Journal of Psychopharmacology

Wilson, Robin P; Bhattacharyya, Sagnik

doi: 10.1177/0269881115612237pmid: 26510450

The prevalence of cannabis use in patients with psychotic mental illness is known to be high and is suspected to exacerbate symptoms and worsen prognosis. We aimed to evaluate evidence of antipsychotic efficacy in reducing the burden of psychotic symptoms and cannabis use in individuals with psychotic mental illness and co-morbid cannabis use. A systematic review was conducted of antipsychotic treatment in those with psychotic mental illness and co-morbid cannabis use. Quality of evidence for each study and outcomes were rated using the ‘GRADE’ approach. Twenty-two studies were identified: 13 experimental and 9 observational, including a total sample of 1543 patients, 761 of whom had a diagnosed cannabis use disorder. The most frequent antipsychotics compared were risperidone, olanzapine and clozapine with olanzapine, risperidone and haloperidol. No clear differences between antipsychotics were demonstrated. Future studies are needed to confirm whether clozapine is superior to other antipsychotics in reducing cannabis use.

Ferraro, Luca; Tiozzo Fasiolo, Laura; Beggiato, Sarah; Borelli, Andrea C; Pomierny-Chamiolo, Lucyna; Frankowska, Malgorzata; Antonelli, Tiziana; Tomasini, Maria C; Fuxe, Kjell; Filip, Malgorzata

doi: 10.1177/0269881115622240pmid: 26755548

Englund, Amir; Atakan, Zerrin; Kralj, Aleksandra; Tunstall, Nigel; Murray, Robin; Morrison, Paul

doi: 10.1177/0269881115615104pmid: 26577065

Rationale:Cannabis is mostly grown under illegal and unregulated circumstances, which seems to favour a product increasingly high in its main cannabinoid ∆-9-tetrahydrocannabinol (THC). ∆-9-tetrahydrocannabivarin (THCV) is a relatively untested cannabinoid which is said to be a cannabinoid receptor neutral antagonist, and may inhibit the effects of THC.Objectives:To explore the safety and tolerability of repeated THCV administration and its effects on symptoms normally induced by THC in a sample of healthy volunteers.Methods:Ten male cannabis users (<25 use occasions) were recruited for this within-subjects, placebo-controlled, double-blind, cross-over pilot study. 10mg oral pure THCV or placebo were administered daily for five days, followed by 1mg intravenous THC on the fifth day.Results:THCV was well tolerated and subjectively indistinguishable from placebo. THC did not significantly increase psychotic symptoms, paranoia or impair short-term memory, while still producing significant intoxicating effects. Delayed verbal recall was impaired by THC and only occurred under placebo condition (Z=-2.201, p=0.028), suggesting a protective effect of THCV. THCV also inhibited THC-induced increased heart rate (Z=-2.193, p=0.028). Nine out of ten participants reported THC under THCV condition (compared to placebo) to be subjectively weaker or less intense (χ2=6.4, p=0.011). THCV in combination with THC significantly increased memory intrusions (Z=-2.155, p=0.031).Conclusion:In this first study of THC and THCV, THCV inhibited some of the well-known effects of THC, while potentiating others. These findings need to be interpreted with caution due to a small sample size and lack of THC-induced psychotomimetic and memory-impairing effect, probably owing to the choice of dose.

Vingerhoets, WAM; Koenders, L; van den Brink, W; Wiers, RW; Goudriaan, AE; van Amelsvoort, T; de Haan, L; Cousijn, J

doi: 10.1177/0269881115620436pmid: 26645206

Cannabis is the most frequently used illicit drug worldwide, but little is known about the mechanisms underlying continued cannabis use. Cue-reactivity (the physical, psychological, behavioural and neural reaction to substance-related cues) might be related to continued cannabis use. In this 3-year prospective neuroimaging study we investigated whether cannabis cue-induced brain activity predicted continued cannabis use and associated problem severity 3 years later. In addition, baseline brain activations were compared between dependent and non-dependent cannabis users at follow-up. Analyses were focussed on brain areas known to be important in cannabis cue-reactivity: anterior cingulate cortex, orbitofrontal cortex, ventral tegmental area, amygdala and striatum. At baseline, 31 treatment-naive frequent cannabis users performed a cue-reactivity functional magnetic resonance imaging task. Of these participants, 23 completed the 3-year follow-up. None of the cue-induced region of interest activations predicted the amount of cannabis use at follow-up. However, cue-induced activation in the left striatum (putamen) significantly and independently predicted problem severity at follow-up (p < 0.001) as assessed with the Cannabis Use Disorder Identification Test. Also, clinically dependent cannabis users at follow-up showed higher baseline activation at trend level in the left striatum compared with non-dependent users. This indicates that neural cue-reactivity in the dorsal striatum is an independent predictor of cannabis use-related problems. Given the relatively small sample size, these results are preliminary and should be replicated in larger samples of cannabis users.

Mokrysz, C; Landy, R; Gage, SH; Munafò, MR; Roiser, JP; Curran, HV

doi: 10.1177/0269881115622241pmid: 26739345

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.

Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J

doi: 10.1177/0269881115612239pmid: 26510449

Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the cerebrospinal fluid levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid-enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared with THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach.

Fluharty, Meg E; Attwood, Angela S; Munafò, Marcus R

doi: 10.1177/0269881115615105pmid: 26561530

The 7.5% carbon dioxide (CO2) inhalation model is used to provoke acute anxiety, for example to investigate the effects of anxiety on cognitive processes, or the efficacy of novel anxiolytic agents. However, little is known about the relationship of baseline anxiety sensitivity or trait anxiety (i.e., anxiety proneness), with an individual’s response to the 7.5% CO2 challenge. We examined data from a number of 7.5% CO2 challenge studies to determine whether anxiety proneness was related to subjective or physiological response. Our findings indicate anxiety proneness is associated with greater subjective and physiological responses. However, anxiety-prone individuals also have a greater subjective response to the placebo (medical air) condition. This suggests that anxiety-prone individuals not only respond more strongly to the 7.5% CO2 challenge, but also to medical air. Implications for the design and conduct of 7.5% CO2 challenge studies are discussed.

González-Sepúlveda, Marta; Pozo, Oscar J; Marcos, Josep; Valverde, Olga

doi: 10.1177/0269881115622238pmid: 26681793

Mood disorders and chronic pain are closely linked, but limited progress has been made in understanding the role of chronic and neuropathic pain in the aetiopathogenesis of depression. To explore the pathological mechanisms that mediate the association between pain and depressive-like behaviours, we studied the time-dependent effect of neuropathic pain on the development of anxiety-like and despair behaviours in CD1 mice. We analysed behavioural data, neuroinflammation reactions and changes in neurotransmitter (glutamate and serotonin) levels in the mouse prefrontal cortex. Sciatic-operated mice displayed long-lasting anxiety-like and despair behaviours, starting 5 and 20 days after partial sciatic nerve ligation, respectively. Glutamatergic neurotransmission and IL-1β cytokine expression were enhanced in the prefrontal cortex of mice with neuropathic pain. We found no change in serotonin metabolism, cytokine IL-6 or brain-derived neurotrophic factor levels. While sciatic-operated mice exposed to intermittent ethanol intake (20% v/v) using the drinking in the dark procedure consumed higher amounts of ethanol than sham-operated mice, thermal allodynia and despair behaviour were not attenuated by ethanol consumption. Our findings reveal an association between glutamatergic neurotransmission and pain-induced mood disorders, and indicate that moderate ethanol consumption does not relieve nociceptive and depressive behaviours associated with chronic pain in mice.

De Santis, Michael; Lian, Jiamei; Huang, Xu-Feng; Deng, Chao

doi: 10.1177/0269881115616383pmid: 26577063

Childhood/adolescent antipsychotic drug (APD) use is exponentially increasing worldwide, despite limited knowledge of the long-term effects of early APD treatment. Whilst investigations have found that early treatment has resulted in some alterations to dopamine and serotonin neurotransmission systems (essential to APD efficacy), there have only been limited studies into potential long-term behavioural changes. This study, using an animal model for childhood/adolescent APD treatment, investigated the long-term effects of aripiprazole, olanzapine and risperidone on adult behaviours of male and female rats. Open-field/holeboard, elevated plus maze (EPM), social interaction and forced swim (FS) tests were then conducted in adult rats. Our results indicated that in the male cohort, early risperidone and olanzapine treatment elicited long-term hyper-locomotor effects (open-field/holeboard and FS tests), whilst a decrease in depressive-like behaviour (in FS test) was observed in response to olanzapine treatment. Furthermore, anxiolytic-like behaviours were found following testing in the open-field/holeboard and EPM in response to all three drug treatments. Effects in the female cohort, however, were to a far lesser extent, with behavioural attributes indicative of an increased depressive-like behaviour and hypo-locomotor activity exhibited in the FS test following early risperidone and olanzapine treatment. These results suggest that various APDs have different long-term effects on the behaviours of adult rats.

Zarrabian, Shahram; Farahizadeh, Maryam; Nasehi, Mohammad; Zarrindast, Mohammad-Reza

doi: 10.1177/0269881115622239pmid: 26755545

Cognitive functions are influenced by memory and anxiety states. However, a non-linear relation has been shown between these two domains. The important role of the hippocampus in memory and emotional responses may link the pathogenesis of anxiety to memory-related GABAergic and glutamatergic processes in the hippocampus. To investigate the role of GABAA receptors in relation to blocking N-methyl-D-aspartate (NMDA) receptors in the CA3 region, and balancing the glutamatergic and GABAergic system activities as an approach for the management of related disorders, the elevated plus-maze test–retest paradigm was used to investigate the anxiolytic-like state on the test day and avoidance memory state on the retest day. The data showed that injection of D-AP5, the NMDA receptor antagonist, induced anxiolytic-like behavior and impaired avoidance memory. Injection of GABAA agonist (muscimol), but not the antagonist (bicuculline), induced avoidance memory impairment. Neither muscimol nor bicuculline altered anxiety-like behaviors. Muscimol pretreatment did not change D-AP5-induced anxiolytic-like behaviors but potentiated avoidance memory impairment. Bicuculline pretreatment blocked D-AP5-induced anxiolytic-like behaviors and contradicted its effect on avoidance memory. Our findings indicate that alteration of the CA3 GABAA receptor activity can effectively affect the anxiolytic-like behaviors and avoidance memory deficit induced by D-AP5.