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Abstract Although 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) has been shown to damage brain serotonin (5-HT) neurons in animals and possibly humans, little is known about the long-term consequences of MDMA-induced 5-HT [...]

Background: Addiction is a worldwide problem with major health complications. Despite intensive treatment, relapse rates remain high. The prevalence of cognitive impairment is high in patients with substance use disorders (SUDs) and is associated with treatment dropout and relapse. Evidence indicates that cognitive function training in persons with SUDs may support treatment. Therefore, the use of web-based tools to test and train cognitive functions is of increasing interest., Objective: The goal of this study was to determine the feasibility and acceptability of a serious gaming smartphone app to test and train cognitive functions in addition to the treatment of SUDs., Methods: A prospective observational study was conducted with 229 patients seeking addiction treatment. The patients were offered 2 smartphone apps in addition to regular care: MyCognition Quotient (MyCQ) assessed cognitive functions and AquaSnap trained these functions. The feasibility was determined based on acceptance rates. The acceptability of the smartphone apps was qualitatively analyzed based on the answers to a questionnaire. Patient characteristics were compared between patients who played and did not play smartphone games. Explorative correlation analyses were performed between the playing time and cognitive assessment scores., Results: Of the 229 patients who were offered the apps, 110 completed the MyCQ assessment, and 59 started playing AquaSnap, yielding acceptance rates of 48.0% and 25.8%, respectively. The group that completed the MyCQ assessment was significantly more educated than the group that did not download the apps (χ 2 2 =7.3; P=.03). The education level did not differ significantly between the group that played AquaSnap and the group that did not (P=.06). There were relatively more women in the AquaSnap playing group than in the nonplaying group (χ 2 1 =6.5; P=.01). The groups did not differ in terms of age, substance use, treatment setting, mood, or quality of life. With respect to acceptability, 83% (38/46) of the patients who filled out the questionnaire enjoyed taking the MyCQ measurement, whereas 41% (14/34) enjoyed playing the AquaSnap game. Furthermore, 76% (35/46) and 68% (23/34) rated the apps MyCQ and AquaSnap, respectively, as easy. More playing minutes was associated with decreased working memory reaction time and executive functioning accuracy., Conclusions: Our study showed that the use of a smartphone app for cognitive assessment in patients with SUDs who are interested and highly educated is feasible and acceptable for the subgroup that was asked to fill out a perception questionnaire. However, the use of a smartphone app for cognitive training was less feasible for this group of patients. Improvement of the training application and enhancement of the motivation of clients are needed. Despite these limitations, the present results provide support for future research investigating the use of smartphone apps for cognitive assessment and training in relation to the treatment of SUDs., (©Thelma Schilt, Elvira Sharine Ruijter, Nikky Godeschalk, Marit van Haaster, Anna E Goudriaan. Originally published in JMIR Formative Research (https://formative.jmir.org), 06.09.2022.)

Objective: Detecting dementia in people who are illiterate or have a low level of education is complicated because many cognitive screening tests are not suitable for these persons. Caregiver or informant-based judgment of cognitive status may aid diagnosis. Our goal was to investigate the diagnostic accuracy of the Informant Questionnaire for Cognitive Decline in the Elderly (IQCODE) in a population of elderly non-Western migrants with a high illiteracy rate. Second, we wanted to investigate the diagnostic accuracy of IQCODE and Rowland Universal Dementia Screening (RUDAS) combined., Method: 109 geriatric outpatients and 20 community controls were included. Geriatricians provided a research diagnosis of intact cognition (n = 27), mild cognitive impairment (MCI; n = 33) or dementia (n = 49). Diagnostic accuracy was calculated for the clinical sample (n = 109). ROC curves for prediction of group status for IQCODE, RUDAS and the combination of both were created., Results: Predictive validity was high for both IQCODE and RUDAS and was highest for the combination (Area Under the Curve .91). Sensitivity, specificity, Youden index, predictive value, and likelihood ratio for IQCODE and RUDAS are reported., Conclusions: In this study in non-Western elderly migrants, half of whom were illiterate, the IQCODE proved to be a valid instrument for dementia detection, and adding the RUDAS increased accuracy. Combining performance-based and informant-based data is recommended to enhance diagnostic precision.

Background: Diagnosing dementia in elderly immigrants is often difficult due to language and cultural barriers, low education, and illiteracy. We compared the diagnostic accuracy of the Rowland Universal Dementia Assessment Scale (RUDAS) to that of the Mini Mental State Examination (MMSE)., Methods: A total of 144 patients (42 with intact cognition, 44 with mild cognitive impairment [MCI], and 58 with dementia) were administered both instruments and were diagnosed by specialists blinded for MMSE and RUDAS results., Results: Areas under the curve for discriminating intact cognition from MCI and dementia were comparable for RUDAS (0.81; 95% confidence interval 0.74-0.88) and MMSE (0.75; 95% confidence interval 0.69-0.85). Education and literacy were not correlated with the RUDAS but had a medium-large correlation with the MMSE (rho = 0.39)., Conclusions: The study provides additional evidence for the usefulness of the RUDAS in a highly illiterate, culturally diverse geriatric outpatient population.

Background: Substance Use Disorders (SUDs) have been associated with impaired neurocognitive functioning, which may (partly) improve with sustained abstinence. New treatments are emerging, aimed at improving cognitive functions, and being tested. However, no integrated review is available regarding neurocognitive recovery following sustained abstinence., Objectives: In this review, results from prospective studies on neurocognitive recovery using neuropsychological assessments before and after sustained abstinence from SUDs are summarized and discussed., Results: Thirty-five prospective studies were selected for this review, including twenty-two alcohol, three cannabis, four cocaine, three (meth)amphetamine, and three opioid studies. Results suggest that some cognitive functions (partially) recover after sustained abstinence, and that there are predictors of an unfavorable course such as poly-substance use and number of previous detoxifications., Conclusions: Prospective studies indicate that sustained abstinence after SUDs generally results in (partial) neurocognitive recovery. However, a final answer regarding full recovery awaits prospective studies with neurocognitive assessments before, during, and after sustained abstinence from SUDs. New interventions that might enhance neurocognitive recovery after abstinence are discussed, including neurocognitive training, medication and neuromodulation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

This article reviews neuropsychological performance in frequent users of cocaine, (meth)amphetamines, ecstasy, opiates, alcohol, and cannabis. We searched the scientific literature published in the last five years, focusing on studies that required at least 2 weeks of abstinence from drug use, and included a control group. All substances of abuse, except cannabis, were associated with sustained deficits in executive functioning, especially inhibition. In addition, verbal memory decrements were consistently found in cocaine, (meth)amphetamines and ecstasy users, but not in heroin or cannabis users. More specific executive functioning deficits were reported depending on the substance of abuse. Cocaine was associated with diminished cognitive flexibility, whereas (meth)amphetamines were associated with worse cognitive planning functions compared to controls. Opiate studies showed lower scores on verbal fluency in opiate dependent subjects compared to controls. Working memory and visuospatial abilities were compromised in alcohol abusers. In ecstasy users, inconsistent findings have been reported across neuropsychological domains, with the exception of inhibition and verbal memory. There was little evidence for sustained cognitive impairments in adult abstinent cannabis users. Recognition of neuropsychological problems related to different substances can help to select subjects that will benefit most from treatment. Furthermore, a better understanding of the neuropsychological impairments in drug abusing individuals could help to explain the remitting course of substance abuse disorders and to improve psychological interventions.

Rationale: Studies reporting ecstasy-induced serotonin-toxicity and (neuro)psychological dysfunctions have been conducted in young adults. Little is known about ecstasy effects later in life, when serotonin levels and cognition decrease as a consequence of normal ageing., Objective: This study aimed to assess whether harmful effects of ecstasy only add to or also interact with age-related neuropsychological decline., Methods: Attention, verbal and visual memory, visuospatial ability, self-reported depression, sensation-seeking and impulsivity were assessed in middle-aged moderate to heavy ecstasy/polydrug users (n = 17) and compared with none or very mild ecstasy using polydrug users (matched for age, gender, intelligence and other drugs; n = 16) and a group of drug-naive controls (n = 20)., Results: Moderate to heavy ecstasy/polydrug users performed significantly worse on a verbal memory task than none or very mild ecstasy using polydrug users and drug naives. Moderate and heavy ecstasy/polydrug users also differed significantly from drug-naives on measures of depression, sensation-seeking and impulsivity but not from none or very mild ecstasy-using polydrug users., Conclusion: This study in middle-aged ecstasy/polydrug users replicated findings of studies in younger ecstasy users, showing a harmful effect of ecstasy on verbal memory. There was no clear support for an interaction between harmful effects of ecstasy use and age-related memory decline or mid-life depression.

Rationale: Ecstasy (+/-3,4-methylenedioxymethamphetamine) is a widely used recreational drug that may damage the serotonin system and may entail neuropsychological dysfunctions. Few studies investigated predictors for ecstasy use. Self-reported impulsivity does not predict the initiation of ecstasy use; the question is if neuropsychological indicators of impulsivity can predict first ecstasy use., Objective: This study tested the hypothesis that a neuropsychological indicator of impulsivity predicts initiation of ecstasy use., Materials and Methods: Decision-making strategy and decision-making reaction times were examined with the Iowa Gambling Task in 149 ecstasy-naive subjects. The performance of 59 subjects who initiated ecstasy use during a mean follow-up period of 18 months (range, 11-26) was compared with the performance of 90 subjects that remained ecstasy-naive., Results: Significant differences in decision-making strategy between female future ecstasy users and female persistent ecstasy-naive subjects were found. In addition, the gap between decision-making reaction time after advantageous choices and reaction time after disadvantageous choices was smaller in future ecstasy users than in persistent ecstasy-naives., Conclusion: Decision-making strategy on a gambling task was predictive for future use of ecstasy in female subjects. Differences in decision-making time between future ecstasy users and persistent ecstasy-naives may point to lower punishment sensitivity or higher impulsivity in future ecstasy users. Because differences were small, the clinical relevance is questionable.

There is ample evidence for decreased verbal memory in heavy Ecstasy users. However, findings on the presence of a dose-response relation are inconsistent, possibly due to individual differences in genetic vulnerability. Catechol-O-methyltransferase (COMT) is involved in the catabolism of Ecstasy. Therefore, COMT gene polymorphisms may moderate this vulnerability. We prospectively assessed verbal memory in subjects with a high risk for future Ecstasy use, and compared 59 subjects after first Ecstasy use with 60 subjects that remained Ecstasy-naive. In addition, we tested the interaction effect of Ecstasy and the functional val (158)met polymorphism on verbal memory. Met-allele carriers were somewhat more sensitive to the effects of Ecstasy on verbal learning than homozygous val-subjects. After correction for the use of other substances this effect was no longer statistically significant. The findings suggest that the COMT gene moderates the negative effect of Ecstasy on memory, but also other drug use seems to play a role.

Background: Neurotoxic effects of ecstasy have been reported, although it remains unclear whether effects can be attributed to ecstasy, other recreational drugs or a combination of these., Aims: To assess specific/independent neurotoxic effects of heavy ecstasy use and contributions of amphetamine, cocaine and cannabis as part of The Netherlands XTC Toxicity (NeXT) study., Method: Effects of ecstasy and other substances were assessed with (1)H-magnetic resonance spectroscopy, diffusion tensor imaging, perfusion weighted imaging and [(123)I]2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane ([(123)I]beta-CIT) single photon emission computed tomography (serotonin transporters) in a sample (n=71) with broad variation in drug use, using multiple regression analyses., Results: Ecstasy showed specific effects in the thalamus with decreased [(123)I]beta-CIT binding, suggesting serotonergic axonal damage; decreased fractional anisotropy, suggesting axonal loss; and increased cerebral blood volume probably caused by serotonin depletion. Ecstasy had no effect on brain metabolites and apparent diffusion coefficients., Conclusions: Converging evidence was found for a specific toxic effect of ecstasy on serotonergic axons in the thalamus.

Heavy ecstasy use has been associated with neurocognitive deficits in various behavioral and brain imaging studies. However, this association is not conclusive owing to the unavoidable confounding factor of polysubstance use. The present study, as part of the Netherlands XTC Toxicity study, investigated specific effects of ecstasy on working memory, attention, and associative memory, using functional magnetic resonance imaging (fMRI). A large sample (n=71) was carefully composed based on variation in the amount and type of drugs that were used. The sample included 33 heavy ecstasy users (mean 322 pills lifetime). Neurocognitive brain function in three domains: working memory, attention, and associative memory, was assessed with performance measures and fMRI. Independent effects of the use of ecstasy, amphetamine, cocaine, cannabis, alcohol, tobacco, and of gender and IQ were assessed and separated by means of multiple regression analyses. Use of ecstasy had no effect on working memory and attention, but drug use was associated with reduced associative memory performance. Multiple regression analysis showed that associative memory performance was affected by amphetamine much more than by ecstasy. Both drugs affected associative memory-related brain activity, but the effects were consistently in opposite directions, suggesting that different mechanisms are at play. This could be related to the different neurotransmitter systems these drugs predominantly act upon, that is, serotonin (ecstasy) vs dopamine (amphetamine) systems.

Rationale: Heavy ecstasy use in humans has been associated with cognitive impairments and changes in cognitive brain function supposedly due to damage to the serotonin system. There is concern that even a single dose of 3,4-methylenedioxymethamphetamine may be neurotoxic, but very little is known about the consequences of a low dose of ecstasy for cognitive brain function., Objectives: The objective of the study was to assess the effects of a low dose of ecstasy on human cognitive brain function using functional magnetic resonance imaging (fMRI)., Materials and Method: We prospectively studied, as part of the NeXT (Netherlands XTC toxicity) study, sustained effects of a low dose of ecstasy on brain function in 25 subjects before and after their first episode of ecstasy use (mean 2.0 +/- 1.4 ecstasy pills, on average 11.1 +/- 12.9 weeks since last ecstasy use), compared to 24 persistent ecstasy-naive controls, also measured twice and matched with the novice users on age, gender, IQ, and cannabis use. Cognitive brain function was measured in the domains of working memory, selective attention, and associative memory using fMRI., Results: No significant effects were found of a low dose of ecstasy on working memory, selective attention, or associative memory neither at the behavioral level nor at the neurophysiological level., Conclusions: This study yielded no firm evidence for sustained effects of a low dose of ecstasy on human cognitive brain function. The present findings are relevant for the development of prevention and harm reduction strategies. Furthermore, the study is relevant to the discussion concerning potential therapeutic use of ecstasy.

Context: Ecstasy (street name for [+/-]-3,4-methylenedioxymethamphetamine [MDMA]) use has been associated with cognitive deficits, especially in verbal memory. However, owing to the cross-sectional and retrospective nature of currently available studies, questions remain regarding the causal direction and clinical relevance of these findings., Objective: To examine the relationship between Ecstasy use and subsequent cognitive performance., Design: A prospective cohort study in Ecstasy-naive subjects with a high risk for future first Ecstasy use, as part of the Netherlands XTC Toxicity study. The initial examination took place between April 10, 2002, and April 28, 2004; follow-up was within 3 years after the initial examination., Setting and Participants: One hundred eighty-eight healthy Ecstasy-naive volunteers (mean age, 22 years) were recruited. Of these, 58 subjects started using Ecstasy (mean cumulative dose, 3.2 tablets; median cumulative dose, 1.5 tablets). They were compared with 60 persistent Ecstasy-naive subjects matched on age, sex, intelligence, and use of substances other than Ecstasy. Differences in cognition between Ecstasy users and Ecstasy-naive subjects were adjusted for differences in cannabis and other recreational drug use., Main Outcome Measures: Change scores between the initial examination and follow-up on neurocognitive tests measuring attention, working memory, verbal and visual memory, and visuospatial ability., Results: At the initial examination, there were no statistically significant differences in any of the neuropsychological test scores between persistent Ecstasy-naive subjects and future Ecstasy users. However, at follow-up, change scores on immediate and delayed verbal recall and verbal recognition were significantly lower in the group of incident Ecstasy users compared with persistent Ecstasy-naive subjects. There were no significant differences on other test scores., Conclusions: Our findings suggest that even a first low cumulative dose of Ecstasy is associated with decline in verbal memory. Although the performance of the group of incident Ecstasy users is still within the normal range and the immediate clinical relevance of the observed deficits is limited, long-term negative consequences cannot be excluded.

Although there are indications that ecstasy users have higher levels of depression, impulsivity, and sensation seeking, it is unknown whether these are consequences of ecstasy use or predisposing factors for starting ecstasy use. We prospectively assessed the predictive value of depression, impulsivity, and sensation seeking on future first time ecstasy use. We also assessed whether depression, impulsivity, and sensation seeking had changed after first ecstasy use. Depression, impulsivity, and sensation seeking were assessed using self-report questionnaires in 188 ecstasy-naive volunteers with high probability for future ecstasy use. After a mean follow-up of 17 months, measurements were repeated in 59 incident ecstasy users (mean 6.0 tablets) and 61 matched persistent ecstasy-naive volunteers. Only experience seeking (subscale of the sensation seeking scale) predicted future ecstasy use (OR -- 1.05, 95% CI 1.00 to 1.10), but after adjustment for potential confounders this was not significant anymore. At follow-up, significant effects of ecstasy use on the general and the disinhibition subscale of the sensation seeking scale were observed (after adjustment for potential confounders: regression coefficient B 0.51, 95% CI 0.20 to 0.83 and B -- 3.25, 95% CI 1.74 to 4.76, respectively). These data indicate that depression, impulsivity, and sensation seeking do not predict first time ecstasy use in a population of young adults with the intention to start using ecstasy and that low level ecstasy use does not seem to cause depression or impulsivity. However, low level ecstasy use may increase (certain aspects of) sensation seeking.

This paper describes the objectives and methods of The Netherlands XTC Toxicity (NeXT) study focussing on the causality, course, and clinical relevance of ecstasy neurotoxicity. Previous studies suggest that ecstasy (3,4 methylene-dioxymethamphetamine, MDMA, XTC) is toxic toward brain serotonin axons, but most of these studies have serious methodological limitations. The current study is a combination of different approaches with three substudies: (1) a crosssectional substudy among heavy ecstasy users and controls with variation in drug use, which will provide information about potential neurotoxic consequences of ecstasy in relation to other drugs; (2) a prospective cohort substudy in ecstasy-naive subjects with high risk for future ecstasy use, which will provide information on the causality and short-term course of ecstasy use and potential neurotoxicity, and (3) a retrospective cohort substudy in lifetime ecstasy users and matched controls of an existing epidemiological sample that will provide information on long-term course and outcome of ecstasy use in the general population. Neurotoxicity is studied using (a) different imaging techniques (beta-CIT SPECT, 1H-MR spectroscopy, diffusion tensor imaging, perfusion weighted imaging and functional magnetic resonance imaging), and (b) neuropsychological and psychiatric assessments of memory, depression, and personality. The combined results will lead to conclusions that can be used in prevention messages, clinical decision making, and the development of an (inter)national ecstasy policy.