Introduction
Drug use is a serious problem worldwide, and global deaths directly related to the use of drugs have been increasing (United Nations Office on Drugs and Crime, 2018). The range of drugs being used illicitly has expanded from heroin and opium to new psychoactive substances (e.g., piperazines) and amphetamine-type stimulants (e.g., methamphetamine; Luo et al., 2018). When used recreationally, methamphetamine leads to increased energy and euphoria, which gives this drug a high potential for abuse and addiction (Panenka et al., 2013). Long-term use of methamphetamine may result in neurotoxic side effects (Long et al., 2017), whereas abuse of this drug has been associated with the shrinkage of the prefrontal cortex and hippocampus damage in the brain, which are related to cognitive disorders (Golsorkhdan et al., 2020; Long et al., 2017). Most previous studies have found that the cognitive function scores of people with methamphetamine addiction are lower than those of healthy controls in the categories of attention, working memory, verbal memory, and executive function (Potvin et al., 2018). Working memory is a temporary and limited storage system for basic information related to other complex tasks (Fattore & Diana, 2016). Executive function refers to be the product of coordinated operation of various processes conducted to achieve specific objectives flexibly (Shuai et al., 2017). Verbal memory refers to the memory of orally expressed information (Kilciksiz et al., 2020).
Studies have shown that the duration required to become addicted to drugs is shorter in women than in men because of the distinct effects of different sex hormones on brain structures (Zhou et al., 2016). Compared with men, women have more difficulty quitting drugs and are more likely to relapse after abstinence (Zhou et al., 2016). Moreover, female methamphetamine users may be more vulnerable to related brain damage, especially in terms of hippocampus-related cognitive disorders (Du et al., 2015). Abuse of methamphetamine in women affects not only their own physical and psychological health but also that of their offspring (Dong et al., 2018). Furthermore, methamphetamine-dependence-related cognitive disorders have frequently been associated with suicidal/violent behaviors (Y. Zhang et al., 2020), which harm the individual users, their families, and the society. Despite the strong evidence supporting the more-potent effects of methamphetamine in women than men (Prakash et al., 2017) and the known negative effects of methamphetamine-induced cognitive impairment on daily functions, no standard treatment is currently available for cognitive impairment in patients with methamphetamine dependence. In addition, few studies have been published on how to effectively improve cognitive function in this population.
The American College of Sports Medicine defines aerobic exercise as to include the wide range of sports that repeatedly and rhythmically use large muscle groups (as cited in Bidonde et al., 2017). It is well documented that exercise not only enhances cardiopulmonary function but also improves brain function (Wilke et al., 2019). Previous studies of the effects of exercise on cognitive function have reported that aerobic exercise programs improve cognitive function in adults with craniocerebral injury (Chin et al., 2015), Type 2 diabetes mellitus (Podolski et al., 2017), and Parkinson's disease (da Silva et al., 2018). Although similar cognitive-function benefits of aerobic exercise have been evidenced in humans and animals (Pietrelli et al., 2018), few studies have been conducted in methamphetamine-dependent populations, with even fewer addressing the subcategory of women. As abusing methamphetamine causes significant harm in women, adopting effective interventions to improve cognitive function in women who abuse methamphetamines is important. In this randomized controlled trial focused on women with methamphetamine dependence enrolled in a detoxification program, aerobic exercise was adopted as the independent variable, and attention, working memory, verbal memory, and executive function were adopted as the dependent variables. The objective of this study was to explore the effects of an aerobic exercise program on cognitive function at two points in time: (a) immediately after completion of the exercise program and (b) at 3 months postintervention.
Methods
Trial Design
This was a randomized controlled trial. Participants were randomly allocated into two groups (1:1), with the study group receiving a 3-month aerobic exercise program in addition to routine medical care in a hospital and the control group receiving routine medical care in a hospital only.
Sample Size
The sample size was calculated using G*Power 3.1.9.7 software, with [alpha] set to .05, power set to 0.9, and the value of effect set to 0.25. Estimating a 20% lost-to-follow-up rate, at least 36 participants were required in each group.
Participants
This study was conducted between December 2016 and October 2018 at a mental hospital in Tianjin, China, where eligible women under detoxification treatment were recruited as participants. Before conducting the intervention, the researchers received professional and unified training and were instructed in the purpose of this study and the inclusion and exclusion criteria in detail. The inclusion and exclusion criteria were evaluated by the researchers using medical records, hospital urine test reports, professional physician diagnoses, and admission assessment reports. Qualified patients were recruited according to their order of hospital admission. Inclusion criteria included (a) being female, (b) age between 18 and 65 years, (c) having a positive methamphetamine urine test result, (d) having received at least 3 months of therapy at the study hospital, (e) having a low-exercise lifestyle (no regular exercise or exercising less than twice weekly), and (f) ability to speak Mandarin and write and read in Chinese. Exclusion criteria included (a) having a physical contradiction that prevents participation such as bone metastases, asthma, hypertension, heart disease, anemia, decreased white blood cell count, imbalance, severe pain, and diabetes mellitus; (b) having other brain-dysfunction-related conditions such as stroke, Alzheimer's disease, dementia, or brain injury; and (c) having serious psychiatric or neurologic sequelae.
Interventions
Aerobic exercise intervention
The aerobic exercise intervention was a supervised, moderate-intensity exercise program conducted in the hospital that was designed jointly by a team of professional rehabilitation therapists, sports coaches, doctors, and nurses. Informed consent was obtained from all of the participants before the intervention. Before the formal intervention, a preexperiment was conducted to ensure the safety of the experimental protocol. An aerobic exercise coach with over 10 years of experience in aerobic exercise practice coached each participant in the movements to ensure the effect of the intervention. In addition, each participant was provided with a guidebook and DVD specially made for the aerobic exercise intervention to help them master the aerobic exercise movements.
The supervision team, which took responsibility for ensuring participant adherence to the intervention, was composed of trained and professional rehabilitation therapists, sports coaches, doctors, and nurses. The doctors and nurses in charge of the patient assumed supervision responsibilities from Monday to Friday to urge the participants to carry out their aerobic exercises in a timely manner. The supervision team also helped ensure participant safety by making sure that participants stopped exercising and received appropriate treatments immediately if they experienced symptoms of discomfort.
The participants attended aerobic exercise sessions in the hospital 5 times every week for 3 months. The study group was divided into three subgroups of 14-16 participants each. At 10 a.m. from Monday to Friday, the participants performed the aerobic exercise intervention at the same time in three spacious rooms. The exercise intervention was not conducted on Saturdays or Sundays. The supervision team visited the three rooms during the intervention sessions to ensure that each participant completed the exercise accurately and similarly.
During each session, the participants completed the whole aerobic exercise under the guidance of the order and sound from the same video made for the aerobic exercise intervention. Each session began with a 5-minute warm-up to ensure exercise safety and lasted for 40 minutes. The participants practiced a series of aerobic exercises for the next 30 minutes, including head movements, shoulder movements, chest movements, waist movements, upper limb movements, and lower limb movements. The sessions ended with 5 minutes of relaxation movements. The participants exercised at a rate that achieved 55%-69% of the maximal heart rate, which could be estimated as the number 220 minus the age of the participant. We used a sports bracelet (model: Mi Band 2) to monitor the heart rate of the participants during each session. Each participant's heart rate reached the ideal heart rate during the intervention.
Routine care group
The participants in the control group received hospital routine care only. Hospital routine care comprised medication care, diet care (nutritional support), health checkup, manual labor (assembling plastic flowers and so on), and discipline education.
Data Collection
Baseline information was collected using face-to-face interviews as soon as the group allocation process was completed. All of the cognitive function tests were administered by a trained neuropsychologist at baseline, immediately after completion of the exercise program (Posttest 1), and 3 months after completion of the intervention (Posttest 2).
Demographic Status
Demographic factors measured in this study included age, educational level, employment status, and marital status. All of the variables except age were categorical.
Clinical Characteristics
Clinical information about methamphetamine abuse included the method of synthetic drug use, daily dose of methamphetamine use, duration of methamphetamine abuse, and duration of abstinence. Cognitive measurements included attention and working memory by Trail Making Test (TMT) and Digit Span Test (DST), verbal memory by Logical Memory (LM) and Memory for Persons Data (MPD), and executive function by Color-Word Stroop Test (CWST).
Attention and Working Memory
DST, designed to measure attention and working memory (Aumont et al., 2019), was derived from the Wechsler Memory Scale-Revised. In the first test, participants were required to recall the numbers forward after being read a series of computer-generated numbers. In the second test, participants were required to recall the same numbers backward. The test finished when participants were not able to recall the digits for two tests in a row. The mean number of the longest span of numbers was recorded as the final score. The test lasted about 5 minutes.
TMT, a subtest of the Wechsler Memory Scale-Third Edition, consists of two parts (TMT-A and TMT-B). TMT-A requires respondents to connect an array of numbers in ascending order in 150 seconds, whereas TMT-B asks respondents to sort an array of numbers and letters in numerical and alphabetical order in 300 seconds. The numbers of correct connections are respectively recorded for the two parts, with lower scores indicating severer cognitive impairment.
Verbal Memory
LM was designed to assess verbal memory from the Wechsler Memory Scale-Third Edition (McDonald et al., 2014). In the LM, respondents are asked to recall a story immediately (LM-I) and once again at 30 minutes (LM-D) after the story was presented. The rate of correctness of the two recalls is recorded.
MPD is also used to assess verbal memory. In the MPD, 15 items are presented. If the respondents are able to immediately recall all of the items correctly in the first two trials, the tests are ended. If this condition is not met, two additional trials are administered until the respondents are able to immediately recall all of the items correctly (MPD-immediate [MPD-1]). After 5 minutes, the respondents are required to recall all of the items (MPD-5 minutes delayed [MPD-2]). After 30 minutes, the delayed recall of respondents is tested (MPD-30 minutes delayed [MPD-D]).
Executive Function
CWST is used to assess executive function. In the CWST, respondents are required to name the color of an incongruent/congruent color word that is written. The number of correct responses (colors named) in 2 minutes is recorded. It is well documented that performance on the CWST correlates with the prefrontal cortex, implicating executive function (Kujach et al., 2018).
Randomization and Blinding
All of the participants in this study were anonymized using codes and randomly assigned (1:1) into the study group or the control group using a computer-generated randomization method. The distribution results were sealed in opaque envelopes by an assistant who was not otherwise involved in this study and turned a blind eye to the identity of the participants.
As the control group did not perform the aerobic exercise, participants could not be blinded to the distribution results. The study group and the control group were assigned to two wards on the second and third floors of the hospital to prevent the two groups from communicating. The researchers, doctors, nurses, rehabilitation therapists, and sports coaches who were involved in the treatment and the intervention were aware of the grouping results of the study. The nurses and doctors involved in treatment received professional training to ensure that the routine care provided to each group was equivalent. The investigator who conducted the baseline information and the neuropsychologist who assessed the cognitive function were specially trained. They did not participate in the intervention and were not aware of the grouping allocation of the participants. In addition, the data analyst was blinded to group assignment.
Ethical Approval
In accordance with the guidance of the ethics committee of the World Health Organization, this study adhered to the relevant rules of the institutional review board and received ethical approval from the Chinese Ethics Committee of Registering Clinical Trials, An-Kang Hospital, and Tianjin Medical University (registration number: ChiCTR-ROC-15006327).
Statistical Analysis
The continuous variables were described statistically in terms of the mean and standard deviation, and the categorical variables were described statistically in terms of proportions. Data were analyzed using SPSS 16.0 (SPSS Inc., Chicago, IL, USA). The demographic and clinical characteristics of the two groups were compared using an independent sample t test for continuous variables and a chi-square test for categorical variables. Scores on the DST, TMT, LM, MPD, and CWST were assessed in accordance with published scoring algorithms. A general linear model repeated-measures analysis of variance was applied to evaluate the effects of the exercise intervention on the cognitive-function variables over 6 months. Time was the within-subject factor, whereas group was the between-subject factor. The result measurement at different time points was taken as the within-subject dependent variables. The main effects for time and group were determined using the three time points (baseline, Posttest 1, and Posttest 2). Sphericity assumed was used to test for a correlation among repetitive measure data. Tests of within-subject comparison were used to analyze the effects of time and the reciprocal action between time and group, and tests of between-subject effects were used to assess the group factors. To prevent false positives, Bonferroni correction was applied to the repeated measurements of paired comparisons (Meng et al., 2020). All of the significance tests were two-sided with a 5% level of significance.
Results
Participants
Of the 108 patients approached, 98 met the inclusion and exclusion criteria and expressed interest to participate. The 10 who did not participate were either ineligible (n = 8) or not interested (n = 2). Reasons for ineligibility included having dyslexia (n = 2), a serious heart disease (n = 1), hypertension (n = 1), severe bone metastases (n = 1), or less than 3 months of scheduled therapy at this hospital (n = 3). Before the formal intervention, the rehabilitation coach gave guidance to each participant on aerobic exercise. Some participants (n = 3) withdrew from the study because of discomfort.
After 3 months, six participants withdrew from the program. The data of the 89 participants (43 in the study group and 46 in the control group) who completed the study were used in the analysis (Figure 1).
As shown in Table 1, most participants had a middle school education (66.3%), were single (79.8%), and were unemployed (78.7%). Regarding drug abuse history, all reported using inhalation/smoking/sniffing. The average methamphetamine abuse time was around 8 years. The statistical tests showed an even distribution of participants across the groups.
Cognitive Outcomes at Baseline
Comparisons of baseline cognitive functioning by DST, TMT, LM, MPD, and CWST scores between the two groups are shown in Table 2. No significant difference was found at baseline in any measure between the two groups (all ps > .05).
Effects of Aerobic Exercise
Attention and working memory
The DST scores of study group participants rose significantly from 7.37 (SD = 1.51) at baseline to 8.63 (SD = 1.20) at completion of the exercise program (Posttest 1) and continued to increase to 9.19 (SD = 1.33) at 3 months after completion of the exercise program (Posttest 2). Postintervention working memory scores as measured by DST were found to be significantly higher in the study group than the control group (F = 5.09, p = .027; Figure 2-A).
A statistically significant difference between the two groups was also found for TMT-A and TMT-B (F = 4.05, p = .047 [Figure 2-B]; F = 4.11, p = .046 [Figure 2-C]). For the study group, there was a rise from 33.23 (SD = 12.16) to 42.14 (SD = 11.90) at Posttest 1 and to 46.19 (SD = 11.38) at Posttest 2 in TMT-A. A similar change was observed for TMT-B as well.
Verbal memory
LM-D performance in the study group began at 28.63 (SD = 12.59) at baseline and increased by about 12 points at Posttest 1 and by another 5 points at Posttest 2, with the magnitude of increase exceeding that of the control group (F = 4.10, p = .046; Figure 2-E).
The study group had significantly better posttest MPD-2 scores (F = 5.62, p = .020) than the control group, improving from 9.74 (SD = 1.58) at baseline to 11.40 (SD = 1.14) at Posttest 1 and to 12.00 at Posttest 2 (SD = 0.93; Figure 2-G). Similar to MPD-2, the study group had significantly improved posttest MPD-D scores, with no significant change observed in the control group (F = 4.81, p = .031). In the study group, MPD-D scores rose from 9.74 (SD = 1.58) at baseline to 11.35 (SD = 1.11) and 11.93 (SD = 1.01) at Posttests 1 and 2, respectively (Figure 2-H). Interestingly, no significant differences in scores between the two groups were found for LM-I (Figure 2-D) and MPD-1 (Figure 2-F).
Executive function
The effect of aerobic exercise on executive function was dramatically greater in the study group than in the control group (F = 4.09, p = .046), with the CWST score in the study group rising from 32.02 (SD = 12.20) at baseline to 42 at Posttest 2 (Figure 2-I).
Discussion
This was the first randomized controlled trial study to explore the effects of aerobic activity on cognitive function in women with methamphetamine dependence and to evaluate changes in these effects over time. The findings of this study are discussed below.
The most significant finding in this study is that the aerobic exercise had significantly beneficial effects on attention, working memory, and executive function and that these beneficial effects were sustained over the 3 months after intervention. This finding was consistent with the outcome from prior animal studies on the effects of exercise (Ghodrati-Jaldbakhan et al., 2017). There are several explanations for the observed changes in attention, working memory, and executive function. First, exercise boosts brain neurotransmitter system efficiency. Neurotransmitters have the function of information transmission among neurons. Brain-derived neutrophil factor (BDNF), which is widely expressed in the hippocampus and cerebral cortex, self-regulates its production during exercise (Walsh & Tschakovsky, 2018). The exercise-induced increase in BDNF levels may enhance attention, working memory, and executive function (de Azevedo et al., 2019; Gokce et al., 2019). Furthermore, insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) may also be increased by exercise (Lin et al., 2018). Second, aerobic exercise may significantly modulate neurogenesis (Rendeiro & Rhodes, 2018). The release of VEGF, BDNF, and IGF is associated with neurogenesis (Ma et al., 2017; Rendeiro & Rhodes, 2018). Neurogenesis induced by aerobic exercise may improve attention, memory, and executive function (Ma et al., 2017). Third, exercise increases synaptic plasticity. VEGF, BDNF, and IGF may significantly mediate synaptic function (Bettio et al., 2019). High levels of neuronal activation may alter the number and composition of membrane receptors as well as the number and shape of dendritic spines, which may change the structural plasticity of the synapse (Rendeiro & Rhodes, 2018). Moreover, enhanced neurogenesis may change the structural plasticity of the synapse (Bettio et al., 2019). Fourth, exercise may irritate vascular proliferation in the hippocampus and cortex (Cooper et al., 2018). VEGF may participate in angiogenesis and change of vascular plasticity (Cooper et al., 2018). Furthermore, aerobic exercise also promotes the perfusion and transportation of oxygen, nutrients, and neurotrophins to regulate the cerebral vascular system and improve brain function (Cooper et al., 2018). Finally, neurogenesis, vascular proliferation, and change of synaptic plasticity may change the structure and function of the brain, including the hippocampus and prefrontal cortex (Nouchi et al., 2014). Memory is closely related to hippocampal function (Olafsdottir et al., 2018), whereas executive function and working memory are closely related to the prefrontal cortex (Kujach et al., 2018; Pietrelli et al., 2018). Therefore, attention, working memory, and executive function are also improved with the improvement of brain structure and brain function.
Another significant finding of this study is that, based on changes in LM-D, MPD-2, and MPD-D, delayed repetition of verbal memory was significantly improved at the conclusion of the aerobic intervention and was sustained for 3 months afterward. In addition, studies of healthy people have shown that people who have exercised for a long time score higher on verbal memory tests (Zhao et al., 2016). This finding may be related to the increase of BDNF level induced by exercise, which may help protect hippocampal volume (Zhao et al., 2016). However, in this study, no significant difference between the study and control groups in terms of immediate repetition of verbal memory was found, with each group showing a rising trend over time, which is attributed to the changes in LM-I and MPD-1. People with methamphetamine-induced brain dysfunction exhibit specific memory disorders, including response inhibition, excessive sensitivity to the influence of interferential stimuli, and difficulties in sustaining attention (Bernhardt et al., 2020; Mizoguchi & Yamada, 2019). The effect found on immediate repetition of verbal memory may be associated with methamphetamine-induced distraction, slow response, and inefficient focus on complex tasks. Further research is necessary to verify the effect of aerobic exercise on verbal memory.
A third significant finding of this study is that cognitive function in the participants improved with duration after withdrawal, as the scores for cognitive function in the control group increased over the 6 months after withdrawal. This finding supports the results of a recent study, which found that methamphetamine-induced cognitive dysfunction would improve somewhat over time after withdrawal (Proebstl et al., 2019). After abstinence, brain functions and structures related to cognitive function improve gradually (Z. Zhang et al., 2018). Therefore, methamphetamine-induced cognitive dysfunction may improve after withdrawal. In addition, the results from this study presented that the rate of improvement in cognitive function resulting from aerobic exercise decreased over the postintervention, 3-month follow-up period. BDNF protein may decrease with time because of the cessation of intervention and the decrease in exercise intensity (Mackay et al., 2017). Moreover, like BDNF, the level of other factors inspired by exercise may decline after cessation of exercise. However, it is encouraging that cognitive function in the study group continued to increase although with a smaller slope until 3 months postintervention. Given the beneficial effects of exercise, the participants may have chosen to continue exercising after the study, resulting in sustained, beneficial effects on cognitive function.
Conclusions
The findings support aerobic exercise as an effective and feasible approach to improving attention, working memory, executive function, and parts of verbal memory in women who are undergoing detoxification for methamphetamine dependence. It is recommended that aerobic exercise be considered as a part of an overall treatment program to facilitate the recovery of cognitive function in these women. Further research is required to prove the long-term efficacy of this treatment and its efficacy on men who abuse methamphetamines.
Study Limitations
Although the abovementioned findings are noteworthy, several limitations should be acknowledged. First, all of the participants were recruited from one hospital in Tianjin City. Thus, the results may not be generalizable to the entire population of women in methamphetamine rehabilitation programs in China or to similar populations in other countries. Second, the cognitive function results in this study may have been affected by subjective factors of the participants, as the control group did not participate in any intervention. However, measures were taken to control contamination between the study group and the control group as much as possible. Third, time was a confounding factor of the effect of aerobic exercise, as the cognitive function of subjects is expected improve with duration of abstinence. Fourth, this study only followed the participants for 6 months in total because of limited resources. Although the positive effect of aerobic exercise on cognitive function in patients was shown over the 6-month study period, the long-term benefits remain unknown. Further research should be conducted to explore the long-term impact of aerobic exercise on cognitive function among the methamphetamine-dependent population as well as other factors that may affect cognitive function in this population.
Implications for Nursing Practice
Clinical doctors and nurses should be conscious of damage to brain structure and function by methamphetamine and of the importance of aerobic exercise for women with methamphetamine dependence. We suggest that healthcare workers be trained in aerobic exercise theory and methods before implementing exercise therapy with patients to provide proper supervision and guidance. In the future, aerobic exercise should be included in the routine care protocol of detoxification programs for women with methamphetamine dependence to improve brain function and increase rehabilitation quality.
Acknowledgments
This study was funded by the Science &Technology Development Fund of Tianjin Education Commission for Higher Education (2017KJ234). The authors are grateful to the staff of the hospital for their great support and contributions to this study. In addition, they are grateful to the study participants for choosing to join this project.
Author Contributions
Study conception and design: SZ, CC
Data collection: CC, ML
Data analysis and interpretation: CC, ML, JL
Drafting of the article: All authors
Critical revision of the article: SZ
References