Subacute changes in brain functional network connectivity after nocturnal sodium oxybate intake are associated with anterior cingulate GABA.

Sodium oxybate (γ-hydroxybutyrate, GHB) is an endogenous GHB/GABAB receptor agonist, clinically used to promote slow-wave sleep and reduce next-day sleepiness in disorders such as narcolepsy and fibromyalgia. The neurobiological signature of these unique therapeutic effects remains elusive. Promising current neuropsychopharmacological approaches to understand the neural underpinnings of specific drug effects address cerebral resting-state functional connectivity (rsFC) patterns and neurometabolic alterations. Hence, we performed a placebo-controlled, double-blind, randomized, cross-over pharmacological magnetic resonance imaging study with a nocturnal administration of GHB, combined with magnetic resonance spectroscopy of GABA and glutamate in the anterior cingulate cortex (ACC). In sum, 16 healthy male volunteers received 50 mg/kg GHB p.o. or placebo at 02:30 a.m. to maximize deep sleep enhancement and multi-modal brain imaging was performed at 09:00 a.m. of the following morning. Independent component analysis of whole-brain rsFC revealed a significant increase of rsFC between the salience network (SN) and the right central executive network (rCEN) after GHB intake compared with placebo. This SN-rCEN coupling was significantly associated with changes in GABA levels in the ACC (pall < 0.05). The observed neural pattern is compatible with a functional switch to a more extrinsic brain state, which may serve as a neurobiological signature of the wake-promoting effects of GHB.

Nocturnal sodium oxybate increases the anterior cingulate cortex magnetic resonance glutamate signal upon awakening.

Clinical guidelines recommend sodium oxybate (SXB; the sodium salt of γ-hydroxybutyrate) for the treatment of disturbed sleep and excessive daytime sleepiness in narcolepsy, yet the underlying mode of action is elusive. In a randomised controlled trial in 20 healthy volunteers, we aimed at establishing neurochemical changes in the anterior cingulate cortex (ACC) following SXB-enhanced sleep. The ACC is a core neural hub regulating vigilance in humans. At 2:30 a.m., we administered in a double-blind cross-over manner an oral dose of 50 mg/kg SXB or placebo, to enhance electroencephalography-defined sleep intensity in the second half of nocturnal sleep (11:00 p.m. to 7:00 a.m.). Upon scheduled awakening, we assessed subjective sleepiness, tiredness and mood and measured two-dimensional, J-resolved, point-resolved magnetic resonance spectroscopy (PRESS) localisation at 3-Tesla field strength. Following brain scanning, we used validated tools to quantify psychomotor vigilance test (PVT) performance and executive functioning. We analysed the data with independent t tests, false discovery rate (FDR) corrected for multiple comparisons. The morning glutamate signal (at 8:30 a.m.) in the ACC was specifically increased after SXB-enhanced sleep in all participants in whom good-quality spectroscopy data were available (n = 16; pFDR < 0.002). Further, global vigilance (10th-90th inter-percentile range on the PVT) was improved (pFDR < 0.04) and median PVT response time was shorter (pFDR < 0.04) compared to placebo. The data indicate that elevated glutamate in the ACC could provide a neurochemical mechanism underlying SXB's pro-vigilant efficacy in disorders of hypersomnolence.

Dexmedetomidine in Psychiatry: Repurposing of its Fast-Acting Anxiolytic, Analgesic and Sleep Modulating Properties.

Drug repurposing is a strategy to identify new indications for already approved drugs. A recent successful example in psychiatry is ketamine, an anesthetic drug developed in the 1960s, now approved and clinically used as a fast-acting antidepressant. Here, we describe the potential of dexmedetomidine as a psychopharmacological repurposing candidate. This α2-adrenoceptor agonist is approved in the US and Europe for procedural sedation in intensive care. It has shown fast-acting inhibitory effects on perioperative stress-related pathologies, including psychomotor agitation, hyperalgesia, and neuroinflammatory overdrive, proving potentially useful in clinical psychiatry. We offer an overview of the pharmacological profile and effects of dexmedetomidine with potential utility for the treatment of neuropsychiatric symptoms. Dexmedetomidine exerts fast-acting and robust sedation, anxiolytic, analgesic, sleep-modulating, and anti-inflammatory effects. Moreover, the drug prevents postoperative agitation and delirium, possibly via neuroprotective mechanisms. While evidence in animals and humans supports these properties, larger controlled trials in clinical samples are generally scarce, and systematic studies with psychiatric patients do not exist. In conclusion, dexmedetomidine is a promising candidate for an experimental treatment targeting stress-related pathologies common in neuropsychiatric disorders such as depression, anxiety disorders, and posttraumatic stress disorder. First small proof-of-concept studies and then larger controlled clinical trials are warranted in psychiatric populations to test the feasibility and efficacy of dexmedetomidine in these conditions.

Gamma-hydroxybutyrate increases brain resting-state functional connectivity of the salience network and dorsal nexus in humans.

According to the triple network hypothesis the brain is equipped with three core neurocognitive networks: the default mode (DMN), the salience (SN), and the central executive (CEN) network. Moreover, the so called dorsal nexus, has met growing interest as it is a hub region connecting these three networks. Assessment of resting-state functional connectivity (rsFC) of these networks enables the elucidation of drug-induced brain alterations. Gamma-hydroxybutyrate (GHB) is a GHB/GABA-B receptor agonist that induces a paradoxical state of mixed stimulation and sedation at moderate doses, which makes it a valuable tool to investigate neural signatures of subjective drug effects. Employing a placebo-controlled, double-blind, randomized, cross-over design, we assessed the effects of GHB (35 mg/kg p. o.) in 19 healthy male subjects on DMN-, SN-, CEN-, and dorsal nexus-rsFC measured by functional magnet resonance imaging and applying independent component as well as seed-based analyses, while subjective drug effects were investigated using visual analog scales (VAS). Subjectively, GHB increased VAS ratings of a general drug effect, stimulation, and sedation. Intrinsic DMN-, and CEN-rsFC remained largely unchanged under GHB, but the drug increased SN-DMN-rsFC and SN-dorsal nexus-rsFC, while dorsal nexus-rsFC was reciprocally increased to both the SN (right anterior insula) and to the CEN (right middle frontal gyrus). Increased sedation significantly predicted the observed SN-dorsal nexus-rsFC. In conclusion, GHB generates a unique stimulant/sedative subjective state that is paralleled by a complex pattern of increased functional connectivity encompassing all three core neurocognitive networks of the brain, while increased SN-dorsal nexus-rsFC was demonstrated to be a potential signature of the sedative component of the drug effect.

Prohedonic properties of gamma-hydroxybutyrate are associated with changes in limbic resting-state functional connectivity.

OBJECTIVE: Gamma-hydroxybutyrate (GHB) is an endogenous GHB-/GABA-B receptor agonist and a narcolepsy treatment. However, GHB is also abused for its prohedonic effects. On a neuronal level, it was shown that GHB increases regional cerebral blood flow in limbic areas such as the right anterior insula (rAI) and the anterior cingulate cortex (ACC). We aimed to further explore the association between the subjective and neuronal signatures of GHB. METHOD: We assessed subjective effects and resting-state functional connectivity (rsFC) of an rAI- and an ACC-seed in 19 healthy male subjects after GHB (35 mg/kg p.o.) using a placebo-controlled, double-blind, randomized, cross-over functional magnet resonance imaging design. RESULTS: GHB increased subjective ratings for euphoria (p < 0.001) and sexual arousal (p < 0.01). Moreover, GHB increased rAI-rsFC to the right thalamus and the superior frontal gyrus and decreased ACC-rsFC to the bilateral paracentral lobule (all p < 0.05, cluster corrected). Moreover, GHB-induced euphoria was associated with rAI-rsFC to the superior frontal gyrus (p < 0.05, uncorrected). CONCLUSIONS: GHB induces prohedonic effects such as euphoria and sexual arousal and in parallel modulates limbic rsFC with areas linked to regulation of mood, cognitive control, and sexual experience. These results further elucidate the drug's effects in neuropsychiatric disorders and as drug of abuse.

Distinctive time-lagged resting-state networks revealed by simultaneous EEG-fMRI.

Functional activation as evidenced by blood oxygen level-dependent (BOLD) functional MRI changes or event-related EEG is known to closely follow patterns of stimulation or self-paced action. Any lags are compatible with axonal conduction velocities and neural integration times. The important analysis of resting state networks is generally based on the assumption that these principles also hold for spontaneous fluctuations in brain activity. Previous observations using simultaneous EEG and fMRI indicate that slower processes, with delays in the seconds range, determine at least part of the relationship between spontaneous EEG and fMRI. To assess this relationship systematically, we used deconvolution analysis of EEG-fMRI during the resting state, assessing the relationship between EEG frequency bands and fMRI BOLD across the whole brain while allowing for time lags of up to 10.5s. Cluster analysis, identifying similar BOLD time courses in relation to EEG band power peaks, showed a clear segregation of functional subsystems of the brain. Our analysis shows that fMRI BOLD increases commonly precede EEG power increases by seconds. Most zero-lag correlations, on the other hand, were negative. This indicates two main distinct neuromodulatory mechanisms: an "idling" mechanism of simultaneous electric and metabolic network anticorrelation and a "regulatory" mechanism in which metabolic network activity precedes increased EEG power by some seconds. This has to be taken into consideration in further studies which address the causal and functional relationship of metabolic and electric brain activity patterns.

Pharmacokinetics and pharmacodynamics of γ-hydroxybutyrate in healthy subjects.

AIMS: γ-Hydroxybutyrate (GHB) is used as a treatment for narcolepsy and alcohol withdrawal and as a recreational substance. Nevertheless, there are limited data on the pharmacokinetics and pharmacokinetic-pharmacodynamic relationships of GHB in humans. We characterized the pharmacokinetic profile and exposure-psychotropic effect relationship of GHB in humans. METHODS: Two oral doses of GHB (25 and 35 mg kg(-1) ) were administered to 32 healthy male subjects (16 for each dose) using a randomized, placebo-controlled, cross-over design. RESULTS: Maximal concentrations of GHB were (geometric mean and 95% CI): 218 (176-270) nmol ml(-1) and 453 (374-549) nmol ml(-1) for the 25 and 35 mg kg(-1) GHB doses, respectively. The elimination half-lives (mean ± SD) were 36 ± 9 and 39 ± 7 min and the AUC∞ values (geometric mean and 95% CI) were 15 747 (12 854-19 290) and 40 113 (33 093-48 622) nmol∙min ml(-1) for the 20 and 35 mg kg(-1) GHB doses, respectively. Thus, plasma GHB exposure (AUC0-∞ ) rose disproportionally (+40%) with the higher dose. γ-Hydroxybutyrate produced mixed stimulant-sedative effects, with a dose-dependent increase in sedation and dizziness. It did not alter heart rate or blood pressure. A close relationship between plasma GHB exposure and its psychotropic effects was found, with higher GHB concentrations associated with higher subjective stimulation, sedation, and dizziness. No clockwise hysteresis was observed in the GHB concentration effect plot over time (i.e., no acute pharmacological tolerance). CONCLUSION: Evidence was found of a nonlinear dose-exposure relationship (i.e., no dose proportionality) at moderate doses of GHB. The effects of GHB on consciousness were closely linked to its plasma exposure and exhibited no acute tolerance.

Sleep deprivation increases dorsal nexus connectivity to the dorsolateral prefrontal cortex in humans.

In many patients with major depressive disorder, sleep deprivation, or wake therapy, induces an immediate but often transient antidepressant response. It is known from brain imaging studies that changes in anterior cingulate and dorsolateral prefrontal cortex activity correlate with a relief of depression symptoms. Recently, resting-state functional magnetic resonance imaging revealed that brain network connectivity via the dorsal nexus (DN), a cortical area in the dorsomedial prefrontal cortex, is dramatically increased in depressed patients. To investigate whether an alteration in DN connectivity could provide a biomarker of therapy response and to determine brain mechanisms of action underlying sleep deprivations antidepressant effects, we examined its influence on resting state default mode network and DN connectivity in healthy humans. Our findings show that sleep deprivation reduced functional connectivity between posterior cingulate cortex and bilateral anterior cingulate cortex (Brodmann area 32), and enhanced connectivity between DN and distinct areas in right dorsolateral prefrontal cortex (Brodmann area 10). These findings are consistent with resolution of dysfunctional brain network connectivity changes observed in depression and suggest changes in prefrontal connectivity with the DN as a brain mechanism of antidepressant therapy action.

Urinary concentrations of GHB and its novel amino acid and carnitine conjugates following controlled GHB administration to humans.

Gamma-hydroxybutyrate (GHB) remains a challenging clinical/forensic toxicology drug. Its rapid elimination to endogenous levels mainly causes this. Especially in drug-facilitated sexual assaults, sample collection often occurs later than the detection window for GHB. We aimed to investigate new GHB conjugates with amino acids (AA), fatty acids, and its organic acid metabolites for their suitability as ingestion/application markers in urine following controlled GHB administration to humans. We used LC-MS/MS for validated quantification of human urine samples collected within two randomized, double-blinded, placebo-controlled crossover studies (GHB 50 mg/kg, 79 participants) at approximately 4.5, 8, 11, and 28 h after intake. We found significant differences (placebo vs. GHB) for all but two analytes at 4.5 h. Eleven hours post GHB administration, GHB, GHB-AAs, 3,4-dihydroxybutyric acid, and glycolic acid still showed significantly higher concentrations; at 28 h only GHB-glycine. Three different discrimination strategies were evaluated: (a) GHB-glycine cut-off concentration (1 µg/mL), (b) metabolite ratios of GHB-glycine/GHB (2.5), and (c) elevation threshold between two urine samples (> 5). Sensitivities were 0.1, 0.3, or 0.5, respectively. Only GHB-glycine showed prolonged detection over GHB, mainly when compared to a second time- and subject-matched urine sample (strategy c).

Psychedelics in the treatment of unipolar and bipolar depression.

This is a narrative review about the role of classic and two atypical psychedelics in the treatment of unipolar and bipolar depression. Since the 1990s, psychedelics experience a renaissance in biomedical research. The so-called classic psychedelics include lysergic acid diethylamide (LSD), psilocybin, mescaline and ayahuasca. Characteristic effects like alterations in sensory perception, as well as emotion- and self-processing are induced by stimulation of serotonin 2A receptors in cortical areas. The new paradigm of psychedelic-assisted psychotherapy suggests a therapeutic framework in which a safely conducted psychedelic experience is integrated into a continuous psychotherapeutic process. First randomized, controlled trials with psilocybin show promising efficacy, tolerability, and adherence in the treatment of unipolar depression. On the other hand, classic psychedelics seem to be associated with the induction of mania, which is an important issue to consider for the design of research and clinical protocols. So called atypical psychedelics are a heterogeneous group with overlapping subjective effects but different neurobiological mechanisms. Two examples of therapeutic value in psychiatry are 3,4-methyl​enedioxy​methamphetamine (MDMA) and ketamine. Since 2020 the ketamine enantiomer esketamine has been granted international approval for treatment-resistant unipolar depression, and also first evidence exists for the therapeutic efficacy of ketamine in bipolar depression. Whether psychedelics will fulfil current expectations and find their way into broader clinical use will depend on future rigorous clinical trials with larger sample sizes. A well-considered therapeutic and legal framework will be crucial for these substances to create new treatment settings and a potential paradigm shift.

Aberrant striatal coupling with default mode and central executive network relates to self-reported avolition and anhedonia in schizophrenia.

BACKGROUND: Avolition and anhedonia are common symptoms in schizophrenia and are related to poor long-term prognosis. There is evidence for aberrant cortico-striatal function and connectivity as neural substrate of avolition and anhedonia. However, it remains unclear how both relate to shared or distinct striatal coupling with large-scale intrinsic networks. Using resting state functional magnetic resonance imaging (rs-fMRI) this study investigated the association of large-scale cortico-striatal functional connectivity with self-reported and clinician-rated avolition and anhedonia in subjects with schizophrenia. METHODS: Seventeen subjects with schizophrenia (SZ) and 28 healthy controls (HC) underwent rs-fMRI. Using Independent Component Analysis (ICA), we assessed Independent Components (ICs) reflecting intrinsic connectivity networks (ICNs), intra intrinsic functional connectivity within the ICs (intra-iFC), and intrinsic functional connectivity between different ICs (inter-iFC). Avolition and anhedonia were assessed using the Self Evaluation Scale for Negative Symptoms and the Brief Negative Symptom Scale. RESULTS: ICA revealed three striatal components and six cortical ICNs. Both self-rated avolition and anhedonia correlated with increased inter-iFC between the caudate and posterior Default Mode Network (pDMN) and between the caudate and Central Executive Network (CEN). In contrast, clinician-rated avolition and anhedonia were not correlated with cortico-striatal connectivity. Group comparison revealed trend-wise decreased inter-iFC between the caudate and Salience Network (SN) in schizophrenia patients compared to HC. DISCUSSION: Self-rated, but not clinician-rated, avolition and anhedonia was associated with aberrant striatal coupling with the default mode and the central executive network. These findings suggest that self-reported and clinician-rated scores might capture different aspects of motivational and hedonic deficits in schizophrenia and therefore relate to different cortico-striatal functional abnormalities.

Towards Extending the Detection Window of Gamma-Hydroxybutyric Acid-An Untargeted Metabolomics Study in Serum and Urine Following Controlled Administration in Healthy Men.

In forensic toxicology, gamma-hydroxybutyrate (GHB) still represents one of the most challenging drugs of abuse in terms of analytical detection and interpretation. Given its rapid elimination, the detection window of GHB in common matrices is short (maximum 12 h in urine). Additionally, the differentiation from naturally occurring endogenous GHB, is challenging. Thus, novel biomarkers to extend the detection window of GHB are urgently needed. The present study aimed at searching new potential biomarkers of GHB use by means of mass spectrometry (MS) metabolomic profiling in serum (up to 16.5 h) and urine samples (up to 8 h after intake) collected during a placebo-controlled crossover study in healthy men. MS data acquired by different analytical methods (reversed phase and hydrophilic interaction liquid chromatography; positive and negative electrospray ionization each) were filtered for significantly changed features applying univariate and mixed-effect model statistics. Complementary to a former study, conjugates of GHB with glycine, glutamate, taurine, carnitine and pentose (ribose) were identified in urine, with particularly GHB-pentose being promising for longer detection. None of the conjugates were detectable in serum. Therein, mainly energy metabolic substrates were identified, which may be useful for more detailed interpretation of underlying pathways but are too unspecific as biomarkers.

Improvement of Emotional Empathy and Cluster B Personality Disorder Symptoms Associated With Decreased Cocaine Use Severity.

Aims: Chronic cocaine users display impaired social cognitive abilities, reduced prosocial behavior, and pronounced cluster B personality disorder (PD) symptoms all contributing to their social dysfunctions in daily life. These social dysfunctions have been proposed as a major factor for maintenance and relapse of stimulant use disorders in general. However, little is known about the reversibility of social cognitive deficits and socially problematic personality facets when stimulant use is reduced or ceased. Therefore, we examined the relation between changing intensity of cocaine use and the development of sociocognitive functioning and cluster B PD symptomatology over the course of 1 year. Methods: Social cognition, social decision-making, and cluster B PD symptoms were assessed in 38 cocaine users (19 with increased and 19 with decreased use) and 48 stimulant-naive healthy controls at baseline and at 1-year follow-up. Cocaine use severity was objectively determined by quantitative 6-month hair analyses. The categorization of the two cocaine user groups was based on a combination of absolute (± 0.5 ng/mg) and relative (± 10%) changes in the cocaine hair concentration between baseline and the 1-year follow-up. Social cognition was assessed using the Multifaceted Empathy Test (MET) and the Movie for the Assessment of Social Cognition (MASC). A combined Distribution/Dictator Game was applied for assessing social decision-making. Cluster B PD symptoms were measured by a Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II) PD questionnaire according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Results: Increased cocaine use was linked to worsened empathy, while decreased cocaine use went along with improved emotional empathy. Moreover, whereas decreased cocaine use was associated with reduced severity of self-reported cluster B PD symptoms, these symptoms remained largely stable in increasers. In contrast to a significant reduction of prosocial behavior at baseline in the combined cocaine user group, specifically decreasers were not statistically distinguishable from controls at the follow-up. Conclusions: Sociocognitive deficits and cluster B PD symptoms of chronic cocaine users are adaptable over time as they covary with the increase or decrease in cocaine use. Hence, abstinence orientation and training of social cognition and interaction might improve social functioning, and should therefore be important therapeutic elements in cocaine addiction treatment.

Neurophysiological signature of gamma-hydroxybutyrate augmented sleep in male healthy volunteers may reflect biomimetic sleep enhancement: a randomized controlled trial.

Gamma-hydroxybutyrate (GHB) is an endogenous GHB/GABAB receptor agonist, which has demonstrated potency in consolidating sleep and reducing excessive daytime sleepiness in narcolepsy. Little is known whether GHB's efficacy reflects the promotion of physiological sleep mechanisms and no study has investigated its sleep consolidating effects under low sleep pressure. GHB (50 mg/kg p.o.) and placebo were administered in 20 young male volunteers at 2:30 a.m., the time when GHB is typically given in narcolepsy, in a randomized, double-blinded, crossover manner. Drug effects on sleep architecture and electroencephalographic (EEG) sleep spectra were analyzed. In addition, current source density (CSD) analysis was employed to identify the effects of GHB on the brain electrical sources of neuronal oscillations. Moreover, lagged-phase synchronization (LPS) analysis was applied to quantify the functional connectivity among sleep-relevant brain regions. GHB prolonged slow-wave sleep (stage N3) at the cost of rapid eye movement (REM) sleep. Furthermore, it enhanced delta-theta (0.5-8 Hz) activity in NREM and REM sleep, while reducing activity in the spindle frequency range (13-15 Hz) in sleep stage N2. The increase in delta power predominated in medial prefrontal cortex, parahippocampal and fusiform gyri, and posterior cingulate cortex. Theta power was particularly increased in the prefrontal cortex and both temporal poles. Moreover, the brain areas that showed increased theta power after GHB also exhibited increased lagged-phase synchronization among each other. Our study in healthy men revealed distinct similarities between GHB-augmented sleep and physiologically augmented sleep as seen in recovery sleep after prolonged wakefulness. The promotion of the sleep neurophysiological mechanisms by GHB may thus provide a rationale for GHB-induced sleep and waking quality in neuropsychiatric disorders beyond narcolepsy.

Effects of gamma-hydroxybutyrate on neurophysiological correlates of performance and conflict monitoring.

Performance and conflict monitoring (PM and CM) represent two essential cognitive abilities, required to respond appropriately to demanding tasks. PM and CM can be investigated using event-related brain potentials (ERP) and associated neural oscillations. Namely, the error-related negativity (ERN) represents a correlate of PM, whereas the N2 component reflects the process of CM. Both ERPs originate in the anterior cingulate cortex (ACC) and PM specifically has been shown to be susceptible to gamma-aminobutyric acid (GABA) A receptor activation. Contrarily, the specific effects of GABAB receptor (GABABR) stimulation on PM and CM are unknown. Thus, the effects of gamma-hydroxybutyrate (GHB; 20 and 35 mg/kg), a predominant GABABR agonist, on behavioral and electrophysiological correlates of PM and CM were here assessed in 15 healthy male volunteers, using the Eriksen-Flanker paradigm in a randomized, double-blind, placebo-controlled, cross-over study. Electroencephalographic (EEG) data were analyzed in the time and time-frequency domains. GHB prolonged reaction times, without affecting error rates or post-error slowing. Moreover, GHB decreased ERN amplitudes and associated neural oscillations in the theta/alpha1 range. Similarly, neural oscillations associated with the N2 were reduced in the theta/alpha1 range, while N2 amplitude was conversely increased. Hence, GHB shows a dissociating effect on electrophysiological correlates of PM and CM. Reduced ERN likely derives from a GABABR-mediated increase in dopaminergic signaling, disrupting the generation of prediction errors, whereas an enhanced N2 suggests an increased susceptibility towards external stimuli. Conclusively, GHB is the first drug reported, thus far, to have opposite effects on PM and CM, underlined by its unique electrophysiological signature.

Identification of new urinary gamma-hydroxybutyric acid markers applying untargeted metabolomics analysis following placebo-controlled administration to humans.

Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid that occurs naturally in the mammalian brain and is prescribed as a medication against narcolepsy or used as a drug of abuse. Particularly, its use as a knock-out drug in cases of drug-facilitated crimes is of major importance in forensic toxicology. Because of its rapid metabolism and resulting narrow detection windows (<12 hours in urine), detection of GHB remains challenging. Thus, there is an urgent call for new markers to improve the reliable detection of GHB use. In the framework of a randomized, placebo-controlled, crossover study in 20 healthy male volunteers, urine samples obtained 4.5 hours post-administration were submitted to untargeted mass spectrometry [MS, quadrupole time of flight (QTOF)] analysis to identify possible new markers of GHB intake. MS data from four different analytical methods (reversed phase and hydrophilic interaction liquid chromatography; positive and negative electrospray ionization) were filtered for significantly changed features applying univariate and multivariate statistics. From the resulting 42 compounds of interest, 8 were finally identified including conjugates of GHB with carnitine, glutamate, and glycine as well as the endogenous compounds glycolate and succinylcarnitine. While GHB conjugates were only detectable in the GHB, but not in the placebo group, glycolate and succinylcarnitine were present in both groups albeit significantly increased through GHB intake. Untargeted metabolomics proved as a suitable tool for the non-hypothesis driven identification of new GHB markers. However, more studies on actual concentrations, detection windows, and stability will be necessary to assess the suitability of these markers for routine application.

The potential impact of biochemical mediators on telomere attrition in major depressive disorder and implications for future study designs: A narrative review.

BACKGROUND: Major depressive disorder (MDD) has been proposed to represent a "disease of premature aging", which is associated with certain biomarkers of cellular ageing and numerous other age-related diseases. Over the last decade, telomere length (TL) arose as a surrogate for cellular aging. Recent data suggests that TL might be reduced in patients with MDD, however, results are still inconclusive. This might be explained by the lack of assessment of potential biochemical mediators that are directly associated with telomere shortening and frequently observed in patients with MDD. METHODS: A narrative review was performed. The PubMed database was searched for relevant studies. RESULTS: We identified four major mediators, which are recurrently reported in patients with MDD and are associated with reduced TL: inflammation/oxidative stress, dysregulation of the hypothalamic-pituitary-adrenal axis, metabolic dysbalance including insulin resistance, and decreased brain-derived neurotrophic factor. These mediators are also mutually associated and were not systematically assessed in current studies investigating TL and MDD, which might explain inconclusive findings across current literature. Finally, we discuss possible ways to assess those mediators and potential implications of such approaches for future research. LIMITATIONS: The majority of identified studies had cross-sectional designs and used heterogeneous methods to assess TL and associated relevant biochemical mediators. CONCLUSIONS: A better understanding of the complex interactions between biochemical mediators, somatic comorbidities and shortened telomeres in patients with MDD might further specify the pathophysiology-based conceptualization and, based on that, personalized treatment of MDD.

Socio-cognitive functioning in stimulant polysubstance users.

BACKGROUND: Using more than one psychotropic substance is accompanied by increased risks for psychiatric and physical disorders. Accordingly, deficits in basal cognitive functions have been consistently associated with polysubstance use (PSU), whereas little is known about potential impairments in more complex socio-cognitive skills, which are relevant for daily-life functioning. Therefore, we investigated the effects of toxicological validated stimulant PSU on social cognition under consideration of potential cumulative effects. METHODS: We compared socio-cognitive performances of 47 individuals with stimulant PSU with 59 matched stimulant-naïve controls using the Multifaceted Empathy Test (MET) and the Movie for the Assessment of Social Cognition (MASC). Additionally, social network size was assessed by the Social Network Questionnaire (SNQ). Hair and urine testing was employed to categorize three PSU subgroups (3, 4, and ≥5 substances used) and to ensure drug abstinence in controls. RESULTS: Individuals with stimulant PSU showed lower emotional empathy (MET) and a smaller social network (SNQ) compared to controls (both with linear trends for increasing number of used substances: p < .05). In contrast, cognitive empathy (MET and MASC) was largely unaffected by PSU. Additional linear regression analyses within PSU individuals revealed number of used substances as the best predictor for inferior performance in emotional empathy (p < .01), while severity of the use of single substances or substance-classes did not show a significant impact. CONCLUSION: These findings demonstrate cumulative adverse effects of stimulant PSU on an important facet of socio-cognitive functioning. Therefore, emotional empathy deficits should be targeted in future interventions and rehabilitations for individuals with PSU.

Novel Psychoactive Substances-Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs.

A feature of human culture is that we can learn to consume chemical compounds, derived from natural plants or synthetic fabrication, for their psychoactive effects. These drugs change the mental state and/or the behavioral performance of an individual and can be instrumentalized for various purposes. After the emergence of a novel psychoactive substance (NPS) and a period of experimental consumption, personal and medical benefits and harm potential of the NPS can be estimated on evidence base. This may lead to a legal classification of the NPS, which may range from limited medical use, controlled availability up to a complete ban of the drug form publically accepted use. With these measures, however, a drug does not disappear, but frequently continues to be used, which eventually allows an even better estimate of the drug's properties. Thus, only in rare cases, there is a final verdict that is no more questioned. Instead, the view on a drug can change from tolerable to harmful but may also involve the new establishment of a desired medical application to a previously harmful drug. Here, we provide a summary review on a number of NPS for which the neuropharmacological evaluation has made important progress in recent years. They include mitragynine ("Kratom"), synthetic cannabinoids (e.g., "Spice"), dimethyltryptamine and novel serotonergic hallucinogens, the cathinones mephedrone and methylone, ketamine and novel dissociative drugs, γ-hydroxybutyrate, γ-butyrolactone, and 1,4-butanediol. This review shows not only emerging harm potentials but also some potential medical applications.

LSD Increases Primary Process Thinking via Serotonin 2A Receptor Activation.

Rationale: Stimulation of serotonin 2A (5-HT2A) receptors by lysergic acid diethylamide (LSD) and related compounds such as psilocybin has previously been shown to increase primary process thinking - an ontologically and evolutionary early, implicit, associative, and automatic mode of thinking which is typically occurring during altered states of consciousness such as dreaming. However, it is still largely unknown whether LSD induces primary process thinking under placebo-controlled, standardized experimental conditions and whether these effects are related to subjective experience and 5-HT2A receptor activation. Therefore, this study aimed to test the hypotheses that LSD increases primary process thinking and that primary process thinking depends on 5-HT2A receptor activation and is related to subjective drug effects. Methods: Twenty-five healthy subjects performed an audio-recorded mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally) and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally). The main outcome variable in this study was primary index (PI), a formal measure of primary process thinking in the imagery reports. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC) rating scale. Results: LSD, compared with placebo, significantly increased primary index (p < 0.001, Bonferroni-corrected). The LSD-induced increase in primary index was positively correlated with LSD-induced disembodiment (p < 0.05, Bonferroni-corrected), and blissful state (p < 0.05, Bonferroni-corrected) on the 5D-ASC. Both LSD-induced increases in primary index and changes in state of consciousness were fully blocked by ketanserin. Conclusion: LSD induces primary process thinking via activation of 5-HT2A receptors and in relation to disembodiment and blissful state. Primary process thinking appears to crucially organize inner experiences during both dreams and psychedelic states of consciousness.