Sex differences in the acute effects of oral THC: a randomized, placebo-controlled, crossover human laboratory study.

RATIONALE: Recent reports have shown increased cannabis use among women, leading to growing concerns about cannabis use disorder (CUD). While there is preclinical evidence suggesting biological sex influences cannabinoid effects, human research remains scant. We investigated sex differences in the acute response to oral tetrahydrocannabinol (THC) in humans. METHODS: 56 healthy men and women with prior exposure to cannabis but no history of CUD participated in a randomized, placebo-controlled, human laboratory study where they received a single 10 mg dose of oral THC (dronabinol). Subjective psychoactive effects were assessed by the visual analog scale of "high", psychotomimetic effects by the Clinician-Administered Dissociative Symptoms Scale and Psychotomimetic States Inventory, verbal learning and memory by Rey Auditory Verbal Learning Test (RAVLT), and physiological effects by heart rate. Outcomes were regularly measured on the test day, except for the RAVLT, which was assessed once. Peak differences from baseline were analyzed using a nonparametric method for repeated measures. RESULTS: Oral THC (10 mg) demonstrated significant dose-related effects in psychotomimetic and physiological domains, but not in RAVLT outcomes. A notable interaction between THC dose and sex emerged concerning the subjective "high" scores, with women reporting heightened sensations (p = 0.05). No other significant effects of sex and THC dose interaction were observed. CONCLUSION: Oral THC (10 mg) yields similar acute psychotomimetic and physiological effects across sexes, but women may experience a pronounced subjective psychoactive effect. Further research is needed to identify individual vulnerabilities and facilitate tailored interventions addressing CUD. CLINICALTRIALS: GOV REGISTRATION: https://clinicaltrials.gov/study/NCT02781519?term=Ranganathan&intr=THC&rank=3 .

Psilocybin pulse regimen reduces cluster headache attack frequency in the blinded extension phase of a randomized controlled trial.

BACKGROUND: In a recent randomized, double-blind, placebo-controlled study, we observed a nonsignificant reduction of attack frequency in cluster headache after pulse administration of psilocybin (10 mg/70 kg, 3 doses, 5 days apart each). We carried out a blinded extension phase to consider the safety and efficacy of repeating the pulse regimen. METHODS: Eligible participants returned to receive a psilocybin pulse at least 6 months after their first round of study participation. Participants kept headache diaries starting two weeks before and continuing through eight weeks after the first drug session. Ten participants completed the extension phase and all ten were included in the final analysis. RESULTS: In the three weeks after the start of the pulse, cluster attack frequency was significantly reduced from baseline (18.4 [95% confidence interval 8.4 to 28.4] to 9.8 [4.3 to 15.2] attacks/week; p = 0.013, d' = 0.97). A reduction of approximately 50% was seen regardless of individual response to psilocybin in the first round. Psilocybin was well-tolerated without any unexpected or serious adverse events. DISCUSSION: This study shows a significant reduction in cluster attack frequency in a repeat round of pulse psilocybin administration and suggests that prior response may not predict the effect of repeated treatment. To gauge the full potential of psilocybin as a viable medicine in cluster headache, future work should investigate the safety and therapeutic efficacy in larger, more representative samples over a longer time period, including repeating the treatment. CLINICAL TRIALS REGISTRATION: NCT02981173.

The "psychiatric" neuron: the psychic neuron of the cerebral cortex, revisited.

Nearly 25 years ago, Dr. Patricia Goldman-Rakic published her review paper, "The 'Psychic' Neuron of the Cerebral Cortex," outlining the circuit-level dynamics, neurotransmitter systems, and behavioral correlates of pyramidal neurons in the cerebral cortex, particularly as they relate to working memory. In the decades since the release of this paper, the existing literature and our understanding of the pyramidal neuron have increased tremendously, and research is still underway to better characterize the role of the pyramidal neuron in both healthy and psychiatric disease states. In this review, we revisit Dr. Goldman-Rakic's characterization of the pyramidal neuron, focusing on the pyramidal neurons of the prefrontal cortex (PFC) and their role in working memory. Specifically, we examine the role of PFC pyramidal neurons in the intersection of working memory and social function and describe how deficits in working memory may actually underlie the pathophysiology of social dysfunction in psychiatric disease states. We briefly describe the cortico-cortical and corticothalamic connections between the PFC and non-PFC brain regions, as well the microcircuit dynamics of the pyramidal neuron and interneurons, and the role of both these macro- and microcircuits in the maintenance of the excitatory/inhibitory balance of the cerebral cortex for working memory function. Finally, we discuss the consequences to working memory when pyramidal neurons and their circuits are dysfunctional, emphasizing the resulting social deficits in psychiatric disease states with known working memory dysfunction.

Sex Differences in the Acute Effects of Oral THC: A Randomized, Placebo-Controlled, Crossover Human Laboratory Study.

Rationale: Recent reports have shown increased cannabis use among women, leading to growing concerns about cannabis use disorder (CUD). Some evidence suggests a faster progression to addiction in women, known as the "telescoping effect." While there is preclinical evidence suggesting biological sex influences cannabinoid effects, human research remains scant. We investigated sex differences in the response to oral tetrahydrocannabinol (THC) in humans. Methods: 56 healthy men and women with prior exposure to cannabis but no history of CUD participated in a randomized, placebo-controlled, human laboratory study where they received a single 10 mg dose of oral THC (dronabinol). Subjective psychoactive effects were assessed by the visual analog scale of "high", psychotomimetic effects by the Clinician-Administered Dissociative Symptoms Scale and Psychotomimetic States Inventory, verbal learning and memory by Rey Auditory Verbal Learning Test (RAVLT), and physiological effects by heart rate. Outcomes were regularly measured on the test day, except for the RAVLT, which was assessed once. Peak differences from baseline were analyzed using a nonparametric method for repeated measures. Results: Oral THC demonstrated significant dose-related effects in psychotomimetic and physiological domains, but not in RAVLT outcomes. A notable interaction between THC dose and sex emerged concerning the subjective "high" scores, with women reporting heightened sensations (p=0.05). No other significant effects of sex and THC dose interaction were observed. Conclusion: Oral THC yields similar psychotomimetic and physiological effects across sexes, but women may experience a pronounced subjective psychoactive effect. Further research is needed to identify individual vulnerabilities and facilitate tailored interventions addressing CUD.

Examining the effects of prenatal alcohol exposure on performance of the sustained attention to response task in children with an FASD.

Prenatal alcohol exposure (PAE), the leading known cause of childhood developmental disability, has long-lasting effects extending throughout the lifespan. It is well documented that children prenatally exposed to alcohol have difficulties inhibiting behavior and sustaining attention. Thus, the Sustained Attention to Response Task (SART), a Go/No-go paradigm, is especially well suited to assess the behavioral and neural functioning characteristics of children with PAE. In this study, we utilized neuropsychological assessment, parent/guardian questionnaires, and magnetoencephalography during SART random and fixed orders to assess characteristics of children 8-12 years old prenatally exposed to alcohol compared to typically developing children. Compared to neurotypical control children, children with a Fetal Alcohol Spectrum Disorder (FASD) diagnosis had significantly decreased performance on neuropsychological measures, had deficiencies in task-based performance, were rated as having increased Attention-Deficit/Hyperactivity Disorder (ADHD) behaviors and as having lower cognitive functioning by their caretakers, and had decreased peak amplitudes in Broadmann's Area 44 (BA44) during SART. Further, MEG peak amplitude in BA44 was found to be significantly associated with neuropsychological test results, parent/guardian questionnaires, and task-based performance such that decreased amplitude was associated with poorer performance. In exploratory analyses, we also found significant correlations between total cortical volume and MEG peak amplitude indicating that the reduced amplitude is likely related in part to reduced overall brain volume often reported in children with PAE. These findings show that children 8-12 years old with an FASD diagnosis have decreased amplitudes in BA44 during SART random order, and that these deficits are associated with multiple behavioral measures.

DNA methylation and the opposing NMDAR dysfunction in schizophrenia and major depression disorders: a converging model for the therapeutic effects of psychedelic compounds in the treatment of psychiatric illness.

Psychedelic compounds are being increasingly explored as a potential therapeutic option for treating several psychiatric conditions, despite relatively little being known about their mechanism of action. One such possible mechanism, DNA methylation, is a process of epigenetic regulation that changes gene expression via chemical modification of nitrogenous bases. DNA methylation has been implicated in the pathophysiology of several psychiatric conditions, including schizophrenia (SZ) and major depressive disorder (MDD). In this review, we propose alterations to DNA methylation as a converging model for the therapeutic effects of psychedelic compounds, highlighting the N-methyl D-aspartate receptor (NMDAR), a crucial mediator of synaptic plasticity with known dysfunction in both diseases, as an example and anchoring point. We review the established evidence relating aberrant DNA methylation to NMDAR dysfunction in SZ and MDD and provide a model asserting that psychedelic substances may act through an epigenetic mechanism to provide therapeutic effects in the context of these disorders.

Preliminary study of the interactive effects of THC and ethanol on self-reported ability and simulated driving, subjective effects, and cardiovascular responses.

RATIONALE: Drug- and alcohol-related motor vehicle accidents are a leading cause of morbidity and mortality worldwide. Compared to alcohol, less is known about the effects of cannabis on driving and even less about their combined effects. OBJECTIVE: To characterize the combined and separate effects of ethanol and tetrahydrocannabinol (THC) on perceived ability to drive, subjective effects, and simulated driving. METHODS: In a within-subject (crossover), randomized, placebo-controlled, double-blind, 2 × 2 design, the effects of oral THC (10 mg [dronabinol] or placebo) and low-dose intravenous ethanol (clamped at BAC 0.04% or placebo) on perceived ability to drive, simulated driving (standard deviation of lateral position [SDLP]), subjective effects (e.g., "high"), and physiological effects (e.g., heart rate) were studied in healthy humans (n = 18). RESULTS: Subjects reported reductions in perceived ability to drive (THC < ethanol < combination) which persisted for ~ 6 h (placebo = ethanol, THC < combination). Ethanol and THC produced synergistic effects on heart rate, significant differences compared to either drug alone on perceived ability to drive and feeling states of intoxication (e.g., high), as well increases in SDLP compared to placebo. CONCLUSIONS: Perceived ability to drive is reduced under the influence of THC against the backdrop of blood alcohol levels that are below the legal limit. People should be aware that the effects of oral THC on driving may persist for up to six hours from administration. Findings are relevant to the increasingly common practice of combining alcohol and cannabinoids and the effects on driving.

Exploratory investigation of a patient-informed low-dose psilocybin pulse regimen in the suppression of cluster headache: Results from a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Using a patient-informed regimen, we conducted an exploratory randomized, double-blind, placebo-controlled study to systematically investigate the effects of psilocybin in cluster headache. BACKGROUND: Sustained reductions in cluster headache burden after limited quantities of psilocybin-containing mushrooms are anecdotally reported, although to date there are no controlled studies investigating these effects. METHODS: Participants were randomized to receive psilocybin (0.143 mg/kg) or placebo (microcrystalline cellulose) in a pulse of three doses, each ~5 days apart. Participants maintained headache diaries starting 2 weeks before and continuing through 8 weeks after the first drug session. A total of 16 participants were randomized to receive experimental drug and 14 were included in the final analysis. RESULTS: In the 3 weeks after the start of the pulse regimen, the change in cluster attack frequency was 0.03 (95% confidence interval [CI] -2.6 to 2.6) attacks/week with placebo (baseline 8.9 [95% CI 3.8 to 14.0]) and -3.2 (95% CI -8.3 to 1.9) attacks/week with psilocybin (baseline 9.6 [95% CI 5.6 to 13.6]; p = 0.251). Group difference in change from baseline had a moderate effect size (d = 0.69). The effect size was small in episodic participants (d = 0.35) but large in chronic participants (d = 1.25), which remained over the entire 8-week period measured (d = 0.81). Changes in cluster attack frequency were not correlated with the intensity of acute psychotropic effects during psilocybin administration. Psilocybin was well-tolerated without any unexpected or serious adverse events. CONCLUSIONS: Findings from this initial, exploratory study provide valuable information for the development of larger, more definitive studies. Efficacy outcomes were negative, owing in part to the small number of participants. The separation of acute psychotropic effects and lasting therapeutic effects underscores the need for further investigation into the mechanism(s) of action of psilocybin in headache disorders.

Nutrition in decompensated liver disease: A regional trainee-led audit investigating patient nutrition and outcomes following admission with decompensated chronic liver disease.

OBJECTIVE: To conduct a regional audit assessing the prevalence and management of malnutrition in decompensated liver disease. METHOD: All adults admitted with decompensated cirrhosis over one-month period to participating trusts were included. Malnutrition was identified using MUST and Royal Free Hospital-Nutritional Prioritisation Tool (RFH-NPT). RESULTS: 47 patients were identified. The prevalence of malnutrition was 76.6%. This was independent of age (<65 versus ≥65; p = 1) or aetiology of liver disease (alcohol-related versus not; p = 0.55). Screening was significantly higher on Gastroenterology wards than other wards (77% versus 23%; p = 0.012). RFH-NPT identified 76.6% of patients as malnourished whereas MUST identified 55.3%. Supplementation was prescribed to 83% of eligible patients. 80% was oral supplementation and 20% received NG feeding. Median length of stay (9 (2-62) days) was higher in those prescribed supplements (11 vs 7 days, p = 0.041). Readmission rates were similar regardless of supplementation. Mortality was higher in malnourished patients (p = 0.03) and in those prescribed nutritional supplements at 1, 3 and 6 months (p = 0.026, p = 0.026 and p = 0.008) respectively, who were more likely to have severe liver disease. CONCLUSION: Prevalence of malnutrition is high in patients with decompensated cirrhosis but independent of age and aetiology and associated with higher Child-Pugh scores. The RFH-NPT was a more sensitive screening tool than MUST. Increased nutritional screening was noted on gastroenterology wards with more intervention in those with severe liver disease. Despite the study's limitations, once malnourished, nutritional intervention did not appear to impact on patient readmission or mortality rates therefore, we propose addressing malnutrition by utilising specialty dietician involvement at an earlier stage.

Exploratory study of the dose-related safety, tolerability, and efficacy of dimethyltryptamine (DMT) in healthy volunteers and major depressive disorder.

There is considerable interest in the therapeutic potential of psychedelic drugs. Dimethyltryptamine (DMT) is a potent, rapid-onset, and short-acting psychedelic drug that has not yet been independently tested for the treatment of depression. The safety, tolerability, and efficacy of intravenous DMT were investigated in treatment-resistant individuals with major depressive disorder (MDD) and healthy controls (HC) in an open-label, fixed-order, dose-escalation (0.1 mg/kg followed by 0.3 mg/kg) exploratory phase 1 study that was conducted in a typical hospital setting with strategic psychoeducation/support, but minimal psychotherapy. Tolerability, safety, cardiovascular function, abuse liability, psychedelic, and psychotomimetic effects, mood, and anxiety were assessed at each dosing session. In addition, depression was measured using the HAMD-17 in MDD participants 1 day after each dosing session. DMT was tolerated by both HC (n = 3) and MDD participants (n = 7) studied; there were no dropouts. HAMD-17 scores decreased significantly (p = 0.017) compared to baseline in MDD participants the day after receiving 0.3 mg/kg DMT (mean difference -4.5 points, 95% CI: -7.80 to -1.20, Hedge's g = 0.75). Adverse events were mostly mild with one self-limited serious event. DMT increased blood pressure, heart rate, anxiety, psychedelic effects, and psychotomimetic effects, which resolved within 20-30 min of injection. There were no dose-related differences in measures of drug reinforcement and abuse liability. In this small exploratory pilot study, intravenous DMT at doses of 0.1 and 0.3 mg/kg was mostly safe and tolerated and may have next-day (rapid) antidepressant effects in patients with treatment-resistant MDD. Further rigorous trials are warranted to replicate these findings and to determine the durability of antidepressant effects.

Fasting plasma glucose, diagnosis of gestational diabetes and the risk of large for gestational age: a regression discontinuity analysis of routine data.

OBJECTIVE: To estimate the causal effects of fasting plasma glucose (FPG) and diagnosis of gestational diabetes (GDM) on birthweight and the risks of large for gestational age (LGA). DESIGN: Regression discontinuity analysis of routine data. SETTING: Two district general hospitals in West Yorkshire, UK. POPULATION: A cohort of 7062 women with singleton pregnancies who were screened for GDM and gave birth to a baby at ≥24 weeks of gestation in 2017-2019, inclusive. METHODS: The causal effects of FPG and GDM diagnosis were estimated using the two-stage least-squares approach, around the diagnostic threshold of FPG ≥ 5.6 mmol/l recommended by the UK's National Institute for Health and Care Excellent (NICE), controlling for ethnicity, maternal age, parity, height and weight. MAIN OUTCOME MEASURES: Birthweight (standardised for sex and gestational age) and large for gestational age (standardised as birthweight above the 90th centile). RESULTS: For each 1 mmol/l increase in FPG the observed birthweight increased by Z-score = 0.48 standard deviations (95% CI 0.39 to 0.57) and the odds of LGA increased by OR = 2.61 (95% CI 1.86 to 3.66). Conversely, GDM diagnosis reduced the observed birthweight by Z = -0.61 (95% CI -0.94 to -0.29) and lowered the odds of LGA by OR = 0.33 (95% CI 0.15 to 0.74). Similar, but less certain, patterns were observed for caesarean section, shoulder dystocia and perinatal death. CONCLUSIONS: The relationship between FPG and LGA is potent but is dramatically reduced by GDM diagnosis (and all the consequences thereof). Women with mild hyperglycaemia (with an FPG of 5.1-5.5 mmol/l) who fall below the current NICE threshold for GDM diagnosis have the highest risks of adverse outcomes, suggesting a need to reconsider their current care. TWEETABLE ABSTRACT: Regression discontinuity analysis shows that untreated mild hyperglycaemia increases the odds of large for gestational age, but that a diagnosis of gestational #diabetes lowers the odds by three times.

Passive Recovery Strategies after Exercise: A Narrative Literature Review of the Current Evidence.

ABSTRACT: Passive recovery techniques are popular and offer a diverse spectrum of options for athletes and the clinicians providing care for them. These techniques are intended to minimize the negative effects of training or competition, thus enabling the athlete a quicker return to peak performance. Current evidence demonstrates improved athlete recovery with compression garments, cold water immersion, partial body cryotherapy, hyperbaric oxygen, and vibratory therapies. Other popular modalities, such as compression devices, whole body cryotherapy, percussive gun-assisted therapy, neuromuscular electrical stimulation, and pulsed electromagnetic therapy lack convincing evidence concerning athlete recovery. This article seeks to review the current literature and offer the reader an updated understanding of the mechanisms for each modality and the evidence regarding each modality's potential benefit in an athlete's recovery strategy.

p62 overexpression induces TDP-43 cytoplasmic mislocalisation, aggregation and cleavage and neuronal death.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) that exist on a spectrum of neurodegenerative disease. A hallmark of pathology is cytoplasmic TDP-43 aggregates within neurons, observed in 97% of ALS cases and ~ 50% of FTLD cases. This mislocalisation from the nucleus into the cytoplasm and TDP-43 cleavage are associated with pathology, however, the drivers of these changes are unknown. p62 is invariably also present within these aggregates. We show that p62 overexpression causes TDP-43 mislocalisation into cytoplasmic aggregates, and aberrant TDP-43 cleavage that was dependent on both the PB1 and ubiquitin-associated (UBA) domains of p62. We further show that p62 overexpression induces neuron death. We found that stressors (proteasome inhibition and arsenic) increased p62 expression and that this shifted the nuclear:cytoplasmic TDP-43 ratio. Overall, our study suggests that environmental factors that increase p62 may thereby contribute to TDP-43 pathology in ALS and FTLD.

Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin.

While anecdotal evidence suggests that select 5-hydroxytryptamine 2A (5-HT2A) receptor ligands, including psilocybin, may have long-lasting therapeutic effects after limited dosing in headache disorders, controlled investigations are lacking. In an exploratory double-blind, placebo-controlled, cross-over study, adults with migraine received oral placebo and psilocybin (0.143 mg/kg) in 2 test sessions spaced 2 weeks apart. Subjects maintained headache diaries starting 2 weeks before the first session until 2 weeks after the second session. Physiological and psychological drug effects were monitored during sessions and several follow-up contacts with subjects were carried out to assure safety of study procedures. Ten subjects were included in the final analysis. Over the 2-week period measured after single administration, the reduction in weekly migraine days from baseline was significantly greater after psilocybin (mean, - 1.65 (95% CI: - 2.53 to - 0.77) days/week) than after placebo (- 0.15 (- 1.13 to 0.83) days/week; p = 0.003, t(9) = 4.11). Changes in migraine frequency in the 2 weeks after psilocybin were not correlated with the intensity of acute psychotropic effects during drug administration. Psilocybin was well-tolerated; there were no unexpected or serious adverse events or withdrawals due to adverse events. This exploratory study suggests there is an enduring therapeutic effect in migraine headache after a single administration of psilocybin. The separation of acute psychotropic effects and lasting therapeutic effects is an important finding, urging further investigation into the mechanism underlying the clinical effects of select 5-HT2A receptor compounds in migraine, as well as other neuropsychiatric conditions. Clinicaltrials.gov : NCT03341689.

Measuring change in facial emotion recognition in individuals with autism spectrum disorder: A systematic review.

LAY ABSTRACT: Children and adults with autism spectrum disorder show difficulty recognizing facial emotions in others, which makes social interaction challenging. While there are many treatments developed to improve facial emotion recognition, there is no agreement on the best way to measure such abilities in individuals with autism spectrum disorder. The purpose of this review is to examine studies that were published between January 1998 and November 2019 and have measured change in facial emotion recognition to evaluate the effectiveness of different treatments. Our search yielded 65 studies, and within these studies, 36 different measures were used to evaluate facial emotion recognition in individuals with autism spectrum disorder. Only six of these measures, however, were used in different studies and by different investigators. In this review, we summarize the different measures and outcomes of the studies, in order to identify promising assessment tools and inform future research.

Design and energetic evaluation of a prosthetic knee joint actuator with a lockable parallel spring.

There are disadvantages to existing damping knee prostheses which cause an asymmetric gait and higher metabolic cost during level walking compared to non-amputees. Most existing active knee prostheses which could benefit the amputees use a significant amount of energy and require a considerable motor. In this work, a novel semi-active actuator with a lockable parallel spring for a prosthetic knee joint has been developed and tested. This actuator is able to provide an approximation of the behavior of a healthy knee during most of the gait cycle of level walking. This actuator is expanded with a series-elastic actuator to mimic the full gait cycle and enable its use in other functional tasks like stair climbing and sit-to-stance. The proposed novel actuator reduces the energy consumption for the same trajectory with respect to a compliant or directly-driven prosthetic active knee joint and improves the approximation of healthy knee behavior during level walking compared to passive or variable damping knee prostheses.

Targeting colon cancer cell NF-κB promotes an anti-tumour M1-like macrophage phenotype and inhibits peritoneal metastasis.

In a model of peritoneal metastasis in immune-competent mice, we show that nuclear factor (NF)-κB inhibition in CT26 colon cancer cells prevents metastasis. NF-κB inhibition, by stable overexpression of IκB-α super-repressor, induced differential polarization of co-cultured macrophages to an M1-like anti-tumour phenotype in vitro. NF-κB-deficient cancer cell-conditioned media (CT26/IκB-α SR) induced interleukin (IL)-12 and nitric oxide (NO) synthase (inducible NO synthase (iNOS)) expression in macrophages. Control cell (CT26/EV) conditioned media induced high levels of IL-10 and arginase in macrophages. In vivo, this effect translated to reduction in metastasis in mice injected with CT26/ IκB-α SR cells and was positively associated with increased CD8(+)CD44(+)CD62L(-) and CD4(+)CD44(+)CD62L(-) effector T cells. Furthermore, inhibition of NF-κB activity induced high levels of NO in infiltrating immune cells and decreases in matrix metalloproteinase-9 expression, simultaneous with increases in tissue inhibitor of metalloproteinases 1 and 2 within tumours. CT26/IκB-α SR tumours displayed increased pro-inflammatory gene expression, low levels of angiogenesis and extensive intratumoral apoptosis, consistent with the presence of an anti-tumour macrophage phenotype. Macrophage depletion reduced tumour size in CT26/EV-injected animals and increased tumour size in CT26/IκB-α SR cells compared with untreated tumours. Our data demonstrate, for the first time, that an important implication of targeting tumour cell NF-κB is skewing of macrophage polarization to an anti-tumour phenotype. This knowledge offers novel therapeutic opportunities for anticancer treatment.