Pharmaceuticals for Cannabis Use Disorder
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Surveillance
January 2022
Visual Abstract
Summary
Pharmacotherapy for the Treatment of Cannabis Use Disorder: A Living Systematic Review
Background
- Past-year daily cannabis use in the US more than doubled from 2002 to 2017, increasing from 1.9 to 4.2%. During that time, the potency of available cannabis also increased.
- Data from national surveys indicate up to a third of regular cannabis users may develop cannabis use disorder (CUD).
- Standard treatment of CUD generally consists of psychotherapy, but pharmacotherapy could offer more accessible and less time-intensive treatment options.
- There are no FDA-approved medications for the treatment of CUD, but many studies have assessed off-label use of medications FDA-approved for other indications. A 2014 Cochrane review examined the benefits and harms of off-label use of pharmacotherapies to treat CUD and was updated in 2020. This report seeks to identify and incorporate new evidence published since the 2020 update.
Methods
Living systematic review
Search:
(Searched May 21, 2021)
- Ovid MEDLINE
- PsycINFO
- Cochrane Database of Systematic Reviews
Screening:
Key Questions
KQ1: What are the benefits and harms of pharmacotherapy for CUD?
KQ2: Are there known subpopulations for whom current pharmacotherapies are most or least effective for CUD?
Study Selection Criteria
| PICOTS Element | Inclusion Criteria | Exclusion Criteria |
| Population | Nonpregnant adults and adolescents with known or suspected CUD | Children and pregnant adults |
| Interventions | Pharmacotherapies identified as a potential treatment for CUD with or without adjunctive treatment (e.g., medication management; CBT) | Pharmacotherapies intended to treat other conditions |
| Comparators | Usual care, placebo, or other interventions (comparison groups must receive the same adjunctive treatments) | No comparator group |
| Outcomes |
Efficacy: abstinence (2+ week continuous abstinence); reduction of cannabis use (e.g., quantitative urine levels; validated self-report measures); withdrawal symptoms; retention in treatment Harms: dropouts due to AE; serious AE (as reported) |
Other outcomes |
| Time of follow-up | Follow-up ≥ 4 weeks | Follow-up < 4 weeks, except for studies of withdrawal. |
| Setting | Outpatient; inpatient; incarceration/detention centers, correctional facilities | Other settings |
| Study design | RCTs | Other study designs |
Abbreviations. AE: adverse events; CBT: cognitive behavioral therapy; CUD: cannabis use disorder; PICOTS: population, interventions, comparators, outcomes, timing, setting; RCT: randomized controlled trial
- Studies (randomized controlled clinical trials) assessed the benefits and harms of pharmacotherapies, with or without adjunctive treatment, as potential treatments for known or suspected CUD in nonpregnant adults and adolescents.
Risk of Bias:
- Cochrane Collaboration tool
Assessing the certainty of the body of evidence:
- Overall certainty of evidence for each outcome was determined using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach
Updates:
- Search to be updated every 6 months with new reports as needed
Findings
As of May 21, 2021:
- 28 eligible studies (2 published since the previous review)
- 27 placebo-controlled trials
- 1 comparative effectiveness trial of 2 antipsychotic medications
- Very low- to low-certainty evidence for all GRADE outcomes: abstinence, cannabis use, treatment retention, dropouts due to adverse events, serious adverse events, and withdrawal symptoms
- Most included interventions did not differ significantly from placebo with respect to efficacy or harms in the treatment of CUD for adults and adolescents
- Antidepressants and cannabinoids provided the largest evidence bases in this review, and were analyzed by mechanisms of action and relative tetrahydrocannabinol (THC) concentrations, respectively
- 7 RCTs reported outcomes by subpopulation, but findings were insufficient to draw decisive conclusions
GRADE Outcomes Summary Table
| Pharmacotherapy | Abstinence | Cannabis Use | Treatment Retention | Harms | Withdrawal Symptoms |
| Antidepressants vs. placebo | |||||
|
SSRIs: escitalopram, fluoxetine, vilazodone 3 RCTs; N = 198 |
⨁◯◯◯ Very low |
⨁⨁◯◯ Low |
⨁⨁◯◯ Low |
⨁⨁◯◯ Low |
⨁◯◯◯ Very low |
|
Bupropion 2 RCTs; N = 92 |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁⨁◯◯ Low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
|
SARIs: nefazodone 1 RCT; N = 66 |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
|
SNRIs: venlafaxine 1 RCT; N = 103 |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
— |
| Antipsychotics vs. placebo | |||||
|
Quetiapine 1 RCT; N = 130 |
— |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
| Antipsychotic vs. antipsychotic | |||||
|
Clozapine vs. ziprasidone 1 RCT; N = 30 |
— |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
— | — |
| Antianxiety medication vs. placebo | |||||
|
Buspirone 2 RCTs; N = 268 |
— |
⨁⨁◯◯ Low |
⨁⨁◯◯ Low |
⨁⨁◯◯ Low |
⨁⨁◯◯ Low |
| Mood stabilizers vs. placebo | |||||
|
Divalproex sodium 1 RCT; N = 25 |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
|
Lithium 1 RCT; N = 31 |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
— |
⨁◯◯◯ Very low |
| Cognitive-enhancing therapies vs. placebo | |||||
|
Atomoxetine 1 RCT; N = 78 |
— |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
— |
| Cannabinoids vs. placebo | |||||
|
High THC to CBD: dronabinol, nabilone 3 RCTs; N = 296 |
⨁⨁◯◯ Low |
⨁⨁◯◯ Low |
⨁⨁◯◯ Low
|
⨁◯◯◯ Very low
|
⨁⨁◯◯ Low |
|
Low THC to CBD: cannabidiol 1 RCT; N = 82 |
Low dose: ⨁⨁◯◯ Low |
Low dose: ⨁⨁◯◯ Low |
⨁⨁◯◯ Low |
⨁◯◯◯ Very low |
Low dose: ⨁⨁◯◯ Low |
|
High dose: ⨁⨁◯◯ Low |
High dose: ⨁⨁◯◯ Low |
High dose: ⨁⨁◯◯ Low |
|||
|
Comparable THC to CBD: nabiximols 3 RCTs; N = 228 |
⨁⨁◯◯ Low |
⨁⨁◯◯ Low |
⨁⨁◯◯ Low |
⨁⨁◯◯ Low |
Low dose: ⨁⨁◯◯ Low |
| Anticonvulsants vs. placebo | |||||
|
Gabapentin 1 RCT; N = 50 |
— |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
|
Topiramate 1 RCT; N = 66 |
— |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
— |
| Glutamatergic modulator vs. placebo | |||||
|
N-acetylcysteine 2 RCTs; N = 418 |
⨁◯◯◯ Very low |
Adolescents and young adults: ⨁◯◯◯ Very low |
⨁⨁◯◯ Low |
⨁⨁◯◯ Low |
— |
|
Adults: ⨁◯◯◯ Very low |
|||||
| Hormones vs. placebo | |||||
|
Oxytocin 1 RCT; N = 16 |
— |
⨁◯◯◯ Very low |
— | — | — |
|
Progesterone 1 RCT; N = 8 |
— | — | — | — |
⨁◯◯◯ Very low |
| Fatty acid amide hydrolase inhibitor vs. placebo | |||||
|
PF-04457845 1 RCT; N = 70 |
— |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
⨁◯◯◯ Very low |
| Cholinesterase inhibitor vs. placebo | |||||
|
Galantamine 1 RCT; N = 32 |
— | — | — | — |
⨁◯◯◯ Very low |
Abbreviations. CBD: cannabidiol; GRADE: Grading of Recommendations, Assessment, Development, and Evaluations approach; RCT: randomized controlled trial; SARI: serotonin antagonist and reuptake inhibitor; SNRI: serotonin-norepinephrine reuptake inhibitors; SSRI: selective serotonin reuptake inhibitor; THC: tetrahydrocannabinol.
Direction of effect: Light grey = no difference from comparator; yellow = significant improvement with intervention; orange = increased risk of harm with intervention; light orange = mixed or conflicting results; — = outcome not assessable
GRADE certainty of evidence: Very low ⨁◯◯◯; Low ⨁⨁◯◯; Moderate ⨁⨁⨁◯; High ⨁⨁⨁⨁
Conclusions
- It remains uncertain whether pharmacotherapy can improve CUD-related outcomes despite a growing body of evidence examining a variety of medications.
- Certain cannabinoid formulations may hold promise for treatment of CUD, but results would need to be replicated in additional studies and across outcomes before being adopted in clinical practice.
- There is a need for more research to identify effective pharmacological treatments for this condition given the increasing use of cannabis in the general population and high prevalence of CUD among current cannabis users.
Gaps in Evidence
- Longer-term, large-scale replication studies would improve our understanding of previously assessed pharmacotherapies for CUD.
- We found limited evidence of the effect of pharmacotherapies for CUD by important subgroups (e.g., age, race or ethnicity, people with comorbidities or other substance use disorders).
- High-quality RCTs are needed to understand the use of pharmacotherapeutics to relieve withdrawal symptoms.
Durbin S, Ayers C, Harrod C, Paynter R, Kansagara D. Pharmacotherapy for the treatment of cannabis use disorder. Portland, OR: The Systematically Testing the Evidence on Marijuana Project, Oregon Health & Science University; 2021.
