Chronic inflammatory pain is associated with persistent sensory and immune dysregulation. We evaluated the therapeutic efficacy of two cannabinoids formulations—Cannabigerol (CBG) and Standardized Full-Spectrum Cannabis Extract (FULL) in a preclinical model of acute and Chronic inflammatory pain and examined their effects on peripheral and central inflammatory mediators. Cannabinoid analgesic effects were assessed in male Wistar Hannover rats using acute (formalin) and chronic inflammatory pain (CFA) models. Treatments were administered at different doses before the formalin test and after CFA as a single dose or once daily for 21 days. Motor function and inflammatory markers (TNF-α and IL-10) were evaluated using actimeter test and ELISA. In the formalin test, both cannabinoids reduced nociceptive behaviors during Phase I, whereas only FULL produced sustained analgesia during Phase II. In the chronic model, single administration produced no significant effects; while repeated treatment (highest doses) improved mechanical thresholds. FULL (10 mg/kg) produced earlier analgesic effects (day 10), while CBG (10 mg/kg) fully restored baseline sensitivity from day 15 onward. In locomotor assessments, both compounds prevented CFA-induced motor impairments, except at the lowest CBG dose. CFA increased tumor necrosis factor-alpha (TNF-α) in the spinal cord, dorsal root ganglia (DRG), and plasma. Both cannabinoids prevented the CFA-induced increase in TNF-α levels in the spinal cord and plasma. Elevated TNF-α in the DRG persisted despite treatment, indicating region-specific regulation. Interleukin-10 (IL-10) levels were unaffected. Both cannabinoids exert analgesic and anti-inflammatory effects, with FULL providing faster acute relief and CBG produced a more prolonged antinociceptive effect.
Acute food-deprivation stress causes relapse to heroin seeking in male rats following punishment-invoked abstinence. Here we tested the generality of the effect by investigating whether forced swim, footshock, or restraint stressors would induce relapse to heroin seeking in male and female rats. In addition, we assessed whether individual traits could predict stress-induced relapse. Rats were first assessed in sucrose preference (SP) test, elevated plus maze (EPM), open field test (OF), and tail-flick (TF) test. Next, rats were trained to self-administer heroin (0.1 mg/kg/infusion, 6 h/day) under a seek-take chain schedule for at least 14 days. Heroin seeking was then punished with footshock (30
Cannabidiol (CBD) has previously been suggested to be an emerging pharmacotherapy for Alcohol Use Disorder (AUD), however, results from clinical studies remain mixed and potential mechanisms remain elusive. The aim of the present study is to investigate the potential for CBD to modulate neurobiological, cognitive and psychological processes during anticipation of threatening stimuli. In a cross-over, double-blind, randomized trial, non-treatment seeking individuals diagnosed with AUD (DSM-V) were recruited to receive either 800mg of CBD or matched placebo, completing two respective fMRI sessions. Region of interest (ROI) and whole-brain analysis were utilized to examine treatment effects on neural activity in response to high vs low threat anticipation stimuli during a fear anticipation continuous performance task (FCPT). Sixteen participants contributed complete FCPT data and fourteen contributed analysable fMRI data. No main treatment effects were observed across cognition, regional or whole-brain activation. Drinking the day before the scan was associated with longer latencies in responses on the continuous performance task. The present findings indicate that CBD did not produce measurable effects on brain activity or cognitive performance during threat anticipation in individuals with AUD suggesting that previously reported neural effects may be more closely related to direct responses to salient stimuli rather than anticipatory processes.
An estimated two-thirds of medical cannabis users in the United States are motivated by chronic pain, but clinical guidance remains guarded as to whether the potential benefit of cannabinoids for pain outweighs potential risks, such as effects on cognition. In a study where participants experienced benefits of cannabinoids for pain and tension, we evaluated cannabis effects on executive function, processing speed, memory, and verbal learning following acute use for chronic, non-specific low back pain. Participants were in one of three self-selected edible cannabis groups: a) CBD-dominant, b) THC-dominant, or c) a mixed ratio of CBD to THC and completed a battery of cognitive tasks at pre-use, 1 h post-use use, and 2 h post-use. Among 183 participants (56.8
Tobacco use is the leading preventable cause of death in the United States. Among the factors that contribute to tobacco initiation, use, and dependence, genetics may exert a strong influence. In mouse models, genetic differences between strains have been studied to investigate the potential drivers for these states. Previous reports indicate that C57BL/6 J (B6J) and C57BL/6N (B6N) mouse substrains show varying behavioral responses towards both natural and drug rewards. However, nicotine reward as assessed by preference for nicotine in the conditioned place preference (CPP) test has not yet been evaluated. Additionally, a point mutation in the cytoplasmic FMRP interacting protein 2 (Cyfip2) gene has been regarded as a potential underlying factor towards these substrain differences. Here, we compare the response to nicotine between B6J and B6N mouse substrains and establish a genetic correlation between Cyfip2 expression and nicotine preference in the brain. We also examine the effects of this mutation on nicotine preference between these substrains. We report reduced preference for nicotine in B6N mice compared to B6J mice and a negative correlation between nicotine CPP scores and Cyfip2 expression in both the hippocampus and prefrontal cortex. In our investigation of the Cyfip2 variant, we found that B6J mice carrying the B6N Cyfip2 mutation showed a lower preference for nicotine while B6N mice carrying the B6J Cyfip2 mutation showed increased preference. This study establishes substrain differences in preference for nicotine in the CPP test and a mutation in the Cyfip2 as the causal variant for this behavior.
Synthetic opioids like fentanyl are contributing to unprecedented overdose rates, yet the neural circuitry underlying fentanyl-associated behaviors remains poorly understood. The ventral tegmental area (VTA) projects to both the nucleus accumbens (NAc) and prefrontal cortex (PFC), forming distinct pathways that are implicated in drug-cue associations, though their specific roles in fentanyl-context encoding are not well defined. This study aimed to determine how VTA-NAc and VTA-PFC circuits contribute to fentanyl-context associations, and to assess the role of downstream dopamine receptor signaling in fentanyl context-seeking. Male and female mice underwent fentanyl conditioned place preference (CPP; 0.2 mg/kg). We locally inhibited dopamine D1 or D2 receptors in NAc or PFC during CPP expression. We used fiber photometry calcium imaging to measure activity in VTA-NAc and VTA-PFC projection neurons, and chemogenetic inhibition to suppress activity during CPP expression. Fentanyl CPP expression was attenuated by blocking D1 but not D2 receptors in PFC, and D2 but not D1 receptors in NAc. We found both VTA-NAc and VTA-PFC exhibited increased calcium activity during fentanyl exposure and during entries to the fentanyl-paired context. We further identified a functional role for VTA-NAc, as chemogenetic inhibition of VTA-NAc, but not VTA-PFC, reduced fentanyl context-seeking. While both VTA-NAc and VTA-PFC pathways are recruited by fentanyl exposure, fentanyl context-seeking relies on different downstream dopamine receptors in NAc vs PFC. Further, activity in VTA-NAc functionally supports the expression of fentanyl CPP. Together, these findings indicate that VTA circuits differentially contribute to fentanyl context-seeking.
Autism spectrum disorder (ASD) is characterized by differences and challenges in social communication and interaction, restricted and repetitive behaviors, and variable cognitive alterations. Cannabidiol (CBD), a non-psychoactive phytocannabinoid with a complex pharmacological profile, has been investigated in preclinical models of ASD, particularly regarding its behavioral and neurobiological effects. To systematically evaluate the behavioral effects of isolated cannabidiol in animal models of ASD and examine associated neurobiological correlates relevant to central nervous system function. A systematic search was conducted in eight electronic databases without date restriction. Preclinical studies assessing isolated CBD in animal models of ASD were included. Owing to methodological heterogeneity, data were synthesized according to the Synthesis Without Meta-analysis (SWiM) guideline, with behavioral outcomes defined as primary endpoints and neurobiological measures as secondary outcomes. The review protocol was registered in PROSPERO (CRD420251003869). Nine studies met the inclusion criteria, predominantly using rodent models, especially valproic acid-induced ASD, as well as zebrafish larvae and one behavioral ASD-like rat model. CBD produced dose-, model-, and treatment-regimen-dependent improvements in repetitive behavior, social interaction, recognition memory, and locomotor hyperactivity. Anxiolytic-like effects were inconsistently reported. Behavioral modulation was accompanied by changes in neurobiological markers, including CB1 receptor expression, parvalbumin-positive interneuron density, oxidative/nitrosative stress parameters, and qualitative neuroanatomical and cellular alterations in brain regions implicated in ASD-related behaviors. However, sex-specific effects could not be adequately assessed because most rodent studies used only males, zebrafish studies were conducted at larval stages, and mixed-sex data were not stratified. Evidence from animal models suggests that isolated CBD exerts promising but heterogeneous behavioral effects in ASD-relevant paradigms, supported by neurobiological changes that may help explain some behavioral outcomes. However, substantial methodological variability, limited sex-specific analyses, and incomplete reporting of bias-control procedures limit certainty, highlighting the need for more rigorous preclinical studies addressing dose-response relationships, mechanisms, sex as a biological variable, safety, long-term outcomes, and translational relevance.
Nicotine vaping is associated with increased alcohol use, including binge drinking, yet the neurobehavioral mechanisms underlying nicotine–alcohol interactions remain poorly understood due to limited translational preclinical models capturing intrapulmonary nicotine exposure effects on binge-like ethanol intake. We establish a mouse model combining nicotine vapor exposure (NVE) with drinking-in-the-dark (DID) to examine effects on binge-like ethanol (EtOH) consumption and determine whether these effects are associated with medial prefrontal cortex (mPFC) activity and nicotinic acetylcholine receptor (nAChR) signaling. Male and female mice were passively exposed to nicotine or vehicle vapor prior to 2-h and 4-h EtOH DID across repeated cycles. EtOH intake, blood ethanol concentrations (BECs), and control solution consumption were measured. Neuronal activation in prelimbic (PrL) and medial orbitofrontal cortex (mOFC) was assessed using c-Fos immunofluorescence. Mecamylamine was used to evaluate nAChR involvement. NVE produced physiologically relevant nicotine exposure and selectively increased EtOH consumption during 2-h and 4-h DID sessions without altering control solution intake. NVE also elevated BECs, which were positively correlated with EtOH consumption. Following DID, NVE was associated with reduced mPFC activity in PrL and mOFC; however, EtOH consumption was inversely correlated specifically with mOFC activity. nAChR blockade attenuated NVE-induced increases in EtOH consumption during 2-h DID only. Passive nicotine vapor exposure enhances binge-like EtOH intake and is associated with reduced mPFC engagement, particularly within mOFC, suggesting a mechanism underlying nicotine–alcohol interactions. These effects are partly mediated by nAChRs, identifying mPFC nAChRs as potential therapeutic targets for nicotine–alcohol polysubstance use.
Access to alternative non-drug rewards is known to influence alcohol use, yet how chronic exposure affects behavioral allocation under concurrent choice conditions remains poorly understood. This study examined the effects of chronic, binge-like ethanol vapor on ethanol self-administration and behavioral allocation in a concurrent operant choice paradigm offering sweetened ethanol and sucrose. Male and female Long Evans rats completed daily concurrent choice sessions in which completion of a fixed-ratio 5 produced 15 s access to either sweetened ethanol or sucrose alone. Following baseline assessment, rats were exposed to seven weeks of ethanol vapor (4 h/day, 4 days/week) or air control conditions while operant testing continued. Ethanol no-choice sessions were conducted to assess behavior in the absence of sucrose. Choice behavior and intake were also evaluated following cessation of vapor exposure. Data were analyzed using mixed-effects models. Replicating our previous findings, concurrent sucrose access reduced ethanol self-administration relative to ethanol no-choice sessions. During vapor exposure, vapor-exposed rats demonstrated progressive reductions in ethanol-directed choice and ethanol intake alongside concurrent increases in sucrose intake, while controls maintained stable behavior. Reverting to ethanol-only no-choice sessions increased ethanol intake across groups; however, vapor-exposed rats continued to consume less ethanol than controls. Following vapor cessation, lower ethanol-directed choice persisted in vapor-exposed rats. These results suggest that exposure to ethanol vapor alone may not be sufficient to increase ethanol-directed behavioral allocation when assessed in a concurrent choice operant paradigm. As such, conclusions drawn from vapor-based models may depend critically on the environmental context, such as availability of alternative reinforcers.
Elevated risk-taking negatively impacts numerous psychiatric populations, yet no targeted pharmacotherapies exist. Treatment development is hindered by an incomplete understanding of mechanisms underlying risk-based decision-making. The Iowa Gambling Task (IGT) is a cross-species translatable assessment providing humans and rodents four options of variably safe (advantageous) and risky (disadvantageous) probabilistic reward/punishment contingencies, enabling study of this behavior in rodents in a manner directly translatable to human populations. Mechanisms underlying the switch from risky to safe decision-making remains unclear, however. Clinical imaging studies implicate the anterior cingulate cortex (ACC) in human IGT performance, but causal relationships between ACC activity and decision-making require confirmation. We used a chemogenetic strategy to determine the contribution of the ACC to mouse IGT performance. The inhibitory DREADD, hM4Di (n = 10) (or mCherry control; n = 9) was virally expressed in ACC of male (n = 7) and female (n = 12) C57BL6/J mice (aged 2 yrs), which received deschloroclozapine (DCZ; 0.1 mg/kg) or vehicle (within-subjects) prior to IGT assessment. Mice were also assessed in the Progressive Ratio Breakpoint Task (PRBT) and behavioral pattern monitor (BPM) to determine whether chemogenetically induced changes in effortful motivation or exploration may have impacted IGT performance. Consistent with our a priori hypothesis, chemogenetic ACC inhibition increased choice of safe options during the middle of the IGT session, without affecting PRBT or BPM behavior. ACC inhibition therefore facilitated learning of IGT contingencies, without affecting effortful motivation or locomotion. These findings support further investigation of the ACC as a therapeutic target for remediation of psychopathology-associated cognitive impairment.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving synapse dysfunction, neuronal death and disorientation of cognitive processes that are caused by the accumulation of amyloid-β (Aβ) along with aberrant phosphorylation of tau. Aberrant proteolytic processing of amyloid precursor protein (APP) promotes Aβ production, which is pro-oxidant, activates microglia, and promotes chronic neuroinflammation. In parallel, neurofibrillary tangle formation, microtubule destabilisation, and impaired axonal transport are the consequences of pathological tau phosphorylation, which together are associated with accelerated neuronal degeneration. Recent findings implicate epitranscriptomic Dysregulation as an important, but understudied, component of AD pathobiology. In particular, emerging evidence suggests that the expression and activity of METTL3 are dynamically regulated throughout the course of AD, with up- or down-regulation at different disease stages, in specific brain regions, and across cell types, indicating that METTL3 signalling is dysregulated rather than uniformly increased or decreased in AD pathogenesis. Therefore, the changes in m6A deposition mediated by METTL3 could be different in various pathological contexts and cell types, with different downstream consequences in terms of neuronal survival, glial activation and inflammatory signalling. Context-dependent dysregulation of this regulatory axis drives a pronounced elevation in important pro-inflammatory mediators and promotes pyroptosis, including NLRP3, IL-1β, and STAT3, thereby enhancing glial activation, inflammasome assembly and caspase-dependent neuronal death. Integrating the Ab-mediated pathology, tau-mediated cytoskeletal dysfunction and chronic neuroinflammation, the METTL3/IGF2BP2 pathway defines a convergence point that helps break down neuronal homeostasis and plasticity. This review compiles new mechanistic truths of how m6A-dependent RNA regulation contributes to the progression of AD and discusses therapeutic opportunities of METTL3/IGF2BP2 axis targeting for novel RNA-based therapies for neurodegenerative disease.
Chronic unpredictable stress (CUS) is a significant contributor to neurobehavioral changes and cognitive impairment, largely driven by disruptions in cellular homeostasis, elevated corticosterone levels and altered neurotransmitter dynamics. The PPAR-γ/MCT1 pathway plays a crucial role in regulating energy balance, modulating glucose and lipid metabolism, making it a potential target for therapeutic interventions. CUS can alter the expression of PPAR-γ MCT1 disrupting glucose and lipid metabolism contributing to metabolic dysregulation and stress -related disorders. This study investigates the neuroprotective effects of INT131, a selective PPAR-γ agonist, in mitigating CUS-induced neurobehavioral deficits through modulation of MCT1 signalling. Swiss albino mice were exposed to varied stressors over 56 days to induce CUS. Behavioral assessments including the elevated plus maze (EPM), tail suspension test (TST), sucrose preference test (SPT), and Morris Water Maze (MWM) were used to evaluate anxiety, depression-like behavior, and memory impairment. INT131 was administered orally at 5 and 10 mg/kg doses. Fluoxetine (20 mg/kg, p.o.) served as the positived neuronal architecte control. INT131 significantly alleviated CUS-induced behavioral abnormalities and normalized corticosterone, serotonin, and dopamine levels. It also attenuated oxidative stress and inflammatory cytokines, reduced acetylcholinesterase activity, and preserved neuronal architecture, as confirmed by histological analysis. Importantly, co-treatment with CHCA (100 mg/kg, i.p.), a selective MCT1 inhibitor, abolished the neuroprotective effects of INT131, indicating MCT1’s mechanistic involvement. This study demonstrates that INT131 exerts robust neuroprotective effects through the PPAR-γ/MCT1 pathway and supports its potential as a candidate for managing stress-related neurobehavioral and cognitive disorders.
Attention-deficit/hyperactivity disorder (ADHD) is associated with executive dysfunction involving inattention and impulsivity, with evidence of disrupted functional expression of the dopamine and noradrenaline transporters. We investigated the dose-dependent modulation of anti-ADHD drugs on selective and sustained visual attention in low-, mid- and high-attention phenotypes. Two mathematical approaches, signal detection theory and theory of visual attention were applied to further characterise the effects and mechanisms. Rats were trained to detect and respond to the presence or absence of a visual target to obtain food reward on a signal detection task. After attentional performance stabilised, the indirect catecholamine agonist, d-amphetamine (0.1; 0.2; 0.4 mg/kg), the dopamine (DA) and noradrenaline (NA) reuptake inhibitor methylphenidate (0.3; 1; 3 mg/kg), and the NA reuptake inhibitor atomoxetine (0.1; 0.3; 1 mg/kg), were administered systemically. Low-dose d-amphetamine produced baseline-dependent effects on attention, improving target discrimination only in rats with lower attentive performance, whereas methylphenidate did not significantly improve attention but increased guessing. In contrast, low-dose atomoxetine selectively impaired attention in low-attentive subjects, whereas high-dose atomoxetine generally impaired discrimination performance. All three drugs had expected effects on motor response output. As well as demonstrating baseline-dependent effects of amphetamine on visual attention, the findings for methylphenidate and atomoxetine suggest important, apparently opposing effects on visual signal detection performance produced via blockade of the DA and NA transporters. The deleterious effects of atomoxetine on performance were especially noteworthy in view of its use as a treatment in ADHD.
Military personnel are exposed to bouts of acute stress during their careers, in which cognitive processes associated with decision-making might simultaneously suffer. Currently, it is still unclear how hormones and neurotransmitters involved in the acute stress response specifically affect these decision-making subprocesses, particularly in the military. We aimed to expose military personnel to pharmacological stress, in which noradrenaline and/or cortisol activity was stimulated. Next, decision-making subprocesses (i.e. working memory, impulse control and risk-taking) were assessed. A sample of 100 Dutch military personnel were recruited. Noradrenaline and/or cortisol activity was stimulated through oral administration of yohimbine and hydrocortisone, respectively. Decision-making subprocesses were assessed through computerised tasks. Induction of stress was confirmed through psychophysiological measures. Working memory seemed subtly affected by stress, as heightened noradrenaline slowed recall while cortisol accelerated it. Inhibition was unaffected by acute stress. Risk-taking was enhanced solely by noradrenaline, contrasting earlier research positing cortisol as a predictor of amplified risk-taking in civilians. Our findings contribute to the existing literature of the effects of acute stress on cognitive processes associated with decision-making, emphasising intricacies of the effects of specific stress hormones and neurotransmitters. Future research is needed to further identify these differential intricacies on cognitive processes, keeping potential differences between demographic subgroups in mind.
Sex differences in the effects of cannabis have been demonstrated in animals, though the human evidence is more equivocal. In particular, more work is needed to better understand interactions between sex and dose in determining acute pharmacological effects of cannabis, especially at higher potencies of Δ9-tetrahydrocannabinol (THC). Sex differences were examined following a range of potencies of smoked cannabis (0
Repeated exposure to psychostimulants can be followed by negative affective mood states when the drug is no longer present. These states can function as powerful negative reinforcers, intensifying drug cravings and increasing the likelihood of continued use. Although negative affective states are highly prevalent among cocaine users, and their severity is closely linked to relapse, the specific genetic factors driving these symptoms remain relatively unknown. Due to their high degree of genetic and neuroanatomical similarity to humans, and the availability of extensive reference genetic, genomic and neurobiological resources, mice provide an appropriate model for investigating the genetic basis of the behavioral traits associated with negative affective states following psychostimulant exposure. We investigated anhedonia- and dysphoria-like behaviors following saline or cocaine exposure across the eight inbred Collaborative Cross (CC)/Diversity Outbred (DO) founder strains to evaluate their feasibility for future genetic mapping studies of cocaine response. Mice were administered cocaine (10 mg/kg) or saline via intraperitoneal (i.p.) injections across 19 days, followed by behavioral assays to assess anhedonia- and dysphoria-like behaviors. We observed significant strain- and sex-dependent variation across all behavioral measures, indicating robust genetic influences on baseline affective traits, and strain-specific modulation by cocaine exposure. Heritability estimates ranged from 0 to 0.86. Our findings demonstrate the utility of genetically diverse mouse populations for exploring the genetic underpinnings of traits relevant to negative reinforcement in cocaine use disorder (CUD) and highlight their value in modeling individual variation in negative affective states in response to cocaine.
Post-traumatic stress disorder (PTSD) is a psychiatric condition triggered by traumatic events and associated with long-lasting neurobiological alterations, particularly in the hippocampus. Although hippocampal dysfunction plays a central role in PTSD pathophysiology, the molecular mechanisms underlying these alterations—especially those involving nitric oxide (NO) signaling and necroptosis-related pathways—remain incompletely understood. Adult male Naval Medical Research Institute (NMRI) mice (n = 70) were randomly assigned to seven groups: control, moderate PTSD (MP), MP + L-arginine (MP-Arg), MP + L-NAME (MP-Nam), severe PTSD (SP), SP + L-arginine (SP-Arg), and SP + L-NAME (SP-Nam). PTSD-like stress was induced using a two-day electric foot shock protocol. Behavioral changes were evaluated using the Open Field Test (OFT), Forced Swim Test (FST), and Tail Suspension Test (TST). L-arginine (200 mg/kg) or L-NAME (50 mg/kg) was administered intraperitoneally 60-min before testing to modulate NO signaling. Hippocampal tissue was analyzed for phosphorylated RIP1, RIP3, and MLKL, and neuronal density in the CA1 region was assessed using Nissl staining. Stress exposure was associated with anxiety- and depression-like behaviors, more pronounced in SP than MP mice. Stress was also associated with reduced CA1 neuronal density and increased phosphorylation of RIP1, RIP3, and MLKL. L-arginine treatment was associated with reduced behavioral impairments and partial preservation of CA1 neuronal integrity, whereas L-NAME treatment was associated with more pronounced behavioral and molecular alterations. These findings suggest an association between NO signaling modulation and necroptosis-related molecular changes in the hippocampus under PTSD-like stress conditions. Further studies are required to clarify causal relationships. Modulation of the Nitric Oxide Pathway and Its Association with Necroptotic Markers and Depression-like Behaviors in a PTSD-like Mouse Model: Neuroprotective Potential of L-Arginine vs. Exacerbating Effects of L-NAME.
Methamphetamine use disorder (MUD) poses significant public health risks, with individuals often exhibiting heightened impulsivity. Traditional electroencephalography (EEG) spectral analyses have yielded inconsistent findings, potentially due to the conflation of periodic and aperiodic activities. The aperiodic component, quantified by the exponent and offset parameters, reflects excitatory/inhibitory (E/I) balance and broadband neural activity, which may be disrupted in addiction. However, its association with impulsivity in MUD remains unexplored. This study aimed to examine aperiodic activity in individuals with MUD and its correlation with impulsivity, using the FOOOF algorithm to decompose EEG signals. The study included 47 male MUD patients and 41 healthy male controls. Resting-state EEG was recorded, and aperiodic components (exponent and offset) were extracted via the FOOOF algorithm. Clinical assessments included the Barratt Impulsiveness Scale (BIS-11), Zung Self-Rating Anxiety/Depression Scales, and visual analogue scales for craving. The aperiodic exponent (t = 3.617, p < 0.001) and offset (t = 2.762, p = 0.007) were significantly reduced in the MUD group compared to controls. Both parameters showed negative correlations with impulsivity measures (e.g., exponent vs. BIS-11 total score: r = -0.345, p = 0.019; offset vs. BIS-11 total: r = -0.389, p = 0.008) and years of methamphetamine use (exponent: r = -0.394, p = 0.023). Reduced aperiodic activity in MUD suggests E/I imbalance, likely associated with dopaminergic dysfunction. The correlations with impulsivity highlight the potential of aperiodic components as biomarkers for behavioral dysregulation in addiction. These findings underscore the transdiagnostic relevance of E/I balance in impulse control.
This paper critiques the use of the term “mysticism” in psychedelic research, arguing its continued use is outdated and misleading. It highlights the confusion stemming from the historical context of “mysticism,” particularly through the works of Walter Stace and Walter Pahnke, whose ideas have shaped the psychedelic discourse despite being flawed and largely unexamined. The paper is divided into two parts: the first is an archaeology that re-evaluates these foundational texts that misled psychedelic discourse; the second is a genealogy that traces how the concept of “mysticism”, with its religious roots, became attached to “psychedelics” and became normalised in second generation psychedelic research. It advocates for rebranding the Mystical Experience Questionnaire (MEQ) to the Psychedelic Experience Questionnaire (PEQ), emphasising that this change accords nicely with the idea of Psychedelic Experience which Walter Pahnke developed in his later research, as a five-part typology, and liberates the instrument from the hangover of a dubious legacy in which the correlation between therapeutic outcomes and mystical experiences invites psychedelic experiences to be shoehorned into a very particular and peculiar quasi-religious construct.
