Critique 275 – Recovery of neuropsychological function following abstinence from alcohol in adults diagnosed with an alcohol use disorder: Systematic review of longitudinal studies

Authors

Powell A; Sumnall H; Smith J; Kuiper R; Montgomery C

Citation

PLoS ONE (2023) https://doi.org/10.1371/journal.pone.0296043

Author’s Abstract

Background Alcohol use disorders (AUD) associate with structural and functional brain differences,including impairments in neuropsychological function; however, reviews (mostly cross-sectional)are inconsistent with regards to recovery of such functions following abstinence.Recovery is important, as these impairments associate with treatment outcomes and qualityof life.

Objective(s) To assess neuropsychological function recovery following abstinence in individuals with a clinical AUD diagnosis. The secondary objective was to assess predictors of neuropsychological recovery in AUD.

Methods Following the preregistered protocol (PROSPERO: CRD42022308686), APA PsycInfo, EBSCO MEDLINE, CINAHL, and Web of Science Core Collection were searched between 1999–2022. Study reporting follows the Joanna Briggs Institute (JBI) Manual for Evidence Synthesis, study quality was assessed using the JBI Checklist for Cohort Studies. Eligible studies were those with a longitudinal design that assessed neuropsychological recovery following abstinence from alcohol in adults with a clinical diagnosis of AUD. Studies were excluded if participant group was defined by another or co-morbid condition/injury, or by relapse. Recovery was defined as function reaching ‘normal’ performance.

Results Sixteen studies (AUD n = 783, controls n = 390) were selected for narrative synthesis. Most functions demonstrated recovery within 6–12 months, including sub-domains within attention, executive function, perception, and memory, though basic processing speed and working memory updating/tracking recovered earlier. Additionally, verbal fluency was not impaired at baseline (while verbal function was not assessed compared to normal levels), and concept formation and reasoning recovery was inconsistent.

Conclusions These results provide evidence that recovery of most functions is possible. While overall robustness of results was good, methodological limitations included lack of control groups, additional methods to self-report to confirm abstinence, description/control for attrition, statistical control of confounds, and of long enough study durations to capture change.

Forum comments

Alcohol use disorder (AUD) is a medical condition characterized by an impaired ability to stop or control alcohol consumption despite adverse social, occupational, or health consequences. It encompasses the conditions that some people refer to as alcohol abuse, alcohol dependence, alcohol addiction, and the colloquial term, alcoholism. Considered a brain disorder, AUD can be mild, moderate, or severe.  It results from the neurotoxicity of alcohol in a chronic high consumption pattern and represents a significant public health challenge globally from an increasingly large burden of disability and mortality (Rehm & Shield, 2013, Grant et al. 2015, Rehm et al., 2015). Indeed, AUD is among the most prevalent of all substance use disorders worldwide (Holt, 2024), duly emphasizing the need for comprehensive understanding and effective interventions.

In individuals with AUD, common visible brain changes occur across structure and function, including within neurotransmitter and metabolic systems (Bühler & Mann, 2011), grey and white matter, and event-related potential markers of attentional capacity (Hamidovic & Wang, 2019). Associated with these brain changes is the impairment of neuropsychological functions which adversely affect quality of life. These functions include inhibition, set-shifting, working memory, problem solving, planning, attention, reasoning/abstraction, processing speed, visuospatial abilities, verbal memory, verbal learning, verbal fluency, visual memory, visual learning and intelligence (Stephan et al., 2017, Bora & Zorlu, 2017). These functional impairments translate into problems at work (e.g., not meeting job requirements), elevated risk of injuries (e.g., endangerment or traffic accidents) and negative consequences in social and family contexts (e.g. neglect of social relationships, aggression toward family members) (Rehm, 2011).

Therefore, the recent systematic review published in PLoS ONE (Powell et al., 2024) which aims to understand whether these with multiple neuropsychological impairments can recover with abstinence is considered important. The paper describes an extensive review of longitudinal studies performed between 2007 and 2023 on recovery of neuropsychological functions during one of possible interventions, namely abstinence following AUD. A similar review (Schulte et al., 2014) was published ten years ago and another smaller review in 2020 (Nixon & Lewis 2020), both of which suggest a reduction in impairment following the initiation of abstinence especially in early weeks of abstinence, with some continuing recovery in later months. Therefore, an updated version with the most recent literature has been needed.

Recovery from AUD is a complex and multifaceted process that involves addressing various physical, psychological, and social aspects of the disorder. Key points regarding recovery from AUD include acknowledging the presence of the disorder and accepting the need for change. Treatment options may include medical interventions, psychotherapy, support groups such as Alcoholics Anonymous (AA), and residential rehabilitation programs. Overall, recovery from AUD is a journey that requires determination, support, and perseverance. Individuals can achieve and maintain sobriety, leading to improved health, relationships, and overall well-being.

The authors of this important systematic review chose to use longitudinal studies because cross-sectional studies provided contradictory results. In their introduction the authors refer two such papers. Although methodologically similar, both reviews of primarily cross-sectional literature, were contradictory: the one study concluding that all assessed domains recovered by a year of abstinence (Stavro et al., 2013), and the other that there was a wide range of continued impairment at this stage (Crowe et al., 2019). Cross-sectional studies and their design flaws may confound other relationships in alcohol research such as the associations between alcohol consumption, abuse and health outcomes in adolescents  Hendriks & Schrieks, 2015, Yaogo et al., 2015).

The Forum specifically supports the authors’ choice to use longitudinal studies only. A cross-sectional approach has the advantage of being able to conclude within a reasonably short study period, but a cross-sectional design has numerous flaws. These flaws include the improbability to enable for all pre-existing differences in the populations of study, e.g. other traits associated with the abuse, genetic factors, family history, etcetera. In the longitudinal design each person is his/her own control. Also, causality of the factor abstinence after long-term alcohol abuse may be more likely to be involved in the outcome parameters studied, because it is monitored for a longer time, excluding those that relapse and excluding those that start abusing alcohol after being abstinent for some time.

The conclusion of this impressive systematic review is surprising, namely that recovery of most functions in AUD is possible. Overall, sub-domains within attention, executive functions, perception, and memory, generally demonstrate recovery between six to 12 months, though basic processing speed recovers within a month, and working memory updating/tracking as early as 18 days, while verbal function demonstrated improvement within a month, but was likely unimpaired to start with. Of course, the brain and human behaviour is extremely flexible, but it still is essential to substantiate that notion with high quality scientific research. It is not only relevant for those treating individuals with AUD. Those seeking treatment should also be reassured that most neuropsychological functions will be restored, although it may take time.

Unfortunately, this review concerns a narrative systematic review. A meta-analytic approach may have offered the opportunity to quantify the recovery of these neuropsychological functions over time. Such a quantification would have been helpful as well. The authors, however, mention that such an approach is currently not possible due to the large numbers of domains and subdomains studied and the vast number of different tests applied in this research area.

Yet, another strength of this study is that the authors have worked following a previously published peer-reviewed protocol (Powell et al., 2022) allowing external independent reviewers to evaluate and improve the protocol proposed. Also, for all studies included a comparator (a control group) was required, in the form of adults aged 18–64 without AUD, adults with a different severity of AUD, or abstinence duration assessed using regression techniques. The control group of adults aged 18-64 without AUD was the control group used in the majority of studies included.

The role of smoking is interesting. Although research on smokers recovering from AUD were included in this systematic review smoking appeared to be a risk factor for full recovery. Studies on smokers were included only when alcohol use disorder was the primary substance use disorder and smoking was not or at best secondary. Several studies have shown that smoking is associated with poorer recovery in multiple neurocognitive domains following treatment for AUD (Durazzo & Meyerhoff, 2020). In those studies, chronic smoking was associated with multiple neurobiological abnormalities in otherwise healthy controls. So, non-smoking AUD recoverees may possess greater neurobiological and neurocognitive resiliency to the adverse consequences of AUD.

We agree with the authors that future research should consider the impacts of identified predictors, like smoking and age, as these may explain some of the variance across the literature. Large scale prospective studies will be needed, because only these studies will develop our understanding of function recovery after abstinence and elucidate what functional differences between individuals with and without AUD may be pre-existing or cyclical.

Specific Comments from Forum Members

Forum member Skovenborg considers that “the findings of two Danish studies, examining brains of alcoholics and controls with stereological techniques, do not support the belief that alcohol dementia results from neocortical nerve-cell death since there was no difference in total neocortical neuron number in the alcoholic and control groups. The study by Jensen & Pakkenberg (1993) found significant reductions in alcoholics compared with controls of the volume/weight ratios of white matter (11%).  The coating of myelin around axons, the myelin sheath, protects the axons and helps speed nerve transmissions. If the myelin sheath is damaged, these nerve signals will travel more slowly or be blocked completely. The selective loss of white matter may cause impaired function due to malfunctional axons.

The study by Korbo (1999) found a statistically significant loss of 37% of the glial cells globally in the hippocampus of the alcoholics compared with controls while no loss of neurons was found in the hippocampus from alcoholics. The results suggest that the observed brain damage in the alcoholic group is potentially reversible since preserved nerve-cell bodies might allow lost or malfunctioning axons to re-established and lost glial cells in the hippocampus replaced with a restored cognitive function as a result after prolonged abstinence.

Several imaging studies found evidence for partial brain recovery with abstinence. Ron et al. (1982) examined one hundred male alcoholics from an inpatient treatment unit by computerized axial tomography. All were without clinically overt signs of brain damage. Fifty age-matched normal volunteers were used for comparison. Radiological indices differed markedly between the two groups, reflecting a high incidence of cortical shrinkage and ventricular dilatation among the alcoholics. The results of follow-up with rescanning indicated that abstinence was strongly related to slow partial resolution of the computerized tomographic (CT) scan changes.

In an assessment of alcoholic brain damage by CT scanning Carlen et al. (1986) found greater cerebral atrophy in alcoholics than aged-matched neurological controls. The cerebral atrophy reversed in some subjects with maintained abstinence: Computerized assessment of cerebral spinal fluid volume (cerebral atrophy) and mean cerebral density showed decreased cerebral spinal fluid volume and increased cerebral density with maintained abstinence over four weeks in a group of 20 alcoholics

Bartsch et al. (2007) investigated global and local brain volume changes in a longitudinal two-timepoint study with T1-weighted MRI at admission and after short-term (6–7 weeks) sobriety follow-up in 15 uncomplicated, recently detoxified alcoholics. Their findings emphasize metabolic as well as regionally distinct morphological capacities for partial brain recovery from toxic insults of chronic alcoholism and substantiate early measurable benefits of therapeutic sobriety suggesting that even the adult human brain and particularly its white matter seems to possess genuine capabilities for regrowth.

Forum member Ellison states that “this is a very important topic but one that is especially difficult to study.  The baseline values of cognitive functions are obviously the key measurements for such analyses, and I am not able to judge whether evaluations performed immediately after stopping alcohol intake (such as baseline studies obtained after 0-2 days) can be compared with those recorded several days or weeks after the beginning of abstinence.  And it is difficult to judge how well each study confirmed no alcohol use during follow up.” 

Concluding comments

As suggested by Forum member Ellison, this well-executed systematic review of longitudinal studies undertaken by Powell et al. (2023) indicates improvement in a number of key cognitive functions and support many previous studies.  Together, these studies provide data that should strengthen efforts by physicians treating patients with alcohol use disorders to encourage their attempts to stop abusive drinking. Furthermore, this promising information should provide clinicians with a message that should encourage more people with AUD to accept treatment. 

References

Bartsch, A.J., Homola, G., Biller, A., Smith, S.M. et al. (2007) Manifestations of early brain recovery associated with abstinence from alcoholism. Brain, 130(Pt 1):36-47.

Bora, E., & Zorlu, N. (2017) Social cognition in alcohol use disorder: a meta‐analysis. Addiction, 112(1):40–8. https://doi.org/10.1111/add.13486

Bühler, M., & Mann, K. (2011) Alcohol and the human brain: a systematic review of different neuroimaging methods. Alcohol Clin Exp Res, 35(10):1771–93. https://doi.org/10.1111/j.1530-0277.2011.01540.x

Carlen, P.L., Penn, R.D., Fornazzari, L., Bennett, J. et al. (1986) Computerized tomographic scan assessment of alcoholic brain damage and its potential reversibility. Alcohol Clin Exp Res, 10(3):226-32.

Crowe, S. F., Cammisuli, D. M., & Stranks, E. K. (2019). Widespread cognitive deficits in alcoholism persistent following prolonged abstinence: An updated meta-analysis of studies that used standardised neuropsychological assessment Ttools. Archives of Clinical Neuropsychology: The Official Journal of the National Academy of Neuropsychologists, 35(1), 31–45. https://doi.org/10.1093/arclin/acy106

Durazzo, T. C., & Meyerhoff, D. J. (2020). Cigarette smoking history is associated with poorer recovery in multiple neurocognitive domains following treatment for an alcohol use disorder. Alcohol (Fayetteville, N.Y.), 85, 135–143. https://doi.org/10.1016/j.alcohol.2019.12.003

Grant, B.F., Goldstein, R.B., Saha, T.D., Chou, S.P., Jung, J., Zhang, H., Pickering, R.P., Ruan, W.J., Smith, S.M., Huang, B., Hasin, D.S. (2015) Epidemiology of DSM-5 Alcohol Use Disorder: Results from the National Epidemiologic Survey on Alcohol and Related Conditions III. JAMA Psychiatry 72, 757–766. https://doi.org/10.1001/jamapsychiatry.2015.0584.

Hamidovic, A., & Wang, Y. (2019) The P300 in alcohol use disorder: A meta-analysis and meta-regression. Prog Neuropsychopharmacol Biol Psychiatry, 95:109716. https://doi.org/10.1016/j.pnpbp.2019.109716

Hendriks, H. F. J., & Schrieks, I. C. (2015). Adolescent alcohol consumption: brain health outcomes. J Child & Adolesc Behav, 3(238). https://doi.org/http://dx.doi.org/10.4172/2375-4494.1000238

Holt, S.R. (2024) Alcohol use disorder: pharmacologic management. UpToDate; https://www.uptodate.com/contents/alcohol-use-disorder-pharmacologic-management

Jensen, G.B., & Pakkenberg, B. (1993) Do alcoholics drink their neurons away? Lancet, 342(8881):1201-4.

Korbo, L. (1999) Glial cell loss in the hippocampus of alcoholics. Alcohol Clin Exp Res, 23(1):164-8.

Nixon, S.J., & Lewis, B. (2020) Brain Structure and function in recovery. Alcohol research: Current Reviews. 40(3): 04. https://arcr.niaaa.nih.gov/volume/40/3/brain-structure-and-function-recovery

Powell, A., Sumnall, H., Smith, J., Kuiper, R., & Montgomery, C. (2022). Recovery of neuropsychological function following abstinence from alcohol in  adults diagnosed with an alcohol use disorder: Protocol for a systematic review of longitudinal studies. PloS One, 17(9), e0274752. https://doi.org/10.1371/journal.pone.0274752

Powell, A., Sumnall, H., Smith, J., Kuiper, R., & Montgomery, C. (2024). Recovery of neuropsychological function following abstinence from alcohol in adults diagnosed with an alcohol use disorder: Systematic review of longitudinal studies. PloS One, 19(1), e0296043. https://doi.org/10.1371/journal.pone.0296043

Rehm, J. (2011) The risks associated with alcohol use and alcoholism. Alcohol Res. Heal, 34, 135–143.

Rehm, J. & Shield, K.D. (2013) Global alcohol-attributable deaths from cancer, liver cirrhosis, and injury in 2010. Alcohol Res, 35, 174–183.

Rehm, J., Anderson, P., Barry, J., Dimitrov, P., Elekes, Z., Feijão, F., Frick, U., Gual, A., Gmel, G. Jr., Kraus, L., Marmet, S., Raninen, J., Rehm, M.X., Scafato, E., Shield, K.D., Trapencieris, M., & Gmel, G. (2015) Prevalence of and potential influencing factors for alcohol dependence in Europe. Eur. Addict. Res. 21, 6–18.

Ron, M.A., Acker, W., Shaw, G.K., & Lishman, W.A. (1982) Computerized tomography of the brain in chronic alcoholism: a Survey and follow-up study. Brain, 105 (Pt 3):497-514.

Schulte, M. H. J., Cousijn, J., den Uyl, T. E., Goudriaan, A. E., van den Brink, W., Veltman, D. J., Schilt, T., & Wiers, R. W. (2014). Recovery of neurocognitive functions following sustained abstinence after substance dependence and implications for treatment. Clinical Psychology Review, 34(7), 531–550. https://doi.org/10.1016/j.cpr.2014.08.002

Stavro, K., Pelletier, J., & Potvin, S. (2013). Widespread and sustained cognitive deficits in alcoholism: a meta-analysis. Addiction Biology, 18(2), 203–213. https://doi.org/10.1111/j.1369-1600.2011.00418.x

Stephan, R.A., Alhassoon, O.M., Allen, K.E., Wollman, S.C., Hall, M., Thomas, W.J., et al. (2017) Meta-analyses of clinical neuropsychological tests of executive dysfunction and impulsivity in alcohol use disorder. Am J Drug Alcohol Abuse. 43(1):24–43. https://doi.org/10.1080/00952990.2016.1206113

Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. 2022 National Survey on Drug Use and Health: Table 5.9B – Alcohol Use Disorder in Past Year: Among People Aged 12 or Older; by Age Group and Demographic Characteristics, Percentages, 2021 and 2022. https://www.samhsa.gov/data/report/2022-nsduh-detailed-tables

WHO. (2018). Global status report on Alcohol and Health – 2018. https://www.who.int/publications/i/item/9789241565639

Yaogo, A., Fombonne, E., Lert, F., & Melchior, M. (2015). Adolescent Repeated Alcohol Intoxication as a Predictor of Young Adulthood Alcohol Abuse: The Role of Socioeconomic Context. Substance Use & Misuse, 50(14), 1795–1804. https://doi.org/10.3109/10826084.2015.1058824

Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members:

Henk Hendriks, PhD, Netherlands

Creina Stockley, PhD, MBA, Independent consultant and Adjunct Senior Lecturer in the School of Agriculture, Food and Wine at the University of Adelaide, Australia

R. Curtis Ellison, MD, Section of Preventive Medicine/Epidemiology, Boston University School of Medicine, Boston, MA, USA

Erik Skovenborg, MD, specialized in family medicine, member of the Scandinavian Medical Alcohol Board,  Aarhus, Denmark

Richard Harding, PhD, Formerly Head of Consumer Choice, Food Standards and Special Projects Division, Food Standards Agency, UK

Tedd Goldfinger, DO, FACC, Desert Cardiology of Tucson Heart Center, University of Arizona School of Medicine, Tucson, AZ, USA

Andrew Waterhouse, PhD, Department of Viticulture and Enology, University of California, Davis.