Clinical trials of medicinal cannabis for appetite-related symptoms from advanced cancer: a survey of preferences, attitudes and beliefs among patients willing to consider participation.

BACKGROUND: Australian clinical trials are planned to evaluate medicinal cannabis in a range of clinical contexts. AIMS: To explore the preferences, attitudes and beliefs of patients eligible and willing to consider participation in a clinical trial of medicinal cannabis for poor appetite and appetite-related symptoms from advanced cancer. METHODS: A cross-sectional anonymous survey was administered from July to December 2015 online and in eight adult outpatient palliative care and/or cancer services. Respondents were eligible if they were ≥18 years, had advanced cancer and poor appetite/taste problems/weight loss and might consider participating in a medicinal cannabis trial. Survey items focused on medicinal rather than recreational cannabis use and did not specify botanical or pharmaceutical products. Items asked about previous medicinal cannabis use and preferences for delivery route and invited comments and concerns. RESULTS: There were 204 survey respondents, of whom 26 (13%) reported prior medicinal cannabis use. Tablets/capsules were the preferred delivery mode (n = 144, 71%), followed by mouth spray (n = 84, 42%) and vaporiser (n = 83, 41%). Explanations for preferences (n = 134) most commonly cited convenience (n = 66; 49%). A total of 82% (n = 168) of respondents indicated that they had no trial-related concerns, but a small number volunteered concerns about adverse effects (n = 14) or wanted more information/advice (n = 8). Six respondents volunteered a belief that cannabis might cure cancer, while two wanted assurance of efficacy before participating in a trial. CONCLUSION: Justification of modes other than tablets/capsules and variable understanding about cannabis and trials will need addressing in trial-related information to optimise recruitment and ensure that consent is properly informed.

Hippocampal harms, protection and recovery following regular cannabis use.

Shifting policies towards legalisation of cannabis for therapeutic and recreational use raise significant ethical issues for health-care providers seeking evidence-based recommendations. We investigated whether heavy cannabis use is associated with persistent harms to the hippocampus, if exposure to cannabidiol offers protection, and whether recovery occurs with abstinence. To do this, we assessed 111 participants: 74 long-term regular cannabis users (with an average of 15.4 years of use) and 37 non-user healthy controls. Cannabis users included subgroups of participants who were either exposed to Δ9-tetrahydrocannabinol (THC) but not to cannabidiol (CBD) or exposed to both, and former users with sustained abstinence. Participants underwent magnetic resonance imaging from which three measures of hippocampal integrity were assessed: (i) volume; (ii) fractional anisotropy; and (iii) N-acetylaspartate (NAA). Three curve-fitting models across the entire sample were tested for each measure to examine whether cannabis-related hippocampal harms are persistent, can be minimised (protected) by exposure to CBD or recovered through long-term abstinence. These analyses supported a protection and recovery model for hippocampal volume (P=0.003) and NAA (P=0.001). Further pairwise analyses showed that cannabis users had smaller hippocampal volumes relative to controls. Users not exposed to CBD had 11% reduced volumes and 15% lower NAA concentrations. Users exposed to CBD and former users did not differ from controls on any measure. Ongoing cannabis use is associated with harms to brain health, underpinned by chronic exposure to THC. However, such harms are minimised by CBD, and can be recovered with extended periods of abstinence.

Cerebellar white-matter changes in cannabis users with and without schizophrenia.

BACKGROUND: The cerebellum is rich in cannabinoid receptors and implicated in the neuropathology of schizophrenia. Long-term cannabis use is associated with functional and structural brain changes similar to those evident in schizophrenia, yet its impact on cerebellar structure has not been determined. We examined cerebellar grey and white matter in cannabis users with and without schizophrenia. METHOD: Seventeen patients with schizophrenia and 31 healthy controls were recruited; 48% of the healthy group and 47% of the patients were long-term heavy cannabis users (mean 19.7 and 17.9 years near daily use respectively). Cerebellar measures were extracted from structural 3-T magnetic resonance imaging (MRI) scans using semi-automated methods, and examined using analysis of covariance (ANCOVA) and correlational analyses. RESULTS: Cerebellar white-matter volume was reduced in cannabis users with and without schizophrenia compared to healthy non-users, by 29.7% and 23.9% respectively, and by 17.7% in patients without cannabis use. Healthy cannabis users did not differ in white-matter volume from either of the schizophrenia groups. There were no group differences in cerebellar grey matter or total volumes. Total cerebellar volume decreased as a function of duration of cannabis use in the healthy users. Psychotic symptoms and illness duration correlated with cerebellar measures differentially between patients with and without cannabis use. CONCLUSIONS: Long-term heavy cannabis use in healthy individuals is associated with smaller cerebellar white-matter volume similar to that observed in schizophrenia. Reduced volumes were even more pronounced in patients with schizophrenia who use cannabis. Cannabis use may alter the course of brain maturational processes associated with schizophrenia.

Dissociable cognitive impairments in problem drinkers.

Patients in a treatment programme for severe alcohol dependence were tested on a battery of tests designed to examine organizational and visuo-spatial abilities. Analysis using a case-study approach indicated independent organizational and visuo-spatial impairments. An understanding of aetiological factors underlying these cognitive deficits and implications for treatment are discussed.

Ecstasy use in Australia: patterns of use and associated harm.

This study explored patterns of ecstasy use and associated harm through the administration of a structured interview schedule to 329 ecstasy users, recruited from three Australian cities. A broad range of ecstasy users were interviewed, but on the whole, the sample was young, relatively well educated and most were employed or students. Patterns of use were varied, although extensive polydrug use was the norm. High rates of intravenous drug use were recorded, which may relate to an over-representation of chaotic intravenous polydrug users. Subjects had experienced an average of eight physical and four psychological side-effects, which they attributed to their ecstasy use in the preceding 6 months. Approximately 40% of the sample also reported financial, relationship and occupational problems. Young, female, polydrug users and those who binged on ecstasy for 48 h or more appeared most at risk of experiencing harm that they related to their ecstasy use. One-fifth of the sample had received treatment for an ecstasy-related problem, most often from a GP or natural therapist, and 7% were currently in treatment. One quarter wanted to reduce their use because of financial, relationship and psychological problems. A total of 15% wanted formal treatment for an ecstasy-related problem and 85% requested more information. These results have implications for the development of policies to respond to drug use among this population.

Event-related potential indices of auditory selective attention in dependent amphetamine users.

BACKGROUND: The aim of the present study was to further investigate a previously reported attention-related impairment in dependent amphetamine users using event-related potential (ERP) indices of selective attention. METHODS: ERPs were recorded during an auditory selective attention task (SAT) that involved detecting infrequent long-duration target tones presented among short-duration tones that varied in location (left vs. right ear) and pitch (low vs. high). Amphetamine users (n = 19) were divided into two groups, high dependence (n = 10) and low dependence (n = 10), based on amphetamine Severity of Dependence Scale scores, and compared to an age-matched control group (n = 9). RESULTS: The high-dependence group showed slowed reaction time and reduced early processing negativity and peak N1 amplitude to location-relevant nontarget stimuli. Poor performance on the SAT was highly correlated with deficits in early processing, which were also related to poor performance on the Wechsler Memory Scale Attention/Concentration index. CONCLUSIONS: It is suggested that severely dependent users suffer an inability to selectively enhance the sensory processing of relevant auditory information. This may produce poor automatic preferential processing of relevant information and increase load on limited attentional resources.

Adverse effects of cannabis.

Cannabis is the most widely used illicit drug in many developed societies. Its health and psychological effects are not well understood and remain the subject of much debate, with opinions on its risks polarised along the lines of proponents' views on what its legal status should be. An unfortunate consequence of this polarisation of opinion has been the absence of any consensus on what health information the medical profession should give to patients who are users or potential users of cannabis. There is conflicting evidence about many of the effects of cannabis use, so we summarise the evidence on the most probable adverse health and psychological consequences of acute and chronic use. This uncertainty, however, should not prevent medical practitioners from advising patients about the most likely ill-effects of their cannabis use. Here we make some suggestions about the advice doctors can give to patients who use, or are contemplating the use, of this drug.

Evoked otoacoustic emissions and auditory selective attention.

The auditory system has an extensive peripheral efferent innervation. The question addressed in this paper is whether the olivocochlear bundle (OCB) efferent system innervating the outer hair cells (OHC) of the cochlea plays a role in selective attention. As evoked otoacoustic emissions (EOAE) provide a measure of the active micromechanical properties of OHCs, they can be used to assess the role of the efferent system in attention. Six experiments using tone-pip EOAEs are reported. In each experiment, EOAEs generated by 1 or 2 kHz tone pips when they were attended were compared with EOAEs to the same stimuli when they were unattended. In three experiments (1-4), a non-linear stimulus difference method was used to record a pure cochlear component of EOAEs. In Exps. 1-5, 1 and 2 kHz tone pips were delivered to the same ear and the difficulty of the subjects' task was manipulated in order to produce a more focussed attentional state or contralateral noise was presented to determine whether attention effects are dependent upon having an already activated efferent system. In Exp.6, the 1 and 2 kHz stimuli were delivered to opposite ears. A total of 70 subjects participated in the six experiments. There were no effects of attention on EOAEs in any of the experiments in the direction of previously reported effects. The results of these first six experiments employing simple attention switches between fixed auditory objects do not support active cochlear involvement in selective attention.

Memory functioning in social drinkers: a study of event-related potentials.

Verbal memory functioning was assessed in light and heavy social drinkers by recording event-related potentials in subjects instructed to memorize lists of words using either repetition or elaborative learning strategies. Although overall performance did not differ significantly between light and heavy drinkers, heavy drinkers showed reduced within-list organization compared with light drinkers. There were statistically significant differences in the event-related potential indices of memory functioning elicited during complex elaborative processing which were consistent with decreased within-list organization in heavy drinkers.

Differential impairments of selective attention due to frequency and duration of cannabis use.

The evidence for long-term cognitive impairments associated with chronic use of cannabis has been inconclusive. We report the results of a brain event-related potential (ERP) study of selective attention in long-term cannabis users in the unintoxicated state. Two ERP measures known to reflect distinct components of attention were found to be affected differentially by duration and frequency of cannabis use. The ability to focus attention and filter out irrelevant information, measured by frontal processing negativity to irrelevant stimuli, was impaired progressively with the number of years of use but was unrelated to frequency of use. The speed of information processing, measured by the latency of parietal P300, was delayed significantly with increasing frequency of use but was unaffected by duration of use. The results suggest that a chronic buildup of cannabinoids produces both short- and long-term cognitive impairments.

Do cognitive impairments recover following cessation of cannabis use?

Our previous research with long term cannabis users established an impaired ability to focus attention and filter out irrelevant information, which was progressive with the cumulative duration of exposure to cannabis. The current study examined these processes in a group of ex-cannabis users. The results suggested a partial recovery of function but the past duration of cannabis use continued to have an adverse effect on the ability to effectively reject complex irrelevant information. There was no indication of improvement with increasing length of abstinence. Whilst relatively subtle in nature, the consequences of such an enduring deficit associated with cannabis use are worthy of further investigation.

Biopsychosocial changes associated with cessation of cannabis use: a single case study of acute and chronic cognitive effects, withdrawal and treatment.

A 35 year old male was cognitively assessed prior to cessation of 18 years of daily cannabis use and monitored for several weeks post cessation. Brain event-related potential (ERP) measures of selective attention reflecting a difficulty in filtering out complex irrelevant information showed no indication of improvement over 6 weeks of abstinence. In contrast, when tested in the acutely intoxicated state prior to cessation of use, a dramatic normalisation of the ERP signature of this individual was observed. A treatment program based on supportive-expressive psychotherapy was administered and depression, anxiety and general psychological health were monitored over the course of withdrawal from cannabis.

The effects of between-source discriminability on attended and unattended auditory ERPs.

Event-related potentials (ERPs) for tone pips from attended and unattended sources, which varied on discriminability, were compared with ERPs for the same stimuli recorded during performance of a visual task. This comparison revealed that Nd, the negative shift of attended relative to unattended ERPs, consisted of three components: a negativity in the attended ERP from 100 to 270 ms, a positivity in the unattended ERP from 170 ms to the end of the epoch, and a second negativity in the attended ERP from 270 to 700 ms. In general, the later onset of early Nd with more difficult between-source discriminations could be attributed to the later onset of the positivity in unattended ERPs. A number of hypotheses were advanced for the origin of the unattended positivity: the suppression of the later of two negative components in the 100-220-ms range, an enhanced P2 component, an endogenous positivity, or the resolution of a protracted negativity elicited by preceding attended stimuli.

Recreational MDMA use in Sydney: a profile of 'Ecstacy' users and their experiences with the drug.

'Ecstasy' (3,4-methylenedioxymethamphetamine or MDMA) is a recreational drug that is gaining popularity world wide. There is a paucity of research regarding the ways in which Ecstasy is used and the nature of its effects. A 'snowball' peer network technique was used to recruit 100 users who completed anonymous questionnaires. The research revealed that Ecstasy is primarily used by infrequent recreational drug users for 'fun' at dance parties and social gatherings. The primary reported effects of Ecstasy were a 'positive mood state' and feelings of intimacy and closeness to others. The secondary effects of Ecstasy were the stimulant effects of energy and activation, and the psychedelic effects of insight and perceptual and sensual enhancement. Ecstasy was reported to share the properties of both amphetamines and hallucinogens in the nature of its side effects and residual effects which were no more severe than those of the latter two classes of drug. It appeared Ecstasy was not conductive to regular and frequent use, because tolerance was reported to develop to the positive effects of Ecstasy, while negative effects increased with use. Although few problems associated with the recreational use of Ecstasy have surfaced to date, animal research has shown it to be neurotoxic to serotonergic nerve terminals. Caution must be observed until further research can determine the level of hazard in humans.

Effects of long-term cannabis use on selective attention: an event-related potential study.

Brain event-related potentials (ERPs) were recorded from nine long-term cannabis users during a complex auditory selective attention task and compared with nine nonuser controls. Stimuli consisted of a random sequence of tones varying in location, pitch and duration. Subjects were instructed to respond to long-duration tones of a particular pitch and location. Cannabis users' task performance was significantly worse than controls. The most striking difference between the ERPs of the two groups was in the greatly enhanced early processing negativity in the user group to short-duration stimuli which matched the target on location only. This is indicative of users engaging in unnecessary pitch processing and thus having difficulty in setting up an accurate focus of attention and in filtering out irrelevant information. The data suggest a dysfunction in the allocation of attentional resources and stimulus evaluation strategies. These results imply that long-term cannabis use may impair the ability to efficiently process information.

Hypothalamic modulation of thermogenesis and energy substrate utilization.

The metabolic effects of electrical stimulation of the hypothalamus were investigated using indirect calorimetry. Stimulation of either the ventromedial hypothalamic nucleus (VMH) or the lateral hypothalamic area (LH) increased both respiratory quotient (RQ) and energy expenditure (EE) in 23 lightly anesthetized rats. The use of a muscle relaxant to reduce motor activity and a regression analysis on the residual activity showed that the metabolic changes were independent of motor activity following LH stimulation. The increased RQ indicates that stimulation increased the dependence on carbohydrates as an energy substrate. The increased EE indicates that the LH modulates EE by mediating thermogenesis. The interpretation of the metabolic changes in RQ and EE following VMH stimulation is complicated by the fact that there were significant relationships between residual activity and metabolic changes in the sedated rats with VMH electrodes. Together, these data suggest that the hypothalamus regulates body weight by controlling energy expenditure, as well as energy intake. At the same time, hypothalamic activity influences which substrate the rat uses for energy.