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Recovery of cognitive functioning following abstinence from ketamine
Addictive Behaviors 99 (2019) 106081
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Recovery of cognitive functioning following abstinence from ketamine a,⁎
a
b,c
Wai Kwong Tang , Chieh Grace Lau , Gabor S. Ungvari , Shih-Ku Lin
d,e
, Hsien-Yuan Lane
f,g,h
T
a
Department of Psychiatry, The Chinese University of Hong Kong, Hong Kong, China Division of Psychiatry, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia Section of Psychiatry, University Notre Dame Australia, Fremantle, Australia d Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan e Department of Psychiatry, Taipei City Hospital, Taipei, Taiwan f Department of Psychiatry, China Medical University Hospital, Taiwan g Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan h Department of Psychology, College of Medical and Health Sciences, Asia University, Taichung, Taiwan b c
HIGHLIGHTS
cognitive improvements were found in visual and verbal memory. • Significant in executive functions improved after abstinence of ketamine. • Performance • Cognitive deficits might be reversed following 12-week of ketamine abstinence. ARTICLE INFO
ABSTRACT
Keywords: Abstinence Cognition Ketamine Recovery
Background: Acute and adverse effects of ketamine on cognitive functioning have been documented. No longitudinal study has examined whether cognitive deficits can be reversed following ketamine abstinence although it has been suggested in some cross-sectional studies. This study aimed to investigate the changes in cognitive functioning among ketamine users following a 12-week abstinence from ketamine. Methods: In this longitudinal study, 114 ketamine users completed clinical and cognitive assessments at both baseline and 12-week follow-up with the following instruments: Severity of Dependence Scale, Beck Depression Inventory (BDI), Anxiety Subscale of the Hospital Anxiety Depression Scale (HADSA), and a cognitive battery. Results: BDI (p < 0.001) and HADSA (p = 0.044) scores were significantly reduced at the 12-week follow-up. Significant improvements were found in Wechsler Adult Intelligence Scale (Third edition) immediate recall (p < 0.001) and delayed recall (p < 0.001) on the Rey-Osterrieth Complex Figure Test, and in delayed recall (p < 0.001), and immediate recall (p = 0.001) on the Logical Memory component of the Wechsler Memory Scale (Third Edition) at the 12-week follow-up. Participants completed the Stroop Inference Test significantly faster (p < 0.001); and required fewer number of attempts (p < 0.001) and produced fewer perseverative errors (p < 0.001) on the Wisconsin Card Sorting Test at the 12-week follow-up. Conclusion: Chronic ketamine users' verbal and visual memory and executive functions improved after 12 weeks of ketamine abstinence.
1. Introduction Ketamine is a commonly abused drug in Hong Kong (Central Registry of Drug Abuse, 2018), East Asia, Australia, North America and Europe (United Nations Office on Drug and Crime, 2010). Lifetime prevalence of ketamine use is 1.5% in 12th grade students in the US, 0.05–1.08% in South American university students, 2.6% in the 16- to 24-year-old population in the UK and 1.7% in youth aged 14 years and
⁎
older in Australia (United Nations Office on Drug Control, 2016). In mainland China, the use of synthetic drugs including ketamine has increased from 5.6% to 53.8% in newly reported drug users (Jia et al., 2015). In Hong Kong, ketamine was the second most commonly abused drug in 2014 (Narcotics Division Security Bureau, 2015). Ketamine is an antagonist of the glutaminergic N-methyl-d-aspartate (NMDA) receptor. It binds noncompetitively to the phencyclidinebinding site of the NMDA receptor and prevents neuronal calcium
Corresponding author at: Department of Psychiatry, The Chinese University of Hong Kong, Ward 7B, Shatin Hospital, Shatin, N.T, Hong Kong, China. E-mail address: [email protected] (W.K. Tang).
https://doi.org/10.1016/j.addbeh.2019.106081 Received 27 February 2019; Received in revised form 6 August 2019; Accepted 6 August 2019 Available online 07 August 2019 0306-4603/ © 2019 Elsevier Ltd. All rights reserved.
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influx. This disrupts cortical–cortical and cortical–subcortical signaling, producing dissociative anesthesia (Bergman, 1999). Ketamine was originally synthesized as a general anesthetic and is currently widely used in both veterinary and human medical practices. Recent evidence suggests that ketamine has a rapid and marked therapeutic effect on depressive symptoms even in patients with refractory depression (Andrade, 2017). The predominant route of ketamine administration for recreational use is intranasal. Intravenous injection is rare. The primary effects of ketamine are anesthesia and sedation. It also leads to changes in perception, which can include out-of-body experiences, color changes, and an altered sense of time (Bokor & Anderson, 2014). Low doses are associated with a feeling of relaxation, which is called “K-land,” whereas high doses produce a dreamlike state called a “K-hole” (Liu, Lin, Wu, & Zhou, 2016). Adverse physiological effects of ketamine include delirium, hyperthermia, impaired motor function, increased heart rate and cardiac output, increased muscle tone, and hypertension (Bokor & Anderson, 2014). Long-term use of ketamine is associated with gastrointestinal toxicity, particularly abdominal pain and abnormal liver function; urological conditions, such as hemorrhagic cystitis; and neuropsychiatric disorders, including a schizophrenia-like syndrome (Kalsi, Wood, & Dargan, 2011). In a study of 200 ketamine users, 51 participants received a psychiatric diagnosis of one or more comorbidities. Mood disorders were identified in 80.4% of the diagnoses, anxiety disorders in 33.3%, and psychotic disorders in 7.8% (Tang et al., 2015). Both acute (Curran & Monaghan, 2001; Curran & Morgan, 2000; Morgan, Mofeez, Brandner, Bromley, & Curran, 2004; Morgan, Riccelli, Maitland, & Curran, 2004) and chronic (Morgan, Muetzelfeldt, & Curran, 2009, 2010) adverse effects of ketamine on cognitive functioning have been documented. Episodic memory (Morgan, Mofeez, et al., 2004), semantic memory (Curran & Monaghan, 2001; Curran & Morgan, 2000; Morgan, Mofeez, et al., 2004), recognition memory (Morgan, Mofeez, et al., 2004; Morgan, Riccelli, et al., 2004) and procedural learning (Morgan, Mofeez, et al., 2004) are impaired following ketamine use in healthy volunteers and recreational users. Compared with non-user controls, heavy ketamine users show impairments in working memory, episodic memory and executive functioning (Morgan et al., 2009). Frequent ketamine users have persistent deficits in spatial working memory and visual recognition memory at 1-year follow-up (Morgan et al., 2010). Reversibility of cognitive impairment in chronic ketamine users has been suggested in some (Morgan et al., 2009; Morgan, Monaghan, & Curran, 2004; Morgan, Rees, & Curran, 2008), but not all (Morgan, Riccelli, et al., 2004) cross-sectional studies. Reversibility of cognitive deficits is limited to visual memory (Morgan et al., 2009; Morgan et al., 2010), visuospatial working memory (Morgan et al., 2009, 2010) and semantic memory (Morgan, Monaghan, & Curran, 2004), while impairments in verbal fluency (Morgan et al., 2010), attentional functioning (Morgan, Monaghan, & Curran, 2004) and episodic memory (Morgan, Monaghan, & Curran, 2004) appear to persist. Two recent cross-sectional studies found positive associations between the period of ketamine abstinence and verbal memory (Wang et al., 2018), verbal fluency (Wang et al., 2018) and executive functioning (Ke et al., 2018) in ketamine-dependent users. Limitations of these studies include their cross-sectional design (Morgan et al., 2009), small sample size (Morgan, Monaghan, & Curran, 2004), recruitment of subjects solely from psychiatric hospitals (Ke et al., 2018), lack of formal assessments of ketamine use disorder or comorbid psychiatric diagnoses (Morgan et al., 2010; Wang et al., 2018), abstinence not verified by urine or blood samples (Morgan, Riccelli, et al., 2004), and making inferences on reversibility based on comparisons of current and ex users (Morgan et al., 2010). No previous study has prospectively followed the natural history of ketamine users into abstinence and examined changes in cognitive function (Morgan et al., 2010). To the best of our knowledge, no study has examined whether
Ketamine users screened (n = 292)
History of one or more mood disorder (n = 56) Current Major Depressive Disorder (n = 19) History of Major Depressive Disorder (n = 19) Dysthymia (n = 13) Phobic Disorder (n = 13) Other Anxiety Disorder (n = 10) Substance induced depression (n = 7) Substance induced psychosis (n = 6) Bipolar affective disorder (n = 2) Insomnia (n = 1) Psychiatric assessment not performed (n=22)
Ketamine users with substance disorder assessment assessed at baseline (n = 214)
Defaulted follow up (n = 100)
Ketamine users assessed at 12-week follow-up (n = 114)
Fig. 1. Recruitment flowchart.
cognitive deficits can be reversed following ketamine abstinence. This provided the impetus for the current longitudinal study, which investigated changes in cognitive functioning following 12 weeks of ketamine abstinence. We hypothesized that cognitive functioning would improve after abstinence. 2. Methods 2.1. Participants Two hundred and ninety-two ketamine users admitted to residential drug rehabilitation services in Hong Kong were recruited between June 2012 and May 2017. During the treatment period, residents were not allowed to leave the residence without permission. The inclusion criteria for the study were (a) aged between 18 and 40; (b) sole ketamine use or combined use with another illicit substance at least 24 times during a 6-month period within the past 2 years (Chen et al., 2005); (c) baseline assessment within the first month of admission; (d) willing to provide a urine sample every 4 weeks to ensure that no psychotropic substance was used during the 12-week study period. The exclusion criteria were (a) inability to provide valid consent; (b) history of neurological, endocrine or any other medical diseases or treatments known to affect the brain; (c) learning disability; (d) current or lifetime DSM-IV Axis I psychiatric disorder; and (e) history of a seropositive test for human immunodeficiency virus. The study protocol was approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong. Informed consent was obtained from all participants. 2.2. Demographic and clinical data Basic demographic data (age, sex, education, employment, marital status and smoking and drinking habits) and patterns of illicit drug use 2
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Table 1 Clinical and demographic characteristics between participants and dropouts.
Female, n (%) Age, years Education, years Age at first use of ketamine, years Total years of ketamine use Frequency of ketamine use in past two years, days/month Frequency of ketamine use in the past 30 days prior the baseline assessment, days/week Days since last use of ketamine, days SDS score BDI score HADSA score
Completed 12-week assessment (n = 114) mean ± SD/n (%)
Defaulted follow up (n = 100) mean ± SD/n (%)
P value
27 (23.7) 27.3 ± 4.3 9.6 ± 1.5 19.0 ± 4.4 6.9 ± 4.0 25.4 ± 8.1 4.8 ± 3.0
13 (13.0) 25.9 ± 3.6 9.4 ± 1.7 18.4 ± 3.8 6.5 ± 3.2 26.9 ± 6.7 5.5 ± 2.6
0.045a 0.016b 0.352b 0.372b 0.513b 0.284b 0.114b
25.6 ± 19.5 8.5 ± 2.9 13.5 ± 8.4 3.6 ± 3.3
26.3 ± 42.6 9.0 ± 2.8 12.8 ± 8.8 3.9 ± 3.0
0.513b 0.224b 0.418b 0.290b
Note: BDI = Beck Depression Inventory; HADSA = Anxiety subscale of the Hospital Anxiety Depression Scale; SDS = Severity of Dependence Scale. a Chi square. b Mann-Whitney U test.
(age at first use, total years of use, frequency of use in the past two years, frequency of use in the last 30 days and the date of last use) were collected at the baseline assessment. The Severity of Dependence Scale (SDS) (Gossop et al., 1995) was used to measure the degree of dependence on different drugs. The SDS comprises five items related to the psychological components of dependence, and measures impaired control, preoccupation and anxiety about drug use. Each item is scored on a 4-point Likert scale (0-3). The total score is obtained by summing the scores for the five items, with higher scores indicating a higher level of dependence. Cronbach's coefficient alpha and the test-retest reliability of the SDS were reported as 0.74 and 0.95, respectively (Tung, Yeung, Chiang, Xu, & Lam, 2014). The severity of depressive symptoms was measured using the Chinese version of the 21-item Beck Depression Inventory (BDI) (Shek, 1990). Each item is scored on a 4-point Likert scale, with higher scores indicating a greater likelihood of depression. This scale has been used with substance abuse patients (Hesse, 2006). Cronbach's alpha for the Chinese version of the BDI was 0.86 (Shek, 1990). Anxiety symptoms were measured using the Anxiety Subscale of the Hospital Anxiety Depression Scale (HADSA) (Leung, Ho, Kan, Hung, & Chen, 1993). Responses to the seven subscales items were recorded on a 4-point Likert scale based on the frequency of anxiety symptoms over the past week. Total scores range from 0 to 21, with higher scores indicating a greater level of anxiety.
cards consecutively, the category was completed and the sorting principle changed to the next principle. Participants had to recognise that the principle had changed and use the feedback to determine the new sorting principle. The WCST consists of six blocks of trials: the first three blocks require novel discrimination learning in which respondents learn to sort stimulus cards first on colour, then on geometric shape and finally on the number of objects on the card. In blocks 4-6, respondents are required to sort on the three previously reinforced sorting rules. The following performance scores are obtained for analyses: the number of attempts required to complete the task and the number of perseverative errors. The Wechsler Adult Intelligence Scale (Third edition) (WAIS III) Digit Span (Wechsler, 1997a), was used to test attention and working memory. The WAIS III-Digit Span consists of two subscales. For the forward subscale, participants heard a list of digits read at a speed of one digit per second and repeated the digits in the same order. The first span included two digits and the last consisted of nine digits. On the backward subscale, participants repeated the digits in reverse order. The first span included two digits and the last consisted of eight digits. There were two trials for each span. The final score was the highest span repeated without error in one of the two trials. Each participant had scores for forward and backward conditions and the maximum score for each condition was 16 and 14, respectively. The total scores for both conditions were computed. The Wechsler Memory Scale (Third edition) (WMS III) Logical Memory (Wechsler, 1997b) measures verbal memory for narrative stories. The administrator read two stories and asked the participants to recall them immediately and after a 20- to 30-minute delay. The first story was repeated once immediately whereas the second story was repeated twice. One point was given for each of 25 correctly recalled details in the immediate and delayed recall trials. The maximum scores for both immediate and delayed recall trials were 25. Fifteen true or false questions were asked for each story, yielding a highest total recognition score of 30. Scores for immediate and delayed recall were entered into the analyses. The Rey-Osterrieth Complex Figure Test (ROCFT) (Osterrieth, 1944; Rey, 1941) was used to evaluate participants' visuospatial organisation, planning, memory and attention. Participants viewed a complex geometric figure and were asked to copy it on paper. The figure and copy were then removed from view and the participants were instructed to reproduce the complex figure from memory 3 minutes later (immediate recall) and then again after a 30-min delay (delay recall). The drawings were scored according to the accuracy and placement of the figure elements. Up to 2 points were given to each of the 18 elements, yielding a total score of 36. Participants were asked to identify the designs that were part of the original figure. The immediate and delayed recall
2.3. Cognitive battery The following tests were administered at baseline and 12-week follow-up, when the BDI and HADSA were also administered. Executive function was assessed with the Stroop Inference Test (Qiu, Luo, Wang, Zhang, & Zhang, 2006; Stroop, 1992) and the Wisconsin Card Sorting Test (WCST) (Heaton, Chelune, Talley, Kay, & Curtiss, 1993). In the Stroop Inference Test, coloured dots, Chinese characters and colour names were used as the printed visual stimuli. In each condition, participants were instructed to read out the visual stimuli as quickly as possible and to leave errors uncorrected. The reaction time and number of errors were recorded for all conditions. Interference (seconds) was calculated as the difference in reaction times between the colour name and coloured dot conditions. The total reaction time was computed. In the WCST, participants were required to sort cards in accordance with one of three sorting principles (colour, shape, number) until 6 categories were completed or after a total of 128 attempts had been made. Participants had to identify the sorting principles by flexibly evaluating the administrator's minimal feedback of ‘right’ or ‘wrong’ to each sorting attempt. After correctly sorting a pre-defined number of 3
Addictive Behaviors 99 (2019) 106081
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Table 2 Use of substances other than ketamine by participants and dropouts.
Cocaine Age of first use, years Total years of use Frequency of use in past two years, days/month Frequency of use in the past 30 days prior the baseline assessment, days/week Days since last use, days Ecstasy Age of first use, years Total years of use Frequency of use in past two years, days/month Frequency of use in the past 30 days prior the baseline assessment, days/week Days since last use, days Methamphetamine Age of first use, years Total years of use Frequency of use in past two years, days/month Frequency of use in the past 30 days prior the baseline assessment, days/week Days since last use, days Sedatives and hypnotics Age of first use, years Total years of use Frequency of use in past two years, days/month Frequency of use in the past 30 days prior the baseline assessment, days/week Days since last use, days Cannabis Age of first use, years Total years of use Frequency of use in past two years, days/month Frequency of use in the past 30 days prior the baseline assessment, days/week Days since last use, days Cough medicine Age of first use, years Total years of use Frequency of use in past two years, days/month Frequency of use in the past 30 days prior the baseline assessment, days/week Days since last use, days Alcohol Total years of use Total number of days used in the past 30 days prior the baseline assessment Total number of treatment for alcohol abuse in lifetime a
Completed 12-week assessment (n = 114) mean ± SD
Defaulted follow up (n = 100) mean ± SD
P value
17.7 ± 3.8 2.9 ± 3.2 7.7 ± 8.1 0.4 ± 1.4
17.0 ± 3.9 4.9 ± 3.9 10.8 ± 11.7 0.1 ± 0.2
0.508 0.123 0.727 0.810
1559.4 ± 1717.0
1641.7 ± 1774.2
0.723
19.0 ± 4.0 3.1 ± 2.5 3.3 ± 8.2 0.3 ± 1.2
17.1 ± 2.8 2.8 ± 2.5 3.1 ± 7.2 0.2 ± 0.8
0.012 0.571 0.341 0.864
1725.9 ± 1519.0
1975.3 ± 1499.3
0.378
20.2 ± 4.9 2.0 ± 3.2 15.4 ± 11.2 0.3 ± 1.3
19.5 ± 4.1 2.3 ± 2.0 12.2 ± 8.3 0.2 ± 0.5
0.946 0.412 0.415 0.545
1043.1 ± 1199.1
1367.8 ± 1569.1
0.739
21.0 ± 4.5 3.6 ± 2.9 11.6 ± 12.0 1.5 ± 2.5
19.3 ± 3.0 4.3 ± 3.1 14.0 ± 11.2 1.7 ± 2.5
0.026 0.121 0.091 0.363
353.9 ± 605.5
226.8 ± 536.1
0.044
17.2 ± 2.7 2.4 ± 2.2 0.9 ± 3.4 0.2 ± 0.7
16.3 ± 2.7 2.3 ± 2.0 1.5 ± 6.7 0.0 ± 0.0
0.081 0.885 0.591 0.251
2943.1 ± 1363.6
2511.6 ± 1177.5
0.178
18.1 ± 2.8 2.3 ± 2.8 9.1 ± 11.6 1.3 ± 2.6
17.5 ± 2.5 3.2 ± 4.2 13.6 ± 14.8 3.2 ± 3.5
0.574 0.748 0.549 0.278
1434.5 ± 1666.9
1203.3 ± 1425.3
0.608
9.8 ± 6.3 1.7 ± 0.4
7.6 ± 6.0 2.0 ± 4.0
0.012 0.121
0.01 ± 0.09
0.0 ± 0.0
0.351
a
Mann-Whitney U test
scores were used in the analyses.
cognitive function scores and p < 0.05 for the other variables.
2.4. Statistical analyses
3. Results
Statistical analyses were performed using SPSS Statistics, Version 24 (IBM Corp. Released 2016. Armonk, NY, USA). The Kolmogorov–Smirnov test was applied to test the normality of all of the variables. Differences in the demographic and clinical data of ketamine users who remained in the study and those who dropped out were compared using χ2 test, Student's t-test, or Mann–Whitney U-test, as appropriate. The paired-sample t-test or Wilcoxon Signed Ranks Test were used to investigate the differences in depressive and anxiety symptoms and cognitive functions between baseline and follow-up assessments. Stratified analysis was performed on subgroups of subjects based on severity of dependence, presence of polysubstance use, baseline cognitive function, and mood symptoms. To adjust for multiple comparisons, the level of significance was set at p < 0.01 for the
Two hundred and ninety-two ketamine users were recruited and screened for study entry; 56 had a history of 1 or more psychiatric disorders, with major depressive disorder being the most common diagnosis (n = 38) and 22 were not assessed for psychiatric disorder. These 78 users did not take part in the investigation. Altogether, 214 ketamine users completed the baseline assessment; of these, 114 were assessed 12 weeks later and participated in the study (Fig. 1). Among the 114 participants, the time since last ketamine use ranged from 4 to 141 days and 78 (68.4%) had used ketamine within the past 30 days. Compared with drop-outs, participants were significantly older (p = 0.016) and more likely to be women (p = 0.045) (Table 1). Compared with drop-outs, participants started to use ecstasy (p = 0.012) and sedatives and hypnotics (p = 0.026) at a significantly 4
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and verbal memory measured by WMS III Logical Memory, including delayed recall (p < 0.001) and immediate recall (p = 0.001). Ketamine users showed significant improvements in executive functions at the 12-week assessment, with decreased time to complete the Stroop Inference Test (p < 0.001), fewer perseverative errors (p < 0.001) and number of attempts (p < 0.001) made to complete the WCST. In the stratified analysis, the change in WCST perseverative errors was significant for participants with SDS scores ≤8 but not for the group with SDS scores > 8 (Table 4). Comparing primary ketamine users with polysubstance users, changes in WMS III Logical Memory scores (immediate and delayed recall) were significant only for the primary ketamine users and changes in WCST perseverative errors were significant only for the polysubstance users (Table 4). In the majority of the cognitive tests (WAIS III Digit span, WMS III Logical Memory, WSCT and Stroop Inference tests), significant changes were observed only in the group with low baseline (Table 5). The change in WAIS III Digit Span total score was significant only in the group with high baseline BDI score, whereas the change in WCST total attempts and perseverative errors were significant only in the low BDI score group (Table 6). Finally, changes in WCST total attempts and preservative errors were significant only in the group with low baseline HADSA score (Table 6).
Table 3 Clinical characteristics and cognitive functioning of ketamine users in baseline and follow-up assessments, n = 114.
BDI score HADSA score WAIS III Digit Span: total WMS III Logical Memory: immediate recall WMS III Logical Memory: delayed recall ROCFT: immediate recall ROCFT: delayed recall WCST: total attempts WCST: perseverative errors Stroop Inference Test: total reaction time (seconds) Stroop Inference Test: interference (seconds)
Baseline mean ± SD
12-week follow-up mean ± SD
P value
13.7 ± 8.4 3.6 ± 3.3 24.0 ± 3.7 17.3 ± 7.6
7.7 ± 7.0 2.9 ± 2.9 24.7 ± 3.3 20.8 ± 7.6
< 0.001a 0.044a 0.012a 0.001b
14.7 ± 8.2
18.8 ± 7.9
< 0.001a
18.6 19.0 98.3 13.7 50.0
23.6 23.0 90.8 10.2 45.5
< 0.001b < 0.001b < 0.001a < 0.001a < 0.001a
± ± ± ± ±
7.2 6.4 22.7 11.1 11.4
10.1 ± 6.1
± ± ± ± ±
6.3 6.1 21.6 9.2 9.8
9.2 ± 5.0
0.096b
Note: BDI = Beck Depressive Inventory; HADSA = Anxiety subscale of the Hospital Anxiety Depression Scale; WAIS III = Wechsler Adult Intelligence Scale (Third edition); WMS III = Wechsler Memory Scale (Third edition); ROCFT = Rey-Osterrieth Complex Figure Test; WCST = Wisconsin Card Sorting Test. a Wilcoxon Signed Ranks. b Paired sample t-test.
4. Discussion To the best of our knowledge, this was the first longitudinal study to investigate cognitive deficits in ketamine users over 12 weeks of abstinence. The main findings were that verbal and visual memory, planning and attention significantly improved at the 12-week followup. Previous cross-sectional studies of current and ex-ketamine users have also suggested the reversibility of cognitive impairment (Morgan et al., 2008; Morgan et al., 2009). Ex-users performed better than current ketamine users on visual memory (Morgan et al., 2009), visuospatial working memory (Morgan et al., 2009) and attention (Morgan et al., 2008) tasks. The results are consistent with those of a 1year longitudinal study (Morgan et al., 2010) in which 25 current and 24 ex-ketamine users were assessed at baseline and 12 months. Ex-users
older age, had significantly more years of alcohol use (p = 0.012), and a longer duration of abstinence from sedatives and hypnotics (p = 0.044). They also started to use cannabis at an older age (p = 0.081) and had fewer days of sedative and hypnotic use per month in the previous 2 years (p = 0.091) (Table 2). Following a 12-week abstinence, ketamine users had statistically significant reductions in depressive (BDI score, p < 0.001) and anxiety symptoms (HADSA score, p = 0.044) at the follow-up. Significant improvements at the 12-week follow-up were found in the following cognitive functions (Table 3): visual memory measured by the ROCFT, including immediate recall (p < 0.001), delayed recall (p < 0.001);
Table 4 Stratified analysis of cognitive functioning and dependence severity and polysubstance use. Baseline mean ± SD
WAIS III Digit Span: total WMS III Logical Memory: immediate recall WMS III Logical Memory: delayed recall ROCFT: immediate recall ROCFT: delayed recall WCST: total attempts WCST: perseverative errors Stroop Inference Test: total reaction time (seconds) Stroop Inference Test: interference (seconds) WAIS III Digit Span: total WMS III Logical Memory: immediate recall WMS III Logical Memory: delayed recall ROCFT: immediate recall ROCFT: delayed recall WCST: total attempts WCST: perseverative errors Stroop Inference Test: total reaction time (seconds) Stroop Inference Test: interference (seconds)
12-week follow-up mean ± .D
P value
Baseline mean ± SD
12-week follow-up mean ± SD
P value
SDS < /=8 24.1 ± 4.1 16.2 ± 7.9 13.6 ± 8.5 18.9 ± 7.8 19.3 ± 7.0 101.2 ± 22.6 14.4 ± 10.8 48.5 ± 11.1
14.9 21.5 19.9 23.6 22.9 94.0 10.2 44.9
0.121a < 0.001a < 0.001a < 0.001b < 0.001b < 0.001b < 0.001b 0.004a
SDS > 8 23.8 ± 3.2 18.3 ± 7.3 16.0 ± 7.5 18.5 ± 6.7 18.9 ± 6.0 95.5 ± 22.6 13.0 ± 12.0 51.5 ± 11.7
24.4 20.3 17.8 23.4 23.0 88.4 10.3 46.1
0.065b < 0.001b < 0.001b < 0.001b < 0.001b 0.005a 0.169a < 0.001b
10.1 ± 6.6
9.9 ± 5.2
0.899a
10.0 ± 5.6
8.4 ± 4.9
0.028a
Primary ketamine users 24.1 ± 4.1 14.9 ± 3.3 16.2 ± 7.9 21.5 ± 7.8 13.6 ± 8.5 19.9 ± 8.4 18.9 ± 7.8 23.6 ± 7.1 19.3 ± 7.0 22.9 ± 7.1 101.2 ± 22.6 94.0 ± 22.0 14.4 ± 11.3 11.1 ± 10.4 48.5 ± 11.1 44.9 ± 8.9
0.064a < 0.001a < 0.001b < 0.001b < 0.001b 0.008a 0.016a < 0.001a
Polysubstance users 23.8 ± 3.2 18.3 ± 7.3 16.0 ± 7.5 18.5 ± 6.7 18.9 ± 6.0 95.5 ± 22.6 13.0 ± 11.1 51.5 ± 11.7
24.4 ± 3.2 20.3 ± 7.5 17.8 ± 7.4 23.4 ± 5.4 23.0 ± 5.1 88.4 ± 21.2 9.4 ± 8.0 46.1 ± 10.7
0.096a 0.018b 0.048b < 0.001b < 0.001b 0.006a 0.003a < 0.001b
10.0 ± 6.5
0.415a
10.1 ± 5.7
9.1 ± 4.9
0.175b
± ± ± ± ± ± ± ±
3.3 7.8 8.4 7.1 7.1 22.0 8.0 8.9
9.3 ± 5.2
± ± ± ± ± ± ± ±
3.2 7.5 7.4 5.4 5.1 21.2 10.6 10.7
Note: BDI = Beck Depressive Inventory; HADSA = Anxiety subscale of the Hospital Anxiety Depression Scale; WAIS III = Wechsler Adult Intelligence Scale (Third edition); WMS III = Wechsler Memory Scale (Third edition); ROCFT = Rey-Osterrieth Complex Figure Test; WCST = Wisconsin Card Sorting Test. a Wilcoxon Signed-Rank. b Paired sample t-test. 5
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Table 5 Stratified analysis of cognitive function and baseline cognitive function. WAIS III Digital Span ≤24 WAIS III Digit Span: total
21.4 ± 2.7
WAIS III Digital Span > 24
23.2 ± 2.8
< 0.001
a
27.2 ± 1.6
WMS III Logical Memory: delayed recall ≤16 WMS III Logical Memory: immediate recall WMS III Logical Memory: delayed recall
14.1 ± 5.9 10.8 ± 5.8
< 0.001 < 0.001a
ROCFT: delayed recall ≤19 ROCFT: immediate recall ROCFT: delayed recall
13.1 ± 5.1 13.9 ± 3.8
20.1 ± 5.6 19.5 ± 5.5
80.6 ± 10.0 5.7 ± 1.8
< 0.001 < 0.001b
26.0 ± 5.9 23.9 ± 6.7
24.2 ± 4.2 24.2 ± 3.9
0.042b 0.386b
27.0 ± 4.9 26.5 ± 4.7
< 0.001a < 0.001b
WCST: perseverative errors > 9 0.264a 0.467a
79.5 ± 1.4 5.7 ± 2.7
119.5 ± 13.5 23.1 ± 10.1
Stroop Inference Test: interference ≤9 Stroop Inference Test: total reaction time (seconds) Stroop Inference Test: interference (seconds)
25.2 ± 4.5 24.2 ± 3.9
ROCFT: delayed recall > 19 b
WCST: perseverative errors ≤9 WCST: total attempts WCST: perseverative errors
0.071a
WMS III Logical Memory: delayed recall > 16 b
18.7 ± 7.2 16.7 ± 7.4
26.6 ± 2.8
44.6 ± 9.1 5.6 ± 2.2
42.5 ± 9.4 7.3 ± 4.3
104.4 ± 23.3 15.5 ± 11.3
< 0.001a < 0.001b
Stroop Inference Test: interference > 9 0.009b 0.023a
55.4 ± 4.2 14.6 ± 5.3
48.4 ± 9.5 11.0 ± 5.1
< 0.001a < 0.001b
Note: BDI = Beck Depressive Inventory; HADSA = Anxiety subscale of the Hospital Anxiety Depression Scale; WAIS III = Wechsler Adult Intelligence Scale (Third edition); WMS III = Wechsler Memory Scale (Third edition); ROCFT = Rey-Osterrieth Complex Figure Test; WCST = Wisconsin Card Sorting Test. a Wilcoxon Signed Ranks Test. b Paired sample t-test. Table 6 Stratified analysis of cognitive functioning and mood symptoms. Baseline mean ± SD
WAIS III Digit Span: total WMS III Logical Memory: immediate recall WMS III Logical Memory: delayed recall ROCFT: immediate recall ROCFT: delayed recall WCST: total attempts WCST: perseverative errors Stroop Inference Test: total reaction time (seconds) Stroop Inference Test: interference (seconds) WAIS III Digit Span: total WMS III Logical Memory: immediate recall WMS III Logical Memory: delayed recall ROCFT: immediate recall ROCFT: delayed recall WCST: total attempts WCST: perseverative errors Stroop Inference Test: total reaction time (seconds) Stroop Inference Test: interference (seconds)
12-week follow-up mean ± SD
P value
Baseline mean ± SD
BDI≤12 24.0 ± 3.3 18.2 ± 7.8 16.0 ± 8.2 19.0 ± 7.2 19.0 ± 7.2 96.8 ± 22.1 13.5 ± 10.9 50.0 ± 11.3
24.3 ± 3.3 20.8 ± 7.1 19.0 ± 7.8 24.2 ± 6.0 23.4 ± 5.9 89.2 ± 19.8 9.2 ± 8.2 45.6 ± 10.4
0.370a 0.002a 0.001a < 0.001a < 0.001a 0.004b < 0.001b < 0.001b
9.9 ± 5.5
8.9 ± 4.9
HADSA≤3 24.3 ± 3.5 18.1 ± 7.6 15.7 ± 8.3 19.4 ± 6.8 19.6 ± 6.7 99.2 ± 23.4 13.5 ± 10.0 40.0 ± 10.6
25.1 20.9 18.9 25.1 24.4 90.9 10.4 45.6
9.5 ± 5.2
9.0 ± 5.0
± ± ± ± ± ± ± ±
3.2 7.3 7.6 5.8 5.7 55.6 9.3 9.9
12-week follow-up mean ± SD
P value
BDI > 12 24.0 ± 4.1 16.3 ± 7.4 13.5 ± 7.8 18.3 ± 7.4 18.3 ± 7.4 99.7 ± 23.6 13.8 ± 11.6 50.1 ± 11.7
25.2 21.0 18.7 22.8 22.6 93.2 11.4 45.4
0.007b < 0.001a < 0.001b < 0.001a < 0.001a 0.018b 0.203b < 0.001b
0.178a
10.2 ± 6.8
9.6 ± 5.3
0.493b
0.025a < 0.001a < 0.001a < 0.001a < 0.001a 0.001b 0.003b < 0.001a
HADSA > 3 23.5 ± 3.9 16.1 ± 7.4 13.3 ± 7.9 17.5 ± 7.6 18.2 ± 6.0 97.1 ± 21.9 13.9 ± 12.7 51.4 ± 12.5
24.1 ± 3.3 20.7 ± 8.1 18.7 ± 8.4 21.3 ± 6.4 21.0 ± 6.3 90.8 ± 20.3 9.8 ± 9.2 45.2 ± 9.8
0.117b < 0.001a < 0.001b < 0.001b < 0.001a 0.074b 0.021b < 0.001b
0.503a
10.9 ± 7.1
9.3 ± 5.2
0.106b
± ± ± ± ± ± ± ±
3.2 8.2 5.2 6.6 6.4 23.6 10.3 9.3
Note: BDI = Beck Depressive Inventory; HADSA = Anxiety subscale of the Hospital Anxiety Depression Scale; WAIS III = Wechsler Adult Intelligence Scale (Third edition); WMS III = Wechsler Memory Scale (Third edition); ROCFT = Rey-Osterrieth Complex Figure Test; WCST = Wisconsin Card Sorting Test. a paired sample t-test. b Wilcoxon Signed-Rank.
showed better visual memory and visuospatial working memory than current users. It is worth noting that Morgan's study, unlike the present one, did not actually follow the users through the process of abstinence and measured cognitive changes before and after abstinence. The current results are in contrast to the study by Morgan, Monaghan, and Curran (2004), which raised the possibility of persistent deficits in attentional functioning in abstinent ketamine users. The inconsistency between the two studies may be due to methodological
differences. The sample size in the Morgan et al. study was only 18, which may be too small to provide adequate statistical power to detect changes. Also, users in the Morgan et al. study only reported reduced use but not abstinence of ketamine, while participants in the current study abstained from ketamine for 12 weeks. We examined the role of possible confounding factors such as dependence severity, polysubstance use, baseline cognitive function, and mood symptoms with the stratified analysis. The most consistent 6
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finding was that low baseline cognitive function predicted improvement in cognitive function following abstinence. Previous studies of subjects with alcohol dependence found that poorer baseline performance was related to greater recovery, possibly because there is more room for recovery when impairment is greater (Schulte et al., 2014). Improvement in the SCST perseverative errors score was observed only in the group with less severe ketamine dependence. As the effect of dependence severity was only apparent in one of the two SCST scores and was not observed in the other executive function test, this result should be interpreted with caution. In subjects with alcohol dependence, the number of previous detoxifications had a negative impact on recovery of cognitive functions (Schulte et al., 2014). In a 2-year followup study of a group of 20 detoxified patients with chronic Korsakoff syndrome, a worse cognitive outcome was associated with a greater number of previous detoxifications (Fujiwara, Brand, Borsutzky, Steingass, & Markowitsch, 2008). In a 6-month prospective study, duration of alcohol use was negatively related to memory improvement after abstinence (Pitel et al., 2009). The extent and duration of dependence were also found to be negatively correlated with neurocognitive recovery in cocaine dependent patients (Schulte et al., 2014). The influence of polysubstance use on cognitive impairment was mixed. Improvement in verbal memory was not observed in the polysubstance users whereas improvement in one of the WCST scores was only observed in the polysubstance group. A study of 565 ketamine users found no significant cognitive differences between those who were heavy users of other drugs and those who were not (Zhang et al., 2018). There are several possible reasons for this finding. First, the participants in the present study had used ketamine for much longer overall or on more days in the past 2 years than other drugs. Second, the effects of different drugs on cognition are similar, mainly because they all cause cognitive impairment through the same dopaminergic transportation pathway (Moghaddam, Adams, Verma, & Daly, 1997). The impact of mood symptoms on cognitive recovery was also mixed. Improved performance in the digit span test was observed only in the group with higher depressive symptoms whereas improvement in the WCST was found in the group with low mood symptoms. In a study of 41 patients with alcohol dependence, improvement in emotional states did not correlate with the change in working memory following abstinence (Petit et al., 2017). Depressive and anxiety symptoms were reduced after a 12-week abstinence from ketamine in this study. A strong association between depression and cognition has been established in polysubstance users (Stevens, Peschk, & Schwarz, 2007) and in young adults with substance abuse disorders (Latvala et al., 2009). This finding is consistent with those reported in methamphetamine and cocaine users. Two studies found that depressive symptoms significantly decreased in methamphetamine-dependent chronic users after 2-3 weeks of abstinence (Bagheri, Mokri, Khosravi, & Kabir, 2015; Zorick et al., 2010). Similarly, the severity of depressive and anxiety symptoms decreased after 4 weeks of abstinence in cocaine-dependents users (Weddington, Brown, Haertzen, et al., 1990). The strengths of this study include its prospective design, large sample size, non-hospital based recruitment of subjects, inclusion of subjects with a diagnosis of substance use disorder, exclusion of subjects with a psychiatric comorbidity, and abstinence verified by urine testing. The major shortcomings of the study were the attrition rate and the characteristics of the study sample. Only 52.9% of recruited ketamine users remained in the study and completed the 12-week followup. The completed and drop-out groups were comparable on most measures, including education and the pattern of ketamine use. The drop-out group was only 1 to 2 years younger, and both groups were in their mid-20s. Most of the participants were men in both groups. These characteristics suggest that the high attrition rate did not result in a strongly biased sample. Participants in the current sample had a history of using other psychotropic drugs in addition to ketamine. It is possible that the observed changes in cognition could have been due to stopping
the use of substances other than ketamine, although this is unlikely, as the frequency of use of these substances was considerably lower than that of ketamine. Alcohol, sedatives and hypnotics, and cough medicine were more likely to have influenced the results as they were more frequently used (1.3 to 1.7 days per week) one month prior to the baseline assessment, compared to cocaine, methamphetamine and ecstasy (0.3 to 0.4 days per week). These drugs might have affected the cognitive performance at baseline and the change in cognitive function at follow-up. Improvement of cognition has been observed following abstinence from alcohol, for instance (Rourke & Grant, 1999). Furthermore, the same set of cognitive tests was conducted twice and a learning effect may have contributed to the observed improvement in performance. In addition, because all of the participants lived in a controlled environment, other factors, such as a regular sleep pattern, balanced diet, and regular exercise might have contributed to the observed changes in cognition. Finally, updated versions of the WAIS and WMS tests were not used because we did not have access to later editions. In conclusion, chronic ketamine users' cognitive performance improved after 12 weeks of abstinence. This is useful information for frontline health care workers in their attempt to motivate chronic users to achieve and maintain abstinence from ketamine. Future research should be conducted in non-residential settings, with the inclusion of a control group and a ketamine-only user group, measures to reduce attrition, longer duration of follow-up, use of an alternative form, and the latest editions of cognitive tests. Declaration of Competing Interest None. Acknowledgements The projected was funded by the Beat Drug Fund. References Andrade, C. (2017). Ketamine for Depression, 1: Clinical Summary of Issues Related to Efficacy, Adverse Effects, and Mechanism of Action. J. Clin. Psychiatry, 74(4), e415–e419. https://doi.org/10.4088/JCP.17f11567. Bagheri, M., Mokri, A., Khosravi, A., & Kabir, K. (2015). Effect of abstinence on depression, anxiety, and quality of life in chronic methamphetamine users in a therapeutic community. Int. J. High Risk Behav. Addict. 4(3), e23903. https://doi.org/10.5812/ ijhrba.23903. Bergman, S. A. (1999). Ketamine: review of its pharmacology and its use in pediatric anesthesia. Anesth. Prog. 46(1), 10–20. Bokor, G., & Anderson, P. D. (2014). Ketamine: an update on its abuse. J. Pharm. Pract. 27(6), 582–586. https://doi.org/10.1177/0897190014525754. Central Registry of Drug Abuse (2018). Common type of drugs abused. Retrieved from Hong Kong Special Administrative Region: https://www.nd.gov.hk/en/statistics_list. htm. Chen, R., Lee, A., Chan, R., Chen, E., Tang, S., & Chum, K. (2005). A study on the cognitive impairment and other harmful effects caused by ketamine abuse. Retrieved from https://www.nd.gov.hk/pdf/Ketamine-eng.pdf. Curran, H. V., & Monaghan, L. (2001). In and out of the K-hole: a comparison of the acute and residual effects of ketamine in frequent and infrequent ketamine users. Addiction, 96(5), 749–760. https://doi.org/10.1080/09652140020039116. Curran, H., & Morgan, C. (2000). Cognitive, dissociative and psychotogenic effects of ketamin in recreational users on the night of drug use and 3 days later. Addiction, 95(4), 575–590. Fujiwara, E., Brand, M., Borsutzky, S., Steingass, H.-P., & Markowitsch, H. J. (2008). Cognitive performance of detoxified alcoholic Korsakoff syndrome patients remains stable over two years. J. Clin. Exp. Neuropsychol. 30(3), 576–587. Gossop, M., Darke, S., Griffiths, P., Hando, J., Powis, B., Hall, W., & Strang, J. (1995). The Severity of Dependence Scale (SDS): psychometric properties of the SDS in English and Australian samples of heroin, cocaine and amphetamine users. Addiction, 90(5), 607–614. https://doi.org/10.1046/j.1360-0443.1995.9056072.x. Heaton, R. K., Chelune, G. J., Talley, J. L., Kay, G. G., & Curtiss, G. (1993). Wisconsin Card Sorting Test manual revised and expanded. USA: Psychological Assessment Resources, Inc. Hesse, M. (2006). The Beck Depression Inventory in patients undergoing opiate agonist maintenance treatment. Br. J. Clin. Psychol. 45(3), 417–425. https://doi.org/10. 1348/014466505x68069. Jia, Z., Liu, Z., Chu, P., McGoogan, J. M., Cong, M., ... Lu, L. (2015). Tracking the
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Recovery of cognitive functioning following abstinence from ketamine a,⁎
a
b,c
Wai Kwong Tang , Chieh Grace Lau , Gabor S. Ungvari , Shih-Ku Lin
d,e
, Hsien-Yuan Lane
f,g,h
T
a
Department of Psychiatry, The Chinese University of Hong Kong, Hong Kong, China Division of Psychiatry, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia Section of Psychiatry, University Notre Dame Australia, Fremantle, Australia d Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan e Department of Psychiatry, Taipei City Hospital, Taipei, Taiwan f Department of Psychiatry, China Medical University Hospital, Taiwan g Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan h Department of Psychology, College of Medical and Health Sciences, Asia University, Taichung, Taiwan b c
HIGHLIGHTS
cognitive improvements were found in visual and verbal memory. • Significant in executive functions improved after abstinence of ketamine. • Performance • Cognitive deficits might be reversed following 12-week of ketamine abstinence. ARTICLE INFO
ABSTRACT
Keywords: Abstinence Cognition Ketamine Recovery
Background: Acute and adverse effects of ketamine on cognitive functioning have been documented. No longitudinal study has examined whether cognitive deficits can be reversed following ketamine abstinence although it has been suggested in some cross-sectional studies. This study aimed to investigate the changes in cognitive functioning among ketamine users following a 12-week abstinence from ketamine. Methods: In this longitudinal study, 114 ketamine users completed clinical and cognitive assessments at both baseline and 12-week follow-up with the following instruments: Severity of Dependence Scale, Beck Depression Inventory (BDI), Anxiety Subscale of the Hospital Anxiety Depression Scale (HADSA), and a cognitive battery. Results: BDI (p < 0.001) and HADSA (p = 0.044) scores were significantly reduced at the 12-week follow-up. Significant improvements were found in Wechsler Adult Intelligence Scale (Third edition) immediate recall (p < 0.001) and delayed recall (p < 0.001) on the Rey-Osterrieth Complex Figure Test, and in delayed recall (p < 0.001), and immediate recall (p = 0.001) on the Logical Memory component of the Wechsler Memory Scale (Third Edition) at the 12-week follow-up. Participants completed the Stroop Inference Test significantly faster (p < 0.001); and required fewer number of attempts (p < 0.001) and produced fewer perseverative errors (p < 0.001) on the Wisconsin Card Sorting Test at the 12-week follow-up. Conclusion: Chronic ketamine users' verbal and visual memory and executive functions improved after 12 weeks of ketamine abstinence.
1. Introduction Ketamine is a commonly abused drug in Hong Kong (Central Registry of Drug Abuse, 2018), East Asia, Australia, North America and Europe (United Nations Office on Drug and Crime, 2010). Lifetime prevalence of ketamine use is 1.5% in 12th grade students in the US, 0.05–1.08% in South American university students, 2.6% in the 16- to 24-year-old population in the UK and 1.7% in youth aged 14 years and
⁎
older in Australia (United Nations Office on Drug Control, 2016). In mainland China, the use of synthetic drugs including ketamine has increased from 5.6% to 53.8% in newly reported drug users (Jia et al., 2015). In Hong Kong, ketamine was the second most commonly abused drug in 2014 (Narcotics Division Security Bureau, 2015). Ketamine is an antagonist of the glutaminergic N-methyl-d-aspartate (NMDA) receptor. It binds noncompetitively to the phencyclidinebinding site of the NMDA receptor and prevents neuronal calcium
Corresponding author at: Department of Psychiatry, The Chinese University of Hong Kong, Ward 7B, Shatin Hospital, Shatin, N.T, Hong Kong, China. E-mail address: [email protected] (W.K. Tang).
https://doi.org/10.1016/j.addbeh.2019.106081 Received 27 February 2019; Received in revised form 6 August 2019; Accepted 6 August 2019 Available online 07 August 2019 0306-4603/ © 2019 Elsevier Ltd. All rights reserved.
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influx. This disrupts cortical–cortical and cortical–subcortical signaling, producing dissociative anesthesia (Bergman, 1999). Ketamine was originally synthesized as a general anesthetic and is currently widely used in both veterinary and human medical practices. Recent evidence suggests that ketamine has a rapid and marked therapeutic effect on depressive symptoms even in patients with refractory depression (Andrade, 2017). The predominant route of ketamine administration for recreational use is intranasal. Intravenous injection is rare. The primary effects of ketamine are anesthesia and sedation. It also leads to changes in perception, which can include out-of-body experiences, color changes, and an altered sense of time (Bokor & Anderson, 2014). Low doses are associated with a feeling of relaxation, which is called “K-land,” whereas high doses produce a dreamlike state called a “K-hole” (Liu, Lin, Wu, & Zhou, 2016). Adverse physiological effects of ketamine include delirium, hyperthermia, impaired motor function, increased heart rate and cardiac output, increased muscle tone, and hypertension (Bokor & Anderson, 2014). Long-term use of ketamine is associated with gastrointestinal toxicity, particularly abdominal pain and abnormal liver function; urological conditions, such as hemorrhagic cystitis; and neuropsychiatric disorders, including a schizophrenia-like syndrome (Kalsi, Wood, & Dargan, 2011). In a study of 200 ketamine users, 51 participants received a psychiatric diagnosis of one or more comorbidities. Mood disorders were identified in 80.4% of the diagnoses, anxiety disorders in 33.3%, and psychotic disorders in 7.8% (Tang et al., 2015). Both acute (Curran & Monaghan, 2001; Curran & Morgan, 2000; Morgan, Mofeez, Brandner, Bromley, & Curran, 2004; Morgan, Riccelli, Maitland, & Curran, 2004) and chronic (Morgan, Muetzelfeldt, & Curran, 2009, 2010) adverse effects of ketamine on cognitive functioning have been documented. Episodic memory (Morgan, Mofeez, et al., 2004), semantic memory (Curran & Monaghan, 2001; Curran & Morgan, 2000; Morgan, Mofeez, et al., 2004), recognition memory (Morgan, Mofeez, et al., 2004; Morgan, Riccelli, et al., 2004) and procedural learning (Morgan, Mofeez, et al., 2004) are impaired following ketamine use in healthy volunteers and recreational users. Compared with non-user controls, heavy ketamine users show impairments in working memory, episodic memory and executive functioning (Morgan et al., 2009). Frequent ketamine users have persistent deficits in spatial working memory and visual recognition memory at 1-year follow-up (Morgan et al., 2010). Reversibility of cognitive impairment in chronic ketamine users has been suggested in some (Morgan et al., 2009; Morgan, Monaghan, & Curran, 2004; Morgan, Rees, & Curran, 2008), but not all (Morgan, Riccelli, et al., 2004) cross-sectional studies. Reversibility of cognitive deficits is limited to visual memory (Morgan et al., 2009; Morgan et al., 2010), visuospatial working memory (Morgan et al., 2009, 2010) and semantic memory (Morgan, Monaghan, & Curran, 2004), while impairments in verbal fluency (Morgan et al., 2010), attentional functioning (Morgan, Monaghan, & Curran, 2004) and episodic memory (Morgan, Monaghan, & Curran, 2004) appear to persist. Two recent cross-sectional studies found positive associations between the period of ketamine abstinence and verbal memory (Wang et al., 2018), verbal fluency (Wang et al., 2018) and executive functioning (Ke et al., 2018) in ketamine-dependent users. Limitations of these studies include their cross-sectional design (Morgan et al., 2009), small sample size (Morgan, Monaghan, & Curran, 2004), recruitment of subjects solely from psychiatric hospitals (Ke et al., 2018), lack of formal assessments of ketamine use disorder or comorbid psychiatric diagnoses (Morgan et al., 2010; Wang et al., 2018), abstinence not verified by urine or blood samples (Morgan, Riccelli, et al., 2004), and making inferences on reversibility based on comparisons of current and ex users (Morgan et al., 2010). No previous study has prospectively followed the natural history of ketamine users into abstinence and examined changes in cognitive function (Morgan et al., 2010). To the best of our knowledge, no study has examined whether
Ketamine users screened (n = 292)
History of one or more mood disorder (n = 56) Current Major Depressive Disorder (n = 19) History of Major Depressive Disorder (n = 19) Dysthymia (n = 13) Phobic Disorder (n = 13) Other Anxiety Disorder (n = 10) Substance induced depression (n = 7) Substance induced psychosis (n = 6) Bipolar affective disorder (n = 2) Insomnia (n = 1) Psychiatric assessment not performed (n=22)
Ketamine users with substance disorder assessment assessed at baseline (n = 214)
Defaulted follow up (n = 100)
Ketamine users assessed at 12-week follow-up (n = 114)
Fig. 1. Recruitment flowchart.
cognitive deficits can be reversed following ketamine abstinence. This provided the impetus for the current longitudinal study, which investigated changes in cognitive functioning following 12 weeks of ketamine abstinence. We hypothesized that cognitive functioning would improve after abstinence. 2. Methods 2.1. Participants Two hundred and ninety-two ketamine users admitted to residential drug rehabilitation services in Hong Kong were recruited between June 2012 and May 2017. During the treatment period, residents were not allowed to leave the residence without permission. The inclusion criteria for the study were (a) aged between 18 and 40; (b) sole ketamine use or combined use with another illicit substance at least 24 times during a 6-month period within the past 2 years (Chen et al., 2005); (c) baseline assessment within the first month of admission; (d) willing to provide a urine sample every 4 weeks to ensure that no psychotropic substance was used during the 12-week study period. The exclusion criteria were (a) inability to provide valid consent; (b) history of neurological, endocrine or any other medical diseases or treatments known to affect the brain; (c) learning disability; (d) current or lifetime DSM-IV Axis I psychiatric disorder; and (e) history of a seropositive test for human immunodeficiency virus. The study protocol was approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong. Informed consent was obtained from all participants. 2.2. Demographic and clinical data Basic demographic data (age, sex, education, employment, marital status and smoking and drinking habits) and patterns of illicit drug use 2
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Table 1 Clinical and demographic characteristics between participants and dropouts.
Female, n (%) Age, years Education, years Age at first use of ketamine, years Total years of ketamine use Frequency of ketamine use in past two years, days/month Frequency of ketamine use in the past 30 days prior the baseline assessment, days/week Days since last use of ketamine, days SDS score BDI score HADSA score
Completed 12-week assessment (n = 114) mean ± SD/n (%)
Defaulted follow up (n = 100) mean ± SD/n (%)
P value
27 (23.7) 27.3 ± 4.3 9.6 ± 1.5 19.0 ± 4.4 6.9 ± 4.0 25.4 ± 8.1 4.8 ± 3.0
13 (13.0) 25.9 ± 3.6 9.4 ± 1.7 18.4 ± 3.8 6.5 ± 3.2 26.9 ± 6.7 5.5 ± 2.6
0.045a 0.016b 0.352b 0.372b 0.513b 0.284b 0.114b
25.6 ± 19.5 8.5 ± 2.9 13.5 ± 8.4 3.6 ± 3.3
26.3 ± 42.6 9.0 ± 2.8 12.8 ± 8.8 3.9 ± 3.0
0.513b 0.224b 0.418b 0.290b
Note: BDI = Beck Depression Inventory; HADSA = Anxiety subscale of the Hospital Anxiety Depression Scale; SDS = Severity of Dependence Scale. a Chi square. b Mann-Whitney U test.
(age at first use, total years of use, frequency of use in the past two years, frequency of use in the last 30 days and the date of last use) were collected at the baseline assessment. The Severity of Dependence Scale (SDS) (Gossop et al., 1995) was used to measure the degree of dependence on different drugs. The SDS comprises five items related to the psychological components of dependence, and measures impaired control, preoccupation and anxiety about drug use. Each item is scored on a 4-point Likert scale (0-3). The total score is obtained by summing the scores for the five items, with higher scores indicating a higher level of dependence. Cronbach's coefficient alpha and the test-retest reliability of the SDS were reported as 0.74 and 0.95, respectively (Tung, Yeung, Chiang, Xu, & Lam, 2014). The severity of depressive symptoms was measured using the Chinese version of the 21-item Beck Depression Inventory (BDI) (Shek, 1990). Each item is scored on a 4-point Likert scale, with higher scores indicating a greater likelihood of depression. This scale has been used with substance abuse patients (Hesse, 2006). Cronbach's alpha for the Chinese version of the BDI was 0.86 (Shek, 1990). Anxiety symptoms were measured using the Anxiety Subscale of the Hospital Anxiety Depression Scale (HADSA) (Leung, Ho, Kan, Hung, & Chen, 1993). Responses to the seven subscales items were recorded on a 4-point Likert scale based on the frequency of anxiety symptoms over the past week. Total scores range from 0 to 21, with higher scores indicating a greater level of anxiety.
cards consecutively, the category was completed and the sorting principle changed to the next principle. Participants had to recognise that the principle had changed and use the feedback to determine the new sorting principle. The WCST consists of six blocks of trials: the first three blocks require novel discrimination learning in which respondents learn to sort stimulus cards first on colour, then on geometric shape and finally on the number of objects on the card. In blocks 4-6, respondents are required to sort on the three previously reinforced sorting rules. The following performance scores are obtained for analyses: the number of attempts required to complete the task and the number of perseverative errors. The Wechsler Adult Intelligence Scale (Third edition) (WAIS III) Digit Span (Wechsler, 1997a), was used to test attention and working memory. The WAIS III-Digit Span consists of two subscales. For the forward subscale, participants heard a list of digits read at a speed of one digit per second and repeated the digits in the same order. The first span included two digits and the last consisted of nine digits. On the backward subscale, participants repeated the digits in reverse order. The first span included two digits and the last consisted of eight digits. There were two trials for each span. The final score was the highest span repeated without error in one of the two trials. Each participant had scores for forward and backward conditions and the maximum score for each condition was 16 and 14, respectively. The total scores for both conditions were computed. The Wechsler Memory Scale (Third edition) (WMS III) Logical Memory (Wechsler, 1997b) measures verbal memory for narrative stories. The administrator read two stories and asked the participants to recall them immediately and after a 20- to 30-minute delay. The first story was repeated once immediately whereas the second story was repeated twice. One point was given for each of 25 correctly recalled details in the immediate and delayed recall trials. The maximum scores for both immediate and delayed recall trials were 25. Fifteen true or false questions were asked for each story, yielding a highest total recognition score of 30. Scores for immediate and delayed recall were entered into the analyses. The Rey-Osterrieth Complex Figure Test (ROCFT) (Osterrieth, 1944; Rey, 1941) was used to evaluate participants' visuospatial organisation, planning, memory and attention. Participants viewed a complex geometric figure and were asked to copy it on paper. The figure and copy were then removed from view and the participants were instructed to reproduce the complex figure from memory 3 minutes later (immediate recall) and then again after a 30-min delay (delay recall). The drawings were scored according to the accuracy and placement of the figure elements. Up to 2 points were given to each of the 18 elements, yielding a total score of 36. Participants were asked to identify the designs that were part of the original figure. The immediate and delayed recall
2.3. Cognitive battery The following tests were administered at baseline and 12-week follow-up, when the BDI and HADSA were also administered. Executive function was assessed with the Stroop Inference Test (Qiu, Luo, Wang, Zhang, & Zhang, 2006; Stroop, 1992) and the Wisconsin Card Sorting Test (WCST) (Heaton, Chelune, Talley, Kay, & Curtiss, 1993). In the Stroop Inference Test, coloured dots, Chinese characters and colour names were used as the printed visual stimuli. In each condition, participants were instructed to read out the visual stimuli as quickly as possible and to leave errors uncorrected. The reaction time and number of errors were recorded for all conditions. Interference (seconds) was calculated as the difference in reaction times between the colour name and coloured dot conditions. The total reaction time was computed. In the WCST, participants were required to sort cards in accordance with one of three sorting principles (colour, shape, number) until 6 categories were completed or after a total of 128 attempts had been made. Participants had to identify the sorting principles by flexibly evaluating the administrator's minimal feedback of ‘right’ or ‘wrong’ to each sorting attempt. After correctly sorting a pre-defined number of 3
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Table 2 Use of substances other than ketamine by participants and dropouts.
Cocaine Age of first use, years Total years of use Frequency of use in past two years, days/month Frequency of use in the past 30 days prior the baseline assessment, days/week Days since last use, days Ecstasy Age of first use, years Total years of use Frequency of use in past two years, days/month Frequency of use in the past 30 days prior the baseline assessment, days/week Days since last use, days Methamphetamine Age of first use, years Total years of use Frequency of use in past two years, days/month Frequency of use in the past 30 days prior the baseline assessment, days/week Days since last use, days Sedatives and hypnotics Age of first use, years Total years of use Frequency of use in past two years, days/month Frequency of use in the past 30 days prior the baseline assessment, days/week Days since last use, days Cannabis Age of first use, years Total years of use Frequency of use in past two years, days/month Frequency of use in the past 30 days prior the baseline assessment, days/week Days since last use, days Cough medicine Age of first use, years Total years of use Frequency of use in past two years, days/month Frequency of use in the past 30 days prior the baseline assessment, days/week Days since last use, days Alcohol Total years of use Total number of days used in the past 30 days prior the baseline assessment Total number of treatment for alcohol abuse in lifetime a
Completed 12-week assessment (n = 114) mean ± SD
Defaulted follow up (n = 100) mean ± SD
P value
17.7 ± 3.8 2.9 ± 3.2 7.7 ± 8.1 0.4 ± 1.4
17.0 ± 3.9 4.9 ± 3.9 10.8 ± 11.7 0.1 ± 0.2
0.508 0.123 0.727 0.810
1559.4 ± 1717.0
1641.7 ± 1774.2
0.723
19.0 ± 4.0 3.1 ± 2.5 3.3 ± 8.2 0.3 ± 1.2
17.1 ± 2.8 2.8 ± 2.5 3.1 ± 7.2 0.2 ± 0.8
0.012 0.571 0.341 0.864
1725.9 ± 1519.0
1975.3 ± 1499.3
0.378
20.2 ± 4.9 2.0 ± 3.2 15.4 ± 11.2 0.3 ± 1.3
19.5 ± 4.1 2.3 ± 2.0 12.2 ± 8.3 0.2 ± 0.5
0.946 0.412 0.415 0.545
1043.1 ± 1199.1
1367.8 ± 1569.1
0.739
21.0 ± 4.5 3.6 ± 2.9 11.6 ± 12.0 1.5 ± 2.5
19.3 ± 3.0 4.3 ± 3.1 14.0 ± 11.2 1.7 ± 2.5
0.026 0.121 0.091 0.363
353.9 ± 605.5
226.8 ± 536.1
0.044
17.2 ± 2.7 2.4 ± 2.2 0.9 ± 3.4 0.2 ± 0.7
16.3 ± 2.7 2.3 ± 2.0 1.5 ± 6.7 0.0 ± 0.0
0.081 0.885 0.591 0.251
2943.1 ± 1363.6
2511.6 ± 1177.5
0.178
18.1 ± 2.8 2.3 ± 2.8 9.1 ± 11.6 1.3 ± 2.6
17.5 ± 2.5 3.2 ± 4.2 13.6 ± 14.8 3.2 ± 3.5
0.574 0.748 0.549 0.278
1434.5 ± 1666.9
1203.3 ± 1425.3
0.608
9.8 ± 6.3 1.7 ± 0.4
7.6 ± 6.0 2.0 ± 4.0
0.012 0.121
0.01 ± 0.09
0.0 ± 0.0
0.351
a
Mann-Whitney U test
scores were used in the analyses.
cognitive function scores and p < 0.05 for the other variables.
2.4. Statistical analyses
3. Results
Statistical analyses were performed using SPSS Statistics, Version 24 (IBM Corp. Released 2016. Armonk, NY, USA). The Kolmogorov–Smirnov test was applied to test the normality of all of the variables. Differences in the demographic and clinical data of ketamine users who remained in the study and those who dropped out were compared using χ2 test, Student's t-test, or Mann–Whitney U-test, as appropriate. The paired-sample t-test or Wilcoxon Signed Ranks Test were used to investigate the differences in depressive and anxiety symptoms and cognitive functions between baseline and follow-up assessments. Stratified analysis was performed on subgroups of subjects based on severity of dependence, presence of polysubstance use, baseline cognitive function, and mood symptoms. To adjust for multiple comparisons, the level of significance was set at p < 0.01 for the
Two hundred and ninety-two ketamine users were recruited and screened for study entry; 56 had a history of 1 or more psychiatric disorders, with major depressive disorder being the most common diagnosis (n = 38) and 22 were not assessed for psychiatric disorder. These 78 users did not take part in the investigation. Altogether, 214 ketamine users completed the baseline assessment; of these, 114 were assessed 12 weeks later and participated in the study (Fig. 1). Among the 114 participants, the time since last ketamine use ranged from 4 to 141 days and 78 (68.4%) had used ketamine within the past 30 days. Compared with drop-outs, participants were significantly older (p = 0.016) and more likely to be women (p = 0.045) (Table 1). Compared with drop-outs, participants started to use ecstasy (p = 0.012) and sedatives and hypnotics (p = 0.026) at a significantly 4
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and verbal memory measured by WMS III Logical Memory, including delayed recall (p < 0.001) and immediate recall (p = 0.001). Ketamine users showed significant improvements in executive functions at the 12-week assessment, with decreased time to complete the Stroop Inference Test (p < 0.001), fewer perseverative errors (p < 0.001) and number of attempts (p < 0.001) made to complete the WCST. In the stratified analysis, the change in WCST perseverative errors was significant for participants with SDS scores ≤8 but not for the group with SDS scores > 8 (Table 4). Comparing primary ketamine users with polysubstance users, changes in WMS III Logical Memory scores (immediate and delayed recall) were significant only for the primary ketamine users and changes in WCST perseverative errors were significant only for the polysubstance users (Table 4). In the majority of the cognitive tests (WAIS III Digit span, WMS III Logical Memory, WSCT and Stroop Inference tests), significant changes were observed only in the group with low baseline (Table 5). The change in WAIS III Digit Span total score was significant only in the group with high baseline BDI score, whereas the change in WCST total attempts and perseverative errors were significant only in the low BDI score group (Table 6). Finally, changes in WCST total attempts and preservative errors were significant only in the group with low baseline HADSA score (Table 6).
Table 3 Clinical characteristics and cognitive functioning of ketamine users in baseline and follow-up assessments, n = 114.
BDI score HADSA score WAIS III Digit Span: total WMS III Logical Memory: immediate recall WMS III Logical Memory: delayed recall ROCFT: immediate recall ROCFT: delayed recall WCST: total attempts WCST: perseverative errors Stroop Inference Test: total reaction time (seconds) Stroop Inference Test: interference (seconds)
Baseline mean ± SD
12-week follow-up mean ± SD
P value
13.7 ± 8.4 3.6 ± 3.3 24.0 ± 3.7 17.3 ± 7.6
7.7 ± 7.0 2.9 ± 2.9 24.7 ± 3.3 20.8 ± 7.6
< 0.001a 0.044a 0.012a 0.001b
14.7 ± 8.2
18.8 ± 7.9
< 0.001a
18.6 19.0 98.3 13.7 50.0
23.6 23.0 90.8 10.2 45.5
< 0.001b < 0.001b < 0.001a < 0.001a < 0.001a
± ± ± ± ±
7.2 6.4 22.7 11.1 11.4
10.1 ± 6.1
± ± ± ± ±
6.3 6.1 21.6 9.2 9.8
9.2 ± 5.0
0.096b
Note: BDI = Beck Depressive Inventory; HADSA = Anxiety subscale of the Hospital Anxiety Depression Scale; WAIS III = Wechsler Adult Intelligence Scale (Third edition); WMS III = Wechsler Memory Scale (Third edition); ROCFT = Rey-Osterrieth Complex Figure Test; WCST = Wisconsin Card Sorting Test. a Wilcoxon Signed Ranks. b Paired sample t-test.
4. Discussion To the best of our knowledge, this was the first longitudinal study to investigate cognitive deficits in ketamine users over 12 weeks of abstinence. The main findings were that verbal and visual memory, planning and attention significantly improved at the 12-week followup. Previous cross-sectional studies of current and ex-ketamine users have also suggested the reversibility of cognitive impairment (Morgan et al., 2008; Morgan et al., 2009). Ex-users performed better than current ketamine users on visual memory (Morgan et al., 2009), visuospatial working memory (Morgan et al., 2009) and attention (Morgan et al., 2008) tasks. The results are consistent with those of a 1year longitudinal study (Morgan et al., 2010) in which 25 current and 24 ex-ketamine users were assessed at baseline and 12 months. Ex-users
older age, had significantly more years of alcohol use (p = 0.012), and a longer duration of abstinence from sedatives and hypnotics (p = 0.044). They also started to use cannabis at an older age (p = 0.081) and had fewer days of sedative and hypnotic use per month in the previous 2 years (p = 0.091) (Table 2). Following a 12-week abstinence, ketamine users had statistically significant reductions in depressive (BDI score, p < 0.001) and anxiety symptoms (HADSA score, p = 0.044) at the follow-up. Significant improvements at the 12-week follow-up were found in the following cognitive functions (Table 3): visual memory measured by the ROCFT, including immediate recall (p < 0.001), delayed recall (p < 0.001);
Table 4 Stratified analysis of cognitive functioning and dependence severity and polysubstance use. Baseline mean ± SD
WAIS III Digit Span: total WMS III Logical Memory: immediate recall WMS III Logical Memory: delayed recall ROCFT: immediate recall ROCFT: delayed recall WCST: total attempts WCST: perseverative errors Stroop Inference Test: total reaction time (seconds) Stroop Inference Test: interference (seconds) WAIS III Digit Span: total WMS III Logical Memory: immediate recall WMS III Logical Memory: delayed recall ROCFT: immediate recall ROCFT: delayed recall WCST: total attempts WCST: perseverative errors Stroop Inference Test: total reaction time (seconds) Stroop Inference Test: interference (seconds)
12-week follow-up mean ± .D
P value
Baseline mean ± SD
12-week follow-up mean ± SD
P value
SDS < /=8 24.1 ± 4.1 16.2 ± 7.9 13.6 ± 8.5 18.9 ± 7.8 19.3 ± 7.0 101.2 ± 22.6 14.4 ± 10.8 48.5 ± 11.1
14.9 21.5 19.9 23.6 22.9 94.0 10.2 44.9
0.121a < 0.001a < 0.001a < 0.001b < 0.001b < 0.001b < 0.001b 0.004a
SDS > 8 23.8 ± 3.2 18.3 ± 7.3 16.0 ± 7.5 18.5 ± 6.7 18.9 ± 6.0 95.5 ± 22.6 13.0 ± 12.0 51.5 ± 11.7
24.4 20.3 17.8 23.4 23.0 88.4 10.3 46.1
0.065b < 0.001b < 0.001b < 0.001b < 0.001b 0.005a 0.169a < 0.001b
10.1 ± 6.6
9.9 ± 5.2
0.899a
10.0 ± 5.6
8.4 ± 4.9
0.028a
Primary ketamine users 24.1 ± 4.1 14.9 ± 3.3 16.2 ± 7.9 21.5 ± 7.8 13.6 ± 8.5 19.9 ± 8.4 18.9 ± 7.8 23.6 ± 7.1 19.3 ± 7.0 22.9 ± 7.1 101.2 ± 22.6 94.0 ± 22.0 14.4 ± 11.3 11.1 ± 10.4 48.5 ± 11.1 44.9 ± 8.9
0.064a < 0.001a < 0.001b < 0.001b < 0.001b 0.008a 0.016a < 0.001a
Polysubstance users 23.8 ± 3.2 18.3 ± 7.3 16.0 ± 7.5 18.5 ± 6.7 18.9 ± 6.0 95.5 ± 22.6 13.0 ± 11.1 51.5 ± 11.7
24.4 ± 3.2 20.3 ± 7.5 17.8 ± 7.4 23.4 ± 5.4 23.0 ± 5.1 88.4 ± 21.2 9.4 ± 8.0 46.1 ± 10.7
0.096a 0.018b 0.048b < 0.001b < 0.001b 0.006a 0.003a < 0.001b
10.0 ± 6.5
0.415a
10.1 ± 5.7
9.1 ± 4.9
0.175b
± ± ± ± ± ± ± ±
3.3 7.8 8.4 7.1 7.1 22.0 8.0 8.9
9.3 ± 5.2
± ± ± ± ± ± ± ±
3.2 7.5 7.4 5.4 5.1 21.2 10.6 10.7
Note: BDI = Beck Depressive Inventory; HADSA = Anxiety subscale of the Hospital Anxiety Depression Scale; WAIS III = Wechsler Adult Intelligence Scale (Third edition); WMS III = Wechsler Memory Scale (Third edition); ROCFT = Rey-Osterrieth Complex Figure Test; WCST = Wisconsin Card Sorting Test. a Wilcoxon Signed-Rank. b Paired sample t-test. 5
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Table 5 Stratified analysis of cognitive function and baseline cognitive function. WAIS III Digital Span ≤24 WAIS III Digit Span: total
21.4 ± 2.7
WAIS III Digital Span > 24
23.2 ± 2.8
< 0.001
a
27.2 ± 1.6
WMS III Logical Memory: delayed recall ≤16 WMS III Logical Memory: immediate recall WMS III Logical Memory: delayed recall
14.1 ± 5.9 10.8 ± 5.8
< 0.001 < 0.001a
ROCFT: delayed recall ≤19 ROCFT: immediate recall ROCFT: delayed recall
13.1 ± 5.1 13.9 ± 3.8
20.1 ± 5.6 19.5 ± 5.5
80.6 ± 10.0 5.7 ± 1.8
< 0.001 < 0.001b
26.0 ± 5.9 23.9 ± 6.7
24.2 ± 4.2 24.2 ± 3.9
0.042b 0.386b
27.0 ± 4.9 26.5 ± 4.7
< 0.001a < 0.001b
WCST: perseverative errors > 9 0.264a 0.467a
79.5 ± 1.4 5.7 ± 2.7
119.5 ± 13.5 23.1 ± 10.1
Stroop Inference Test: interference ≤9 Stroop Inference Test: total reaction time (seconds) Stroop Inference Test: interference (seconds)
25.2 ± 4.5 24.2 ± 3.9
ROCFT: delayed recall > 19 b
WCST: perseverative errors ≤9 WCST: total attempts WCST: perseverative errors
0.071a
WMS III Logical Memory: delayed recall > 16 b
18.7 ± 7.2 16.7 ± 7.4
26.6 ± 2.8
44.6 ± 9.1 5.6 ± 2.2
42.5 ± 9.4 7.3 ± 4.3
104.4 ± 23.3 15.5 ± 11.3
< 0.001a < 0.001b
Stroop Inference Test: interference > 9 0.009b 0.023a
55.4 ± 4.2 14.6 ± 5.3
48.4 ± 9.5 11.0 ± 5.1
< 0.001a < 0.001b
Note: BDI = Beck Depressive Inventory; HADSA = Anxiety subscale of the Hospital Anxiety Depression Scale; WAIS III = Wechsler Adult Intelligence Scale (Third edition); WMS III = Wechsler Memory Scale (Third edition); ROCFT = Rey-Osterrieth Complex Figure Test; WCST = Wisconsin Card Sorting Test. a Wilcoxon Signed Ranks Test. b Paired sample t-test. Table 6 Stratified analysis of cognitive functioning and mood symptoms. Baseline mean ± SD
WAIS III Digit Span: total WMS III Logical Memory: immediate recall WMS III Logical Memory: delayed recall ROCFT: immediate recall ROCFT: delayed recall WCST: total attempts WCST: perseverative errors Stroop Inference Test: total reaction time (seconds) Stroop Inference Test: interference (seconds) WAIS III Digit Span: total WMS III Logical Memory: immediate recall WMS III Logical Memory: delayed recall ROCFT: immediate recall ROCFT: delayed recall WCST: total attempts WCST: perseverative errors Stroop Inference Test: total reaction time (seconds) Stroop Inference Test: interference (seconds)
12-week follow-up mean ± SD
P value
Baseline mean ± SD
BDI≤12 24.0 ± 3.3 18.2 ± 7.8 16.0 ± 8.2 19.0 ± 7.2 19.0 ± 7.2 96.8 ± 22.1 13.5 ± 10.9 50.0 ± 11.3
24.3 ± 3.3 20.8 ± 7.1 19.0 ± 7.8 24.2 ± 6.0 23.4 ± 5.9 89.2 ± 19.8 9.2 ± 8.2 45.6 ± 10.4
0.370a 0.002a 0.001a < 0.001a < 0.001a 0.004b < 0.001b < 0.001b
9.9 ± 5.5
8.9 ± 4.9
HADSA≤3 24.3 ± 3.5 18.1 ± 7.6 15.7 ± 8.3 19.4 ± 6.8 19.6 ± 6.7 99.2 ± 23.4 13.5 ± 10.0 40.0 ± 10.6
25.1 20.9 18.9 25.1 24.4 90.9 10.4 45.6
9.5 ± 5.2
9.0 ± 5.0
± ± ± ± ± ± ± ±
3.2 7.3 7.6 5.8 5.7 55.6 9.3 9.9
12-week follow-up mean ± SD
P value
BDI > 12 24.0 ± 4.1 16.3 ± 7.4 13.5 ± 7.8 18.3 ± 7.4 18.3 ± 7.4 99.7 ± 23.6 13.8 ± 11.6 50.1 ± 11.7
25.2 21.0 18.7 22.8 22.6 93.2 11.4 45.4
0.007b < 0.001a < 0.001b < 0.001a < 0.001a 0.018b 0.203b < 0.001b
0.178a
10.2 ± 6.8
9.6 ± 5.3
0.493b
0.025a < 0.001a < 0.001a < 0.001a < 0.001a 0.001b 0.003b < 0.001a
HADSA > 3 23.5 ± 3.9 16.1 ± 7.4 13.3 ± 7.9 17.5 ± 7.6 18.2 ± 6.0 97.1 ± 21.9 13.9 ± 12.7 51.4 ± 12.5
24.1 ± 3.3 20.7 ± 8.1 18.7 ± 8.4 21.3 ± 6.4 21.0 ± 6.3 90.8 ± 20.3 9.8 ± 9.2 45.2 ± 9.8
0.117b < 0.001a < 0.001b < 0.001b < 0.001a 0.074b 0.021b < 0.001b
0.503a
10.9 ± 7.1
9.3 ± 5.2
0.106b
± ± ± ± ± ± ± ±
3.2 8.2 5.2 6.6 6.4 23.6 10.3 9.3
Note: BDI = Beck Depressive Inventory; HADSA = Anxiety subscale of the Hospital Anxiety Depression Scale; WAIS III = Wechsler Adult Intelligence Scale (Third edition); WMS III = Wechsler Memory Scale (Third edition); ROCFT = Rey-Osterrieth Complex Figure Test; WCST = Wisconsin Card Sorting Test. a paired sample t-test. b Wilcoxon Signed-Rank.
showed better visual memory and visuospatial working memory than current users. It is worth noting that Morgan's study, unlike the present one, did not actually follow the users through the process of abstinence and measured cognitive changes before and after abstinence. The current results are in contrast to the study by Morgan, Monaghan, and Curran (2004), which raised the possibility of persistent deficits in attentional functioning in abstinent ketamine users. The inconsistency between the two studies may be due to methodological
differences. The sample size in the Morgan et al. study was only 18, which may be too small to provide adequate statistical power to detect changes. Also, users in the Morgan et al. study only reported reduced use but not abstinence of ketamine, while participants in the current study abstained from ketamine for 12 weeks. We examined the role of possible confounding factors such as dependence severity, polysubstance use, baseline cognitive function, and mood symptoms with the stratified analysis. The most consistent 6
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finding was that low baseline cognitive function predicted improvement in cognitive function following abstinence. Previous studies of subjects with alcohol dependence found that poorer baseline performance was related to greater recovery, possibly because there is more room for recovery when impairment is greater (Schulte et al., 2014). Improvement in the SCST perseverative errors score was observed only in the group with less severe ketamine dependence. As the effect of dependence severity was only apparent in one of the two SCST scores and was not observed in the other executive function test, this result should be interpreted with caution. In subjects with alcohol dependence, the number of previous detoxifications had a negative impact on recovery of cognitive functions (Schulte et al., 2014). In a 2-year followup study of a group of 20 detoxified patients with chronic Korsakoff syndrome, a worse cognitive outcome was associated with a greater number of previous detoxifications (Fujiwara, Brand, Borsutzky, Steingass, & Markowitsch, 2008). In a 6-month prospective study, duration of alcohol use was negatively related to memory improvement after abstinence (Pitel et al., 2009). The extent and duration of dependence were also found to be negatively correlated with neurocognitive recovery in cocaine dependent patients (Schulte et al., 2014). The influence of polysubstance use on cognitive impairment was mixed. Improvement in verbal memory was not observed in the polysubstance users whereas improvement in one of the WCST scores was only observed in the polysubstance group. A study of 565 ketamine users found no significant cognitive differences between those who were heavy users of other drugs and those who were not (Zhang et al., 2018). There are several possible reasons for this finding. First, the participants in the present study had used ketamine for much longer overall or on more days in the past 2 years than other drugs. Second, the effects of different drugs on cognition are similar, mainly because they all cause cognitive impairment through the same dopaminergic transportation pathway (Moghaddam, Adams, Verma, & Daly, 1997). The impact of mood symptoms on cognitive recovery was also mixed. Improved performance in the digit span test was observed only in the group with higher depressive symptoms whereas improvement in the WCST was found in the group with low mood symptoms. In a study of 41 patients with alcohol dependence, improvement in emotional states did not correlate with the change in working memory following abstinence (Petit et al., 2017). Depressive and anxiety symptoms were reduced after a 12-week abstinence from ketamine in this study. A strong association between depression and cognition has been established in polysubstance users (Stevens, Peschk, & Schwarz, 2007) and in young adults with substance abuse disorders (Latvala et al., 2009). This finding is consistent with those reported in methamphetamine and cocaine users. Two studies found that depressive symptoms significantly decreased in methamphetamine-dependent chronic users after 2-3 weeks of abstinence (Bagheri, Mokri, Khosravi, & Kabir, 2015; Zorick et al., 2010). Similarly, the severity of depressive and anxiety symptoms decreased after 4 weeks of abstinence in cocaine-dependents users (Weddington, Brown, Haertzen, et al., 1990). The strengths of this study include its prospective design, large sample size, non-hospital based recruitment of subjects, inclusion of subjects with a diagnosis of substance use disorder, exclusion of subjects with a psychiatric comorbidity, and abstinence verified by urine testing. The major shortcomings of the study were the attrition rate and the characteristics of the study sample. Only 52.9% of recruited ketamine users remained in the study and completed the 12-week followup. The completed and drop-out groups were comparable on most measures, including education and the pattern of ketamine use. The drop-out group was only 1 to 2 years younger, and both groups were in their mid-20s. Most of the participants were men in both groups. These characteristics suggest that the high attrition rate did not result in a strongly biased sample. Participants in the current sample had a history of using other psychotropic drugs in addition to ketamine. It is possible that the observed changes in cognition could have been due to stopping
the use of substances other than ketamine, although this is unlikely, as the frequency of use of these substances was considerably lower than that of ketamine. Alcohol, sedatives and hypnotics, and cough medicine were more likely to have influenced the results as they were more frequently used (1.3 to 1.7 days per week) one month prior to the baseline assessment, compared to cocaine, methamphetamine and ecstasy (0.3 to 0.4 days per week). These drugs might have affected the cognitive performance at baseline and the change in cognitive function at follow-up. Improvement of cognition has been observed following abstinence from alcohol, for instance (Rourke & Grant, 1999). Furthermore, the same set of cognitive tests was conducted twice and a learning effect may have contributed to the observed improvement in performance. In addition, because all of the participants lived in a controlled environment, other factors, such as a regular sleep pattern, balanced diet, and regular exercise might have contributed to the observed changes in cognition. Finally, updated versions of the WAIS and WMS tests were not used because we did not have access to later editions. In conclusion, chronic ketamine users' cognitive performance improved after 12 weeks of abstinence. This is useful information for frontline health care workers in their attempt to motivate chronic users to achieve and maintain abstinence from ketamine. Future research should be conducted in non-residential settings, with the inclusion of a control group and a ketamine-only user group, measures to reduce attrition, longer duration of follow-up, use of an alternative form, and the latest editions of cognitive tests. Declaration of Competing Interest None. Acknowledgements The projected was funded by the Beat Drug Fund. References Andrade, C. (2017). Ketamine for Depression, 1: Clinical Summary of Issues Related to Efficacy, Adverse Effects, and Mechanism of Action. J. Clin. Psychiatry, 74(4), e415–e419. https://doi.org/10.4088/JCP.17f11567. Bagheri, M., Mokri, A., Khosravi, A., & Kabir, K. (2015). Effect of abstinence on depression, anxiety, and quality of life in chronic methamphetamine users in a therapeutic community. Int. J. High Risk Behav. Addict. 4(3), e23903. https://doi.org/10.5812/ ijhrba.23903. Bergman, S. A. (1999). Ketamine: review of its pharmacology and its use in pediatric anesthesia. Anesth. Prog. 46(1), 10–20. Bokor, G., & Anderson, P. D. (2014). Ketamine: an update on its abuse. J. Pharm. Pract. 27(6), 582–586. https://doi.org/10.1177/0897190014525754. Central Registry of Drug Abuse (2018). Common type of drugs abused. Retrieved from Hong Kong Special Administrative Region: https://www.nd.gov.hk/en/statistics_list. htm. Chen, R., Lee, A., Chan, R., Chen, E., Tang, S., & Chum, K. (2005). A study on the cognitive impairment and other harmful effects caused by ketamine abuse. Retrieved from https://www.nd.gov.hk/pdf/Ketamine-eng.pdf. Curran, H. V., & Monaghan, L. (2001). In and out of the K-hole: a comparison of the acute and residual effects of ketamine in frequent and infrequent ketamine users. Addiction, 96(5), 749–760. https://doi.org/10.1080/09652140020039116. Curran, H., & Morgan, C. (2000). Cognitive, dissociative and psychotogenic effects of ketamin in recreational users on the night of drug use and 3 days later. Addiction, 95(4), 575–590. Fujiwara, E., Brand, M., Borsutzky, S., Steingass, H.-P., & Markowitsch, H. J. (2008). Cognitive performance of detoxified alcoholic Korsakoff syndrome patients remains stable over two years. J. Clin. Exp. Neuropsychol. 30(3), 576–587. Gossop, M., Darke, S., Griffiths, P., Hando, J., Powis, B., Hall, W., & Strang, J. (1995). The Severity of Dependence Scale (SDS): psychometric properties of the SDS in English and Australian samples of heroin, cocaine and amphetamine users. Addiction, 90(5), 607–614. https://doi.org/10.1046/j.1360-0443.1995.9056072.x. Heaton, R. K., Chelune, G. J., Talley, J. L., Kay, G. G., & Curtiss, G. (1993). Wisconsin Card Sorting Test manual revised and expanded. USA: Psychological Assessment Resources, Inc. Hesse, M. (2006). The Beck Depression Inventory in patients undergoing opiate agonist maintenance treatment. Br. J. Clin. Psychol. 45(3), 417–425. https://doi.org/10. 1348/014466505x68069. Jia, Z., Liu, Z., Chu, P., McGoogan, J. M., Cong, M., ... Lu, L. (2015). Tracking the
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