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Perilla frutescens is an ingredient for cooking and for Japanese traditional medicine formulations. Essential oils extracted from P. frutescens are classified according to their composition, which are genetically regulated. Here, we extracted five types of essential oil from P. frutescens and studied their sedative activities. We grew P. frutescens strains that give oils of type PK, PA, PP, EK, and C, and extracted the essential oils by hydrodistillation. We then measured the spontaneous locomotor activity of mice who had inhaled the oils in an open field test. All types of essential oil except the PK type decreased the spontaneous locomotor activity of mice. The effective doses were 4.0 × 10 -3 to 4.0 × 10 -2  mg/cage (PA type), 4.0 × 10 -4  mg/cage (PP type), 4.0 × 10 -5  mg/cage (EK type), and 4.0 × 10 -5 to 4.0 × 10 -3  mg/cage (C type). Our results show that the essential oils of type PA, PP, EK, and C have a sedative effect.

Agarwood is known to have a sedative effect and the less studied volatile aromatic constituents it contains may have contribution to the activity. In this study, two Kyara grade (highest-grade agarwood in Japan) samples were extracted using headspace-solid phase microextraction (HS-SPME) and analyzed through gas chromatography-mass spectrometry (GC-MS). Six low molecular weight aromatic compounds (LACs) and one structurally simple compound (diethylene glycol monoethyl ether) present in the aromas were individually evaluated for inhalational sedative activity in mice through open field test. Doses of 0.0001 g/L to 1 g/L were prepared for each compound and administered to mice ( n = 6/dose/compound). Results revealed all compounds decreased spontaneous motor activity at almost all doses. Strongest sedative activity of each compound reduced total spontaneous motor activity by more than half against control, demonstrating their contribution to agarwood aroma and potential as independent sedating agents. Mixtures of compounds using their most effective dose were made and evaluated again for inhalational sedative effect. Interestingly, the combination of all compounds showed no significant effect and even caused stimulation in mice movements. This result suggests antagonistic-like interaction between the compounds, which is probably due to structural similarities. Consequently, it implies the other constituents present in agarwood, along with LACs, are also important to the overall sedative activity.

Lantana camara Linn. (Verbenaceae) is used traditionally for its numerous medicinal properties such as antimalarial, antibacterial, anticancer and anti-inflammatory. In the present study, we investigated the chemical composition of essential oil from the leaves of L. camara (LCEO) occurring in the Republic of Benin (West Africa) in comparison with LCEOs from other regions; evaluated its sedative effects in mice via inhalation administration; and identified the compounds responsible for activity. LCEO was extracted by hydrodistillation and chemical analyses of the oil were performed by GC and GC/MS. The oil was dominated by monoterpene hydrocarbons (60.58%) and oxygenated monoterpenes (33.39%), among which sabinene (38.81%) and 1,8-cineole (28.90%) were the most abundant. LCEO administered via inhalation to mice significantly decreased locomotor activity in a dose-dependent manner, mainly at the doses of 0.0004 and 0.04 mg per 400 μL of triethyl citrate (TEC). The oil was fractionated to give two fractions, which were further investigated, and revealed that both sabinene and 1,8-cineole were the principal active compounds. The results of the present study indicated that via inhalation administration, LCEO and its main constituents could be considered as promising candidates for the management of dementia, insomnia, attention deficit hyperactivity disorder and other central nervous system-associated diseases.

The sedative effects of the essential oil released by living Ocimum basilicum (basil) plants were investigated using a mouse activity monitoring system. Ocimum basilicum plants were grown in a hydroponic chamber, and either the headspace air from the hydroponic chamber or the essential oil extracted from mature plants was administered by the inhalation route to mice in an open field test. The most effective dose of O. basilicum essential oil for reducing the locomotor activity of the mice was found to be 4.0 × 10 -3  mg per cage. The headspace air was administered to mice held in a glass cage via a Teflon tube connected to a hydroponic chamber containing O. basilicum plants. A significant decrease in locomotor activity was observed when the hydroponic chamber contained nine plants. The results of this study demonstrate that the headspace air of living basil plants could effectively reduce the locomotor activity of mice.

Spikenard, the dried roots of Nardostachys chinensis, contains sesquiterpenoids and is widely used as an herbal tranquilizer. We previously demonstrated that spikenard vapor showed a sedative effect when administered by inhalation, and we identified hydrocarbon sesquiterpenoids as active components. Here we investigated the other components that contribute to the effects of spikenard. Six oxygenated sesquiterpenoids, including aristolane- and guaiane-types, were isolated from an acetone extract of spikenard. We evaluated the sedative activities of these oxygenated compounds using an inhalation administration method in a caffeine-treated excitatory mouse model. We identified aristolen-1(10)-en-9-ol and patchouli alcohol as highly effective sedative components. These compounds inhibited locomotion in mice by approximately 60% at a dose of 300 µg/cage. In addition, aristolen-1(10)-en-9-ol prolonged pentobarbital-induced sleep to the same extent as 1 mg/kg diazepam. This effect completely disappeared with the administration of the GABAA-benzodiazepine receptor antagonist flumazenil (3 mg/kg), suggesting that the sedative effect of aristolen-1(10)-en-9-ol is expressed via the GABAergic system. Furthermore, differently from diazepam, inhalation of aristolen-1(10)-en-9-ol for 1 h did not affect the motor coordination in the rota-rod test. In the present study, we identified active components and provided evidence supporting the traditional sedative use of spikenard. Our research suggests that aristolen-1(10)-en-9-ol may be an effective aromatherapy, providing mild sedation., (Georg Thieme Verlag KG Stuttgart · New York.)

The sedative activity of eight aromatic natural medicines that are traditionally used in Japanese scent sachets was examined using an open field test with mice. Galangal (Kaempferia galanga), patchouli (Pogostemon cablin), sandalwood (Santalum album), spikenard (Nardostachys chinensis), cinnamon (Cinnamomum cassia), clove (Syzygium aromaticum), star anise (Illicium verum), and borneol (Dryobalanops aromatica) distilled oils were used. These natural medicines have various pharmacological effects. For example, galangal has insecticidal activity and clove extracts possess strong total antioxidant activity. Aromatherapy, a well-known complementary medicine system that uses inhalation, has recently attracted much attention. The sedative activity of inhaled aromatic compounds or essential oils has been examined by measuring the spontaneous motor activity of mice in an open field test. The galangal, patchouli, sandalwood, spikenard, and borneol oils showed significant sedative effects. The effect was stronger for a mixture of the five oils than for any of the single oils. This suggests that the oil mixture may have synergistic activity. Sedative activity was not observed when inactive oils (cinnamon, clove, and star anise) were added to the mixture of the five active oils., (Georg Thieme Verlag KG Stuttgart · New York.)

Dried Nardostachys chinensis roots contain sesquiterpenoids that are widely used as herbal tranquilizers. We previously identified the highly sedative sesquiterpenoid valerena-4,7(11)-diene (VLD) from this plant. In the present study, we investigated stress reducing effects of VLD and the associated mechanisms of action. Application of 15-min restraint stresses induced excitatory behaviors in mice. Immobility times in the forced swim test and sleeping times in the pentobarbital sleep test were shortened in the stressed group by 47% and 43%, respectively, compared with the control group. Furthermore, restraint stress increased serum corticosterone levels by 75%, and cerebral serotonin (5-HT) and dopamine (DA) levels. Inhaled VLD (300 µg/cage) suppressed stress-induced excitatory behaviors and significantly reduced stress-induced blood corticosterone, cerebral 5-HT, and DA levels. These results suggest that VLD interacts with the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenomedullary system. These interactions appear to involve GABAergic and D2 antagonist activities. Moreover, tests in anosmic and intravenously treated mice showed that the sedative effect of inhaled VLD was expressed via olfactory stimulation and pulmonary absorption. Although more studies are required to further elucidate the properties of this compound, our studies suggest that VLD may be an effective anti-stress aromatherapy for humans.

Terpinolene is a cyclic monoterpene compound found in some Labiatae herbs. In our previous study, we evaluated the sedative effect of inhaled essential oils of Microtoena patchoulii leaves in mice and isolated terpinolene as an active ingredient. We investigated the structure-activity relationships of terpinolene to identify the structural part essential to its sedative effect. Comparison of terpinolene analog activities showed that a double bond in the side-chain or pi bonds in the six-membered ring play important roles in the sedative effect. In another experiment using olfactory impaired mice, we further revealed that inhaled terpinolene exerted the effect after nasal absorption into the body.

The aromatherapeutical potential of Piper guineense essential oil was investigated in mice via inhalation administration, and the active compounds were identified. An open field test and light/dark transition test were used to evaluate the sedative and anxiolytic activities of this essential oil, respectively. P. guineense essential oil showed significant sedative activity at an effective dose of 4.0 × 10(-5) mg per cage compared to the control group. It also showed potent anxiolytic effect at a dose of 4.0 × 10(-6) mg per cage. The main compounds of P. guineense essential oil were linalool (41.8%) and 3,5-dimethoxytoluene (10.9%). These two main compounds were shown to play a major role in the sedative activity of P. guineense essential oil. These results suggest that inhalation of P. guineense essential oil might induce a mild tranquilizing effect.

Benzylacetone is released by heated agarwood, when inhaled it has a potent effect on reducing the locomotor activity of mice. This study investigated the relationships between the sedative activities of benzylacetone and its derivatives as well as the chemical structures of these compounds by comparing their activities in mice treated with a series of compounds. It was demonstrated that benzylacetone-like compounds had sedative activities and their intensities varied depending on the functional group in the carbon chain, the substituent in the benzene ring, and their combinations. A quantitative structure-activity relationship study was carried out using a series of 17 benzylacetone derivatives to determine the structural features with significant for the sedative activity.

Microtoena patchoulii (Labiatae) is a perennial herb that grows in southern China. In the present study, the sedative activity of the essential oil of the leaves was evaluated using mice when the volatile oil was administered by inhalation. The inhalation of the oil by mice significantly reduced the spontaneous motor activity. Fractionation of the oil revealed that the main constituents in the oil were 1-octen-3-ol, terpinolene, patchouli alcohol, and methyl salicylate. Each 1-octen-3-ol, terpinolene, or patchouli alcohol significantly reduce the locomotor activity when it was administered singly. However, the essential oil fraction containing both patchouli alcohol and methyl salicylate did not exhibit any effects. It is suggested that methyl salicylate might negate the sedative effect of patchouli alcohol, and that the concentration ratios of the compounds in vapor would play important roles as sedatives. In order to clarify the mechanism of action, the effects of these compounds on caffeine-induced excitation and pentobarbital-induced elongation of sleeping time in mice were tested. Each 1-octen-3-ol or terpinolene reduced the locomotor activity excited by caffeine to those of normal levels. Elongation of sleeping time induced by pentobarbital was further elongated by the inhalation of terpinolene, but not by that of 1-octen-3-ol. It is indicated that terpinolene is a potent suppressor of the central nervous system.

A concise synthesis of valerena-4,7(11)-diene with potent sedative activity was achieved in three steps involving, reduction of carboxylic acid, bromination of the resulting alcohol, and reduction of the bromide from valerenic acid in a 63% total yield. This synthetic method makes it possible to provide further materials for biological testing to realize comprehensive SAR studies.

Valerena-4,7(11)-diene and beta-maaliene were isolated from spikenard for the first time, and the effects of inhaling these compounds were investigated. Both compounds reduced the locomotor activity of mice dose-dependently, even at a low dose. Valerena-4,7(11)-diene had a particularly profound effect, with the strongest sedative activity observed at a dose of 0.06%. Caffeine-treated mice that showed an area under the curve (AUC) for locomotor activity that was double that of controls were calmed to normal levels by administration of valerena-4,7(11)-diene. The continuous sleep time of pentobarbital-treated mice was prolonged by about 2.7 times with valerena-4,7(11)-diene, an effect similar to that of chlorpromazine administered orally.

Agarwood oil and spikenard extract were examined for their sedative activity using a spontaneous vapor administration system. It was shown that inhalation of agarwood oil vapor sedated mice. The main volatile constituents of the oil were found to be benzylacetone [agarwood oil from a Hong Kong market (1)], or alpha-gurjunene and (+)-calarene [agarwood oil made in Vietnam (2)]. A hexane extract of spikenard contained a lot of calarene, and its vapor inhalation had a sedative effect on mice. Individual principles benzylacetone, calarene, and alpha-gurjunene were administered to mice, which reproduced the result of the corresponding oil or extract. However, the most effective dose of the compounds was lower than their original content in the oil and extract (benzylacetone 0.1%, calarene 0.17%, alpha-gurjunene 1.5%).