Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration-effect relations using the IB-de-risk tool.

Background: Preclinical research suggests that cannabidiol (CBD) may have therapeutic potential in pathological anxiety. Dosing guidelines to inform future human studies are however lacking.

Aim: We aimed to predict the therapeutic window for anxiety-reducing effects of CBD in humans based on preclinical models.

Evaluation of simulated driving in comparison to laboratory-based tests to assess the pharmacodynamics of alprazolam and alcohol.

Rationale: Assessment of the effects of medicines on the risks of car driving must be derived from laboratory tests, simulated driving or real on-road driving tests. Relevance of tests is determined by their sensitivity and predictive ability for the probability of accidents or damage. This cannot be determined directly, but methods should be able to at least detect the effects of a positive control in dosage known to be clearly associated with increased risk.

The selective orexin-2 receptor antagonist seltorexant improves sleep: An exploratory double-blind, placebo controlled, crossover study in antidepressant-treated major depressive disorder patients with persistent insomnia.

Background: Insomnia is common in patients with major depressive disorder. Although antidepressants improve mood, insomnia often persists as a result of physiological hyperarousal. The orexin-2 receptor is increasingly being recognized as a new target for the treatment of persistent insomnia in major depressive disorder .

Biomarkers, designs, and interpretations of resting-state fMRI in translational pharmacological research: A review of state-of-the-Art, challenges, and opportunities for studying brain chemistry.

A decade of research and development in resting-state functional MRI (RSfMRI) has opened new translational and clinical research frontiers. This review aims to bridge between technical and clinical researchers who seek reliable neuroimaging biomarkers for studying drug interactions with the brain. About 85 pharma-RSfMRI studies using BOLD signal (75% of all) or arterial spin labeling (ASL) were surveyed to investigate the acute effects of psychoactive drugs.

Pharmacokinetics and pharmacodynamics of oral mecamylamine - development of a nicotinic acetylcholine receptor antagonist cognitive challenge test using modelling and simulation.

A pharmacologic challenge model with a nicotinic antagonist could be an important tool not only to understand the complex role of the nicotinic cholinergic system in cognition, but also to develop novel compounds acting on the nicotinic acetylcholine receptor. The objective was to develop a pharmacokinetic-pharmacodynamic (PKPD) model using nonlinear mixed effects (NLME) methods to quantitate the pharmacokinetics of three oral mecamylamine doses (10, 20 and 30 mg) and correlate the plasma concentrations to the pharmacodynamic effects on a cognitive and neurophysiologic battery of tests in healthy subjects. A one-compartment linear kinetic model best described the plasma concentrations of mecamylamine.

The use of a battery of pain models to detect analgesic properties of compounds: a two-part four-way crossover study.

Aim: The aim was to investigate the ability of a battery of pain models to detect analgesic properties of commonly used analgesics in healthy subjects.

Methods: The battery consisted of tests eliciting electrical, mechanical and thermal (contact heat and cold pressor)-pain and included a UVB model, the thermal grill illusion and a paradigm of conditioned pain modulation. Subjects were administered fentanyl 3 μg kg , phenytoin 300 mg, (S)-ketamine 10 mg and placebo (part I), or imipramine 100 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo (part II).

Pharmacokinetics and pharmacodynamics of a new highly concentrated intranasal midazolam formulation for conscious sedation.

Aim: To evaluate the pharmacokinetics, pharmacodynamics, nasal tolerance and effects on sedation of a highly concentrated aqueous intranasal midazolam formulation (Nazolam) and to compare these to intravenous midazolam.

Methods: In this four-way crossover, double-blind, double-dummy, randomized, placebo-controlled study, 16 subjects received 2.5 mg Nazolam, 5.

Effects of a single, oral 60 mg caffeine dose on attention in healthy adult subjects.

Caffeine induces positive effects on sustained attention, although studies assessing the acute effects of low caffeine dose (<75 mg) on sustained attention are limited and use short-term tests. Therefore, we investigated the acute effects of a 60 mg dose of caffeine on sustained attention in tests lasting up to 45 minutes using 82 low or non-caffeine-consuming healthy male ( n=41) and female ( n=41) adults aged between 40 and 60 years. Vigilance was measured using Mackworth Clock test, Rapid Visual Information Processing Test, adaptive tracking test, saccadic eye movement and attention switch test.

Pharmacological interactions between brivaracetam and ethanol in healthy males.

This double-blind, randomized, three-way crossover study explored the potential pharmacokinetic and pharmacodynamic interactions between ethanol and brivaracetam in 18 healthy males, as required for the development of CNS-active drugs. Subjects received (A) ethanol+brivaracetam, (B) ethanol placebo+brivaracetam and (C) ethanol+brivaracetam placebo. Ethanol was infused as a 5.

Time related effects on functional brain connectivity after serotonergic and cholinergic neuromodulation.

Psychopharmacological research, if properly designed, may offer insight into both timing and area of effect, increasing our understanding of the brain's neurotransmitter systems. For that purpose, the acute influence of the selective serotonin reuptake inhibitor citalopram (30 mg) and the acetylcholinesterase inhibitor galantamine (8 mg) was repeatedly measured in 12 healthy young volunteers with resting state functional magnetic resonance imaging (RS-fMRI). Eighteen RS-fMRI scans were acquired per subject during this randomized, double blind, placebo-controlled, crossover study.

Model-based exposure-response analysis to quantify age related differences in the response to scopolamine in healthy subjects.

Aim: Subjects with increasing age are more sensitive to the effects of the anti-muscarinic agent scopolamine, which is used (among other indications) to induce temporary cognitive dysfunction in early phase drug studies with cognition enhancing compounds. The enhanced sensitivity has always been attributed to incipient cholinergic neuronal dysfunction, as a part of the normal aging process. The aim of the study was to correlate age-dependent pharmacodynamic neuro-physiologic effects of scopolamine after correcting for differences in individual exposure.

The effects of the nonselective benzodiazepine lorazepam and the α2 /α3 subunit-selective GABAA receptor modulators AZD7325 and AZD6280 on plasma prolactin levels.

Compounds with selectivity for GABAA receptor subtypes may differ significantly from nonselective benzodiazepines in their dopaminergic effects in vivo. To explore the exact role of the GABAA receptor subtypes in the regulation of prolactin secretion and the differential effects of selective and nonselective GABA receptor modulators, the effects of the nonselective benzodiazepine lorazepam, as well as two novel α2 /α3 subunit-selective GABAA receptor modulators AZD7325 and AZD6280, on prolactin levels were measured in healthy male volunteers. Following administration of lorazepam at 2 mg doses and AZD6280 at 10 mg and 40 mg doses, prolactin levels increased significantly compared with placebo (difference 42.

Reliability of System Identification Techniques to Assess Standing Balance in Healthy Elderly.

Objectives: System identification techniques have the potential to assess the contribution of the underlying systems involved in standing balance by applying well-known disturbances. We investigated the reliability of standing balance parameters obtained with multivariate closed loop system identification techniques.

Methods: In twelve healthy elderly balance tests were performed twice a day during three days.

NS11821, a partial subtype-selective GABAA agonist, elicits selective effects on the central nervous system in randomized controlled trial with healthy subjects.

NS11821 is a partial GABAA agonist with relatively dominant α2,3 and α5 subtype efficacy but negligible α1 agonism. This first-in-human study was performed in healthy male subjects using a single-dose, parallel, double blind, placebo-controlled, randomized, dose-escalation study design. In total six cohorts (N=48) were enrolled.

Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on Δ(9)-tetrahydrocannabinol challenge tests.

Aim: The severe psychiatric side effects of cannabinoid receptor type 1 (CB1 ) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of different CB1 antagonists in Δ(9) -tetrahydrocannabinol (THC) challenge tests in healthy volunteer were constructed.

Methods: The pharmacokinetic models of THC and four CB1 antagonists were built separately.

Single-dose serotonergic stimulation shows widespread effects on functional brain connectivity.

The serotonergic system is widely distributed throughout the central nervous system. It is well known as a mood regulating system, although it also contributes to many other functions. With resting state functional magnetic resonance imaging (RS-fMRI) it is possible to investigate whole brain functional connectivity.

Lessons Learned and Potentials for Improvement in CNS Drug Development: ISCTM Section on Designing the Right Series of Experiments.

Once a molecule has been characterized as engaging an identified target at the appropriate location (affinity and potency), the next step involves designing experiments that will determine its pharmacodynamic activities both for efficacy (on target) and safety-tolerability (on/off target). Two expert presentations focused on looking back at completed programs and two concentrated on looking forward at ongoing programs. Specific discussions pertain to assessment of pharmacologic agonists (mGluR2/3, k-opiate, peroxisome proliferator-activated receptor gamma) and antagonists (orexin and cannabinoid) in disorders of cognition, mood, and anxiety.

Population pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term pharmacokinetics.

Δ(9)-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug.

Pharmacokinetic and pharmacodynamic interactions between almorexant, a dual orexin receptor antagonist, and desipramine.

Almorexant is a dual orexin receptor antagonist (DORA) with sleep-enabling effects in humans. Insomnia is often associated with mental health problems, including depression. Hence, potential interactions with antidepressants deserve attention.

Delta-9-tetrahydrocannabinol-induced dopamine release as a function of psychosis risk: 18F-fallypride positron emission tomography study.

Cannabis use is associated with psychosis, particularly in those with expression of, or vulnerability for, psychotic illness. The biological underpinnings of these differential associations, however, remain largely unknown. We used Positron Emission Tomography and (18)F-fallypride to test the hypothesis that genetic risk for psychosis is expressed by differential induction of dopamine release by Δ(9)-THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis).

Placebo- and amitriptyline-controlled evaluation of central nervous system effects of the NK1 receptor antagonist aprepitant and intravenous alcohol infusion at pseudo-steady state.

Recent interest in NK1 receptor antagonists has focused on a potential role in the treatment of drug addiction and substance abuse. In the present study, the potential for interactions between the NK1 receptor antagonist aprepitant and alcohol, given as an infusion at a target level of 0.65 g/L, was evaluated.

Tolerability, pharmacokinetics, and pharmacodynamics of single-dose almorexant, an orexin receptor antagonist, in healthy elderly subjects.

Sleep disorders are common in the elderly population. Orexin receptor antagonism has been proposed as a new sleep-enabling approach to treat insomnia. The tolerability, pharmacokinetics, and pharmacodynamics of ascending single doses of almorexant, a dual orexin receptor antagonist, were investigated in healthy elderly male and female subjects.

Differential and distributed effects of dopamine neuromodulations on resting-state network connectivity.

Dopaminergic medications, used to treat neurochemical pathology and resultant symptoms in neuropsychiatric disorders, are of mixed efficacy and regularly associated with behavioural side effects. The possibility that dopamine exerts both linear and nonlinear ('inverted U-shaped') effects on cognitive neurocircuitry may explain this outcome variability. However, it has proven to be difficult to characterise neural manifestations of psychopharmacological effects in humans.

Peripheral selectivity of the novel cannabinoid receptor antagonist TM38837 in healthy subjects.

Aim: Cannabinoid receptor type 1 (CB1 ) antagonists show central side effects, whereas beneficial effects are most likely peripherally mediated. In this study, the peripherally selective CB1 antagonist TM38837 was studied in humans.

Methods: This was a double-blind, randomized, placebo-controlled, crossover study.

Guidelines for the recording and evaluation of pharmaco-sleep studies in man: the International Pharmaco-EEG Society (IPEG).

The International Pharmaco-EEG Society (IPEG) presents guidelines summarising the requirements for the recording and computerised evaluation of pharmaco-sleep data in man. Over the past years, technical and data-processing methods have advanced steadily, thus enhancing data quality and expanding the palette of sleep assessment tools that can be used to investigate the activity of drugs on the central nervous system (CNS), determine the time course of effects and pharmacodynamic properties of novel therapeutics, hence enabling the study of the pharmacokinetic/pharmacodynamic relationship, and evaluate the CNS penetration or toxicity of compounds. However, despite the presence of robust guidelines on the scoring of polysomnography -recordings, a review of the literature reveals inconsistent -aspects in the operating procedures from one study to another.