Psychostimulant dependence is a major public health issue in many parts of the world associated with a wide range of psychological, medical and social problems. Psychosocial interventions are the mainstay of treatment for psychostimulant problems, although their effectiveness is compromised by poor uptake and compliance. Despite increasing knowledge of the neurobiological consequences of psychostimulant use, no medications to date have been any more successful than placebo in reducing psychostimulant use in dependent patients. Modafinil is a non-amphetamine type psychostimulant that may have potential as an agonist pharmacotherapy for psychostimulant dependence. The aim of this thesis was to examine the safety, efficacy and cost-effectiveness of modafinil 200 mg/day over ten weeks plus a four session brief CBT intervention for methamphetamine and cocaine dependence through two concurrent randomised placebo controlled trials. There were no statistically significant differences between modafinil and placebo in treatment retention, medication adherence, psychostimulant abstinence, psychostimulant craving or severity of psychostimulant dependence. Methamphetamine-dependent subjects tended to provide more illicit psychostimulant negative urine samples while in treatment than those who received placebo. There appeared to be a reduction in self-reported days of psychostimulant use among methamphetamine-dependent subjects who received modafinil compared to placebo, but the effect size was too small to be statistically significant in this sample. The reduction in self-reported psychostimulant use did reach statistical significance in methamphetamine-dependent subjects with no other substance dependence. Uptake of counselling was the most significant predictor of reduced psychostimulant use post treatment, and the addition of counselling improved the cost-effectiveness of modafinil relative to placebo. Modafinil appeared to be safe, well-tolerated, and non-reinforcing in this treatment population. Compared to placebo, there was a significant increase in weight in subjects who completed the 10-week course of treatment, and a significant decrease in systolic blood pressure in methamphetamine-dependent subjects who received modafinil. The results support further trials of modafinil in methamphetamine-dependent patients, although future trials in cocaine-dependent patients from this treatment population were not likely to be viable. Modafinil appeared to be modestly effective in reducing, but not stopping, methamphetamine use in selected patients. Multi-centre trials with larger sample sizes, and measures sensitive enough to detect quantitative changes in psychostimulant use would be needed to confirm the findings. Blood pressure and weight may be important indicators of clinical outcome, and warrant particular attention in future trials, particularly given the cardio-toxicity of both methamphetamine and cocaine. Strategies to enhance medication adherence including a higher dose and counselling adherence are recommended to improve outcomes. Given the predominance of behavioural and psychosocial factors in psychostimulant dependence, it is likely that the role of medications such as modafinil will be as an adjunct to psychosocial therapy.

Psychostimulant dependence is a major public health issue in many parts of the world associated with a wide range of psychological, medical and social problems. Psychosocial interventions are the mainstay of treatment for psychostimulant problems, although their effectiveness is compromised by poor uptake and compliance. Despite increasing knowledge of the neurobiological consequences of psychostimulant use, no medications to date have been any more successful than placebo in reducing psychostimulant use in dependent patients. Modafinil is a non-amphetamine type psychostimulant that may have potential as an agonist pharmacotherapy for psychostimulant dependence. The aim of this thesis was to examine the safety, efficacy and cost-effectiveness of modafinil 200 mg/day over ten weeks plus a four session brief CBT intervention for methamphetamine and cocaine dependence through two concurrent randomised placebo controlled trials. There were no statistically significant differences between modafinil and placebo in treatment retention, medication adherence, psychostimulant abstinence, psychostimulant craving or severity of psychostimulant dependence. Methamphetamine-dependent subjects tended to provide more illicit psychostimulant negative urine samples while in treatment than those who received placebo. There appeared to be a reduction in self-reported days of psychostimulant use among methamphetamine-dependent subjects who received modafinil compared to placebo, but the effect size was too small to be statistically significant in this sample. The reduction in self-reported psychostimulant use did reach statistical significance in methamphetamine-dependent subjects with no other substance dependence. Uptake of counselling was the most significant predictor of reduced psychostimulant use post treatment, and the addition of counselling improved the cost-effectiveness of modafinil relative to placebo. Modafinil appeared to be safe, well-tolerated, and non-reinforcing in this treatment population. Compared to placebo, there was a significant increase in weight in subjects who completed the 10-week course of treatment, and a significant decrease in systolic blood pressure in methamphetamine-dependent subjects who received modafinil. The results support further trials of modafinil in methamphetamine-dependent patients, although future trials in cocaine-dependent patients from this treatment population were not likely to be viable. Modafinil appeared to be modestly effective in reducing, but not stopping, methamphetamine use in selected patients. Multi-centre trials with larger sample sizes, and measures sensitive enough to detect quantitative changes in psychostimulant use would be needed to confirm the findings. Blood pressure and weight may be important indicators of clinical outcome, and warrant particular attention in future trials, particularly given the cardio-toxicity of both methamphetamine and cocaine. Strategies to enhance medication adherence including a higher dose and counselling adherence are recommended to improve outcomes. Given the predominance of behavioural and psychosocial factors in psychostimulant dependence, it is likely that the role of medications such as modafinil will be as an adjunct to psychosocial therapy.