This is the first study to detect a reliable treatment effect for levodopa and, in doing so, to show how the magnitude of this effect depends on conditions of the behavioral therapy platform. The most robust levodopa-placebo difference emerged in the behavioral therapy platform that included VBRT. Levodopa+VBRT was superior across cocaine use outcomes when compared to the other treatment combinations.
Levodopa-treated subjects had lower cocaine use rates, longer periods of continuous abstinence, and less craving compared to patients assigned to placebo. These findings stand in contrast to those reported in an earlier medication screening trial in which levodopa, (tested at a lower dose, 300/75 mg/d) showed no advantage over placebo (Shoptaw et al., 2005
). Additionally, Mooney et al. (Mooney et al., 2007
) documented the safety and feasibility of levodopa/carbidopa therapy (800/200 mg/d) in an initial safety trial and in a subsequent dose ranging study but reported no clear decrease in cocaine use as a function of levodopa dose. Given the apparent safety and tolerability of levodopa (Mooney et al., 2007
), the present results are highly encouraging with regard to the potential utility of levodopa pharmacotherapy in reducing cocaine use when combined with appropriate behavioral interventions.
There is consensus in the scientific community that combining behavioral treatments and pharmacological agents provides more effective treatment than either constituent therapy alone in most cases (Carroll et al., 2004b
; Onken et al., 1995
; Stitzer and Walsh, 1997
; Volkow et al., 2004
). Carroll (Carroll et al., 2004b
) however, specifically stated that determinations of optimal behavioral therapy platform-pharmacotherapy combinations should be evidence based, not arbitrarily determined. The process should involve consideration of the specific strengths and weaknesses of the medication, as well as the potential targets of the behavioral therapy platform (Carroll et al., 2004b
). Levodopa's strengths, i.e., safety, tolerability and compliance, are offset by modest direct pharmacotherapeutic effects (Mooney et al., 2007
; Shoptaw et al., 2005
). Still, our finding that a high intensity behavioral therapy platform enhances the pharmacotherapy efficacy provides the evidence for a balanced, tenable therapy combination using the criteria specified by Carroll (Carroll et al., 2004b
). That we did not observe a linear relationship between therapy “dose” or intensity and medication effect suggests that levodopa was effective because of its unique interaction with VBRT. Findings from this trial add to other recent reports showing a significant and specific synergism between contingency management and cocaine pharmacotherapy (Kosten et al., 2003
; Poling et al., 2006
; Schmitz et al., 1998
Although not designed to investigate treatment mechanisms, the trial permits speculation that might direct future research to elucidate the underpinnings of enhanced effectiveness of the levodopa contingency management combination. One explanation comes from recent models of dopamine and reward saliency. Koob and others (Koob and Le Moal, 2001
) have proposed that chronic cocaine use produces persistent diminution of brain reward function, resulting in a condition in which the saliency of drug-related cues far exceeds the saliency value of natural non-drug reinforcers (Ahmed et al., 2002
; Ahmed and Koob, 1998
; Koob and Le Moal, 1997
). Contingency management increases availability of non-drug or environmental reinforcers directly competing with drug use. To the extent that processes related to reward saliency are mediated via dopamine transmission (e.g. Berridge and Robinson, 1998
; Volkow, 2004
), levodopa administration might compensate for dopamine-related deficits and thus enhance saliency of contingently delivered reinforcers, thus improving responsiveness to this behavioral intervention. Conversely, this proposed mechanism suggests that in the absence of alternative reinforcers the therapeutic efficacy of levodopa would be diminished, precisely the observation in the non-voucher conditions. If confirmed as the treatment mechanism, levodopa and other dopamine-augmentation strategies could be used as a way to enhance the efficacy of contingency management.
Early onset of levodopa treatment benefit suggests that it may also attenuate cocaine withdrawal symptoms, necessarily by the same dopaminergic mechanism. This is supported by the decreased self-reported cocaine craving in subjects receiving active medication. Theoretical arguments concerning dopaminergic perturbations contributing to persistent craving have been posited by Gawin, Dackis and others (Dackis and Gold, 1985
; Gawin and Ellinwood, 1988
). Empirical evidence for the perspective comes from McDougle et al. (McDougle et al., 1992
) who, using a levodopa challenge paradigm, demonstrated increased dopamine responsivity during early cocaine abstinence. Wolfsohn (Wolfsohn and Angrist, 1990
) initially reported rapid resolution of abstinence symptoms in 8 patients receiving levodopa on a detoxification unit, but failed to replicate these preliminary results in a later placebo-controlled study (Wolfsohn et al., 1993
). Further studies that include measures of cocaine withdrawal symptoms are needed to clarify the extent to which reduction of withdrawal is a mediator of levodopa's effects on cocaine use.
Interestingly, our study did not find strong and reliable advantages of contingency management procedures relative to the non-voucher therapies. In non-medication studies of behavior therapy for cocaine dependence, the relative advantage of VBRT in reducing cocaine use has been robust (e.g., Higgins et al., 1994
; Higgins et al., 1991
; Rawson et al., 2006
). Possible explanations may have to do with differences in the implementation of VBRT. In the present study contingent rewards were distributed once per week, whereas standard procedures recommend delivery of the earned reinforcer immediately following the target behavior, i.e., urine test results. Given that immediacy of contingent reinforcement is a robust predictor of behavioral response in both human laboratory (Roll et al., 2000
) and treatment research (Lussier et al., 2006
), the delayed procedure used here may have weakened the contingency management effect. Our contingency management procedure also differed in that it was not integrated with the other behavioral interventions (i.e., ClinMan, CBT) but rather delivered in parallel as a standalone intervention. Therapists delivering CBT did not address whether or not their patients were earning voucher rewards, which may have removed an important source of support and encouragement toward achieving targeted behaviors.
As with other cocaine clinical trials, the majority of individuals who began treatment did not complete it. Although we applied current intent-to-treat analytic strategies for handling missing data (Bryk and Raudenbush, 1992
), high rates of attrition can complicate interpretation of true treatment effects (Nich and Carroll, 2002
). In this study, small group sizes, combined with slightly higher retention in the levodopa + VBRT, may have introduced bias in the analysis of certain outcomes, particularly those that rely on length of time in treatment (e.g., continuous abstinence rates). Interpretability of the present findings is further affected by the additive design used in constructing the levels of behavior therapy. Because VBRT was added to a behavioral platform consisting of ClinMan+CBT, the data do not allow conclusions regarding the separate and independent effects of this component. Moreover, we cannot rule out the possibility that better CBT attendance in the VBRT group accounted for observed treatment differences.
Despite limitations of the current study, the results support the inclusion of levodopa into the treatment armamentarium for cocaine dependence, specifically as an adjunctive pharmacotherapy for patients receiving abstinence-based contingency management procedures.