CADTH Health Technology Review

Cannabis for Opioid Use Disorder

Rapid Review

Authors: Eugenia Palylyk-Colwell, Sharon Bailey

Key Messages

• Evidence is inconsistent and of very low to moderate quality for the clinical effectiveness of cannabis regarding treatment retention and adherence, craving and withdrawal symptoms, or illicit opioid or other substance use. There is lack of consensus in the included publications as to whether use of cannabis in opioid use disorder is beneficial or detrimental.

• No evidence of an impact of cannabis on quality of life, functioning, satisfaction, relapse, hospitalizations, or overdoses in people with opioid use disorder was identified.

• One evidence-based guideline developed by health care and allied health professionals in Canada strongly recommends against the use of cannabinoids for the treatment of opioid use disorder in the primary care setting due to no or inconclusive evidence.

Context and Policy Issues

Opioid use disorder (OUD) is a challenging form of addiction caused by the misuse of prescribed, diverted, or illicitly obtained opioids.¹ It is a chronic, relapsing disorder that is often associated with increased opioid-related morbidity and death.^1,2 In Canada, the opioid crisis and related harms continue to have a detrimental effect on affected individuals, their families, communities, and the health care system.³ From April 2018 to March 2019, OUD accounted for the highest rates of hospitalizations for opioid-related harms in Canada, exceeding those due to opioid-related poisoning (overdoses) and adverse drug reactions to prescribed opioids.⁴

A national clinical practice guideline for the management of OUD that was intended to promote the use of evidence-based treatments for the clinical management of OUD in Canada was published in 2018.² The guideline strongly recommends the use of opioid agonist treatment (OAT) with buprenorphine-naloxone as the preferred first-line treatment for OUD with methadone used as a second-line treatment if patients fail to respond to buprenorphine-naloxone, or if the combination is not the preferred option.² Alternative or adjunct treatment options include OAT with slow-release oral morphine, withdrawal management alone (without transition to OAT), psychosocial treatment interventions, or oral naltrexone.² The use of cannabis for the management of OUD is not mentioned in the 2018 national guideline.

There has been growing interest in the use of cannabis for OUD to mitigate opioid withdrawal symptoms, reduce opioid consumption and cravings, improve OUD treatment retention, and to prevent relapses, overdoses, and opioid-related deaths.⁵ Cannabis is viewed as an appealing option because many of the barriers that prevent people with OUD accessing traditional OAT do not apply to cannabis due to its legalization in Canada.⁶ Due to emerging data and the relatively favourable safety profile of cannabis, further investigation of cannabis as a treatment option for OUD may be warranted.⁵ Use of cannabis for management of OUD, however, is not without risks (e.g., cognitive impairment, addiction potential, greater risk for other substance use disorders).⁷ For this reason, it is suggested that the evaluation of cannabis for OUD should be held to the same evidence base for efficacy, safety, and comparative effectiveness as has been required for other treatments that are used for the management of OUD.⁷

Given the increasing interest in the use of cannabis for OUD, questions have arisen concerning potential coverage of cannabis as a component of opioid treatment programs (OTPs). In consideration of this, a review of the clinical effectiveness of cannabis in OUD is needed to determine if cannabis could have a beneficial effect on treatment outcomes in people with OUD or mitigate serious consequences of OUD, such as hospitalizations or overdoses. Thus, the aim of this report is to summarize the evidence on the clinical effectiveness of cannabis for the management of OUD and to identify evidence-based guidelines to inform decisions about the use of cannabis for people with OUD in Canadian clinical practice.

Research Questions

1. What is the clinical effectiveness of cannabis for the management of opioid use disorder?

2. What are the evidence-based guidelines regarding the use of cannabis for the management of opioid use disorder?

Methods

Literature Search Methods

A limited literature search was conducted by an information specialist on key resources including MEDLINE, PsycInfo, the Cochrane Database of Systematic Reviews, the international HTA database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were OUD and cannabis as intervention. CADTH-developed search filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, network meta-analyses, any types of clinical trials or observational studies, and guidelines. Comments, newspaper articles, editorials, and letters were excluded. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2017 and August 5, 2022.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published before 2017. Systematic reviews in which all relevant studies were captured in other more recent or more comprehensive systematic reviews were excluded. Reports of primary studies retrieved by the search were excluded if they were captured in 1 or more included systematic review. Guidelines with unclear methodology were also excluded.

Critical Appraisal of Individual Studies

The included publications were critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)⁸ for systematic reviews, the Downs and Black checklist⁹ for non-randomized studies, and the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument¹⁰ for guidelines. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.

Table 1: Selection Criteria

Summary of Evidence

Quantity of Research Available

A total of 499 citations were identified in the literature search. Following screening of titles and abstracts, 472 citations were excluded and 27 potentially relevant reports from the electronic search were retrieved for full-text review. Two potentially relevant publications were retrieved from the grey literature search for full-text review. Of these potentially relevant articles, 22 publications were excluded for various reasons, and 7 publications met the inclusion criteria and were included in this report. These comprised 5 systematic reviews, 1 non-randomized study, and 1 evidence-based guideline. Appendix 1 presents the PRISMA¹¹ flow chart of the study selection.

Additional references of potential interest are provided in Appendix 6.

Summary of Study Characteristics

Five systematic reviews,^12-16 1 non-randomized study,¹⁷ and 1 evidence-based guideline¹⁸ are included in this report.

Three systematic reviews^12,13,15 had inclusion criteria that were broader than those of the current review. One systematic review¹² included both human and animal studies as well as people with substance use disorders other than OUD, 1 systematic review¹³ examined the effects of co-occurring substances in addition to cannabis on treatment outcomes in people with OUD, and 1 systematic review¹⁵ evaluated the effects of cannabis on people with mental disorders in addition to those with opioid dependence. Only the subset of primary studies from these systematic reviews that met the inclusion criteria for the current review are presented in this report.

There were 4 primary studies^19-22 identified in the literature search results that met the inclusion criteria for this review but were excluded due to their inclusion in the systematic reviews that have been included in the current report.

Additional details regarding the characteristics of the included publications are provided in Appendix 2.

There was some overlap in the primary studies included in the systematic reviews and the degree of overlap is summarized in Appendix 5.

Study Design

The primary studies included in the systematic reviews were mainly non-randomized studies (e.g., prospective cohort studies, retrospective cohort studies, retrospective chart reviews, cross-sectional studies, and secondary analyses of clinical trials) as well as a small number of randomized controlled trials (RCTs). A meta-analysis was attempted in 1 systematic review¹⁶ of the 5 included systematic reviews^12-16; however, due to high heterogeneity the results could only be described qualitatively. In the 3 systematic reviews^12,13,15 with broader inclusion criteria than those of the current review, there were 2 RCTs in each of 2 systematic reviews^12,15 (i.e., 4 unique RCTs) and 1 RCT and 7 non-randomized studies in 1 systematic review¹³ that were relevant to the current review. Overall, the number of non-randomized studies included in the remaining 2 systematic reviews^14,16 ranged from 23 to 41. The systematic reviews were published from 2019 to 2022 and the latest search dates were between July 2018 and February 2021. The follow-up in the primary studies included in the systematic reviews ranged from 1 hour to 11 years.

The 1 included non-randomized study,¹⁷ published in 2022, was a retrospective cohort study that was conducted at a single methadone maintenance treatment (MMT) clinic in patients with OUD, with or without a diagnosis of schizophrenia or chronic psychosis. Records for all patients (categorized as cannabis-users or non-users based on urinary drug screening [UDS]) admitted to the clinic over a 23-year period were studied to ascertain if there was a relationship between cannabis use, treatment retention, and survival status.

The 1 included evidence-based guideline,¹⁸ published in 2019, was developed by the Patients, Experience, Evidence, Research (PEER) group comprising members from various health care practices and locations in Canada with experience managing OUD. Evidence for the guideline was identified from a systematic review²³ of systematic reviews and RCTs, which was current up to June 2018. The evidence was graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework and the recommendations, which were developed by consensus among the committee members, underwent an extensive peer-review process.

Country of Origin

The first authors of the included systematic reviews were from France,¹² US,¹³ Canada,^14,16 and Germany.¹⁵ The primary studies within the 3 systematic reviews^12,13,15 with broad inclusion criteria that were relevant to the current review were from the US and Israel.

The authors of the non-randomized study¹⁷ were from Israel. The evidence-based guideline¹⁸ was developed by health care and allied health professionals in Canada.

Patient Population

For the current review, the terms: opioid dependence, heroin-use disorder, and people with substance use disorder where the substance was identified as opioids, or people who used opioids and were in an opioid treatment study were all considered synonymous with OUD. Two systematic reviews^14,16 specifically enrolled people with OUD. The relevant patient populations in the remaining 3 systematic reviews included people with substance (opioid) use disorder,¹² people who used opioids and were included in an original opioid treatment study in the US,¹³ and patients with opioid dependence.¹⁵ One systematic review¹³ included adults (³ 18 years of age) whereas the remaining 4 systematic reviews did not specify an age range for inclusion. None of the 5 included systematic reviews reported details on baseline patient demographic or disease characteristics.

The 1 non-randomized study¹⁷ enrolled adult (³ 18 years of age) people with OUD who were admitted to a MMT program with or without a diagnosis of schizophrenia/chronic psychosis and at least 1 attempt at residential treatment with the goal of total abstinence. Of the total enrolled, 50 (5.7%) people had schizophrenia/chronic psychosis whereas 827 (94.3%) people did not. Mean (SD) age at admission was approximately 39.6 (9.9 years), and the study population was predominantly male (74.6%) with a history of prior cannabis use (80.2%) and mean (SD) duration of opioid misuse of approximately 17.2 (10.0) years.

The target population in the included PEER guideline¹⁸ is patients with OUD who are treated in a primary care setting. The intended users of the guideline are primary care practitioners and patients with OUD.

Interventions and Comparators

For almost all clinical effectiveness outcomes considered in this report, comparisons in the non-randomized studies were between the use of cannabis and that of no use of cannabis (i.e., alone or in combination with other interventions such as methadone, buprenorphine, naltrexone, counseling, behavioural therapy, or mixed modalities). For the relevant RCTs identified in the 3 systematic reviews with broad inclusion criteria,^12,13,15 2 RCTs evaluated cannabidiol 400 mg or 800 mg single doses versus placebo once daily for 3 consecutive days,¹² and 2 RCTs evaluated dronabinol 30 mg/day versus placebo.¹⁵ For the remaining relevant RCT identified in 1 systematic review,¹³ although the intervention and comparator were buprenorphine and methadone, respectively, marijuana (cannabinoids) was evaluated as a co-occurring substance and predictor of treatment retention.

In the included non-randomized study,¹⁷ the comparison was between cannabis use versus no cannabis use.

The PEER guideline¹⁸ evaluated various pharmacotherapies for the treatment of OUD including buprenorphine-naloxone, methadone, naltrexone, and cannabis. Evidence for cannabis in OUD was derived from 1 RCT that compared dronabinol 30 mg/day versus placebo, which was also included in 1 systematic review¹⁵ that has been included in the current review.

Outcomes

The outcomes derived from the included systematic reviews and non-randomized study were treatment retention and adherence,^13-17 craving and opioid withdrawal symptoms,^12,14,15 illicit opioid, other substance, or polydrug use,^13,14,16 psychological or physiologic responses,^14,15 survival,¹⁷ criminal activity and risky behaviour,¹⁶ and safety.¹⁵

In general, the treatment outcomes measured in the primary studies were not well defined in the included systematic reviews. Treatment retention was typically measured as the proportion of people remaining in treatment at the end of the study.¹³ Treatment adherence was reported in only 1 systematic review¹⁴ and the method of determining adherence was either not defined in the publication or was inferred by UDS or pill count.

In 2 relevant RCTs included in 1 systematic review,¹² craving was measured using a visual analogue scale, and positive and negative effects were measured using the Positive and Negative Affect Schedule following exposure to neutral and drug-related cues (e.g., videos, neutral objects, or heroin-related paraphernalia), although no further details were provided. In 1 relevant RCT included in 1 systematic review,¹⁵ the severity of opioid withdrawal symptoms was measured by the Subjective Opiate Withdrawal Scale. In 5 primary studies included in 1 systematic review¹⁴ the effects of cannabis versus no cannabis (measured by UDS or self-report) were assessed on opioid craving and withdrawal, but no details were provided on the severity of craving or withdrawal symptoms.

In 3 systematic reviews,^13,14,16 that reported the impact of cannabis on illicit opioid, other substance, or polydrug use, outcomes were determined by positive UDS or self-reported drug use.

In 2 systematic reviews^14,15 that reported psychological or physiologic responses, the primary studies ascertained cannabis use (or non-use) by UDS or self-report and the method of measurement of the responses were either not described or were determined by measuring vital signs during withdrawal sessions. The association between cannabis and criminal activity or risky behaviours was reported in 1 systematic review¹⁶; however, no details on how these data were derived was provided.

In the 1 non-randomized study,¹⁷ survival status of included patients was retrieved from the Israeli National Population Registry, which records all deaths in Israel.

In the 2 relevant RCTs included in 1 systemic review¹⁵ that reported on safety, adverse events (AEs) were reported by the study investigators or following once weekly review of medication tolerability with a research psychiatrist.

Clinical effectiveness evidence for cannabis considered for the PEER guideline¹⁸ comprised 1 RCT that was also included in 1 systematic review¹⁵ included in the current review.

Summary of Critical Appraisal

An overview of the critical appraisal of the included publications is summarized in the following text. Additional details regarding the strengths and limitations of included publications are provided in Appendix 3.

Systematic Reviews

In all 5 systematic reviews,^12-16 the review objective was clearly described and a PRISMA flow diagram detailing study selection, and adequate details on the included primary studies were provided. In 3 systematic reviews,^12,14,16 the authors stated that the review was designed according to PRISMA guidelines, whereas in 1 systematic review,¹⁵ the authors stated that the review followed guidance from the Centre for Reviews and Dissemination and the Cochrane Collaboration. Following well established processes for developing and conducting systematic reviews increases transparency in the methodology and confidence that the systematic review was done appropriately.

Study protocols were registered in PROSPERO for 3 systematic reviews.^14-16 For the other 2 systematic reviews,^12,13 it was unclear if the review methods were established before the conduct of the review. Access to the review protocol and literature search strategy facilitates reproducibility of the reviews and apprises 1 to any protocol deviations that may have occurred. The research question and inclusion criteria included the components of PICO (population, intervention, comparator, outcome) in 3 systematic reviews,^14-16 whereas in 2 systematic reviews,^12,13 only the literature search terms were provided. In all but 1 systematic review,¹² literature searches were conducted in multiple databases. It is possible that by not adhering to a PICO framework for study selection or by not searching multiple databases that important primary studies could have been missed.

Selection of studies was done independently by 2 reviewers (and disagreements resolved by an additional reviewer or by consensus) in 4 systematic reviews.^13-16 Agreement rates between reviewers were reported in 2 systematic reviews.^13,16 In 1 systematic review, there was no explanation provided pertaining to study selection.¹² Lists of excluded studies were not provided in any of the included systematic reviews, although in 1 systematic review,¹⁵ the authors stated that a list of excluded studies was available upon request. Data extraction was performed independently by 2 or more reviewers according to standardized methods in 3 systematic reviews,^13,15,16 with agreement rates between reviewers reported in 1 systematic review.¹³ In 1 systematic review,¹⁴ data extraction was done by 1 reviewer but was checked for accuracy and completeness by another reviewer, and in 1 systematic review¹² the process for data extraction was not mentioned. By conducting study selection or data extraction in duplicate, the potential for errors in study selection and data abstraction are mitigated.

The risk of bias in individual primary studies was not assessed in 1 systematic review¹²; however, it was assessed separately by 2 reviewers in the other 4 systematic reviews,^13-16 with each systematic review using a different instrument such as the Quality in Prognostic Studies tool,²⁴ National Heart, Lung, and Blood Institute Quality Assessment Tool for Observational and Cross-Sectional Studies,²⁵ the Cochrane Risk of Bias tool,²⁶ and the Newcastle-Ottawa scale.²⁷ In 1 systematic review,¹⁶ the overall quality of the evidence was assessed using GRADE methodology.²⁸ All of the tools used to assess risk of bias have been published and are frequently used to assess the methodological quality and risk of bias in systematic reviews. In general, the risk of bias in the included primary studies was assessed as low to high and the quality of evidence as very low to moderate across the systematic reviews that assessed risk of bias and quality of evidence.

A meta-analysis of primary studies was planned in 1 systematic review¹⁶; however, due to high heterogeneity across included studies the authors opted to describe the individual studies and results qualitatively instead.

The source of funding of the individual primary studies was reported in 1 systematic review,¹⁵ but not the others. The source of funding and conflict of interest declarations by the authors were available for all included systematic reviews.

Non-Randomized Study

In the included non-randomized study,¹⁷ the objective, inclusion criteria, and patient characteristics were clearly reported, and the main study findings were presented with estimates of random variability, appropriate statistical testing, and actual P values. Included patients were representative of the entire population from which they were derived because the records for all patients with OUD admitted to the single centre (MMT clinic) of the study were analyzed. All patients were also followed up in a similar manner (i.e., 1 year from admission to the MMT clinic).

Patients, health care practitioners, and study authors were not blinded to the intervention. Moreover, the study was not randomized and there was no description of potential confounders. As a result, it is not known if potential confounders could have influenced the study results because due to lack of randomization it is not known if potential confounders were distributed equally across the included patients. This was a single centre study that derived information about patients treated over a 23-year time frame. Therefore, it is unclear if the treatment setting and patient population are representative of other treatment settings or current OTPs given expected clinical practice changes over this time period.

In this study, cannabis use was based on UDS; however, urine samples were analyzed for cannabis only during the 1st and 13th months of treatment. Patients were categorized as being cannabis-users or non-users based on a positive UDS at either of these time points. Measurement of cannabis use in this manner may not be representative of the overall pattern of cannabis use over the duration of the study and could either have under- or overestimated cannabis use in the study population.

Guideline

The included PEER guideline¹⁸ was of high quality. A rigorous guideline development process was undertaken including a systematic review that has been published.²³ The objective, intended users, target population were clearly described and the guideline committee membership reflected various health care practices and locations across Canada with experience managing OUD. Key questions and recommendations were developed through consensus and the quality of the evidence was rated according to GRADE methodology.²⁸ Draft recommendations underwent an extensive peer-reviewed process involving health care professionals and people with lived experience with OUD.

Summary of Findings

The main findings from the included systematic reviews^12-16 and non-randomized study¹⁷ are summarized in this section. A detailed summary of the study findings by outcome is provided in Appendix 4. All included systematic reviews reported study findings as narrative summaries and not as quantitative summary estimates, therefore, the current report also includes narrative summaries of the findings. Although a meta-analysis was planned for 1 systematic review,¹⁶ the high heterogeneity in the included studies precluded the ability to do so and instead the authors described the included studies and their results qualitatively. There was some overlap in the primary studies that were included in the systematic reviews and so the narrative summaries from these systematic reviews may include some of the same studies. A citation matrix illustrating the degree of overlap is provided in Appendix 5.

Clinical Effectiveness of Cannabis for the Management of OUD

Evidence regarding the clinical effectiveness of cannabis for the management of OUD was available from 5 systematic reviews^12-16 and 1 non-randomized study.¹⁷ Most of the evidence is derived from non-randomized studies (e.g., prospective cohort, retrospective cohort, cross-sectional studies, and secondary analyses of clinical trials) although there were 5 RCTs included among the primary studies in the systematic reviews.

No evidence on the clinical effectiveness of cannabis for the management of OUD on quality of life, functioning, participant satisfaction, relapse, or serious sequelae such as hospitalization or overdose was identified.

Treatment Retention and Adherence

Four systematic reviews^13-16 and 1 non-randomized study¹⁷ reported on treatment retention in OTPs by people with OUD who used cannabis. One systematic review¹³ reported that based on 6 studies (1 RCT and 5 non-randomized), co-occurring use of marijuana statistically significantly reduced treatment retention. In another systematic review,¹⁵ based on 1 RCT that assessed dronabinol versus placebo, there was no statistically significant difference in treatment retention between groups. In most of the primary studies included in each of 2 systematic reviews,^14,16 there was no statistically significant association between cannabis use and treatment retention. For example, in 1 systematic review,¹⁴ 17 of 23 non-randomized studies reported no statistically significant association between cannabis use and treatment retention, whereas 5 studies suggested there was a negative effect of cannabis on treatment retention and 5 studies reported statistically significantly higher treatment retention in cannabis users, although there were inconsistencies between the latter studies related to the frequency of cannabis use. In the other systematic review,¹⁶ 8 of 11 non-randomized studies reported no statistically significant association between cannabis use and treatment retention; however, 3 studies reported there was a statistically significant association between cannabis use and treatment retention. A subgroup analysis by country in this systematic review¹⁶ found cannabis use to be associated with decreased treatment retention in studies conducted in the US and with increased retention times in studies conducted in Israel. Although a meta-analysis had been planned in this systematic review¹⁶ to examine the effect of cannabis use on treatment retention, due to significant heterogeneity and high risk of bias among the studies, the authors chose not to do so, and the review concluded that there was no consensus among studies that cannabis use is associated with longer treatment retention.

Treatment adherence according to cannabis use in people with OUD was assessed in 1 systematic review.¹⁴ Based on 6 non-randomized studies; cannabis was not found to be statistically significantly associated with treatment adherence in 3 studies, whereas 1 study reported cannabis users were significantly more likely to adhere to treatment. The remaining 2 studies reported that based on an inverted U-shaped dose-response curve, intermittent cannabis users had statistically significantly improved adherence versus non-users or consistent users of cannabis.

In the non-randomized study,¹⁷ cumulative 1-year treatment retention was statistically significantly longer in patients in the study cohort who did not use cannabis compared with cannabis users. Among patients in the subset with schizophrenia or chronic psychosis, cumulative 1-year treatment retention did not differ between cannabis users and non users.

Craving and Opioid Withdrawal

Three systematic reviews^12,14,15 reported on craving and opioid withdrawal symptoms in people with OUD who used cannabis. In 2 RCTs included in 1 systematic review,¹² compared with placebo, use of cannabidiol for 3 consecutive days was associated with reduced cue-induced craving and anxiety and treatment effect lasted 7 days. Based on 5 non-randomized studies included in another systematic review,¹⁴ the effect of cannabis use on opioid craving or withdrawal was inconsistent, as 3 studies reported there was no statistically significant relationship and 2 studies reported a statistically significant reduction in at least 1 measurement of opioid withdrawal in cannabis users. In 1 placebo-controlled RCT in opioid dependent patients undergoing inpatient detoxification and naltrexone induction that was included in 1 systematic review,¹⁵ use of dronabinol was associated with statistically significant lower severity of withdrawal symptoms as measured by the Subjective Opiate Withdrawal Scale; however, rates of successful induction onto extended-release naltrexone did not differ between dronabinol and placebo.

Illicit Opioid, Other Substance, or Polydrug Use

Three systematic reviews^13,14,16 reported on illicit opioid, other substance (e.g., alcohol, cocaine, or crack), or polydrug use in people with OUD who were cannabis-users versus non-users with mixed findings. In the first systematic review,¹³ based on 2 non-randomized studies, marijuana use was associated with a non-statistically significant increase in opioid abstinence outcomes in 1 study and a statistically significant increased likelihood of having a positive UDS for opioids in the other study. Overall, this systematic review found that co-occurring substance use was associated with negative treatment outcomes, regardless of the intervention used.¹³

The second systematic review¹⁴ included 11 non-randomized studies that examined the relationship between cannabis use and use of alcohol, cocaine/crack, and benzodiazepines during treatment in people with OUD. Of these, 3 studies reported a statistically significant increased use of alcohol among cannabis users. In 9 studies that examined use of cannabis and cocaine or crack, 5 studies found no correlation of cannabis use, 2 studies reported statistically significant increased use of cocaine in cannabis users, and 2 studies supported inverse relationships between the frequency of cannabis use and use of cocaine or crack. In 7 studies that examined benzodiazepine use among cannabis users, 3 studies reported statistically significant increased benzodiazepine use whereas 4 studies did not detect significant differences in the use of benzodiazepines according to cannabis use.

The third systematic review¹⁶ included 12 non-randomized studies that examined the relationship between cannabis use and continued or illicit opioid use in people with OUD receiving MMT. The results of these studies were inconsistent as 8 studies reported no statistically significant association between cannabis use and illicit or other opioid use, whereas 4 studies reported an association between cannabis use and illicit opioid or other drug use. Some of the included studies also reported on the association between cannabis use and other drug use (e.g., cocaine, benzodiazepines, alcohol, stimulants, etc.) but with highly inconsistent results. Although a meta-analysis was planned to examine the effects of cannabis use on continued opioid use, due to significant heterogeneity among the studies and high risk of bias, it was not possible to do so, and it was concluded that there was no consensus among studies that cannabis use is associated with reduced opioid use.¹⁶

Psychological or Physiologic Responses

Two systematic reviews^14,15 reported on some measure of psychological or physiologic health in relation to cannabis use in patients with OUD. In 1 systematic review¹⁴ that included 6 non-randomized studies providing information for this outcome, 2 studies reported statistically significantly worse health indicators (e.g., poor appetite, poor physiologic functioning) in cannabis users and 4 studies did not find a significant relationship between cannabis and measures of psychological health. In the other systematic review,¹⁵ 1 included RCT investigated the use of dronabinol versus placebo on physiologic outcomes. Use of dronabinol in patients undergoing withdrawal from oxycodone was associated with dose-dependent sustained sinus tachycardia along with anxiety and panic, as well as significant increases in heart rate compared to placebo.

Additional Clinical Outcomes

The non-randomized study¹⁷ examined survival status in relation to cannabis use in patients with OUD receiving MMT. Survival since admission to the MMT program did not statistically significantly differ according to cannabis use on admission.

One systematic review¹⁶ examined the association between cannabis use and criminal activity (based on 2 non-randomized studies) and on risky behaviour (e.g., HIV infection) based on 1 non-randomized study. For criminal activity, the 2 studies differed in that 1 study reported cannabis use was not associated with any differences in criminal activity and 1 study reported that cannabis use was a significant predictor of criminal activity at 12 months. For risky behaviours, 1 study reported that cannabis use was not related to any risk behaviours.

Safety

One systematic review¹⁵ included 2 RCTs that reported on AEs and safety associated with use of dronabinol. In 1 RCT, no significant differences in the frequency of AEs between dronabinol and placebo were observed; however, a post-hoc analysis of participants who also smoked marijuana regularly during the outpatient phase had lower rates of insomnia and anxiety and were more likely to complete the 8-week trial. users and non-users were observed. In the other RCT, use of dronabinol in people undergoing withdrawal from oxycodone was associated with dose-dependent serious AEs (e.g., sinus tachycardia, increased heart rate).

Guidelines Regarding the Use of Cannabis for the Management of OUD

The 1 included evidence-based guideline¹⁸ recommended against the use of cannabinoids for management of OUD (i.e., strong recommendation, very low-quality evidence). This recommendation was based on no systematic review evidence and very low-quality evidence from 1 RCT due to inconsistency, imprecision, and risk of bias.²³

Limitations

Four^13-16 of the 5 included systematic reviews were conducted using rigorous methodology and practices for systematic reviews; however, all are limited by the quality of the available evidence. The quality of the evidence was rated by the systematic review authors as very low to moderate and associated with a low to high risk of bias in the 4 systematic reviews^13-16 that conducted risk of bias assessments. In a quality assessment according to GRADE conducted in 1 systematic review,¹⁶ it was noted that the overall quality of evidence was very low due to inconsistency, imprecision, and high risk of bias.

Most of the included evidence was derived from observational, non-randomized trials (e.g., prospective cohort, retrospective cohort, cross-sectional, and secondary analysis studies). Further, in most studies use of cannabis in people with OUD was not the focus of the study, but rather the concomitant use of cannabis was evaluated along with pharmacologic therapy (e.g., methadone, buprenorphine, naltrexone) or other treatment modalities for OUD. No meta-analyses of the available evidence could be conducted due to high heterogeneity among the primary studies, therefore, only narrative summaries (as opposed to quantitative summary estimates) are available for the assessment of clinical effectiveness of cannabis for OUD.¹⁶

One systematic review¹⁵ reported AE and safety data pertaining to dronabinol, an oral synthetic delta-9-tetrahydrocannabinol analogue and cannabinoid-1 receptor agonist. Dronabinol was approved for use as an antiemetic in Canada in the past, but its authorization was cancelled post-market and it is no longer commercially available in Canada.²⁹

No evidence on the clinical effectiveness of cannabis for the management of OUD on quality of life, functioning, participant satisfaction, relapse, or serious sequelae such as hospitalization or overdose was identified.

An inherent drawback to investigating cannabis use as an intervention is the lack of standardization of the active ingredients contained in cannabis, as well as the dose, frequency of administration, route of administration, or source as these are highly variable. Many primary studies included in the systematic reviews did not differentiate between medical use or recreational use of cannabis. Further, in these studies cannabis use versus non-use was typically based on the results of UDS for cannabis or self-reporting. The frequency of UDS for cannabis and for opioids (as a measure of treatment adherence or to verify the use of illicit opioids) was often not reported. In the included non-randomized study,¹⁷ cannabis users and non users were categorized as such based on the results of a UDS obtained after the 1st and 13th month of MMT treatment. The results may not be representative of the overall pattern of cannabis use over the duration of the study and could likely under- or overestimate the frequency of cannabis use in the study population.

Two of the included systematic reviews^14,16 were conducted by authors in Canada. Given that the included primary studies in these reviews were generally of low quality and associated with methodological limitations, inconsistency, and imprecision, it is difficult to determine if the results are generalizable to Canadian clinical practice.

There is a lack of RCT evidence that focuses on cannabis use as a specific intervention for the management of OUD. Moreover, there is also a lack of evidence-based guidelines to guide treatment decision-making in people with OUD, most likely due to the paucity of high-quality evidence for use of cannabis in OTPs.

Conclusions and Implications for Decision- or Policy-Making

This report summarizes the available evidence on the clinical effectiveness of cannabis for the management of OUD from 5 systematic reviews^12-16 and 1 non-randomized study.¹⁷ One evidence-based guideline¹⁸ for the management of OUD in primary care is also included.

Overall, the evidence identified for the clinical effectiveness of cannabis in OUD is considered to be of very low to moderate quality and associated with high heterogeneity, inconsistency, imprecision, and risk of bias.^13-16 Generally the authors of the systematic reviews included in this report^12-16 are in agreement that there is no consensus that use of cannabis is associated with improved treatment outcomes in people with OUD or that the available evidence supports cannabis use in this setting as either beneficial or detrimental. Notably, these findings are aligned with a 2017 CADTH Rapid Response report on the use of medical cannabis in residential transition or addition programs in which no relevant literature regarding the clinical effectiveness, cost-effectiveness, or evidence-based guidelines regarding the use of medical cannabis in adults with addictions being treated in residential transition or addiction programs was found.³⁰

The 1 evidence-based guideline¹⁸ identified in the current review was developed by a committee of health care and allied health professionals in Canada. The guideline recommends against the use of cannabinoids for the management of OUD in primary care (i.e., strong recommendation, very low-quality evidence) due to no or inconclusive RCT evidence identified for cannabinoids for OUD.²³

The limitations of the included publications should be considered in the interpretation of the findings of this report. Most of the available evidence is derived from non-randomized, observational studies in which the objective was not to specifically investigate cannabis use versus non-use on treatment outcomes in people with OUD. In the future, well-designed RCTs that specifically evaluate a standardized form of cannabis (i.e., dose, route of administration, source) as a focused intervention in people with OUD are needed to inform the clinical effectiveness of cannabis for the treatment of people with OUD, which in turn will be beneficial for clinical and policy decisions.

The implications of increased access to medical and non-medical cannabis in Canada and other countries extend not only to coverage decisions regarding cannabis for people with OUD, but also to how cannabis use could impact prescribing practices and treatment approaches for people with OUD. People in OTPs may be required to undergo regular UDS or to enter into a treatment agreement. The concomitant use of cannabis could pose a treatment barrier if it is perceived that an individual is non-adherent with treatment due to a positive UDS or reported use of cannabis.^14,23

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Appendix 1: Selection of Included Studies

Figure 1: Selection of Included Studies

Appendix 2: Characteristics of Included Publications

Note that this appendix has not been copy-edited.

Table 2: Characteristics of Included Systematic Reviews

ADHD = attention deficit hyperactivity disorder; AE = adverse event; CBD = cannabidiol; CO₂ = carbon dioxide; HIV = HIV; HRQoL = health-related quality of life; MOUD = medication-based treatment of opioid use disorder; MMT = methadone maintenance treatment; NA = not applicable; NR = not reported; RCT = randomized controlled trial; SUD = substance use disorder; SR = systematic review.

Table 3: Characteristics of Included Primary Clinical Studies

DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revised; MMT = methadone maintenance treatment; OUD = opioid use disorder; SD = standard deviation.

^aUrine test to assess prior cannabis use was done in the first month of treatment.

Appendix 3: Critical Appraisal of Included Publications

Note that this appendix has not been copy-edited.

Table 5: Strengths and Limitations of Systematic Reviews Using AMSTAR 2⁸

AMSTAR 2 = A MeaSurement Tool to Assess systematic Reviews 2; CI = confidence interval; CINAHL = Cumulative Index to Nursing and Allied Health Literature; EBM = evidence-based medicine; GRADE = Grading of Recommendations Assessment, Development, and Evaluation; PICO = population, intervention, comparator, outcome; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-analyses; RCT = randomized controlled trial; RoB = risk of bias.

Table 6: Strengths and Limitations of the Primary Clinical Study Using the Downs and Black Checklist⁹

AE = adverse event; CI = confidence interval; MMT = methadone maintenance treatment; OTP = opioid treatment program; OUD = opioid use disorder; SD = standard deviation.

Table 7: Strengths and Limitations of the Guideline Using AGREE II¹⁰

AGREE II = Appraisal of Guidelines for Research and Evaluation II.

^aDetails pertaining to the systematic review and a comprehensive evidence review is available in a co-publication to the guidelines.²³

Appendix 4: Main Study Findings

Note that this appendix has not been copy-edited.

Table 8: Summary of Findings by Outcome — Treatment Retention and Adherence

CI = confidence interval; MMT = methadone maintenance treatment; OTP = opioid treatment program; NR = not reported; RCT = randomized clinical trial; SR = systematic review; UDS = urinary drug sample.

Table 9: Summary of Findings by Outcome — Craving and Opioid Withdrawal Symptoms

CBD = cannabidiol; DB = double-blind; OUD = opioid use disorder; PANAS = Positive and Negative Affect Schedule; RCT = randomized controlled trial; SOES = Subjective Opiate Withdrawal Scale VAS = visual analogue scale.

Table 10: Summary of Findings by Outcome — Illicit Opioid, Other Substance, or Polydrug Use

MOUD = medication-based treatment of opioid use disorder; MMT = methadone maintenance treatment; OTP = opioid treatment program; OUD = opioid use disorder; SR = systematic review; UDS = urinary drug sample.

Table 11: Summary of Findings by Outcome — Psychological or Physiologic Responses

CO₂ = carbon dioxide; RCT = randomized controlled trial; UDS = urinary drug sample.

Table 12: Summary of Findings by Outcome — Additional Clinical Outcomes

CI = confidence interval; HIV = HIV; UDS = urinary drug sample.

Table 13: Summary of Findings by Outcome — Safety

AE = adverse event; RCT = randomized controlled trial NA = not applicable; NR = not reported.

Table 14: Summary of Recommendations in Included Guideline

OUD = opioid use disorder; PEER = Patients, Experience, Evidence, Research group.

Appendix 5: Overlap Between Included Systematic Reviews

Note that this appendix has not been copy-edited.

Table 15: Overlap in Relevant Primary Studies Between Included Systematic Reviews

Appendix 6: References of Potential Interest

Note that this appendix has not been copy-edited.

The following publications were identified because they provide additional information to corroborate the findings of this report (i.e., previous CADTH reports) or additional guidance on the management of OUD or the prescribing of cannabis for medical use.

Previous CADTH Reports

Medical cannabis in residential transition or addiction programs: a review of clinical and cost-effectiveness and guidelines. (CADTH Rapid response report: summary with critical appraisal). Ottawa (ON): CADTH; 2017: https://www.cadth.ca/medical-cannabis-residential-transition-or-addiction-programs-review-clinical-and-cost. Accessed 2022 Sep 3.

Guidelines and Recommendations

Busse JW, Vankrunkelsven P, Zeng L, at al. Medical cannabis or cannabinoids for chronic pain: a clinical practice guideline. BMJ. 2021;374:n2040. .PubMed

Bruneau J, Ahamad K, Goyer M, et al. Management of opioid use disorders: a national clinical practice guideline. CMAJ. 2018;190(9):E247-e257.

CRISM national guideline for the clinical management of opioid use disorder. Canadian Research Initiative on Substance Misuse; 2018: https://crism.ca/projects/opioid-guideline/. Accessed 2022 Sep 3.

Guidance in authorizing cannabis products within primary Care. Mississauga (ON): College of Family Physicians of Canada; 2021: https://www.cfpc.ca/CFPC/media/PDF/CFPC-Guidance-in-Cannabis-Within-Primary-Care.pdf. Accessed 2022 Sep 3.

National Institute for Health and Care Excellence. Cannabis-based medicinal products. (NICE guideline NG144) 2021; https://www.nice.org.uk/guidance/ng144. Accessed 2022 Sep 3.

Rieb LM, Samaan Z, Furlan AD, et al. Canadian Guidelines on Opioid Use Disorder Among Older Adults. Can Geriatr J. 2020;23(1):123-134. PubMed