Retraining the Brain After Chronic Opioid Exposure

Substance use disorders are associated with harm to the brain and its function. Recent research suggests that compromise to these neural/behavioral systems can be improved with cognitive retraining, but few studies have looked at its benefits in opioid use disorder patients. This randomized controlled trial investigated the effects of working memory retraining on cognitive and substance use changes in opioid use disorder patients treated with methadone.


Opioid use disorder is associated with working memory impairment that may persist during pharmacotherapy (e.g., methadone) and abstinence. Working memory is one cognitive function that is shown to be impaired after chronic opioid exposure and is essential for monitoring and regulating other cognitive activities. Specifically, working memory is the ability to temporarily hold and manipulate information in mind (e.g., keeping a phone number conscious while you dial the number) and use that information to facilitate other functions like decision making and selective attention. Those who can hold more information in mind at a given time will be more equipped to solve complex problems and optimally interact with their environment. Cognitive difficulties in these areas predict worse treatment outcomes and increase susceptibility to relapse.

Cognitive retraining might help improve brain function and ultimately aid addiction recovery. Analogous to physical therapy exercises after physical injury, cognitive exercises can help to retrain mental ‘muscles’ and facilitate improvement of function. However, cognitive retraining is a relatively new area of research and few studies have investigated its potential benefits in opioid use disorder patients. To address this gap in the literature, the current study assessed the effects of working memory training on cognitive ability and recovery outcomes in individuals undergoing methadone treatment.


The authors conducted a randomized controlled trial of working memory retraining in 56 individuals receiving methadone treatment for opioid use disorder.


Outpatient methadone clinics were located in Baltimore, Maryland. Ongoing heroin, cocaine, and/or alcohol use was present for most participants. Training occurred over 25 sessions, 3-5 times per week (i.e. for 5-9 weeks). The experimental group (n=28) received working memory retraining exercises that increased in difficulty across the sessions, as their performance improved. An active control group (n=28) received the same set of exercises, but difficulty remained unchanged regardless of their performance.

Neuropsychological tests were used to assess a variety of cognitive functions among experimental and active control groups, prior to working memory training (baseline) and following completion of all working memory training sessions (follow-up). Urinalysis screening was used to compare group changes in the odds of any substance use throughout the study (from baseline to follow-up).


Neuropsychological performance (change after retraining sessions)

The experimental group showed unique improvements in memory-related functions from pre-training to post-training that were not seen in the active control group, including some working memory (i.e. ability to hold on to and manipulate information in short-term memory) and episodic memory (defined here as recall and recognition of previously learned information) tasks. The experimental retraining did not appear to have a significant effect on metamemory (awareness of one’s own memory skills), psychomotor speed (ability to understand incoming information and respond in a timely manner), reasoning (ability to identify patterns, and trends in new information and use it to solve problems), or response inhibition (behavioral self-control).

Substance Use was more improved in the experimental group

Overall, the group that got the working memory training that increased in difficulty had better substance use outcomes than the control group, which got the working memory training that didn’t change in difficulty. Use of any substance (cocaine, opioids, benzodiazepines, & cannabis), as measured by urine toxicology screens, increased over time in the active control group and remained constant in the experimental group. Furthermore, self-report measures of substance use frequency increased in the active control group and decreased in the experimental control group.



Studies like these provide important insight to potential mechanisms for enhancing recovery. A growing literature suggests the positive effects of different types of cognitive retraining techniques for improving recovery from various substance use disorders. Despite the negative effects of chronic heavy opioid use on the brain, this study suggests that brain function can be improved, and that this recovery of function during methadone treatment may be accompanied by better recovery outcomes. Although retraining improved cognitive function, it only did so in domains of cognition that were similar to those taxed in training exercises. More specifically, cognitive rehabilitation of memory-focused functions did not translate to other cognitive areas.

Opioid use disorder is associated with impairment in a broad range of cognitive functions. Retraining exercises that specifically address each function independently via a comprehensive training program may be needed to aptly address these deficits. Nonetheless, this report highlights the potential for cognitive retraining to not only enhance cognitive repair during treatment, but to also support recovery by reducing substance use. Thus, more work is needed to realize the full potential of cognitive retraining programs as adjuncts to existing opioid use disorder therapies, and to determine whether the cognitive improvement itself is responsible for improved recovery outcomes or if other factors explain the findings.

  1. At baseline, participants in the experimental group spent significantly more money on heroin per week. This might point to larger quantities used at each use-occasion and more severe opioid use disorder relative to the control group. Although it is unclear, these differences could potentially result in more room to improve cognitive function and reduce substance use during treatment and recovery.
  2. Although all participants were methadone patients, it is unclear if opioid use disorder was their primary substance use problem. Alcohol use and cocaine use were common among both groups and these substances are associated with unique cognitive consequences. Understanding the different contributions of specific substance use disorders and their interactions will be important for informing individualized treatment and recovery.
  3. On average, participants were in their third month of methadone treatment. Cognitive functions in other domains may have improved across this unassessed three-month period and it is unclear if working memory retraining may have facilitated these cognitive gains. Given that the first months of treatment are sensitive periods of recovery with heightened vulnerability to relapse, additional research is needed in the early stages of treatment to determine the full potential of retraining exercises across many different domains (e.g., attention, decision making, and problem solving in addition to working memory) to benefit treatment retention and recovery trajectories.


  • For individuals & families seeking recovery: Although substance use disorders are accompanied by cognitive impairment, the brain can change again and improve in functioning. While this area of study is in its early stages, it is possible that improvement in cognitive function might enhance addiction recovery progress.  Exercising the brain could help to facilitate this cognitive improvement and help support recovery. More research is needed to develop widely available and effective cognitive retraining therapies, but this line of study shows great promise.
  • For scientists: Cognitive deficits commonly accompany substance use disorders and these impairments can negatively impact recovery processes. This study suggests that cognitive retraining has significant potential to enhance treatment approaches and facilitate successful recovery outcomes, at least in methadone patients. Cognition as a predictor of treatment and recovery outcomes, and as a potential therapeutic target for enhancing long-term outcomes, has been relatively underappreciated in the broader addictions literature. It is important to identify whether different and more comprehensive approaches to cognitive retraining (i.e. training that spans multiple cognitive domains, rather than a single function) can yield added benefits for those seeking substance use treatment. The necessary duration of training needed to reap these benefits, the populations that improve most, and the periods of recovery most sensitive to the effects of retraining require further study. Mediation analyses will also help determine the exact mechanisms that account for improved substance use outcomes after cognitive retraining.
  • For policy makers: Cognitive deficits commonly accompany substance use disorders and these impairments can negatively impact recovery processes. Cognitive retraining has significant potential to enhance treatment approaches and facilitate successful recovery outcomes. Studies like this emphasize the relationship between cognition, treatment, and recovery and extend the therapeutic potential of cognitive training to opioid use disorder patients receiving agonist therapies. Given the societal and personal burden of addiction, additional funding is needed to explore the full extent of cognitive retraining benefits and its application to different substance use disorder cohorts. Investigating therapies like these can ultimately lead to the development of widely available, effective, and relatively inexpensive clinical approaches to addiction treatment.
  • For treatment professionals and treatment systems: Addiction recovery is a complex multidimensional process influenced by a variety of factors. Addiction-related cognitive injury is not only a consequence of chronic heavy substance use, but also a predictor of recovery outcomes. Analogous to physical therapy exercises after physical injury, cognitive exercises can help to retrain mental ‘muscles’ and facilitate improvement of function. Approaching treatment from multiple angles and tackling more than the physiological and psychological dependence accompanying substance use disorders can ultimately benefit patients seeking long-term recovery. Although this line of work is relatively new and standardized validated retraining therapies are not yet widely available, findings like these are encouraging and suggest that engaging patients in cognitive exercises that adapt to baseline skills and their growth might be effective and inexpensive clinical options.


Rass, O., Schacht, R. L., Buckheit, K., Johnson, M. W., Strain, E. C., & Mintzer, M. Z. (2015). A randomized controlled trial of the effects of working memory training in methadone maintenance patients. Drug & Alcohol Dependence, 156, 38-46.