Background:Chronic neuropathic pain is common after spinal cord injury (SCI), yet current treatments have limited efficacy and significant side effects. Cannabidiol (CBD), a non-intoxicating component of cannabis, has demonstrated efficacy in preclinical neuropathic pain models. Here, we investigated the effect of high-dose (up to 800 mg/day) CBD on chronic neuropathic pain in SCI. Methods:This randomised, double-blinded, placebo-controlled, crossover clinical trial was conducted at Neuroscience Research Australia. Adults with SCI and neuropathic pain (≥three months duration) were recruited. Participants were randomised to one of two treatment orders by an unblinded investigator who had no participant contact. Participants and all other investigators were blinded. Participants consumed oral CBD and placebo over two six-week treatment periods separated by a four-week washout. Treatment was titrated up to 800 mg/day of CBD over two-weeks. The primary outcome was change in self-reported pain intensity on a zero (no pain) to ten (worst pain imaginable) Visual Analogue Scale. Statistical comparisons included CBD versus placebo treatment, and pre-treatment (inactive phase) versus on-treatment (active phase). Outcomes were analysed by modified intention-to-treat. The study is registered with anzctr.org.au, ACTRN12622000634774 (not recruiting). Findings:Forty participants were randomised (August 1, 2022 to December 16, 2024) and 38 included in the primary analysis (n = 6 female). A significant treatment by phase interaction effect (p < 0.001) was observed on self-reported pain. Pairwise comparison showed lower pain intensity during the active phase with CBD (mean ± SEM: 3.82 ± 0.23) compared to placebo (mean difference = -0.54, SEM = 0.15, p < 0.001), with a 95% confidence interval for the difference of -0.88 to -0.21. Treatments did not differ during the inactive phase (mean difference <0.01, SEM = 0.17, p = 1.00, 95% CI = -0.38 to 0.38). Adverse events, nearly all minor, were reported by 68.4% of participants during CBD (n = 67 events), and by 52.6% during placebo (n = 51 events) treatment. Interpretation:In this placebo-controlled trial, CBD significantly reduced the self-reported intensity of neuropathic pain and was generally well-tolerated. While modest in magnitude, the observed effect supports further research into high-dose CBD for chronic neuropathic pain. Funding:Spinal Cord Injury Research Grant NSW Health and the Lambert Initiative for Cannabinoid Therapeutics at The University of Sydney.

Aerobic exercise can reduce withdrawal symptoms from tobacco and other drugs but its potential to alleviate cannabis withdrawal remains unexplored. This study investigated whether aerobic exercise can reduce the severity of cannabis withdrawal. Forty-six adults were randomised to (i) 35 min of aerobic cycling exercise (n=24), or (ii) stretching (n=22) each day for seven days. Withdrawal, cravings, exertion, free-fatty acids, triglycerides, and cannabinoids were measured during sessions. We hypothesised that exercise would cause release of THC from fat stores and reduce withdrawal in this way. Self-reported withdrawal and plasma cannabinoids decreased across the inpatient stay, however there were no significant differences between the cycling and stretching groups in withdrawal symptoms, cannabis craving, or plasma cannabinoids, despite significantly greater objective and perceived exertion in the cycling group. Exercise did not increase plasma cannabinoid concentrations despite a slight increase in free-fatty acid and triglycerides. Cannabis use was greatly reduced post-trial, with a third of participants remaining abstinent throughout the 28-day post-treatment period. The absence of between-group differences in withdrawal prevents us from concluding that aerobic exercise confers benefits for individuals undergoing inpatient cannabis withdrawal. Mild stretching exercises are easily integrated into clinical services and self-guided withdrawal attempts and may have beneficial effects. Trial Registration: Australian New Zealand Clinical Trials Registry (ACTRN12615000211561) https://www.anzctr.org.au.

Urine testing is used in a variety of contexts to identify cannabis use. Most tests target 11-nor-9-carboxy-Δ⁹-tetrahydrocannabinol (11-COOH-THC), the terminal metabolite of Δ⁹-tetrahydrocannabinol (THC), the principal intoxicant in cannabis. Different authorities use different threshold concentrations to define a positive test. This systematic review synthesised the urinary THC and THC-metabolite concentrations reported in prior studies involving administration of cannabis/cannabis-based products (acute and repeated dosing) and users of such products (during use and extended abstinence). The overall objectives were to: (1) clarify how different use patterns affect these concentrations; and (2) contextualise the thresholds applied in key contexts - specifically, workplaces (and workplace-aligned contexts, e.g., criminal justice) and competitive sport. Ninety-two eligible studies were identified and included. Typical workplace threshold (15 ng/mL total 11-COOH-THC): Low single doses (i.e., 1.0-5.0 mg) and very low repeated doses (i.e., <1.0 mg/day) of THC were sometimes sufficient to exceed the workplace threshold, particularly with oral ingestion. Weekly to daily cannabis users could remain above this threshold for weeks following cessation. World Anti-Doping Agency (WADA) Decision Limit (180 ng/mL total 11-COOH-THC): Low-to-moderate oral doses (i.e., 10 mg) and moderate inhaled doses (i.e., 15-20 mg) of THC were sometimes sufficient to exceed the WADA Decision Limit, as was weekly cannabis use. Weekly to daily cannabis users often fell below this threshold within a week of cessation, although heavy users took longer. This synthesis may assist policymakers in selecting appropriate urine-testing thresholds and in educating individuals about the risks of testing positive following different patterns of cannabis use.

Insomnia disorder is harmful and requires novel treatments. Cannabinol, an oxidative by-product of Δ9-tetrahydrocannabinol, is claimed to be a hypnotic, but its effects on objective sleep and insomnia remain unknown. This randomized, double-blind, placebo-controlled, three-arm, single-night crossover trial evaluated the acute efficacy and safety of cannabinol for insomnia disorder. Twenty adults (aged 25-65) with physician-diagnosed insomnia disorder (meeting DSM-5 and ICSD-3 criteria; Insomnia Severity Index ≥ 15) were enrolled at the Woolcock Institute of Medical Research (Sydney, Australia) between August 2022 and September 2023. Participants received a single 2 mL oral dose of 30 mg (1.5%) or 300 mg (15%) cannabinol, or matched placebo (2-week washout). All participants (17 female and 3 males; mean ± SD age 42 ± 13 years) completed the protocol and were statistically analysed. The primary outcome was wake after sleep onset (WASO) minutes, measured by overnight polysomnography. Cannabinol did not significantly change WASO (300 mg: -6.3 min [95% CI: -18.2, +5.5], p = 0.29, dz = -0.22; 30 mg: -4.0 min [-15.9, +7.9], p = 0.50, dz = 0.11). However, 300 mg cannabinol increased non-rapid eye movement-2 sleep (p = 0.03, dz = 0.54), subjective sleep quality (p = 0.005, dz = 0.56); and reduced sleep onset latency (p = 0.004, dz = -0.74) and electroencephalographic arousal indices (p = 0.02, dz = -0.65). There were 247 mild-to-moderate adverse events across arms. Larger, longer trials are warranted. ClinicalTrials.gov Identifier: NCT05344170.

Alcohol remains one of the leading contributors to road crashes worldwide. It can also serve as a benchmark for interpreting the impairing effects of other substances. Understanding how alcohol influences different aspects of driving behaviour is therefore important. This study investigated the effects of acute alcohol consumption on driving performance, oculomotor behaviour and altruistic driving decisions to calibrate an integrated, multi-measure simulated driving scenario for use as an impairment benchmarking tool. Thirty-seven participants completed a randomised, double-blind, placebo-controlled, crossover trial involving target blood alcohol concentrations (BACs) of 0.00% (placebo), ∼0.05%, and ∼ 0.08%, followed by simulated driving and cognitive testing. Alcohol impaired simulated driving performance: Lateral vehicle control declined at both 0.05% and 0.08% BAC, while effects on longitudinal control (e.g., speed, headway distance) were more apparent at 0.08% BAC. Alcohol also altered oculomotor behaviour in a non–dose-dependent manner, with blink duration increasing more consistently at 0.05% than at 0.08% BAC, and horizontal spread of gaze narrowing only under higher task demands. Altruistic driving behaviour did not differ significantly between treatments, although participants tended to allow fewer merging vehicles at the higher BAC. This research demonstrates the differing sensitivities of behavioural and oculomotor measures to alcohol-induced impairment and provides context for interpreting the magnitude of impairment produced by other factors (e.g., other substances, fatigue, distraction). This work can help guide evidence-based policy and inform assessments of relative driving risk.

INTRODUCTION:In January 2020, the government of the Australian Capital Territory (ACT) decriminalised the possession and cultivation of cannabis for personal use. This study explored the driving-related attitudes, beliefs and behaviours of ACT residents who are legally cultivating and consuming cannabis. METHODS:A two-part cross-sectional study was conducted. Part-1: Cannabis users residing in the ACT were invited to complete an online survey. Part-2: Survey respondents who reported 'currently growing' cannabis were invited to submit a sample of their home-grown cannabis for phytocannabinoid analysis. Data from Parts 1 and 2 were used to estimate participants' usual Δ9-tetrahydrocannabinol (THC) intakes. RESULTS:N = 385 cannabis users completed all or part of the online survey and N = 52 submitted cannabis samples for phytocannabinoid analysis. Most participants (N = 224/330; 67.9%) reported waiting ≥7 h following cannabis use before driving. However, 21.5% (N = 71/330) reported waiting ≤3 h. These individuals had the highest cannabis and THC intakes of the sample (where known). Further analyses revealed that individuals who expressed less concern about roadside drug testing and the effects of non-medicinal and medicinal cannabis on driving, and who used cannabis more frequently, in larger amounts, and exclusively for non-medicinal purposes were more likely to report shorter 'wait times'. DISCUSSION AND CONCLUSION:A small proportion of cannabis users in the ACT appear to be driving shortly (i.e., ≤3 h) after consuming considerable quantities of cannabis and THC. This behaviour puts them at risk of driving while impaired and incurring legal sanctions. Interventions alerting these individuals to these possible risks are, therefore, warranted.

Cannabinoids, particularly Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have gained popularity as alternative sleep aids; however, their effects on sleep architecture and next-day function remain poorly understood. Here, in a pilot trial, we examined the effects of a single oral dose containing 10 mg THC and 200 mg CBD (THC/CBD) on objective sleep outcomes and next-day alertness using 256-channel high-density EEG in 20 patients with DSM-5 diagnosed insomnia disorder (16 female; mean (SD) age, 46.1 (8.6) years). We showed that THC/CBD decreased total sleep time (-24.5 min, p = 0.05, d = -0.5) with no change in wake after sleep onset (+10.7 min, p > 0.05) compared to placebo. THC/CBD also significantly decreased time spent in REM sleep (-33.9 min, p < 0.001, d = -1.5) and increased latency to REM sleep (+65.6 min, p = 0.008, d = 0.7). High-density EEG analysis revealed regional decreases in gamma activity during N2 sleep, and in delta activity during N3 sleep, and a regional increase in beta and alpha activity during REM sleep. While there was no observed change in next-day objective alertness, a small but significant increase in self-reported sleepiness was noted with THC/CBD (+0.42 points, p = 0.02, d = 0.22). No changes in subjective sleep quality, cognitive performance, or simulated driving performance were observed. These findings suggest that a single dose of cannabinoids, particularly THC, may acutely influence sleep, primarily by suppressing REM sleep, without noticeable next-day impairment (≥ 9 h post-treatment). Australian New Zealand Clinical Trial Registry (ACTRN12619000714189) https://www.anzctr.org.au/.

BACKGROUND:Cannabidiol (CBD), a non-intoxicating phytocannabinoid, is used by athletes to enhance recovery and manage other conditions (e.g., poor sleep, anxiety). Although CBD is not prohibited by the World Anti-Doping Agency (WADA), other cannabinoids found in "broad-spectrum" CBD products (e.g., cannabigerol (CBG), cannabidivarin (CBDV)), remain prohibited. OBJECTIVES:This study aimed to determine whether 10-wk use of a broad-spectrum CBD product (150 mg·day -1 (containing trace concentrations of CBG)) could lead to detectable concentrations of prohibited cannabinoids in urine and plasma. The influence of moderate-intensity exercise was also assessed. METHODS:Thirty-six healthy individuals (47% male) self-administered either a broad-spectrum CBD product ( n = 31, CBD) or a visually identical placebo ( n = 5, PLA) for 10 wk. After 10 wk, participants completed a fasted, 90-min bout of moderate-intensity exercise (55% V̇O 2peak ). Blood and urine samples were collected at baseline (presupplementation) and pre- and postexercise. RESULTS:No cannabinoids or metabolites were detected at baseline in either the PLA or CBD group. Following 10 wk of supplementation, urinary concentrations of CBD and its metabolites (6-OH-CBD, 7-COOH-CBD, 7-OH-CBD) were present. CBG and CBDV were also detected in 42% and 68% of preexercise samples, respectively. Urinary concentrations of 6-OH-CBD ( P = 0.006), 7-OH-CBD ( P = 0.009), CBD ( P = 0.043), CBG ( P = 0.0023), and CBDV ( P = 0.033) also increased from pre- to postexercise. CBG and CBDV were detected in 74% and 84% of postexercise samples, respectively. Concentrations of ∆ 9 -THC or its metabolites (11-OH-THC, 11-COOH-THC) were not present at any timepoint. CONCLUSIONS:Daily use of a broad-spectrum CBD supplement resulted in detectable urinary concentrations of WADA-prohibited cannabinoids in urine. Exercise appeared to increase concentrations of these cannabinoids. Therefore, athletes should avoid consuming broad-spectrum CBD products, given the potential associated anti-doping risks.

The Australian Capital Territory (ACT), a region that includes Australia’s capital, Canberra, decriminalised small-scale cannabis cultivation and possession in January 2020. Here, we examined cannabis use and cultivation behaviours, experiences and attitudes of current and past small-scale ACT cannabis cultivators. ACT residents (n = 311) who currently cultivate or have previously cultivated cannabis completed a cross-sectional online survey (‘CAN-ACT’) and provided home-grown cannabis for phytocannabinoid analysis (optional). Reasons for cultivation included a preference for home-grown cannabis to self-supply, enjoyment of the process and avoiding criminal networks. Cannabis intake was a median of 1 gram on a typical day used and the number of plants grown per year was a median of 4. Various cultivation challenges were identified, most commonly mould, nutrient deficiency and spider mites. Cannabis samples (n = 71) generally exhibited moderate THC content (mean 8.99 ± SEM 0.51% [w/w]) and low CBD content (< 0.1%). Few samples exceeded contaminant guidelines for heavy metals or pesticides. Respondents identified various grey areas in current legislation that might lead to inadvertent criminal activity, and many (52%) remained anxious about arrest. In general, recent legislative changes appear to support community needs. Options for further legislative refinement are discussed.

Head impacts, particularly, non-concussive impacts, are common in sport. Yet, their effects on the brain remain poorly understood. Here, we investigated the acute effects of non-concussive impacts on brain microstructure, chemistry, and function using magnetic resonance imaging (MRI) and other techniques. Fifteen healthy male soccer players participated in a randomised, controlled, crossover pilot trial. The intervention was a non-concussive soccer heading task (‘Heading’) and the control was an equivalent ‘Kicking’ task. Participants underwent MRI scans 45 min post-task which took 60 min to complete. Blood was also sampled, and cognitive function assessed, pre-, post-, 2.5 h post-, and 24 h post-task. Brain chemistry: Heading increased total N-acetylaspartate (p = 0.012; g = 0.66) and total creatine (p = 0.010; g = 0.77) levels in the primary motor cortex (but not the dorsolateral prefrontal cortex) as assessed via proton magnetic resonance spectroscopy. Glutamate-glutamine, myoinositol, and total choline levels were not significantly altered in either region. Brain structure: Heading had no significant effects on diffusion weighted imaging metrics. However, two blood biomarkers expressed in brain microstructures, glial fibrillary acidic protein and neurofilament light, were elevated 24 h (p = 0.014; g = 0.64) and 7-days (p = 0.046; g = 1.19) post-Heading (vs. Kicking), respectively. Brain Function: Heading decreased tissue conductivity in 11 clusters located in the white matter of the frontal, occipital, temporal and parietal lobes, and cerebellum (p’s < 0.001) as assessed via electrical properties tomography. However, no significant differences were identified in: (1) connectivity within major brain networks as assessed via resting-state functional MRI; (2) cerebral blood flow as assessed via pseudo continuous arterial spin labelling; (3) activity within electroencephalography frequencies (infra-slow [0.03–0.06 Hz], theta [4–8 Hz], alpha [9–12 Hz], or beta [13–25 Hz]); or (4) cognitive (memory) function. This study identified chemical, microstructural and functional brain alterations in response to an acute non-concussive soccer heading task. These alterations appear to be subtle, with some only detected in specific regions, and no corresponding cognitive deficits observed. Nevertheless, our findings suggest that individuals should exercise caution when performing repeated non-concussive head impacts in sport. Trial registration ACTRN12621001355864. Date of registration: 7/10/2021. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382590 isReview=true .

Athletes report using cannabidiol (CBD), a non-intoxicating constituent of Cannabis sativa L., to enhance post-exercise recovery and manage other health conditions (e.g., poor sleep, anxiety, concussion). However, whether CBD influences performance-related outcomes remains unclear. This study investigated the acute effects of a low, nutraceutical (50 mg) and moderate, therapeutic (300 mg) dose of CBD on physiological and subjective responses to endurance exercise in trained runners. A randomised double-blind, placebo-controlled, crossover clinical trial was conducted at the University of Sydney between 24th October 2022 and 4th March 2024. Twenty-five participants (16 male; V̇ O2max = 53.1 ± 7.5 mL·min kg−1) received either 0 (placebo), 50 or 300 mg CBD 1.5 h prior to completing a 60-min, submaximal intensity ( 70 V̇ O2max) treadmill run (RUN 1), followed by an incremental run to volitional exhaustion (RUN 2). Neither dose of CBD altered subjective responses (i.e., affective valence, enjoyment, perceived exertion, pain) during RUN 1, nor enjoyment, mood or anxiety following RUN 1 and 2 (p’s > 0.05). CBD also had a limited effect on exercise physiology and performance, with heart rate, exercise efficiency (i.e., V̇ O2), V̇ O2peak and time to exhaustion (TTE) unchanged relative to placebo (p’s > 0.05). However, 300 mg CBD decreased the respiratory exchange ratio during RUN 1 (p = 0.030) and 50 mg CBD increased blood glucose upon cessation of RUN 2 (p = 0.003), compared to placebo. There was no effect of either dose on plasma concentrations of muscle damage markers, creatine and myoglobin (p’s > 0.05), but a Treatment x Time x Sex interaction was identified for the gastrointestinal barrier function marker, lipopolysaccharide, with post hoc analyses revealing higher concentrations in females Post RUN 2 on 50 mg (p = 0.032), but not 300mg CBD (p = 1.000), compared to placebo. CBD (50 mg, 300 mg; acute) does not appear to alter the subjective experience of submaximal intensity exercise, impact endurance performance (i.e., TTE) or have compelling effects on physiological responses to exercise. Use of CBD by athletes is, therefore, unlikely to be ergolytic or ergogenic at low to moderate doses. The trial was approved by the Sydney Local Health District’s Human Research Ethics Committee (2021/ ETH11945; X21-0392) and registered prospectively with the Australia and New Zealand Clinical Trials Registry (ACTRN12622000717752).

Δ9-tetrahydrocannabinol (THC), the principal intoxicant in cannabis, is a highly lipophilic substance that is readily stored in fat. Preclinical research suggests that fat-stored THC can be released into circulation under lipolytic conditions, such as stress. However, compelling evidence of this phenomenon is lacking in humans. Here, we investigated the effects of acute stress on blood (plasma) THC (and 11-COOH-THC) concentrations as well as indices of intoxication (e.g., cognitive function, subjective drug effects) in ‘regular’ (i.e., > 3 days/week) cannabis users. Fifteen volunteers (n = 9 female; cannabis use: 5.0 ± 1.5 days/week) participated in a single-arm (i.e., pre-/post-intervention) trial. The intervention (stressor) was cold water immersion (CWI); specifically, 10 min at 10 °C. Plasma cannabinoid concentrations, cognitive function and subjective drug effects were measured pre-, shortly post- and 2 h post-intervention. Measures of stress (e.g., heart rate [HR], blood pressure [BP], subjective ratings) and lipolysis (i.e., plasma free fatty acid [FFA] and glycerol concentrations) were also obtained. CWI produced a small but significant stress response, characterised by increased HR and systolic BP and decreased subjective “calmness”. It also increased plasma FFA and glycerol concentrations, albeit modestly. However, neither plasma THC nor 11-COOH-THC concentrations increased from pre- to post-intervention. Cognitive function also remained unchanged, while subjective drug effects were negligible. Stress induced via brief CWI does not appear to increase blood cannabinoid concentrations or induce intoxication in moderate cannabis users.

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.

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.

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

Background Head impacts, particularly, non-concussive impacts, are common in sport. Yet, their effects on the brain are poorly understood. Here, we investigated the acute effects of non-concussive impacts on brain microstructure, chemistry, and function using magnetic resonance imaging (MRI) and other techniques. Results Fifteen healthy male soccer players completed this randomised, controlled, crossover trial. Participants completed a soccer heading task (‘Heading’; the Intervention) and an equivalent ‘Kicking’ task (the Control); followed by a series of MRI sequences between ~ 60–120 minutes post-tasks. Blood was also sampled, and cognitive function assessed, pre-, post-, 2.5 hours post-, and 24 hours post-tasks. Brain chemistry: Heading increased total N-acetylaspartate (p = 0.012) and total creatine (p = 0.010) levels in the primary motor cortex (but not the dorsolateral prefrontal cortex) as assessed via proton magnetic resonance spectroscopy. Glutamate-glutamine, myoinositol, and total choline levels were not altered in either region. Brain structure: Heading had no effect on diffusion weighted imaging metrics. However, two blood biomarkers expressed in brain microstructures, glial fibrillary acidic protein and neurofilament light, were elevated 24 hours (p = 0.014) and ~ 7-days (p = 0.046) post-Heading (vs. Kicking), respectively. Brain function: Heading decreased tissue conductivity in five brain regions (p’s < 0.001) as assessed via electrical properties tomography. However, no differences were identified in: (1) connectivity within major brain networks as assessed via resting-state functional MRI; (2) cerebral blood flow as assessed via pseudo continuous arterial spin labelling; (3) electroencephalography frequencies; or (4) cognitive (memory) function. Conclusions This study identified chemical, microstructural and functional brain alterations in response to an acute non-concussive soccer heading task. These alterations appear to be subtle, with some only detected in specific regions, and no corresponding functional deficits (e.g., cognitive, adverse symptoms) observed. Nevertheless, our findings emphasise the importance of exercising caution when performing repeated non-concussive head impacts in sport. Trial registration ACTRN12621001355864. Date of registration 7/10/2021. URL https//www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382590&isReview=true

Abstract Background Exercise is known to improve health. However, it can be unpleasant, often inducing negative feelings, or ‘affect’. Cannabidiol (CBD), a non-intoxicating constituent of the cannabis plant, has been reported to enhance the subjective experience of exercise; specifically, in trained individuals performing fixed-intensity endurance activity. Here, we investigated the effects of CBD on subjective responses to exercise under more ecologically valid conditions; namely, in recreationally active individuals performing self-paced endurance activity. Methods A randomised, double-blind, placebo-controlled, crossover trial was conducted at Griffith University between July 17 and August 28, 2023. Griffith University students studying sports nutrition were invited to take part, with eligible volunteers ≥ 18 years of age and able to perform endurance exercise. Participants ingested placebo or 150 mg CBD in two soft-gel capsules 90 min before completing a self-paced 25-lap (10 km) run around an outdoor athletics track (400 m, synthetic). The primary outcomes were affective valence during exercise, assessed on completion of laps 6, 12, 18 and 24 using the ‘Feelings Scale’, and positive and negative affect, assessed at baseline, pre-run and post-run using the ‘Positive and Negative Affect Schedule’. Exercise enjoyment, motivation and self-efficacy, the core features of the ‘runner’s high’ (i.e., euphoria, pain, anxiety, sedation), perceived exertion and run time were also assessed. Results Fifty-two participants were randomised and 51 were included in the final sample (n = 22 female; 22 [21–25] years). Exercise induced negative affect (i.e., at the time of undertaking) and increased pain. CBD did not counteract either response. In fact, CBD had no significant effects on any of the outcomes measured. In contrast, exercise, once completed, increased positive affect, and decreased negative affect and anxiety. Conclusions CBD (150 mg, oral) does not appear to enhance the subjective experience of self-paced endurance exercise in recreationally active individuals. Nor, however, does it appear to compromise it. These findings suggest that CBD use is safe under exercise conditions and unlikely to impede physical activity participation. Our study also reaffirms the powerful mood-enhancing effects of exercise. Trial Registration Registered with the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) on May 31, 2023 (Trial ID: ACTRN12623000593639).

IntroductionThe non-intoxicating plant-derived cannabinoid, cannabidiol (CBD), has demonstrated therapeutic potential in a number of clinical conditions. Most successful clinical trials have used relatively high (≥300 mg) oral doses of CBD. Relatively few studies have investigated the efficacy of lower (<300 mg) oral doses, typical of those available in over-the-counter CBD products.MethodsWe present a protocol for a randomised, double-blind, placebo-controlled, parallel-group clinical trial investigating the effects of a low oral dose (150 mg) of CBD on acute psychosocial stress, situational anxiety, motion sickness and cybersickness in healthy individuals. Participants (n=74) will receive 150 mg of CBD or a matched placebo 90 min before completing three virtual reality (VR) challenges (tasks) designed to induce transient stress and motion sickness: (a) a 15 min ‘Public Speaking’ task; (b) a 5 min ‘Walk the Plank’ task (above a sheer drop); and (c) a 5 min ‘Rollercoaster Ride’ task. The primary outcomes will be self-reported stress and nausea measured on 100 mm Visual Analogue Scales. Secondary outcomes will include salivary cortisol concentrations, skin conductance, heart rate and vomiting episodes (if any). Statistical analyses will test the hypothesis that CBD reduces nausea and attenuates subjective, endocrine and physiological responses to stress compared with placebo. This study will indicate whether low-dose oral CBD has positive effects in reducing acute psychosocial stress, situational anxiety, motion sickness and cybersickness.Ethics and disseminationThe University of Sydney Human Research Ethics Committee has granted approval (2023/307, version 1.6, 16 February 2024). Study findings will be disseminated in a peer-reviewed journal and at academic conferences.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN12623000872639).

PURPOSE: To examine the acute effects of soccer heading on brain chemistry and function using advanced neuroimaging techniques. METHODS: Fourteen male soccer players (age: 26 ± 5 years [Mean ± SD]) completed two trials at Neuroscience Research Australia. On one occasion, they performed a ‘Heading’ task (Head) involving 20 headers in 20 mins (launched at 35 km·h-1 over 12 m) and on the other, an equivalent ‘Kicking’ task (Control). The trials were separated by ≥7 days and the order randomized. Neuroimaging scans were obtained 45mins post-task. Magnetic resonance spectroscopy was used to measure brain chemistry (glutamate/glutamine [Glx], N-acetylaspartate, creatine, choline, and inositol; i.u.) in the dorsolateral prefrontal (dlPFC) and motor cortices (M1). Brain function was assessed using: 1) arterial spin labelling measuring cerebral blood flow (CBF; mL/min/100 g), 2) electroencephalography (acquired 2 hrs post-task) measuring alpha (α), beta, delta, and infra-slow frequency power (μV2), and 3) cognitive function using the spatial working memory (SWM) task for errors and strategy, and paired associates learning task for errors at pre-, 0 hrs post-, 2 hrs post-, and 24 hrs post-task. Results presented as Mean ± SD. RESULTS:Brain Chemistry: The Glx signal was higher on the Head trial in the M1 (Head: 2.03 ± 0.21; Control: 1.90 ± 0.20, p = 0.03), but not the dlPFC (Head: 2.34 ± 0.28; Control: 2.33 ± 0.33, p = 0.87). There were no differences in any other metabolite between trials for either brain region (all p’s > 0.05). Brain Function: There were no changes in global CBF (Head: 18.8 ± 3.8; Control: 18.9 ± 2.9, p = 0.83), or individual voxels when using cluster analyses (all p’s > 0.05). There were no changes in global α frequency power (Head: -5.63 ± 0.74; Control: -5.39 ± 0.97, p = 0.15), nor in other frequencies (all p’s > 0.05). No Intervention x Time interaction was observed on SWM errors (Head: pre: 1.46 ± 4.12, 0 hrs post: 1.57 ± 4.78, 2 hrs post: 0.50 ± 1.40, 24 hrs post: 0.86 ± 2.21; Control: pre: 1.21 ± 2.99, 0 hrs post: 0.93 ± 1.69, 2 hrs post: 0.29 ± 0.61, 24 hrs post: 0.08 ± 0.28, p = 0.65), or any other cognitive function outcome. CONCLUSION: Our results suggest that this soccer heading task led to an acute brain chemical but not functional change, from the techniques utilized in this study. Funder: Lambert Initiative for Cannabinoid Therapeutics

Abstract Introduction There is a clear need for novel interventions for insomnia disorder. Growing evidence suggests a role of the endogenous cannabinoid system in regulating circadian sleep-wake cycles, highlighting a potential avenue for novel therapeutics. Cannabinol (CBN), a trace cannabinoid formed through oxidation of delta-9-tetrahydrocannbinol (THC), is hypothesised to impact sleep. Despite anecdotal and ­preclinical evidence, the effects of CBN isolate on sleep have never examined through well-designed clinical trial procedures. Methods This randomised, double-blind, placebo-controlled, three-arm, crossover, single-site, pilot study will investigate the acute effects of oral dose CBN at 30 and 300 mg in twenty patients with clinician-diagnosed insomnia disorder (and Insomnia Severity Index [ISI] Score ≥15). Across three treatment sessions, each separated by two-weeks washout, participants will receive two doses of CBN and matched placebo, at random. Participants will undergo overnight sleep assessment using in-laboratory polysomnography and next-day neurobehavioral function tests. The primary outcomes are CBN (30 and 300 mg) effects on sleep continuity (wake after sleep onset minutes), compared to placebo, measured using polysomnography. Results Secondary outcomes include changes to sleep micro-architecture, traditional sleep staging, and absolute spectral power during non-rapid eye movement sleep. Various other subjective and objective safety measures will be obtained. Conclusion This study will provide novel preliminary data on the effects of CBN on sleep and next-day function in adults living with insomnia disorder which will inform the design of larger clinical trials. Support (if any)