Cannabidiol as a Harm Reduction Strategy for People Who Use Drugs: A Rapid Review
Le cannabidiol comme stratégie de réduction des méfaits pour les personnes qui utilisent des drogues : une revue rapide et des aperçus cliniques
Department of Public Health Sciences, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
Department of Medicine, Faculty of Medicine, 8166University of British Columbia, Vancouver, BC, Canada
School of Nursing, Thompson Rivers University, Kamloops, BC, Canada
The CannSolve Clinic, Kamloops, BC, Canada
Department of Emergency Medicine, Faculty of Medicine, 8166University of British Columbia, Vancouver, BC, Canada
BC Centre on Substance Use and Department of Medicine, 8166University of British Columbia, Vancouver, BC, Canada
Department of Psychology, 8166University of British Columbia, Kelowna, BC, Canada
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.comAbstract
Objective
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.
Résumé
Objectif
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.
Introduction
The 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.1bibr2-07067437231183525bibr3-07067437231183525-4 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. 9
CBD 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.
Method
The rapid review process was guided by the methodology presented by the Cochrane Rapid Reviews Methods Group 19 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 Selection
For 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 Synthesis
Data 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 Bias
Results
We 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).9,24bibr25-07067437231183525bibr26-07067437231183525bibr27-07067437231183525bibr28-07067437231183525bibr29-07067437231183525bibr30-07067437231183525bibr31-07067437231183525bibr32-07067437231183525bibr33-07067437231183525bibr34-07067437231183525bibr35-07067437231183525bibr36-07067437231183525bibr37-07067437231183525bibr38-07067437231183525bibr39-07067437231183525bibr40-07067437231183525bibr41-07067437231183525bibr42-07067437231183525bibr43-07067437231183525bibr44-07067437231183525bibr45-07067437231183525-46
Study Characteristics
Study characteristics are displayed in Tables 1table2-07067437231183525 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.9,24bibr25-07067437231183525bibr26-07067437231183525-27,30bibr31-07067437231183525bibr32-07067437231183525-33,38bibr39-07067437231183525-40,43,44,46,49 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.
| Primary research | ||||||
| Study | Study type | Drug | Sample | Intervention | Primary outcomes | Key results |
| Hurd et al.29 | RCT | Opioid | Abstinent individuals with heroin use disorder (N = 42) | Oral CBD 400 mg, 1×/day for 3 days (n = 14) Oral CBD 800 mg, 1×/day for 3 days (n = 13) Placebo, 1×/day for 3 days (n = 15) | Drug-cue-induced craving and anxiety | CBD 400 mg (mean diff = 0.44) and 800 mg (mean diff = 0.23) had significantly reduced cue-induced craving scores compared to placebo (mean diff = 0.93) The CBD 800 mg group retained significantly reduced craving scores (mean diff = 0.39) compared to placebo (mean diff = 0.94) up to 7 days post-dose (P = 0.017) The CBD 400 mg group (mean diff = −0.14) and 800 mg group (mean diff = −0.03) had significantly reduced drug-induced anxiety scores compared to placebo (mean diff = 0.53) up to 7 days post-dose Most significant reduction in craving and anxiety within 24 h post-CBD ingestion No effect of CBD on the out-of-clinic heroin craving questionnaire compared to placebo at any time CBD is well tolerated with no serious adverse events |
| Meneses-Gaya et al.34 | RCT | Cocaine | Cocaine-dependent men (N = 31) | Oral CBD 300 mg, 1×/day for 10 days (n = 14) Placebo, 1×/day for 10 days (n = 17) | Craving intensity, anxiety, depression, sleep, adverse events | No difference in the reduction of cocaine craving levels between CBD and placebo (P = 0.116) No difference in measures of anxiety (P = 0.80), depression (P = 0.46), and sleep (P = 0.37) between CBD and placebo CBD is well tolerated with no serious adverse events |
| Mongeau-Pérussea et al.37 | RCT | Cocaine | Individuals with moderate to severe cocaine use disorder (N = 78) | Oral CBD 800 mg, 1×/day for 13 weeks (n = 40) Placebo, 1×/day for 13 weeks (n = 38) | Drug-cue-induced craving, time-to-relapse | Drug-cue-induced craving (mean CBD = 4.69, mean placebo = 3.21; P = 0.069) and stress (mean CBD = 1.50, mean placebo = 1.46; P = 0.887), daily craving (P = 0.698), withdrawal symptoms (P = 0.662), sustained abstinence (CBD = 41%, placebo = 50.1%; P = 0.089), and time-to-relapse (hazard ratio = 1.20, P = 0.51) did not differ between CBD and placebo Only 3 participants did not relapse (CBD, n = 1; placebo, n = 2) CBD was well tolerated with few serious adverse events |
| Mongeau-Pérussea et al.36 | RCT | Cocaine | Individuals with moderate to severe cocaine use disorder (N = 78) | Oral CBD 800 mg, 1×/day for 13 weeks (n = 40) Placebo, 1×/day for 13 weeks (n = 38) | Anxiety (Beck Anxiety Inventory, Visual Analogue Scale), stress response | No difference in anxiety scores via the Beck Anxiety Inventory (P = 0.27) or Visual Analogue Scale (P = 0.18) between CBD and placebo CBD did not decrease anxiety after stressful (P = 0.14) or cocaine (P = 0.885) scenarios compared with placebo There was no statistically significant difference in cortisol levels between CBD and placebo groups (P = 0.76) |
| Rizkallaha et al.41 | RCT | Cocaine | Individuals with moderate to severe cocaine use disorder (N = 78) | Oral CBD 800 mg, 1×/day for 13 weeks (n = 40) Placebo, 1×/day for 13 weeks (n = 38) | Cognitive function (visual memory, inhibition, and risky decision-making) | CBD did not improve cognitive function compared to placebo (Pattern Recognition Memory P = 0.080, Stop Signal Task P = 0.644, Cambridge Gambling Task: quality of decision-making: P = 0.994; deliberation time: P = 0.507; delay aversion: P = 0.968; risk-taking: P = 0.914) |
| Hurd et al.28 | Pilot clinical trial | Opioid | Abstinent individuals with heroin use disorder (N = 9) | Oral CBD 400 mg, 1×/day for 3 days (n = 2) Oral CBD 800mg, 1×/day for 3 days (n = 4) Placebo, 1×/day for 3 days (n = 3) | Drug-cue-induced craving and anxiety | Decreased subjective cue-induced drug craving 1 h post-dose for CBD (mean = 0.83) compared to placebo (mean = 2.67) Decreased general drug craving from baseline between CBD (mean = −16.33) and placebo (mean = −4.33) up to 7 days post-dose |
| Suzuki et al.47 | Open-label pilot study | Opioid | Individuals with opioid use disorder on buprenorphine (N = 5) | Oral CBD 600 mg, 1×/day for 3 days (n = 5) | Drug-cue-induced craving | Drug-cue-induced craving was significantly lower after CBD dosing compared with baseline (0.4 vs. 3.2, paired t-test, P = 0.0046) No significant changes in secondary measures of depression, anxiety, pain, or opioid withdrawal were noted CBD was well tolerated |
| Roser et al.48 | Cross-sectional survey study | Polydrug use | Individuals with substance use disorder (N = 495) | Smoked CBD at unspecified doses | Prevalence and motives of CBD use | 34.3% of patients reported trying CBD once, with 9% reporting regular use for over a year Of those reporting regular use, 40% self-reported improvements in relaxation and sleep and 30% reported reduction in pain and anxiety |
| Valleriani et al.45 | Qualitative | Polydrug use ∼50% drug of choice = stimulants ∼50% drug of choice = opioids | Individuals who unregulated drugs accessing a low-barrier cannabis distribution program (N = 23) | Variable combination of inhalation and edible THC and CBD products | Experience in accessing a cannabis distribution program | The use of CBD was popular Reported benefits included reduced pain, reduced cravings, better sleep, more energy, and general feelings of wellness CBD viewed as generally inaccessible due to the cost |
| Meyer et al.35 | Case report | Cocaine | A 30-year-old male patient diagnosed with schizophrenia, personality disorder, cannabis use disorder, cocaine use disorder | CBD-rich cigarettes, ∼20 cigarettes/day for ∼400 mg of CBD/day + methylphenidate | Reduction in cocaine and cannabis use improved psychiatric symptoms | Stopped cocaine and high-dose THC use Improved psychotic symptoms and general functioning No further hospitalizations |
| Shaw and Marcu42 | Case report | Opioid | A 27-year-old male with 8 years of severe opioid use disorder | Sublingual CBD tincture, 200 mg 3×/day (600 mg/day) for 10 days | Withdrawal symptoms | Reduction in clinical opioid withdrawal scale scores from 14 to 5 on day 2, complete resolution by day 7 Successful transition to naltrexone-based abstinence maintenance therapy |
| Reviews | ||||||
| Study | Review type | Drug | Main conclusions | Cited evidence | ||
| Bonaccorso et al.25 | Systematic | Opioid | CBD may reduce drug-induced craving for opioids Need for large-scale RCTs | Hurd et al.28 | ||
| Daldegan-Bueno et al.27 | Systematic | Cocaine | CBD alone is not a sufficient agent to reduce cocaine craving and relapse It may have more significant therapeutic potential in alleviating comorbid symptoms associated with cocaine use Substantial need for more controlled trials with varied doses, administration protocols, and populations | Mongeau-Perusse et al. 37 ; Meneses-Gaya et al. 34 | ||
| McKee et al.33 | Systematic | Opioid | CBD may reduce drug-induced craving and anxiety for opioids Favourable safety profile Quality of evidence low to moderate, larger RCTs needed | Hurd et al.29 | ||
| Paulus et al.40 | Systematic | Opioids Cocaine | Evidence does not support the use of CBD in reducing cocaine craving/relapse but does support reducing cue-induced craving and anxiety for opioids Once-daily dosing may explain the lack of efficacy for cocaine use disorder Available evidence paresis spared, need for more human research | Meneses-Gaya et al. 34 ; Mongeau-Pérusse et al.37; Hurd et al.28; Hurd et al.29 | ||
| Tang et al.49 | Systematic | Opioids Cocaine | CBD might not be an ideal treatment for crack cocaine withdrawal CBD could be a potential treatment for opioid abuse | Hurd et al.29; Meneses-Gaya et al. 34 | ||
| Babalonis and Walsh24 | Comprehensive | Opioid | CBD may reduce drug-induced craving and anxiety for opioids | Hurd et al.29 | ||
| Britch et al.26 | Comprehensive | Opioid | CBD may reduce drug-induced craving and anxiety for opioids Favourable safety profile and low abuse liability | Hurd et al.29 | ||
| Karimi-Haghighi et al.30 | Comprehensive | Opioid Cocaine | CBD may reduce drug-induced craving and anxiety for opioids Cocaine craving, anxiety, and relapse rates unaffected by CBD Potential utility in substance use disorders as antipsychotic More trials are needed to establish the actual clinical utility | Hurd et al.29; Meneses-Gaya et al. 34 ; Mongeau-Pérusse et al.37 | ||
| Kudrich et al.31 | Comprehensive | Opioid | CBD may reduce drug-induced craving and anxiety for opioids Favourable safety profile Growing evidence suggests that CBD may reduce symptoms commonly observed in opioid use disorder patients undergoing withdrawal (e.g., anxiety, pain, insomnia, craving, nausea, vomiting, muscle spasms, and blood pressure), but more clinical research is needed Future RCTs should investigate CBD as an adjunctive treatment in clinical settings | Hurd et al.29 | ||
| Legare et al.32 | Comprehensive | Opioid | CBD may reduce drug-induced craving and anxiety for opioids Has therapeutic potential for opioid use disorder Not an effective replacement for OUD but may serve as a valuable adjunct to traditional medication-assisted treatments | Hurd et al.29 | ||
| Morel et al.38 | Comprehensive | Opioid | CBD may reduce drug-induced craving and anxiety for opioids Need for improved outcome measures and biomarkers | Hurd et al.29 | ||
| Navarrete et al.9 | Comprehensive | Opioid | CBD may reduce drug-induced craving and anxiety, reduce heart rates, and reduce cortisol levels Minimal evidence | Hurd et al.29 | ||
| Pauli et al.39 | Comprehensive | Opioid | CBD reduced in-and-out-of-clinic opioid cravings No serious adverse effects A larger sample size needed to form definitive conclusions | Hurd et al.28 | ||
| Sloan et al.43 | Comprehensive | Opioid | CBD may blunt cue-induced craving in opioid dependence following a period of abstinence May be helpful in combination with naltrexone to block the priming effects of craving and relapse Safe to administer in combination with low doses of fentanyl, lack of studies examining higher dose opioids | Hurd et al.28 | ||
| Spanagel44 | Comprehensive | Opioid | CBD has a good safety profile, but clinical evidence is mixed Acute CBD administration may significantly reduce cue-induced cravings with long-lasting beneficial effects on craving Need larger RCTs | Hurd et al.29 | ||
| Wiese and Wilson-Poe46 | Comprehensive | Opioid | CBD may reduce drug-induced craving and anxiety Promising therapeutic potential as CBD appears neither intoxicating nor rewarding and has a favourable safety profile Further research is warranted to explore as an adjunct or alternative treatment for opioid use disorder | Hurd et al.29 | ||
| Study | Item | Overall rating | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | ||
| Bonaccorso et al. 25 | Y | N | Y | Y | N | Y | PY | Y | N | N | NA | NA | N | Y | NA | Y | Critically low |
| McKee et al. 33 | Y | N | Y | Y | Y | Y | PY | Y | Y | N | NA | NA | Y | Y | NA | Y | Low |
| Paulus et al. 40 | Y | N | Y | N | N | N | PY | Y | N | N | NA | NA | N | Y | NA | Y | Critically low |
| Tang et al. 49 | Y | N | Y | PY | Y | Y | PY | PY | Y | N | NA | NA | N | Y | NA | Y | Low |
| Study | Item | Total | Quality | |||||
|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | |||
| Babalonis and Walsh 24 | 2 | 1 | 0 | 2 | 2 | 2 | 9 | Moderate |
| Britch et al. 26 | 1 | 1 | 0 | 2 | 2 | 2 | 8 | Moderate |
| Daldegan-Bueno et al. 27 | 2 | 2 | 2 | 2 | 2 | 2 | 12 | High |
| Karimi-Haghighi et al. 30 | 2 | 2 | 0 | 2 | 2 | 2 | 10 | Moderate |
| Kudrich et al. 31 | 2 | 2 | 2 | 2 | 2 | 2 | 12 | High |
| Legare et al. 32 | 2 | 1 | 1 | 2 | 2 | 2 | 10 | Moderate |
| Morel et al. 38 | 2 | 2 | 2 | 2 | 2 | 2 | 12 | High |
| Navarrete et al. 9 | 2 | 2 | 2 | 2 | 2 | 2 | 12 | High |
| Pauli et al. 39 | 2 | 2 | 0 | 2 | 2 | 2 | 10 | Moderate |
| Sloan et al. 43 | 2 | 2 | 0 | 2 | 2 | 2 | 10 | Moderate |
| Spanagel 44 | 2 | 1 | 0 | 2 | 2 | 2 | 9 | Moderate |
| Wiese and Wilson-Poe 46 | 1 | 0 | 0 | 2 | 2 | 2 | 7 | Low |
Summary of Findings
There 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 withdrawal 42 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. 35
Polydrug 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 cross-sectional 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 Evidence
All 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.
Quality of Evidence
The 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 low25,40 or low33,49 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).9,24,26,27,30bibr31-07067437231183525-32,38,39,43,44 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.
Discussion
This 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.
Considerations for Current Evidence
There 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.57bibr58-07067437231183525bibr59-07067437231183525bibr60-07067437231183525-61 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 Directions
The 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 under-researched 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.31,63bibr63-07067437231183525-65 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.
Conclusion
The 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.