Evaluation of Naltrexone as a treatment for amphetamine dependence

Abstract: Amphetamine addiction is a disease that affects millions of people worldwide and lacks effective treatment. An estimated 35 million persons are reported to abuse amphetamines, which is more than the total number of cocaine and heroin abusers combined. A majority of intravenous drug users in Sweden abuse amphetamine, pushing this disorder to the forefront of psychiatric problems. At present, there is no approved pharmacotherapy for amphetamine dependence. Several lines of evidence point towards involvement of the endogenous opioid system in the pathophysiology of stimulant addiction. The opioid antagonist naltrexone has shown to modulate some of the behavioral and neurochemical effects of amphetamine in animal models. The aim of this thesis was to investigate naltrexone in humans as a potential pharmacotherapy for the treatment of amphetamine dependence. In the first study, we examined the effect of an acute dose of naltrexone in drugnaïve individuals. Structured batteries of subjective, physiological and behavioral measures were systematically administered to investigate the interaction effect of naltrexone and amphetamine. The results demonstrated that pre-treatment with naltrexone significantly reduces the subjective effects of amphetamine. Pre-treatment with naltrexone had no effect on the physiological and behavioral measures. In the next study, we examined the effect of an acute dose of naltrexone on the subjective, physiological and biochemical effects of amphetamine in dependent individuals, using a double-blind placebo controlled design. Pre-treatment with naltrexone significantly attenuated the subjective effects of amphetamine. In addition, craving for amphetamine was blunted by naltrexone. This data provide the proof-ofconcept that naltrexone not only dampens the subjective effect of amphetamine in the event of drug use, but also decreases the likelihood of additional drug consumption Thereafter, we investigated the effect of chronic treatment with naltrexone in amphetamine dependent individuals, in an open-label design. The aim was to assess the tolerability and compliance to naltrexone in this new population. Twelve weeks of treatment with naltrexone led to a reduction in both frequency and quantity of drug consumption. Overall, the results showed that naltrexone was well tolerated with minimal side effects. Finally, we investigated naltrexone for the treatment of amphetamine dependence in a randomized placebo-controlled trial. Patients either received 12-weeks of treatment with naltrexone or placebo. Twice-weekly urine toxicology tests were performed and in addition patients received weekly relapse prevention therapy. The results indicate that treatment with naltrexone reduced the percentage of amphetaminepositive urine samples in patients with chronic amphetamine dependence. Continued treatment with naltrexone also led to a reduction in craving as compared to placebo. In addition, the medical safety of naltrexone was further confirmed in this population. In conclusion, naltrexone pharmacotherapy significantly reduces the reinforcing effects of amphetamine in acute and chronic dosing models. Taken together, this thesis provides support for the potential use of naltrexone as a treatment for amphetamine dependence.