Benefits and Harms of Plant-Based Cannabis for Posttraumatic Stress Disorder. A Systematic Review

Maya E. O’Neil, PhD; Shannon M. Nugent, PhD; Benjamin J. Morasco, PhD; Michele Freeman, MPH; Allison Low, BA; Karli Kondo, PhD; Bernadette Zakher, MBBS; Camille Elven, MD; Makalapua Motu’apuaka, BA; Robin Paynter, MLIS; and Devan Kansagara, MD, MCR

Annals of Internal Medicine, 2020

doi : 10.7326/M17-0477

 

Background : Cannabis is available from medical dispensaries for treating posttraumatic stress disorder (PTSD) in many states of the union, yet its efficacy in treating PTSD symptoms remains uncertain.

Purpose : To identify ongoing studies and review existing evidence regarding the benefits and harms of plant-based cannabis preparations in treating PTSD in adults.

Data Sources : MEDLINE, the Cochrane Library, and other sources from database inception to March 2017.

Study Selection : English-language systematic reviews, trials, and observational studies with a control group that reported PTSD symptoms and adverse effects of plant-based cannabis use in adults with PTSD.

Data Extraction : Study data extracted by 1 investigator was checked by a second reviewer; 2 reviewers independently assessed study quality, and the investigator group graded the overall strength of evidence by using standard criteria.

Data Synthesis : Two systematic reviews, 3 observational studies, and no randomized trials were found. The systematic reviews reported insufficient evidence to draw conclusions about benefits and harms. The observational studies found that compared with nonuse, cannabis did not reduce PTSD symptoms. Studies had medium and high risk of bias, and overall evidence was judged insufficient. Two randomized trials and 6 other studies examining outcomes of cannabis use in patients with PTSD are
ongoing and are expected to be completed within 3 years.

Limitation : Very scant evidence with medium to high risk of bias.

Conclusion : Evidence is insufficient to draw conclusions about the benefits and harms of plant-based cannabis preparations in patients with PTSD, but several ongoing studies may soon provide important results.

Primary Funding Source : U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. (PROSPERO: CRD42016033623)

 

Cannabis use has become more common in the United States—the number of persons reporting past-year cannabis use nearly doubled between 2001 and 2013 to 1 in 10 adults (1). Cannabis has been legalized for recreational purposes in 8 states of the union and the District of Columbia and for medical use in 28 states and the District of Columbia (2– 4). Many states list posttraumatic stress disorder (PTSD) as an indication for cannabis use (5). More than one third of patients seeking cannabis for medical purposes in states where it is legal list PTSD as the primary reason for their request (6 – 8). However, little comprehensive and critically appraised information is available about the benefits and harms of cannabis use for treating PTSD. The objectives of this systematic review were to assess the benefits and harms of plant-based cannabis use in patients with PTSD and to identify ongoing studies in this area.

METHODS

This article is part of a larger report commissioned by the Veterans Health Administration (8). The review plan was posted to a publicly accessible Web site before the study was initiated (9).

Data Sources and Searches

We searched Ovid MEDLINE, EMBASE, PubMed, PsycINFO, the Published International Literature on
Traumatic Stress database, Evidence-Based Medicine Reviews (Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, Health Technology Assessment Database, and Cochrane Central Register of Controlled Trials), and gray literature sources from database inception through March 2017. We obtained additional articles from systematic reviews, reference lists, and experts and also searched for ongoing, unpublished, or recently completed studies at ClinicalTrials.gov, the International Clinical Trials Registry Platform, the International Standard Randomised Controlled Trials Number registry, the National Institutes of Health Reporter, and the Agency for Healthcare Research and Quality Grants On-Line Database. The searches, developed in consultation with a research librarian, were limited to Englishlanguage literature (Appendix A of the Supplement, available at Annals.org).

Study Selection

We included studies (systematic reviews, controlled clinical trials, and observational studies using
control groups) of nonpregnant adults with PTSD that assessed the effects of plant-based cannabis preparations or whole-plant extracts, such as nabiximols, a nonsynthetic pharmaceutical product with a standard composition and dosage. (For selection criteria, see Appendix B of the Supplement, available at Annals.org). We did not include synthesized, pharmaceutically prepared cannabinoids, such as dronabinol and nabilone, because they are not available in dispensaries, and the efficacy of synthetic cannabinoid preparations was examined in a recent review (10, 11). We broadly defined plant-based cannabis preparations to include any preparation of the plant or its extracts to capture the wide variety of products available in U.S. dispensaries (12).

We dual-screened 5% of identified abstracts and all full-text articles; disagreements were resolved by a
third reviewer. We included only systematic reviews that reported their search strategy, inclusion and exclusion criteria, and risk-of-bias assessment of included studies (13). We included all individual studies meeting inclusion criteria that either were published after the end search date of a selected review or had not been included in a previous systematic review. We also identified all ongoing studies (trials and observational and mixed-methods studies) examining the benefits or harms of cannabis use in patients with PTSD.

Data Extraction and Quality Assessment

One investigator extracted study details (such as design, setting, patient population, intervention, followup, co-interventions, health outcomes, health care use, and harms), whereas a second investigator reviewed the accuracy of the data extracted. Two reviewers independently assessed study quality as low, medium, or high risk of bias, considering the potential sources of bias most relevant to this evidence base by adapting an existing assessment tool (14, 15) (Appendix C of the Supplement, available at Annals.org). Disagreements were resolved by consensus.

Data Synthesis and Analysis

We qualitatively synthesized the evidence and did not conduct a meta-analysis because of the small number of studies and their marked clinical heterogeneity. Our main outcome of interest was effects on PTSD symptoms and severity. Secondary outcomes of interest included quality of life, mental health, and health care use. After group discussion, we classified the overall strength of evidence for each outcome as high, moderate, low, or insufficient on the basis of the consistency, coherence, and applicability of the body of evidence as well as the internal validity of individual studies (16, 17).

Role of the Funding Source

The U.S. Department of Veterans Affairs (VA) Quality Enhancement Research Initiative supported the review but had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

RESULTS

Of 13 764 screened titles and abstracts, 2 systematic reviews (18, 19) and 3 primary studies (20–22) were
selected (Figure). Most individual studies of cannabis use in patients with PTSD that were excluded were cross-sectional or did not include a comparison group. Benefits and Harms of Cannabis for Treating PTSD

Systematic Reviews

The authors of the 2 selected systematic reviews searched the literature to March 2015 and September
2015, respectively (18, 19). In the first review, Wilkinson and colleagues (18) looked at 3 studies of nabilone (a synthetic cannabis) (23–25) and 3 studies of plantbased cannabis that reported on PTSD symptoms; of the latter group, 2 studies were prospective, open-label trials without a control group (26, 27) and 1 was a case series ([28], as cited in [18]). The authors considered the evidence insufficient to determine whether cannabis (in either plant-based or synthetic form) is effective in treating PTSD. In the second review, Walsh and colleagues (19) evaluated 4 observational studies of synthetic and non-synthetic cannabis preparations that reported on PTSD symptoms (20, 24, 27, 29). Although cannabis was associated with less severe PTSD symptoms in 3 cross-sectional studies (24, 27, 29), 1 retrospective cohort study (described in detail later) found that cannabis was associated with worsening PTSD symptoms (20). This review (19) also included 3 prospective studies of potential harms associated with cannabis use in patients with PTSD (7, 30, 31) and noted that cannabis use disorder in these patients was associated with negative treatment and cessation outcomes.

Of note, none of those 3 studies met our selection criteria for individual study review, and strength of evidence was not formally rated in the second review.

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