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Ceramides induce important intracellular signaling pathways, modulating proliferation, migration, apoptosis, and inflammation. However, the relevance of the ceramide metabolism in the reconvalescence phase after stroke is unclear. Besides its well-known property as a selective serotonin reuptake inhibitor, fluoxetine has been reported to inhibit the acid sphingomyelinase (ASM), a key regulator of ceramide levels which derives ceramide from sphingomyelin. Furthermore, fluoxetine has shown therapeutic potential in a randomized controlled rehabilitation trial in stroke patients. Our aim was to investigate and modulate ceramide concentrations in the peri-infarct cortex, whose morphological and functional properties correlate with long-term functional outcome in stroke. We show that certain ceramide species are modulated after experimental stroke and that these changes do not result from alterations of ASM activity, but rather from nontranscriptional induction of the ceramide de novo pathway. Unexpectedly, although reducing lesion size, fluoxetine did not improve functional outcome in our model and had no significant influence on ASM activity or the concentration of ceramides. The ceramide metabolism could emerge as a potential therapeutic target in the reconvalescence phase after stroke, as its accumulation in the peri-infarct cortex potentially influences membrane functions as well as signaling events in the tissue essential for neurological recovery.
Cerumen was found to be a promising alternative specimen for the detection of drugs. In a pilot study, drugs of abuse were identified at a higher detection rate and a longer detection window in cerumen than in urine. In this study, cerumen from subjects was analyzed after they ingested the designer stimulant 4-fluoroamphetamine (4-FA) in a controlled manner. Methods: Twelve subjects ingested placebo and 100 mg of 4-FA. Five of them were also given 150 mg of 4-FA in 150 mL Royal Club bitter lemon drink at least after 7 days. Cerumen was sampled using cotton swabs at baseline, 1 h after the ingestion of the drug and at the end of the study day (12 h). After extraction with ethyl acetate followed by solid-phase extraction, the extracts were analyzed using liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). Results and discussion: In the cerumen of all 12 subjects, 4-FA was detected 12 h after its ingestion; in most subjects, cerumen was detected after 1 h of ingestion, ranging from 0.06 to 13.90 (median 1.52) ng per swab. The detection of 4-FA in cerumen sampled 7 days or more after the first dose suggested a long detection window of cerumen. Conclusions: Cerumen can be successfully used to detect a single drug ingestion even immediately after the ingestion when a sufficient amount of cerumen is used.
With obesity having doubled in the last decade, hypertension is on the rise. In one-third of hypertensive patients the metabolic syndrome is present. This might be one factor for the increasing number of prescriptions for angiotensin receptor blockers and calcium-channel blockers besides a more favorable risk-to-benefit ratio. The aim of the present study was to evaluate a therapeutic drug monitoring (TDM) method for assessment of adherence based on cut-offs in inpatients and to compare it to an established urine drug screening in outpatients. A method for quantification of calcium-channel blockers and angiotensin receptor blockers using high-performance liquid chromatography-tandem mass spectrometric analysis (LC-MS/MS) was developed and validated. The method was applied to serum samples of 32 patients under supervised medication to establish cut-off values for adherence assessment based on dose-related concentrations (DRC, calculated from pharmacokinetic data). Furthermore, corresponding urine and blood samples of 42 outpatients without supervised medication were analysed and the results compared with regard to adherence assessment. All serum concentrations measured for amlodipine (n = 40), lercanidipine (n = 14), candesartan (n = 10), telmisartan (n = 4) and valsartan (n = 10) in inpatients were above the patient specific lower DRC confirming adherence. Of 42 outpatients the identification of analytes in urine as well as the quantification in serum exhibited differing results. According to urinalysis, adherence was demonstrated in only 87.0% of prescriptions, compared to 91.3% for serum analyses. Differences were observed for amlodipine, lercanidipine and candesartan which can be explained by a higher specificity of the serum analysis approach due to pharmacokinetics. The present study confirms that assessing adherence based on serum drug concentrations with individually calculated lower DRCs is more accurate than using qualitative urine analysis. In particular, drugs with low bioavailability, low renal excretion or high metabolism rate such as lercanidipine and candesartan may lead to underestimation of adherence via urine analysis.
Detection of antihypertensive drugs in biological samples is an important tool to assess the adherence of hypertensive patients. Urine and serum/plasma screenings based on qualitative results may lead to misinterpretations regarding drugs with a prolonged detectability. The aim of the present study was to develop a method that can be used for therapeutic drug monitoring (TDM) of antihypertensive drugs with focus on adherence assessment. Therefore, a method for quantification of four diuretics and four β-blockers using high-performance liquid chromatography-mass spectrometric analysis (LC-MS/MS) of combined acidic and basic serum extracts was developed and validated. The method was applied to 40 serum samples from 20 patients in a supervised medication setting (trough and peak serum samples). Literature data on therapeutic concentration ranges, as well as dose-related drug concentrations (calculated from data of pharmacokinetic studies) were used to evaluate adherence assessment criteria. Concentrations were measured for bisoprolol (n = 9 patients), metoprolol (n = 7), nebivolol (n = 1), canrenone (n = 2, metabolite of spironolactone), hydrochlorothiazide (n = 10) and torasemide (n = 8). The measured concentrations were within the therapeutic reference ranges, except for 24% of the samples (mainly β-blockers). In contrast, all measured concentrations were above the lower dose-related concentration (DRC), which appears superior in evaluating adherence. In conclusion, the quantitative analysis of antihypertensive drugs in serum samples and its evaluation on the basis of the individually calculated lower DRC is a promising tool to differentially assess adherence. This method could possibly detect a lack of adherence or other causes of insufficient therapy more reliably than qualitative methods.
Resting state fMRI has been employed to identify alterations in functional connectivity within or between brain regions following acute and chronic exposure to Δ9-tetrahydrocannabinol (THC), the psychoactive component in cannabis. Most studies focused a priori on a limited number of local brain areas or circuits, without considering the impact of cannabis on whole-brain network organization. The present study attempted to identify changes in the whole-brain human functional connectome as assessed with ultra-high field (7T) resting state scans of cannabis users (N = 26) during placebo and following vaporization of cannabis. Two distinct data-driven methodologies, i.e. network-based statistics (NBS) and connICA, were used to identify changes in functional connectomes associated with acute cannabis intoxication and history of cannabis use. Both methodologies revealed a broad state of hyperconnectivity within the entire range of major brain networks in chronic cannabis users compared to occasional cannabis users, which might be reflective of an adaptive network reorganization following prolonged cannabis exposure. The connICA methodology also extracted a distinct spatial connectivity pattern of hypoconnectivity involving the dorsal attention, limbic, subcortical and cerebellum networks and of hyperconnectivity between the default mode and ventral attention network, that was associated with the feeling of subjective high during THC intoxication. Whole-brain network approaches identified spatial patterns in functional brain connectomes that distinguished acute from chronic cannabis use, and offer an important utility for probing the interplay between short and long-term alterations in functional brain dynamics when progressing from occasional to chronic use of cannabis.
Availability of novel psychoactive substances (NPS) exponentially increased over the last years. Risk evaluations of NPS are hampered by the lack of pharmacological studies in humans on health parameters. The aim of the present study was to evaluate safety and neurocognitive function of healthy volunteers (N = 12) who received single doses of 100 and 150 mg 4-fluoroamphetamine (4-FA), a phenethylamine that has been associated with severe cardiovascular and cerebrovascular complications. The study was set-up as a placebo controlled, within subject, phase 1 trial as it was the first to administer 4-FA to humans under controlled conditions. Overall, 4-FA produced a strong elevation in blood pressure up until 4-5 h after administration that was followed by a sustained increase in heart rate. After an interim review of safety data from five participants, a decision was taken to cancel administration of 150 mg. We subsequently obtained complete datasets for placebo and 100 mg 4-FA treatments only. Effects of 4-FA on mood and neurocognitive function were most distinct at 1 h post drug and included significant elevations of vigor, friendliness, elation, arousal, positive mood, as well as improvements in attention and motor performance. Negative affect was also reported as time progressed in the acute phase and even more so during the subacute phase. Overall, the influence of 4-FA on vital signs, mood, and neurocognition was similar to that observed with other stimulants. Present findings confirm clinical observations of acute toxicity among 4-FA users and warrant warnings about potential health risks associated with 4-FA use.
Background: Prospective memory is the ability to recall intended actions or events at the right time or in the right context. While cannabis is known to impair prospective memory, the acute effect of cocaine is unknown. In addition, it is not clear whether changes in prospective memory represent specific alterations in memory processing or result from more general effects on cognition that spread across multiple domains such as arousal and attention.
Aims: The main objective of the study was, therefore, to determine whether drug-induced changes in prospective memory are memory specific or associated with more general drug-induced changes in attention and arousal.
Methods: A placebo-controlled, three-way, cross-over study including 15 regular poly-drug users was set up to test the influence of oral cocaine (300 mg) and vaporised cannabis (300+150 ‘booster’ µg/kg bodyweight) on an event-based prospective memory task. Attentional performance was assessed using a divided attention task and subjective arousal was assessed with the Profile of Mood States questionnaire.
Results: Results showed that cocaine enhanced prospective memory, attention and arousal. Mean performance of prospective memory and attention, as well as levels of arousal were lowest during treatment with cannabis as compared with placebo and cocaine as evinced by a significantly increased trend across treatment conditions. Prospective memory performance was only weakly positively associated to measures of attention and arousal.
Conclusion: Together, these results indicate that cocaine enhancement of prospective memory performance cannot be fully explained by parallel changes in arousal and attention levels, and is likely to represent a direct change in the neural network underlying prospective memory.
The dopamine β-hydroxylase (DβH) enzyme transforms dopamine into noradrenaline. We hypothesized that individuals with low activity DBH genotypes (rs1611115 CT/TT) are more sensitive to the influence of cannabis and cocaine on cognitive impulse control and functional connectivity in the limbic ‘reward’ circuit because they experience a drug induced hyperdopaminergic state compared to individuals with high activity DBH genotypes (rs1611115 CC). Regular drug users (N = 122) received acute doses of cannabis (450 μg/kg THC), cocaine HCl 300 mg and placebo. Cognitive impulse control was assessed by means of the Matching Familiar Figures Test (MFFT). Resting state fMRI was measured in a subset of participants to determine functional connectivity between the nucleus accumbens (NAc) and (sub)cortical areas. The influence of cannabis and cocaine on impulsivity and functional connectivity significantly interacted with DBH genotype. Both drugs increased cognitive impulsivity in participants with CT/TT genotypes but not in CC participants. Both drugs also reduced functional connectivity between the NAc and the limbic lobe, prefrontal cortex, striatum and thalamus and primarily in individuals with CT/TT genotypes. Correlational analysis indicated a significant negative association between cognitive impulsivity and functional connectivity in subcortical areas of the brain. It is concluded that interference of cannabis and cocaine with cognitive impulse control and functional corticostriatal connectivity depends on DBH genotype. The present data provide a neural substrate and behavioral mechanism by which drug users can progress to drug seeking and may also offer a rationale for targeted pharmacotherapy in chronic drug users with high risk DBH genotypes.
Aim: Exposure to opioids has been associated with epigenetic effects. Studies in rodents suggested a role of varying degrees of DNA methylation in the differential regulation of μ-opioid receptor expression across the brain.
Methods: In a translational investigation, using tissue acquired postmortem from 21 brain regions of former opiate addicts, representing a human cohort with chronic opioid exposure, μ-opioid receptor expression was analyzed at the level of DNA methylation, mRNA and protein.
Results & conclusion: While high or low μ-opioid receptor expression significantly correlated with local OPRM1 mRNA levels, there was no corresponding association with OPRM1 methylation status. Additional experiments in human cell lines showed that changes in DNA methylation associated with changes in μ-opioid expression were an order of magnitude greater than differences in brain. Hence, different degrees of DNA methylation associated with chronic opioid exposure are unlikely to exert a major role in the region-specificity of μ-opioid receptor expression in the human brain.
The analysis of ethanol and of its congeners in blood plays an important role in forensic cases, especially when allegations are made that alcohol has been consumed after an accident. In alcoholic beverages, congener alcohols are by-products and are generated during fermentation. The assay of these compounds in serum samples and beverages has been previously performed using headspace-gas chromatography-flame ionization detection methods (HS-GC-FID). As an alternative, a robust headspace-gas chromatography-mass spectrometry (HS-GC-MS) procedure was developed and validated, which has the following advantages:
- Simultaneous determination of ethanol, congener alcohols and other
endogenous substances.
- Reduction of matrix interference by increasing selectivity and
specificity.
- Clear separation of the positional isomers 3-methyl-1-butanol and
2-methyl-1-butanol.
There has been a renewed interest in the potential use of psychedelics for the treatment of psychiatric conditions. Nevertheless, little is known about the mechanism of action and molecular pathways influenced by ayahuasca use in humans. Therefore, for the first time, our study aims to investigate the human metabolomics signature after consumption of a psychedelic, ayahuasca, and its connection with both the psychedelic-induced subjective effects and the plasma concentrations of ayahuasca alkaloids.
Plasma samples of 23 individuals were collected both before and after ayahuasca consumption. Samples were analysed through targeted metabolomics and further integrated with subjective ratings of the ayahuasca experience (i.e., using the 5-Dimension Altered States of Consciousness Rating Scale [ASC]), and plasma ayahuasca-alkaloids using integrated network analysis. Metabolic pathways enrichment analysis using diffusion algorithms for specific KEGG modules was performed on the metabolic output.
Compared to baseline, the consumption of ayahuasca increased N-acyl-ethanolamine endocannabinoids, decreased 2-acyl-glycerol endocannabinoids, and altered several large-neutral amino acids (LNAAs). Integrated network results indicated that most of the LNAAs were inversely associated with 9 out of the 11 subscales of the ASC, except for tryptophan which was positively associated. Several endocannabinoids and hexosylceramides were directly associated with the ayahuasca alkaloids. Enrichment analysis confirmed dysregulation in several pathways involved in neurotransmission such as serotonin and dopamine synthesis.
In conclusion, a crosstalk between the circulating LNAAs and the subjective effects is suggested, which is independent of the alkaloid concentrations and provides insights into the specific metabolic fingerprint and mechanism of action underlying ayahuasca experiences.
Cannabis is the most commonly used illicit drug in the world. However, because of a changing legal landscape and rising interest in therapeutic utility, there is an increasing trend in (long-term) use and possibly cannabis impairment. Importantly, a growing body of evidence suggests that regular cannabis users develop tolerance to the impairing, as well as the rewarding, effects of the drug. However, the neuroadaptations that may underlie cannabis tolerance remain unclear. Therefore, this double-blind, randomized, placebo-controlled, cross-over study assessed the acute influence of cannabis on the brain and behavioral outcomes in two distinct cannabis user groups. Twelve occasional and 12 chronic cannabis users received acute doses of cannabis (300-μg/kg delta-9-tetrahydrocannabinol) and placebo and underwent ultrahigh field functional magnetic resonance imaging and magnetic resonance spectroscopy. In occasional users, cannabis induced significant neurometabolic alterations in reward circuitry, namely, decrements in functional connectivity and increments in striatal glutamate concentrations, which were associated with increases in subjective high and decreases in performance on a sustained attention task. Such changes were absent in chronic users. The finding that cannabis altered circuitry and distorted behavior in occasional, but not chronic users, suggests reduced responsiveness of the reward circuitry to cannabis intoxication in chronic users. Taken together, the results suggest a pharmacodynamic mechanism for the development of tolerance to cannabis impairment, of which is important to understand in the context of the long-term therapeutic use of cannabis-based medications, as well as in the context of public health and safety of cannabis use when performing day-to-day operations.
Assessment of the acute effects of 2C-B vs. psilocybin on subjective experience, mood, and cognition
(2023)
2,5-dimethoxy-4-bromophenethylamine (2C-B) is a hallucinogenic phenethylamine derived from mescaline. Observational and preclinical data have suggested it to be capable of producing both subjective and emotional effects on par with other classical psychedelics and entactogens. Whereas it is the most prevalently used novel serotonergic hallucinogen to date, it's acute effects and distinctions from classical progenitors have yet to be characterized in a controlled study. We assessed for the first time the immediate acute subjective, cognitive, and cardiovascular effects of 2C-B (20 mg) in comparison to psilocybin (15 mg) and placebo in a within-subjects, double-blind, placebo-controlled study of 22 healthy psychedelic-experienced participants. 2C-B elicited alterations of waking consciousness of a psychedelic nature, with dysphoria, subjective impairment, auditory alterations, and affective elements of ego dissolution largest under psilocybin. Participants demonstrated equivalent psychomotor slowing and spatial memory impairments under either compound compared with placebo, as indexed by the Digit Symbol Substitution Test, Tower of London, and Spatial Memory Task. Neither compound produced empathogenic effects on the Multifaceted Empathy Test. 2C-B induced transient pressor effects to a similar degree as psilocybin. The duration of self-reported effects of 2C-B was shorter than that of psilocybin, largely resolving within 6 hours. Present findings support the categorization of 2C-B as a psychedelic of moderate experiential depth at doses given. Tailored dose-effect studies are needed to discern the pharmacokinetic dependency of 2C-B's experiential overlaps.
Cannabis is the most commonly used illicit drug in the world. However due to a changing legal landscape, and rising interest in therapeutic utility, there is an increasing trend in (long-term) use and possibly, cannabis impairment. Importantly, a growing body of evidence suggests regular cannabis users develop tolerance to the impairing, as well as the rewarding, effects of the drug. However, the neuroadaptations that may underlie cannabis tolerance remain unclear. Therefore, this double-blind, randomized, placebo controlled, cross-over study assessed the acute influence of cannabis on brain and behavioral outcomes in two distinct cannabis user groups. Twelve occasional (OUs) and 12 chronic (CUs) cannabis users received acute doses of cannabis (300 μg/kg THC) and placebo, and underwent ultra-high field functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS). In OUs, cannabis induced significant neurometabolic alterations in reward circuitry, namely decrements in functional connectivity and increments in striatal glutamate concentrations, which were associated with increases in subjective high and decreases in performance on a sustained attention task. Such changes were absent in CUs. The finding that cannabis altered circuitry and distorted behavior in OUs, but not CUs, suggests reduced responsiveness of the reward circuitry to cannabis intoxication in chronic users Taken together, the results suggest a pharmacodynamic mechanism for the development of tolerance to cannabis impairment.
Resting state fMRI has been employed to identify alterations in functional connectivity within or between brain regions following acute and chronic exposure to Δ9-tetrahydrocannabinol (THC), the psychoactive component in cannabis. Most studies focused a priori on a limited number of local brain areas or circuits, without considering the impact of cannabis on wholebrain network organization. The present study attempted to identify changes in the wholebrain human functional connectome as assessed with ultra-high field (7T) resting state scans of occasional (N=12) and chronic cannabis users (N=14) during placebo and following vaporization of cannabis. Two distinct data-driven methodologies, i.e. network-based statistics (NBS) and connICA, were used to identify changes in functional connectomes associated with acute cannabis intoxication and chronic cannabis use. Both methodologies revealed a broad state of hyperconnectivity within the entire range of major brain networks in chronic cannabis users compared to occasional cannabis users, which might be reflective of an adaptive network reorganization following prolonged cannabis exposure. The connICA methodology also extracted a distinct spatial connectivity pattern of hypoconnectivity involving the dorsal attention, limbic, subcortical and cerebellum networks and of hyperconnectivity between the default mode and ventral attention network, that was associated with the feeling of subjective high during THC intoxication across both user groups. Whole-brain network approaches identified spatial patterns in functional brain connectomes that distinguished acute from chronic cannabis use, and offer an important utility for probing the interplay between short and long-term alterations in functional brain dynamics when progressing from occasional to chronic use of cannabis.
Assessment of the acute effects of 2C-B vs psilocybin on subjective experience, mood and cognition
(2023)
2,5-dimethoxy-4-bromophenethylamine (2C-B) is a hallucinogenic phenethylamine derived from mescaline. Observational and preclinical data have suggested it to be capable of producing both subjective and emotional effects on par with other classical psychedelics and entactogens. Whereas it is the most prevalently used novel serotonergic hallucinogen to date, it’s acute effects and distinctions from classical progenitors have yet to be characterised in a controlled study. We assessed for the first time the immediate acute subjective, cognitive, and cardiovascular effects of 2C-B (20 mg) in comparison to psilocybin (15mg) and placebo in a within-subjects, double-blind, placebo-controlled study of 22 healthy psychedelic-experienced participants. 2C-B elicited alterations of waking consciousness of a psychedelic nature, with dysphoria, subjective impairment, auditory alterations, and affective elements of ego dissolution largest under psilocybin. Participants demonstrated equivalent psychomotor slowing and spatial memory impairments under either compound compared to placebo, as indexed by the Digit Symbol Substitution Test (DSST), Tower of London (TOL) and Spatial Memory Task (SMT). Neither compound produced empathogenic effects on the Multifaceted Empathy Test (MET). 2C-B induced transient pressor effects to a similar degree as psilocybin. The duration of self-reported effects of 2C-B was shorter than that of psilocybin, largely resolving within 6 hours. Present findings support the categorisation of 2C-B as a subjectively “lighter” psychedelic. Tailored dose-effect studies are needed to discern the pharmacokinetic dependency of 2C-B’s experiential overlaps.
Rationale: Studies have suggested mental health improvements following the use of the psychotropic plant concoction ayahuasca in non-clinical and clinical samples.
Objectives: The present observational study assessed depressive symptomatology in 20 clinically depressed patients (symptom score > 13 on the Beck’s Depression Inventory) before attendance of an ayahuasca ceremony and 1 month and 1 year after. Secondary measures included ratings of altered states of consciousness and ego dissolution during the ayahuasca ceremony as well as global measures of mindfulness, satisfaction with life, depression, anxiety, and stress.
Results: Twenty participants completed baseline and 1-day follow-up, 19 completed measures at 1-month follow-up, and 17 completed measures at 1-year follow-up. BDI scores reduced from baseline (M = 22.7) to all post-ceremony measures (Ms 11.45, 12.89, and 8.88, for 1-day, 1-month, and 1-year follow-up, respectively). After 1 day, 12/20 participants were in remission (BDI < 13). Remission rates after 1 month and 1 year were 13/19 and 12/17, respectively. Three participants remained mildly depressed (BDI 14–19) at the 1-month and 1-year follow-up. Two participants did not respond and remained at a moderate/severe level of depression at 1-year follow-up. Reductions on the secondary mental health measures and increases in mindfulness and satisfaction with life were found up to 1 year post-ceremony. Improvements in clinical depression and mental health correlated with levels of experienced ego dissolution and oceanic boundlessness during the ceremony up to 1 month after the ceremony. Engagement in additional mental health treatments or use of another psychedelic during study participation may have contributed to improved mental health ratings at 1-year follow-up.
Conclusion: Ayahuasca produces long-term mental health improvements in clinically depressed patients, which highlights its therapeutic potential.
The knowledge that brain functional connectomes are both unique and reliable has enabled behaviourally relevant inferences at a subject level. However, it is unknown whether such “fingerprints” persist under altered states of consciousness. Ayahuasca is a potent serotonergic psychedelic which elicits a widespread dysregulation of functional connectivity. Used communally in religious ceremonies, its shared use may highlight relevant novel interactions between mental state and FC inherency. Using 7T fMRI, we assessed resting-state static and dynamic FCs for 21 Santo Daime members after collective ayahuasca intake in an acute, within-subject study. Here, connectome fingerprinting revealed a shared functional space, accompanied by a spatiotemporal reallocation of keypoint edges. Importantly, we show that interindividual differences in higher-order FCs motifs are relevant to experiential phenotypes, given that they can predict perceptual drug effects. Collectively, our findings offer an example as to how individualised connectivity markers can be used to trace a subject’s functional connectome across altered states of consciousness.