GABA-B receptor function in healthy volunteers, a pharmacokinetic and pharmacodynamic study of two doses of baclofen compared to placebo

AIMS AND HYPOTHESIS To assess the subjective and objective effects of baclofen on brain function in healthy volunteers. BACKGROUND Recent evidence suggests baclofen, a γ-aminobutyric acid type B (GABA-B) receptor agonist, reduces alcohol consumption and craving and promotes abstinence in alcoholics. However, characterisation of the GABA-B receptor system in clinical addiction is limited, and it is unclear why some patients require, or tolerate, higher doses to treat alcoholism. This study assesses the effects of baclofen on brain function in healthy volunteers to inform future studies investigating the sensitivity of GABA-B receptors in alcohol addiction. METHODS Eight healthy male volunteers completed a double blind randomised 3-way cross over study, receiving oral placebo (vitamin C 100mg), 10mg and 60mg baclofen. Subjective and objective measurements were taken at baseline (before medication) and at +30mins, 1, 2, 3, 4 and 6 hours after dosing. Objective measures included blood plasma samples, heart rate and blood pressure. Subjective measures included; the Subjective High Assessment Questionnaire (SHAS), visual analogue scales for sleepy, relaxed, tense and alert and a motor coordination task (zig-zag task). Pharmacokinetic data was obtained using liquid chromatography mass-spectrometry (LC-MS) to measure plasma baclofen concentrations. RESULTS 60mg Baclofen showed changes in subjective measures peaking at 2 hours post dosing compared with placebo, including a significant increase (p<0.05) in total SHAS scores with individual items, including feeling ‘drunk or intoxicated’, effects of alcohol and ‘muddled or confused’ particular affected.. Systolic blood pressure was significantly increased (p<0.05) at the 2 hours post 60mg dose. For both 10mg and 60mg baclofen, peak plasma concentration was achieved 60 minutes post dose. Pharmacokinetic data will be presented. There were no significant changes in these measures between 10mg Baclofen and placebo. CONCLUSIONS The objective and subjective measures used in this study are able to differentiate between placebo and 60mg baclofen. These findings will inform further research investigating the sensitivity of GABA-B receptors in alcohol addiction

Dissolved nitrogen in West Greenland waters

The nitrogen tension in several water masses in the West Greenland coastal region departs only about 5% from the value of the atmosphere. Significantly higher values of nitrogen tension were found in the upper layers of waters near glacier fronts. These values are attributed to the solution of gases trapped in the glacier ice and released to the water under considerable hydrostatic pressure

Correction to: The hidden therapist: evidence for a central role of music in psychedelic therapy.

The article The hidden therapist: evidence for a central role of music in psychedelic therapy, written by Mendel Kaelen, Bruna Giribaldi, Jordan Raine, Lisa Evans, Christopher Timmerman, Natalie Rodriguez, Leor Roseman, Amanda Feilding, David Nutt, Robin Carhart-Harris, was originally published electronically on the publisher's internet portal

Microdosing psychedelics: More questions than answers? An overview and suggestions for future research

Background: In the past few years, the issue of \u2018microdosing\u2019 psychedelics has been openly discussed in the public arena where claims have been made about their positive effect on mood state and cognitive processes such as concentration. However, there are very few scientific studies that have specifically addressed this issue, and there is no agreed scientific consensus on what microdosing is. Aim: This critique paper is designed to address questions that need to be answered by future scientific studies and to offer guidelines for these studies. Approach: Owing to its proximity for a possible approval in clinical use and short-lasting pharmacokinetics, our focus is predominantly on psilocybin. Psilocybin is allegedly, next to lysergic acid diethylamide (LSD), one of the two most frequently used psychedelics to microdose. Where relevant and available, data for other psychedelic drugs are also mentioned. Conclusion: It is concluded that while most anecdotal reports focus on the positive experiences with microdosing, future research should also focus on potential risks of (multiple) administrations of a psychedelic in low doses. To that end, (pre)clinical studies including biological (e.g. heart rate, receptor turnover and occupancy) as well as cognitive (e.g. memory, attention) parameters have to be conducted and will shed light on the potential negative consequences microdosing could have

Validated method for the quantification of baclofen in human plasma using solid-phase extraction and liquid chromatography–tandem mass spectrometry

A highly sensitive and fully validated method was developed for the quantification of baclofen in human plasma. After adjusting the pH of the plasma samples using a phosphate buffer solution (pH 4), baclofen was purified using mixed mode (C8/cation exchange) solid-phase extraction (SPE) cartridges. Endogenous water-soluble compounds and lipids were removed from the cartridges before the samples were eluted and concentrated. The samples were analyzed using triple-quadrupole liquid chromatography–tandem mass spectrometry (LC–MS-MS) with triggered dynamic multiple reaction monitoring mode for simultaneous quantification and confirmation. The assay was linear from 25 to 1,000 ng/mL (r2 > 0.999; n = 6). Intraday (n = 6) and interday (n = 15) imprecisions (% relative standard deviation) were <5%, and the average recovery was 30%. The limit of detection of the method was 5 ng/mL, and the limit of quantification was 25 ng/mL. Plasma samples from healthy male volunteers (n = 9, median age: 22) given two single oral doses of baclofen (10 and 60 mg) on nonconsecutive days were analyzed to demonstrate method applicability

Cerebral blood flow predicts differential neurotransmitter activity

Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans

Theoretical investigations of a highly mismatched interface: the case of SiC/Si(001)

Using first principles, classical potentials, and elasticity theory, we investigated the structure of a semiconductor/semiconductor interface with a high lattice mismatch, SiC/Si(001). Among several tested possible configurations, a heterostructure with (i) a misfit dislocation network pinned at the interface and (ii) reconstructed dislocation cores with a carbon substoichiometry is found to be the most stable one. The importance of the slab approximation in first-principles calculations is discussed and estimated by combining classical potential techniques and elasticity theory. For the most stable configuration, an estimate of the interface energy is given. Finally, the electronic structure is investigated and discussed in relation with the dislocation array structure. Interface states, localized in the heterostructure gap and located on dislocation cores, are identified

Bayesian hierarchical clustering for studying cancer gene expression data with unknown statistics

Clustering analysis is an important tool in studying gene expression data. The Bayesian hierarchical clustering (BHC) algorithm can automatically infer the number of clusters and uses Bayesian model selection to improve clustering quality. In this paper, we present an extension of the BHC algorithm. Our Gaussian BHC (GBHC) algorithm represents data as a mixture of Gaussian distributions. It uses normal-gamma distribution as a conjugate prior on the mean and precision of each of the Gaussian components. We tested GBHC over 11 cancer and 3 synthetic datasets. The results on cancer datasets show that in sample clustering, GBHC on average produces a clustering partition that is more concordant with the ground truth than those obtained from other commonly used algorithms. Furthermore, GBHC frequently infers the number of clusters that is often close to the ground truth. In gene clustering, GBHC also produces a clustering partition that is more biologically plausible than several other state-of-the-art methods. This suggests GBHC as an alternative tool for studying gene expression data. The implementation of GBHC is available at https://sites. google.com/site/gaussianbhc

Effects of classic psychedelic drugs on turbulent signatures in brain dynamics

Psychedelic drugs show promise as safe and effective treatments for neuropsychiatric disorders, yet their mechanisms of action are not fully understood. A fundamental hypothesis is that psychedelics work by dose-dependently changing the functional hierarchy of brain dynamics, but it is unclear whether different psychedelics act similarly. Here, we investigated the changes in the brain’s functional hierarchy associated with two different psychedelics (LSD and psilocybin). Using a novel turbulence framework, we were able to determine the vorticity, that is, the local level of synchronization, that allowed us to extend the standard global time-based measure of metastability to become a local-based measure of both space and time. This framework produced detailed signatures of turbulence-based hierarchical change for each psychedelic drug, revealing consistent and discriminate effects on a higher level network, that is, the default mode network. Overall, our findings directly support a prior hypothesis that psychedelics modulate (i.e., “compress”) the functional hierarchy and provide a quantification of these changes for two different psychedelics. Implications for therapeutic applications of psychedelics are discussed