Traditional medicine has long used aromatic plant-derived compounds such as lavender extract as treatments for anxiety, but how these compounds might work at the neuronal level isn’t fully understood. A team of scientists in Japan has now demonstrated that the smell of the aromatic lavender-derived alcohol, linalool, exerts anxiolytic effects in mice by acting on the same gamma-aminobutyric acid A receptors (GABA A Rs) that respond to the anxiolytic drug benzodiazepam. However, while diazepam in the bloodstream acts directly on GABA A receptors, the Kagoshima University team found that linalool vapor acted via the animals’ olfactory system—its relaxing effects weren’t evident in mice that couldn’t smell.

The researchers, headed by Hideki Kashiwadani, Ph.D., of Kagoshima University, suggest that while further studies will be needed to more thoroughly evaluate the target, effects, and potential side effects of linalool, the new findings indicate that the compound could feasibly be used to help reduce patients’ anxiety in clinical settings. “These findings nonetheless bring us closer to clinical use of linalool to relieve anxiety—in surgery for example, where pretreatment with anxiolytics can alleviate preoperative stress and thus help to place patients under general anesthesia more smoothly,” Dr. Kashiwadani comments. “Vaporized linalool could also provide a safe alternative for patients who have difficulties with oral or suppository administration of anxiolytics, such as infants or confused elders.”

The team’s findings are reported in Frontiers in Behavioral Neuroscience, in a paper titled, “Linalool odor-induced anxiolytic effects in mice.”

Anxiety disorders are one of the most common types of mental health disorder, the authors write. First-line drug therapies include azapirons and serotonin selective reuptake inhibitors (SSRIs) that act on serotonergic synaptic transmission, along with benzodiazepines that act via GABAergic transmission. However, the team notes, the side effects of these drugs can be worse than the anxiety itself.

Plant-derived aromatic compounds, including lavender extract, have been used in folk medicines to treat anxiety for many years. “However, the neuronal mechanisms underlying the reported anxiolytic effects of the odorous compounds have not yet been fully revealed,” the team states. “Previously, several studies have examined that linalool inhalation induced anxiolytic effects. However, because the contribution of the olfactory system was not directly examined, the nature of how linalool may induce the effects was not revealed.”

The researchers now report on studies that involved carrying out classical tests for anxiety on male mice, immediately after the animals were exposed to linalool vapor. Results of the light/dark box test and elevated plus maze test suggested that linalool vapor exposure produced dose-related anxiolytic effects that in some cases were comparable to those produced by diazepam treatment. However, unlike benzodiazepam or linalool injections, exposure to linalool odor didn’t cause motor impairment, and the test results suggested that the effects of linalool odor were anxiolytic, rather than sedative.

Significantly, linalool vapor only exerted its effects in mice that had a sense of smell. Exposure to linalool vapor had anxiolytic effects in anosmic mice. These animals had been pretreated with a compound that destroyed their olfactory receptors. Similarly, animals that were pretreated with a compound flumazenil, which blocks the benzodiazepine site on GABA A Rs, also didn’t respond to the linalool vapor, “indicating that GABAergic transmission via benzodiazepine-responsive GABA A Rs was essential for the anxiolytic effects,” the authors state. “When combined, these results suggest that linalool does not act directly on GABA A receptors like benzodiazepines do—but must activate them via olfactory neurons in the nose in order to produce its relaxing effects,” Dr. Kashiwadani notes.

Interestingly, previous studies have found that other odors, including (+)-limonene—which is found in citrus fruit peel—also have anxiolytic effects when inhaled. However, in the case of (+)-limonene, pretreatment using flumazenil doesn’t block its relaxing effects. “Taken together with our results, it is possible that there may be at least two parallel anxiolytic pathways involving benzodiazepine-responsive GABA A Rs-dependent, and -independent systems evoked by olfactory input.”

Prior research had found that administering linalool systemically via intraperitoneal injection also induced anxiolytic effects, leading to the assumption that inhaled linalool acts via glutamatergic neurotransmission after it enters the bloodstream via absorption through the airways. However, Dr. Kashiwadani suggests, “Our study opens the possibility that relaxation seen in mice fed or injected with linalool could, in fact, be due to the smell of the compound emitted in their exhaled breath.”

“These results provide information about the potential central neuronal mechanisms underlying the odor-induced anxiolytic effects and the foundation for exploring clinical application of linalool odor in anxiety treatments,” the authors write. “Linalool odor-induced anxiolytic effects may be applicable for preoperative patients because pretreatment with anxiolytics can alleviate preoperative stress and thus contribute to placing patients under general anesthesia more smoothly. In addition, for patients who may have difficulties with oral or suppository administration of anxiolytics, such as infants, utilizing linalool odor to help reduce anxiety may be a convenient and promising alternative.”