Background: Posttraumatic stress disorder (PTSD) is a common and debilitating psychiatric disorder. Existing PTSD treatments have very significant limitations. Current evidence-based treatments for PTSD include trauma-focussed psychotherapy and antidepressant medications, including selective serotonin reuptake inhibitors and the serotonin noradrenaline reuptake inhibitor venlafaxine. Many patients are unable to tolerate trauma-focussed psychotherapy. Uptake is relatively low and dropout rates are high. In addition, up to 50% of patients fail to respond to this therapy. Antidepressant medications have small clinical effects and are associated with unpleasant side effects that can lead to non-adherence. There is an urgent need for new treatments for PTSD that are effective and well-tolerated. Silexan has the potential to provide a transformative alternative to these treatments. It is an orally administered lavender oil preparation whose main constituents are the monoterpenoids linalool and linalyl acetate. It is available over-the-counter in 14 countries, including Australia and the United States. It has a novel pharmacodynamic profile that includes potent inhibition of voltage-gated calcium channels and reduction of serotonin 1A receptor binding potential. Silexan is an effective treatment for Generalized Anxiety Disorder (GAD) and other anxiety disorders. A 2019 independent meta-analysis of data from five randomized controlled trials involving 1,320 participants with anxiety disorders found that Silexan 160 mg out-performed paroxetine and lorazepam in reducing anxiety symptoms. Silexan is also well-tolerated. The only adverse effects that have been identified so far are mild gastrointestinal symptoms and these are uncommon. Promising pilot data suggest that Silexan may also be effective and well-tolerated in PTSD.
Hypothesis: The primary hypothesis is that Silexan, as an adjunct to treatment-as-usual, over 12 weeks will be superior to placebo in improving PTSD symptoms in adults with PTSD.
Specific aims: The trial aims to investigate the effectiveness of adjunctive Silexan, compared with placebo, over 12 weeks in improving PTSD symptoms. The primary outcome measure will be the between-group change from baseline in the total symptom severity score on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5).
Study design: The trial is a phase 3, 12-week, multi-site, parallel-arm, randomized, placebo-controlled, double-blind trial. Participants will be adults with PTSD without comorbid psychosis, bipolar disorder, moderate or severe substance use disorder or Borderline Personality Disorder. Participants randomized to the Silexan arm will receive Silexan 160 mg daily for 12 weeks in addition to their usual prescribed medications. Participants randomized to the placebo arm will receive capsules containing an inert placebo. The target sample size will be 250 participants, or 125 per arm. The study will recruit 278 participants to account for a 10% drop-out rate.
Clinical impact: There is an urgent need to develop new treatments for PTSD that are effective and well-tolerated. This trial has the potential to provide definitive evidence of the efficacy of Silexan in adult PTSD. Silexan is safe, well-tolerated, currently available and affordable, facilitating a rapid translation into clinical care. If Silexan is found to be an effective treatment for PTSD, the pool of patients who could potentially benefit from this treatment includes any adults with PTSD.
