Ravi K. Das

Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: A randomised, double-blind, placebo-controlled study in cannabis users

Acute administration of the primary psychoactive constituent of cannabis, Δ-9-tetrahydrocannabinol (THC), impairs human facial affect recognition, implicating the endocannabinoid system in emotional processing. Another main constituent of cannabis, cannabidiol (CBD), has seemingly opposite functional effects on the brain. This study aimed to determine the effects of THC and CBD, both alone and in combination on emotional facial affect recognition. 48 volunteers, selected for high and low frequency of cannabis use and schizotypy, were administered, THC (8 mg), CBD (16 mg), THC+CBD (8 mg+16 mg) and placebo, by inhalation, in a 4-way, double-blind, placebo-controlled crossover design. They completed an emotional facial affect recognition task including fearful, angry, happy, sad, surprise and disgust faces varying in intensity from 20% to 100%. A visual analogue scale (VAS) of feeling ‘stoned’ was also completed. In comparison to placebo, CBD improved emotional facial affect recognition at 60% emotional intensity; THC was detrimental to the recognition of ambiguous faces of 40% intensity. The combination of THC+CBD produced no impairment. Relative to placebo, both THC alone and combined THC+CBD equally increased feelings of being ‘stoned’. CBD did not influence feelings of ‘stoned’. No effects of frequency of use or schizotypy were found. In conclusion, CBD improves recognition of emotional facial affect and attenuates the impairment induced by THC. This is the first human study examining the effects of different cannabinoids on emotional processing. It provides preliminary evidence that different pharmacological agents acting upon the endocannabinoid system can both improve and impair recognition of emotional faces.

Cannabidiol reduces cigarette consumption in tobacco smokers: Preliminary findings

The role of the endocannabinoid system in nicotine addiction is being increasingly acknowledged. We conducted a pilot, randomised double blind placebo controlled study set out to assess the impact of the ad-hoc use of cannabidiol (CBD) in smokers who wished to stop smoking. 24 smokers were randomised to receive an inhaler of CBD (n=12) or placebo (n=12) for one week, they were instructed to use the inhaler when they felt the urge to smoke. Over the treatment week, placebo treated smokers showed no differences in number of cigarettes smoked. In contrast, those treated with CBD significantly reduced the number of cigarettes smoked by ~40% during treatment. Results also indicated some maintenance of this effect at follow-up. These preliminary data, combined with the strong preclinical rationale for use of this compound, suggest CBD to be a potential treatment for nicotine addiction that warrants further exploration.

Associations between cigarette smoking and cannabis dependence: A longitudinal study of young cannabis users in the United Kingdom

Highlights • We studied the extent that cigarette smoking predicts level of cannabis addiction.• We tested whether cigarette smoking mediates the effect of cannabis use on dependence.• We interviewed 298 cannabis and tobacco users, of which 65 were followed up.• Cigarette smoking accounted for 29% of the variance in cannabis dependence.• Cigarette smoking mediated the relationship between cannabis use and dependence.

Rewriting the valuation and salience of alcohol-related stimuli via memory reconsolidation.

The transient period of memory instability that can be triggered when memories are retrieved under certain conditions offers an opportunity to modify the maladaptive memories at the heart of substance use disorders (SUDs). However, very well-learned memories (such as those in excessive drinking and alcohol use disorders) are resistant to destabilisation when retrieved or may not destabilise at all. Memory retrieval and intervention procedures that reliably destabilise and update maladaptive motivational memories may help to improve the long-term treatment of SUDs. In 59 hazardous drinkers, we tested a novel retrieval procedure for destabilising well-learned cue-drinking memory networks that maximises prediction error (PE) via guided expectancy violation during retrieval of these memories. This was compared with a retrieval procedure without PE and no-retrieval controls. We subsequently counterconditioned alcohol cues with disgusting tastes and images in all groups and assessed responding to alcohol stimuli 1 week later. Counterconditioning following PE retrieval produced generalised reductions in oculomotor attentional bias, explicit valuation and outcome expectancies in response to alcohol cues 1 week after intervention, evidence of updating of distributed motivational drinking memory networks. These findings demonstrate that well-learned cue-drinking memories can be destabilised and that learning history need not constrain memory destabilisation if PE is maximised at retrieval. Broad rewriting of diverse aspects of maladaptive memory by counterconditioning is achievable following this procedure. The procedure described may provide a platform for the development of novel memory-modifying interventions for SUDs.

Acute and chronic effects of ketamine on semantic priming modeling schizophrenia

Acute administration of the N-methyl-d-aspartate receptor antagonist ketamine induces schizophrenia-like symptoms in healthy volunteers; furthermore, a window on ketamines chronic effects is provided by regular recreational users. The current study utilized both acute ketamine administration in healthy volunteers and chronic ketamine abusers to investigate semantic processing, one of the key cognitive deficits in schizophrenia. Semantic processing was examined using a semantic priming paradigm. In experiment 1, acute effects of low (75 ng/mL) and high (150 ng/mL) ketamine doses were compared in aplacebo-controlled double-blind independent group design with 48 participants. In experiment 2, 19 regular recreational ketamine users were compared with 19 ketamine-naive polydrug controls and 26 non-drug-using controls. In both experiments, semantic priming parameters were manipulated to distinguish between ketamines effects on (1) automatic and strategic processing and (2) the facilitation and inhibition components of semantic priming for strongly (directly) related primes and targets. Acute effects of ketamine on semantic priming for weakly (indirectly) related primes and targets were also assessed in experiment 1. Acutely, ketamine impaired the employment of strategic mechanisms but not automatic processing within both the direct and indirect semantic priming tasks. Acute ketamine administration also induced clear schizophrenia-like symptoms. Schizotypy traits in the cognitive and perceptual domains tended to correlate with increased semantic priming in long-term ketamine users. In summary, acute and chronic ketamine-induced changes partially mirrored the findings on semantic priming in schizophrenia.

The effects of N-methyl d-aspartate and B-adrenergic receptor antagonists on the reconsolidation of reward memory: A meta-analysis

Pharmacological memory reconsolidation blockade provides a potential mechanism for ameliorating the maladaptive reward memories underlying relapse in addiction. Two of the most promising classes of drug that interfere with reconsolidation and have translational potential for human use are N-methyl-D-aspartate receptor (NMDAR) and B-Adrenergic receptor (B-AR) antagonists. We used meta-analysis and meta-regression to assess the effects of these drugs on the reconsolidation of reward memory in preclinical models of addiction. Pharmacokinetic, mnemonic and methodological factors were assessed for their moderating impact on effect sizes. An analysis of 52 independent effect sizes (NMDAR=30, B-AR=22) found robust effects of both classes of drug on memory reconsolidation, but a far greater overall effect of NMDAR antagonism than B-AR antagonism. Significant moderating effects of drug dose, relapse process and primary reinforcer were found. The findings suggest that reward memory reconsolidation can be robustly targeted by NMDAR antagonists and to a lesser extent, by B-AR antagonists. Implications for future clinical work are discussed.

The effects of cognitive reappraisal following retrieval-procedures designed to destabilize alcohol memories in high-risk drinkers

RationaleAddiction is a disorder of motivational learning and memory. Maladaptive motivational memories linking drug-associated stimuli to drug seeking are formed over hundreds of reinforcement trials and accompanied by aberrant neuroadaptation in the mesocorticolimbic reward system. Such memories are resistant to extinction. However, the discovery of retrieval-dependent memory plasticity has opened up the possibility of permanent modification of established (long-term) memories during ‘reconsolidation’.ObjectivesHere, we investigate whether reappraisal of maladaptive alcohol cognitions performed after procedures designed to destabilize alcohol memory networks affected subsequent alcohol memory, craving, drinking and attentional bias.MethodsForty-seven at-risk drinkers attended two sessions. On the first lab session, participants underwent one of two prediction error-generating procedures in which outcome expectancies were violated while retrieving alcohol memories (omission and value prediction error groups). Participants in a control group retrieved non-alcohol memories. Participants then reappraised personally relevant maladaptive alcohol memories and completed measures of reappraisal recall, alcohol verbal fluency and craving. Seven days later, they repeated these measures along with attentional bias assessment.ResultsOmission prediction error (being unexpectedly prevented from drinking beer), but not a value prediction error (drinking unexpectedly bitter-tasting beer) or control procedure (drinking unexpectedly bitter orange juice), was associated with significant reductions in verbal fluency for positive alcohol-related words. No other statistically robust outcomes were detected.ConclusionsThis study provides partial preliminary support for the idea that a common psychotherapeutic strategy used in the context of putative memory retrieval-destabilization can alter accessibility of alcohol semantic networks. Further research delineating the necessary and sufficient requirements for producing alterations in alcohol memory performance based on memory destabilization is still required.

A comparison of emotion regulation strategies in response to craving cognitions: Effects on smoking behaviour, craving and affect in dependent smokers

AIM The effects of three emotion regulation strategies that targeted smoking-related thoughts were compared on outcomes relevant to smoking cessation. METHOD Daily smokers applied defusion (n = 25), reappraisal (n = 25) or suppression (n = 23) to thoughts associated with smoking during a cue-induced craving procedure. Smoking behaviour, approach/avoidance behavioural bias, and subjective measures of experiential avoidance, craving, and affect were assessed during the experimental session, with additional behavioural and subjective outcomes assessed at 24 h and seven day follow-up. The influence of baseline group differences in smoking level and nicotine dependence were explored statistically. RESULTS Defusion and reappraisal were associated with greater restraint in smoking behaviour in the immediate post-session period as well as reduction in smoking at seven day follow-up compared to suppression. Relative to suppression, reduced subjective craving was seen in the reappraisal group, and reduced experiential avoidance in the defusion group. Differences in approach/avoidance responses to smoking and neutral cues were observed only between the suppression and reappraisal groups. Although suppression was rated as lower in both credibility and strategy-expectancy compared to defusion and reappraisal, neither credibility nor expectancy mediated the effect of any strategy on changes in levels of smoking. CONCLUSION Defusion and reappraisal produced similar benefits in smoking-related behavioural outcomes but, relative to suppression, were associated with distinctive outcomes on experiential avoidance and craving. The effects appear to be independent of perceived expectancy and credibility of the different strategies. Overall, the results suggest a role for reappraisal and defusion strategies in the development of psychological treatments for addiction-related disorders.

Superstitious conditioning as a model of delusion formation following chronic but not acute ketamine in humans

BackgroundKetamine has previously been shown to induce delusion-like or referential beliefs, both acutely in healthy volunteers and naturalistically among nonintoxicated users of the drug. Delusions are theoretically underpinned by increased superstitious conditioning or the erroneous reinforcement of random events.Materials and methodsUsing a novel and objectively measured superstitious conditioning task, experiment 1 assessed healthy volunteers before and during placebo (n = 16), low-dose (n = 15), and high-dose ketamine (n = 16) under randomized and double-blind conditions. Experiment 2 used the same task to compare ketamine users (n = 18), polydrug controls (n = 19), and nondrug-using controls (n = 17).ResultsIn experiment 1, ketamine produced dose-dependent psychotomimetic effects but did not cause changes in superstitious conditioning. Experiment 2 found increased levels of superstitious conditioning among ketamine users compared to polydrug and nondrug-using controls, respectively, as evidenced by both objective task responses and subjective beliefs following the task.ConclusionsResults indicate that chronic but not acute exposure to ketamine may increase the propensity to adopt superstitious conditioning. These findings are discussed in terms of acute and chronic ketamine models of delusion-like belief formation in schizophrenia.

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

RationaleDrug 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.MethodsDependent (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.ResultsCompared 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.ConclusionsNicotine 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.