Efficacy of N-acetylcysteine on the Craving Symptoms of Abstinent Hospitalized Patients with Cocaine Addiction

Cocaine abuse is associated with serious physical, psychiatric and social problems. Addiction results in the compulsive use of a substance with loss of control and persistence despite the negative consequences.The act of re-engaging in the search for drugs is called relapse and a particularly insidious aspect of addiction is that vulnerability to relapse lasts for many years after stopping drug use.

The main reason why people continue to use cocaine is because of its influence on the reward system.Indeed, this substance makes it possible to increase the level of dopamine, particularly in the nucleus accumbens.This increase in dopamine is not related to the hedonic pleasure that consumption provides. Instead, it imprints a positive value to enhancers and facilitates the learning of reward associations through the modulation of the cortical and subcortical regions of the brain.In other words, it suggests that users become sensitive to a series of stimuli that combine with a rewarding feeling, which drives them to consume when they encounter them.

Initial investigations regarding the effect of dopamine on the reward system were conducted primarily on the mesolimbic dopaminergic pathway linking the ventral tegmental area to the nucleus accumbens. More recent work has now recognized the role of mesocortical and mesostriatal pathways, but dopamine is far from being the only neurotransmitter involved.

Glutamate also plays a central role in the neuroadaptive changes resulting from chronic exposure to cocaine. Preclinical research has shown that intense exposure to cocaine increases the extracellular level of glutamate in the nucleus accumbens. Cocaine-induced chronic adaptations to glutamatergic homeostasis within the nucleus accumbens include downregulation of the cystine-glutamate (also called xc) exchanger on glial cells and the glial glutamate transporter 1 (GLT-1).

The cystine-glutamate exchanger is an amino acid anti porter that is generally involved in the exchange of extracellular L-cystine (L-Cys2) and intracellular L-glutamate (L-Glu) across the cell plasma membrane. Existing data indicate that these exchanges being diminished, they contribute to abnormal glutamate signaling in the corticostriatal pathway and that these cocaine-induced changes in the Xc system are necessary to restore consumption behavior in the rodent. This imbalance between synaptic and non-synaptic glutamate in the corticostriatal pathway impairs communication between the prefrontal cortex and the nucleus accumbens. As a result, long-term use of cocaine decreases an individual's ability to inhibit the research and consumption behaviors of the product. This results in a relapse syndrome characteristic of addictions.The Xc system would therefore be a potential therapeutic target for the treatment of cocaine addiction.

N-acetylcysteine (NAC) has been used for a long time, mainly as mucolytic. It has also been used as a glutathione antioxidant precursor in the treatment of paracetamol overdose for more than 30 years. NAC has shown beneficial effects in animal models of cocaine addiction by reversing neuroplasticity and reducing the risk of restoring consumer behavior in rodents. One study has even shown that NAC administered to rodents before they consume cocaine prevents the installation of research behavior due to plasticity. Its ability to regulate the activity of the cystine-glutamate antiporter and the biosynthesis of glutathione would be key to its therapeutic efficacy. NAC would also have the ability to reverse the disruption of GLT-1 receptor function. An interesting study has also shown that NAC-treated rats show an attenuation of dopamine increase in the nucleus accumbens when cocaine is taken, which deserves further investigation.

Four studies showed NAC's potential to reduce craving, desire to consume, and cocaine search in abstinent consumers. However these studies present only preliminary data because the samples are not large enough and they are mostly open studies (participants are informed about the nature and dosage of the medication, without placebo group). A more recent study of a larger sample of subjects still actively using cocaine found that NAC reduces craving and increases time to relapse only in a small subset of subjects who are already abstinent, particularly with the highest doses.This study was a double blind study with a placebo group. This suggests that NAC is potentially effective in preventing relapse in abstinent patients and ineffective in reducing current consumption.

A question that arises is the frequency with which NAC should be administered. In the majority of the studies cited above, the product was administered several times over a shorter or longer period. However, studies have shown that a single dose (2400 mg on a human) can have measurable neurochemical effects, although it is not clear that these changes are sufficient to produce measurable changes in behavior.Clinical trials have used doses ranging from 1200 to 3600 mg daily for varying periods of time, and further studies would also be needed to determine the optimal amount to avoid a relapse.

The latest study on the subject suggested that NAC may be useful for preventing relapse of abstinent patients rather than reducing the consumption of patients still taking cocaine. However, this effect was not part of the main assumptions and was highlighted in additional exploratory analyzes. The vast majority of patients in this study were therefore not abstinent.

In this study, therefore, the investigators will only test a sample of newly detoxified (and therefore abstinent) patients who have taken a 3-4 week course of treatment, in order to increase the power of the analyzes and determine if NAC can be a useful medication candidate to avoid relapse in patients with cocaine dependence.