While many people think marijuana is harmless, some people do become addicted to it. Roughly one million people receive substance abuse treatment for cannabis each year (“Results from the 2010 National Survey on Drug Use and Health: Summary of National Findings,” report from the Substance Abuse and Mental Health Services Administration, http://1.usa.gov/154HYiq) and the majority resume using marijuana following program discharge.
So how can you help prevent a patient from relapsing? Contemporary relapse prevention involves a combination of psychological interventions and medications called medication-assisted treatment (MAT). While this paradigm is effective for treating alcoholism and opioid addiction, it hasn’t panned out very well for cannabis use disorder. Although many medications have been studied, only one is potentially ready for prime time.
Cannabis is associated with a withdrawal syndrome that has finally been recognized by the Diagnostic and Statistical Manual of Mental Disorders. Symptoms, which can be distressing, lead some patients to resume using cannabis to relieve their discomfort.
Although there are no medications approved by the US Food and Drug Administration (FDA) for cannabis withdrawal, a blizzard of off-label options has been studied: baclofen (Lioresal), bupropion (Wellbutrin), divalproex (Depakote), dronabinol (Marinol), gabapentin (Neurontin), mirtazapine (Remeron), nefazodone (Serzone), and quetiapine (Seroquel) (Benyamina A et al, Expert Rev Neurother 2008;8(3):479–491; Weinstein AM and Gorelick DA, Curr Pharm Des 2011;17(14):1351–1358). Most have been a bust with the exception of gabapentin and dronabinol. A very notable failure was the ever ubiquitous quetiapine—widely prescribed for anxiety and insomnia—which actually increased cannabis use compared to placebo (Cooper ZD et al, Addict Biol: Epub ahead of print).
In a positive trial involving gabapentin, patients received a total of 1,200 mg per day in divided doses for 12 weeks (Mason BJ et al, Neuropsychopharma-cology 2012;37(7):1689–1698). All patients also received weekly individual counseling and could avail themselves of any other support they found helpful. Symptoms of withdrawal, including mood, sleep problems, and cravings, were all improved compared to placebo. Only 36% of the original 50 patients completed the trial but with equal attrition from both groups. Gabapentin was well tolerated and only one patient dropped out due to an adverse event (headache).
Dronabinol is a prescription form of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound in marijuana. The FDA approved it on a priority basis as an orphan drug back in 1985. Dronabinol is currently indicated as an appetite stimulant for patients with acquired immunodeficiency syndrome (AIDS) and for nausea and vomiting in cancer patients (package insert for Marinol, Unimed Pharmaceuticals, Inc., 2006, http://1.usa.gov/13V6k0Y). It is a Schedule III controlled substance taken by mouth as a capsule.
A small pilot study involving eight outpatients investigated the use of dronabinol for withdrawal suppression (Budney AJ et al, Drug Alcohol Depend 2007;86:22–29). Patients received placebo, 10 mg or 30 mg three times per day. Dronabinol improved symptoms of withdrawal—mood, sleep, and cravings—compared to placebo with the high-dose condition generally approximating “smoking as usual.” There were no significant adverse events or patient drop outs. Similar results were found in a subsequent substitution trial that is reviewed below.
Although the evidence base is slim, gabapentin appears to be a live option for withdrawal management. Dronabinol is also theoretically in the mix as an option, however, risks including abuse, diversion, and possible psychosis will probably prevent most clinicians from using this medication.
Substitution (also known as agonist or maintenance) therapy involves replacing a patient’s drug of choice with a drug-like analog. The medication prevents withdrawal, craving, and drug seeking. This strategy was first used for opioid addiction where methadone was substituted for heroin (Dole VP and Nyswander M, JAMA 1965;193(8):646–650). Agonist therapy is now routinely used for opioid and nicotine use disorders.
On face value, substituting dronabinol for marijuana has a lot of intuitive appeal (think nicotine patches and gum). However, intuition collided with reality and came up a little short (Levin FR et al, Drug Alcohol Depend 2011;116(1–3):142–150).
After a one-week placebo run-in period, patients were then randomized to either 20 mg of dronabinol two times per day (n=79) or placebo (n=77). Dronabinol was then titrated to the target dose over one week, maintained for six weeks, and then tapered off over two weeks. Patients in both groups were followed for a total of 12 weeks and received concurrent motivational enhancement therapy. The primary outcome was continuous abstinence during weeks seven and eight.
Ninety-nine patients (63%) completed the trial with greater retention in the group receiving dronabinol (77% versus 61%; P=0.02). There was no difference between the two groups for the primary outcome: 17.7% of the dronabinol group was abstinent during the tail end of the maintenance phase versus 15.6% for placebo (P=0.69). A separate drill down on average marijuana use per day found a complicated relationship between baseline marijuana use, treatment allocation, and time, with no difference in cannabis use between groups late in the trial.
Although one could speculate that a higher dose of dronabinol might have met with greater success, we currently don’t have enough evidence to recommend dronabinol as a substitution strategy.
A bevy of other medications have been evaluated as a means of promoting abstinence and/or maintaining remission (Benyamina, op cit; Weinstein and Gorelick, op.cit). So far, only gabapentin has shown any promise in a high quality clinical trial.
In the study by Mason et al, outlined previously, gabapentin also reduced cannabis use and cannabis-related physical and psychological problems compared to placebo. Although results were statistically significant they are probably not clinically significant. For example, gabapentin led to fewer days of marijuana use per week but the difference was less than one day. By the end of the trial, patients receiving gabapentin and placebo were both using marijuana about one day per week.
CATR’s Take: The pharmacy cupboard is pretty bare when it comes to medications for cannabis addiction. Gabapentin is the only medication that appears to offer legitimate benefit for withdrawal suppression and there are no real contenders for reducing cannabis use or preventing relapse. Psychological interventions will remain the mainstay of treatment for the foreseeable future.