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Introduction Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults. Methods Eligible healthy adults received 6–8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC–MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods. Results No psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied. Conclusions The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild–moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose. Clinical Trials Identifier NCT02163707.

The aim of this study is to define, for the first time, human methylone and HMMC plasma pharmacokinetics following controlled administration of 50–200 mg methylone to 12 male volunteers. A new LC-MS/MS method was validated to quantify methylone, MDMA, and their metabolites in plasma. The study was a randomized, cross-over, double-blinded and placebo-controlled study, with a total of 468 plasma samples collected. First, 10 µL of MDMA-d5, MDA-d5 and methylone-d3 internal standards were added to 100 µL of plasma. Two mL of chloroform and ethyl acetate 9:1 (v/v) were then added, mixed well and centrifuged. The supernatant was fortified with 0.1 mL acidified methanol and evaporated under nitrogen. Samples were reconstituted with a mobile phase and injected into the LC-MS/MS instrument. The method was fully validated according to OSAC guidelines (USA). Methylone plasma concentrations increased in a dose-proportional manner, as demonstrated by the increasing maximum concentration (Cmax) and area under the curve of concentrations (AUC). Methylone Cmax values were reported as 153, 304, 355 and 604 ng/mL, AUC0–24 values were reported as 1042.8, 2441.2, 3524.4 and 5067.9 h·ng/mL and T1/2 values as 5.8, 6.4, 6.9 and 6.4 h following the 50, 100, 150 and 200 mg doses, respectively. Methylone exhibited rapid kinetics with a Tmax of 1.5 h for the 50 mg dose and 2 h approximately after all the other doses. HMMC exhibited faster kinetics compared to methylone, with a Cmax value that was 10–14-fold lower and an AUC0–24 value that was 21–29-fold lower. Methylone pharmacokinetics was linear across 50–200 mg oral doses in humans, unlike the previously described non-linear oral MDMA pharmacokinetics. An LC-MS/MS method for the quantification of methylone, MDMA and their metabolites in human plasma was achieved. Methylone exhibited linear pharmacokinetics in humans with oral doses of 50–200 mg.

Heterozygous mutations in the GBA1 gene, encoding the enzyme glucocerebrosidase (GCase), are major risk factors for Parkinson’s Disease (PD). Ambroxol, a small chaperone originally used as a mucolytic agent, has been shown to cross the blood–brain barrier, enhance GCase activity, and reduce α-synuclein levels, making it a promising therapeutic candidate for disease-modifying effects in GBA1-associated PD (GBA1-PD). This study aimed to develop a method to quantify ambroxol levels in human plasma and cerebrospinal fluid (CSF) using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Ambroxol was determined by online solid-phase extraction (SPE), coupled with LC-MS/MS, by gradient elution on a monolithic column. Detection employed a 3200 QTRAP tandem mass spectrometer in the positive electrospray ionization mode. Calibration curves exhibited linearity across the analyzed ranges in both plasma and CSF. The recovery rate ranged from 106.7% to 113.5% in plasma and from 99.0% to 103.0% in CSF. No significant matrix effect was observed. Intra-day and inter-day precisions were below 11.8% in both matrices, and accuracy ranged from 89.9% to 103.1% in plasma and from 96.3% to 107.8% in CSF. We evaluated and confirmed the stability of the analyte in plasma and CSF across various storage conditions. The method was successfully validated according to European Medicine Agency (EMA) guidelines and its applicability was confirmed in the context of a multicenter, randomized, double-blind, placebo-controlled, phase II study, designed to monitor the ambroxol levels in the plasma and CSF of GBA1-PD.

The tissue diagnosis of amyloidosis and confirmation of fibril protein type, which are crucial for clinical management, have traditionally relied on Congo red (CR) staining followed by immunohistochemistry (IHC) using fibril protein specific antibodies. However, amyloid IHC is qualitative, non‐standardised, requires operator expertise, and not infrequently fails to produce definitive results. More recently, laser dissection mass spectrometry (LDMS) has been developed as an alternative method to characterise amyloid in tissue sections. We sought to compare these techniques in a real world setting. During 2017, we performed LDMS on 640 formalin‐fixed biopsies containing amyloid (CR+ve) comprising all 320 cases that could not be typed by IHC (IHC−ve) and 320 randomly selected CR+ve samples that had been typed (IHC+ve). In addition, we studied 60 biopsies from patients in whom there was a strong suspicion of amyloidosis, but in whom histology was non‐diagnostic (CR–ve). Comprehensive clinical assessments were conducted in 532 (76%) of cases. Among the 640 CR+ve samples, 602 (94%) contained ≥2 of 3 amyloid signature proteins (ASPs) on LDMS (ASP+ve) supporting the presence of amyloid. A total of 49 of the 60 CR‐ve samples were ASP–ve; 7 of 11 that were ASP+ve were glomerular. The amyloid fibril protein was identified by LDMS in 255 of 320 (80%) of the IHC–ve samples and in a total of 545 of 640 (85%) cases overall. The LDMS and IHC techniques yielded discordant results in only 7 of 320 (2%) cases. CR histology and LDMS are corroborative for diagnosis of amyloid, but LDMS is superior to IHC for confirming amyloid type.

Aflatoxins (AFs) frequently contaminate food and animal feeds, especially in (sub) tropical countries. If animals consume contaminated feeds, AFs (mainly aflatoxin B1 (AFB1), B2 (AFB2), G1 (AFG1), G2 (AFG2) and their major metabolites aflatoxin M1 (AFM1) and M2 (AFM2)) can be transferred to edible tissues and products, such as eggs, liver and muscle tissue and milk, which ultimately can reach the human food chain. Currently, the European Union has established a maximum level for AFM1 in milk (0.05 µg kg−1). Dietary adsorbents, such as bentonite clay, have been used to reduce AFs exposure in animal husbandry and carry over to edible tissues and products. To investigate the efficacy of adding bentonite clay to animal diets in reducing the concentration of AFB1, AFB2, AFG1, AFG2, and the metabolites AFM1 and AFM2 in animal-derived foods (chicken muscle and liver, eggs, and cattle milk), chicken and cattle plasma and cattle ruminal fluid, a sensitive and selective ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method has been developed. High-throughput sample preparation procedures were optimized, allowing the analysis of 96 samples per analytical batch and consisted of a liquid extraction using 1% formic acid in acetonitrile, followed by a further clean-up using QuEChERS (muscle tissue), QuEChERS in combination with Oasis® Ostro (liver tissue), Oasis® Ostro (egg, plasma), and Oasis® PRiME HLB (milk, ruminal fluid). The different procedures were validated in accordance with European guidelines. As a proof-of-concept, the final methods were used to successfully determine AFs concentrations in chicken and cattle samples collected during feeding trials for efficacy and safety evaluation of mycotoxin detoxifiers to protect against AFs as well as their carry-over to animal products.

PurposeThe recent release of a medical cannabis strain has given a new impulse for the study of cannabis in Italy. The National Health Service advises to consume medical cannabis by vaporizing, in decoction or oil form. This is the first study that explores the pharmacokinetics and tolerability of a single oral dose of cannabis as decoction (200 ml) or in olive oil (1 ml), as a first step to improve the prescriptive recommendations.MethodsThis is a single-center, open-label, two-period crossover study designed to assess the pharmacokinetics and tolerability of oral cannabis administered to 13 patients with medication overuse headache (MOH). A liquid chromatography tandem-mass spectrometry (LC-MS/MS) method was conducted for the quantification of THC, CBD, 11-OH-THC, THC-COOH, THC-COOH-glucuronide, THCA-A, and CBDA. Blood pressure, heart rate, and a short list of symptoms by numerical rating scale (NRS) were assessed.ResultsDecoctions of cannabis showed high variability in cannabinoids content, compared to cannabis oil. For both preparations, THCA-A and CBDA were the most widely absorbed cannabinoids, while THC and CBD were less absorbed. The most important differences concern the bioavailability of THC, higher in oil (AUC0–24 7.44, 95% CI 5.19, 9.68) than in decoction (AUC0–24 3.34, 95% CI 2.07, 4.60), and the bioavailability of CBDA. No serious adverse events were reported.ConclusionsCannabis decoction and cannabis oil showed different pharmacokinetic properties, as well as distinct consequences on patients. This study was performed in a limited number of patients; future studies should be performed to investigate the clinical efficacy in larger populations.

Dietary advanced glycation end products (AGEs) are believed to contribute to pathogenesis of diabetes and cardiovascular disease. The objective of this study was to determine if a diet high in red and processed meat and refined grains (HMD) would elevate plasma concentrations of protein-bound AGEs compared with an energy-matched diet high in whole grain, dairy, nuts and legumes (HWD). We conducted a randomized crossover trial with two 4-week weight-stable dietary interventions in 51 participants without type 2 diabetes (15 men and 36 women aged 35.1 ± 15.6 y; body mass index (BMI), 27.7 ± 6.9 kg/m2). Plasma concentrations of protein-bound Nε-(carboxymethyl) lysine (CML), Nε-(1-carboxyethyl) lysine (CEL) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS). The HMD significantly increased plasma concentrations (nmol/mL) of CEL (1.367, 0.78 vs. 1.096, 0.65; p < 0.01; n = 48) compared with the HWD. No differences in CML and MG-H1 between HMD and HWD were observed. HMD increased plasma CEL concentrations compared with HWD in individuals without type 2 diabetes.

The purpose of this study was to investigate whether acupuncture is effective at treating dry eye disease among postmenopausal women and to identify the possible mechanisms. Twenty-eight postmenopausal women with dry eye disease were randomly divided into two groups: an acupuncture plus artificial tears (AC + AT) group and an artificial tears (AT) only group. After baseline examination of clinical parameters and tear sample collection, each patient received the designated modality of topical therapy for 2 months. Post-treatment documentation of clinical parameters was recorded, and tear samples were collected. Tear samples from the AC + AT group were subjected to two-dimensional nano-liquid chromatography coupled with tandem mass spectrometry (2D nano-LC-MS/MS). Western blot analysis was also performed on tear samples from both groups. After treatment, the Ocular Surface Disease Index scores, symptom assessment scores, scores of sign assessment, and tear break-up time were significantly improved in both groups ( =0.000). Symptom assessment scores were significantly improved in the AC + AT group ( =0.000) compared with the AT group. 2D nano-LC-MS/MS identified 2,411 proteins, among which 142 were downregulated and 169 were upregulated. After combined AC + AT treatment, the abundance of secreted proteins was increased, whereas that of cytoplasmic proteins decreased (Pearson's test, =0.000, =0.000, respectively). Proteins involved in immunity and regulation were also more abundant (Pearson's test, =0.040, =0.016, respectively), while components and proliferation-related proteins were downregulated (Pearson's test, =0.003, =0.011, respectively). AC + AT treatment increased protein synthesis and secretion, and improved clinical symptoms. These results indicate that acupuncture may be a complimentary therapy for treating postmenopausal dry eye disease.

A novel method for the quantification of the sulfur-containing metabolites of formaldehyde (thiazolidine carboxylic acid (TCA) and thiazolidine carbonyl glycine (TCG)) and acetaldehyde (methyl thiazolidine carboxylic acid (MTCA) and methyl thiazolidine carbonyl glycine (MTCG)) was developed and validated for human urine and plasma samples. Targeting the sulfur-containing metabolites of formaldehyde and acetaldehyde in contrast to the commonly used biomarkers formate and acetate overcomes the high intra- and inter-individual variance. Due to their involvement in various endogenous processes, formate and acetate lack the required specificity for assessing the exposure to formaldehyde and acetaldehyde, respectively. Validation was successfully performed according to FDA’s Guideline for Bioanalytical Method Validation (2018), showing excellent performance with regard to accuracy, precision, and limits of quantification (LLOQ). TCA, TCG, and MTCG proved to be stable under all investigated conditions, whereas MTCA showed a depletion after 21 months. The method was applied to a set of pilot samples derived from smokers who consumed unfiltered cigarettes spiked with 13C-labeled propylene glycol and 13C-labeled glycerol. These compounds were used as potential precursors for the formation of 13C-formaldehyde and 13C-acetaldehyde during combustion. Plasma concentrations were significantly lower as compared to urine, suggesting urine as suitable matrix for a biomonitoring. A smoking-related increase of unlabeled biomarker concentrations could not be shown due to the ubiquitous distribution in the environment. While the metabolites of 13C-acetaldehyde were not detected, the described method allowed for the quantification of 13C-formaldehyde uptake from cigarette smoking by targeting the biomarkers 13C-TCA and 13C-TCG in urine.Graphical abstract

The adherence assessment based on the combination of nevirapine (NVP) and its two metabolites (2-hydroxynevirapine and 3-hydroxynevirapine) would more comprehensively and accurately reflect long-term adherence than that of a single prototype. This study aimed to develop a specific, sensitive and selective method for simultaneous detection of the three compounds in hair and explore whether there was consistency among the three compounds in assessing long-term adherence. Furthermore, 75 HIV-positive patients who were taking the NVP drug were randomly recruited and divided into two groups (high-and low-adherence group). All participants self-reported their days of oral drug administration per month and provided their hair strands closest to the scalp at the region of posterior vertex. The concentrations of three compounds in the hair were determined using a developed LC-MS/MS method in multiple reaction monitoring. This method showed good performances in limit of quantification and accuracy with the recoveries from 85 to 115% and in precision with the intra-day and inter-day coefficients of variation within 15% for the three compounds. The population analysis revealed that patients with high-adherence showed significantly higher concentrations than those with low-adherence for all three compounds. There were significantly moderate correlations of nevirapine with 2-hydroxynevirapine and 3-hydroxynevirapin and high correlation between 2-hydroxynevirapine and 3-hydroxynevirapin. The two NVP’s metabolites showed high consistency with NVP in evaluating long-term adherence.