- Email: [email protected]
Research reports
The International Journal of Aromatherapy (2006) 16, 101–104
The International Journal of
Aromatherapy intl.elsevierhealth.com/journals/ijar
Research reports B. Harris
*
Au Village, 83840 La Martre, Provence, France
Sage and memory Salvia officinalis has a long history of use for improving memory and delaying age-related cognitive decline. Spanish sage, Salvia lavandulaefolia is now thought to be a more suitable essential oil for treatment as its toxic thujone content is considerably less. A previous study found that single doses of S. lavandulaefolia essential oil significantly improved the memory of volunteers for a word recall task. Therefore, the present study (Tildesley et al., 2005), examined the dose- and time-dependent acute cognitive and mood effects of the essential oil. Single doses of placebo (sunflower oil), 25 ll and 50 ll of the essential oil were administered orally in capsules to 24 healthy young volunteers, separated by a 7-day washout period. Cognitive performance was assessed before the treatments and at 1, 2.5, 4 and 6 h post treatment using the cognitive drug research (CDR) computerised test battery. The primary outcome measures were derived from the battery by factor analysis and the global ‘quality of memory’ measure. Computerised serial sevens and serial threes tests was also utilised, whereby the participants had to count backwards in multiples of seven or three, respectively, from a given number. The Bond-Lader visual analogue scales were used to assess subjective mood ratings. The administration of the essential oil at both doses showed a consistent improvement on the * Tel./fax: +33 494 84 29 93. E-mail address: [email protected].
0962-4562/$ - see front matter c 2006 Published by Elsevier Ltd. doi:10.1016/j.ijat.2006.05.002
‘speed memory’ factor and an improvement on the ‘secondary memory’ factor for the 25 ll dose only. For the serial subtraction tasks, both doses of essential oil resulted in a sustained improvement in the speed of performance, with the higher dose resulting in more subtractions than placebo at the final testing session. Improvements in mood were seen with both doses of essential oil. This was most pronounced with the 50 ll dose, where there were significant positive effects in all three mood factors of selfrated ‘alertness’, ‘contentedness’ and ‘calmness’. The 25 ll dose was associated with a significant improvement in the ‘calmness’ factor only. The results suggested that the essential oil of Salvia lavandulaefolia is capable of acute modulation of mood and cognition in healthy young adults and that the memory enhancement may be due to more efficient retrieval of target material. These positive behavioural effects could be applied to those suffering from age-related or disease-related declines in mental functioning.
Nicotine addiction Nicotine is an agonist of nicotinic acetylcholine receptors that facilitate dopamine release in the ventral tegmental area and nucleus accumbens of the brain. Like other addictive drugs, the repeated administration of nicotine can produce behavioural sensitisation to a subsequent exposure to the drug, as evidenced by an increased locomotor response.
102 Behavioural sensitisation is thought to involve the dopamine system of the nucleus accumbens, and plays a crucial role in certain aspects of drug addiction. It is postulated that the inhalation of an essential oil may correct a reversible malfunction of the body by direct activation of a specific brain pathway. A Korean team (Zhao et al., 2005) investigated the effects of the inhalation of the essential oil of Angelica gigas (Korean Dang Gui) on chronic nicotine-induced dopamine release from the nucleus accumbens and behavioural sensitisation in rats. Rats were given repeated subcutaneous injections of either saline or nicotine (0.4 mg/kg) twice daily for seven days, followed by one systemic challenge injection of nicotine (0.4 mg/kg) four days later. For a direct local challenge, nicotine (3 mM) dissolved in microdialysis fluid was infused locally into the nucleus accumbens via a dialysis probe. Extracellular dopamine levels in the nucleus accumbens were measured via implanted microdialysis cannulae. The perfusion rate was 1.5 ll/min. The same nicotine pre-treatment design was used to evaluate behavioural sensitisation by measuring locomotor activity, which was recorded on a video tracking system. The experiments were also carried out after essential oil inhalation immediately before the nicotine challenge; the saline controls were also exposed to the fragrance to determine the effect of the oil alone on dopamine levels. Inhalation of the essential oil was carried out in a cage that was capped and allowed the minimum of breathing air to escape. Two grams of essential oil were placed into the cage 24 h before the start of the microdialysis sessions. The inhalation of the essential oil of Mentha arvensis var. piperascens was used as a control. It was found that nicotine-pretreated rats had a greater increase in locomotor activity after systemic challenge than saline-treated rats. Nicotine-pretreated rats demonstrated a larger increase in dopamine release than saline-pretreated rats after local challenge. Inhalation of the essential oil significantly decreased dopamine release in the nucleus accumbens and locomotor activity induced by nicotine challenge. Dopamine release and locomotor activity were unaffected by essential oil inhalation in the saline-treated group. The results suggested that the inhalation of the essential oil of Angelica gigas inhibited nicotine-induced neurochemical and behavioural sensitisation, implying that it may be effective in treating nicotine addiction by modulation of dopamine release in the nucleus accumbens.
B. Harris
Menopausal treatment? Ether inhalation is an experimental animal model for stress that causes an increase in plasma adrenocorticotropic hormone (ACTH) and a decrease in catecholamine. These same changes occur in human depression, which is one of the symptoms of the menopause. As the function of the ovaries decreases, there is also hormonal imbalance based on increasing gonadotropin and decreasing oestrogen levels. A Japanese study (Yamada et al., 2005) assessed the effects of lavander essential oil and linalool on plasma ACTH, catecholamine and gonadotropin (luteinizing hormone, LH, and follicle-stimulating hormone, FSH) levels in an experimental menopausal model using female rats under ether-inhalation. The essential oil of Lavandula burnatii super was used in preference to other species due to its pleasant fragrance, economical price and high linalool content. Ovariectomised rats inhaled either the essential oil or linalool that was placed on cotton inside the cages for 10 min twice a day for three days. After the final inhalation the rats inhaled ether for 20 min, after which blood samples were obtained. As expected, ether inhalation produced an increase in plasma ACTH levels. This increase was reduced by the inhalation of lavender vapour and was significantly diminished by the inhalation of linalool. The decrease in catecholamine levels caused by ether inhalation was restored to almost normal by lavender vapour inhalation, whilst linalool affected noradrenaline and dopamine levels. Neither lavender nor linalool affected FSH levels; linalool significantly decreased LH levels and lavender had a lesser effect. The results indirectly suggest that the decrease in ACTH levels and thus the decrease in LH levels and the restoration of catecholamine level in rats after ether inhalation is via augmentation of dopaminergic or noradrenergic activity, caused by inhalation of either lavender or linalool vapour. The results also imply that the inhalation of either linalool or Lavandula burnatii essential oil vapour may relieve the mood fluctuations of the menopausal syndrome.
Antiinflammatory geranium It had previously been shown that geranium essential oil suppressed cellular inflammation and neutrophil accumulation to inflammatory sites, suggesting that geranium oil may suppress symptoms
Research reports of inflammatory disease linked with neutrophil activities. A Japanese group (Maruyama et al., 2006) investigated the effects of geranium essential oil (botanical species not stated) on carrageenaninduced foot oedema and collagen-induced arthritis in mice. These are models for acute and chronic inflammation, respectively, which are accompanied by neutrophil accumulation. Carrageenan (10 mg) was injected into mice footpads to cause oedema. Photos were taken before, 6 and 24 h after injection and the foot thickness measured from the photos to calculate the oedema. A geranium oil solution (containing 5 ll of pure oil) was administered intraperitoneally 10 min after the carrageenan, whilst control mice received dimethyl sulphoxide (DMSO). The myeloperoxidase (MPO) activity within each foot was determined 24 h after the carrageenan injection and this was representative of the number of neutrophils present. Arthritis was induced in mice by the subcutaneous injection of a collagen II solution and the test mice were given the geranium oil as before from day 0 to 21, five days a week; controls received DMSO. The paws were measured twice a week from day 0 to 39 and the arthritis scored using a macroscopic system based on the number of joints involved. Carrageenan increased the footpad thickness of the control mice after 6 h and the swelling continued for 24 h; by contrast, in mice treated with geranium oil the thickness was significantly suppressed. MPO activity in the footpads was markedly increased after carrageenan injection in comparison to the controls, and geranium oil significantly suppressed this increase. This suggested that the geranium oil lowered neutrophil accumulation in the injected feet. Of the mice injected with collagen II, most of them developed oedema; 6 out of 10 on day 21 and 7 out of 10 on day 39. In the geranium oil group, only one animal demonstrated oedema and there was a statistical difference between the control and the geranium groups on day 10 and after day 17. The body weights of mice treated with geranium oil decreased immediately after injection but gradually recovered. Two mice died on days 18 and 21. From the results, it was clear that the intraperitoneal injection of 5 ll of geranium oil suppressed carrageenan-induced oedema and collagen-induced arthritis. Neutrophil accumulation, as indicated by MPO activity, was also decreased. Collagen-induced arthritis in mice has many characteristics in common with human rheumatoid arthritis and is used as an animal model for the dis-
103 ease. Geranium oil suppressed the swelling and the effect continued after cessation of the injection. This is the first report of geranium oil suppressing the later phase of an inflammatory response as well as the earlier phase during in vivo experiments. The cellular mechanism involved in the activity of geranium oil remains unknown, but is thought to involve the inhibition of the inflammatory response to cytokines such as TNF-a. The suppression of the onset of symptoms may be also partially attributed to the inhibition of neutrophil infiltration. As the injection of 5 ll of geranium oil produced toxic effects, it was thought that cutaneous application may be advantageous since previous experiments using this route of administration did not elicit toxic responses.
Anticancer eugenol The activities of eugenol have been reported in a number of studies; generally at low concentrations it acts as an antioxidant and antiinflammatory agent but at high concentrations it acts as a pro-oxidant resulting from the production of free radicals. Programmed cell death, known as apoptosis, is known to be linked in many cases to mitochondrial permeability transition (PT). This leads to dissipation of inner transmembrane potential, triggering the release of cytochrome c into the cytosol and subsequent cell death. As part of screening program for natural anticancer agents, a Korean study (Yoo et al., 2005) investigated the effects of eugenol obtained from the essential oil of Eugenia caryophyllata, on human leukaemia (HL-60) cells. The cytotoxicity (IC50) of eugenol was found to be 23.7 lM for HL-60 cells and it was less toxic to a number of other cell lines, e.g. for the SNU-C5 human colon cancer cell line the IC50 was 120.4 lM. The induction of DNA fragmentation was demonstrated by incubating HL-60 cells with different concentrations of eugenol for various time spans. Fragmentation was time-and concentrationdependent, but was blocked by pre-treatment with an antioxidant. The measurement of reactive oxygen species (ROS) within the cells indicated that following treatment with 40 lM of eugenol, there was significant generation of ROS. This indicated that eugenol induced apoptosis via ROS generation. Further experiments showed that eugenol also induced apoptosis by depleting intracellular reduced glutathione and protein thiols in a concentration- and time-dependent manner, with significant differences being observed as early as
104 15 min incubation with eugenol concentrations of 20–60 lM. The ROS produced by the rapid depletion of intracellular thiols may play a critical role in eugenol-induced apoptosis. Eugenol also caused the loss of mitochondrial membrane potential (a hallmark of PT), thereby releasing cytochrome c into the cytosol of human leukaemia cells. Work is currently underway to determine whether eugenol can be developed into a chemotherapeutic agent.
References Maruyama N, Ishibashi H, Hu W, Morofuji S, Inouye S, Yamaguchi H, et al.. Suppression of carrageenan- and collagen II-
B. Harris induced inflammation in mice by geranium oil. Mediat Inflamm 2006:1–7. Tildesley NTJ, Kennedy DO, Perry EK, Ballard CG, Wesnes KA, Scholey AB. Positive modulation of mood and cognitive performance following administration of acute doses of Salvia lavandulaefolia essential oil to healthy young volunteers. Physiol Behav 2005;83:699–709. Yamada K, Mimaki Y, Sashida Y. Effects of inhaling the vapour of Lavandula burnatii super-derived essential oil and linalool on plasma adrenocorticotropic hormone (ACTH), catcholamine and gonadotropin levels in experimental menopausal rats. Biol Pharm Bull 2005;28:378–9. Yoo C-B, Han K-T, Cho K-S, Ha J, Park H-J, Nam J-H, et al. Eugenol isolated from the essential oil of Eugenia caryophyllata induces a reactive oxygen species-mediated apoptosis in HL-60 human promyelocytic leukaemia cells. Cancer Lett 2005;225:41–52. Zhao RJ, Koo BS, Kim GW, Jang EY, Lee JR, Kim MR, et al. The essential oil from Angelica gigas Nakai suppresses nicotine sensitisation. Biol Pharm Bull 2005;28:2323–6.
The International Journal of
Aromatherapy intl.elsevierhealth.com/journals/ijar
Research reports B. Harris
*
Au Village, 83840 La Martre, Provence, France
Sage and memory Salvia officinalis has a long history of use for improving memory and delaying age-related cognitive decline. Spanish sage, Salvia lavandulaefolia is now thought to be a more suitable essential oil for treatment as its toxic thujone content is considerably less. A previous study found that single doses of S. lavandulaefolia essential oil significantly improved the memory of volunteers for a word recall task. Therefore, the present study (Tildesley et al., 2005), examined the dose- and time-dependent acute cognitive and mood effects of the essential oil. Single doses of placebo (sunflower oil), 25 ll and 50 ll of the essential oil were administered orally in capsules to 24 healthy young volunteers, separated by a 7-day washout period. Cognitive performance was assessed before the treatments and at 1, 2.5, 4 and 6 h post treatment using the cognitive drug research (CDR) computerised test battery. The primary outcome measures were derived from the battery by factor analysis and the global ‘quality of memory’ measure. Computerised serial sevens and serial threes tests was also utilised, whereby the participants had to count backwards in multiples of seven or three, respectively, from a given number. The Bond-Lader visual analogue scales were used to assess subjective mood ratings. The administration of the essential oil at both doses showed a consistent improvement on the * Tel./fax: +33 494 84 29 93. E-mail address: [email protected].
0962-4562/$ - see front matter c 2006 Published by Elsevier Ltd. doi:10.1016/j.ijat.2006.05.002
‘speed memory’ factor and an improvement on the ‘secondary memory’ factor for the 25 ll dose only. For the serial subtraction tasks, both doses of essential oil resulted in a sustained improvement in the speed of performance, with the higher dose resulting in more subtractions than placebo at the final testing session. Improvements in mood were seen with both doses of essential oil. This was most pronounced with the 50 ll dose, where there were significant positive effects in all three mood factors of selfrated ‘alertness’, ‘contentedness’ and ‘calmness’. The 25 ll dose was associated with a significant improvement in the ‘calmness’ factor only. The results suggested that the essential oil of Salvia lavandulaefolia is capable of acute modulation of mood and cognition in healthy young adults and that the memory enhancement may be due to more efficient retrieval of target material. These positive behavioural effects could be applied to those suffering from age-related or disease-related declines in mental functioning.
Nicotine addiction Nicotine is an agonist of nicotinic acetylcholine receptors that facilitate dopamine release in the ventral tegmental area and nucleus accumbens of the brain. Like other addictive drugs, the repeated administration of nicotine can produce behavioural sensitisation to a subsequent exposure to the drug, as evidenced by an increased locomotor response.
102 Behavioural sensitisation is thought to involve the dopamine system of the nucleus accumbens, and plays a crucial role in certain aspects of drug addiction. It is postulated that the inhalation of an essential oil may correct a reversible malfunction of the body by direct activation of a specific brain pathway. A Korean team (Zhao et al., 2005) investigated the effects of the inhalation of the essential oil of Angelica gigas (Korean Dang Gui) on chronic nicotine-induced dopamine release from the nucleus accumbens and behavioural sensitisation in rats. Rats were given repeated subcutaneous injections of either saline or nicotine (0.4 mg/kg) twice daily for seven days, followed by one systemic challenge injection of nicotine (0.4 mg/kg) four days later. For a direct local challenge, nicotine (3 mM) dissolved in microdialysis fluid was infused locally into the nucleus accumbens via a dialysis probe. Extracellular dopamine levels in the nucleus accumbens were measured via implanted microdialysis cannulae. The perfusion rate was 1.5 ll/min. The same nicotine pre-treatment design was used to evaluate behavioural sensitisation by measuring locomotor activity, which was recorded on a video tracking system. The experiments were also carried out after essential oil inhalation immediately before the nicotine challenge; the saline controls were also exposed to the fragrance to determine the effect of the oil alone on dopamine levels. Inhalation of the essential oil was carried out in a cage that was capped and allowed the minimum of breathing air to escape. Two grams of essential oil were placed into the cage 24 h before the start of the microdialysis sessions. The inhalation of the essential oil of Mentha arvensis var. piperascens was used as a control. It was found that nicotine-pretreated rats had a greater increase in locomotor activity after systemic challenge than saline-treated rats. Nicotine-pretreated rats demonstrated a larger increase in dopamine release than saline-pretreated rats after local challenge. Inhalation of the essential oil significantly decreased dopamine release in the nucleus accumbens and locomotor activity induced by nicotine challenge. Dopamine release and locomotor activity were unaffected by essential oil inhalation in the saline-treated group. The results suggested that the inhalation of the essential oil of Angelica gigas inhibited nicotine-induced neurochemical and behavioural sensitisation, implying that it may be effective in treating nicotine addiction by modulation of dopamine release in the nucleus accumbens.
B. Harris
Menopausal treatment? Ether inhalation is an experimental animal model for stress that causes an increase in plasma adrenocorticotropic hormone (ACTH) and a decrease in catecholamine. These same changes occur in human depression, which is one of the symptoms of the menopause. As the function of the ovaries decreases, there is also hormonal imbalance based on increasing gonadotropin and decreasing oestrogen levels. A Japanese study (Yamada et al., 2005) assessed the effects of lavander essential oil and linalool on plasma ACTH, catecholamine and gonadotropin (luteinizing hormone, LH, and follicle-stimulating hormone, FSH) levels in an experimental menopausal model using female rats under ether-inhalation. The essential oil of Lavandula burnatii super was used in preference to other species due to its pleasant fragrance, economical price and high linalool content. Ovariectomised rats inhaled either the essential oil or linalool that was placed on cotton inside the cages for 10 min twice a day for three days. After the final inhalation the rats inhaled ether for 20 min, after which blood samples were obtained. As expected, ether inhalation produced an increase in plasma ACTH levels. This increase was reduced by the inhalation of lavender vapour and was significantly diminished by the inhalation of linalool. The decrease in catecholamine levels caused by ether inhalation was restored to almost normal by lavender vapour inhalation, whilst linalool affected noradrenaline and dopamine levels. Neither lavender nor linalool affected FSH levels; linalool significantly decreased LH levels and lavender had a lesser effect. The results indirectly suggest that the decrease in ACTH levels and thus the decrease in LH levels and the restoration of catecholamine level in rats after ether inhalation is via augmentation of dopaminergic or noradrenergic activity, caused by inhalation of either lavender or linalool vapour. The results also imply that the inhalation of either linalool or Lavandula burnatii essential oil vapour may relieve the mood fluctuations of the menopausal syndrome.
Antiinflammatory geranium It had previously been shown that geranium essential oil suppressed cellular inflammation and neutrophil accumulation to inflammatory sites, suggesting that geranium oil may suppress symptoms
Research reports of inflammatory disease linked with neutrophil activities. A Japanese group (Maruyama et al., 2006) investigated the effects of geranium essential oil (botanical species not stated) on carrageenaninduced foot oedema and collagen-induced arthritis in mice. These are models for acute and chronic inflammation, respectively, which are accompanied by neutrophil accumulation. Carrageenan (10 mg) was injected into mice footpads to cause oedema. Photos were taken before, 6 and 24 h after injection and the foot thickness measured from the photos to calculate the oedema. A geranium oil solution (containing 5 ll of pure oil) was administered intraperitoneally 10 min after the carrageenan, whilst control mice received dimethyl sulphoxide (DMSO). The myeloperoxidase (MPO) activity within each foot was determined 24 h after the carrageenan injection and this was representative of the number of neutrophils present. Arthritis was induced in mice by the subcutaneous injection of a collagen II solution and the test mice were given the geranium oil as before from day 0 to 21, five days a week; controls received DMSO. The paws were measured twice a week from day 0 to 39 and the arthritis scored using a macroscopic system based on the number of joints involved. Carrageenan increased the footpad thickness of the control mice after 6 h and the swelling continued for 24 h; by contrast, in mice treated with geranium oil the thickness was significantly suppressed. MPO activity in the footpads was markedly increased after carrageenan injection in comparison to the controls, and geranium oil significantly suppressed this increase. This suggested that the geranium oil lowered neutrophil accumulation in the injected feet. Of the mice injected with collagen II, most of them developed oedema; 6 out of 10 on day 21 and 7 out of 10 on day 39. In the geranium oil group, only one animal demonstrated oedema and there was a statistical difference between the control and the geranium groups on day 10 and after day 17. The body weights of mice treated with geranium oil decreased immediately after injection but gradually recovered. Two mice died on days 18 and 21. From the results, it was clear that the intraperitoneal injection of 5 ll of geranium oil suppressed carrageenan-induced oedema and collagen-induced arthritis. Neutrophil accumulation, as indicated by MPO activity, was also decreased. Collagen-induced arthritis in mice has many characteristics in common with human rheumatoid arthritis and is used as an animal model for the dis-
103 ease. Geranium oil suppressed the swelling and the effect continued after cessation of the injection. This is the first report of geranium oil suppressing the later phase of an inflammatory response as well as the earlier phase during in vivo experiments. The cellular mechanism involved in the activity of geranium oil remains unknown, but is thought to involve the inhibition of the inflammatory response to cytokines such as TNF-a. The suppression of the onset of symptoms may be also partially attributed to the inhibition of neutrophil infiltration. As the injection of 5 ll of geranium oil produced toxic effects, it was thought that cutaneous application may be advantageous since previous experiments using this route of administration did not elicit toxic responses.
Anticancer eugenol The activities of eugenol have been reported in a number of studies; generally at low concentrations it acts as an antioxidant and antiinflammatory agent but at high concentrations it acts as a pro-oxidant resulting from the production of free radicals. Programmed cell death, known as apoptosis, is known to be linked in many cases to mitochondrial permeability transition (PT). This leads to dissipation of inner transmembrane potential, triggering the release of cytochrome c into the cytosol and subsequent cell death. As part of screening program for natural anticancer agents, a Korean study (Yoo et al., 2005) investigated the effects of eugenol obtained from the essential oil of Eugenia caryophyllata, on human leukaemia (HL-60) cells. The cytotoxicity (IC50) of eugenol was found to be 23.7 lM for HL-60 cells and it was less toxic to a number of other cell lines, e.g. for the SNU-C5 human colon cancer cell line the IC50 was 120.4 lM. The induction of DNA fragmentation was demonstrated by incubating HL-60 cells with different concentrations of eugenol for various time spans. Fragmentation was time-and concentrationdependent, but was blocked by pre-treatment with an antioxidant. The measurement of reactive oxygen species (ROS) within the cells indicated that following treatment with 40 lM of eugenol, there was significant generation of ROS. This indicated that eugenol induced apoptosis via ROS generation. Further experiments showed that eugenol also induced apoptosis by depleting intracellular reduced glutathione and protein thiols in a concentration- and time-dependent manner, with significant differences being observed as early as
104 15 min incubation with eugenol concentrations of 20–60 lM. The ROS produced by the rapid depletion of intracellular thiols may play a critical role in eugenol-induced apoptosis. Eugenol also caused the loss of mitochondrial membrane potential (a hallmark of PT), thereby releasing cytochrome c into the cytosol of human leukaemia cells. Work is currently underway to determine whether eugenol can be developed into a chemotherapeutic agent.
References Maruyama N, Ishibashi H, Hu W, Morofuji S, Inouye S, Yamaguchi H, et al.. Suppression of carrageenan- and collagen II-
B. Harris induced inflammation in mice by geranium oil. Mediat Inflamm 2006:1–7. Tildesley NTJ, Kennedy DO, Perry EK, Ballard CG, Wesnes KA, Scholey AB. Positive modulation of mood and cognitive performance following administration of acute doses of Salvia lavandulaefolia essential oil to healthy young volunteers. Physiol Behav 2005;83:699–709. Yamada K, Mimaki Y, Sashida Y. Effects of inhaling the vapour of Lavandula burnatii super-derived essential oil and linalool on plasma adrenocorticotropic hormone (ACTH), catcholamine and gonadotropin levels in experimental menopausal rats. Biol Pharm Bull 2005;28:378–9. Yoo C-B, Han K-T, Cho K-S, Ha J, Park H-J, Nam J-H, et al. Eugenol isolated from the essential oil of Eugenia caryophyllata induces a reactive oxygen species-mediated apoptosis in HL-60 human promyelocytic leukaemia cells. Cancer Lett 2005;225:41–52. Zhao RJ, Koo BS, Kim GW, Jang EY, Lee JR, Kim MR, et al. The essential oil from Angelica gigas Nakai suppresses nicotine sensitisation. Biol Pharm Bull 2005;28:2323–6.