However, although these interventions have been associated with positive CUD outcomes, sustained abstinence is still only achieved in a minority of youth with CUD and treatment response tends to wane at follow-ups . Furthermore, most psychosocial treatment interventions require multiple sessions over several weeks or months and require high motivation and patient stability. Combining brief evidence-based psychosocial treatment options with pharmacotherapy represents a potentially important avenue to reach young cannabis users and improve treatment outcomes, e.g., through a potential increase in short-term recovery, which may help increase motivation into longer-term psychosocial interventions. Despite great effort, there are no approved pharmacotherapies for CUD in youth or adults. A 2019 Cochrane review found that abstinence at the end of treatment was no more likely with active pharmacotherapy with selective serotonin reuptake inhibitor  antidepressants, mixed action antidepressants, anticonvulsants and mood stabilisers, buspirone and N-acetylcysteine compared to placebo . Of note, one RCT among adolescents with CUD  found that eight-week treatment with N-acetylcysteine doubled the odds of abstinence from cannabis during treatment compared to placebo . However, a subsequent larger RCT in adults with CUD  did not find evidence for benefits of 12-week N-acetylcysteine treatment on abstinence from cannabis compared to placebo . Of relevance, abstinence at the end of treatment may not be a developmentally-appropriate intervention goal in cannabis using youth , and recent expert consensus on clinical outcomes for CUD trials recommend that sustained abstinence should not be the primary outcome for all clinical trials of CUD . Thus, taking a harm reduction approach in treatment of CUD may weigh towards future studies on how to best attract youth with a frequent cannabis use/CUD to treatment that does not require abstinence, but targets reduction in use and in adverse consequences related to use.

The growing research and recognition of medical cannabis grow supplies indicate the potential utility of cannabinoid-based-medicines as a strategy in treatment of CUD. Although it may sound initially counterintuitive, cannabinoids are receiving growing global interest as a safe and tolerated option for individuals with CUD. Because the divide between recreational and medical use of a drug may often overlap, the use of cannabis in CUD treatment makes it imperative to address the many questions in order to be able to minimize potential harms of medical cannabis use. Generally speaking, an increasing number of countries have recognized potential medicinal uses of cannabinoid-based products and cannabinoids across Europe , the U. S. , Canada , and Australia , providing greater flexibility for prescribers and facilitating research which has been difficult to conduct due to restrictions laid down on cannabinoid medicinal products . For example, there has been an increase in synthetic cannabinoid formulations such as nabilone  licensed for the treatment of chemotherapy-induced nausea and vomiting, as well as nabiximols  for the treatment of spasticity and multiple sclerosis, and Epidiolex  for the treatment of severe treatment resistant epilepsy in children . So far, all studies on use of cannabinoids in treatment of CUD have been conducted in adults, while studies in youth are lacking. In the next sections, we review evidence from studies examining the effects of cannabinoids on cannabis use pathology among adult non-treatment seekers and patients in treatment and discuss the relevance of these findings for youth. Studies were found by searching PubMed, Embase, and PsycInfo databases with the terms “cannabis use disorder” or “cannabis dependence” or “cannabis treatment” combined with “cannabinoid” or “tetrahydrocannabinol” or “THC” or “cannabidiol” or “CBD” or “fatty acid amide hydrolase inhibitor” or “FAAH inhibitor”; and by checking reference lists of existing studies and reviews up to June 1st 2021. We did not include qualitative studies and case studies. THC is a partial agonist at CB1 and CB2 receptors . Partial agonist action at CB1 receptor is responsible for the psychotropic effects associated with cannabis use as well as potentially therapeutic effects such as pain- and appetite-modulating actions. These clinical effects are mediated through CB1 receptor activation via inhibition of nociception, activation of reward pathways and regulation of mood, memory, and cognition.A number of studies have examined the effect of dronabinol or nabilone  or nabiximols  on CUD symptoms in adults .

In general, THC based medicines are aimed at ameliorating cannabis withdrawal symptoms and craving when patients with CUD cease or reduce their use of illicit cannabis, because such compounds directly substitute the cannabis THC content. This treatment principle is similar to opioid and nicotine replacement therapy and is thought to provide a safer alternative that better facilitates participation in psychosocial and other treatment interventions . By this mechanism, THC based cannabinoid agonist medicines may help decrease the risk of relapse due to withdrawal symptoms . Several laboratory studies have shown that dronabinol can reduce withdrawal symptoms in adult non-treatment seeking daily cannabis users ). In an inpatient setting  , 10 mg of dronabinol 5 times/day decreased withdrawal symptoms and craving and produced no intoxication, compared to placebo. In an outpatient setting  , dronabinol  dose-dependently decreased withdrawal symptoms compared to placebo, with greater reductions following the high dose . However, the high dose produced symptoms of cannabis intoxication and drug effects compared to placebo. Vandrey et al. replicated the ability of dronabinol to dose-dependently decrease withdrawal symptoms in adult, daily cannabis users . There was a significant effect of the high dose on dry mouth, rapid heart rate and flushing, and decrements in a minority of the cognitive performance measures. There is also some evidence that dronabinol combined with an alpha2-adrenergic receptor agonist, lofexidine , produces synergistic effects for decreasing withdrawal symptoms, craving and relapse in adult non-treatment seeking daily cannabis users. A randomized controlled trial with cannabis dependent adults  compared dronabinol with placebo over 12 weeks with concomitant weekly MI. Compared to placebo, dronabinol improved treatment retention and reduced withdrawal symptoms, but not cannabis use and 2-week abstinence. An RCT  with cannabis dependent adults compared a higher dose of concurrent dronabinol and lofexidine with placebo over 11 weeks with concomitant weekly MI, and found no effect of drug treatment on 3-week abstinence, withdrawal symptoms, or treatment retention. A laboratory study of nabilone , which has a higher bioavailability than dronabinol, found that compared to placebo, 6 and 8 mg nabilone/day decreased withdrawal symptoms and relapse behavior in adult non-treatment seeking daily cannabis users . Nabilone did not increase ratings of “liking” or “desire to take again” compared to placebo, but 8 mg/day worsened cognitive task performance. A pilot RCT comparing placebo and nabilone  over 10 weeks in adults with cannabis dependence , found that nabilone was safe and tolerated, but had no effect on cannabis use compared to placebo. So far, findings from studies examining nabiximols’ efficacy on cannabis use pathology in adults are more mixed. A proof of concept study of fixed and self-titrated nabiximols use  in non-treatment seeking cannabis dependent adults , showed that high fixed doses were well tolerated and reduced withdrawal symptoms, but not craving, compared to placebo .

Self-titrated doses were lower and had limited efficacy compared to high fixed doses. A two-site inpatient RCT in treatment-seeking adult patients with CUD receiving 6 days of nabiximols  or placebo with concomitant MI/CBT during a 9-day admission, found that nabiximols reduced withdrawal and improved treatment retention , but did not reduce cannabis use, dependence or cannabis-related problems compared to placebo . Nabiximols was not associated with greater intoxication or adverse events. A pilot, outpatient RCT  in treatment seeking cannabis dependent adults  receiving 12-week treatment with self-titrated nabiximols use or placebo, concurrent with weekly MI and CBT, found that nabiximols was well tolerated with no serious adverse events, but had no effect on withdrawal symptoms, cannabis use and abstinence, compared to placebo. In contrast, a multi-site, outpatient RCT  in cannabis dependent adults receiving 12-week treatment with self-titrated nabiximols use or placebo, concurrent with 6 sessions of CBT, found that nabiximols was well tolerated with few adverse events, had no effect on withdrawal symptoms, craving and cannabis-related problems, but reduced cannabis use during the trial, compared with placebo. The reduction in cannabis use in the nabiximols group, compared to placebo, was maintained 12 weeks after treatment . To summarize, the evidence from placebo-controlled laboratory studies suggests that treatment with dronabinol dose-dependently decrease withdrawal symptoms, with some evidence that higher doses produce cannabis intoxication and drug liking. Evidence from large placebo-controlled RCTs in cannabis dependent adults  combining dronabinol with MI over 11-12 weeks partly supports this: 40 mg/day reduced withdrawal symptoms and improved treatment retention, but not cannabis use and abstinence , but a higher dose, 60 mg/day combined with lofexidine had no effect on neither withdrawal symptoms nor abstinence or treatment retention . Nabilone has been less examined, but the evidence from placebo-controlled studies is similar: a laboratory study suggests that 6 or 8 mg/day reduces withdrawal symptoms , and a small RCT  in cannabis dependent adults found no effect on cannabis use. Evidence from placebo-controlled studies of nabiximols combined with MI and CBT is more mixed: out of the three conducted RCTs in cannabis grow facility dependent adults, self-titrated nabiximols reduced withdrawal symptoms, but had no effect on cannabis use, dependence or cannabis-related problems in one study; had no effect on neither withdrawal symptoms nor cannabis use or abstinence in another study with a higher dose; and had no effect on withdrawal symptoms, craving and cannabis-realted problems, but reduced cannabis use in a large study. Recently, studies have also examined the effect of FAAH inhibitors or CBD in adults with CUD .

FAAH forms a part of the endocannabinoid system by breaking down endocannabinoids such as anandamide. By inhibiting this breakdown process, FAAH inhibitors increase endocannabinoid levels, which may represent a therapeutic mechanism for the treatment of CUD. Preclinical research has shown that FAAH inhibitors can attenuate cannabis withdrawal symptoms in THC-dependent mice . So far, only one RCT has examined the effects of FAAH inhibitor treatment on cannabis use and cannabis pathology in humans . In a double-blind, place-controlled, parallel group phase 2a trial in adults with cannabis dependence , participants received 4 mg daily PF-04457845  or placebo  during 4 weeks. Relative to placebo, treatment with PF-04457845 reduced symptoms of cannabis withdrawal, and self-reported cannabis use at 4 weeks, which was confirmed by lower urinary THC-COOH concentrations. Further, there was no difference between reported adverse events and retention in the two groups. A novel strategy with promising findings is also underway in preclinical and clinical studies of CBD . For example, preclinical studies show that CBD attenuates drug-seeking behavior , and a study found that CBD reversed the reinforcing effects of cannabis in youth , supporting CUD treatment potential. The multiple receptor mechanisms of CBD outlined earlier are believed to form the neurobiological underpinnings of the effects of CBD on the regulation of reinforcing, motivational and withdrawal-related effects as documented in preclinical and clinical studies . It is still not known precisely how CBD interacts with the dopaminergic system to modify the motivational effects of psychoactive drugs, but available data suggest a role for CBD in regulating the activity of the mesolimbic dopaminergic system . This role has been emphasized by the localization of cannabinoid receptors in the mesolimbic circuit orchestrating the synthesis and release of dopamine . Apart from the interaction with the endocannabinoid system through alteration of endocannabinoid signaling, the effect of CBD on drug addiction has been shown to involve modest affinity agonist action at 5-HT1A receptors . So far, two studies have examined the effects of CBD in adult cannabis users . A pragmatic open-label clinical trial evaluated the effect of 10 weeks of 200 mg daily CBD administration on psychological symptoms and cognition in adults with frequent cannabis use , while participants continued cannabis use . Compared with baseline, participants reported fewer depressive and psychotic symptoms, but more state anxiety symptoms after CBD treatment, and demonstrated improvement in attentional switching, verbal learning, and memory. CBD was well tolerated with no reported side effects, in line with a recent meta-analysis of CBD clinical trials reflecting that CBD tends to be very well-tolerated with few serious adverse effects.