Journal of Traumatic Stress Disorders & Treatment ISSN: 2324-8947

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Research Article, J Trauma Stress Disor Treat Vol: 11 Issue: 3

Effect of Medical Cannabis Authorization on Post-Traumatic Stress Disorder-related Mental Health Symptoms and Psychopharmacotherapy: A Cohort Study

Cerina Lee MPH1, Dean T. Eurich1, Jason R. B. Dyck2, Elaine Hyshka1, John G. Hanlon3,4, Arsene Zongo5,6*

1School of Public Health, University of Alberta, Edmonton, Alberta, Canada

2Cardiovascular Research Centre, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada

3St. Michael’s Hospital Department of Anesthesia, Ontario, Canada

4Department of Anesthesiology and Pain Medicine, University of Toronto, Ontario, Canada

5Faculty of Pharmacy, Université Laval, Quebec City, Quebec, Canada

6Population Health and Optimal Health Practices Research Unit, CHU de Québec - university Laval Research Centre, Quebec City, Quebec, Canada

*Corresponding Author: Arsene Zongo
CHU de Quebec -Université Laval Research Center, Population Health and Optimal Health Practices Research Unit, 1050 Chemin Ste-Foy, Quebec City, Quebec, Canada
Tel:
418 682 7511 #81971
E-mail: [email protected]

Received: 23-Feb-2022, Manuscript No. JTSDT-22-58064;
Editor assigned: 26-Feb-2022, PreQC No. JTSDT-22-58064(PQ);
Reviewed: 14-March-2022, QC No. JTSDT-22-58064;
Revised: 23-March-2022, Manuscript No. JTSDT-22-58064(R);
Published: 30-March-2022, DOI:10.4172/2324-8947.1000287

Citation: Cerina Lee MPH, Dean T. Eurich, Jason R. B. Dyck, Hyshka E, Hanlon JG, et al (2022) Effect of Medical Cannabis Authorization on Post-Traumatic Stress Disorder-related Mental Health Symptoms and Psychopharmacotherapy: A Cohort Study. J Trauma Stress Disor Treat 11:3.

Abstract

Background: Post traumatic stress disorder (PTSD) is a serious mental health disorder that can occur after the experience of a traumatic event. With increasing legalization of medical cannabis worldwide, there is both growing interest on its use to treat and manage PTSD. The objective of this study was assess the effect of medical cannabis authorization on mental health and psychopharmacotherapy among patients with post-traumatic stress disorder (PTSD) in Ontario, Canada.

Methods: This is a retrospective cohort study of patients aged ≥ 18 years, with PTSD who received medical cannabis authorization. Five PTSD-related outcomes were assessed from administrative data 6-months before and after cannabis authorization: Physician claims and emergency visits for any mental disorder; emergency department visits for depression/anxiety; dispensation of medications including psychotherapeutic drugs and prazosin. Interrupted time series analyses assessed the change in each outcome.

Results: Overall, >90% of individuals studied were between 18 and 60 years of age, and 55% (n=584) were female. Medical cannabis authorization did not have any significant effect on the four PTSD-related outcomes with the exception for the total number of days’ supply of psychotherapeutic drugs or prazosin that showed a temporal significant increase of days’ supply following cannabis authorization (+ 4567 days’ supply per 10,000 patients).

Conclusions: This longitudinal study found no significant association between medical cannabis authorization and improved outcomes for patients with PTSD. Continued surveillance of patients utilizing medical cannabis for PTSD treatment and management is warranted by clinicians to understand the long-term potential benefits and harms of ongoing use

Keywords: Post traumatic stress disorder, Mental Health

Introduction

Post-traumatic stress disorder (PTSD) [1] is a serious mental health disorder resulting from a traumatic experience or event. Its main symptoms include anxiety, depression and most commonly, disturbances in sleep. Military and veteran populations in North America have one of the highest prevalence rates of PTSD when compared to members of the general population [2,3]. Common therapies include psychotherapy, and medications such as prazosin [4,5,6], an alpha1-adrenoceptor blocker – typically for those with recurring sleep problems and nightmares due to PTSD— and psychotherapeutic drugs [6]. Studies [7] have found a direct correlation between PTSD symptomatology and motivation to use cannabis as a coping mechanism for nightmares and sleep apnea. Indeed, growing legalization and societal acceptance of cannabis in North America, has been accompanied by an upward trend of using cannabis in various therapeutic interventions – with one major area being for the treatment of PTSD and PTSD-related symptoms (anxiety, depression and sleep problems) [8,9].

Animal model studies have reported that the endocannabinoid system does play a role in emotional states associated psychiatric conditions, including PTSD [10]. Indeed, some suggest that cannabinoids present a new potential therapeutic opportunity to decrease symptoms of traumatic memory experiences by interfering with the memory retrieval process [11,7]. Observational studies [12,8] have shown that cannabis has been frequently used in the veteran population for PTSD, specifically to improve sleep [13], however, the majority of these studies are short-term case studies [14,15]. Particularly, in the veteran population [4], PTSD-related symptoms have been shown to be significantly alleviated by cannabis use, but many studies did not differentiate between non-medical and medical cannabis use [16-18]. Recent systematic reviews [19,9, 20-22] report that there is very low or limited high-quality evidence to support medical cannabis as an effective treatment for PTSD symptoms. However, some [23] have concluded that robust longitudinal studies may support future evidence of a therapeutic benefit for alleviation of psychiatric disorders in certain populations where primary line of psychotherapy treatment has been unsuccessful. Conversely, other studies [24-26] have shown the opposite effect, in which long-term cannabis use increases the risk of cannabis use disorder, misuse and dependence for people with pre-existing psychiatric conditions.

Current clinical practice recommendations from both the United States [27] and Canada [28] state that there is only low-quality evidence available that support medical cannabis as a second-line alternative treatment for PTSD; and that it is unknown whether its prolonged use can be effective in the long-term. Thus, published literature concur that there is a need to clarify and build evidence on efficacy, safety and harms of medical cannabis use on PTSD and PTSD-related symptoms [29,30].

To address this gap, this longitudinal cohort study aimed to assess the association between medical cannabis authorization to patients with PTSD in Ontario (Canada), and 1) their healthcare utilization (emergency department visits and outpatient visits) for PTSD-related symptoms (anxiety, depression, and any mental and behavioural disorders); and 2) use of psychotherapeutic drugs and prazosin.

We hypothesized that medical cannabis authorization would be associated with a decreased 1) healthcare utilization for PTSD-related symptoms, and 2) use of psychotherapeutic drugs.

Methods

Study design

This longitudinal cohort study of patients was a part of a larger study that assesses the health outcomes of patients who received authorization to use medical cannabis for a variety of health reasons and conditions in Ontario, Canada between 2014 and 2020. We used an interrupted time series (ITS) design to assess the association between cannabis authorization and the study outcomes.

Study population

Cannabis was legalized for medical use since 2001 in Canada. Conditions for legal medical use include obtaining an authorization from a healthcare provider, among others. The present study population was thus made of patients who received a medical authorization to use cannabis to treat a health condition at specialized cannabis clinics in Ontario, Canada between 2014 and 2020. Patients could be referred to the cannabis clinics either by their physician or via self-referral. As part of the cannabis authorization and intake process, each patient seeking medical cannabis met with a trained counselor who performed an initial assessment including the primary medical complaints that constitute their rationale for requesting a medical cannabis authorization. Following their initial intake interview, the patient was referred to a physician for further clinical assessment. Forms of authorized cannabis use included inhaled (smoked or vaporized) and orally consumed (oils).

Inclusion criteria: For the present analysis, we included patient’s 18 years of age, of any sex and ethnicity, and were identified in the electronic medical data as having a PTSD during their initial visit in the cannabis clinics. Moreover, all patients were residents of Ontario and insured by the Ontario Health Insurance Plan (OHIP).

Exclusion Criteria: We excluded patients who had less than 7 months (210 days) of follow-up in the cannabis clinics. This restriction was to ensure that we had sufficient health data to assess our study outcomes.

Data sources

Two types of data were used for the analysis: 1) electronic medical records collected from patients who attended and followed-up up at specialized cannabis clinics; and 2) administrative health data (Tables 1-3).

Clinical data: These data were collected during the initial and follow-up visits of patients in the cannabis clinics. Informed consent was provided by the patient at the time of first intake, which allows data to be collected and used for clinical and research purposes. Data collected included sociodemographic variables (age, sex, income, etc.), medical complaints for seeking cannabis, and other baseline relevant information such as anxiety (based on Generalized Anxiety Disorder 7-item questionnaire (GAD-7)), depression (Patient Health Questionnaire 9-item (PHQ-9)), drug and alcohol use disorders (CAGE-AID questionnaire), pain (Brief Pain Inventory (BPI) questionnaire), etc. All data were electronically captured. Identification of patients with PTSD and their baseline characteristics were based on these self-reported clinical data.

Administrative data: This data was provided by the Ontario Institute for Clinical Evaluative Sciences (ICES). The ICES Data Repository consists of patient-level, coded and linkable health data sets. It encompasses publicly funded administrative health services records for the Ontario population eligible for universal health coverage. These data include individual data files for each beneficiary, inpatient files, physician billings (inpatient and outpatient physician services) and prescription drug claims. The Ontario Health Insurance Plan (OHIP) contains information on physician services, including diagnostic codes based on the International Classification of Diseases system- ninth Revision codes (ICD-9 codes). The Discharge Abstract Database (DAD) and the National Ambulatory Care Reporting System (NACRS) contain all data on hospitalizations and emergency department visits, respectively. For each emergency visit or hospitalization, up to 25 possible diagnoses were registered according to the International Classification of Diseases system- tenth Revision codes (ICD‐10) (Table S1). The administrative databases were linked using the unique and encrypted patient health insurance number and covered the period of 2013 to 2020. All data were released as de-identified data and are only accessible through the ICES Data & Analytic Virtual Environment (IDAVE).

Measures

Primary outcomes

As depression and anxiety are highly prevalent mental health symptoms among patients with PTSD, we assessed the trends of Emergency department (ED) visits for anxiety or depression before and after cannabis authorization to the PTSD patients (See Figure 1 for study population). This outcome was assessed using the ICD- 10 F380, F381, F388, F341, F348, F349, F32, F33, F39, F40, and F4. Practically, the total number of ED visits for anxiety or depression was assessed in 30-day windows, i.e. six 30-day windows before cannabis authorization and six after (Table S2). For patients without the specified visit, the event count within the 30-day windows was set at zero. The first 30-day period following cannabis authorization was excluded as follow-up visits were usually scheduled during this period and do not necessary reflect an issue with cannabis treatment.

For primary outcome, we also assessed the trends in the dispensation of any psychotherapeutic drug or prazosin. This outcome was assessed for only patients who had at least one claim for any drug within the Ontario Drug Benefit (ODB) database in the period before cannabis authorization - to ensure that they were all covered by the Ontario drug plan (Figures S1, S2). As the number of days’ supply differs by drugs and by patients, this outcome was assessed as the total number of days’ supply in each 30-day time window. Drug identification number (DIN) for psychotherapeutic agents and prazosin, dispensation dates and number of days’ supply for each drug were used to assess the total days’ supply within each time window.

Secondary outcomes

For secondary mental health outcomes, we assessed 1) ED visits for any mental and behavioural disorder and 2) physician claims for any mental and behavioural disorders. ED visits for any mental disorder were assessed from the NACRS data using ICD-10 codes F00 to F99 (Table S2). Physician claims for any mental and behavioural disorders were assessed as the number of distinct physician claims in each 30-day time window using the OHIP data and ICD-9 codes 290 to 319. Details for the codes are provided in Supplemental Table 2.

Finally, we assessed the total number of distinct individuals with a dispensation of any psychotherapeutic drug or prazosin in each time window. This outcome was examined to assess whether trends in drug claims were driven by patients with a high volume of drug dispensations.

Other variables

Patient’s baseline characteristics were primarily assessed from the self-reported clinical data. However, sociodemographic characteristics such as age at cannabis authorization, sex, income, and the area of residence (rural versus urban) were assessed from the administrative data. We also considered patients’ comorbid conditions including diabetes, congestive heart failure, chronic obstructive pulmonary disease, asthma, cancer, musculoskeletal issues, pain, neurologic disorders, fatigue, metabolic disease, mental health, and behavioral disorders.

Data Analysis

All data are expressed descriptively using means (standard deviations) or proportions as appropriate according to the group. We conducted ITS analyses to assess the effect of medical cannabis authorization on our selected outcomes [31]. ITS [32] is a quasiexperimental design that allows comparison of trends in an outcome before and after an intervention [31,33]. The initial or immediate change is the level of change following the intervention (i.e., a drop or jump in the outcome following the intervention) [32]. In the present study, this was the change observed in the second 30-day time window post-cannabis authorization, i.e., the period following a lag period of 30 days from cannabis authorization date (rationale for including a lag period is provided below in the outcomes definition section). The temporal change is the slope derived from post-intervention time windows accounting for the baseline trend [31]. A change in trend can be an increase or decrease in the slope of the post-intervention period as compared to the pre-intervention period [32]. A least squares regression accounting for auto-correlation (autoregression models), and time trend was used to model the rate or proportion relative to each outcome.

Sensitivity analysis

In secondary analysis, we extended the follow-up post-cannabis authorization to twelve continuous 30-day time windows to further assess the trends of our selected outcomes in longer follow-up. This follow-up was based on administrative data as it allowed to include a high number of patients. Data were analysed using SAS version 9.4.

Ethics

Research ethics approval was obtained from the University of Alberta Health Research Ethics Board (PRO 00083651), Veritas Research Ethics Board (Ontario) (16111-13:21:103-01-2017), and the CHU de Quebec Research Ethics Board (2022-5999).

Results

Overall, 60690 adult patients who received medical cannabis authorization were linked to the administrative databases. From the clinical data, 2444 adult patients were identified as patients with PTSD during the patient initial visit in the cannabis clinics. For mental health-related outcomes, 1050 patients had had at least 210 days of follow up in the cannabis clinics and were included in the primary analysis (Figure 1). At baseline, more than 90% of those patients were below the age of 60, 55% of patients were male, 63.5% of patients currently smoked cigarettes, 36% were using other medications, 66.7% had anxiety, 51% had depression, and 62.8% had pain (Table 1). Of those with GAD-7 and PHQ-9 values at baseline. 58.8% of patients were categorized as having severe anxiety (GAD-7 score of 15-21) and 28.2% with severe depression (PHQ-9 score of 20-27) (Table 1). Approximately 87% of patients lived in urban settings and approximately 36% of patients were concurrently using other medications. For drug-related outcomes analysis, 586 patients were included.

Figure 1: Selection of the study sample to assess trends in healthcare utilization for mental health-related outcomes (outcomes 1, 2 and 3).

Characteristic N Percentage
    (%)
Age (years)    
18 to £30 154 14.7
31-40 281 26.8
41-50 290 27.6
51-60 237 22.6
61-70 76 7.2
>70 12 1.1
Sex    
Female 584 55.6
Male 466 44.4
Mean income
£$44,999
$45,000-$59,999
³$60,000
  510
438
102
  48.6
41.7
9.7
Rurality    
No 915 87.1
Yes 135 12.9
Smoking cigarette 671  
Drink alcohol 174 16.6
Use of other medications 382 36.4
Selected morbidities
ADHD 71 6.8
All pain (any pain except cancer-related pain) 707 67.3
Anxiety 701 66.8
Autoimmune disease 397 37.8
Bipolar 75 7.1
Cancer 35 3.3
COPD 17 1.6
Depression 535 51.0
Diabetes 18 1.7
Fatigue 25 2.4
Insomnia 185 17.6
Neurological disorders 71 6.8
Panic disorders 162 15.4
GAD-7 score between 15-21(severe anxiety)* 202 59.6
PHQ-9 score between 20-27 (severe depression)* 97 28.4

Table 1: Baseline characteristics of patients authorized for medical cannabis who had with PTSD with at least 210 days follow-up in cannabis clinic (n=1050).

ITS Analysis Results

Primary outcomes

The primary ITS analysis results were based upon the follow-up appointments in the cannabis clinics. The monthly rates per patient of each outcome before and after cannabis authorization are presented in Supplemental Table 2 and roughly showed no trend overtime.

Emergency department visit for anxiety or depression (n=1050)

Medical cannabis authorization was associated with an initial significant decrease of ED visits for depression and anxiety (-72 visits per 10,000 patients). However, the temporal change was not significant (+ 0.2 visit per 10,000 patients) (Table 2).

Outcome Difference in outcome
Immediate change* Temporal change**
Events/ 10,000 patients 95% Confidence Interval P-value Events/ 10,000 patient 95% Confidence Interval  P-value
Primary outcomes
ED visits for depression or anxiety (n=1050) -72.65 -155.16,
9.85
0.0403 0.272 -20.25, 20.79 0.9715
Days of supply of psychotherapeutic agents (n=586) 4369 -17146.6, 25885.0 0.5883 4567 -784.1, 9918.0 -0.0453
Secondary outcomes
ED visits for any mental or behavioural disorder (n=1050) -38.28 -192.19, 115.64 0.5094 -4.90 -43.18, 33.38 0.7316
Physician claims for any mental or behavioral disorder (n=1050) 3970 -1133.5, 9072.9 0.0628 -205 -1473.8, 1064.6 0.6663  
Patients with claim for psychotherapeutic agent (% modeled) (n=586) 52.82 -337.1,
442.8
0.7166 37.06 -59.9, 134.0 0.3197

Table 2: Interrupted time series analysis of primary and secondary outcomes 180 days before and 210 days after cannabis authorization to patients with PTSD, with follow-up based on appointments in the cannabis clinics.

Total number of days of supply for psychotherapeutic agent or prazosin (n=586)

The initial change in days’ supply for psychotherapeutic agents or prazosin was not statistically significant (+4369 days supply per 10,000 patients). However, the analysis showed a significant increased temporal trend for this outcome after cannabis authorization compared to the period before (+ 4567 days’ supply per 10,000 patients) (Table 2).

Secondary outcomes

Emergency department visits for any mental and behavioral disorders (n=1050)

A non-significant initial decrease of ED visits for any mental and behavioural disorders was observed following cannabis authorization (-38 visits per 10,000 patients). A non-significant temporal decrease in trend was also observed (-5 visits per 10,000 patients) following cannabis authorization compared to the pre-authorization trend (Table 2).

Physician visits for any mental and behavioural disorders (n=1050)

The segmented regression results presented in Table 2 showed that cannabis authorization was associated with an initial but nonsignificant increase in physician visits for reasons related to any mental and behavioural disorders (+3947 visits per 10,000 patients). There was a post-cannabis authorization temporal non-significant decrease in physician visits compared to the period before cannabis authorization (-203 visits/10,000 patients).

Total number of distinct individuals with at least one claim of any psychotherapeutic agent or prazozin (n=586).

Both the initial and temporal changes were non-significant for this outcome (+53 and +37 patients with a claim for psychotherapeutic agents or prazosin per 10,000 patients, respectively) (Table 2).

Sensitivity Analysis Results

Based on the administrative follow-up data, 2408 patients for mental health-related outcomes and 1329 patients for drug-related outcomes had follow-up ≥ 365 days post-cannabis authorization. For these analyses, no significant initial and temporal changes were observed for ED visit for anxiety and depression, ED visit for any mental disorder, physician claim for any mental disorder, and patients with a claim of psychotherapeutic agent or prazosin (Table 2). However, the total days’ supply for psychotherapeutic agents or prazosin – was the only outcome that showed a significant increased temporal change (+ 4103 days’ supply per 10,000 patients) (Table 2).

Outcome Difference in outcome
Immediate change* Temporal change**
Events/ 10,000 patients 95% Confidence Interval  P-value Events/ 10,000 patients 95% Confidence Interval   P-value
Primary outcomes
ED visits for depression or anxiety (n=2408) -24.52 -89.92, 40.88 0.3169 -3.54 -19.89, 12.80 0.5576
Days of supply of psychotherapeutic agents per patient (n=1329) 7442 -5683.0, 20568.0 0.1394 4103 822.0, 7384.0 0.0041
Secondary outcomes
ED visits for any mental or behavioural disorder (2408) 8.57 -78.65, 95.78 0.7894 -11.99 -33.78, 9.81 0.1507
Physician claims for any mental or behavioral disorder (n=2408) 2293 -124.03, 5826.5 0.0948 269 -614.1, 1152.2 0.4130
Patients with claim for psychotherapeutic agent (% modeled) (n=1329) 45.56 -193.5, 284.6 0.6057 57.27 -2.5, 117.0 0.0196

Table 3: Interrupted time series analysis of selected outcomes 180 days before and 365 days after cannabis authorization to patients with PTSD, with follow-up based on administrative data (sensitivity analysis).

Discussion

This population-based study of patients in Ontario, Canada, showed that authorization of medical cannabis did not have any significant effect on the selected PTSD-related outcomes. Except for total number of days’ supply of psychotherapeutic drugs or prazosin for which we observed a temporal significant increase of days’ supply following cannabis authorization, no statistically significant changes were observed for the other outcomes. The reason for the increase in prazosin could be related to medical cannabis being ineffective or may be related to simply better management of their PTSD after being actively followed in the cannabis clinics. However, it may also indicate that a longer follow-up period (longer than 365 days) may be needed to see differences in the other 4 outcomes on PTSD symptomatology.

In comparison to existing literature, our findings are consistent with observational studies that report that cannabis had no effect on PTSD symptoms. Conversely, in comparison to other studies, recent systematic reviews and literature reviews [22, 9, 2, 29, 7, 34, 20, 8] have consistently reported that improvements in PTSD symptomology have been observed with cannabis use but its effects may be short-term and highly dependent upon the ratio of THC: CBD. Indeed, systematic reviews [23,21] emphasize this conflicting data and how evidence is still premature- thus, rendering a definitive correlation to be impossible between medical cannabis use and PTSD symptomatology. There are very few observational studies assessing medical cannabis and PTSD but extant research has shown that medical cannabis was effective for coping-oriented [15,35] use for severe levels of PTSD symptomatology, specifically for military veterans (3,26,15) and for those with severe sleep disorders/problems [13]. Outside of the military veteran population, there is a lack of epidemiological evidence at the population-level on its direct effects on PTSD symptoms. From an endocannabinoid physiological perspective, other researchers [10] claim that medical cannabis is a promising second-line of treatment option for PTSD in reducing levels of anxiety, paranoia and depression. Case series [14] and other cohort studies’ [12,16] results have also reported that medical cannabis use may provide short-term temporary relief for PTSD symptom severity; however, with unknown long-term effects. Conversely, there are a plethora of observational studies and systematic reviews that focus on the opposite effect of cannabis [24], which did not show benefit nor worsening [17] of PTSD symptoms over time [25]. Comparatively, our findings align with the clinical recommendations from both the United States and Canada on the use of medical cannabis for PTSD. In the United States [27], a current review has found only limited evidence that medical cannabis is fully efficacious in reducing PTSD symptoms.

The main strengths of this study are the larger sample of patients relative to previous studies, the combination of clinical and administrative data, and the possibility to account for the trends of the studied outcomes prior to cannabis authorization. However, the study is not without limitations. Firstly, potential spectrum bias was a concern as our cohort is based on patients who have individually sought authorization for medical cannabis. Attrition bias may also be a limitation as only a certain proportion of baseline medical cannabis patients completed their follow-up. From this, it may be possible that those who did not follow-up may have had differences in PTSD symptoms. Secondly, we could not differentiate PTSD severity in patients; it is possible that individuals with more severe PTSD may have experienced different outcomes post-medical cannabis use than lower levels of PTSD. Thirdly, although patients were medically authorized and patients were followed-up in the clinics until they stopped using cannabis or left the clinics for other reasons, we cannot ensure that the products were consumed as authorized by physicians or if patients elected to use alternative treatments or agents than what was authorized. Lastly, we did not account for the type of cannabis product, cultivar, strain, frequency of consumption and route of administration in our analysis.

The study found that medical cannabis authorization showed no significant effect on PTSD-related outcomes over time, although a possible increased use of psychotherapeutic drugs and prazosin was observed. Overall, our findings contribute to the current literature for physicians currently authorizing medical cannabis in the treatment of PTSD. Future long-term epidemiological studies are critically needed to fully assess cannabis’s exact interaction with PTSD symptoms and medication. Ideally, well-controlled clinical trials would be needed to fully elucidate cannabis’s potential benefits on PTSD.

Acknowledgements

DTE, AZ, JRBD, JGH, EH designed the study and DTE and JRBD acquired the data. AZ analyzed the data. CL and AZ drafted the manuscript. All other authors revised it critically for important intellectual content and approved the final version to be published. All authors are accountable for the work and integrity of the work. The corresponding author and guarantor accept full responsibility of the work and/or conduct of the study, had access to the data and controlled the decision to publish. AZ attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

AZ affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and if relevant) have been explained.

Contribution to the Field Statement

Cannabis is increasingly used for therapeutic purposes, particularly for mental health conditions/disorders such as post-traumatic stress disorder (PTSD). However, evidence to support many of the claimed indications and most importantly, the safety of cannabis for medical use for PTSD is lacking. This longitudinal cohort study is part of a large study assessing the health outcomes of medical cannabis among patients who received medical authorization to use cannabis for a wide range of health conditions in Ontario between 2014 and 2017. Specifically, this study assessed the effect of medical cannabis authorization on mental health-related healthcare utilization (physician visits and emergency department visits) and the use of psychotherapeutic agents among patients with PTSD who were authorized to use cannabis between 2014-2020 in Ontario, Canada. The study found that, among 60690 adult patients who received medical cannabis authorization, there was no significant association between authorization and improved PTSD outcomes. However, the study also provides some interesting results that can contribute to a better benefitrisk assessment during cannabis authorization for medical use and for public health perspectives.

Ethics approval and consent to participate

All procedures were approved the Alberta Health Research Ethics board of the University of Alberta. Ethics approval was obtained for the study from the University of Alberta Health Research Ethics Board (PRO 00083651), Veritas Research Ethics Board in Ontario (16111-13:21:103-01-2017) and from the CHU de Quebec Research Center Research Ethics Board (#CER: 2022-5999). Patients and the public were not involved in the design, conduct and reporting of this research project as it was not applicable to this project.

Acknowledgments/Disclaimer

This study made use of de-identified data from the Ontario administrative data, which is managed by ICES with support from its funders and partners: Canada’s Strategy for Patient-Oriented Research (SPOR), the Ontario SPOR Support Unit, the Canadian Institutes of Health Research and the Government of Ontario. The opinions, results and conclusions reported are those of the authors. No endorsement by ICES or any of its funders or partners is intended or should be inferred. Parts of this material are based on data and information compiled and provided by Canadian Institute of Health Information (CIHI). However, the analyses, conclusions, opinions and statements expressed herein are only those of the authors.

Availability of data and materials

The dissemination of data results to study participants and or patient organizations in this research project is not possible/applicable as the data are de-identified. Being administrative health data, the data cannot be shared publicly. However, requests for the data can be sent to ICES. No special access privileges were granted to the authors.

Competing interests

JRBD was a former member on the board of directors of Aurora Cannabis Inc., which is a for-profit, company licensed for the cultivation and sale of medical cannabis. In the past, JGH has worked as a paid advisor and speaker for Canadian Cannabis Clinics, but currently has no ties with the CCCs. JRBD has a financial interest in Aurora Cannabis Inc. DTE and JRBD hold a Mitacs Grant with Aurora as a partner. Mitacs is a national, not-for-profit organization that works with universities, private companies, and both federal and provincial governments, to build partnerships and administer research funding that supports industrial and social innovation in Canada. AZ, DTE, CL, and EH do not have any past or present financial interest in the companies involved; and have no conflicts of interest to declare. Moreover, the above-mentioned entities, research funders and companies listed were not involved in any aspect of the design or write-up of the study and all analysis was performed independent from the funders and companies.

Funding

This study was funded by a Canadian Institutes of Health research Project grant (CIHR PS 159668) to DTE, JGH, EH, and JRBD.

References

  1. Bailey CR, Cordell E, Sobin SM, Neumeister A (2013) Recent progress in understanding the pathophysiology of post-traumatic stress disorder: implications for targeted pharmacological treatment. CNS Drugs 27: 221-32.
  2. Indexed at, Google Scholar, Cross Ref

  3. Cohen J, Wei Z, Phang J, Laprairie RB, Zhang Y, et al. (2020) Cannabinoids as an Emerging Therapy for Posttraumatic Stress Disorder and Substance Use Disorders. J Clin Neurophysiol37(1): 28-34.
  4. Indexed at, Google Scholar, Cross Ref

  5. Betthauser K, Pilz J, Vollmer LE (2015) Use and effects of cannabinoids in military veterans with posttraumatic stress disorder. Am J Health Syst Pharm72(15): 1279-1284.
  6. Indexed at, Google Scholar, Cross Ref

  7. Watkins LE, Sprang KR, Rothbaum BO (2018) Treating PTSD: A Review of Evidence-Based Psychotherapy Interventions. Front Behav Neurosci 12:258.
  8. Indexed at, Google Scholar, Cross Ref

  9. Green B (2014) Prazosin in the treatment of PTSD. J Psychiatr Pract20: 253-9.
  10. Indexed at, Google Scholar, Cross Ref

  11. Dierks MR, Jordan JK, Sheehan AH (2007) Prazosin treatment of nightmares related to posttraumatic stress disorder. Ann Pharmacother41(6): 1013-1017.
  12. Indexed at, Google Scholar, Cross Ref

  13. Mizrachi Zer-Aviv T, Segev A, Akirav I (2016) Cannabinoids and post-traumatic stress disorder: Clinical and preclinical evidence for treatment and prevention. Behav Pharmacol27(7): 561-569.
  14. Indexed at, Google Scholar, Cross Ref

  15. Forsythe ML, Boileau AJ (2021) Use of cannabinoids for the treatment of patients with post-traumatic stress disorder. J Basic Clin Physiol Pharmacol.
  16. Indexed at, Google Scholar, Cross Ref

  17. Hindocha C, Cousijn J, Rall M, Bloomfield MAP (2020) The Effectiveness of Cannabinoids in the Treatment of Posttraumatic Stress Disorder (PTSD): A Systematic Review. J Dual Diagn16(1): 20-139.
  18. Indexed at, Google Scholar, Cross Ref

  19. Steardo L, Carbone EA, Menculini G, Moretti P, Steardo L, et al. (2021) Endocannabinoid System as Therapeutic Target of PTSD: A Systematic Review. Life (Basel)11(3):214.
  20. Indexed at, Google Scholar, Cross Ref

  21. Berardi A, Schelling G, Campolongo P (2016) The endocannabinoid system and Post Traumatic Stress Disorder (PTSD): From preclinical findings to innovative therapeutic approaches in clinical settings. Pharmacol Res111: 668-678.
  22. Indexed at, Google Scholar, Cross Ref

  23. Lafrance EM, Glodosky NC, Bonn-Miller M, Cuttler C (2020) Short and Long-Term Effects of Cannabis on Symptoms of Post-Traumatic Stress Disorder. J Affect Disord, 274: 298-304.
  24. Indexed at, Google Scholar, Cross Ref

  25. Bonn-Miller MO, Babson KA, Vandrey R (2014) Using cannabis to help you sleep: heightened frequency of medical cannabis use among those with PTSD. Drug Alcohol Depend 136: 162-165.
  26. Indexed at, Google Scholar, Cross Ref

  27. Elms L, Shannon S, Hughes S (2019) Cannabidiol in the Treatment of Post-Traumatic Stress Disorder: A Case Series. J Altern Complement Med 25(4): 392-397.
  28. Indexed at, Google Scholar, Cross Ref

  29. Elliott L, Golub A, Bennett A, Guarino H (2015) PTSD and Cannabis-Related Coping Among Recent Veterans in New York City. Contemp Drug Probl42(1): 60-76.
  30. Indexed at, Google Scholar, Cross Ref

  31. Metrik J, Stevens AK, Gunn RL, Borsari B, Jackson KM, et al. (2020). Cannabis use and posttraumatic stress disorder: prospective evidence from a longitudinal study of veterans. Psychol Med 1-11.
  32. Indexed at, Google Scholar, Cross Ref

  33. Ruglass LM, Shevorykin A, Radoncic V, Smith KM, Smith PH, et al. (2017) Impact of Cannabis Use on Treatment Outcomes among Adults Receiving Cognitive-Behavioral Treatment for PTSD and Substance Use Disorders. J Clin Med 6(2): 14.
  34. Indexed at, Google Scholar, Cross Ref

  35. Jetly R, Heber A, Fraser G, Boisvert D (2015) 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. Psychoneuroendocrinology51: 585-588.
  36. Indexed at, Google Scholar, Cross Ref

  37. Orsolini L, Chiappini S, Volpe U, Berardis D, Latini R, et al. (2019) Use of Medicinal Cannabis and Synthetic Cannabinoids in Post-Traumatic Stress Disorder (PTSD): A Systematic Review. Medicina (Kaunas) 55(9): 525.
  38. Indexed at, Google Scholar, Cross Ref

  39. O'neil ME, Nugent SM, Morasco BJ, Freeman M, Low A, et al. (2017) Benefits and Harms of Plant-Based Cannabis for Posttraumatic Stress Disorder: A Systematic Review. Ann Intern Med 167(5): 332-340.
  40. Indexed at, Google Scholar, Cross Ref

  41. Shishko I, Oliveira R, Moore TA, Almeida K (2018) A review of medical marijuana for the treatment of posttraumatic stress disorder: Real symptom re-leaf or just high hopes? Ment Health Clin 8: 86-94.
  42. Indexed at, Google Scholar, Cross Ref

  43. Black N, Stockings E, Campbell G, Tran LT, Zagic D, et al. (2019) Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis. Lancet Psychiatry6(12): 995-1010.
  44. Indexed at, Google Scholar, Cross Ref

  45. Sarris J, Sinclair J, Karamacoska D, Davidson M, Firth J, et al. (2020) Medicinal cannabis for psychiatric disorders: a clinically-focused systematic review. BMC Psychiatry20(1): 24.
  46. Indexed at, Google Scholar, Cross Ref

  47. Steenkamp MM, Blessing EM, Galatzer-Levy IR, Hollahan LC, Anderson WT, et al. (2017) Marijuana and other cannabinoids as a treatment for posttraumatic stress disorder: A literature review. Depress Anxiety 34(3): 207-216.
  48. Indexed at, Google Scholar, Cross Ref

  49. Wilkinson ST, Stefanovics E, Rosenheck RA (2015) Marijuana use is associated with worse outcomes in symptom severity and violent behavior in patients with posttraumatic stress disorder. J Clin Psychiatry 76(9): 1174-80.
  50. Indexed at, Google Scholar, Cross Ref

  51. Bujarski SJ, Galang JN, Short NA, Trafton JA, Gifford EV, et al.(2016) Cannabis use disorder treatment barriers and facilitators among veterans with PTSD. Psychol Addict Behav30 (1): 73-81.
  52. Indexed at, Google Scholar, Cross Ref

  53. Washington DC. (2017b) The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research.
  54. Indexed at, Google Scholar, Cross Ref

  55. Allan GM, Fiznley CR, Ton J, Perry D, Ramji J, et al. (2018) Systematic review of systematic reviews for medical cannabinoids: Pain, nausea and vomiting, spasticity, and harms. Can Fam Physician64(2): e78-e94.
  56. Indexed at, Google Scholar

  57. Dagan Y, YagerJ (2020) Cannabis and Complex Posttraumatic Stress Disorder: A Narrative Review With Considerations of Benefits and Harms. J Nerv Ment Dis 208(8): 619-627.
  58. Indexed at, Google Scholar, Cross Ref

  59. Ottawa (2017). Medical Marijuana for Post-Traumatic Stress Disorder: A Review of Clinical Effectiveness and Guidelines.
  60. Indexed at

  61. Bernal JL, Cummins S, Gasparrini A (2017) Interrupted time series regression for the evaluation of pulic health interventions: a tutorial. Int J Epidemiol46(1): 348-355.
  62. Indexed at, Google Scholar, Cross Ref

  63. Wagner AK, Soumerai SB, Zhang F, Ross-Degnan D (2002) Segmented regression analysis of interrupted time series studies in medication use research. J Clin Pharm Ther 27(4): 299-309.
  64. Indexed at, Google Scholar, Cross Ref

  65. Hamilton I, Lloyd C, Hewitt C, Godfrey C (2014) Effect of reclassification of cannabis on hospital admissions for cannabis psychosis: a time series analysis. Int J Drug Policy 25(1): 151-6.
  66. Indexed at, Google Scholar, Cross Ref

  67. Rehman Y, Saini A, Huazng S, Sood E, Gill R, et al. (2021) Cannabis in the management of PTSD: a systematic review. AIMS Neurosci8(3): 414-434.
  68. Indexed at, Google Scholar, Cross Ref

  69. Lake S, Kerr T, Buxton J, Wzalsh Z, Marshall BD, et al. (2020) Does cannabis use modify the effect of post-traumatic stress disorder on severe depression and suicidal ideation? Evidence from a population-based cross-sectional study of Canadians. J Psychopharmacol34(2): 181-188.
  70. Indexed at, Google Scholar, Cross Ref

Figure S1: Selection of PTSD patients to assess trends in drug-related outcomes (outcomes 4 and 5).

Figure S2:Study design for assessing drug-related outcomes among patients with PTSD.

Outcomes Data sources ICD-9 codes ICD-10 codes
ED visit for any mental and behavioural disorders NACRS NA F00 to F99
ED visits for depression and anxiety NACRS NA F380, F381, F388, F341, F348, F349,
F32, F33, F39, F40, F41,
Physician claim for mental and behavioural disorders OHIP 290 to 319 NA
Table S1: Health conditions and ICD-9 or ICD-10 codes defining PTSD-related ED visits or hospitalizations.
Outcome ED visits for
anxiety or
depression per month
ED visits for any
mental or behavioural disorder
Physician claims for any mental or behavioural disorder Total number of days of supply for psychotherapeutic agent or prazosin Total number of patients with at least one claim of psychotherapeutic agent or prazosin/month
30-day Time window* Total (rate: total/1050) Total (rate: total/1050) Total (rate: total/1050) (Total days of supply/586) (% patient with psycho drug= total/586)
-6 (-180 to -150 days) 8 (0.008) 17 (0.016) 1223 (1.16) 6511 (11.11) 132 (0.23%)
-5 6 (0.006) 9 (0.009) 1153 (1.10) 5537 (9.45) 127 (0.22%)
-4 11 (0.010) 18 (0.017) 1210 (1.15) 5618 (9.59) 117 (0.20%)
-3 11 (0.010) 15 (0.014) 1053 (1.00) 5282 (9.01) 114 (0.19%)
-2 11 (0.010) 20 (0.019) 1029 (0.98) 5117 (8.73) 111 (0.19%)
-1 9 (0.009) 16 (0.015) 1099 (1.04) 5192 (8.86) 123 (0.21%)
NR 11 (0.010) 2243 (2.14) 5997 (10.23) 121 (0.21%)
1 NR 15 (0.014) 1147 (1.09) 5390 (9.20) 118 (0.20%)
2 7 (0.007) 13 (0.012) 1586 (1.51) 4933 (8.42) 108 (0.18%)
3 NR 15 (0.014) 1277 (1.22) 5671 (9.68) 121 (0.21%)
4 NR 10 (0.009) 1060 (1.01) 5184 (8.85) 113 (0.19%)
5 9 (0.009) 22 (0.021) 1193 (1.14) 5824 (9.94) 114 (0.19%)
6 8 (0.008) 12 (0.011) 1046 (1.00) 5188 (8.85) 112 (0.19%)

Supplemental Table 2: Trends of selected outcomes 180 days before and 210 days after cannabis authorization to patients with PTSD.

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