Acute dose-dependent effects and self-guided titration of continuous N,N-dimethyltryptamine infusions in a double-blind placebo-controlled study in healthy participants.

N,N-dimethyltryptamine (DMT) is a serotonergic psychedelic that is known for its short-lasting effects when administered intravenously. Several studies have investigated the administration of intravenous boluses or combinations of a bolus and a subsequent continuous infusion. However, data on dose-dependent acute effects and pharmacokinetics of continuous DMT infusions are lacking.

The psychoplastogens ibogaminalog and ibogainalog induce antidepressant-like activity in naïve and depressed mice by mechanisms involving 5-HT receptor activation and serotonergic transmission.

The antidepressant-like activity of two psychoplastogens, ibogainalog (IBG) and ibogaminalog (DM506), was studied in naïve mice using the forced swim test (FST) and tail suspension test (TST). The behavioral results showed that a single administration of 25 mg/kg DM506 or 10 mg/kg IBG induced antidepressant-like activity in naïve mice in a volinanserin-sensitive manner that persisted for 72 h. Similar results were observed using the chronic immobilization stress (CIS) test, in which depression symptoms were reduced for 48 h.

Non-hallucinogenic compounds derived from iboga alkaloids alleviate neuropathic and visceral pain in mice through a mechanism involving 5-HT receptor activation.

The aim of this study was to determine the anti-hypersensitivity activity of novel non-hallucinogenic compounds derived from iboga alkaloids (i.e., ibogalogs), including tabernanthalog (TBG), ibogainalog (IBG), and ibogaminalog (DM506), using mouse models of neuropathic (Chronic Constriction Injury; CCI) and visceral pain (dextrane sulfate sodium; DSS).

Derivatization-free determination of chiral plasma pharmacokinetics of MDMA and its enantiomers.

3,4-Methylenedioxymethamphetamine (MDMA) is an entactogen with therapeutic potential. The two enantiomers of MDMA differ regarding their pharmacokinetics and pharmacodynamics but the chiral pharmacology of MDMA needs further study in clinical trials. Here, an achiral and an enantioselective high performance liquid chromatography-tandem mass spectrometry method for the quantification of MDMA and its psychoactive phase I metabolite 3,4-methylenedioxyamphetamine (MDA) in human plasma were developed and validated.

Pharmacokinetics-Based Pediatric Dose Evaluation and Optimization Using Saliva - A Case Study.

Understanding pharmacokinetics (PK) in children is a prerequisite to determine optimal pediatric dosing. As plasma sampling in children is challenging, alternative PK sampling strategies are needed. In this case study we evaluated the suitability of saliva as alternative PK matrix to simplify studies in infants, investigating metamizole, an analgesic used off-label in infants.

Acute effects of intravenous DMT in a randomized placebo-controlled study in healthy participants.

N,N-dimethyltryptamine (DMT) is distinct among classic serotonergic psychedelics because of its short-lasting effects when administered intravenously. Despite growing interest in the experimental and therapeutic use of intravenous DMT, data are lacking on its clinical pharmacology. We conducted a double-blind, randomized, placebo-controlled crossover trial in 27 healthy participants to test different intravenous DMT administration regimens: placebo, low infusion (0.

Classic psychedelics do not affect T cell and monocyte immune responses.

Introduction: Classic psychedelics have been shown to exert therapeutic potential for the treatment of various psychiatric disorders, neuropsychiatric diseases, and neuronal damage. Besides their psychopharmacological activity, psychedelics have been reported to modulate immune functions. There has thus far been a sparse exploration of the direct immune-modulating effect of psychedelics on human immune cells .

Phosphatidylinositol 4,5-bisphosphate (PIP) facilitates norepinephrine transporter dimerization and modulates substrate efflux.

The plasmalemmal norepinephrine transporter (NET) regulates cardiovascular sympathetic activity by clearing extracellular norepinephrine in the synaptic cleft. Here, we investigate the subunit stoichiometry and function of NET using single-molecule fluorescence microscopy and flux assays. In particular, we show the effect of phosphatidylinositol 4,5-bisphosphate (PIP) on NET oligomerization and efflux.

The feasibility of pragmatic influenza vaccine randomized controlled real-world trials in Denmark and England.

We estimated the frequency of non-specific influenza-associated clinical endpoints to inform the feasibility of pragmatic randomized controlled trials (RCT) assessing relative vaccine effectiveness (rVE). Hospitalization rates of respiratory, cardiovascular and diabetic events were estimated from Denmark and England's electronic databases and stratified by age, comorbidity and influenza vaccination status. We included a seasonal average of 4.

Safety of recombinant quadrivalent influenza vaccine compared to inactivated influenza vaccine in Chinese adults: An observational study.

Background: Recombinant influenza vaccine (RIV) has been in use in US adults since 2013. This study evaluated the safety of quadrivalent recombinant influenza vaccine (RIV4, Flublok® Quadrivalent, Sanofi Pasteur) compared with standard-dose quadrivalent inactivated influenza vaccine (SD-IIV4) in self-identified Chinese adults at Kaiser Permanente Northern California (KPNC).

Methods: This study evaluated adults aged 18-64 years within KPNC during the 2018-2019 influenza season who self-identified as Chinese (NCT03694392).

Unique features of a recombinant haemagglutinin influenza vaccine that influence vaccine performance.

The influenza vaccine field has been constantly evolving to improve the speed, scalability, and flexibility of manufacturing, and to improve the breadth and longevity of the protective immune response across age groups, giving rise to an array of next generation vaccines in development. Among these, the recombinant influenza vaccine tetravalent (RIV4), using a baculovirus expression vector system to express recombinant haemagglutinin (rHA) in insect cells, is the only one to have reached the market and has been studied extensively. We describe how the unique structural features of rHA in RIV4 improve protective immune responses compared to conventional influenza vaccines made from propagated influenza virus.

(2-Aminopropyl)benzo[β]thiophenes (APBTs) are novel monoamine transporter ligands that lack stimulant effects but display psychedelic-like activity in mice.

Derivatives of (2-aminopropyl)indole (API) and (2-aminopropyl)benzofuran (APB) are new psychoactive substances which produce stimulant effects in vivo. (2-Aminopropyl)benzo[β]thiophene (APBT) is a novel sulfur-based analog of API and APB that has not been pharmacologically characterized. In the current study, we assessed the pharmacological effects of six APBT positional isomers in vitro, and three of these isomers (3-APBT, 5-APBT, and 6-APBT) were subjected to further investigations in vivo.

Illuminating the norepinephrine transporter: fluorescent probes based on nisoxetine and talopram.

The utilization of fluorescent ligands to study the monoamine transporters (MATs) has increased our knowledge of their function and distribution in live cell systems. In this study, we extend SAR for nisoxetine and talopram as parent compounds, to identify high affinity rhodamine-labeled fluorescent probes for the norepinephrine transporter (NET). Nisoxetine-based fluorescent probe demonstrated high binding affinity ( = 43 nM) for NET and an overall selectivity compared to the other transporters for dopamine (DAT; = 1540 nM) and serotonin (SERT; = 785 nM) in competitive radioligand binding assays.

Molecular and clinical aspects of potential neurotoxicity induced by new psychoactive stimulants and psychedelics.

New psychoactive stimulants and psychedelics continue to play an important role on the illicit new psychoactive substance (NPS) market. Designer stimulants and psychedelics both affect monoaminergic systems, although by different mechanisms. Stimulant NPS primarily interact with monoamine transporters, either as inhibitors or as substrates.

The Interaction of Organic Cation Transporters 1-3 and PMAT with Psychoactive Substances.

Organic cation transporters 1-3 (OCT1-3, SLC22A1-3) and the plasma membrane monoamine transporter (PMAT, SLC29A4) play a major role in maintaining monoaminergic equilibrium in the central nervous system. With many psychoactive substances interacting with OCT1-3 and PMAT, a growing literature focuses on characterizing their properties via in vitro and in vivo studies. In vitro studies mainly aim at characterizing compounds as inhibitors or substrates of murine, rat, and human isoforms.

α-PPP and its derivatives are selective partial releasers at the human norepinephrine transporter: A pharmacological characterization of interactions between pyrrolidinopropiophenones and high and low affinity monoamine transporters.

While classical cathinones, such as methcathinone, have been shown to be monoamine releasing agents at human monoamine transporters, the subgroup of α-pyrrolidinophenones has thus far solely been characterized as monoamine transporter reuptake inhibitors. Herein, we report data from previously undescribed α-pyrrolidinopropiophenone (α-PPP) derivatives and compare them with the pharmacologically well-researched α-PVP (α-pyrrolidinovalerophenone). Radiotracer-based in vitro uptake inhibition assays in HEK293 cells show that the investigated α-PPP derivatives inhibit the human high-affinity transporters of dopamine (hDAT) and norepinephrine (hNET) in the low micromolar range, with α-PVP being ten times more potent.