Salience attribution and its relationship to cannabis-induced psychotic symptoms.

BACKGROUND: Cannabis is a widely used drug associated with increased risk for psychosis. The dopamine hypothesis of psychosis postulates that altered salience processing leads to psychosis. We therefore tested the hypothesis that cannabis users exhibit aberrant salience and explored the relationship between aberrant salience and dopamine synthesis capacity. METHOD: We tested 17 cannabis users and 17 age- and sex-matched non-user controls using the Salience Attribution Test, a probabilistic reward-learning task. Within users, cannabis-induced psychotic symptoms were measured with the Psychotomimetic States Inventory. Dopamine synthesis capacity, indexed as the influx rate constant K i cer , was measured in 10 users and six controls with 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine positron emission tomography. RESULTS: There was no significant difference in aberrant salience between the groups [F 1,32 = 1.12, p = 0.30 (implicit); F 1,32 = 1.09, p = 0.30 (explicit)]. Within users there was a significant positive relationship between cannabis-induced psychotic symptom severity and explicit aberrant salience scores (r = 0.61, p = 0.04) and there was a significant association between cannabis dependency/abuse status and high implicit aberrant salience scores (F 1,15 = 5.8, p = 0.03). Within controls, implicit aberrant salience was inversely correlated with whole striatal dopamine synthesis capacity (r = -0.91, p = 0.01), whereas this relationship was non-significant within users (difference between correlations: Z = -2.05, p = 0.04). CONCLUSIONS: Aberrant salience is positively associated with cannabis-induced psychotic symptom severity, but is not seen in cannabis users overall. This is consistent with the hypothesis that the link between cannabis use and psychosis involves alterations in salience processing. Longitudinal studies are needed to determine whether these cognitive abnormalities are pre-existing or caused by long-term cannabis use.

Drug cue induced overshadowing: selective disruption of natural reward processing by cigarette cues amongst abstinent but not satiated smokers.

BACKGROUND: Addicts show both reward processing deficits and increased salience attribution to drug cues. However, no study to date has demonstrated that salience attribution to drug cues can directly modulate inferences of reward value to non-drug cues. Associative learning depends on salience: a more salient predictor of an outcome will 'overshadow' a less salient predictor of the same outcome. Similarly, blocking, a demonstration that learning depends on prediction error, can be influenced by the salience of the cues employed. METHOD: This study investigated whether salient drug cues might interact with neutral cues predicting financial reward in an associative learning task indexing blocking and overshadowing in satiated smokers (n=24), abstaining smokers (n=24) and non-smoking controls (n=24). Attentional bias towards drug cues, craving and expired CO were also indexed. RESULTS: Abstaining smokers showed drug cue induced overshadowing, attributing higher reward value to drug cues than to neutral cues that were equally predictive of reward. Overshadowing was positively correlated with expired CO levels, which, in turn, were correlated with craving in abstainers. An automatic attentional bias towards cigarette cues was found in abstainers only. CONCLUSIONS: These findings provide the first evidence that drug cues interact with reward processing in a drug dependent population.

Sub-chronic impact of cannabinoids in street cannabis on cognition, psychotic-like symptoms and psychological well-being.

BACKGROUND: Cannabis varies considerably in levels of its two major constituent cannabinoids - (delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Recently, we found evidence that those who smoked cannabis containing detectable levels of CBD had fewer psychotic-like symptoms than those whose cannabis had no CBD. The present study aimed, first, to replicate those findings and, second, to determine whether protective effects of CBD may extend to other harms of cannabis, such as memory impairment and reduced psychological well-being. METHOD: A total of 120 current cannabis smokers, 66 daily users and 54 recreational users were classified into groups according to whether analysis of their hair revealed the presence or absence of CBD and high versus low levels of THC. All were assessed on measures of psychosis-like symptoms, memory (prose recall; source memory) and depression/anxiety. RESULTS: Lower psychosis-like symptoms were found in those whose hair had CBD compared with those without. However, this was seen only in recreational users, who had higher levels of THC in their hair. Higher THC levels in hair were associated with increased depression and anxiety. Prose recall and source memory were poorer in daily users with high THC levels in hair while recognition memory was better in individuals with CBD present in hair. CONCLUSIONS: CBD attenuates the psychotic-like effects of cannabis over time in recreational users. Higher THC negatively impacts on memory and psychological well-being. These findings raise concerns for the harms stemming from use of varieties such as 'skunk' (sensimillia), which lack any CBD but currently dominate the supply of cannabis in many countries.

Neurocognitive function and schizophrenia-proneness in individuals dependent on ketamine, on high potency cannabis ('skunk') or on cocaine.

BACKGROUND: Ketamine, psychostimulants and cannabis have all been associated with psychotic phenomena but no study has directly compared users of these drugs. AIMS: The aim of this study was to assess schizophrenia proneness and neurocognitive function in individuals dependent upon ketamine, cannabis and cocaine. METHOD: 130 volunteers - 29 'skunk' users, 22 cocaine users, 21 ketamine users, along with 28 'recreational' poly-drug users and 30 drug-naïve controls - were assessed on the Schizophrenia Proneness Instrument, Adult version (SPI-A). They were specifically asked to rate symptoms when not under the acute influence of a psychoactive drug. RESULTS: Ketamine and skunk users manifested the greatest attentional and cognitive disturbances. The symptom profile of the dependent ketamine users was very similar to that of prodromal individuals who transitioned to psychosis. CONCLUSIONS: Given the recent rapid rise in use of high potency cannabis and of ketamine, these findings are important and clinicians should be careful to rule out the effects of persistent drug use, especially in users of ketamine or skunk, when assessing an individual's risk of psychosis. A longitudinal study is needed to differentiate which basic symptoms persist following abstention from ketamine and skunk.

Acute cannabis use causes increased psychotomimetic experiences in individuals prone to psychosis.

BACKGROUND: Epidemiological evidence suggests a link between cannabis use and psychosis. A variety of factors have been proposed to mediate an individual's vulnerability to the harmful effects of the drug, one of which is their psychosis proneness. We hypothesized that highly psychosis-prone individuals would report more marked psychotic experiences under the acute influence of cannabis. METHOD: A group of cannabis users (n=140) completed the Psychotomimetic States Inventory (PSI) once while acutely intoxicated and again when free of cannabis. A control group (n=144) completed the PSI on two parallel test days. All participants also completed a drug history and the Schizotypal Personality Questionnaire (SPQ). Highly psychosis-prone individuals from both groups were then compared with individuals scoring low on psychosis proneness by taking those in each group scoring above and below the upper and lower quartiles using norms for the SPQ. RESULTS: Smoking cannabis in a naturalistic setting reliably induced marked increases in psychotomimetic symptoms. Consistent with predictions, highly psychosis-prone individuals experienced enhanced psychotomimetic states following acute cannabis use. CONCLUSIONS: These findings suggest that an individual's response to acute cannabis and their psychosis-proneness scores are related and both may be markers of vulnerability to the harmful effects of this drug.

Journey through the K-hole: phenomenological aspects of ketamine use.

Although recreational use of the dissociative anaesthetic drug ketamine is currently increasing, little is known about the phenomenological aspects of its use. We therefore designed a structured interview to examine initiation experiences, positive and negative effects of ketamine use, and concerns about the drug and its long-term effects. Ninety participants (30 frequent users, 30 infrequent 'recreational' users and 30 ex-users who had abstained from use for at least 3 months) were interviewed and reported drug use was verified by hair sample analysis. The most appealing aspects of ketamine for two-thirds of users were "melting into the surrounding", "visual hallucinations", "out-of-body experiences" and "giggliness". Unappealing effects for half of users were "memory loss" and "decreased sociability". Frequent ketamine users expressed more concerns than other groups about long-term effects on physical health problems, especially K-cramps and cystitis, whereas ex-users were more concerned about mental health problems. Addictive/dependent patterns of behaviour were also a concern: the majority of frequent users reported using the drug without stopping until supplies ran out and the mean increase in dosage in this group was six-fold from initiation to current use. We have identified specific health issues which seem uniquely related to ketamine use. Additionally, the dependence on ketamine frequently reported by users may be a cause for concern as its popularity grows and substance misuse services should be made aware of this when clients present in the future.

Ketamine for the treatment of addiction: Evidence and potential mechanisms.

Ketamine is a dissociative anaesthetic drug which acts on the central nervous system chiefly through antagonism of the n-methyl-d-aspartate (NMDA) receptor. Recently, ketamine has attracted attention as a rapid-acting anti-depressant but other studies have also reported its efficacy in reducing problematic alcohol and drug use. This review explores the preclinical and clinical research into ketamine's ability to treat addiction. Despite methodological limitations and the relative infancy of the field, results thus far are promising. Ketamine has been shown to effectively prolong abstinence from alcohol and heroin in detoxified alcoholics and heroin dependent individuals, respectively. Moreover, ketamine reduced craving for and self-administration of cocaine in non-treatment seeking cocaine users. However, further randomised controlled trials are urgently needed to confirm ketamine's efficacy. Possible mechanisms by which ketamine may work within addiction include: enhancement of neuroplasticity and neurogenesis, disruption of relevant functional neural networks, treating depressive symptoms, blocking reconsolidation of drug-related memories, provoking mystical experiences and enhancing psychological therapy efficacy. Identifying the mechanisms by which ketamine exerts its therapeutic effects in addiction, from the many possible candidates, is crucial for advancing this treatment and may have broader implications understanding other psychedelic therapies. In conclusion, ketamine shows great promise as a treatment for various addictions, but well-controlled research is urgently needed. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

The effects of cannabidiol on impulsivity and memory during abstinence in cigarette dependent smokers.

Acute nicotine abstinence in cigarette smokers results in deficits in performance on specific cognitive processes, including working memory and impulsivity which are important in relapse. Cannabidiol (CBD), the non-intoxicating cannabinoid found in cannabis, has shown pro-cognitive effects and preliminary evidence has indicated it can reduce the number of cigarettes smoked in dependent smokers. However, the effects of CBD on cognition have never been tested during acute nicotine withdrawal. The present study therefore aimed to investigate if CBD can improve memory and reduce impulsivity during acute tobacco abstinence. Thirty, non-treatment seeking, dependent, cigarette smokers attended two laboratory-based sessions after overnight abstinence, in which they received either 800 mg oral CBD or placebo (PBO), in a randomised order. Abstinence was biologically verified. Participants were assessed on go/no-go, delay discounting, prose recall and N-back (0-back, 1-back, 2-back) tasks. The effects of CBD on delay discounting, prose recall and the N-back (correct responses, maintenance or manipulation) were null, confirmed by a Bayesian analysis, which found evidence for the null hypothesis. Contrary to our predictions, CBD increased commission errors on the go/no-go task. In conclusion, a single 800 mg dose of CBD does not improve verbal or spatial working memory, or impulsivity during tobacco abstinence.

AKT1 genotype moderates the acute psychotomimetic effects of naturalistically smoked cannabis in young cannabis smokers.

Smoking cannabis daily doubles an individual's risk of developing a psychotic disorder, yet indicators of specific vulnerability have proved largely elusive. Genetic variation is one potential risk modifier. Single-nucleotide polymorphisms in the AKT1 and catechol-O-methyltransferase (COMT) genes have been implicated in the interaction between cannabis, psychosis and cognition, but no studies have examined their impact on an individual's acute response to smoked cannabis. A total 442 healthy young cannabis users were tested while intoxicated with their own cannabis-which was analysed for delta-9-tetrahydrocannbinol (THC) and cannabidiol content-and also ± 7 days apart when drug-free. Psychotomimetic symptoms and working memory were assessed on both the sessions. Variation at the rs2494732 locus of the AKT1 gene predicted acute psychotic response to cannabis along with dependence on the drug and baseline schizotypal symptoms. Working memory following cannabis acutely was worse in females, with some suggestion of an impact of COMT polymorphism on working memory when drug-free. These findings are the first to demonstrate that AKT1 mediates the acute response to cannabis in otherwise healthy individuals and implicate the AKT1 pathway as a possible target for prevention and treatment of cannabis psychosis.

The effects of nicotine dependence and acute abstinence on the processing of drug and non-drug rewards.

RATIONALE: Drug addiction may be characterised by a hypersensitivity to drug rewards and a hyposensitivity to non-drug rewards. This imbalance may become further polarised during acute abstinence. OBJECTIVES: (i) Examine the differences between dependent and occasional smokers in choices for, motivation for and self-reported wanting and liking of cigarette and non-drug rewards. (ii) Examine the effects of 12-h nicotine abstinence on these metrics. METHODS: Dependent (n = 20) and occasional, non-dependent smokers (n = 20) were tested after ad libitum smoking and ≥12-h of nicotine abstinence. A novel task was developed (Drug, Reward and Motivation-Choice (DReaM-Choice)) in which different rewards (cigarettes, music and chocolate) could be won. In each trial, participants chose between two rewards and then could earn the chosen reward via repeated button-pressing. Participants subsequently 'consumed' and rated subjective liking of the rewards they had won. RESULTS: Compared with occasional smokers, dependent smokers made more choices for (p < 0.001), pressed more for (p = 0.046) and reported more wanting (p = 0.007) and liking (p < 0.001) of cigarettes, and also made fewer choices for chocolate (p = 0.005). There were no differences between the groups on button-pressing for chocolate or music. However, the balance between drug and non-drug reward processing was different between the groups across all metrics. Twelve-hour nicotine abstinence led to more cigarette choices (p < 0.001) and fewer music choices (p = 0.042) in both groups. CONCLUSIONS: Nicotine dependence was associated with a hypersensitivity to cigarette rewards, but we found little evidence indicating a hyposensitivity to non-drug rewards. Our findings question the moderating influence of dependence on how acute nicotine abstinence affects reward processing.

Effects of ecstasy on cooperative behaviour and perception of trustworthiness: a naturalistic study.

BACKGROUND: Acute recreational use of 3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') can promote pro-social effects which may alter interpersonal perceptions. AIMS: To explore such effects, this study investigated whether acute recreational use of ecstasy was associated with changes in individual perception of trustworthiness of people's faces and co-operative behaviours. METHOD: An independent group, repeated measures design was used in which 17 ecstasy users were tested on the night of drug use (day 0) and again three days later (day 3); 22 controls were tested on parallel days. On each day, participants rated the trustworthiness of 66 faces, carried out three co-operative behaviour tasks (public good; dictator; ultimatum game) and completed mood self-ratings. RESULTS: Acute ecstasy use was associated with increased face trustworthiness ratings and increased cooperative behaviour on the dictator and ultimatum games; on day 3 there were no group differences on any task. Self-ratings showed the standard acute ecstasy effects (euphoria, energy, jaw clenching) with negative effects (less empathy, compassion, more distrust, hostility) emerging on day 3. CONCLUSIONS: Our findings of increased perceived trustworthiness and co-operative behaviours following use of ecstasy suggest that a single dose of the drug enhances aspects of empathy. This may in turn contribute to its popularity as a recreational drug and potentially to its enhancement of the therapeutic alliance in psychotherapy.

Attentional bias to incentive stimuli in frequent ketamine users.

BACKGROUND: The attention-grabbing properties of drugs to drug-using individuals have been well documented and recent research has begun to suggest that such attentional bias may be related to the severity of drug dependency. Dependence on ketamine has been reported anecdotally but no systematic study has investigated this phenomenon. We aimed to explore attentional biases to incentive stimuli in different populations of ketamine users. METHOD: Using a dot-probe paradigm, attentional bias to both drug-related and money-related stimuli was investigated in 150 participants: 30 frequent ketamine users, 30 infrequent ketamine users, 30 ex-ketamine users, 30 poly-drug users and 30 non-drug-using controls. Two stimulus presentation times were used (200 and 2000 ms) to investigate whether attentional bias was as a result of an automatic or a more conscious attentional shift. Participants also rated the degree to which stimuli used in the dot-probe paradigm were pleasurable. RESULTS: Frequent ketamine users demonstrated an attentional bias to both types of incentive stimuli only at the short stimulus presentation interval and this was significantly correlated with degree of ketamine use. No attentional biases were observed in any of the other groups. All groups rated money stimuli as more pleasurable than neutral stimuli. CONCLUSIONS: These data support incentive models of drug use and demonstrate the ability of the attentional bias paradigm to discriminate recreational drug users from those with more dependent patterns of use. Ketamine is a potentially dependence-forming drug.