Characterizing smoking topography of cannabis in heavy users

Rationale  

Little is known about the smoking topography characteristics of heavy cannabis users. Such measures may be able to predict cannabis use-related outcomes and could be used to validate self-reported measures of cannabis use.     

Verbal learning and memory in adolescent cannabis users,alcohol users and non-users

Rationale  

Long-term heavy cannabis use can result in memory impairment. Adolescent users may be especially vulnerable to the adverse neurocognitive effects of cannabis.     

Alterations to pre-pulse inhibition (PPI) in chronic cannabis users are secondary to sustained attention deficits

Rationale  

Given the hypothesised association between cannabis use and schizophrenia, and the well documented alterations in pre-pulse inhibition (PPI) that are observed in schizophrenia, it is of interest to examine the effects of cannabis use on PPI.     

Altered parahippocampal functioning in cannabis users is related to the frequency of use

Rationale  

Converging lines of evidence suggest an association between cannabis use and impaired episodic memory as well as related associative learning. These deficits have been associated with the duration, frequency, and age of onset of cannabis use. However, it remains unclear whether these parameters of use differently impact memory-related hippocampal functioning.     

Examining the effects of former cannabis use on cerebellum-dependent eyeblink conditioning in humans

Rationale  

Previous work in humans has shown that chronic cannabis users exhibit disruptions in classical eyeblink conditioning (EBC), a form of associative learning that is known to be dependent on the cerebellum. Based upon previous work in animals, it was hypothesized that these learning deficits were related to cannabinoid receptor (CB1R) downregulation. However, it remains unclear whether there is a recovery of cerebellum-dependent learning after the cessation of cannabis use.     

A follow-up study: acute behavioural effects of Δ9-THC in female heterozygous Neuregulin 1 transmembrane domain mutant mice

Rationale  

Heavy cannabis use is linked with an increased risk for schizophrenia. We showed previously that male heterozygous neuregulin 1 transmembrane domain (Nrg1 HET) mice are more sensitive to some effects of the psychotropic cannabis constituent Δ⁹-tetrahydrocannabinol (THC). We report data from a follow-up study in female Nrg1 HET mice, investigating THC effects on behaviours with some relevance to schizophrenia.     

Acute effects of MDMA (3,4-methylenedioxymethamphetamine) on EEG oscillations: alone and in combination with ethanol or THC (delta-9-tetrahydrocannabinol)

Rationale  

Typical users of 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”) are polydrug users, combining MDMA with alcohol or cannabis [most active compound: delta-9-tetrahydrocannabinol (THC)].     

Dopaminergic augmentation of delta-9-tetrahydrocannabinol (THC) discrimination: possible involvement of D2-induced formation of anandamide

Rational  

Although delta-9-tetreahydrocannabinol (THC)-induced elevations in accumbal dopamine levels are believed to play an important role in the abuse-related effects of cannabis, little direct evidence has been provided that the dopaminergic system is involved in the psychotropic effects of THC.     

Cannabis use and cognitive functions in at-risk mental state and first episode psychosis

Background

Meta-analyses suggest that schizophrenia patients with a history of cannabis use have less impaired cognitive functioning compared to patients without cannabis use.

Aims

The objective of this study was to assess the association between recency and frequency of cannabis use and cognitive functioning in at-risk mental state for psychosis (ARMS) and first episode psychosis (FEP) individuals.

Methods

One hundred thirty-six participants completed a cognitive test battery and were assessed for current and past cannabis use. Analyses of covariance models were applied to evaluate the main effects of cannabis use and patient group (ARMS vs. FEP) as well as their interactions on cognitive functioning.

Results

No differences were observed in cognitive performance between current, former, and never users, and there were no significant interactions between cannabis use and patient group. Furthermore, within the group of current cannabis users, the frequency of cannabis use was not significantly associated with cognitive functioning.

Conclusion

The results of the present study do not support the notion that FEP patients and ARMS individuals with a history of cannabis use have less impaired cognitive functioning compared to those without cannabis use.     

Chronic cannabis users show altered neurophysiological functioning on Stroop task conflict resolution

Rationale  

Chronic cannabis use has been related to deficits in cognition (particularly memory) and the normal functioning of brain structures sensitive to cannabinoids. There is increasing evidence that conflict monitoring and resolution processes (i.e. the ability to detect and respond to change) may be affected.     

Chronic use of cannabis and poor neural efficiency in verbal memory ability

Introduction  

The endogenous cannabinoid system is sensitive to the introduction of exogenous cannabinoids such as delta-9-tetrahydrocannabinol, which are known to impact upon memory functioning. We sought to examine the impact of chronic cannabis use upon memory-related brain function via examination of the subsequent memory effect (SME) of the event-related potential (ERP).     

Developmental consequences of perinatal cannabis exposure: behavioral and neuroendocrine effects in adult rodents

Rationale  

Cannabis is the most commonly used illicit drug among pregnant women. Since the endocannabinoid system plays a crucial role in brain development, maternal exposure to cannabis derivatives might result in long-lasting neurobehavioral abnormalities in the exposed offspring. It is difficult to detect these effects, and their underlying neurobiological mechanisms, in clinical cohorts, because of their intrinsic methodological and interpretative issues.     

∆<Superscript>9</Superscript>-Tetrahydrocannabinol-dependent mice undergoing withdrawal display impaired spatial memory

Rationale  

Cannabis users display a constellation of withdrawal symptoms upon drug discontinuation, including sleep disturbances, irritability, and possibly memory deficits. In cannabinoid-dependent rodents, the CB₁ antagonist rimonabant precipitates somatic withdrawal and enhances forskolin-stimulated adenylyl cyclase activity in cerebellum, an effect opposite that of acutely administered ∆⁹-tetrahydrocannabinol (THC), the primary constituent in cannabis.     

Neural responses to subliminally presented cannabis and other emotionally evocative cues in cannabis-dependent individuals

Rationale

Addiction theories posit that drug-related cues maintain and contribute to drug use and relapse. Indeed, our recent study in cocaine-dependent patients demonstrated that subliminally presented cocaine-related stimuli activate reward neurocircuitry without being consciously perceived. Activation of reward neurocircuitry may provoke craving and perhaps prime an individual for subsequent drug-seeking behaviors.

Objectives

Using an equivalent paradigm, we tested whether cannabis cues activate reward neurocircuitry in treatment-seeking, cannabis-dependent individuals and whether activation was associated with relevant behavioral anchors: baseline cannabis craving (drug-seeking behavior) and duration of use (degree of conditioning).

Methods

Twenty treatment-seeking, cannabis-dependent individuals (12 males) underwent event-related blood oxygen level-dependent functional magnetic resonance imaging during exposure to 33-ms cannabis, sexual, and aversive cues presented in a backward-masking paradigm. Drug use history and cannabis craving were assessed prior to imaging.

Results

Participants showed increased activity to backward-masked cannabis cues in regions supporting reward detection and interoception, including the left anterior insula, left ventral striatum/amygdala, and right ventral striatum. Cannabis cue-related activity in the bilateral insula and perigenual anterior cingulate cortex was positively associated with baseline cannabis craving, and cannabis cue-related activity in the medial orbitofrontal cortex was positively correlated with years of cannabis use. Neural responses to backward-masked sexual cues were similar to those observed during cannabis cue exposure, while activation to aversive cues was observed only in the left anterior insula and perigenual anterior cingulate cortex.

Conclusions

These data highlight the sensitivity of the brain to subliminal reward signals and support hypotheses promoting a common pathway of appetitive motivation.     

Single doses of THC and cocaine decrease proficiency of impulse control in heavy cannabis users

BACKGROUND AND PURPOSE

Cannabis is the most popular drug used in the European Union, closely followed by cocaine. Whereas cannabis impairs neurocognitive function in occasional cannabis users, such impairments appear less prominent in heavy users, possibly as a result of tolerance. The present study was designed to assess whether the impairing effects of Δ⁹-tetrahydrocannabinol (THC) in heavy cannabis users would present in a wide range of neuropsychological functions or selectively affect specific performance domains. We also assessed the acute effects of cocaine on neurocognitive functions of heavy cannabis users.

EXPERIMENTAL APPROACH

Heavy cannabis users, who had a history of cocaine use (n = 61), participated in a double-blind, placebo-controlled, three-way crossover study. Subjects received single doses of cocaine HCl (300 mg), cannabis (THC μg·kg⁻¹) and placebo, and completed a number of tests measuring impulse control and psychomotor function.

KEY RESULTS

Single doses of cannabis impaired psychomotor function and increased response errors during impulsivity tasks. Single doses of cocaine improved psychomotor function and decreased response time in impulsivity tasks, but increased errors.

CONCLUSIONS AND IMPLICATIONS

Heavy cannabis users display impairments in a broad range of neuropsychological domains during THC intoxication. Impairments observed in psychomotor tasks, but not in impulsivity tasks, appeared smaller in magnitude as compared with those previously reported in occasional cannabis users. Heavy cannabis users were sensitive to the stimulating and inhibitory effects of cocaine on psychomotor function and impulsivity respectively. The reduction in proficiency in impulse control may put drug users at increased risk of repeated drug use and addiction.     

Association of abnormal semantic processing with delusion-like ideation in frequent cannabis users: an electrophysiological study

Rationale

Frequent cannabis use is a risk marker for schizophrenia and delusions, but the neurocognitive mechanisms of this relationship remain unclear.

Objectives

We sought evidence that cannabis users have deficits in processing relationships between meaningful stimuli, similar to abnormalities reported in schizophrenia, and that these deficits are associated with delusion-like ideation. We used the N400 event-related brain potential (ERP) waveform as a neurophysiological probe of activation of concepts in semantic memory. We hypothesized that cannabis users would exhibit larger (more negative) than normal N400 amplitudes in response to stimuli meaningfully related to a preceding prime—reflecting deficient activation of concepts related to the prime. We further hypothesized that the magnitude of this abnormality would correlate with severity of delusion-like ideation.

Methods

We recorded ERPs in 24 frequent cannabis users and 24 non-using comparison participants who viewed prime words followed by targets which were either words related or unrelated to the prime or pronounceable nonwords. The participants’ task was to indicate whether the target was a word. Delusion-like ideation was measured via the Schizotypal Personality Questionnaire.

Results

Contrary to our hypothesis, cannabis users exhibited smaller than normal N400s to both related and unrelated targets. These abnormalities correlated with delusion-like ideation in cannabis users only.

Conclusions

The results are consistent with a generalized abnormality of activation within semantic memory neural networks in cannabis users. Further research is needed to investigate whether such an abnormality plays a role in the development of delusion-like ideation in cannabis users.     

Acute effects of THC on time perception in frequent and infrequent cannabis users

Rationale

Cannabinoids have been shown to alter time perception, but existing literature has several limitations. Few studies have included both time estimation and production tasks, few control for subvocal counting, most had small sample sizes, some did not record subjects’ cannabis use, many tested only one dose, and used either oral or inhaled administration of Δ⁹-tetrahydrocannabinol (THC), leading to variable pharmacokinetics, and some used whole-plant cannabis containing cannabinoids other than THC. Our study attempted to address these limitations.

Objectives

This study aims to characterize the acute effects of THC and frequent cannabis use on seconds-range time perception. THC was hypothesized to produce transient, dose-related time overestimation and underproduction. Frequent cannabis smokers were hypothesized to show blunted responses to these alterations.

Methods

IV THC was administered at doses from 0.015 to 0.05 mg/kg to 44 subjects who participated in several double-blind, randomized, counterbalanced, crossover, placebo-controlled studies. Visual time estimation and production tasks in the seconds range were presented to subjects three times on each test day.

Results

All doses induced time overestimation and underproduction. Chronic cannabis use had no effect on baseline time perception. While infrequent/nonsmokers showed temporal overestimation at medium and high doses and temporal underproduction at all doses, frequent cannabis users showed no differences. THC effects on time perception were not dose related.

Conclusions

A psychoactive dose of THC increases internal clock speed as indicated by time overestimation and underproduction. This effect is not dose related and is blunted in chronic cannabis smokers who did not otherwise have altered baseline time perception.     

Quantifying cannabis use with the Timeline Followback approach: A psychometric evaluation

Background

In the absence of a standardized cannabis unit, self-report instruments are inadequate for accurate quantification of cannabis use. The study extends the feasibility of using a cannabis substitute to reliably and validly measure quantity of cannabis use.

Method

Ninety-eight adult Australian cannabis users (M age = 27.98, SD = 11.10; 65.31% male) completed a 90-day Timeline Followback interview regarding their cannabis use, utilizing the cannabis substitute Marijuanilla to report on quantity of use. Ninety-two of these individuals completed the interview at two time-points, and 56 of these participants had collaterals corroborate their cannabis use reports.

Results

Inter-rater reliability was excellent, while test–retest reliability was good to excellent. Intra-class correlation coefficients between participant and collateral reports, while similar to previous research, were unacceptable. Quantity of cannabis use statistically significantly added to frequency of use in predicting cannabis problems and dependence severity. Concurrent and discriminant validity were established with single-item and positive impression management measures, respectively. In addition, Marijuanilla appeared similar to one specimen of street seized cannabis, but not to two others. Importantly, participants’ cravings to use cannabis did not increase as a result of using the cannabis substitute to report on their cannabis use.

Conclusions

These data suggest that utilizing Marijuanilla to facilitate the reporting of grams of cannabis use may be reliable and valid; however, such comprehensive assessment may only be necessary for clinical trials and epidemiological studies, which rely on precise estimates of cannabis use.     

Cannabis,Cigarettes, and Their Co-Occurring Use: Disentangling Differences in Gray Matter Volume

Background:

Structural magnetic resonance imaging techniques are powerful tools for examining the effects of drug use on the brain. The nicotine and cannabis literature has demonstrated differences between nicotine cigarette smokers and cannabis users compared to controls in brain structure; however, less is known about the effects of co-occurring cannabis and tobacco use.

Methods:

We used voxel-based morphometry to examine gray matter volume differences between four groups: (1) cannabis-dependent individuals who do not smoke tobacco (Cs); (2) cannabis-dependent individuals who smoke tobacco (CTs); (3) cannabis-naïve, nicotine-dependent individuals who smoke tobacco (Ts); and (4) healthy controls (HCs). We also explored associations between gray matter volume and measures of cannabis and tobacco use.

Results:

A significant group effect was observed in the left putamen, thalamus, right precentral gyrus, and left cerebellum. Compared to HCs, the Cs, CTs, and Ts exhibited larger gray matter volumes in the left putamen. Cs also had larger gray matter volume than HCs in the right precentral gyrus. Cs and CTs exhibited smaller gray matter volume than HCs in the thalamus, and CTs and Ts had smaller left cerebellar gray matter volume than HCs.

Conclusions:

This study extends previous research that independently examined the effects of cannabis or tobacco use on brain structure by including an examination of co-occurring cannabis and tobacco use, and provides evidence that cannabis and tobacco exposure are associated with alterations in brain regions associated with addiction.