Table 2.

Principal characteristics of clinical studies carried out with Citrus aurantium essential oil.

Authors	Indication	Study design	Subjects (number and age)	Treatment	Principal endpoints	Adverse effects	Outcome
Fernandes Pimenta, et al., 2016	Anxiety in patients with chronic myeloid leukemia (CML)	Randomized controlled study	N = 42 of both sexes. Average age: 45 ± 5 years.	Participants were randomly divided into three groups. Group 1 received 10 mg diazepam as oral dose; Group 2 received C. aurantium essential oil (EO) 10 mL diffused in the room through an electric dispenser. Group 3 (placebo) was exposed to the vaporization of saline solution. In the last two groups, the exposure lasted 30min.	The evaluation was performed through psychometric scales STAI-S [State-Trait Anxiety Inventory (STAI)] and physiological measurements (blood pressure and cardiac and respiratory frequency).	Not reported.	Inhalation of C. aurantium was associated with a decrease in the STAI-S scores, suggesting an anxiolytic effect. In patients exposed to C. aurantiumEO or with diazepam, there was a decrease in the systolic blood pressure. A change in all the physiological measurements was observed in the group exposed to C. aurantium. The results showed that C. aurantium exhibits an anxiolytic effect and reduces the signs and symptoms associated with anxiety in patients with CML.
Pei-Hsin et al., 2010	Anxiety, stress and physiological parameters in patients subjected to colonoscopy	Randomized controlled trial.	N = 27 subjects: 13 in control group and 14 in Neroli group. Average age: 52.26 ± 17.79 years.	Aromatherapy was then carried out by inhalation of Sunflower oil (control group) and Neroli oil (experimental group). One drop (50 ml) of Sunflower oil or Neroli oil placed in handhold-nebulizer was supplied for five minutes.	The anxiety index was evaluated by STAI-S before aromatherapy and after colonoscopy; postprocedural pain index was measured by visual analogue scale (VAS). Systolic and diastolic blood pressure, heart rate and respiratory rate were evaluated before and after aromatherapy.	Not reported	There was no significant difference of procedural anxiety by STAI-S score and procedural pain by VAS before or after aromatherapy. The physiological parameters showed a significant lower pre- and postprocedural systolic blood pressure in Neroli group than control group.
Akhlaghi et al., 2011	Anxiety in ASA physical status I (healthy) patients scheduled for lower limb minor operation under general anesthesia.	Randomized controlled double-blind study	60 outpatients, scheduled for elective minor surgery Age range: 15-60 years.	Participants were divided into two groups of 30 receiving oral Citrus aurantium blossom distillate (CABd 1 mL.kg-1) or placebo, respectively, two hours before surgery.	Preoperative anxiety was assessed using both State-Trait Anxiety Inventory (STAI state) and Amsterdam Preoperative Anxiety and Information Scale (APAIS). Heart rate and blood pressure were measured two hours before operation just before premedication.	Not observed.	Patients treated with CABd were significantly less anxious than patients of placebo group (p < 0.05).
Hasheminia et al., 2014	Moderate and high anxiety before and during surgical removal of an impacted mandibular third molar.	Randomized controlled clinical trial.	N = 56; Age range: 15-45; mean age fragrance group: 26.4 ± 5.3 years, mean age no fragrance group: 27.5 ± 5.7 years.	Patients were divided into two groups: fragrance group (19 males, 9 females), control group (12 males, 16 females). Patients of the fragrance condition were exposed to 5 drops (0.25 mL) of C. aurantium essential oil poured in 5 L of water and diffused using an electrical dispenser. Patients in the control condition were exposed in the same environment to diffusion of water without fragrance. All the patients (control and experimental) waited about 10 min in the waiting room.	The dental anxiety scale (DAS) questionnaire was used to determine the anxiety level of the patients prior to surgery Mean blood pressure, respiratory rate, and pulse rate were also evaluated.	Not reported	Orange fragrance is effective in reducing anxiety linked to surgical removal of impacted mandibular third molar. Mean blood pressure, respiratory rate, and pulse rate, during surgery, were significantly reduced.
Namazi et al., 2014	Anxiety during labor in primiparous pregnant women.	Randomized controlled trial	126 primiparous women divided into two groups: aromatherapy (n = 63) and control (n = 63). Age range: 18-35 years. Mean age: 26.43 ± 3.21 aroma therapy group; 26.60 ± 3.40.	100 mL of the distillate contained 8 mL C. aurantium essential oil. Gauzes impregnated with 4 mL of C. aurantium distillate and normal saline were attached to the collar of the participants in the aromatherapy and control groups, respectively. The gauzes were changed every 30 minutes.	Intensity of anxiety was measured at baseline and after the intervention at dilations of 3-4 and 6-8 cm. Data were collected using a demographic and obstetric questionnaire, an examination and observation checklist including vital signs, vaginal examination, uterine contractions, and fetal heart rate, and Spielberger state-trait anxiety questionnaire.	Not observed	The levels of anxiety at dilations of 3-4 and 6-8 cm were significantly lower in the aromatherapy group compared with the control group.
Chaves Neto et al., 2017	Anxiolytic effect of Citrus aurantium L. in Crack Users subjected to Simulated Public Speaking (SPS).	Randomized controlled clinical trial.	51 volunteers, subdivided into three groups: Control Group: non-crack users who were not internal to the therapeutic communities (n=17) mean age of 28 years (± 2.01); Nonusers EO Group: non-crack users who were not internal to the therapeutic communities (n=17), mean age of 24 years (± 0.7282) Users EO Group, users of crack that were internal to the therapeutic communities (n=17), mean age of 30 years (± 2,125).	Citrus aurantium essential oil was administered by nebulization, 2 drops (0.1 mL) in 1.9mL of distilled water solution with an emulsifier (Tween 80 at 12%), for each subject. Control Group experienced received only the distilled water with an emulsifier.	The Simulated Public Speaking (SPS) method was used. Physiological measures were assessed at specific phases during the experiment. Psychological measures of anxiety were assessed using the Trait-State Anxiety Inventory (IDATE) and the Humor Analog Scale (HAS).	Not reported	Nebulization of Citrus aurantium L. EO provided an acute anxiolytic effect in crack cocaine users exposed to SPS.