Treating cocaine dependence by targeting underlying cognitive processes

Dual process models posit that there is a competition between two qualitatively
different processing systems that contribute to behavior. Reflective processes
include emotion regulation and conscious deliberations, while impulsive
processes include automatic appraisals of stimuli in terms of motivational
significance and automatic stimulus-response associations. An imbalance between
these processing types has been proposed to play an important role in
addiction, characterized by an imbalance between a relatively dysfunctional
reflective system and a hyperactive impulsive system. These processes have been
investigated in cocaine users, in some studies with neuroimaging. Investigating
underlying neural processes is important because it can explain changes in
neurocognitive performance. Furhtermore, these processes appear to predict
relapse.
In chronic cocaine users, it was found that WM performance was worse compared
to controls and that this was associated with years and quantity of use. When
performing WM tasks during fMRI, attenuated responses in prefrontal and
cingulate cortices, and striatal regions were found. Using a Stroop task, it
was found that cocaine users show increased attentional bais for
cocaine-related words. The underlying neural processes of this increased
motivation can be investigated using cue reactivity tasks during functional
magnetic resonance imaging (fMRI). Higher brain activation in several regions
as a response to cocaine-related compared to neutral stimuli have been found in
cocaine dependents.

When automatic impulses interfere with personal goals, impulses need to be
overridden to achieve that goal. This ability is refered to as executive
functioning. Deficits in executive functioning are associated with several
substance use disorders and dependencies. Therefore, cognitive control
processes are a plausible target in the treatment of substance addiction. For
instance, chronic alcohol users show lower levels of working memory (WM), and
it has been found that WM training improved working memory, but also reduced
alcohol intake for more than 1 month after training in problem drinkers. One
recent study tested WM-training in stimulant abusers and found that training
reduced cognitive impulsivity (delay discounting). Taken together, these
findings suggest that WM-training can strengthen the reflective system in
cocaine abusers.

One way to decrease the impact of the hyperactive impulsive system is by using
an approach bias training, for which positive clinical effects have been found
in alcoholic patients. However, effects on craving were minimal and this method
has not been tested in cocaine abusers. Craving is an important predictor of
relapse, therefore it is important to know how it is manifested during
treatment. A promising drug for treating substance use disorder by diminishing
craving is N-acetylcysteine (NAC). NAC is an amino acid cystine prodrug. NAC
treatment normalizes glutamate homeostasis, of which its role in the
continuation of and relapse into substance abuse has been highlighted. NAC
administration prevents relapse to drug-seeking behavior in rats treated with
cocaine. In humans, pilot studies have shown that NAC decreases cue-induced
craving for cocaine, the rewarding effect of smoking, and marijuana use and
craving.

The objective of this study is to investigate the effectivity on reducing or
cessation of cocaine use of 1) working memory training, 2) N-acetylcysteine, 3)
the combination of working memory training and N-acetylcysteine. Clinical
measures (cocaine use, craving, impulsivity) and brain processes (cue
reactivity, working memory related activation, and glutamate homeostasis) are
investigated.

To study the efficacy of working memory training and/or N-acetylcysteine, a
dubble blind, randomised, placebo controlled study will be performed.
Participants are randomly assigned to 1 of 2 conditions:

1) working memory training + N-acetylcysteine
2) working memory training + placebo


Several baseline and post-treatment measures will be obtained. Measurements
will also be obtained during treatment by means of ecological momentary
assessment (EMA), to monitor craving and cognitive functioning at home.
Furthermore, brain activation patterns underlying the cognitive processes and
brain glutamate concentrations will be assessed before and after treatment to
investigate their mediating role in the alteration of cognitive processes
underlying cocaine addiction and, hence, the effectiveness of treatment.

25 men receive 25 days of working memory training and 2400 mg N-acetylcysteine
per day
25 men receive 25 days of working memory training and placebo


Before and after this 25-day period, there is another assessment during which
they fill out questionnaires, perform computer tasks and undergo the MRI
protocol.

Participants will come to the study location twice. During these visits, which
will take 3 hours, they fill out questionnaires, perform computer tasks and
undergo the MRI protocol. Between these two visits is a 25-day period, during
which exists of three components.

1) working memory training
Subjects will train online once daily. The training exists of three different
tasks and is performed at home on a pc.

2) N-acetylcysteine or placebo
Subjects will take N-acetylcysteine (2400 mg/day) or placebo twice daily

3) Ecological momentary assessment
At least twice daily, subjects answer several demographic questions (what they
used that they, current location, mood) and indicate how much craving they
experience. Subsequently, they perform a cocaine Stroop task to measure their
attentional bias.

Risks:
The risks concerning the MRI scanner are negligible. Also, the risks concerning
the N-acetylcysteine are negligible. Several studies have been conducted on the
tolerance of similar and higher doses of N-acetylcysteine.