Prospective memory impairment in long-term opiate users

Rationale

Opiate use is associated with a range of neurological and cognitive deficits. However, to date, no studies have assessed whether these cognitive deficits extend to the ability to perform intended actions in the future (i.e. prospective memory). Reduced ability in this area might be anticipated due to impaired executive functions and episodic memory associated with long-term opiate use.

Objectives

The main objectives of this study are to assess the performance of long-term opiate users on a laboratory measure of prospective memory which closely simulates the types of prospective memory tasks encountered in everyday life (‘Virtual Week’) and to investigate the extent to which prospective memory performance is related to executive functions and episodic memory ability.

Methods

Twenty-six long-term heroin users enrolled in an opiate substitution program, and 30 controls with no previous history of drug use were tested on Virtual Week. Retrospective memory and executive functions were also assessed.

Results

Long-term opiate users were significantly impaired on prospective memory performance compared with controls (p?=?0.002, η² _p?=?0.17), and these deficits did not vary as a function of prospective memory task type (regular, irregular, event, time). The findings also suggest that retrospective memory difficulties contribute to the prospective memory difficulties seen in opiate users (r _s ?=?0.78, p?<?0.001) but that executive dysfunction is less influential.

Conclusions

Prospective memory is sensitive to long-term opiate use. Importantly, opiate users suffer from generalised deficits in prospective memory, regardless of the task demands, which may have significant implications for day-to-day functioning. These results may therefore contribute to the development of clinical intervention strategies to reduce the negative impact of prospective memory failures in daily life.     

Subjective effects of 3,4-methylenedioxymethamphetamine in recreational users

3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy) is a serotonergic neurotoxin in laboratory animals that has been used for recreational purposes by humans. The subjective effects of this drug were determined in recreational users at a university campus. Of individuals who had admitted to using MDMA recreationally, 100 of 143 agreed to complete a detailed questionnaire concerning the subjective effects of this Schedule I compound. The most common effect of MDMA was a heightened sense of "closeness" with other people (90% of subjects). Tachycardia, dry mouth, bruxism and/or trismus were reported by the majority of users. These effects probably result from the amphetaminelike properties of the drug. Visual hallucinations were reported by 20% of users. Untoward side effects were most common on the day following the use of MDMA, with complaints of muscle aches, fatiguability, depression, and difficulty concentrating noted by 21% to 36% of subjects. Sixty-seven percent of frequent users of the drug (six or more separate doses) reported that the "positive" effects of the drug decreased with successive doses while the "negative" effects increased. Although these observations should be considered preliminary, they represent the first documentation of the subjective effects of MDMA in recreational users and confirm previous reports obtained from patients treated with this drug.     

Prospective memory impairment in former users of methamphetamine

Rationale  Considerable research indicates that methamphetamine use is associated with neurocognitive impairment, but no empirical study to date has assessed whether these difficulties extend to memory for future intentions (prospective memory). Objectives  The present study assessed prospective performance on a laboratory measure of prospective memory that closely represents the types of prospective memory tasks that actually occur in everyday life and provides an opportunity to investigate the different sorts of prospective memory failures that occur (“Virtual Week”). Materials and methods  Twenty adults with confirmed history of methamphetamine use and dependence, currently engaged in rehabilitation and confirmed to be abstinent for an average period of 6 months, and 20 methamphetamine-naive participants were tested on Virtual Week. Various other aspects of cognitive function were also assessed, including retrospective memory and executive functioning. Results  Methamphetamine users were significantly impaired on Virtual Week, and these deficits did not vary as a function of specific prospective memory task demands. Of all the cognitive measures, cognitive inhibition shared greatest variance with group effects on the prospective memory measure. Conclusions  Prospective memory performance is sensitive to prior methamphetamine use even well into abstinence. Methamphetamine users experience generalized difficulties with prospective memory, suggesting that these deficits are likely to have important implications for day-to-day functioning.     

Acute and chronic effects of ketamine upon human memory: a review

Introduction Ketamine is attracting increasing research interest not only because of its powerful amnestic effects but also as a putative model of schizophrenia and as a substance with an expanding following of recreational users.Objective This article reviews the existing literature on the effects of acute ketamine on the memory of healthy volunteers and of repeated doses of ketamine in recreational users.Current trends Although there have been relatively few, often methodologically diverse, studies to date of the mnemonic effects of ketamine, there is an emerging consensus that an acute dose of the drug impairs the manipulation of information in working memory and produces decrements in the encoding of information into episodic memory. Preliminary evidence suggests that ketamine may differ from other classic amnestic drugs in impairing aspects of semantic memory. Acute-on-chronic effects in ketamine users generally mimic the pattern seen in controlled studies with healthy volunteers. However, chronic ketamine use may be associated with a more specific pattern of memory decrements and with episodic memory impairment, which might not abate following cessation of use.Future trends An important aim of future research should be to detail the specificity of ketamine’s amnestic effects on both a neuropharmacological and a cognitive level.     

Reliability,convergent and structural validity and cut-off score of the Severity of Dependence Scale for recreational ketamine users

Background and aimsThere is a lack of instruments for measuring ketamine substance use disorders. The aims were (i) to estimate the reliability and provide evidence of validity of the Severity of Dependence Scale (SDS) in a sample of recreational users, and (ii) propose a cut-off point to determine the presence of dependence.MethodsWe conducted a web-based cross-sectional survey with recreational users who accessed webs related to recreational drug use and harm reduction. 264 recreational ketamine users who had taken it in the past month participated in the study. The Spanish version of the SDS was used. Information on ketamine use-related problems and ketamine use patterns was also collected.ResultsThe reliability estimation calculated by the Cronbach’s alpha coefficient was 0.776. SDS showed evidence of convergent validity based on relationships with other variables. Two comparisons were made in this study to analyze the Receiver Operating Characteristic Curve. For frequency of use in the last month the area under curve (AUC) was 0.835 (CI = 0.775-0.895) with optimal discrimination at an SDS score of 3. For having been in treatment for decreasing or quitting ketamine use the AUC was 0.902 (CI = 0.840-0.963) and the cut-off point was 4. Confirmatory factor analysis showed a one-dimensional structure when Items 3 and 4 were correlated.ConclusionsThis study has provided evidence of reliability and validity of the ketamine version of the SDS for recreational users. Considering that ketamine use is linked to young people and its strong potential for causing serious impairment, a cut-off of 3 is proposed as indicative of dependence.     

The effects of a subpsychotic dose of ketamine on recognition and source memory for agency: implications for pharmacological modelling of core symptoms of schizophrenia.

Ketamine is increasingly used to model the cognitive deficits and symptoms of schizophrenia. We investigated the extent to which ketamine administration in healthy volunteers reproduces the deficits in episodic recognition memory and agency source monitoring reported in schizophrenia. Intravenous infusions of placebo or 100 ng/ml ketamine were administered to 12 healthy volunteers in a double-blind, placebo-controlled, randomized, within-subjects study. In response to presented words, the subject or experimenter performed a deep or shallow encoding task, providing a 2(drug) x 2(depth of processing) x 2(agency) factorial design. At test, subjects discriminated old/new words, and recalled the sources (task and agent). Data were analyzed using multinomial modelling to identify item recognition, source memory for agency and task, and guessing biases. Under ketamine, item recognition and cued recall of deeply encoded items were impaired, replicating previous findings. In contrast to schizophrenia, there was a reduced tendency to externalize agency source guessing biases under ketamine. While the recognition memory deficit observed with ketamine is consistent with previous work and with schizophrenia, the changes in source memory differ from those reported in schizophrenic patients. This difference may account for the pattern of psychopathology induced by ketamine.     

Prospective memory,everyday cognitive failure and central executive function in recreational users of Ecstasy

Chronic use of MDMA (3,4-methylenedioxymethamphetamine), or Ecstasy, is believed to lead to impaired psychological performance, including well-documented decrements in laboratory and field tests of retrospective memory. Less is known about the impact of Ecstasy on aspects of 'everyday' memory, despite obvious concerns about such effects. The three studies reported here focused on the impact of chronic Ecstasy use on prospective memory (PM), associated central executive function and other aspects of day-to-day cognition. In study 1 46 regular Ecstasy users were compared with 46 Ecstasy-free controls using the Prospective Memory Questionnaire (PMQ). Ecstasy users reported significantly more errors in PM (remembering to do something in the future); these findings persisted after controlling for other drug use and the number of strategies used to aid memory. No difference was found between representative subgroups on the Lies Scale of the Eysenck Personality Questionnaire. In study 2 a different group of 30 regular Ecstasy users and 37 Ecstasy-free controls was assessed on the PMQ and on a central executive task comprising verbal fluency measures. The results confirmed the significant impairments in long- and short-term PM and revealed corresponding impairments in verbal fluency. In study 3 15 Ecstasy users, 15 cannabis users and 15 non-drug users were assessed using the Cognitive Failures Questionnaire, which requires participants to provide ratings of the frequency of various day-to-day cognitive slips. The results indicate that the Ecstasy users did not perceive their general cognitive performance to be worse than that of controls. Taken together, these results suggest that Ecstasy users have impaired PM that cannot be explained by an increased propensity to exaggerate cognitive failures. These may be attributable, in part, to central executive deficits that are due to frontal lobe damage associated with Ecstasy use. Copyright 2001 John Wiley & Sons, Ltd.     

Cognitive performance in recreational ecstasy polydrug users: a two-year follow-up study

There is important preclinical evidence of long lasting neurotoxic and selective effects of ecstasy MDMA on serotonin systems in non-human primates. In humans long-term recreational use of ecstasy has been mainly associated with learning and memory impairments. The aim of the present study was to investigate the neuropsychological profile associated with ecstasy use within recreational polydrug users, and describe the cognitive changes related to maintained or variable ecstasy use along a two years period. We administered cognitive measures of attention, executive functions, memory and learning to three groups of participants: 37 current polydrug users with regular consumption of ecstasy and cannabis, 23 current cannabis users and 34 non-users free of illicit drugs. Four cognitive assessments were conducted during two years. At baseline, ecstasy polydrug users showed significantly poorer performance than cannabis users and non-drug using controls in a measure of semantic word fluency. When ecstasy users were classified according to lifetime use of ecstasy, the more severe users (more than 100 tablets) showed additional deficits on episodic memory. After two years ecstasy users showed persistent deficits on verbal fluency, working memory and processing speed. These findings should be interpreted with caution, since the possibility of premorbid group differences cannot be entirely excluded. Our findings support that ecstasy use, or ecstasy/cannabis synergic effects, are responsible for the sub-clinical deficits observed in ecstasy polydrug users, and provides additional evidence for long-term cognitive impairment owing to ecstasy consumption in the context of polydrug use.     

Monoaminergic dysfunction in recreational users of dexamphetamine

Preclinical studies suggest that dexamphetamine (dAMPH) can lead to monoaminergic neurotoxicity. This exploratory study aimed to investigate effects of recreational dAMPH use on the dopamine (DA) and noradrenaline (NA) systems in humans. To that purpose, eight male abstinent dAMPH (26.0±4.0 years) users and 10 age- and IQ-matched male healthy control subjects (23.0±3.8) underwent neuropsychological testing sensitive to DAergic function and single photon emission computed tomography (SPECT) scanning with [¹²³I]FP-CIT to determine striatal DA transporter (DAT) binding. In addition, changes in cerebral blood flow (CBF) induced by the DA/NA reuptake inhibitor methylphenidate (MPH) were measured using pharmacological magnetic resonance imaging (phMRI). Performance of dAMPH users was significantly worse on executive function and verbal memory tasks. Striatal DAT binding ratios were on average lower in dAMPH users (near-significant, p=0.05). In addition, CBF in control subjects decreased significantly in response to MPH in gray matter and basal ganglia, among which the striatum, thalamus and hippocampus by 10% to 29%. However, in dAMPH users the CBF response was blunted in most brain areas studied, only decreasing in the hippocampus and orbitofrontal cortex. When comparing groups, CBF response was found to be significantly different in the thalamus with a decrease for healthy controls and a blunted response in dAMPH users. Collectively, our findings of a blunted hemodynamic response in monoaminergic regions, in combination with indications for lower striatal DAT binding and poorer behavioral measures are likely to represent DAergic dysfunction in dAMPH users, although NAergic dysfunction may also play a role.     

The effects of a subanesthetic dose of ketamine on verbal memory in normal volunteers

Rationale N-methyl-d-aspartate (NMDA) glutamate receptor antagonists have been reported to induce schizophrenia-like symptoms in humans, including memory impairments. Although the NMDA receptor has been shown to impair memory acquisition by disrupting long-term potentiation (LTP), limited research has been done on studying the effects of NMDA antagonists on the post-LTP cascade of events implicated in consolidation as measured by administering the drug after the initial learning experience.Objective The purpose of this experiment was to examine the effect of ketamine on mental status and to identify NMDA antagonist-induced memory deficits by comparing the recall performance of items presented both immediately before and during ketamine infusion.Methods Thirteen normal controls received a 60-min infusion of ketamine in a randomized double-blind, cross-over design. Mental status was evaluated with the Brief Psychiatric Rating Scale and the Clinician-Administered Dissociative States Scale. The first 12-item word list was presented immediately before infusion, and two lists were subsequently presented during the infusion. Verbal memory performance was assessed by measuring the delayed cued recall of each list 30 min after its presentation.Results At the beginning, subjects experienced perceptual and reality distortion symptoms, followed later by mild subjective effects. Ketamine significantly reduced the delayed recall of words presented immediately before, but not during, drug infusion. Ketamine-induced decrements in verbal recall correlated significantly with plasma ketamine levels.Conclusion This study characterizes the behavioral effects associated with ketamine and suggests that ketamine decreases verbal memory performance by interfering with early consolidation processes.     

Behavioral analysis of diazepam-induced memory deficits: evidence for sedation-like effects

Rats were trained on a nonmatching-to-sample task with delays of 2, 5, and 10 min. Subsequently, performance was assessed in three groups of rats following treatment with saline or diazepam (2.0 mg/kg) administered acutely or tested chronically in six administrations. Relative to treatment with saline, diazepam produced a deficit in discrimination performance, which was greater in the acutely treated rats than in those treated chronically. The deficit was not dependent on the length of the delays. Diazepam-treated animals differed from controls in erring on trials in which they failed to investigate both test objects, failed to investigate the test object for a long enough period of time, and displaced the test object on the preferred side of the apparatus. The hypothesis that these effects represented a sedation-like reduction in behavioral variability was also supported by evidence of a diazepam-induced decrease in gross bodily activity, increase in inactivity, and increase in latencies to respond to objects. No support was found for the involvement of diazepam-induced changes in habituation, extinction, or reward effects.     

The general well-being of recreational drug users: a survey on the WWW

American drug policy is predicated upon a dichotomy between legal drugs and illegal drugs - good drugs that enhance health and bad drugs which damage health. The fact of psychiatric co-morbidity between substance misuse disorders and other mental disorders is commonly taken to mean that drug use is damaging to mental health. The purpose of this study was to examine the mental well-being of a sample of occasional, recreational drug users. DRUGNET was an on-line survey of recreational drug use by non-deviant adults via the WWW. Volunteer subjects (n=906) completed the survey over the internet between March and September 1997. Mental health was assessed utilizing the General Well-being Schedule (GWBS). A complete demographic profile of the sample was taken. The GWBS correlated with frequency of use, intoxication levels and types of drugs consumed. This study demonstrates the existence of healthy, normally functioning adults who occasionally use psychoactive drugs.     

Paradoxical sleep and memory: Long-term disruptive effects of anisomycin

The effects of the protein synthesis inhibitor Anisomycin (ANI) on Paradoxical Sleep (PS or REM sleep), slow wave sleep (SWS), and retention of one-trial inhibitory avoidance training was examined in mice in three separate experiments. In Experiment 1, mice injected with ANI 120 mg/kg and 210 mg/kg exhibited reductions in PS for 9 consecutive hours and ANI 40 mg/kg treated mice for 6 consecutive hours with no PS rebound in all three groups. ANI increased SWS commencing 3 hr postinjection, continuing for 9 consecutive hours and then returning to saline control levels. There were no significant differences between ANI-treated groups in the degree of SWS augmentation. In Experiment 2, Part A, ANI 120 mg/kg and 210 mg/kg but not ANI 40 mg/kg impaired retention measured 72 hr after training. In Experiment 2, Part B, ANI 120 mg/kg and 210 mg/kg induced amnesia from 3 to 9 hr post-training but ANI 40 mg/kg was effective only from 3 to 6 hr. In Experiment 3, the gradient of memory trace susceptibility to disruption by ECS was extended to 3 hr post-training in mice given immediate post-training injections of ANI 40 mg/kg. ANI 20 mg/kg and ANI 10 mg/kg alone or in combination with ECS was ineffective in extending the lability of the memory trace. The results of this study indicate that PS in the 3 hr period after aversively motivated training is not essential for memory processing. We suggest that memory stability and maintenance is dependent on PS occurring over a protracted time period.     

Long-term neuropsychological effects of ecstasy in middle-aged ecstasy/polydrug users

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.     

Auditory event-related potentials (P3) and cognitive performance in recreational ecstasy polydrug users: evidence from a 12-month longitudinal study

RATIONALE: There is important preclinical evidence of the long-lasting neurotoxic and selective effects of ecstasy (MDMA) on serotonin systems in nonhuman primates. In humans, long-term recreational use of ecstasy has been mainly associated with memory impairment. OBJECTIVE: The first aim of our study was to evaluate the cognitive and electrophysiological long-term alterations associated with lifetime ecstasy use within a sample of ecstasy polydrug users along a 1-year follow-up. Our second aim was to explore the relationship between specific cognitive functions and P300 (P3) event-related potentials (ERPs) in ecstasy users. MATERIALS AND METHODS: We conducted auditory P3 latency and amplitude and administered a battery of cognitive tests to three groups of subjects: 14 current ecstasy polydrug users, 13 current cannabis users, and 22 controls free of illicit drugs in two evaluations during 1 year. RESULTS: We found significant differences between ecstasy users and controls on cognitive measures of word fluency, processing speed, and memory recognition after 1-year follow-up. We found no significant differences between ecstasy and cannabis users or cannabis users and controls on cognitive tests. Lifetime ecstasy use was associated with poorer memory recognition. No group differences were shown on P3 latency or amplitude. Significant correlations emerged between P3 latency and cannabis lifetime use (higher cannabis use was related to faster latency, showing a paradoxical effect) but not with ecstasy exposure. CONCLUSIONS: Our findings provide evidence of mild long-term cognitive deficits among ecstasy polydrug users. Both ecstasy use and the dynamic interaction between ecstasy and cannabis effects may account for these deficits. No significant P3 alterations were found in ecstasy users.