Haithem Chtioui

Long-term effects of cannabis on brain structure.

The dose-dependent toxicity of the main psychoactive component of cannabis in brain regions rich in cannabinoid CB1 receptors is well known in animal studies. However, research in humans does not show common findings across studies regarding the brain regions that are affected after long-term exposure to cannabis. In the present study, we investigate (using Voxel-based Morphometry) gray matter changes in a group of regular cannabis smokers in comparison with a group of occasional smokers matched by the years of cannabis use. We provide evidence that regular cannabis use is associated with gray matter volume reduction in the medial temporal cortex, temporal pole, parahippocampal gyrus, insula, and orbitofrontal cortex; these regions are rich in cannabinoid CB1 receptors and functionally associated with motivational, emotional, and affective processing. Furthermore, these changes correlate with the frequency of cannabis use in the 3 months before inclusion in the study. The age of onset of drug use also influences the magnitude of these changes. Significant gray matter volume reduction could result either from heavy consumption unrelated to the age of onset or instead from recreational cannabis use initiated at an adolescent age. In contrast, the larger gray matter volume detected in the cerebellum of regular smokers without any correlation with the monthly consumption of cannabis may be related to developmental (ontogenic) processes that occur in adolescence.

Weed or wheel! FMRI, behavioural, and toxicological investigations of how cannabis smoking affects skills necessary for driving

Marijuana is the most widely used illicit drug, however its effects on cognitive functions underling safe driving remain mostly unexplored. Our goal was to evaluate the impact of cannabis on the driving ability of occasional smokers, by investigating changes in the brain network involved in a tracking task. The subject characteristics, the percentage of Δ9-Tetrahydrocannabinol in the joint, and the inhaled dose were in accordance with real-life conditions. Thirty-one male volunteers were enrolled in this study that includes clinical and toxicological aspects together with functional magnetic resonance imaging of the brain and measurements of psychomotor skills. The fMRI paradigm was based on a visuo-motor tracking task, alternating active tracking blocks with passive tracking viewing and rest condition. We show that cannabis smoking, even at low Δ9-Tetrahydrocannabinol blood concentrations, decreases psychomotor skills and alters the activity of the brain networks involved in cognition. The relative decrease of Blood Oxygen Level Dependent response (BOLD) after cannabis smoking in the anterior insula, dorsomedial thalamus, and striatum compared to placebo smoking suggests an alteration of the network involved in saliency detection. In addition, the decrease of BOLD response in the right superior parietal cortex and in the dorsolateral prefrontal cortex indicates the involvement of the Control Executive network known to operate once the saliencies are identified. Furthermore, cannabis increases activity in the rostral anterior cingulate cortex and ventromedial prefrontal cortices, suggesting an increase in self-oriented mental activity. Subjects are more attracted by intrapersonal stimuli (“self”) and fail to attend to task performance, leading to an insufficient allocation of task-oriented resources and to sub-optimal performance. These effects correlate with the subjective feeling of confusion rather than with the blood level of Δ9-Tetrahydrocannabinol. These findings bolster the zero-tolerance policy adopted in several countries that prohibits the presence of any amount of drugs in blood while driving.

THCCOOH concentrations in whole blood: Are they useful in discriminating occasional from heavy smokers?

Some forensic and clinical circumstances require knowledge of the frequency of drug use. Care of the patient, administrative, and legal consequences will be different if the subject is a regular or an occasional cannabis smoker. To this end, 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) has been proposed as a criterion to help to distinguish between these two groups of users. However, to date this indicator has not been adequately assessed under experimental conditions. We carried out a controlled administration study of smoked cannabis with a placebo. Cannabinoid levels were determined in whole blood using tandem mass spectrometry. Significantly high differences in THCCOOH concentrations were found between the two groups when measured during the screening visit, prior to the smoking session, and throughout the day of the experiment. Receiver operating characteristic (ROC) curves were determined and two threshold criteria were proposed in order to distinguish between these groups: a free THCCOOH concentration below 3 µg/L suggested an occasional consumption (≤ 1 joint/week) while a concentration higher than 40 µg/L corresponded to a heavy use (≥ 10 joints/month). These thresholds were tested and found to be consistent with previously published experimental data. The decision threshold of 40 µg/L could be a cut-off for possible disqualification for driving while under the influence of cannabis. A further medical assessment and follow-up would be necessary for the reissuing of a driving license once abstinence from cannabis has been demonstrated. A THCCOOH level below 3 µg/L would indicate that no medical assessment is required.

Cannabis and Its Effects on Driving Skills

Traffic policies show growing concerns about driving under the influence of cannabis, since cannabinoids are one of the most frequently encountered psychoactive substances in the blood of drivers who are drug-impaired and/or involved in accidents, and in the context of a legalization of medical marijuana and of recreational use. The neurobiological mechanisms underlying the effects of cannabis on safe driving remain poorly understood. In order to better understand its acute and long-term effects on psychomotor functions involved in the short term ability and long-term fitness to drive, experimental research has been conducted based on laboratory, simulator or on-road studies, as well as on structural and functional brain imaging. Results presented in this review show a cannabis-induced impairment of actual driving performance by increasing lane weaving and mean distance headway to the preceding vehicle. Acute and long-term dose-dependent impairments of specific cognitive functions and psychomotor abilities were also noted, extending beyond a few weeks after the cessation of use. Some discrepancies found between these studies could be explained by factors such as history of cannabis use, routes of administration, dose ranges, or study designs (e.g. treatment blinding). Moreover, use of both alcohol and cannabis has been shown to lead to greater odds of making an error than use of either alcohol or cannabis alone. Although the correlation between blood or oral fluid concentrations and psychoactive effects of THC needs a better understanding, blood sampling has been shown to be the most effective way to evaluate the level of impairment of drivers under the influence of cannabis. The blood tests have also shown to be useful to highlight a chronic use of cannabis that suggests an addiction and therefore a long-term unfitness to drive. Besides blood, hair and repeated urine analyses are useful to confirm abstinence.

Pharmacokinetics of Pomalidomide in a Patient Receiving Hemodialysis Using a High-Cutoff Filter

To the Editor: Pomalidomide is an oral immunomodulatory drug with antitumoral efficacy against relapsed or refractory multiple myeloma. It binds moderately (16%-42%) to plasma proteins. It is mainly eliminated by cytochrome-mediated hydroxylation in the liver. Its high plasma free fraction and low molecular weight (273 g/mol) make it susceptible to glomerular filtration. Despite that,,4% of the dose is excreted unchanged in urine, suggesting that substantial tubular reabsorption may occur. Pomalidomide elimination does not seem to be substantially affected by moderately decreased kidney function, but data from patients with advanced kidney failure are limited and clinical trials regarding its disposition in this subpopulation are ongoing. In theory, pomalidomide could be significantly removed by hemodialysis because this technique replaces glomerular filtration without affecting further reabsorption. The FDA recently published updated pomalidomide dosage recommendations for patients requiring dialysis, advising a 25% dose reduction (ie, 3 mg/d). Per the manufacturer, there is an increase in pomalidomide’sAUC (of 38%) and the rate of severe adverse events (by 64%) in dialysis patients. Multiple myeloma is frequently associated with alterations in kidney function, and high-cutoff (HCO) dialysis is increasingly used in this condition to ensure blood purification and remove nephrotoxic light chains. However, data regarding pomalidomide disposition during HCO dialysis are lacking. HCO dialysis implies longer, more frequent sessions, using higher filter permeability for substances in the molecular weight range of 15 to 45 kDa, and requiring albumin substitution; it may therefore lead to higher drug elimination compared to traditional intermittent hemodialysis. We report the pharmacokinetics of pomalidomide during HCO dialysis in a patient with multiple myeloma and kidney failure.

OATP1B1 and DAA treatment for hepatitis C in patients with hepatocellular carcinoma

I read with great interest the article by Soria et al. on viral relapses in hepatitis C virus (HCV)infected patients with hepatocellular carcinoma (HCC) who are treated with direct-acting antivirals (DAAs). By the current state of knowledge, the complex issue of HCC recurrence after DAA therapy remains unclear, and several authors have emphasized the need for further investigation. In this context, raising the question of the influence of HCC itself on the outcome of hepatitis C treatment with DAAs is of considerable interest. A recent study suggests that the presence of active HCC at the time of HCV treatment initiation is associated with reduced chances of achieving a sustained virologic response. A clear explanation is still lacking, but the possibility of unequal drug distribution to the HCC area has been hypothesized. In the case series presented by Soria et al., all five patients with active HCC diagnosed within 5-42 weeks after DAA initiation experienced viral relapse. However, it is not clear whether all patients had active HCC while being treated with DAAs. Among other hypotheses, the authors propose reduced uptake of DAA into HCC cells due to down-regulation of the OATP1B1 (SLCO1B1) influx membrane transporter as a possible reason for DAA failure. This hypothesis is attractive, but the authors should have stressed that it may apply only to two out of the five reported patients with HCC. According to the data of the manufacturers, sofosbuvir, ledipasvir, daclatasvir, and ribavirin are not substrates of the OATP1B1 transporter. Thus, their intracellular disposition should not be altered by reduced OATP1B1 expression. Moreover, daclatasvir is an inhibitor of OATP1B1 and may impair the transport of substrate drugs through OATP1B1. In fact, only paritaprevir and simeprevir are substrates of OATP1B1. Presenting the hypothesis in the light of the affinity of the DAAs for the OATP1B1 transporter may have generated a more balanced discussion. To add another level of complexity, little is known about the replication of HCV in HCC cells in vivo. Further work will be required to address this important issue. Haithem Chtioui, M.D. Division of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois University of Lausanne Lausanne, Switzerland

Sofosbuvir and ribavirin before liver re-transplantation for graft failure due to recurrent hepatitis C: a case report

BackgroundRecurrent hepatitis C virus infection after liver transplantation is associated with reduced graft and patient survival. Re-transplantation for graft failure due to recurrent hepatitis C is controversial and not performed in all centers.Case presentationWe describe a 54-year-old patient with hepatitis C virus genotype 1b infection and a null response to pegylated interferon-α and ribavirin who developed decompensated graft cirrhosis 6 years after a first liver transplantation. Treatment with sofosbuvir and ribavirin allowed for rapid negativation of serum HCV RNA and was well tolerated despite advanced liver and moderate renal dysfunction. Therapeutic drug monitoring did not reveal any clinically significant drug-drug interactions. Despite virological response, the patient remained severely decompensated and re-transplantation was performed after 46 days of undetectable serum HCV RNA. The patient is doing well 12 months after his second liver transplantation and remains free of hepatitis C virus.ConclusionsThe use of directly acting antivirals may allow for successful liver re-transplantation for recipients who remain decompensated despite virological response and is likely to improve the outcome of liver re-transplantation for end-stage recurrent hepatitis C.

Acute Effects of Cannabis Smoking on Skills Related to Driving: an fMRI Study.

Introduction : Driving is a complex everyday task requiring mechanisms of perception, attention, learning, memory, decision making and action control, thus indicating that involves numerous and varied brain networks. If many data have been accumulated over time about the effects of alcohol consumption on driving capability, much less is known about the role of other psychoactive substances, such as cannabis (Chang et al.2007, Ramaekers et al, 2006). Indeed, the solicited brain areas during safe driving which could be affected by cannabis exposure have not yet been clearly identified. Our aim is to study these brain regions during a tracking task related to driving skills and to evaluate the modulation due to the tolerance of cannabis effects. Methods : Eight non-smoker control subjects participated to an fMRI experiment based on a visuo-motor tracking task, alternating active tracking blocks with passive tracking viewing and rest condition. Half of the active tracking conditions included randomly presented traffic lights as distractors. Subjects were asked to track with a joystick with their right hand and to press a button with their left index at each appearance of a distractor. Four smoking subjects participated to the same fMRI sessions once before and once after smoking cannabis and a placebo in two independent cross-over experiments. We quantified the performance of the subjects by measuring the precision of the behavioural responses (i.e. percentage of time of correct tracking and reaction times to distractors). Functional MRI data were acquired using on a 3.0T Siemens Trio system equipped with a 32-channel head coil. BOLD signals will be obtained with a gradient-echo EPI sequence (TR=2s, TE=30ms, FoV=216mm, FA=90°, matrix size 72×72, 32 slices, thickness 3mm). Preprocessing, single subject analysis and group statistics were conducted on SPM8b. Results were thresholded at p 30 for spatial extent. Results : Behavioural results showed a significant impairment in task and cognitive test performance of the subjects after cannabis inhalation when comparing their tracking accuracy either to the controls subjects or to their performances before the inhalation or after the placebo inhalation (p<0.001 corrected). In controls, fMRI BOLD analysis of the active tracking condition compared to the passive one revealed networks of polymodal areas in superior frontal and parietal cortex dealing with attention and visuo-spatial coordination. In accordance to what is known of the visual and sensory motor networks we found activations in V4, frontal eye-field, right middle frontal gyrus, intra-parietal sulcus, temporo-parietal junction, premotor and sensory-motor cortex. The presence of distractors added a significant activation in the precuneus. Preliminary results on cannabis smokers in the acute phase, compared either to themselves before the cannabis inhalation or to control subjects, showed a decreased activation in large portions of the frontal and parietal attention network during the simple tracking task, but greater involvement of precuneus, of the superior part of intraparietal sulcus and middle frontal gyrus bilaterally when distractors were present in the task. Conclusions : Our preliminary results suggest that acute cannabis smoking alters performances and brain activity during active tracking tasks, partly reorganizing the recruitment of brain areas of the attention network.