Favourable outcome after prolonged veno-venous extracorporeal membrane oxygenation (V-V ECMO) support for Pneumocystis jirovecii pneumonia in a renal transplant recipient.

A 27-year-old man, with a history of renal transplantation, presented with acute kidney failure and Pneumocystis jirovecii pneumonia. The patient developed severe acute respiratory failure and required support by veno-venous extracorporeal membrane oxygenation for a total of 59 days. During this period, the patient had extremely low tidal volumes using a lung protective ventilation strategy and intermittent prone positioning was used to optimise oxygenation. There was full recovery of pulmonary and partial recovery of renal function.

Psychiatric symptoms caused by cannabis constituents: a systematic review and meta-analysis.

BACKGROUND: Approximately 188 million people use cannabis yearly worldwide, and it has recently been legalised in 11 US states, Canada, and Uruguay for recreational use. The potential for increased cannabis use highlights the need to better understand its risks, including the acute induction of psychotic and other psychiatric symptoms. We aimed to investigate the effect of the cannabis constituent Δ9-tetrahydrocannabinol (THC) alone and in combination with cannabidiol (CBD) compared with placebo on psychiatric symptoms in healthy people. METHODS: In this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO for studies published in English between database inception and May 21, 2019, with a within-person, crossover design. Inclusion criteria were studies reporting symptoms using psychiatric scales (the Brief Psychiatric Rating Scale [BPRS] and the Positive and Negative Syndrome Scale [PANSS]) following the acute administration of intravenous, oral, or nasal THC, CBD, and placebo in healthy participants, and presenting data that allowed calculation of standardised mean change (SMC) scores for positive (including delusions and hallucinations), negative (such as blunted affect and amotivation), and general (including depression and anxiety) symptoms. We did a random-effects meta-analysis to assess the main outcomes of the effect sizes for total, positive, and negative PANSS and BPRS scores measured in healthy participants following THC administration versus placebo. Because the number of studies to do a meta-analysis on CBD's moderating effects was insufficient, this outcome was only systematically reviewed. This study is registered with PROSPERO, CRD42019136674. FINDINGS: 15 eligible studies involving the acute administration of THC and four studies on CBD plus THC administration were identified. Compared with placebo, THC significantly increased total symptom severity with a large effect size (assessed in nine studies, with ten independent samples, involving 196 participants: SMC 1·10 [95% CI 0·92-1·28], p<0·0001); positive symptom severity (assessed in 14 studies, with 15 independent samples, involving 324 participants: SMC 0·91 [95% CI 0·68-1·14], p<0·0001); and negative symptom severity with a large effect size (assessed in 12 studies, with 13 independent samples, involving 267 participants: SMC 0·78 [95% CI 0·59-0·97], p<0·0001). In the systematic review, of the four studies evaluating CBD's effects on THC-induced symptoms, only one identified a significant reduction in symptoms. INTERPRETATION: A single THC administration induces psychotic, negative, and other psychiatric symptoms with large effect sizes. There is no consistent evidence that CBD induces symptoms or moderates the effects of THC. These findings highlight the potential risks associated with the use of cannabis and other cannabinoids that contain THC for recreational or therapeutic purposes. FUNDING: UK Medical Research Council, Maudsley Charity, Brain and Behavior Research Foundation, Wellcome Trust, and the UK National Institute for Health Research.

Subjective Effects of Ethanol, Morphine, Δ(9)-Tetrahydrocannabinol, and Ketamine Following a Pharmacological Challenge Are Related to Functional Brain Connectivity.

This analysis examines the neuronal foundation of drug-induced psychomimetic symptoms by relating the severity of these symptoms to changes in functional connectivity for a range of different psychoactive compounds with varying degrees of psychomimetic effects. The repeated measures design included 323 resting-state functional magnetic resonance imaging time series and measures of subjective effects in 36 healthy male volunteers. Four different pharmacological challenges with ethanol, morphine, Δ(9)-tetrahydrocannabinol, and ketamine (12 subjects per drug) were applied. A set of 10 "template" resting-state networks was used to determine individual connectivity maps. Linear regression was used for each individual subject to relate these connectivity maps to three clusters of drug-induced subjective psychomimetic effects ("perception," "relaxation," and "dysphoria") as measured with visual analogue scales. Group analysis showed that the subjective effects of perception correlated significantly across drugs with the connectivity of the posterior cingulate cortex and precentral gyrus with the sensorimotor network (p < 0.005, corrected). No significant correlations were found for relaxation or dysphoria. The posterior cingulate cortex has a role in visuospatial evaluation and the precentral gyrus has been associated with auditory hallucinations. Both the posterior cingulate cortex and the precentral gyrus show changes in activation in patients with schizophrenia, which can be related to the severity of positive symptoms (i.e., hallucinations and delusions), and have previously been related to changes induced by psychoactive drugs. The similarity of functional connectivity changes for drug-induced psychomimetic effects and symptoms of psychosis provides further support for the use of pharmacological challenges with psychomimetic drugs as models for psychosis.

Optimizing the glutamatergic challenge model for psychosis, using S+ -ketamine to induce psychomimetic symptoms in healthy volunteers.

The psychomimetic effects that occur after acute administration of ketamine can constitute a model of psychosis and antipsychotic drug action. However, the optimal dose/concentration has not been established and there is a large variety in outcome measures. In this study, 36 healthy volunteers (21 males and 15 females) received infusions of S(+)-ketamine or placebo to achieve pseudo-steady state concentrations of 180 and 360 ng/mL during two hours. The target of 360 ng/mL induced increasingly more intensive effects than expected, and the targets were subsequently reduced to 120 and 240 ng/mL, which were considered tolerable. There was a clear, concentration-dependent psychomimetic effect as shown on all subscales of the positive and negative syndrome scale (e.g. positive subscale +43.7%, 95%CI 34.4-53.7%, p < 0.0001 for 120 ng/mL and +70.5%, 95%CI 59.0-82.8%, p < 0.0001 for 240 ng/mL) and different visual analogue scales. The startle reflex was inhibited (prepulse inhibition) by both main target concentrations to a similar extent, suggesting a maximum effect. Ketamine was found to constitute a robust model for induction of psychomimetic symptoms and the optimal concentration range for a drug interaction study would be between 100 and 200 ng/mL.

The influence of personality on the sensitivity to subjective effects of Δ9-tetrahydrocannabinol.

The effects of drugs are not only determined by their pharmacological action, but also by user characteristics. This analysis explored the influence of personality on the differences in subjective effects in response to a standardized pharmacological challenge with the cannabinoid CB1/CB2 partial agonist Δ9-tetrahydrocannabinol (THC). To express the sensitivity to THC, pharmacokinetic­pharmacodynamic (PK­PD) non-linear mixed effects modelling was applied to the subjective response of 184 healthy subjects to a pharmacological challenge with inhalation of THC. The subjective effects were measured using visual analogue scales and described by three clusters: 'perception', 'relaxation' and 'dysphoria'. The sensitivity for THC (described as EC50) was related to scores on Cloninger׳s temperament and character inventory (TCI) using multiple linear regression. Effect compartment models were used to describe the PK­PD relations of THC. Within the multivariate model, 'harm avoidance' was significantly correlated with changes in 'perception', and 'self-transcendence' with changes in 'dysphoria'. Within the psychobiological model of personality, 'harm avoidance' is related to serotonergic systems. Subjects with either very low (easy-going) or very high (cautious) scores were less sensitive to THC-induced changes in 'perception'. 'Self-transcendence' relates to schizotypy. Subjects with more schizotypy were more sensitive to the dysphoric subjective effects of THC.

Profiling the subjective effects of Δ9-tetrahydrocannabinol using visual analogue scales.

The subjective effects of cannabis and its main psychoactive component Δ(9) -tetrahydrocannabinol (THC) have played an important part in determining the therapeutic potential of cannabinoid agonists and antagonists. The effects mainly consist of feeling high, changes in perception, feelings of relaxation and occasionally dysphoric reactions. These effects are captured by two of the most frequently used visual analogue scales (VASs) in clinical (pharmacologic) research to measure subjective effects: VAS Bond and Lader (alertness, calmness and mood) and VAS Bowdle (psychedelic effects). In this analysis, the effects of THC on these VASs were compared within a total of 217 subjects who participated in 10 different studies. Not surprisingly, the item feeling high was found to be the best predictor for the effect of THC. Three separate clusters that describe the spectrum of subjective effects of THC were identified using different statistical methods, consisting of VAS "time", "thoughts" and "high" ("perception"), VAS "drowsy", "muzzy", "mentally slow" and "dreamy" ("relaxation") and VAS "voices", "meaning" and "suspicious" ("dysphoria"). These results provide experimental evidence that THC can evoke different classes of effects. These distinct subjective clusters could represent effects on various systems in the brain, which can be used to further differentiate the involvement of endocannabinoid systems in health and disease.

Does olanzapine inhibit the psychomimetic effects of Δ9-tetrahydrocannabinol?

Δ9-Tetrahydrocannabinol (THC) produces transient psychomimetic effects in healthy volunteers, constituting a pharmacological model for psychosis. The dopaminergic antagonist haloperidol has previously been shown to reduce these effects. This placebo-controlled, cross-over study in 49 healthy, male, mild cannabis users aimed to further explore this model by examining the effect of a single oral dose of olanzapine (with dopaminergic, serotonergic, adrenergic, muscarinergic and histaminergic properties) or two oral doses of diphenhydramine (histamine antagonist) on the effects of intrapulmonarily administered THC. Transient psychomimetic symptoms were seen after THC administration, as measured on the positive and negative syndrome scale (20.6% increase on positive subscale, p<0.001) and the visual analogue scale for psychedelic effects (increase of 10.7 mm on feeling high). Following the combination of THC and olanzapine, the positive subscale increased by only 13.7% and feeling high by only 8.7 mm. This reduction of THC effects on the positive subscale failed to reach statistical significance (p=0.066). However, one-third of the subjects did not show an increase in psychomimetic symptoms after THC alone. Within responders, olanzapine reduced the effects of THC on the positive subscale (p=0.005). Other outcome measures included pharmacokinetics, eye movements, postural stability, pupil/iris ratio, and serum concentrations of cortisol and prolactin.