August 2023Systematic Review: Cannabidiol as a Harm Reduction Strategy for People Who Use Drugs: A Rapid Review

Cannabidiol as a Harm Reduction Strategy for People Who Use Drugs: A Rapid ReviewLe cannabidiol comme stratégie de réduction des méfaits pour les personnes qui utilisent des drogues : une revue rapide et des aperçus cliniquesLindsay A. Lo, MPH^1,*, Caroline A. MacCallum, MD^2,*

, Kate Nanson, BScN³

, Michael Koehn, MACP⁴

, Ian Mitchell, MD⁵, Michael-John Milloy, PhD⁶, Zach Walsh, PhD⁷, and Florriann Fehr, PhD³img1

The Canadian Journal of Psychiatry / La Revue Canadienne de Psychiatrieimg3

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DOI: 10.1177/07067437231183525
TheCJP.ca | LaRCP.caimg2

AbstractObjective: The drug poisoning crisis throughout North America necessitates novel harm reduction approaches. Emerging evidence suggests that cannabidiol (CBD) may have some utility as a harm reduction modality for those with problematic substance use. This rapid review aimed to synthesize available evidence on CBD as a potential harm reduction tool for people who use drugs while providing clinical and research insights.Method: A systematic search in EMBASE, MEDLINE, CENTRAL, and CINAHL was completed in July 2022. For inclusion, studies had to meet the following criteria: (1) drawn from an adult population of people who use drugs; (2) investigates CBD as an intervention for problematic substance use or harm reduction–related outcomes; (3) be published after the year 2000 and in English; and (4) be primary research or a review article. A narrative synthesis was used to group outcomes relevant to harm reduction and provide clinical and research insights.Results: We screened 3,134 records, of which 27 studies (5 randomized trials) were included. The evidence remains limited, but available studies support the potential utility of CBD to reduce drug-induced craving and anxiety in opioid use disorder. There were low-quality studies suggesting that CBD may improve mood and general well-being of people who use drugs. Evidence suggests that CBD monotherapy may not be an adequate harm reduction strategy for problematic substance use but rather an adjunct to the standard of care.Conclusion: Low-quality evidence suggests that CBD may reduce drug cravings and other addiction-related symptoms and that CBD may have utility as an adjunct harm reduction strategy for people who use drugs. However, there is a significant need for more research that accurately reflects CBD dosing and administration regimens used in a real-world context. La crise d’empoisonnement à la drogue dans toute l’Amérique du Nord nécessite de nouvelles approches de réduction des méfaits. Les données probantes émergentes suggèrent que le cannabidiol (CBD) peut être d’une certaine utilité comme modalité de réduction des méfaits aux personnes ayant une utilisation de drogues problématique. La présente revue rapide visait à synthétiser les données probantes disponibles sur le CBD à titre d‘outil potentiel de réduction des méfaits pour les personnes qui utilisent des drogues tout en procurant des aperçus cliniques et de recherche.Méthode : Une recherche systématique dans EMBASE, MEDLINE, CENTRAL, et CINAHL a été effectuée en juillet 2022. Pour être incluses, les études devaient satisfaire aux critères suivants : (1) tirées d’une population adulte de personnes utilisant des drogues; (2) recherche le CBD comme intervention pour l’usage problématique de substances ou des résultats liés à la réduction des méfaits; (3) publiés après l’an 2000 en anglais; et (4) recherche primaire ou article de synthèse. Une synthèse narrative a servi à grouper les résultats liés à la réduction des méfaits et offrant des aperçus de recherche.Résultats : Nous avons examiné 3,134 dossiers, dont 27 études (5 essais randomisés) ont été incluses. Les données probantes demeurent limitées mais les études disponibles soutiennent l’utilité potentielle du CBD pour réduire l’état de manque induit par la drogue et l’anxiété dans les troubles liés à l’utilisation d’opioïdes. Des études de faible qualité suggéraient que le CBD peut améliorer l’humeur et le bien-être général des personnes qui utilisent des drogues. Les données probantes suggèrent que la monothérapie au CBD n’est peut-être pas une stratégie adéquate de réduction des méfaits pour l’utilisation de substances problématique, mais plutôt un complément à la norme de soins.Conclusion : Des données probantes de faible qualité suggèrent que le CBD peut réduire l’état de manque de drogues et d’autres symptômes liés à la dépendance et que le CBD peut avoir une utilité comme complément d’une stratégie de réduction des méfaits pour les personnes qui utilisent des drogues. Cependant, il y a un besoin significatif de plus de recherche qui reflète précisément le dosage et le régime d’administration utilisés en situation réelle.Keywords
cannabidiol, CBD, harm reduction, addiction, drug craving, drug substitutionIntroductionThe worsening drug poisoning crisis throughout the USA and Canada has necessitated exploring novel harm reduction approaches. There is growing evidence that cannabis may be a promising harm reduction strategy for people who use drugs (PWUD). Cannabis use has been associated with reducing the use of or substituting other drugs.^1-4 Additionally, it has been associated with alleviating symptoms such as nausea, anxiety, and insomnia, commonly present in substance use disorders.^5,6 Recent cohort studies revealed that individuals at high risk of overdose commonly substitute cannabis for more harmful drugs (e.g., stimulants and opioids) as a harm reduction strategy.⁷ Further, individuals reporting difficulty accessing addiction treatment or who used substances with limited treatment options, such as methamphetamines, had a higher likelihood of using cannabis as a harm reduction strategy.⁸ These findings highlight the potential harm-reducing impacts of cannabis among PWUD.The 2 primary cannabinoids in cannabis are tetrahydrocannabinol (THC) and cannabidiol (CBD). The vast majority of evidence for cannabis as a harm reduction strategy is focused on THC-dominant products or does not distinguish between cannabinoids. However, preclinical and emerging clinical evidence has shown that CBD may act as an anxiolytic, antidepressant, and antipsychotic, as well as having procognitive and neuroprotective effects.⁹ Given the close connection that problematic substance use has on mood and cognition,^10,11 there may be a role for CBD in problematic substance use. Further, preclinical and some clinical evidence suggests that CBD may have a role in regulating reinforcement, motivation, and withdrawal-related effects of various addictive substances.⁹CBD is non-intoxicating and has a significantly reduced side effect profile compared to THC.^12,13 The lower risk of abuse and severe adverse psychiatric events,^14,15 such as psychosis, is particularly desirable as the negative impact of high-dose THC is a common concern regarding the use of cannabis within this population. As such, there has been growing interest in how CBD, specifically, can be utilized as a harm reduction tool.The COVID-19 pandemic and measures meant to mitigate the pandemic, such as self-isolation and border closures, worsened the opioid poisoning crisis by disrupting the drug supply and increasing the number of people using drugs in isolation.^16,17 Between April and December 2020, 5,148 apparent opioid toxicity deaths occurred in Canada alone, representing an 89% increase from the same time frame in 2019.¹⁸ This highlights the apparent need to urgently scale up existing evidence-based responses to overdose, such as opioid agonist therapies for people living with opioid use disorders and supervised drug consumption sites, as well as develop and evaluate innovative harm reduction strategies. Although there is widespread popular interest in the therapeutic use of CBD, there remains a paucity of information on the potential utility of CBD for harm reduction in PWUD. Thus, this rapid review sought to synthesize available evidence on CBD as a harm reduction modality for PWUD. We aimed to (1) assess the potential benefits and risks of CBD for PWUD related to harm reduction and (2) assess gaps in research.MethodThe rapid review process was guided by the methodology presented by the Cochrane Rapid Reviews Methods Group¹⁹ and PRISMA reporting guidelines.²⁰ Research aims, eligibility, and search strategies were collaboratively agreed upon by a multidisciplinary group of authors, including clinicians, academic researchers, and community harm reduction counsellors. A systematic search in EMBASE, MEDLINE, CENTRAL, and CINAHL was completed capturing literature from 1 January 2000 to 10 March 2023. Search terms for CBD were combined with search terms for harm reduction, substance use disorder, or substance use treatment using Boolean operators. Complete search strategies are presented in Supplemental Appendix 1.Inclusion Criteria and Study SelectionFor inclusion, studies had to meet the following criteria: (1) be drawn from an adult population of PWUD, (2) evaluates CBD as an intervention for problematic substance use or harm reduction–related outcomes, (3) be published after the year 2000 and in English, and (4) be primary research or a review article. Given the dearth of literature on this topic, there were no restrictions on study design. Non-peer-reviewed articles (e.g., op-eds, commentaries, and editorials) and articles investigating cannabis use without specific investigation or discussion of CBD were excluded. Author LL assessed study eligibility, while KN and CM verified the results.Data Extraction and SynthesisData were extracted and synthesized by LL, with verification by KN and CM. A narrative synthesis was used to group outcomes into themes and considerations relevant to harm reduction by LL and CM. Following this, all research team members provided feedback to produce the final results.Assessment of BiasThe quality of systematic reviews was assessed by AMSTAR.²¹ The quality of narrative reviews was assessed using SANRA.²² The quality of randomized controlled trials (RCTs) was assessed using RoB2.²³ResultsWe identified 3,968 potential records from databases. After the removal of duplicates, 3,134 studies were screened, from which 129 full-text documents were reviewed, and 27 studies were included (Figure 1).^9,24-46Study CharacteristicsStudy characteristics are displayed in Tables 1 to 3. Of the included studies, there were 3 RCTs reported across 5 (18.52%) studies,^{29,34,36,37,41} 1 (3.7%) pilot clinical trial,²⁸ 1 (3.7%) open-label pilot study,⁴⁷ 1 (3.7%) cross-sectional survey study,⁴⁸ 1 (3.7%) qualitative study,⁴⁵ 2 (8.33%) case reports,^35,42 and 16 (59.26%) reviews.^{9,24-27,30-33,38-40,43,44,46,49} Evidence was primarily available for the use of CBD adjunctively to opioids and cocaine. Two studies focused on polydrug-using samples.^45,48 Within the 16 reviews, the same 5 relevant studies were cited.^{28,29,34,36,37} Seven studies used oral isolate CBD products ranging from 400 to 800 mg of CBD,^{29,34,36,37,41,47} 1 case report used a sublingual isolate CBD tincture of 600 mg/day,⁴² 1 case report used whole-plant CBD-rich cigarettes at a dose of ∼400 mg/day,³⁵ and 2 observational studies involved participants using a combination of whole-spectrum CBD products with variable dosing.^45,48 All of the RCTs used a once-per-day dosing regimen.Summary of FindingsThere remains limited available evidence in humans for using CBD as a harm reduction strategy in PWUD. Available studies support the utility of CBD for reducing drug-induced craving and anxiety in opioid use disorder and the potential attenuation of the drug-cue-induced stress response. Potential benefits were not observed in higher-quality studies for cocaine use disorder. Similar conclusions were reported in all 16 reviews. CBD was safe and well tolerated within the included RCTs. Evidence is insufficient to draw definitive conclusions on other outcomes relevant to harm reduction such as mood, mental health, or withdrawal management. Detailed study findings are presented in Table 1.Opioids. One RCT reported that acute CBD administration of 400 and 800 mg oral CBD significantly reduced cue-induced craving and anxiety compared to placebo.²⁹ Differences were most pronounced within 24 h post-CBD ingestion. However, differences in placebo were also detected 7 days post-dose. Two pilot studies similarly reported success in the reduction of drug-cue-induced craving.^28,47 Evidence is insufficient to assess other relevant outcomes such as managing withdrawal⁴² and anxiety or depression,^28,47 as evidence for these outcomes was only available from pilot studies and 1 case report, with mixed findings being reported.Cocaine. One RCT reported across 3 manuscripts examined 800 mg/day of CBD in individuals with cocaine use disorder and found no evidence that CBD was more efficacious compared to placebo in improving cognitive outcomes, modulating anxiety symptoms or cortisol levels, reducing cravings and withdrawal symptoms, or preventing the resumption of cocaine use.^36,37,41 Similarly, another RCT investigating 300 mg/day of oral CBD cocaine-dependent individuals found no difference in craving levels, anxiety, depression, or sleep compared to the placebo.³⁴ One case report reported a cessation of cocaine use and improved mental health following the use of high-dose CBD cigarettes (400 mg/day); however, given the low quality of evidence, no conclusions can be drawn.³⁵Fig1Polydrug use. Two studies, 1 qualitative and 1 cross-sectional survey, examined CBD in samples composed of polydrug use.^45,48 The qualitative study examining experiences of PWUD accessing a cannabis distribution program reported high popularity of CBD use in their sample.⁴⁵ Participants reported improved pain, reduced cravings, better sleep, more energy, and general feelings of wellness.⁴⁵ The crosssectional study reported a low prevalence of frequent CBD use overall (9%), with self-reported benefits in frequent CBD consumers, including improved relaxation, anxiety, sleep, and pain.⁴⁸ The quality of this evidence does not permit definitive conclusions to be drawn.Gaps in EvidenceAll studies noted the need for more human research, particularly larger-scale clinical trials. Several reviews highlighted the need to expand research using varied CBD dosing and administration tactics.^27,40 Specifically, the lack of efficacy seen in the cocaine studies was noted to potentially be impacted by the once-per-day dosing regimen used within the trials. However, this may be relevant for all of the included RCTs. It was noted that research examining CBD as an adjunctive treatment, in addition to an alternative treatment, for problematic substance use was a worthwhile focus.^32,43,46 Additionally, there is a gap in human evidence for the impact of CBD on methamphetamine disorders. Finally, only 1 study reported the lived experience of PWUD using CBD,⁴⁵ presenting another critical gap in the literature. More broadly, reconciling the positive reports of CBD from those with lived experience and the mixed outcomes of clinical research remains a challenge.Tab1Tab1aTab1bTab1cTab1dQuality of EvidenceThe quality of included studies was assessed to be low. All RCTs were assessed as having a high risk of bias (Figure 2).^{29,34,36,37,41} This was primarily due to the potential for missing outcome data, a common research challenge within this population, and a lack of published study protocols. The 2 case reports, 2 pilot studies, 1 cross-sectional survey study, and 1 qualitative study were considered to also have a high risk of bias due to study design.^{28,35,42,45,47,48}The 4 systematic reviews assessed with AMSTAR-2 were rated critically low^25,40 or low^33,49 quality primarily due to no predefined protocols, no discussion on the funding source included studies, and no bias assessment (Table 2). For the remaining narrative reviews, 11/12 were assessed with SANRA as being moderate or high quality (Table 3).^{9,24,26,27,30-32,38,39,43,44} However, we still considered these lower-quality evidence as they only contained evidence from RCTs judged to be a high risk of bias and would have been rated as low or critically low quality using the AMSTAR-2 criteria for systematic reviews. It should be noted that all reviews converged on similar conclusions for each of the studies regardless of quality rating.DiscussionThis rapid review sought to assess the available evidence on the utility of CBD as a harm reduction strategy for PWUD. The amount and quality of available evidence on this topic remain low. Of the limited evidence, there is some indication that CBD may help reduce opioid drug craving and anxiety. There is limited support for cocaine drug craving and relapse as of now. There was some indication that CBD may be beneficial in improving mood and general well-being, which warrants further investigation. These findings largely reflect how current research focuses on CBD as a replacement for traditional medication-assisted treatments or monotherapy for problematic substance use. Several key research insights are discussed below, contributing an important extension to the literature base that allows for the contextualization of findings and guidance of future directions with real-world utility.Fig2Tab2Tab3Considerations for Current EvidenceThere are several important considerations when evaluating the results of the available studies. First, as with any pharmacotherapy, the dosing regimen of cannabis significantly impacts efficacy. The duration of action for cannabis ranges between 2–4 h for inhalation and 6–8 h for ingestion.⁵⁰ Similar to any condition causing 24-h symptomatology, ideal treatment for problematic substance use would provide relief around the clock. All of the current RCTs used once-per-day dosing, leaving a large window of the day without symptom control. Additionally, daytime versus night-time symptom management typically requires different approaches. In a real-world clinical context, it is common to use CBD to manage daytime symptoms and THC to manage night-time symptoms (e.g., sleep issues).^51,52 Using the same treatment regimen for day and night may limit the efficacy of the cannabis treatment plan.Second, access to supportive psychosocial strategies (e.g., mental health support, group therapy, mindfulness, and cognitive behavioural therapy) should also be considered. Psychosocial interventions have been identified as an essential aspect of successfully treating opioid use disorder.⁵³ No opioid studies had supportive care integrated into the study protocol. While several studies investigating CBD for cocaine use did provide supportive care (detox and group therapy), they only dosed once per day, which may have diminished the overall treatment efficacy.Finally, another concept to consider is that of the entourage effect, which refers to the concept of the sum of the whole plant, including all the cannabinoids and terpenes being synergistic and more significant as a whole versus a single CBD molecule.⁵⁴ Most of these studies used isolate CBD versus whole-plant or “full-spectrum” products. There is emerging evidence for other significant cannabinoids and terpenes that may benefit this patient population. For example, preclinical evidence shows the acid precursor cannabidiolic acid (CBDA) may be helpful for stress and anxiety,⁵⁵ while the cannabinoid cannabigerol (CBG) was self-reported to improve sleep, anxiety, depression, and pain in humans.⁵⁶ Terpenes such as myrcene, linalool, and beta-caryophyllene also may have sedative or anxiolytic effects.^57-61 Improved sleep and anxiety may help improve mood and general well-being, which may reduce harm.Together, these factors must be considered when looking at evidence of CBD’s efficacy to improve outcomes and reduce harm related to problematic substance use. There is a great need for further research that more closely replicates real-life addiction management strategies better. Research evaluating psychosocial and mental health support interventions with appropriate dosing regimens should be prioritized.Research Gaps and Future DirectionsThe first clinical trial for using CBD in the context of problematic substance use was in 2015. Since that time, only a handful of other studies have been published. There is a great need for more human research, particularly larger-scale clinical trials. Considering the worsening conditions of the opioid epidemic, this strategy should have an increase in research funding. With a paucity of clinical trials, we encourage publishing case reports in which CBD is used as a harm reduction tool for problematic substance use. This may help inform clinical trial dosing and protocols. Mixed-methods evaluations will also be crucial for reconciling and contextualizing outcomes of standardized assessments with reports of those with lived experience of CBD use.More specifically, there is a need to investigate varied dosing and administration tactics (e.g., variations in CBD full-spectrum flower products, day vs. night dosing regimens, dosing frequency, and route of administration) and strategies facilitating comprehensive management over an extended period of time. The use of CBD adjunctively to standard pharmacotherapy and psychosocial interventions, rather than a replacement or monotherapy for substance use treatment, should be the focus of future research.^31,32,46 Additionally, as there is currently no evidence on the impact of CBD on methamphetamine use and current treatments are limited in efficacy, this is also a worthwhile future direction.Finally, the potential for CBD to improve comorbid symptoms (e.g., mood, mental health, and insomnia) is an underresearched area and may enhance understanding of the mechanisms that underlie some of the potential beneficial effects of CBD to help overcome or reduce the harms of problematic substance use. When considering harm reduction strategies for reducing negative consequences associated with drug use,⁶² interventions that promote feelings of well-being, health, and improved mood may be of crucial importance. In other clinical populations, CBD has been associated with the reduction of a variety of symptoms (e.g., anxiety, low mood, pain, insomnia, nausea, and muscle spasms) that are commonly observed in individuals with problematic substance use, particularly when undergoing withdrawal or treatment.^31,63-65 Given its low abuse potential and limited side effects,^13,14 CBD may be desirable for many patients. As such, the actual utility of CBD to reduce harm may be a supportive strategy to existing treatment approaches such as traditional medication-assisted treatments (e.g., Opioid agonist therapy (OAT)) and supportive psychosocial strategies. There is a significant need to investigate this potential in well-designed studies that replicate real-world dosing protocols (e.g., multiple daily doses) over an adequate period of time to detect effects.ConclusionThe use of CBD as a harm reduction tool for PWUD is an emerging area of interest. To date, research remains limited. There is some evidence that CBD may help reduce opioid drug craving and anxiety, which may be 1 tool in decreasing the risk of relapse and overdose. However, evidence is not sufficient to suggest that CBD alone is an adequate treatment to reduce problematic substance use. Nonetheless, the potential for improved well-being combined with a reduction in drug craving may allow for greater adherence and engagement in other treatment modalities (e.g., therapy and OAT) and should be a focus of future research. Further, there is little risk of harm associated with the use of CBD, making it a desirable adjunct pharmacotherapy option. There is a great need for more research in this area that accurately reflects treatment and dosing regimens used in a real-world context to better evaluate CBD’s utility as a harm reduction tool for PWUD.Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Outside of submitted work, CM is the Medical Director of Greenleaf Medical Clinic and Chief Medical Officer for Translational Life Sciences. She is on the Board of Directors for The Green Organic Dutchman. She is an advisor to PreveCeutical, Pinnacle Care, Africanna, EO Care, Andira Medicine, Active Patch Technologies, and Dosist. Additionally, she has provided medical consultation and/or received support for industry-sponsored continuing medical education from Aleafia, Aurora, Canopy, Spectrum, Tilray, Emerald Health, and Syqe Medical. MK is the director of The CannSolve Clinic. IM authorizes cannabis through The CannSolve Clinic. He has provided industry-sponsored continuing medical education and/or consulting for Tilray, Unipharm, Maricann, Shoppers Drug Mart, Lancaster House, and MDBriefCase. He has been the qualified investigator in an industrysponsored (Tilray) study of cannabis for post traumatic stress disorder (PTSD). M-JM holds the Canopy Growth professorship in cannabis science at the University of British Columbia, a position established through arm’s length gifts to the university from Canopy Growth, a licensed producer of cannabis, and the Government of British Columbia’s Ministry of Mental Health and Addictions. ZW has received research funding from Tilray and Doja, licensed producers of cannabis, and was a Research Director for Indigenous Bloom. The authors LL, KN, and FF declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.FundingThe authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Interior Universities Research Coalition (IURC) Ministry of Health (MoH) Research Grant awarded to authors FF and ZW on behalf of “The Maverick Cannabis Project” to the School of Nursing, Thompson Rivers University, and the Department of Psychology, University of British Columbia-Okanagan Campus (Grant number 451078).Data AvailabilityData and materials associated with this rapid review are available upon request.ORCID iDsCaroline A. MacCallum

https://orcid.org/0000-0002-7889-3959Kate Nanson

https://orcid.org/0000-0002-1739-9121Michael Koehn

https://orcid.org/0000-0002-0390-2574Supplemental MaterialSupplemental material for this article is available online.References

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¹ Department of Public Health Sciences, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada² Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada³ School of Nursing, Thompson Rivers University, Kamloops, BC, Canada⁴ The CannSolve Clinic, Kamloops, BC, Canada⁵ Department of Emergency Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada⁶ BC Centre on Substance Use and Department of Medicine, University of British Columbia, Vancouver, BC, Canada⁷ Department of Psychology, University of British Columbia, Kelowna, BC, Canada*These authors share first co-authorship.Corresponding author:
Caroline A. MacCallum, MD, Department of Medicine, Faculty of Medicine, University of British Columbia, 2194 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada.
Email: info@drcarolinemaccallum.comJournal CoverOtsukaLundbeckEditorial BoardJournal infoSystematic Review: Cannabidiol as a Harm Reduction Strategy for People Who Use Drugs: A Rapid ReviewOriginal Research: Effects of Buprenorphine/Naloxone and Methadone on Depressive Symptoms in People"Original Research: The Differential Relation of Emotional, Physical, and Sexual AbuseOriginal Research: Social Disparities in Mental Health Service Use Among Children and YouthOriginal Research: Does the Ranking Matter? A Retrospective Cohort StudyOriginal Research: The Health and Psychosocial Profiles of Adults Who Sought Mental HealthResearch Letter: Access to Telephone and Internet-Based Telemedicine in Canadian HouseholdsSAGE authorservicesSAGE Reviewer RewardsCPA Save the Date 2023 Annual ConferenceThank you to CPA Members