To our knowledge, this is the first controlled clinical trial to evaluate agonist substitution pharmacotherapy for cannabis dependence. Dronabinol was superior to placebo in promoting retention in treatment and reducing withdrawal symptoms. However, the overall proportion of patients achieving sustained abstinence was low, and there was no evidence for an advantage of dronabinol over placebo on the outcome of marijuana use. The low overall abstinence rate is similar to low rates found in other observational studies and clinical trials for cannabis dependence (Budney et al., 2006
; Carpenter et al., 2009
; Dennis et al., 2004
; Hughes et al., 2008
; Levin et al., 2004
; McRae et al., 2009
; Nordstrom and Levin, 2007
) and highlights the need to develop medications. Effective agonist treatments for other drug problems (e.g. nicotine replacement, varenicline, methadone, buprenorphine) reduce withdrawal symptoms, improve treatment retention, reduce the reinforcing effects of the addictive drug, and promote abstinence (Comer et al., 2001
; Garrison and Dugan, 2009
; Mattick et al., 2009
; Schottenfeld et al., 2008
; Stead et al., 2008
). Thus, dronabinol displayed some of the characteristics of an effective agonist treatment and represents a promising first step.
The findings suggest several future directions for the development of medication treatments for cannabis dependence. Among agonist treatments, dronabinol seems most analogous to nicotine replacement, in that it provides the primary pharmacologically active plant compound, delivered with slow pharmacokinetics--slow absorption compared to the spike in nicotine or THC blood level after smoking, and the ability to sustain a steady blood level, opposing withdrawal. Nicotine replacement has only a modest effect size for sustaining abstinence in nicotine dependence, but its effect can be augmented by combination with other medications, such as bupropion (Shah et al., 2008
) or behavioral treatments (Reus and Smith, 2008
). This suggests that future studies should test combinations of dronabinol with other treatments with complementary mechanisms.
In human laboratory models developed to test candidate medications for cannabis dependence, dronabinol reduced withdrawal symptoms (Budney et al., 2007
; Haney et al., 2004
), but failed to reduce cannabis self-administration (Hart et al., 2002
). In the same laboratory model, the combination of dronabinol and the alpha-2 receptor agonist lofexidine reduced both withdrawal symptoms and cannabis self-administration (Haney et al., 2008
). The correspondence between the findings with dronabinol alone (reduced withdrawal, but not cannabis taking behavior) and the results of the present clinical trial suggests the predictive validity and promise of the laboratory models, and suggests these models should continue to be used to rapidly screen medications or combinations for treatment of cannabis dependence. The findings also suggest the dronabinol/lofexidine combination has promise and should be tested in clinical trials for cannabis dependence.
The more powerful agonist treatments block the subjective and reinforcing effects of their target addictive drug, either through high receptor affinity, as in the case of varenicline for nicotine dependence and buprenorphine for opioid dependence--both are high affinity partial agonists (Lutfy and Cowan, 2004
; Rollema et al., 2007
) --or through induction of tolerance as in the case of methadone maintenance (Martin et al., 2009
). Dronabinol, being in essence orally bioavailable THC, has the same affinity at the CB1 receptor as smoked THC. One laboratory study suggested dronabinol did modestly attenuate the positive effects of smoked marijuana (Hart et al., 2002
), perhaps through induction of tolerance. Agonist treatments, particularly methadone, depend on achieving a sufficiently high dose to induce tolerance (Donny et al., 2005
; Martin et al., 2009
). The dose of dronabinol used in the present study, 20 mg twice a day, was well tolerated, and future clinical trials might consider using higher doses. An outpatient study in non-treatment seekers compared 2 dronabinol doses (30 and 90 mg/day in divided doses) to placebo and found that both doses mitigated withdrawal symptoms, but the higher dose produced additional suppression of withdrawal such that symptom ratings were no different than a smoking-as-usual condition (Budney et al., 2007
). Minimal side effects were noted at either dose. Moreover, in the laboratory setting, higher doses than those used in our clinical trial were well-tolerated, although they did not reduce self-administration (Haney et al., 2008
; Hart et al., 2002
). Thus, we cannot be completely sure that “more would be better” but would be worthy of further investigation. Also, the field should seek to develop alternative high affinity CB1 receptor partial agonists.
Another possible explanation for the lack of an effect of dronabinol on cannabis use is a low motivation to quit. Budney et al. (2006)
noted that marijuana-abusing treatment seekers report dissatisfaction with multiple areas of functioning and concerns about future health, but no immediate or dramatic socioeconomic or psychosocial problems as often seen with cocaine, heroin, or alcohol dependence. Consequences of use are often long-term and more subtle (Budney et al., 1998
; Levin et al., 2006
). Thus, trying to initiate change over a relatively short period (i.e. patients in the present trial were maintained on the maximum dronabinol dose for only 6 weeks), may have been inadequate. Instead a longer maintenance period may be required. For some individuals they may initially want to cut down first and if they are maintained on an agonist treatment for a prolonged period they may eventually choose or be able to quit. This has been demonstrated in nicotine dependent populations with nicotine replacements (Wang et al., 2008
). However, since there are no empirical data to support this in cannabis-dependent populations, this possibility is highly speculative.
Motivational enhancement therapy was incorporated into the behavioral platform of the present trial, but more powerful behavioral approaches to enhance motivation might be needed. Voucher-incentives contingent on abstinence have been applied in adolescent and adult populations in cannabis-dependent patients with notable success (Budney et al., 2006
; Stanger et al., 2009
). Moreover, several pharmacologic trials in cocaine-dependent patients have found a synergy between abstinence-based vouchers combined with various medications (Kosten et al., 2003
; Poling et al., 2006
; Schmitz et al., 2008
An impediment to combining voucher incentives contingent on abstinence with dronabinol is the fact that dronabinol tests positive on urine drug screens needed to confirm abstinence. In the present study, tetrahydrocannabivirin, a cannabinoid found in marijuana but not in dronabinol, was explored as an objective urine marker for marijuana use. However, urine tetrahyrdocannabavirin displayed poor sensitivity for cannabis use, perhaps because it is often not present in strains of marijuana now commonly consumed (Levin et al., 2010
While low motivation to quit is a possible reason for the low rates of abstinence, even with dronabinol administration, the craving and withdrawal symptoms associated with marijuana cessation may impede success unless the pharmacologic agent is potent enough to mitigate these symptoms. Budney et al. (2008)
found that cannabis and nicotine withdrawal share several similarities in terms of withdrawal symptoms. Thus, the physiologic and psychologic symptoms associated with cannabis withdrawal may be underappreciated. Supporting this, Hughes et al. (2008)
found that marijuana users who are interested in quitting make numerous unsuccessful quit attempts.
Strengths of the present study included good protocol adherence, supported by voucher incentives contingent on adherence, good medication compliance assessed with the riboflavin method, a manual-guided platform treatment, and a sample size sufficient to detect clinically meaningful effects sizes in the range between small and medium. Reliance on self-report for measurement of cannabis use is a potential limitation. However, self-report using the timeline followback method (Sobell and Sobell, 1992
) has been the gold-standard for numerous large clinical trials in alcohol-dependent samples (Johnson et al., 2005
; Anton et al., 2006
), and has shown good correspondence with urine tests in other clinical trials for drug dependence (Nunes et al., 1995
). We adapted the timeline followback for precise measurement of quantities of cannabis (Mariani et al., 2010
), and the strong association between self-report cannabis use and urine THC levels within the placebo group supported the validity of the self-reports using this approach. While these data are encouraging, replication and extension of these findings are needed to further validate this approach.
In conclusion, agonist substitution pharmacotherapy with dronabinol, a synthetic form of THC, showed promise for treatment of cannabis dependence, reducing withdrawal symptoms and improving retention in treatment, although it failed to improve abstinence. The trial showed that among adult cannabis-dependent patients, dronabinol was well accepted, with good adherence and few adverse events. Future studies should consider testing higher doses of dronabinol, with longer trial lengths, combining dronabinol with other medications acting through complementary mechanisms (Haney et al., 2008
) or more potent behavioral interventions. Moreover, the field should particularly seek to develop high affinity CB1 partial agonists.