Cardio-metabolic health effects of CPAP treatment for sleep apnoea during weight loss: A randomised controlled pilot trial.

BACKGROUND AND AIMS: This study assessed whether the addition of continuous positive airway pressure (CPAP) during weight loss would enhance cardiometabolic health improvements in patients with obesity and Obstructive Sleep Apnoea (OSA). METHODS AND RESULTS: Patients with overweight or obesity, pre-diabetes and moderatesevere OSA were randomised to receive CPAP therapy with a weight loss programme (CPAP+WL) or a weight loss programme alone (WL alone). PRIMARY OUTCOME: 2-hour glucose assessed by an oral glucose tolerance test. SECONDARY OUTCOMES: 24 hr blood pressure, body composition (DEXA) and fasting blood markers. 17 patients completed 3-month follow-up assessments (8 CPAP+WL and 9 WL alone). Overall, participants in both groups lost ∼12 kg which reduced polysomnography determined OSA severity by ∼45 %. In the CPAP+WL group, CPAP use (compliance 5.29 hrs/night) did not improve any outcome above WL alone. There was no improvement in 2-hour glucose in either group. However, in the pooled (n = 17) analysis there were overall improvements in most outcomes including insulin sensitivity (.000965 units, p = .008), sleep systolic BP (- 16.2 mmHg, p = .0003), sleep diastolic BP (-9.8 mmHg, p = 0.02), wake diastolic BP (- 4.3 mmHg, p = .03) and sleepiness (Epworth Sleepiness Score -3.2, p = .0003). In addition, there were reductions in glucose area under the curve (-230 units, p = .009), total (-0.86 mmol/L, p = 0.006) and LDL cholesterol (-0.58 mmol/L, p = 0.007), triglycerides (-0.75 mmol/L, p = 0.004), fat mass (-7.6 kg, p < .0001) and abdominal fat (-310 cm3, p < .0001). CONCLUSION: Weight loss reduced OSA and improved sleepiness and cardiometabolic health. These improvements were not further enhanced by using CPAP. Results suggest weight loss should be the primary focus of treatment for patients with OSA and obesity.

Decentralized clinical trials for medications to reduce the risk of dementia: Consensus report and guidance.

INTRODUCTION: Recent growth in the functionality and use of technology has prompted an increased interest in the potential for remote or decentralized clinical trials in dementia. There are many potential benefits associated with decentralized medication trials, but we currently lack specific recommendations for their delivery in the dementia field. METHODS: A modified Delphi method engaged an expert panel to develop recommendations for the conduct of decentralized medication trials in dementia prevention. A working group of researchers and clinicians with expertise in dementia trials further refined the recommendations. RESULTS: Overall, the recommendations support the delivery of decentralized trials in dementia prevention provided adequate safety checks and balances are included. A total of 40 recommendations are presented, spanning aspects of decentralized clinical trials, including safety, dispensing, outcome assessment, and data collection. DISCUSSION: These recommendations provide an accessible, pragmatic guide for the design and conduct of remote medication trials for dementia prevention. HIGHLIGHTS: Clinical trials of medication have begun adopting decentralized approaches. Researchers in the field lack guidance on what would be appropriate circumstances and frameworks for what would be appropriate circumstances and frameworks for the use of decentralized trial methods in dementia prevention. The present report provides consensus-based expert recommendations for decentralized clinical trials for dementia prevention.

Different heart rate variability profile during sleep in mid-later life adults with remitted early-onset versus late-onset depression.

BACKGROUND: In mid-later life adults, early-onset and late-onset (i.e., onset ≥50 years) depression appear to be underpinned by different pathophysiology yet have not been examined in relation to autonomic function. Sleep provides an opportunity to examine the autonomic nervous system as the physiology changes across the night. Hence, we aimed to explore if autonomic profile is altered in mid-later life adults with remitted early-onset, late-onset and no history of lifetime depression. METHODS: Participants aged 50-90 years (n = 188) from a specialised clinic underwent a comprehensive clinical assessment and completed an overnight polysomnography study. General Linear Models were used to examine the heart rate variability differences among the three groups for four distinct sleep stages and the wake after sleep onset. All analyses controlled for potential confounders - age, sex, current depressive symptoms and antidepressant usage. RESULTS: For the wake after sleep onset, mid-later life adults with remitted early-onset depression had reduced standard deviation of Normal to Normal intervals (SDNN; p = .014, d = -0.64) and Shannon Entropy (p = .004, d = -0.46,) than those with no history of lifetime depression. Further, the late-onset group showed a reduction in high-frequency heart rate variability (HFn.u.) during non-rapid eye movement sleep stage 2 (N2; p = .005, d = -0.53) and non-rapid eye movement sleep stage 3 (N3; p = .009, d = -0.55) when compared to those with no lifetime history. LIMITATIONS: Causality between heart rate variability and depression cannot be derived in this cross-sectional study. Longitudinal studies are needed to examine the effects remitted depressive episodes on autonomic function. CONCLUSION: The findings suggest differential autonomic profile for remitted early-onset and late-onset mid-later life adults during sleep stages and wake periods. The differences could potentially serve as peripheral biomarkers in conjunction with more disease-specific markers of depression to improve diagnosis and prognosis.

Evaluating possible 'next day' impairment in insomnia patients administered an oral medicinal cannabis product by night: a pilot randomized controlled trial.

Cannabis and its major constituents, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are being widely used to treat sleep disturbances. However, THC can cause acute cognitive and psychomotor impairment and there are concerns that driving and workplace safety might be compromised the day after evening use. Here, we examined possible 'next day' impairment following evening administration of a typical medicinal cannabis oil in adults with insomnia disorder, compared to matched placebo. This paper describes the secondary outcomes of a larger study investigating the effects of THC/CBD on insomnia disorder. Twenty adults [16 female; mean (SD) age, 46.1 (8.6) y] with physician-diagnosed insomnia who infrequently use cannabis completed two 24 h in-laboratory visits involving acute oral administration of combined 10 mg THC and 200 mg CBD ('THC/CBD') or placebo in a randomised, double-blind, crossover trial design. Outcome measures included 'next day' (≥9 h post-treatment) performance on cognitive and psychomotor function tasks, simulated driving performance, subjective drug effects, and mood. We found no differences in 'next day' performance on 27 out of 28 tests of cognitive and psychomotor function and simulated driving performance relative to placebo. THC/CBD produced a small decrease (-1.4%, p=.016, d=-0.6) in accuracy on the Stroop-Colour Task (easy/congruent) but not the Stroop-Word Task (hard/incongruent). THC/CBD also produced a small increase (+8.6, p=.042, d=0.3) in self-ratings of Sedated at 10 h post-treatment, but with no accompanying changes in subjective ratings of Alert or Sleepy (p's>0.05). In conclusion, we found a lack of notable 'next day' impairment to cognitive and psychomotor function and simulated driving performance following evening use of 10 mg oral THC, in combination with 200 mg CBD, in an insomnia population who infrequently use cannabis.

Insulin Delivery to the Brain via the Nasal Route: Unraveling the Potential for Alzheimer's Disease Therapy.

This comprehensive review delves into the potential of intranasal insulin delivery for managing Alzheimer's Disease (AD) while exploring the connection between AD and diabetes mellitus (DM). Both conditions share features of insulin signalling dysregulation and oxidative stress that accelerate inflammatory response. Given the physiological barriers to brain drug delivery, including the blood-brain barrier, intranasal administration emerges as a non-invasive alternative. Notably, intranasal insulin has shown neuroprotective effects, impacting Aß clearance, tau phosphorylation, and synaptic plasticity. In preclinical studies and clinical trials, intranasally administered insulin achieved rapid and extensive distribution throughout the brain, with optimal formulations exhibiting minimal systemic circulation. The detailed mechanism of insulin transport through the nose-to-brain pathway is elucidated in the review, emphasizing the role of olfactory and trigeminal nerves. Despite promising prospects, challenges in delivering protein drugs from the nasal cavity to the brain remain, including enzymes, tight junctions, mucociliary clearance, and precise drug deposition, which hinder its translation to clinical settings. The review encompasses a discussion of the strategies to enhance the intranasal delivery of therapeutic proteins, such as tight junction modulators, cell-penetrating peptides, and nano-drug carrier systems. Moreover, successful translation of nose-to-brain drug delivery necessitates a holistic understanding of drug transport mechanisms, brain anatomy, and nasal formulation optimization. To date, no intranasal insulin formulation has received regulatory approval for AD treatment. Future research should address challenges related to drug absorption, nasal deposition, and the long-term effects of intranasal insulin. In this context, the evaluation of administration devices for nose-to-brain drug delivery becomes crucial in ensuring precise drug deposition patterns and enhancing bioavailability.

Detection of Δ9 -tetrahydrocannabinol (THC) in oral fluid using two point-of-collection testing devices following oral administration of a THC and cannabidiol containing oil.

Point-of-collection testing (POCT) devices are widely used in roadside and workplace drug testing to identify recent cannabis use by measuring the presence of Δ9 -tetrahydrocannabinol (THC) in oral fluid (OF). However, the performance of POCT devices with oral medicinal cannabis products remains poorly described. In a randomised, double-blinded, crossover trial, adults with insomnia disorder (n = 20) received a single (2 mL) oral dose of oil containing 10 mg THC + 200 mg cannabidiol, or placebo, prior to sleep. Participants were tested with the Securetec DrugWipe® 5S (10 ng/mL THC cut-off) and Dräger DrugTest® 5000 (25 ng/mL THC cut-off) POCT devices at baseline (pre-treatment) and then at 0.5, 10, and 18 h post-treatment. An OF sample, taken at each time point, was also analysed using liquid chromatography-tandem mass spectrometry. Large individual variability in OF THC concentrations was observed 0.5 h post-treatment (range: 0-425 ng/mL; mean (SD) 48.7 (107.5) ng/mL). Both the Securetec DrugWipe® 5S and DrugTest® 5000 demonstrated poor sensitivity to THC at 0.5 h post-treatment (25% and 50%, respectively). At 10 and 18 h post-treatment, all participant OF THC concentrations were below screening cut-offs, and all test results were negative. These findings highlight the relatively poor sensitivity of both devices in detecting recent use of an oral medicinal cannabis product. They also suggest a low probability of obtaining a positive THC result the morning after ('one-off') use. Further research is required to establish the probability of obtaining a positive THC result with regular medicinal cannabis use.

A systematic review on adherence to continuous positive airway pressure (CPAP) treatment for obstructive sleep apnoea (OSA) in individuals with mild cognitive impairment and Alzheimer's disease dementia.

Obstructive sleep apnoea (OSA) is highly prevalent in mild cognitive impairment (MCI) and Alzheimer's disease (AD). The gold standard treatment for OSA is continuous positive airway pressure (CPAP). Long-term, well-powered efficacy trials are required to understand whether CPAP could slow cognitive decline in individuals with MCI/AD, but its tolerability in this group remains uncertain. The present review investigates CPAP adherence among individuals with OSA and MCI/AD. Electronic searches were performed on 8 databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Six independent studies and four secondary analyses included 278 unique participants (mean age = 72.1 years). In five of the retained studies, around half of participants (45% N = 85 MCI, 56% N = 22 AD) were adherent to CPAP, where ≥4 h use per night was considered adherent. Three of the retained studies also reported average CPAP use to range between 3.2 and 6.3 h/night. CPAP adherence in individuals with MCI and AD is low, albeit similar to the general elderly population. Reporting adherence in future studies as both average duration as well as using a binary cut-off would improve our understanding of the optimum CPAP use in dementia clinical trials and care.

REducing Sleep Apnoea for the PrEvention of Dementia (REShAPED): Protocol for a multi-site feasibility randomised controlled trial.

There is accumulating evidence that has linked OSA with increased risk of cognitive decline and dementia. Here we present the protocol for an Australian, multi-site randomised controlled, parallel open-label trial which will evaluate the feasibility for a full-scale trial investigating the effects of treating OSA on cognitive decline in older adults at risk of dementia within memory clinic settings. We will randomise 180 older adults to either the treatment intervention group or control group for 2 years. Inclusion criteria include: 50-85 years; mild-severe OSA (defined average ODI ≥ 10 with 3% oxygen desaturation determined by wrist oximetry over two nights); and subjective cognitive complaints or mild cognitive impairment. The treatment intervention arm aims to achieve an optimal treatment response based on reducing hypoxic burden with either CPAP, mandibular advancement splint, positional therapy, or oxygen therapy. Furthermore, participants will receive up to 8 sessions which involve motivational interviewing, collaborative goal setting, and behavioural sleep management. The control arm will not receive OSA treatment as part of this trial, however there will be no OSA treatment restrictions, and any treatment will be documented. Primary outcomes are 1) acceptability based upon willingness of participants to be randomised; 2) alleviating hypoxic burden by reducing OSA severity; 3) tolerability of the trial burden based upon collection of outcomes over the 2-year follow-up. Secondary outcomes include safety and cognitive function. Outcomes will be collected at 0, 6 and 24-months. This feasibility study aims to will provide the basis for a larger longer-term trial of dementia prevention.

Sleep Deficiency and Cardiometabolic Disease.

Epidemiologic studies have demonstrated that short sleep duration is associated with an increased risk of cardio-metabolic health outcomes including cardiovascular disease mortality, coronary heart disease, type 2 diabetes mellitus, hypertension, and metabolic syndrome. Experimental sleep restriction studies have sought to explain these findings. This review describes the main evidence of these associations and possible mechanisms explaining them. Whether sleep extension reverses these now widely acknowledged adverse health effects and the feasibility of implementing such strategies on a public health level is discussed.

Does daily energy and macronutrient intake differ between work and non-workdays in shift workers? A mixed methods study.

Shift workers are at increased risk of obesity and metabolic diseases, but their eating patterns on work and non-workdays are understudied. We aimed to examine whether energy intake and macronutrient intake of day and night shift nurses were different during work and non-workdays. We used a mixed-methods approach to study food intake of shift working nurses from two hospitals during day and night shifts. Participants completed baseline questionnaires about eating behaviour, sleep, chronotype, mood and shift work disorder. Participants then completed a 4-d food diary which included a non-workday prior to the first shift, the first and last shift (either day or night) and the following non-workday. After completion of the food diaries, we used semi-structured interviews to explore the qualitative aspects of eating behaviours. Seventy-nine shift-working nurses participated in the study. Daily energy intake was not significantly different on work and non-workdays in day or night shift workers (p > 0.05). Whilst macronutrient consumption was also not different between day and night shift workers (p > 0.05), sugar intake was higher in day compared to night shift workers (p = 0.02) on the non-workday prior to the first workday. In qualitative interviews, participants reported their eating to be different on day and night shifts as well as work and non-workdays. Eating behaviour in day and night shift workers was highly influenced by food availability, convenience, peers, and family members. Nurses qualitatively report that night and day shifts result in them eating differently despite no statistically discernible difference in energy intake.

Cannabinol (CBN; 30 and 300 mg) effects on sleep and next-day function in insomnia disorder ('CUPID' study): protocol for a randomised, double-blind, placebo-controlled, cross-over, three-arm, proof-of-concept trial.

OBJECTIVE: Insomnia is the most prevalent sleep disorder, with few effective pharmacotherapies. Anecdotal reports and recent preclinical research suggest that cannabinol (CBN), a constituent of Cannabis sativa derived from delta-9-tetrahydrocannabinol, could be an effective treatment. Despite this, the isolated effects of CBN on sleep have yet to be systematically studied in humans. METHODS: The present protocol paper describes a randomised, double-blind, placebo-controlled, single-dose, three-arm, cross-over, proof-of-concept study which investigates the effects of CBN on sleep and next-day function in 20 participants with clinician-diagnosed insomnia disorder and an Insomnia Severity Index Score ≥15. Participants receive a single fixed oral liquid dose of 30 mg CBN, 300 mg CBN and matched placebo, in random order on three treatment nights; each separated by a 2-week wash-out period. Participants undergo overnight sleep assessment using in-laboratory polysomnography and next-day neurobehavioural function tests. The primary outcome is wake after sleep onset minutes. Secondary outcomes include changes to traditional sleep staging, sleep-onset latency and absolute spectral power during non-rapid eye movement (NREM) sleep. Tertiary outcomes include changes to sleep spindles during NREM sleep, arousal indices, absolute spectral power during REM sleep and subjective sleep quality. Safety-related and exploratory outcomes include changes to next-day simulated driving performance, subjective mood and drug effects, postural sway, alertness and reaction time, overnight memory consolidation, pre and post-sleep subjective and objective sleepiness; and plasma, urinary, and salivary cannabinoid concentrations. The study will provide novel preliminary data on CBN efficacy and safety in insomnia disorder, which will inform larger clinical trials. ETHICS AND DISSEMINATION: Human Research Ethics Committee approval has been granted by Bellberry (2021-08-907). Study findings will be disseminated in a peer-reviewed journal and at academic conferences. TRIAL REGISTRATION NUMBER: NCT05344170.

Pilot Randomized, Double-Blind, Placebo-Controlled Crossover Trial Evaluating the Feasibility of an Intranasal Oxytocin in Improving Social Cognition in Individuals Living with Alzheimer's Disease.

Background: Individuals living with Alzheimer's disease (AD) demonstrate extensive deficits in social cognition. To date, no studies have investigated the feasibility of an intranasal oxytocin (INOT) treatment to improve social cognition in individuals living with AD. Objective: We conducted a pilot trial to determine recruitment feasibility, enrolment acceptability, and adherence to an INOT treatment to inform on the subsequent design of a future randomized controlled trial (RCT). We also estimated the effect sizes of potential social cognitive function outcome measures related to participants and their caregivers. Methods: Four individuals with AD were enrolled in a single-center, randomized, double-blind, placebo-controlled crossover trial involving a one-week treatment period with both INOT (72 IU twice daily) and placebo. Results: All participants reported no treatment-causative or serious adverse events following repeated INOT administration. While enrolment acceptability (100%) and INOT adherence (placebo, 95%; INOT, 98%) were excellent, feasibility of recruitment was not acceptable (i.e., n = 4/58 individuals screened met inclusion criteria). However, positive/large effects were associated with secondary outcomes of self-reported health and wellbeing, caregiver 'burden', intimacy and interpersonal-bonding, following repeated INOT administration. No positive effects were associated with participant outcomes of social cognition. Conclusion: This pilot RCT provides first evidence that INOT administration in individuals living with AD is safe and well-tolerated. Despite limitations in sample size, moderate-to-large effect size improvements were identified in participant health outcomes as well as core social cognitive functions and 'burden' as reported by a caregiver. This suggests potential broad-ranging beneficial effects of INOT which should be assessed in future RCTs.

Strategies to Assess the Effect of Continuous Positive Airway Pressure on Long-Term Clinically Important Outcomes among Patients with Symptomatic Obstructive Sleep Apnea: An Official American Thoracic Society Workshop Report.

Continuous positive airway pressure (CPAP) is the first-line treatment for obstructive sleep apnea (OSA). Although CPAP improves symptoms (e.g., daytime sleepiness), there is a lack of high-quality evidence that CPAP prevents many long-term outcomes, including cognitive impairment, myocardial infarction, and stroke. Observational studies suggest that patients with symptoms may be particularly likely to experience these preventive benefits with CPAP, but ethical and practical concerns limited the participation of such patients in prior long-term randomized trials. As a result, there is uncertainty about the full benefits of CPAP, and resolving this uncertainty is a key priority for the field. This workshop assembled clinicians, researchers, ethicists, and patients to identify strategies to understand the causal effects of CPAP on long-term clinically important outcomes among patients with symptomatic OSA. Quasi-experimental designs can provide valuable information and are less time and resource intensive than trials. Under specific conditions and assumptions, quasi-experimental studies may be able to provide causal estimates of CPAP's effectiveness from generalizable observational cohorts. However, randomized trials represent the most reliable approach to understanding the causal effects of CPAP among patients with symptoms. Randomized trials of CPAP can ethically include patients with symptomatic OSA, as long as there is outcome-specific equipoise, adequate informed consent, and a plan to maximize safety while minimizing harm (e.g., monitoring for pathologic sleepiness). Furthermore, multiple strategies exist to ensure the generalizability and practicality of future randomized trials of CPAP. These strategies include reducing the burden of trial procedures, improving patient-centeredness, and engaging historically excluded and underserved populations.

Heart rate variability during slow wave sleep is linked to functional connectivity in the central autonomic network.

Reduced heart rate variability can be an early sign of autonomic dysfunction in neurodegenerative diseases and may be related to brain dysfunction in the central autonomic network. As yet, such autonomic dysfunction has not been examined during sleep-which is an ideal physiological state to study brain-heart interaction as both the central and peripheral nervous systems behave differently compared to during wakefulness. Therefore, the primary aim of the current study was to examine whether heart rate variability during nocturnal sleep, specifically slow wave (deep) sleep, is associated with central autonomic network functional connectivity in older adults 'at-risk' of dementia. Older adults (n = 78; age range = 50-88 years; 64% female) attending a memory clinic for cognitive concerns underwent resting-state functional magnetic resonance imaging and an overnight polysomnography. From these, central autonomic network functional connectivity strength and heart rate variability data during sleep were derived, respectively. High-frequency heart rate variability was extracted to index parasympathetic activity during distinct periods of sleep, including slow wave sleep as well as secondary outcomes of non-rapid eye movement sleep, wake after sleep onset, and rapid eye movement sleep. General linear models were used to examine associations between central autonomic network functional connectivity and high-frequency heart rate variability. Analyses revealed that increased high-frequency heart rate variability during slow wave sleep was associated with stronger functional connectivity (F = 3.98, P = 0.022) in two core brain regions within the central autonomic network, the right anterior insular and posterior midcingulate cortex, as well as stronger functional connectivity (F = 6.21, P = 0.005) between broader central autonomic network brain regions-the right amygdala with three sub-nuclei of the thalamus. There were no significant associations between high-frequency heart rate variability and central autonomic network connectivity during wake after sleep onset or rapid eye movement sleep. These findings show that in older adults 'at-risk' of dementia, parasympathetic regulation during slow wave sleep is uniquely linked to differential functional connectivity within both core and broader central autonomic network brain regions. It is possible that dysfunctional brain-heart interactions manifest primarily during this specific period of sleep known for its role in memory and metabolic clearance. Further studies elucidating the pathophysiology and directionality of this relationship should be conducted to determine if heart rate variability drives neurodegeneration, or if brain degeneration within the central autonomic network promotes aberrant heart rate variability.

The relationship between midlife dyslipidemia and lifetime incidence of dementia: A systematic review and meta-analysis of cohort studies.

Introduction: We conducted a systematic review and meta-analysis to review the relationship between midlife dyslipidemia and lifetime incident dementia. Methods: The databases Medline, Embase, Scopus, Web of Science, and Cochrane were searched from inception to February 20, 2022. Longitudinal studies examining the relationship between midlife lipid levels on dementia, dementia subtypes, and/or cognitive impairment were pooled using inverse-variance weighted random-effects meta-analysis. Results: Seventeen studies (1.2 million participants) were included. Midlife hypercholesterolemia was associated with increased incidence of mild cognitive impairment (effect size [ES] = 2.01; 95% confidence interval [CI] 1.19 to 2.84; I2 = 0.0%) and all-cause dementia (ES = 1.14; 95% CI: 1.07 to 1.21; I2 = 0.0%). Each 1 mmol/L increase in low-density lipoprotein was associated with an 8% increase (ES = 1.08, 95% CI: 1.03 to 1.14; I2 = 0.3%) in incidence of all-cause dementia. Discussion: Midlife dyslipidemia is associated with an increased risk of cognitive impairment in later life.

Current Insights into the Risks of Using Melatonin as a Treatment for Sleep Disorders in Older Adults.

Exogenous melatonin is commonly used for sleep disorders in older adults, and its use is increasing over time. It appears to have modest efficacy in treating insomnia and circadian rhythm sleep-wake disorders. Melatonin is commonly perceived to be a safe alternative to other hypnotics and is available without prescription in some jurisdictions. New evidence suggests that endogenous melatonin has pleomorphic effects on multiple organ systems, many of which are poorly understood. This narrative review summarizes the current evidence regarding the safety of melatonin in older adults (defined by age over 65 years). Melatonin appears to have a favorable safety profile in this population, however there is a dearth of evidence regarding the safety of prolonged use. There are several factors which increase the risk of adverse effects of melatonin in older adults, and these should be taken into consideration when prescribing to this population.

How long does a single oral dose of cannabidiol persist in plasma? Findings from three clinical trials.

A growing number of clinical trials (CTs) are investigating the therapeutic potential of cannabidiol (CBD), a non-intoxicating phytocannabinoid found in Cannabis sativa. These CTs often use crossover experimental designs requiring 'washout' (clearance) periods. However, the length of time CBD persists in plasma (its 'window of detection') is unclear and could be significant. Indeed, the structurally related phytocannabinoid, Δ9 -tetrahydrocannabinol (THC), has a long window of detection in plasma. We investigated the extent to which CBD and its major metabolites persist in plasma. Data from three CTs that measured plasma cannabinoid concentrations ≥7 days after administering a single oral dose of CBD were pooled. The CBD doses were as follows: CT #1: 300 mg; CT #2: 200 mg (and 10 mg THC); and CT #3: 15, 300 and 1500 mg (one per treatment session). Thirty-two participants were included in the analysis, 17 of whom (from CT #3) provided repeated measures. Overall, 0% (15 mg), 60% (200 mg), 28% (300 mg) and 100% (1500 mg) of participants had detectable concentrations (i.e., >0.25 ng·ml-1 ) of CBD in plasma ≥7 days post-treatment (some, several weeks post-treatment). A zero-inflated negative binomial mixed-effects regression analysis (R2 m = 0.44; R2 c = 0.73) predicted that, on average, a 13 day washout period would reduce plasma CBD concentrations to 'zero' (i.e., <0.25 ng·ml-1 ) if a single oral dose of 300 mg was consumed. Higher doses require longer washout periods; concomitant medications may also affect clearance. In conclusion, CBD has a long window of detection in plasma. Crossover studies involving CBD should, therefore, be conducted with caution, particularly when higher doses and/or chronic dosing regimens are used.

Actigraphic and melatonin alignment in older adults with varying dementia risk.

Circadian rhythms alter with ageing and may be aetiologically linked to neurodegeneration. This study explored the association between clinical markers and 1) dim light melatonin onset (DLMO) time and 2) phase angle derived from sleep midpoint, in older adults with varying dementia risks. Participants completed 14 days of actigraphy followed by in-lab measurement of salivary melatonin, from which DLMO time and phase angle were computed. Eighty participants (age = 65.5, SD = 9.6), 44 males (55%), MMSE (28.6, SD = 1.5) were included in the analysis. Sex (t = 2.15, p = .04), sleep onset (r = 0.49, p < .001) and midpoint (r = 0.44, p < .001) also correlated with DLMO time. Multiple linear regression showed chronotype, average actigraphy-derived light exposure during the DLMO window (window 2 h prior to DLMO to 2 h post), early biological day (6-10 h post DLMO time) and late biological day (10-14 h post DLMO time) were predictive of DLMO time (adjusted R2 = 0.75). Sleep offset, depression severity, average light exposure during the early biological night and early and late biological day were shown to be predictive variables in the estimation of phase angle (adjusted R2 = 0.78). The current study highlights the potential use of clinical variables, such as actigraphy-derived light, as circadian markers in ageing which could be easily implemented into existing clinical practice and could yield potential targets focusing on chronotherapeutic interventions.

The Effect of Light Therapy on Electroencephalographic Sleep in Sleep and Circadian Rhythm Disorders: A Scoping Review.

Light therapy is used to treat sleep and circadian rhythm disorders, yet there are limited studies on whether light therapy impacts electroencephalographic (EEG) activity during sleep. Therefore, we aimed to provide an overview of research studies that examined the effects of light therapy on sleep macro- and micro-architecture in populations with sleep and circadian rhythm disorders. We searched for randomized controlled trials that used light therapy and included EEG sleep measures using MEDLINE, PubMed, CINAHL, PsycINFO and Cochrane Central Register of Controlled Trials databases. Five articles met the inclusion criteria of patients with either insomnia or delayed sleep−wake phase disorder (DSWPD). These trials reported sleep macro-architecture outcomes using EEG or polysomnography. Three insomnia trials showed no effect of the timing or intensity of light therapy on total sleep time, wake after sleep onset, sleep efficiency and sleep stage duration compared to controls. Only one insomnia trial reported significantly higher sleep efficiency after evening light therapy (>4000 lx between 21:00−23:00 h) compared with afternoon light therapy (>4000 lx between 15:00−17:00 h). In the only DSWPD trial, six multiple sleep latency tests were conducted across the day (09:00 and 19:00 h) and bright light (2500 lx) significantly lengthened sleep latency in the morning (09:00 and 11:00 h) compared to control light (300 lx). None of the five trials reported any sleep micro-architecture measures. Overall, there was limited research about the effect of light therapy on EEG sleep measures, and studies were confined to patients with insomnia and DSWPD only. More research is needed to better understand whether lighting interventions in clinical populations affect sleep macro- and micro-architecture and objective sleep timing and quality.