Neurocognitive function in recreational ketamine: a scoping review

NEUROCOGNITIVE FUNCTION IN RECREATIONAL KETAMINE: A SCOPING REVIEW FUNCIONAMIENTO NEUROCOGNITIVO EN EL USO RECREATIVO DE LA DE KETAMINA: UNA REVISIÓN DE ALCANCE Carolina Bellas-Arnosi Facultad de Psicología, Universidad de Santiago de Compostela. https://orcid.org/0000-0002-2948-7874 Socorro Rodríguez-Holguín Facultad de Psicología, Universidad de Santiago de Compostela. https://orcid.org/0000-0003-1502-987X Marta Beranuy Facultad de Ciencias de la Salud, Universidad Pública de Navarra.Grupo de Investigación en Ciberpsicología, Universidad Internacional de La Rioja. https://orcid.org/0000-0003-3226-9082 Fran Calvo Departament de Pedagogia, Institut de Recerca sobre Qualitat de Vida, Universitat de Girona. https://orcid.org/0000-0002-0300-8548 Contact information of corresponding author Marta Beranuy Adress: Campus Arrosadia, Calle Cataluña, s/n, 31006, Pamplona (Navarra), Spain. Telephone number: +34 948 169 000 Email: [email protected] Como citar: Bellas-Arnosi, C., Rodríguez-Holguín, S., Beranuy, M. & Calvo, F. (2024). Neurocognitive function in recreational ketamine: a scoping review. Health and Addictions / Salud y Drogas, 24(1),111-129. https://doi.org/10.21134/haaj.v24i1.782 Vol. 24. Núm. 1, 111-129 2024 HEALTH AND ADDICTIONS/SALUD Y DROGAS DOI: 10.21134/haaj.v24i1.782 ISSN 1578-5319 - ISSNe 1988-205X Recibido: 30/05/2022 / Aceptado: 29/11/2023 NEUROCOGNITIVE FUNCTION IN RECREATIONAL KETAMINE: A SCOPING REVIEW Health and Addictions / Salud y Drogas. Vol. 24 (1) 111-129 2024. 112 Resumen Introducción: La ketamina es un anestésico disociativo que actúa como antagonista de los receptores NMDA, que desempeñan un papel crucial en el fortalecimiento del aprendizaje y la memoria. No es de extrañar que su uso repetido pueda estar asociado al deterioro de las funciones cognitivas. Objetivo: El objetivo de este trabajo es realizar una revisión de alcance de los efectos neurocognitivos del uso recreativo de la ketamina. Método: Se realizó una búsqueda bibliográfica en PyscINFO, PubMed, Scopus y Web of Science para el periodo 2000-2020. Finalmente, se incluyeron en la revisión 25 artículos originales. Resultados y conclusiones: Los resultados revelan que 1) el consumo agudo de ketamina produce déficits en la memoria de trabajo, la memoria semántica y la memoria episódica, 2) el consumo frecuente de ketamina se ha asociado con el deterioro de la memoria episódica y, posiblemente, del aprendizaje, la función ejecutiva, la atención y la memoria semántica, 3) las personas diagnosticadas con trastorno por consumo de ketamina presentan déficits en la memoria episódica visual y verbal, la memoria de trabajo y la atención, 4) los déficits detectados pueden mejorar e incluso revertir tras un periodo de abstinencia. Palabras clave Ketamina, neurocognitivo, uso de sustancias, abstinencia, revisión narrativa. Abstract Introduction: Ketamine is a dissociative anesthetic that acts as an antagonist to NMDA receptors, which play a crucial role in strengthening learning and memory. Not surprisingly, its repeated use may be associated with impaired cognitive functions. Objective: The aim of this paper is to carry out a scoping review of the scientific literature on the neurocognitive effects of recreational ketamine use. Method: A bibliographic search was conducted in PyscINFO, PubMed, Scopus and Web of Science for the period 2000-2020. Eventually, 25 original articles were included in the review. Results and conclusions: The findings reveal that 1) acute ketamine use produces deficits in working memory, semantic memory, and episodic memory, 2) frequent ketamine use has been associated with impairment in episodic memory and possibly in learning, executive function, attention, and semantic memory, 3) people diagnosed with ketamine use disorder have deficits in visual and verbal episodic memory, working memory and attention, 4) deficits detected may improve and even be reverted after a period of abstinence. Keywords Ketamine, neurocognitive, drug use, abstinence, narrative review. Bellas-Arnosi, et al., 2024 Health and Addictions / Salud y Drogas. Vol. 24 (1) 111-129 2024. 113 Ketamine is a dissociative anesthetic used mainly in veterinary and human medicine with limited use in humans due to side effects such as hallucinations and vivid dreams. Such effects have been reported by patients that undergo surgical procedures where ketamine is used as an anesthetic (Muetzelfeldt et al., 2008). Its consideration as a dissociative anesthetic is due to the fact that the substance produces a functional and electrophysiological dissociation between the limbic and thalamocortical systems, depressing the thalamocortical pathways and activating the limbic system, although some studies have suggested that excitation occurs in both systems (Cruz et al., 2009). Pharmacologically, ketamine acts as a non-competitive antagonist of N-methyl-D- aspartate (NMDA) receptors. In addition to binding to these, it also interacts with central and spinal opioid receptors and with cholinergic muscarinic receptors, noradrenergic receptors and serotonergic receptors (Centro de información de Medicamentos, 2020). However, both its analgesic action and effects at a psychological level are associated with its activity on NMDA glutamatergic receptors. Such receptors are known for their role as mediators of sensory inputs at spinal, cortical and thalamic levels, and as moderators of emotional responses, learning and memory (Sassano-Higgins et al., 2016). Ketamine is causing high concern because of its use in Asia (during the period 2013-2017, 89% of global ketamine was seized in Asia) and its increasing use in other regions(United Nations Office on Drugs and Crime, 2019). Although in the European framework its use is less frequent when compared to other substances, over the last few years it has increased in countries such as the Czech Republic, Spain and the United Kingdom. In Spain, the rate of lifetime ketamine use is 0.9 per 100 inhabitants (in the population aged 15-64). The prevalence increases up to 1.7% in the 25-34 age group (Delegación del Gobierno para el Plan Nacional sobre Drogas, 2019). The increase in the prevalence of the use of this substance outside the clinical setting makes it essential to evaluate its short- and long-term effects, in order to understand the risks to which users may be exposed. The main acute effects caused by ketamine are: numbness, loss of balance and dizziness that can result in potentially dangerous falls for the user (Jansen, 2000) ; at a psychological level, it can transiently induce symptoms similar to schizophrenia. The long-term effects of its use seem to especially affect the urinary system, where it can produce ulcerative cystitis, and the gastrointestinal system, giving rise to “K cramps” or abdominal pains derived from the use of the substance (Sassano-Higgins et al., 2016). At a psychiatric level, its prolonged use can induce depressive symptomatology and delusional thinking (Morgan & Curran, 2012; Sassano-Higgins et al., 2016). Lastly, at a cognitive level, its use is associated with the impairment of memory, learning and some executive functions (Tang et al., 2019). The increasing trend that appears to be observed in recreational ketamine use may constitute a public health problem that should be managed with the support of existing scientific evidence. Given that no reviews have been found in recent years on the neurocognitive effects derived from recreational ketamine use, it is essential to update this information. Thus, the aim of the present work is to perform a scoping review of the scientific literature available from 2000 to 2020, on the neurocognitive effects of recreational ketamine use. Method The bibliographic search for this scoping review was performed using the following databases: PyscINFO, Scopus, Web of Science (WOS) and PubMed. The search strategy included the following terms: “ketamine” AND “abuse” AND “cognitive”. The term “cognitive” was selected instead of “neurocognitive” due to the fact that it yielded a larger number of articles and also included all results pertaining to the second term. The three selected terms had to be included in all fields (Psycinfo), in the title, abstract or keywords (Scopus and WOS) or in the title and abstract (PubMed). The search covered publications between 1st January 2000 and 31st December 2020, in English or Spanish. The final search strategy used in PubMed was (“Ketamine”[Title/Abstract] AND “Abuse”[Title/Abstract] AND “Cognitive”[Title/Abstract] AND 2002/01/01:2020/12/31[Date - Publication]) AND (“Ketamine”[Title/Abstract] AND “Abuse”[Title/Abstract] AND “Cognitive”[Title/Abstract]) AND 2002/01/01:2020/12/31[Date - Publication]. Inclusion criteria were: 1) empirical studies with human subjects, 2) exploration of neurocognitive functioning using neuropsychological assessment techniques, and 3) in samples of recreational ketamine users (frequent, infrequent, polydrug users, with ketamine use disorder or former users). Exclusion criteria were: 1) review articles and grey NEUROCOGNITIVE FUNCTION IN RECREATIONAL KETAMINE: A SCOPING REVIEW Health and Addictions / Salud y Drogas. Vol. 24 (1) 111-129 2024. 114 literature, 2) studies not assessing neurocognitive functioning or assessing neurocognitive functioning by selfreport, and 3) studies that did not to explore the effects of recreational ketamine use (e.g. studies on schizophrenia or on the therapeutic and controlled use of ketamine). Figure 1 shows the search strategy and article selection. Figure 1. Flow chart, following the different phases of the review. Results A total of 209 articles were initially selected (43 in PsycINFO, 18 in PubMED, 69 in Web of Science and 79 in Scopus). After removing duplicates, the number was narrowed down to 130, of which 43 were excluded in the first screening as they did not fit the objective of the study. This left 87 articles, 62 of which were excluded because they did not meet the inclusion criteria. In the end, 25 original articles were included. All 25 articles were published in English. The temporal distribution of the results is homogeneous over the 20-year period that the present study considers, with years 2018 and 2013 standing out with six and three articles, respectively. The manuscripts were published in 11 different journals. “Addiction” was the most used source. The studies were conducted in three different countries: 12 in China, 11 in the UK and two in Taiwan. The articles were Bellas-Arnosi, et al., 2024 Health and Addictions / Salud y Drogas. Vol. 24 (1) 111-129 2024. 115 classified according to the characteristics of the sample used in each study (table 1); publications that studied frequent ketamine users make up the largest category (n=12). The variables related to the ketamine use of participants in the 25 studies are heterogeneous. The most common criterion employed to classify frequent ketamine users (FKU) was having used ketamine 24 times or more over a six month period in the last two years (Liang et al., 2020; Liang et al., 2013; Liang et al., 2014; Tang et al., 2013; Zhang et al., 2018, 2020), followed by having done so more than four times a week (Morgan et al., 2009, 2010; Morgan et al., 2008). The most frequently used criterion for selecting non-frequent users of ketamine was to use less than four times a week (Morgan et al., 2009, 2010). The most frequently used criterion to constitute groups of former ketamine users (EKU) was sustained abstinence for at least one month (Morgan et al., 2009, 2010; Tang et al., 2013). Three studies were conducted with subjects that had been diagnosed with ketamine use disorder (KUD) according to the diagnostic criteria set by the DSM-IV-TR for substance dependence (Cheng et al., 2018; Ke et al., 2018; Wang et al., 2018) or by using a dependence test (Morgan et al., 2012) (Severity Dependence Scale, SDS). One aspect that should be taken into account is the fact that four of the cross-sectional studies that were reviewed (Liang et al., 2020; Liang et al., 2013; Liang et al., 2014; Zhang et al., 2018) did not include a clinical diagnosis (KUD) as a requirement to be part of the sample. However, it was assessed using the SDS, and the mean scores exceeded the cut-off point considered for dependence by Morgan et al. (2012). A wide variety of instruments were used to assess episodic (visual and verbal) declarative memory and its different sub-processes (recall and familiarity) (e.g., Wechsler Memory Scale -WMS III-, Rey-Osterrieth Complex Figure test -ROCF-, Chinese Auditory-Verbal Learning Test -CAVLT-, Continuous Visual Memory Test -CVMT-, source memory task, prose recall task), semantic memory (e.g., Verbal Fluency test), attention (Digit Span Test -DVT- or the arithmetic subtest of the WAIS-III), and executive functions such as working memory (Digit Span Task, the Spatial Working Memory of the CANTAB or the 2-back task), response inhibition (Stroop test) or concept formation skills and cognitive flexibility (Wisconsin Card Sorting Task -WCST). Processing speed (Symbols and Digits Test -SDMT-) and implicit memory (priming tasks) were also assessed. Table 1 shows the tests in more detail and Table 2 presents the results of the studies. The twenty-five articles that were reviewed explore, using neuropsychological tests, neurocognitive functioning associated with acute, frequent, and prolonged ketamine use. The reviewed papers explored episodic (recall and familiarity) and semantic declarative memory, attention, and executive functions (working memory, response inhibition and planning, among others). Other processes such as processing speed and implicit memory were also assessed to a lesser extent. Special emphasis was placed on declarative memory, since it seems to be the most affected dimension, as already indicated by previous reviews (Morgan & Curran, 2006). The role of the NMDA receptor in memory and learning processes could explain this impact (Tsien et al., 1996). NEUROCOGNITIVE FUNCTION IN RECREATIONAL KETAMINE: A SCOPING REVIEW Health and Addictions / Salud y Drogas. Vol. 24 (1) 111-129 2024. 116 Table 1. Author information, aims, sample characteristics and methods of the articles included in the review. Author/s Aim Sample characteristics Methods Acute ketamine use C urran and Morgan (2000) To examine the acute and residual effects of ketamine on cognitive function and schizotypal and dissociative symptomatology in recreational users. Total (n=39) KU (n=20, consumption in the last 30 minutes); CGP (n=19). Prose recall; Verbal fluency;Speed of comprehension test; Serial sevens; Digit cancellation task; Word -stem completion task; Word -subtraction task; Curran and Monaghan (2001) Examine whether frequent use of ketamine produces chronic effects (ensure that they are chron ic and not persistent). Total (n=37, polydrug users, ketamine use 30 minutes before): FKKU (n=18, >2 times per month); NFKU (n=19, ≤2 times per month). Prose recall; Verbal fluency; Speed of comprehension test; Serial sevens task; Digit cancellation task. Morgan, Ricelli et al. (2004) To determine whether ketamine use is associated with deficits in episodic memory. Total (n=40) KU (n=20, ketamine use in the last 10 minutes); CGP (n=20) Source memory task Uhlhaas et al. (2007) To determine whether repeat users have deficits in pe rceptual organisation. Total (n=32) KU (n=16, consumption in the last 15 minutes); CGP (n=16). Contour integration test Frequent users Morgan et al. (2006) Examining semantic priming following repeated self - administration by recreational ketamine users T otal (n=32) KU (n=16, ≥2 times per month); CGP (n=16). Semantic priming task with a manipulation of frequency (high and low) and stimulus onset asynchrony (SOA: short -200 msec, long- 750 msec). Morgan et al. (2008) To explore the attentional biases of diff erent populations of ketamine users with respect to incentive stimuli. Total (n=150) FKU (n=30, >4 times/week); NFKU (n=30, <4 times/week, but ≥1 time/month); EKU (n=30, abstinent ≥3 months); CGP (n=30); CG (n=30)) Dot -probe task; Two times of stimulus presentation (200 and 2000ms); 2 types of stimuli: drug -related or money-related.. Morgan et al. (2009)* To determine how variations in ketamine use (including abstinence) affect neurocognitive function. Total (n=150) FKU (n=30, >4 times/week); NFKU (n=30, < 4 times/week, but ≥1 time per month); EKU (n=30, abstinent ≥1 month); CGP (n=30); CG (n=30) Tasks from the Cambridge Automated Neuropsychological Test Assessment Battery (CANTAB): Pattern Recognition Memory (PRM), Spatial Working Memory (SWM), Stockings of Cambridge (SOC). Source memory task; Prose recall (Rivermead Behavioural Memory Test); Fluency tasks (verbal and category); Hayling test. Stefanovic et al. (2009) Experiment 2. To assess cognitive functioning at the level of semantic processing in a grou p of ketamine users. FKU (n=22, ≥1 time/month for at least 1 year) CGP (n= 26) CG (n= 48) Direct semantic priming task (SOA: automatic -250 msec, strategic 750 msec). Chan et al. (2013) To investigate the effects of repeated ketamine self - Total (n=55) Symbol Digit Modalities Test (SDMT); Digit Vigilance Test (DVT); Bellas-Arnosi, et al., 2024 Health and Addictions / Salud y Drogas. Vol. 24 (1) 111-129 2024. 117 administration on frontal fluency, att ention, learning, and both verbal and non verbal memory. KU (n=25, ≥1 time/month in the last 2 years); CG (n=30) Stroop Color–Word Test (Stroop; Lee & Chan, 2000); Chinese Audito ry-Verbal Learning Test (CAVLT); Continuous Visual Memory Test (CVMT); Verbal Fluency Test (VFT); Ruff Figural Fluency Test (RFFT) Liang et al. (2013)* To compare the cognitive functioning of current and former polydrug users of ketamine with individuals who do not use illicit drugs. Total (n=200) PKU [n=100, PKU (≥24 times over 6 months in the last 2 years), ECKP (abstinent ≥ 30 days)]; CG (n= 100). Logical Memory and Word List subtests (WMS -III); Rey-Osterrieth Complex Figure Test (ROCF); Stroop Test; Wisconsin Card Sorting Test (WCST); Modified V erbal Fluency Test (MVFT); Digit Span Backwards Test (DSB). Liang et al. (2014) To explore gender differences in the effects of ketamine on cognitive functions in ketamine users. Total (n=200) KU (n=100, ≥24 times over 6 months in the last 2 years, 47♀ and 53♂); CG (n=100, 42♀ and 58 ♂) Logical Memory and Word List subtests (WMS -III); Stroop Test; Modified Verbal Fluency Test (MVFT); Wisconsin Card Sorting Test (WCST); Digit Span backwards task (DSB); ROCF Test. Tang et al. (2013)* Examining the co gnitive functions of young ketamine users. Total (n=200) FKU (n=100, ≥24 times over 6 months in the last 2 years): FKU (n=51, in the last month) and ECKF (n=49, abstinent ≥1 month). CG (n=100). Digit -symbol coding subtest (WAIS-III); Arithmetic subtest (WAISIII); Digit span subtest (WAIS -III); Logical memory subtest (WMSIII); ROCF test; Stroop test. Zeng et al. (2016) To compare ketamine, methadone and non-users on its impulsivity, antisocial personality and cognitive skills. Total (n=170) KU (n=51); MU (n=59); CG (n=60). Stop -signal test; Stroop test; 2-back task; Iowa Gambling Task. Zhang et al. (2018) To examine cognitive deficits in chronic ketamine users. To explore synergistic effects between ketamine and other drugs. Total (n=829) FKU (n= 565, ≥24 times over 6 months in the last 2 years): KU (n=286) and PKU (n=279). CG (n=261). Digit Span Subtest (WMS -III); Logical Memory Subtest (WMS-III); ROCF Test; Stroop Test; Wisconsin Card Sorting Test (WCST). Liang et al. (2020) To measure w hite matter volume and its relationship with cognitive and depressive symptoms in KU (FKF or PKU) compared to CG. FKU (n=39, K ≥24 times over 6 months in the last 2 years, other substances <1 time per month in the last 2 years). PKU (n=41, K+other substances ≥24 times over 6 months in the last 2 years). CG (n=46). WAIS-III (Digit Span Forward and Backward, Arithmetic); WMS-III Logic Memory delay recall, retention and recognition; WMS -III Word List delay recall and retention; Rey -Osterrieth Complex Figure te st Learning (WMS-III Logic Memory immediate recall, WMS -III Word List immediate recall; Modified Verbal Fluency Test; Stroop interference; Wisconsin Card Sorting Test; Digit Symbol Coding; Modified Boston Naming test. Zhang et al. (2020) To assess the cog nitive functioning of chronic ketamine users and to examine whether there is a relationship between these and early treatment dropout. Total (n=397). FKU (n=286, K ≥24 times over 6 months in the last 2 years, other drugs <24 times over 6 months in the last 2 years): Completers (n=165); Dropouts (n=121). Digit Span Subtest (WMS -III); Logical Memory Subtest (WMS-III); ROCF Test; Stroop Test; W isconsin Card Sorting Test (WCST). NEUROCOGNITIVE FUNCTION IN RECREATIONAL KETAMINE: A SCOPING REVIEW Health and Addictions / Salud y Drogas. Vol. 24 (1) 111-129 2024. 118 CG (n=111). Ketamine use disorder Morgan et al. (2012) To assess neurocognitive functioning in people dependent on ketamine, cannabis and cocaine. Total (n=130) KUD (n=21); ACAN (n=29); CANUD (n=22); PDU - cannabis, cocaine and ketamine - (n=28); CG (n=30). Prose recall; Digit span (forward and backwards); Verbal fluency; Category fluency. Cheng et al. (2018) To compare neurocognitive functioning, in relation to symptoms of psychosis, in KUD with psychosis with that of KUD without psychosis and people with a schizophrenia diagnosis. Total (n=149) KUD No psychosis (n=51), KUD Psychosis (23), SZ (n=75) (SZ=schizophrenia diagnosis) Cogstate Battery: Detection Task, Identification Task, One Back Task, Two Back Task, International shopping List Task and Delayed Recall Task, Groton Maze Learning Task and Delayed Recall Task, Social Emotional Cognition Task Ke et al. (2018) To examine the cognitive functioning of chronic ketamine users. Total (n=128) KUD (n=63); CG (n=65). Immediate/Delayed Visual Reproduction Test (WMS-RC); Immediate/Delayed Logical Memory Test (WMS -RC); Stroop Test; WCST; Continuous Performance Test (CPT). Siu et al. (2018) Evaluating the impact of a short -term inpatient and community support programme for ketamine abuse rs. Total (n= 118) KUD treatment (n=84) No KUD treatment (n=34) The Montreal Cognitive Assessment (MoCA) Wang et al. (2018) To assess the long -term consequences of chronic ketamine use Total (n=165) KUD (n=58); MAUD (n=49); CG (n=58) Brief Assessment of C ognition in Schizophrenia (BACS) Prospective studies on ketamine use Morgan, Monaghan et al. (2004) Follow - up of a cohort assessed 3 years earlier; analyse deficits observed 3 days after use. Total (n=28) KU (n=18); CGP (n=10) Speed of comprehension; Semantic (category) fluency; Prose recall; Digit cancellation task; Serial sevens task; Phonological (verbal) fluency. Morgan et al. (2010)* To assess the cognitive consequences of long -term ketamine use (1 -year follow-up). Total (n=150) FKU (n=30, ≥ 4 times a week); NFKU (n=30, < 4 times a week and minimum one month); EKU (n=30, ≥1 month of abstinence); CGP (n=30); CG (n=30). Tasks from the Cambridge Automated Neuropsychological Test Assessment Battery (CANTAB): Pattern Recognition Memory (PRM), Spatial Working Memory (SWM), Stockings of Cambridge (SOC). Source memory task; Prose recall (Rivermead Behavioural Memory Test); Fluency tasks (verbal and category). Abstinent users Tang et al. (2019) Investigating changes in cognitive function of abstinent ketamine users. KU in 12-week abstinence (n=114, use of ketamine or ketamine with any other illicit substance ≥24 times / 6 months). Stroop Test; WCST; Digit Span (WAIS -III); Logical Memory (WMSIII); ROCFT Test. Man (2020) To evaluate the cognitive and vocational impact of 3 interventions [Virtual Reality, Mentored Coaching and Waiting List (CG)] with ketamine users. KU in abstinence and treatment or waiting list (n=90, ≥24 times over 6 months in the last 2 years, no other drug use 1 or more times over the last 2 years). Does not specify length of abstinence. Digit Vigilance Test (DVT); Rivermead Behavioural Memory Test (RBMT); Wisconsin Card Sorting Test (WCST). Bellas-Arnosi, et al., 2024 Health and Addictions / Salud y Drogas. Vol. 24 (1) 111-129 2024. 119 Table 2. Results and conclusions of the articles included in the review Study Results and conclusions Curran and Morgan (2000) Day 0: lower CK performance in Prose Recall, Verbal Fluency, Category Generation, Comprehension Speed, Serial Subtraction Task, Digit Cancellation Task than GCP. Day 3: CK improvement in Prose recall, Verbal fluency, Serial subtraction task. Similar speed KU and CGP in Digit Cancellatio n Task. No improvement in Category generation. Word -stem completion task: No differences between groups. Ketamine appears to induce acute deficits in working, episodic and semantic memory. Three days after use, recreational users show impairments in semantic memory. Curran and Monaghan (2001) Day 0: similar score on prose recall, category generation, FKU lower performance than NFKU on verbal fluency and speed of comprehension. Day 3: NFKU performs better than FK on prose recall, category generation. Both groups perform better than Day 0 on speed of c omprehension. No between -group differences in serial subtraction task and digit cancellation. Frequent ketamine use produces long-term impairments in episodic memory and in aspects of semantic memory retrieval. Morgan, Ricelli et al. (2004) Day 3: KU show persistent deficits in source memory, but not in item recognition. Repeated ketamine use may produce chronic deficits in episodic memory. Uhlhaas et al. (2007) Day 0: KU made more errors. Day 3: errors made by both groups were similar (both made fewer errors). On the night of consumption, ketamine produces a dysfunction in contour integration, but this did not occur 3 days later, when participants were not under the effects of the drug. Morgan et al. (2006) KU showed inverse priming for low-frequency words in the long SOA and significantly less than CGP. Significant correlation of KU: days per month of consumption and the effect of short/long SOA on priming. The effect of reverse priming is indicative of alt erations in processing. Decreased priming for low-frequency words suggests that long-term ketamine use may impair semantic storage. Morgan et al. (2008) CKF showed an attentional bias to both types of incentive stimuli in the short stimulus presentation interval, which correlated significantly with the degree of ketamine consumption. No attentional bias was observed in any of the other groups. All groups rated money -related stimuli as more pleasant than neutral stimuli. Morgan et al. (2009)* FKU is associated with deficits in working memory, episodic memory and aspects of executive functioning. NFKU does not appear to produce neurocognitive deficits. No significant worsening in KUD (possible reversibility of deficits in frequent users). FKU group wors e performance in PRM, SWM, SOC and source memory task. No between -group differences in prose recall task, fluency tasks and Hayling test. 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