The efficacy of nabilone, a synthetic cannabinoid, in the treatment of PTSD-associated nightmares: A preliminary randomized, double-blind, placebo-controlled cross-over design study
Introduction
Post-Traumatic Stress Disorder (PTSD) is a common disorder in which, following exposure to traumatic events, patients develop a set of characteristic symptoms including intrusive distressing memories, avoidant behaviours, persistent negative cognitions and heightened perceptions of threat. Sleep disturbance is present in up to 90% of cases (Maher et al., 2006). One of these, recurrent nightmares, can be disabling and refractory to usual psychotherapeutic and pharmacologic approaches. (Gehrman and Harb, 2010, Nappi et al., 2012, Wittmann et al., 2007). Chronic nightmares have a debilitating effect on sleep continuity and may possibly re-traumatize patients. To date, only prazosin, an alpha-1 adrenoreceptor antagonist, has shown level-A evidence as treatment for PTSD nightmares. (Aurora et al., 2010). Prazosin has also demonstrated effectiveness against PTSD nightmares in a military cohort (Raskind et al., 2013).
The effect of nabilone on PTSD-related nightmares was discovered serendipitously and later tested in a 47-subject open label study showing nightmare suppression in 72% of the sample (Fraser, 2009). In that study the average therapeutic dose was 0.5 mg with a range of 0.25–4.0 mg.
The endocannabinoid system may be involved in the pathophysiology of PTSD. One recent imaging study implicates a lower endocannabinoid tone in PTSD, specifically in the amygdala–hippocampal–cortico-striatal circuitry (Neumeister et al., 2013).
Nabilone, a synthetic cannabinoid with CB1 receptor agonist, available in Canada since 1985, was initially developed as an antiemetic for chemotherapy-induced nausea. Nabilone absorption is rapid and complete. After first pass hepatic metabolization, its bioavailability is ∼20%. Peak serum concentration occurs after ∼2 h. Its half-life is ∼2 h. The active metabolite (carbinol) has an approximate half-life of 35 h. Nabilone is generally safe, well-tolerated, does not produce a positive urine test for cannabis and has little or no street value (Fraser and Meatherall, 1989, Ware and St-Arnaud-Trempe, 2010). It also appears to have analgesic properties and is being used in pain clinics (Wissel et al., 2006).
As suggested by Friedman (2013), the current pharmacological armamentarium for treating PTSD lacks specificity and efficacy. There is a need for investigation of drugs with varying profiles to target specific symptoms of PTSD. We therefore tested the nabilone would have greater efficacy than placebo in suppressing PTSD nightmares as measured by the CAPS nightmare subscales.
Section snippets
Methods
Currently-serving Canadian male military personnel, ages 18 to 65, referred to a military trauma clinic, with a current diagnosis of PTSD as per DSM-IV-TR, derived from the Clinician-Administered PTSD Scale (CAPS) were screened for participation in the study. Inclusion criteria required that the traumatic event for which the subject was diagnosed with PTSD was of operational origin, and had occurred at least 2 years prior to screening for this study. A history of current distressing nightmares
Results
The sample consisted of 10 Caucasian males with a mean age of 43.6 years ± 8.2 (median 44), all and with an initial Global Impression of Severity of PTSD of 3.3 ± 0.9 at screening (4 = extreme). At baseline, all subjects reported distressing dreams in the past week. One subject did not complete Period II as he was posted to another location during the study. His results for the single arm completed are included in the analysis.
Subjects were on nabilone in either Period I or Period II. Investigators
Discussion
This is the first double-blind, placebo-controlled trial using nabilone, a synthetic cannabinoid, to treat PTSD-related nightmares in a male military population with chronic PTSD. As well, it is one of very few randomized controlled trials of any kind for PTSD in an active duty military sample.
While encouraging, the results are derived from a very small sample. This study replicated positive results in reduction of PTSD nightmares found in an earlier open-label trial. A retrospective study of
Role of funding sources
Funding was provided by the Canadian Forces Surgeon General's Health Research Program.
Disclaimer
Opinions expressed or implied in this publication are those of the authors and do not represent the views or policy of the Department of National Defence or the Canadian Armed Forces.
Conflicts of interest
No author is declaring a conflict of interest.
Acknowledgements
The authors would like to thank Dr. B. Murray Stein, University of California San Diego, and Dr. Jitender Sareen, University of Manitoba, for reviewing this manuscript. The authors would like to thank Valeant Canada for supplying the capsules of Cesamet (nabilone) and placebo for this study.
Disclaimer for role of pharmaceutical company: Valeant Canada had no role in the design and conduct of this study; collection, management, analysis and interpretation of the data; and preparation, review or
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