Nabiximols, a combined THC and cannabidiol (CBD) product that is formulated as an oral (buccal) spray, has been shown to improve withdrawal symptoms without improving abstinence rates. Oral CBD has not shown efficacy in reducing the signs or symptoms of cannabis use, and likely has no benefit in cannabis use withdrawal symptoms. The CB-1 receptor antagonist rimonabant has shown efficacy in reducing the effects of cannabis in users, but with a risk for serious psychiatric side effects.Naltrexone, a mu opioid receptor antagonist, has shown mixed results for cannabis use disorder—both increasing the subjective effects of cannabis when given acutely, but potentially decreasing the overall use of cannabis with chronic administration. N-acetylcysteine (NAC) has shown some limited benefit in decreasing cannabis use in adolescents, though not with adults. Lithium, a mood stabilizer, has shown mixed results for treating symptoms of cannabis withdrawal, but is likely ineffective. Quetiapine, a second-generation antipsychotic, has been shown to treat cannabis withdrawal related insomnia and decreased appetite at the expense of exacerbating cravings. Oxytocin, a neuropeptide that the body produces, has shown some benefit in reducing the use of cannabis when administered intranasally in combination with motivational enhancement therapy sessions, though the treatment effect did not persist between sessions.Finally, CB1 antagonists such as rimonabant have been tested for utility in CUD. These drugs are effective at blocking the subjective effects of cannabis intoxication as well as the somatic components. This is accomplished by preventing THC binding to the CB1 receptor, effectively eliminating the ability to get high.
Zolpidem, a GABA-A receptor agonist and "Z-hypnotic" medication, has shown some efficacy in treating insomnia due to cannabis withdrawal, though there is a potential for misuse. Entacapone was well tolerated and decreased cannabis cravings in a trial on a small number of patients. Topiramate, an antiepileptic drug, has shown mixed results in adolescents, reducing the volume of cannabis consumption without significantly increasing abstinence, with somewhat poor tolerability. Gabapentin, an indirect GABA modulator, has shown some preliminary benefit for reducing cravings and cannabis use.The agonist substitution approach is one that draws upon the analogy of the success of nicotine replacement therapy for nicotine addiction. Dronabinol, which is synthetic THC, has shown benefit in reducing cravings and other symptoms of withdrawal, though without preventing relapse or promoting abstinence. Combination therapy with dronabinol and the alpha 2 adrenergic receptor agonist lofexidine have shown mixed results, with possible benefits towards reducing withdrawal symptoms. However, overall, the combination of dronabinol and lofexidine is likely not effective for the treatment of cannabis use disorder. Nabilone, a synthetic THC analogue, has shown benefits in reducing symptoms of withdrawal such as difficulty sleeping, and decreased overall cannabis use. Despite its psychoactive effects, the slower onset of action and longer duration of action of nabilone make it less likely to be abused than cannabis itself, which makes nabilone a promising harm reduction strategy for the treatment of cannabis use disorder. The combination of nabilone and zolpidem has been shown to decrease sleep-related and mood-related symptoms of cannabis withdrawal, in addition to decreasing cannabis use.