Safety and Tolerability of N‐Acetylcysteine in Cocaine‐Dependent Individuals

Abstract

A double-blind placebo-controlled crossover Phase I trial was conducted to assess the safety and tolerability of N-Acetylcysteine (NAC) in healthy, cocaine-dependent humans. Thirteen participants attended a three-day hospitalization in which they received placebo or NAC. Subjects were crossed over to receive the opposite medication condition during a second three-day hospitalization, which occurred the following week. Across placebo and NAC conditions, only mild side effects were noted, and the number of subjects reporting side effects did not differ. There were trends for a greater reduction in withdrawal symptoms and craving within the NAC condition. These preliminary results suggest that NAC is well tolerated in healthy, cocaine-dependent individuals and may reduce cocainerelated withdrawal symptoms and craving. (Am J Addict 2006;15:105-110) Although overall rates of cocaine use and the number of individuals seeking treatment for cocaine dependence has declined over the last decade, cocaine continues to be the most frequently mentioned illicit drug in drug-related emergency department reports. 1 Cocaine use has been associated with numerous adverse health consequences. 2-4 Crack cocaine use has also been associated with multiple high-risk sexual practices 5 as well as criminal activity. 6 At the present time, there is no effective FDA-approved treatment for cocaine dependence, despite over two decades of intense research. A pharmacological treatment that could serve as an effective adjunct to psychosocial treatment for cocaine dependence would constitute a major public health advancement.Preclinical investigations have suggested that cocaine-seeking behavior is mediated by levels of glutamate within the nucleus accumbens. 7 Specifically, studies have shown that cocaine addiction results in a neuroadaptation characterized by lower basal levels of glutamate in the accumbens. 8 The lower basal level of glutamatergic tone results in an exaggerated release of glutamate within the nucleus accumbens during acute cocaine challenge, which in turn

RepeatedN-Acetylcysteine Administration Alters Plasticity-Dependent Effects of Cocaine

“…The present data reveal that system x c Ϫ represents a novel target capable of preventing plasticity that underlies behaviors used to model aspects of addiction and are consistent with clinical studies indicating efficacy for N-acetylcysteine as an anticraving agent for cocaine addiction (Larowe et al, 2006;Mardikian et al, 2007). Aside from system x c Ϫ, numerous mechanisms may be capable of releasing glutamate into the extrasynaptic compartment including vesicular release from astrocytes (Bezzi et al, 2004;Zhang et al, 2004), nonvesicular release from astrocytic gap junction hemichannels (Ye et al, 2003), volume-sensitive organic anion channels (Strange et al, 1996;Basarsky et al, 1999), or hydrolysis of N-acetylaspartylglutamate (Blakely et al, 1988;Zhou et al, 2005).…”

“…It may seem paradoxical that targeting cystine-glutamate exchange, which increases nonvesicular glutamate, is effective in reducing cocaine-induced behaviors in rodents or drug craving and use in humans because these behaviors require increased glutamate signaling (Cornish and Kalivas, 2000;Baker et al, 2003;Di Ciano and Everitt, 2003;McFarland et al, 2003;Larowe et al, 2006;Mardikian et al, 2007). However, this may reflect the existence of multiple, functionally distinct pools of glutamate.…”

N-acetyl Cysteine Treatment Rescues Cognitive Deficits Induced by Mitochondrial Dysfunction in G72/G30 Transgenic Mice

“…These findings support the hypothesis that oxidative stress caused the spatial learning deficit of G72 transgenic mice. However, NAC also modulates levels of extrasynaptic glutamate (Odlaug and Grant, 2007) and thus stimulates metabotropic glutamate receptors (mGluRs) (Baker et al, 2003;Chen et al, 2010;Lafleur et al, 2006;LaRowe et al, 2006). Although we have not observed any treatment effect in Wt animals, we cannot exclude the possibility that an NAC-induced elevation of extracellular glutamate contributed to the cognitive improvement in G72Tg animals.…”

Oxidative stress in psychiatric disorders: evidence base and therapeutic implications

“…Preclinical evidence has indicated antioxidants to be promising in alcohol (Amanvermez and Agara, 2006), heroin (Zhou and Kalivas, 2007) and cocaine dependence (Baker et al, 2003). Pilot clinical trial data of NAC in cocaine dependence have been promising, suggesting that craving and withdrawal symptoms (LaRowe et al, 2006) as well as cue-evoked desire are reduced with the administration of NAC (LaRowe et al, 2007).…”