Reviewed: Kasper S, Gastpar M, Müller WE, et al. Lavender oil preparation Silexan is effective in generalized anxiety disorder – a randomized, double-blind comparison to placebo and paroxetine [published online ahead of print January 23, 2014]. Int J Neuropsychopharmacol. doi: 10.1017/S1461145714000017.

Generalized anxiety disorder (GAD) can be a highly disruptive condition, and is characterized by anxiety along with restlessness, fatigue, concentration problems, tension, irritability, and/or sleep problems, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR). Lavender (Lavandula angustifolia, Lamiaceae) has been used for mental health problems,¹ and the lavender product used in this study has been shown in clinical trials to reduce symptoms of anxiety.^2,3 This randomized, double-blind, placebo-controlled trial investigated two dosages of an oral lavender flower essential oil product (Silexan™*; Dr. Willmar Schwabe GmbH & Co.; Karlsruhe, Germany) in comparison with the selective serotonin reuptake inhibitor paroxetine in patients diagnosed with GAD. Dr. Willmar Schwabe GmbH & Co. funded the study.

The primary objective of this study was to demonstrate the superiority of Silexan over placebo, as measured by the Hamilton Anxiety Rating Scale (HAM-A) total score. This scale assesses 14 symptoms of anxiety and is a standard severity scale used in most anxiety studies with pharmaceuticals. A secondary objective was to compare the anxiolytic efficacy of Silexan with that of paroxetine (originally marketed as Paxil^® [GlaxoSmithKline; Brentford, UK]). Participants were screened for exclusion criteria and underwent a washout period (three to seven days) before the study. Treatment was given for 10 weeks, with measurements of safety and efficacy at two, four, six, eight, and 10 weeks. The study included a week of “down-titration” after week 10 to account for any withdrawal problems caused by paroxetine and to determine if there were any discontinuation effects. During this period, patients took capsules every other day. However, those in the Silexan groups took only the placebo during the withdrawal phase.

A total of 616 male and female patients were enrolled from 57 general and psychiatric practices in Germany. Of these, 539 patients were randomized and 536 received treatment. Patients were between 18 and 65 years old and diagnosed with GAD as outlined in DSM-IV-TR with a severity score of ≥ 18 on the HAM-A (with scores ≥ two for anxious mood and tension symptoms and ≤ 21 for psychic anxiety). The Covi Anxiety Scale (CAS) also was used, and included patients had scores of at least nine. Those with any additional psychiatric illnesses were excluded, and other psychiatric medications were not allowed during the study or during the 30 days prior to the study.

Silexan is produced from steam-distilled fresh flowering tops of lavender and is standardized to contain approximately 70% of the compounds linalool and linalyl acetate. Silexan was provided in either 80 or 160 mg doses, and paroxetine was administered in capsules of 20 mg. The Silexan placebos were masked through the inclusion of 1/1,000 dilution of lavender oil (0.08 mg) per capsule, and patients consumed all capsules without chewing. Patients consumed one capsule of Silexan and one placebo, or two placebos daily.

Any change in HAM-A total score after 10 weeks, or end of treatment for early withdrawals, were the primary outcomes. The main secondary outcome was a decrease in HAM-A score of 50% or more (considered a response), or a decrease in HAM-A score of more than 10 points (considered a remission). Changes in scores from CAS, Hamilton Rating Scale for Depression (HAM-D), and Clinical Global Impressions (CGI) scales were used as secondary outcomes as well. Adverse events recordings were from spontaneous reports only. Safety and efficacy were determined at baseline and weeks two, four, six, eight, and 10.

The randomization included 128 patients in the 160 mg/day Silexan group, 135 in the 80 mg/day Silexan group, 137 in the paroxetine group, and 136 in the placebo group. [Note: It is not mentioned why three patients did not start treatment.] When the study commenced, the majority of patients (60-74% in each group) also had vascular, musculoskeletal, metabolic, or nutritional health problems. The average time period that patients had GAD was 2.5 years, and current episodes of GAD averaged about one year. All patients had HAM-A scores over 18 at baseline, with CGI illness severity scores ranging from “moderate” to “marked” GAD severity. Patients in the 160 mg/day Silexan group showed significantly higher CAS and Sheehan Disability Scale (SDS) scores (P=0.03 and 0.01, respectively), as well as a significantly lower SF-36 mental health scores (a health survey, P=0.02) compared to placebo at baseline.

For the main study analysis, the full analysis set (FAS) was used, which consists of all patients randomly assigned minus those without efficacy data after the start of the study (121 patients in the 160 mg/day Silexan group, 135 in the 80 mg/day Silexan group, 132 in the paroxetine group, and 135 in the placebo group). Patients were withdrawn from the study for adverse events (AEs), reversal of consent, efficacy problems, or loss to follow up.

According to the FAS analysis, after four weeks of the study and at all other later time points, consumption of 160 mg/day Silexan resulted in a significantly greater reduction in HAM-A score compared to those in the placebo group (P<0.01). Also, after six weeks of treatment and all other later time points, those taking 80 mg/day Silexan had a significantly greater change in HAM-A scores compared to placebo (P=0.02). At week six, the change in HAM-A scores in those taking paroxetine approached significance compared to those in the placebo group (P=0.06), but HAM-A score changes were not significantly different from placebo thereafter.

A significantly greater percentage of patients in the 160 mg/day Silexan group showed an improvement of ≥ 50% (considered responders) in HAM-A score compared to the placebo group (60.3% vs. 37.8%, P<0.001). This also was seen in those taking 80 mg/day of Silexan (51.9% vs. 37.8%, P<0.05). Of those taking 160 mg/day of Silexan, there were significantly more participants with HAM-A scores of < 10 (considered remission) compared to those in the placebo group (46.3% vs. 29.6%, P<0.001). Compared to the placebo group, each of the three treatment groups contained a greater percentage of patients classified as “much/very much improved” with “moderate/marked” therapeutic effects, according to the CGI, with the differences significant for both Silexan groups (P<0.001) and the paroxetine group (P<0.01).

AEs were reported by 25.0% of those in the 160 mg/day Silexan group, 34.8% of those taking 80 mg/day Silexan, 40.9% of those taking paroxetine, and 30.9% in the placebo group. The AEs consisted of gastrointestinal disorders, infections, and nervous system problems. No AEs associated with down-titration withdrawal were observed in any of the groups.

According to the HAM-A scores, both dosages of Silexan were efficacious in treating GAD and were more efficacious than the dosage of paroxetine used in the study. Additionally, those taking Silexan had a similar incidence of AEs compared to placebo, suggesting that the product is well tolerated. Despite these results, there are some weaknesses of this study. For example, it is unclear why the final analysis was done on the FAS group as opposed to the per-protocol group, which would have accounted for all patients withdrawn from the study. Also, no biochemical markers for safety from the routine laboratory measurements were reported, and — aside from AE reports (which were only voluntary) — all data relied on questionnaires. Further basic research and clinical trials are necessary to confirm the speculated mechanisms of action behind the bioactivity reported here.

—Amy C. Keller, PhD

*Also sold as Lavela WS 1265™ (Integrative Therapeutics, LLC; Green Bay, WI) and CalmAid^® (Nature’s Way Products, Inc.; Lehi, UT).

References

1. Blumenthal M, Goldberg A, Brinckmann J, eds. Herbal Medicine: Expanded Commission E Monographs. Austin, TX: American Botanical Council; Newton, MA: Integrative Medicine Communications; 2000.
2. Kasper S, Anghelescu IG, Dienel A. Efficacy of Silexan (WS® 1265) in patients with restlessness and sleep disturbances. In: Annual Congress of the German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN). Berlin, Germany; 2010.
3. Kasper S, Gastpar M, Müller WE, et al. Silexan, an orally administered Lavandula oil preparation, is effective in the treatment of subsyndromal anxiety disorder: a randomized, double-blind, placebo controlled trial. Int Clin Psychopharmacol. September 2010;25(5):277-287.