By Ingrid Martin, MD
Fellow in Integrative Medicine,
Department of Family Medicine,
Maine Medical Center,
Portland, ME

Dr. Martin reports no financial relationships relevant to this field of study.

Summary Points

  • A randomized, double-blind, placebo-controlled trial of lavender oil found it to be more effective for generalized anxiety disorder than placebo or SSRIs.
  • Although the results of the study were positive, it is important to note that the study was funded by the Schwabe company, which manufactures the product studied in this trial.
  • Since alternatives to SSRIs and benzodiazepines are needed for anxiety, independently funded study of this preparation should be conducted.

SYNOPSIS: This randomized, double-blind, placebo-controlled study of an oral preparation of the essential oil of lavender showed that it is more effective for the treatment of generalized anxiety disorder than either placebo or an SSRI.

SOURCE: Kasper S, et al. Lavender oil preparation Silexan is effective in generalized anxiety disorder — a randomized, double-blind comparison to placebo and paroxetine. Int J Neuropsychopharmacol 2014;17:859-869.

The purpose of this study was to investigate the anxiolytic efficacy of Silexan, which is an oral herbal medication prepared from the fresh flowering tops of Lavandula angustifolia by steam distillation, with standardization of the main constituents of linalool and linalyl acetate. The study was designed as a randomized, double-blind, multicenter trial, in a two-stage design. A total of 616 patients were recruited and 536 of these were treated. All participants were male and female outpatients, between 18 and 65 years old, from 57 psychiatric and general practices in Germany. They all met the DSM-IV criteria for moderate to severe generalized anxiety disorder (GAD), with specific criteria measured by the Hamilton Anxiety Rating scale (HAMA) and Covi anxiety scale, and they had been suffering from GAD for an average of about 2.5 years. The main exclusion criteria were the presence of another DSM-IV-TR Axis I diagnosis (including major depression) in the 6 months before the study, patients with predominant and/or severe depressive symptoms, risk of suicide, substance abuse, and schizophrenia. The four treatment groups (described below) were comparable at baseline.

There was an initial treatment-free screening and washout period of 3-7 days duration. Participants meeting the selection criteria were then randomized into four groups receiving 10 weeks treatment with either 80 mg of Silexan, 160 mg of Silexan, 20 mg of paroxetine, or placebo, with efficacy and safety assessments performed after 2, 4, 6, 8, and 10 weeks. Other than the paroxetine, psychiatric medications were not allowed during the study or for 30 days prior to screening. The treatment phase was followed by a 1-week weaning phase to document possible withdrawal effects. Patients taking paroxetine took the active drug every other day, while patients taking Silexan took a placebo for this week. Although this was initially designed as a two-stage study, it was terminated without a second part, as the anxiolytic efficacy of Silexan was already considered to be demonstrated in the interim analysis after the first part of the study.

The study used the HAMA scale to assess participants at the 2-week follow-up visits, and all study groups showed a decrease in total score during treatment. The HAMA is a rating scale to assess the severity of anxiety, with a possible score of 0-56. A score of 18-24 indicates mild-to-moderate anxiety severity, with scores 25-30 indicating moderate-to-severe anxiety.

Improvements in HAMA were significantly greater for both Silexan groups than for the placebo or paroxetine groups, with decreases as follows: Silexan 160 mg/d (14.1 ± 9.3), Silexan 80 mg/d (12.8 ± 8.7), paroxetine (11.3 ± 8.0), and placebo (9.5 ± 9.0). Responders were classified as having a decrease in HAMA total score by at least 50% from their baseline, and those in remission classified as having a HAMA total score of < 10 points by the end of treatment. The percentage of patients who responded to treatment according to this pre-specified HAMA criteria were as follows: 60.3% of the Silexan 160 mg/d group were classified as responders and 46.3% were in remission, compared to 51.9% and 33.3% for Silexan 80 mg/d; 43.2% and 34.1% for paroxetine; and 37.8% and 29.6% in the placebo group (P = 0.01).

Gastrointestinal disorders, infections, and nervous system disorders were the most common adverse events across all study groups. The severity of these were not discussed, but it is mentioned that a total of 5 “serious adverse events” were reported during and up to 1 month after randomized treatment (Silexan 160 mg/d 2; 80 mg/d 2; paroxetine 1). The percentage of adverse effects were similar in the placebo group (30.9%) and both the Silexan groups (25.0% for the 160 mg/d group, and 34.8% for the 80 mg/d group), while the paroxetine group had a higher rate of adverse events (40.9%). The only class of adverse events that was significantly (> 3%) higher in the Silexan groups over placebo was gastrointestinal disorders. Intention-to-treat analysis included dropouts and those who did not adhere to protocol, although subsets that excluded these groups were also analyzed.

The authors concluded that Silexan showed convincing anxiolytic efficacy as well as a favorable safety profile. Silexan at daily doses of 160 mg or 80 mg given for 10 weeks is at least as efficacious as paroxetine in reducing the primary symptoms of anxiety in patients suffering from GAD. The dosages were safe and, unlike paroxetine, adverse event rates with Silexan did not exceed those of placebo. They added that the preparation had a profound beneficial effect on comorbid depression.

COMMENTARY

Essential oils of aromatic plants have been extensively studied and used for their psychological effects, especially their effects on depression and anxiety. Most of these studies have utilized aromatics either topically or inhaled — in massages, baths, and various diffusion modalities. The results have generally been favorable, with many studies showing at least a slight improvement in anxiety and depression, whatever the modality employed.1 However, the use of essential oils internally has generally been frowned on in the United States due to safety concerns, such as hepatotoxicity and central nervous system effects. This is not the case in Europe, where essential oils in capsules are sold over the counter in many pharmacies for the treatment of viral respiratory infections, gastrointestinal disorders, insomnia, mood disturbances, and so on. The German Commission E has approved for internal use specific essential oils, including fennel, anise, caraway, cinnamon bark, eucalyptus, and lavender (L. angustifolia).2 The amount of essential oil found in a capsule of Silexan is 80 mg, which is about four drops, a tiny amount considering that the LD50 for L. angustifolia is > 5g/kg.3 Silexan is just one of the brands of encapsulated essential oil available in Europe, and any form of lavender (L. angustifolia) diluted in vegetable oil and put into a capsule may well be just as effective for anxiety. However, consumers who are considering making their own would need to be knowledgeable about proper dilution methods and be aware that other species of lavender, such as spike lavender (Lavandula spica) or lavandin, (Lavandula latifolia) have significantly higher camphor content, which can cause epileptiform convulsions if taken internally.

This interesting study compares lavender taken internally with paroxetine, one of the recommended first-line treatments for GAD, with the effects of lavender at 6 weeks appearing to be more favorable in both efficacy and safety than the SSRI. The HAMA scale has limitations, given the fact that it is clinically scored, and, therefore, is somewhat subjective. However, it is widely used to document the results of pharmacotherapy and psychotherapy. An increase or decrease of 12 or 14 points, such as seen in this study, is of definite clinical and not just statistical significance. Previous studies on the benefits of paroxetine for anxiety have shown, as in this particular trial, that it has only a modest advantage over placebo for the treatment of anxiety or depression.4 However, given the side effects of selective serotonin reuptake inhibitors (SSRIs) — which commonly include sexual dysfunction, insomnia, drowsiness, weight gain, and headaches, and rarely include increased suicidal ideation in children and serotonin syndrome — the benefit may not be substantial enough to justify using paroxetine, or SSRIs in general, as first-line treatment for anxiety if another treatment is available.

Certainly the benefits of this oral preparation of lavender appear to be consistently positive: Other studies have found similarly high rates of response to Silexan for anxiety. A randomized, double-blind, placebo-controlled study of Silexan for subsyndromal anxiety in 2010 concluded, “Silexan was superior to placebo regarding the percentage of responders (76.9 vs 49.1%, P < 0.001) and remitters (60.6 vs 42.6%, P = 0.009),” with HAMA and PSQI scores used to measure outcomes.4 Studies have also shown consistently low safety concerns about Silexan.5,6 This particular study is well designed, with double-blinding (almost impossible to perform in topical aromatherapy trials, and achieved here by use of tiny amounts of lavender oil in the paroxetine and placebo capsules to give them a similar fragrance to the Silexan), effective number of randomized participants, full reporting of data, including patients who did not finish the trial or who had serious protocol violations, and total and subgroup analyses.

However, there are limitations to this study. The authors acknowledge that the results may have been influenced by a larger number of premature withdrawals from the paroxetine group and the fact that only 20 mg/d of paroxetine was used (with 20-50 mg/d being the usual therapeutic dose). Other limitations include the fact that 75% of participants were female, although this could be justified by the fact that women are twice as likely to suffer from anxiety disorders as men;7 subgroup analysis in the study showed no substantial differences in response between males and females. Another issue is that only two of the participants were not Caucasian, although other ethnic groups were not excluded according to the authors.

Perhaps the most serious drawback is that Silexan is manufactured by Dr Willmar Schwabe GmbH & Co. (it is sold in Germany as “Lasea,” and in the United States as “Calm Aid” by Nature’s Way, a Schwabe subsidiary). The study was completely funded by the Schwabe company, and five of the seven authors have received grant support from, or are members of advisory boards for, Schwabe. The remaining two authors are both employees of Schwabe. However, positive the results, this fact must surely weigh heavily against them, with numerous studies showing the negative effects of what is known as “funding bias.”8 Since alternatives to SSRIs and benzodiazepines are greatly needed for anxiety, the next step should be an independently funded study of this apparently useful preparation.

REFERENCES

  1. Lee YL, et al. A systematic review on the anxiolytic effects of aromatherapy in people with anxiety symptoms. J Altern Complement Med 2011;17:101-108.
  2. Blumenthal M, et al. Herbal Medicine: Expanded Commission E Monographs. Newton, MA: Integrative Medicine Communications. 2000: 226-229.
  3. Tisserand R, Balacs T. Essential Oil Safety: A Guide for Health Care Professionals. London: Churchill Livingstone 1995.
  4. Sugarman MA, et al. The efficacy of paroxetine and placebo in treating anxiety and depression: A meta-analysis of change on the Hamilton Rating Scales. PLoS One 2014;9:e106337.
  5. Kasper S, 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 2010;25:277-287.
  6. Woelk H, Schläfke S. A multi-center, double-blind, randomised study of the Lavender oil preparation Silexan in comparison to Lorazepam for generalized anxiety disorder. Phytomedicine 2010;17:94-99.
  7. Kessler RC, et al. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:617-627.
  8. Lexchin J, et al. Pharmaceutical industry sponsorship and research outcome and quality: Systematic review. BMJ 2003;326:1167-1170.