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Cannabis use has been associated with altered sensory gating and neural oscillations. However, it is unclear which constituent in cannabis is responsible for these effects, or whether these are cannabinoid receptor 1 (CB1R) mediated. Therefore, the present study in humans and rats examined whether cannabinoid administration would disrupt sensory gating and evoked oscillations utilizing electroencephalography (EEG) and local field potentials (LFPs), respectively. Human subjects (n = 15) completed four test days during which they received intravenous delta-9-tetrahydrocannabinol (Δ 9 -THC), cannabidiol (CBD), Δ 9 -THC + CBD, or placebo. Subjects engaged in a dual-click paradigm, and outcome measures included P50 gating ratio (S2/S1) and evoked power to S1 and S2. In order to examine CB1R specificity, rats (n = 6) were administered the CB1R agonist CP-55940, CP-55940+AM-251 (a CB1R antagonist), or vehicle using the same paradigm. LFPs were recorded from CA3 and entorhinal cortex. Both Δ 9 -THC (p < 0.007) and Δ 9 -THC + CBD (p < 0.004) disrupted P50 gating ratio compared to placebo, while CBD alone had no effect. Δ 9 -THC (p < 0.048) and Δ 9 -THC + CBD (p < 0.035) decreased S1 evoked theta power, and in the Δ 9 -THC condition, S1 theta negatively correlated with gating ratios (r = −0.629, p < 0.012 (p < 0.048 adjusted)). In rats, CP-55940 disrupted gating in both brain regions (p < 0.0001), and this was reversed by AM-251. Further, CP-55940 decreased evoked theta (p < 0.0077) and gamma (p < 0.011) power to S1, which was partially blocked by AM-251. These convergent human/animal data suggest that CB1R agonists disrupt sensory gating by altering neural oscillations in the theta-band. Moreover, this suggests that the endocannabinoid system mediates theta oscillations relevant to perception and cognition. [ABSTRACT FROM AUTHOR]

Despite major advances in our understanding of the brain using traditional neuroscience, reliable and efficacious treatments for drug addiction have remained elusive. Hence, the time has come to utilize novel approaches, particularly those drawing upon contemporary advances in fields outside of established neuroscience and psychiatry. Put another way, the time has come for a paradigm shift in the addiction sciences. Apropos, a revolution in the area of human health is underway, which is occurring at the nexus between enteric microbiology and neuroscience. It has become increasingly clear that the human microbiota (the vast ecology of bacteria residing within the human organism), plays an important role in health and disease. This is not surprising, as it has been estimated that bacteria living in the human body (approximately 1kg of mass, roughly equivalent to that of the human brain) outnumber human cells 10 to 1. While advances in the understanding of the role of microbiota in other areas of human health have yielded intriguing results (e.g., Clostridium difficile, irritable bowel syndrome, autism, etc.), to date, no systematic programs of research have examined the role of microbiota in drug addiction. The current hypothesis, therefore, is that gut dysbiosis plays a key role in addictive disorders. In the context of this hypothesis, this paper provides a rationale for future research to target the "gut-brain axis" in addiction. A brief background of the gut-brain axis is provided, along with a series of hypothesis-driven ideas outlining potential treatments for addiction via manipulations of the "ecology within." [ABSTRACT FROM AUTHOR]

Evidence has accumulated over the past several decades suggesting that both exocannabinoids and endocannabinoids play a role in the pathophysiology of schizophrenia. The current article presents evidence suggesting that one of the mechanisms whereby cannabinoids induce psychosis is through the alteration in synchronized neural oscillations. Neural oscillations, particularly in the gamma (30–80 Hz) and theta (4–7 Hz) ranges, are disrupted in schizophrenia and are involved in various areas of perceptual and cognitive function. Regarding cannabinoids, preclinical evidence from slice and local field potential recordings has shown that central cannabinoid receptor (cannabinoid receptor type 1) agonists decrease the power of neural oscillations, particularly in the gamma and theta bands. Further, the administration of cannabinoids during critical stages of neural development has been shown to disrupt the brain’s ability to generate synchronized neural oscillations in adulthood. In humans, studies examining the effects of chronic cannabis use (utilizing electroencephalography) have shown abnormalities in neural oscillations in a pattern similar to those observed in schizophrenia. Finally, recent studies in humans have also shown disruptions in neural oscillations after the acute administration of delta-9-tetrahydrocannabinol, the primary psychoactive constituent in cannabis. Taken together, these data suggest that both acute and chronic cannabinoids can disrupt the ability of the brain to generate synchronized oscillations at functionally relevant frequencies. Hence, this may represent one of the primary mechanisms whereby cannabinoids induce disruptions in attention, working memory, sensory-motor integration, and many other psychosis-related behavioral effects. [ABSTRACT FROM AUTHOR]

Abstract: Background: Although the incidence of cannabis abuse/dependence in Americans is rising, the neurobiology of cannabis addiction is not well understood. Imaging studies have demonstrated deficits in striatal D2/D3 receptor availability in several substance-dependent populations. However, this has not been studied in currently using chronic cannabis users. Objective: The purpose of this study was to compare striatal D2/D3 receptor availability between currently using chronic cannabis users and healthy controls. Methods: Eighteen right-handed males age 18–34 were studied. Ten subjects were chronic cannabis users; eight were demographically matched controls. Subjects underwent a [11C]raclopride (RAC) PET scan. Striatal RAC binding potential (BPND) was calculated on a voxel-wise basis. Prior to scanning, urine samples were obtained from cannabis users for quantification of urine Δ-9-tetrahydrocannabinol (THC) and THC metabolites (11-nor-Δ-9-THC-9-carboxylic acid; THC-COOH and 11-hydroxy-THC;OH-THC). Results: There were no differences in D2/D3 receptor availability between cannabis users and controls. Voxel-wise analyses revealed that RAC BPND values were negatively associated with both urine levels of cannabis metabolites and self-report of recent cannabis consumption. Conclusions: In this sample, current cannabis use was not associated with deficits in striatal D2/D3 receptor availability. There was an inverse relationship between chronic cannabis use and striatal RAC BPND. Additional studies are needed to identify the neurochemical consequences of chronic cannabis use on the dopamine system. [Copyright &y& Elsevier]

Abstract: While CB1 knockout mice exhibit striking impairments on a cerebellar-dependent task called delay eyeblink conditioning (dEBC), these animals demonstrate intact forebrain-dependent trace EBC (tEBC). Although heavy human cannabis users also show impaired delay EBC, their performance on tEBC is currently unknown. Therefore, 13 heavy cannabis users and 13 cannabis naive controls completed a tEBC procedure. The cannabis group exhibited similar rates of conditioned responding compared to controls in the acquisition and extinction phase. Consistent with reports of overt attentional abnormalities, the cannabis group exhibited decreased N100 ERP amplitudes to the tone CS that were unrelated to mean levels of conditioning across blocks during the acquisition phase. The lack of a significant effect of heavy cannabis use on tEBC reported here, combined with the previous report of impaired dEBC in such users, mirrors the findings observed in CB1 knockout mice, and suggests that the cannabinoid system differentially mediates forebrain- and cerebellar-dependent learning processes in both humans and animals. [Copyright &y& Elsevier]

Abstract: While cannabis is associated with positive syndrome schizophrenia (SZ), it is unclear whether cannabinoids are also related to negative symptoms such as affective blunting. We examined whether cannabis use is associated with schizotypy and utilized event-related potentials (ERPs) to assess affect processing. Cannabis users demonstrated increased P300 amplitudes for unpleasant trait words, and demonstrated higher positive syndrome schizotypy which correlated with levels of cannabis use. The cannabis group also exhibited lower negative syndrome schizotypy. The lack of blunted responses during the affect ERP and decreased negative subscale schizotypy scores provide evidence that the endocannabinoid theory of schizophrenia may be primarily relevant in relation to positive syndrome SZ. [Copyright &y& Elsevier]

Abstract: Studies have demonstrated that selective attention can modulate the steady-state evoked potential to repetitive visual and tactile stimulation. However, examinations of the effect of attention on the auditory steady-state response (ASSR) have proven equivocal. The current experiment therefore utilized EEG to examine the effect of attention on the ASSR in healthy humans (n =15). Auditory click trains in the beta (20Hz) and gamma (40Hz) ranges were randomly presented binaurally in an oddball discrimination paradigm (each frequency served as the oddball (target) in each of two blocks). A Fast Fourier Transform was used to assess the effect of attention on the ASSR (signal power), and phase consistency across trials was assessed using the phase-locking factor (PLF). As expected, both 20 and 40Hz targets elicited a robust P300 response, with maximal amplitudes over parietal regions. For the ASSR, it was found that EEG signal power was larger to 40Hz targets compared to 40Hz frequent stimuli across all frontocentral electrodes. No differences in signal power were observed during 20Hz stimulation. Finally, increased PLF values were observed for 40Hz targets compared to frequent trials. These results provide evidence that selective attention can enhance signal power and phase-locking of the ASSR, particularly to auditory stimulation in the gamma range. [Copyright &y& Elsevier]

Abstract: Objective: Cannabis use often induces subjective distortions of perception. However, little work has been done examining the electroencephalographic (EEG) correlates of early sensory processing in cannabis users. The present study therefore examined visual function in cannabis users as assessed via the steady state visual evoked potential. (SSVEP). Methods: SSVEPs were examined in current cannabis users (n=17; 59% male; mean age=23.2 (S.D.=5.3)) and drug-naive controls (n=16; 38% male; mean age=21.3 (S.D.=3.1)) to periodic photic stimulation presented at 18 and 25Hz. The visual SSVEP was quantified via spectral power and the phase-locking factor (PLF) at each frequency of stimulation. The transient N160 event-related potential (ERP) was also evaluated at stimulus onset. Results: The results showed that for both frequencies, female subjects in general displayed larger visual SSVEPs. A significant gender X group interaction also occurred at 18Hz of stimulation, and age of onset of cannabis use positively correlated with 18Hz spectral power values. Finally, the transient N160 component was shown to be reduced in cannabis users, regardless of gender. Conclusions: The present study was the first to demonstrate altered visual SSVEPs in cannabis users, and extends previous research demonstrating increased steady state responses in female subjects. While decreased SSVEPs provide initial evidence of altered oscillatory properties in primary visual circuits, reduction of the transient N160 component suggests disruption of later-stage visual processing in cannabis users. Significance: These data provide evidence of cannabinoid modulation of sensory/perceptual function in the visual system, and indicates that cannabis use may affect the oscillatory properties of sensory cortical circuits. [Copyright &y& Elsevier]

Background Drugs that induce psychosis may do so by increasing the level of task-irrelevant random neural activity or neural noise. Increased levels of neural noise have been demonstrated in psychotic disorders. We tested the hypothesis that neural noise could also be involved in the psychotomimetic effects of delta-9-tetrahydrocannabinol (Δ 9 -THC), the principal active constituent of cannabis. Methods Neural noise was indexed by measuring the level of randomness in the electroencephalogram during the prestimulus baseline period of an oddball task using Lempel-Ziv complexity, a nonlinear measure of signal randomness. The acute, dose-related effects of Δ 9 -THC on Lempel-Ziv complexity and signal power were studied in humans ( n = 24) who completed 3 test days during which they received intravenous Δ 9 -THC (placebo, .015 and .03 mg/kg) in a double-blind, randomized, crossover, and counterbalanced design. Results Δ 9 -THC increased neural noise in a dose-related manner. Furthermore, there was a strong positive relationship between neural noise and the psychosis-like positive and disorganization symptoms induced by Δ 9 -THC, which was independent of total signal power. Instead, there was no relationship between noise and negative-like symptoms. In addition, Δ 9 -THC reduced total signal power during both active drug conditions compared with placebo, but no relationship was detected between signal power and psychosis-like symptoms. Conclusions At doses that produced psychosis-like effects, Δ 9 -THC increased neural noise in humans in a dose-dependent manner. Furthermore, increases in neural noise were related with increases in Δ 9 -THC-induced psychosis-like symptoms but not negative-like symptoms. These findings suggest that increases in neural noise may contribute to the psychotomimetic effects of Δ 9 -THC. [ABSTRACT FROM AUTHOR]

Background: Salvia divinorum (Salvia) is an increasingly popular recreational drug amongst adolescents and young adults. Its primary active ingredient, Salvinorin A (SA)—a highly selective agonist at the κ opiate receptor—is believed to be one of the most potent naturally occurring hallucinogens. However, there is little experimental data on the effects of SA in humans. Methods: In a 3-day, double-blind, randomized, crossover, counterbalanced study, the behavioral, subjective, cognitive, psychophysiological, and endocrine effects of 0 mg, 8 mg, and 12 mg of inhaled SA were characterized in 10 healthy individuals who had previously used Salvia. Results: SA produced psychotomimetic effects and perceptual alterations, including dissociative and somaesthetic effects, increased plasma cortisol and prolactin, and reduced resting electroencephalogram spectral power. The SA administration was associated with a rapid increase of its levels in the blood. SA did not produce euphoria, cognitive deficits, or changes in vital signs. The effects were transient and not dose-related. SA administration was very well-tolerated without acute or delayed adverse effects. Conclusions: SA produced a wide range of transient effects in healthy subjects. The perceptual altering effects and lack of euphoric effects would explain its intermittent use pattern. Such a profile would also suggest a low addictive potential similar to other hallucinogens and consistent with κ opiate receptor agonism. Further work is warranted to carefully characterize a full spectrum of its effects in humans, to elucidate the underlying mechanisms involved, and to explore the basis for individual variability in its effects. [ABSTRACT FROM AUTHOR]

Introduction Cannabis and agonists of the brain cannabinoid receptor (CB 1 R) produce acute memory impairments in humans. However, the extent to which cannabinoids impair the component processes of encoding and retrieval has not been established in humans. The objective of this analysis was to determine whether the administration of Δ 9 -Tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, impairs encoding and/or retrieval of verbal information. Materials and methods Healthy subjects were recruited from the community. Subjects were administered the Rey-Auditory Verbal Learning Test (RAVLT) either before administration of THC (experiment #1) ( n = 38) or while under the influence of THC (experiment #2) ( n = 57). Immediate and delayed recall on the RAVLT was compared. Subjects received intravenous THC, in a placebo-controlled, double-blind, randomized manner at doses known to produce behavioral and subjective effects consistent with cannabis intoxication. Results Total immediate recall, short delayed recall, and long delayed recall were reduced in a statistically significant manner only when the RAVLT was administered to subjects while they were under the influence of THC (experiment #2) and not when the RAVLT was administered prior. Conclusions THC acutely interferes with encoding of verbal memory without interfering with retrieval. These data suggest that learning information prior to the use of cannabis or cannabinoids is not likely to disrupt recall of that information. Future studies will be necessary to determine whether THC impairs encoding of non-verbal information, to what extent THC impairs memory consolidation, and the role of other cannabinoids in the memory-impairing effects of cannabis. Clinical Trial Information: Cannabinoids, Neural Synchrony, and Information Processing (THC-Gamma) http://clinicaltrials.gov/ct2/show/study/NCT00708994 NCT00708994 Pharmacogenetics of Cannabinoid Response http://clinicaltrials.gov/ct2/show/NCT00678730 NCT00678730 [ABSTRACT FROM AUTHOR]

Background: Although the incidence of cannabis abuse/dependence in Americans is rising, the neurobiology of cannabis addiction is not well understood. Imaging studies have demonstrated deficits in striatal D(2)/D(3) receptor availability in several substance-dependent populations. However, this has not been studied in currently using chronic cannabis users.Objective: The purpose of this study was to compare striatal D(2)/D(3) receptor availability between currently using chronic cannabis users and healthy controls.Methods: Eighteen right-handed males age 18-34 were studied. Ten subjects were chronic cannabis users; eight were demographically matched controls. Subjects underwent a [(11)C]raclopride (RAC) PET scan. Striatal RAC binding potential (BP(ND)) was calculated on a voxel-wise basis. Prior to scanning, urine samples were obtained from cannabis users for quantification of urine Δ-9-tetrahydrocannabinol (THC) and THC metabolites (11-nor-Δ-9-THC-9-carboxylic acid; THC-COOH and 11-hydroxy-THC;OH-THC).Results: There were no differences in D(2)/D(3) receptor availability between cannabis users and controls. Voxel-wise analyses revealed that RAC BP(ND) values were negatively associated with both urine levels of cannabis metabolites and self-report of recent cannabis consumption.Conclusions: In this sample, current cannabis use was not associated with deficits in striatal D(2)/D(3) receptor availability. There was an inverse relationship between chronic cannabis use and striatal RAC BP(ND). Additional studies are needed to identify the neurochemical consequences of chronic cannabis use on the dopamine system. [ABSTRACT FROM AUTHOR]

Abstract: Accumulating evidence indicates that cannabis use may be a risk factor for schizophrenia (SZ), and chronic cannabis users score higher than non-users on measures of schizotypal personality traits. The purpose of the present study was to investigate the relations between normal personality, schizotypy, and cannabis use. Sixty-two chronic cannabis users and 45 cannabis-naïve controls completed a measure of normal personality, the NEO-Five Factor Inventory (NEO-FFI), and two measures of schizotypy, the schizotypal personality questionnaire (SPQ) and perceptual aberration scale (PAS). Substance use was assessed using the SCID I alcohol/drug module and a locally developed drug use questionnaire. On the NEO-FFI, users scored higher than controls on openness, but lower on agreeableness and conscientiousness, and endorsed greater schizotypy on the SPQ and PAS. Higher neuroticism predicted greater schizotypy in both groups, and, higher Extraversion predicted lower negative-syndrome schizotypy among users. Finally, duration of cannabis use was positively correlated with scores on the SPQ and PAS among users, suggesting a relation between overall cannabis use chronicity and schizotypy. These data show that cannabis users differ from non-users on dimensions of normal personality and schizotypy, and provide further evidence that cannabis use is associated with increased levels of psychosis-related personality traits. [Copyright &y& Elsevier]

Abstract: Although accumulating evidence suggests that cerebellar abnormalities may be linked to the symptoms and course of schizophrenia, few studies have related structural and functional indices of cerebellar integrity. The present study examined the relationship between the volume of specific subregions of the cerebellum and cerebellar function, as measured by eyeblink conditioning (EBC). Nine individuals with schizophrenia and six healthy comparison participants completed structural magnetic resonance imaging of the brain and a delay EBC procedure. Volumetric measurements were taken for the whole brain, whole cerebellum, cerebellar anterior lobules I–V and posterior lobules VI–VII. The schizophrenia group had smaller cerebellar anterior lobes and exhibited impaired EBC relative to the comparison group. In the comparison group, larger anterior volume correlated with earlier conditioned response onset latencies and increased amplitudes of the unconditioned blink response during paired trials (i.e., when the conditioned and unconditioned stimuli co-occurred). The findings that smaller anterior cerebellar volumes and EBC impairments were associated with schizophrenia are consistent with non-human studies showing that anterior cerebellar abnormalities are associated with deficits in delay EBC. The lack of a significant correlation between indices of EBC and cerebellar volume within the schizophrenia group suggests an aberrant relationship between cerebellar structure and function. [Copyright &y& Elsevier]