensity and pleasantness separately in Japanese participants

For the human study, participants were recruited from Kao employees who were not involved in olfaction-related research. The researchers genotyped 91 people and compared perception in the 31 participants shown in the main results: 19 with at least one functional IA copy and 12 with only TS copies. A separate description in the original Methods gives a breakdown totaling 32 participants; this article follows the 31 shown in the Results and figures.

First, the researchers diluted purified ABXP to different concentrations and measured detection thresholds by asking participants to select the one odor-containing bottle from three bottles. They also presented 24 samples in random order: four ambroxide-related samples, 19 other fragrance materials, and the solvent. Participants rated intensity and pleasantness separately. The experimenter administering the tests was not told the participants’ genotypes.

The groups did not differ significantly in detection threshold for purified ABXP (p = 0.20). Nor was there a significant difference in intensity (p = 0.56), a pattern also seen across the four ambroxide-related samples. The small sample cannot rule out smaller differences, but many participants with only the TS variant could still detect the odor. Receptors other than OR7A17 are therefore thought to contribute to perceiving ambroxide.

By contrast, the group carrying only TS copies rated purified ABXP as less pleasant (p = 0.017). All four related samples showed differences in the same direction, but not all were statistically significant: clear differences were found for ABXP and Ambrox Super, while ABX and CETALOX did not reach significance.

OR7A17 genotype reportedly explained 14.7% of the variation in ABXP pleasantness ratings in this group. That figure does not mean that the receptor determines preference as a whole. Other receptors, experience, and environmental factors may contribute to the remaining individual variation.

Woody qualities and changes after prolonged smelling

The study examined not only pleasantness but also what kind of odor participants perceived. When they rated the applicability of 15 descriptors, the group with only TS copies gave lower ratings to the woody and grassy qualities of purified ambroxide. Both differences were significant in uncorrected tests (p = 0.008 and 0.010, respectively). Ratings for the descriptor “chemical” also tended to be lower.

The researchers then tested whether smelling ambroxide ABX continuously for two minutes changed the perceived qualities of other woody fragrance materials. Among IA carriers, seven people initially described Orbitone as woody or grassy; six of those seven no longer selected that woody quality after prolonged exposure. The same change was not seen in the TS-only group, and Iso E Super showed a tendency in a similar direction.

The authors interpret these changes in odor quality as involving adaptation in a pathway that includes OR7A17. However, smelling ambroxide does not selectively switch off OR7A17 alone, so the causal effect of that receptor in isolation was not fully disentangled.

A clue to pleasantness in one group of participants

An important feature of this study is that it connects receptor differences not only to whether someone can smell a compound, but also to its pleasantness and woody quality. The authors suggest that neural input originating at OR7A17 supports part of ambroxide’s pleasant impression.

The human study involved a small Japanese sample and did not broadly examine genotypes of other receptors. No correction for multiple comparisons was identified for the tests comparing intensity and pleasantness across the 24 samples. For the 15-descriptor comparisons, however, the supplementary data report adjusted p values: the woody, grassy, and chemical descriptors for purified ambroxide each had an adjusted p = 0.093 and were not significant at the 5% level. These associations are best read as clues worth testing in larger samples and replicating in other populations.

Summary

OR7A17 responded well to ambroxide, but it was not a receptor that responded equally to every similarly amber-scented fragrance material. Comparing people whose genetic variants behaved differently in cells showed that those without the functional variant rated purified ambroxide as less pleasant and less woody.

There were no significant differences in detection threshold or intensity. The findings suggest that being able to perceive an odor and finding it pleasant cannot be captured by a single scale. This is a concrete example of research approaching individual differences in fragrance preference through receptor function.

The study received funding from the US NSF and NIH. At the time of the research, four of the five authors were affiliated with Kao, which had filed a patent application related to OR7A17. The remaining author disclosed royalties from ChemCom, research funding from Givaudan, and consulting fees from Kao.

References

Takase D, Shirai T, Misawa K, Matsunami H, Yoshikawa K. An odorant receptor for a key odor constituent of ambergris. Communications Biology. 2025;8:792. doi:10.1038/s42003-025-08229-y.