H.V. Curran

Cannabidiol attenuates the appetitive effects of Δ9-tetrahydrocannabinol in humans smoking their chosen cannabis.

Worldwide cannabis dependence is increasing, as is the concentration of Δ9-tetrahydrocannabinol (THC) in street cannabis. At the same time, the concentration of the second most abundant cannabinoid in street cannabis, cannabidiol (CBD), is decreasing. These two cannabinoids have opposing effects both pharmacologically and behaviorally when administered in the laboratory. No research has yet examined how the ratio of these constituents impacts on the appetitive/reinforcing effects of cannabis in humans. A total of 94 cannabis users were tested 7 days apart, once while non-intoxicated and once while acutely under the influence of their own chosen smoked cannabis on dependence-related measures. Using an unprecedented methodology, a sample of cannabis (as well as saliva) was collected from each user and analyzed for levels of cannabinoids. On the basis of CBD : THC ratios in the cannabis, individuals from the top and bottom tertiles were directly compared on indices of the reinforcing effects of drugs, explicit liking, and implicit attentional bias to drug stimuli. When intoxicated, smokers of high CBD : THC strains showed reduced attentional bias to drug and food stimuli compared with smokers of low CBD : THC. Those smoking higher CBD : THC strains also showed lower self-rated liking of cannabis stimuli on both test days. Our findings suggest that CBD has potential as a treatment for cannabis dependence. The acute modulation of the incentive salience of drug cues by CBD may possibly generalize to a treatment for other addictive disorders.

Neuropsychological and psychiatric functioning in sheep farmers exposed to low levels of organophosphate pesticides.

The study aim was to determine whether low level exposure to organophosphate pesticides (OPs) causes neuropsychological or psychiatric impairment. Methodological weaknesses of earlier studies were addressed by: recruiting participants who had retired on ill health grounds; excluding participants with a history of acute poisoning, medical or psychiatric conditions that might account for ill health; and exploring factors which may render some individuals more vulnerable to the effects of OPs than others. Performance on tests of cognition and mood of 127 exposed sheep farmers (67 working, 60 retired) was compared with 78 unexposed controls (38 working, 40 retired) and published test norms derived from a cross section of several thousand adults in the general population. Over 40% of the exposed cohort reported clinically significant levels of anxiety and depression compared to less than 23% of controls. Exposed subjects performed significantly worse than controls and standardisation samples on tests of memory, response speed, fine motor control, mental flexibility and strategy making, even after controlling for the effects of mood. The pattern was similar for both working and retired groups. The cognitive deficits identified cannot be attributed to mood disorder, malingering, a history of acute exposure or genetic vulnerability in terms of PON1(192) polymorphisms. Results suggest a relationship may exist between low level exposure to organophosphates and impaired neurobehavioural functioning and these findings have implications for working practice and for other occupational groups exposed to OPs such as aviation workers and Gulf War veterans.

Psychopharmacological analysis of implicit and explicit memory: a study with lorazepam and the benzodiazepine antagonist flumazenil

Recent studies have suggested that the benzodiazepine (BZ) lorazepam (LZ) differs from other BZs in its impairing effects on implicit memory tasks. The present study was designed to assess whether this atypical effect withstood the experimental rigour of Schacters retrieval intentionality criterion and further, whether it could be reversed by the BZ antagonist, flumazenil (FL). The separate and combined effects of LZ, FL and placebo (PL) were assessed on indices of memory, sedation, and attention in 48 healthy volunteers. LZ disrupted performance on both explicit and implicit memory tasks, induced motor sedation and impaired focussed attention. FL attenuated LZ-induced attentional deficits but did not affect motor sedation. FL also attenuated LZ-induced impairment on the implicit retrieval task. On the explicit retrieval task FL attenuated LZ-induced impairment for words which had been deeply processed at study but not words which had been shallowly processed. A subsequent recognition test showed LZ impaired recognition memory only when accompanied by recollective experience and flumazenil again attenuated this effect. FL itself lowered performance on several measures, reflecting intrinsic activity of this “antagonist”. Assessment of the relationship between the mnestic and other effects of the drugs suggested that attentional effects contribute to, but do not explain, effects on implicit memory tasks. These results imply that the apparent atypical effects of LZ on implicit memory tasks are mediated by the same BZ receptor complex as mediates LZs other effects.

Are IQ and educational outcomes in teenagers related to their cannabis use? A prospective cohort study

There is much debate about the impact of adolescent cannabis use on intellectual and educational outcomes. We investigated associations between adolescent cannabis use and IQ and educational attainment in a sample of 2235 teenagers from the Avon Longitudinal Study of Parents and Children. By the age of 15, 24% reported having tried cannabis at least once. A series of nested linear regressions was employed, adjusted hierarchically by pre-exposure ability and potential confounds (e.g. cigarette and alcohol use, childhood mental-health symptoms and behavioural problems), to test the relationships between cumulative cannabis use and IQ at the age of 15 and educational performance at the age of 16. After full adjustment, those who had used cannabis ⩾50 times did not differ from never-users on either IQ or educational performance. Adjusting for group differences in cigarette smoking dramatically attenuated the associations between cannabis use and both outcomes, and further analyses demonstrated robust associations between cigarette use and educational outcomes, even with cannabis users excluded. These findings suggest that adolescent cannabis use is not associated with IQ or educational performance once adjustment is made for potential confounds, in particular adolescent cigarette use. Modest cannabis use in teenagers may have less cognitive impact than epidemiological surveys of older cohorts have previously suggested.

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.

Special issue on impulsivity and compulsivity.

This ‘Special issue on impulsivity and compulsivity’revisits a theme first explored by Psychopharmacology in1999 (146, 339–491). That issue of the journal focused onimpulsivity and represented somewhat of a landmark forthis topic in Psychopharmacology and perhaps for the fieldin general. It contained several now highly cited papers byseveral notable researchers in the field, including twoseminal theoretical reviews. One was by John Evenden(‘Varieties of impulsivity’ Evenden 1999) and has beencited 481 times at last count on the ISI Web of Knowledge.The other, on impulsivity, frontostriatal dysfunction anddrug abuse, was by David Jentsch and Jane Taylor (1999)and has been cited no fewer than 555 times.As Evenden’s review presciently anticipated, impulsivitycan be defined in several ways, reflecting what may be amultifaceted construct, engaging several distinct neuralsystems (Dalley et al. 2011). Most definitions emphasisethe tendency towards maladaptive premature behaviour, theloss of motor or response inhibition, the performance of‘automatic urges or impulses’, the tendency to avoid delayand rapidly discount the value of delayed rewards (‘impul-sive choice’) and the lack of reflection in making decisions,often of a highly ‘risky’ type. In general, advances inunderstanding of impulsivity have stemmed from advancesin its measurement in both humans and experimentalanimals, which may often proceed in parallel, usinganalogous tests such as the temporal discounting of rewardor stop signal inhibition. Many of these methods arerepresented in this special issue. Roige et al. provide adetailed and timely review of the considerable and excitingrecent work in mice (including genetic strains) on the samefive-choice serial reaction attentional task used by Dalley etal. to measure impulsivity in rats.Impulsivity refers to a constellation of traits that may befound in several neuropsychiatric disorders, includingattention deficit/hyperactivity disorder (ADHD), substanceabuse including alcoholism and cigarette smoking, mania,antisocial behaviour, as well as pathological aggression anddepression (i.e. suicide). There have been suggestions thatforms of impulsivity can be endophenotypes or intermedi-ate phenotypes for some disorders. For example, rats thatexhibit premature behaviour in the five-choice task appearto have a propensity for compulsive cocaine-seekingbehaviour, even before they are actually exposed to thedrug (Dalley et al. 2011). It is also possible that someabused drugs themselves may also cause impulsive behav-iours (Perry and Carroll 2008). Impulsive behaviour mayalso be especially important in the relapse to drug seeking,as they may share overlapping neural mechanisms (see inthis issue the study by Verdejo-Garcia et al.). Several formsof impulsivity are also prominent in ADHD, which oftenresponds to treatment with the indirect catecholamine

Are adolescents more vulnerable to the harmful effects of cannabis than adults? A placebo-controlled study in human males

Preclinical research demonstrates that cannabinoids have differing effects in adolescent and adult animals. Whether these findings translate to humans has not yet been investigated. Here we believe we conducted the first study to compare the acute effects of cannabis in human adolescent (n=20; 16–17 years old) and adult (n=20; 24–28 years old) male cannabis users, in a placebo-controlled, double-blind cross-over design. After inhaling vaporized active or placebo cannabis, participants completed tasks assessing spatial working memory, episodic memory and response inhibition, alongside measures of blood pressure and heart rate, psychotomimetic symptoms and subjective drug effects (for example, ‘stoned’, ‘want to have cannabis’). Results showed that on active cannabis, adolescents felt less stoned and reported fewer psychotomimetic symptoms than adults. Further, adults but not adolescents were more anxious and less alert during the active cannabis session (both pre- and post-drug administration). Following cannabis, cognitive impairment (reaction time on spatial working memory and prose recall following a delay) was greater in adults than adolescents. By contrast, cannabis impaired response inhibition accuracy in adolescents but not in adults. Moreover, following drug administration, the adolescents did not show satiety; instead they wanted more cannabis regardless of whether they had taken active or placebo cannabis, while the opposite was seen for adults. These contrasting profiles of adolescent resilience (blunted subjective, memory, physiological and psychotomimetic effects) and vulnerability (lack of satiety, impaired inhibitory processes) show some degree of translation from preclinical findings, and may contribute to escalated cannabis use by human adolescents.

Effects of a low dose of alcohol on recollective experience of illusory memory.

Abstract Rationale: Memory illusions are currently a focus of memory research. Studies using the Deese/Roediger and McDermott paradigm have shown a differential pattern of illusory memories is associated with amnesia and ageing. The effects of pharmacological agents in this paradigm are not yet known. Objective: Using this paradigm, the present study investigated the effects of a low dose of alcohol upon recollective experience of illusory memories. Methods: A double-blind cross-over design was used to compare the effects of alcohol (0.26–0.28 g.kg–1) with a matched placebo drink. Results: High levels of false recognition were obtained across both treatments, replicating previous results. Although the small dose of alcohol employed did not produce gross changes in measures of false memory, it did modify the pattern of recollective experience in terms of remember and know responses. Specifically, it increased the level of remember responses for falsely recognised items (critical lures). Conclusion: These results are discussed in terms of ethanol’s effects on false recognition of information which was not presented during the study episode. The effects of low dose alcohol on illusory memory are similar to the pattern found in ageing rather than that found in organic amnesia.

Episodic foresight deficits in long-term opiate users.

RationaleThere is considerable literature showing that opiate use is associated with a range of neurocognitive deficits, including deficits in executive control and episodic memory. However, no study to date has assessed whether these neurocognitive difficulties extend to the ability to mentally time travel into one’s personal future. This is a surprising omission given that executive control and episodic memory are considered to be critical for episodic foresight. In addition, opiate-related brain changes have been identified in the neural regions that underlie the capacity for episodic foresight.ObjectiveIn the present study, we assessed how episodic foresight is affected in the context of chronic opiate use, as well as the degree to which any deficits are related to difficulties with executive control and episodic memory.Methods and ResultsForty-eight long-term heroin users enrolled in an opiate substitution program and 48 controls were tested. The results showed that, relative to controls, the clinical group exhibited significant impairment in episodic foresight but not episodic memory (as indexed by an adapted version of the Autobiographical Interview). For executive function, the clinical group was impaired on only one of three measures (Inhibition).ConclusionsThese data provide important preliminary evidence that episodic foresight might be particularly susceptible to the neurocognitive effects of opiate use, as the difficulties identified were not secondary to more general executive control or episodic memory impairment. Because a number of widely used relapse prevention protocols require the ability to mentally project into the future, these data have potentially important practical implications in relation to the treatment of substance dependence disorders.

Acute memory and psychotomimetic effects of cannabis and tobacco both ‘joint’ and individually: a placebo-controlled trial

Background Cannabis and tobacco have contrasting cognitive effects. Smoking cannabis with tobacco is prevalent in many countries and although this may well influence cognitive and mental health outcomes, the possibility has rarely been investigated in human experimental psychopharmacological research. Method The individual and interactive effects of cannabis and tobacco were evaluated in 24 non-dependent cannabis and tobacco smokers in a randomized, placebo-controlled, double-blind, 2 (cannabis, placebo) × 2 (tobacco, placebo) crossover design. Verbal memory (prose recall), working memory (WM) performance including maintenance, manipulation and attention (N-back), psychotomimetic, subjective and cardiovascular measures were recorded on each of four sessions. Results Cannabis alone impaired verbal memory. A priori contrasts indicated that tobacco offset the effects of cannabis on delayed recall. However, this was not supported by linear mixed model analysis. Cannabis load-dependently impaired WM. By contrast, tobacco improved WM across all load levels. The acute psychotomimetic effects and ratings of ‘stoned’ and ‘dizzy’ induced by cannabis were not altered by tobacco. Cannabis and tobacco had independent effects on increasing heart rate and interacting effects on increasing diastolic blood pressure. Conclusions Relative to placebo, acute cannabis impaired verbal memory and WM. Tobacco enhanced performance on WM, independently of cannabis. Moreover, we found some preliminary evidence that tobacco may offset the effects of cannabis on delayed, but not immediate, verbal recall. In contrast, the psychotomimetic and subjective effects of cannabis were unaffected by tobacco co-administration. By reducing the cognitive impairment from cannabis, tobacco co-administration may perpetuate use despite adverse health consequences.