Elsevier

Psychoneuroendocrinology

Volume 51, January 2015, Pages 585-588
Psychoneuroendocrinology

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

https://doi.org/10.1016/j.psyneuen.2014.11.002Get rights and content

Highlights

  • Clinical trial of novel agent to treat PTSD related nightmares.

  • Double-blind RCT with cross over design.

  • Trial involved a synthetic endocannabinoid (nabilone).

  • Reduction in PTSD-related nightmares was demonstrated.

  • Medication was well tolerated.

Summary

Objective

Investigate the efficacy of nabilone capsules (NAB) in reducing the frequency and intensity of nightmares in subjects with PTSD.

Patients and methods

Canadian male military personnel with PTSD, who despite standard treatment continued to experience trauma-related nightmares, received double-blind treatment with 0.5 mg NAB or placebo (PBO), and then titrated to the effective dose (nightmare suppression) or reaching a maximum of 3.0 mg. Subjects were followed for 7 weeks and then, following a 2-week washout period, were titrated with the other study treatment and followed for an additional 7 weeks. The modified intent-to-treat (mITT) population, which included all treated subjects that met inclusion/exclusion criteria, was analyzed.

Results

Ten subjects were included in the mITT population. The mean reduction in nightmares as measured by the CAPS Recurring and Distressing Dream scores were −3.6 ± 2.4 and −1.0 ± 2.1 in the NAB and PBO groups, respectively (p = 0.03). Mean global improvement as measured by the Clinical Global Impression of Change (CGI-C) was 1.9 ± 1.1 (i.e. much improved) and 3.2 ± 1.2 (i.e. minimally improved) in the NAB and PBO groups, respectively (p = 0.05) Five out of 10 (50%) were much improved on NAB versus 1 out of 9 (11%) on PBO. Results for the General Well Being Questionnaire (WBQ) were 20.8 ± 22 and −0.4 ± 20.6 in the NAB and PBO groups, respectively (p = 0.04). The proportion of subjects who experienced a treatment-related occurrence of adverse events was 50% in the NBO group and 60% in the PBO group. No event was severe nor resulted in a drop-out. This study is registered with Health Canada.

Conclusion

In this small sample NAB provided significant relief for military personnel with PTSD, indicating that it shows promise as a clinically-relevant treatment for patients with nightmares and a history of non-response to traditional therapies. These findings need to be replicated in a larger cohort. There is a need for further exploration of the effect of nabilone on other symptoms of PTSD such as re-experiencing, hyper vigilance and insomnia.

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

References (13)

  • C.M. Nappi et al.

    Treating nightmares and insomnia in posttraumatic stress disorder: a review of current evidence

    Neuropharmacology

    (2012)
  • R.N. Aurora et al.

    Best practice guide for the treatment of nightmare disorder in adults

    J. Clin. Sleep Med.

    (2010)
  • C. Cameron et al.

    Use of a synthetic cannabinoid in a correctional population for PTSD related insomnia and nightmares, chronic pain, harm reduction and other indications: a retrospective evaluation

    J. Clin. Psychopharmacol.

    (2014)
  • A.D. Fraser et al.

    Lack of interference by nabilone in the EMIT d.a.u. cannabinoid assay, Abbott TDx cannabinoid assay, and a sensitive TLC assay for delta 9-THC-carboxilic acid

    J. Anal. Toxicol.

    (1989)
  • G.A. Fraser

    The use of a synthetic cannabinoid in the management of treatment-resistant nightmares in posttraumatic stress disorder (PTSD)

    CNS Neurosci. Ther.

    (2009)
  • M.J. Friedman

    Toward rational pharmacotherapy for posttraumatic stress disorder: reprise

    Am. J. Psychiatry

    (2013)
There are more references available in the full text version of this article.

Cited by (0)

View full text