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Validity of the VR cue exposure scene | AD | We recruited 30 AD patients to undergo cue exposure through this VR cue exposure scene. The results showed that all AD patients reported that the scene was realistic, and the scene effectively induced the cue reactivity of AD patients. | PMC10726483 | |
Participants | PMC10726483 | |||
Sample size | alcohol-dependent | The estimated sample size was calculated using the G*Power 3.1.9.7 sample size calculator. Sample size calculation was based on Wilcoxon-Mann-Whitney test (two groups), whereby the type I error was 0.05, the power was 0.8, the allocation ratio was 1:1, and the effect size was set as 0.84, which was cited from a randomized trial that compared the efficacy of virtual reality therapy and general treatment in alleviating alcohol craving in alcohol-dependent patients [ | PMC10726483 | |
Recruit participants | cardiovascular and cerebrovascular diseases, psychiatric, alcohol dependence, epilepsy | MAY, ALCOHOL WITHDRAWAL, EPILEPSY | From May 2022 to October 2022, 57 male patients with alcohol dependence who were hospitalized in the Fifth Department of Psychiatry, Second Affiliated Hospital of Xinxiang Medical University were recruited and divided into the study group (n = 29) and the control group (n = 28) according to a random number table.Inclusion criteria: ① meet the diagnostic criteria for alcohol dependence in ICD-10; ② aged 18 ~ 50 years, Han nationality, primary school education or higher, right-handed; ③ acute withdrawal treatment ≥ 7 days, Clinical Alcohol Withdrawal Symptoms Rating Scale (CIWA-Ar) < 8; ④ normal vision or corrected vision; ⑤ normal hearing or corrected hearing; ⑥ no history of abuse of other psychoactive substances (except tobacco). Exclusion criteria: ① serious physical illnesses such as cardiovascular and cerebrovascular diseases; ② serious neurological illnesses such as epilepsy; ③ combined with other psychiatric illnesses; ④ unable to adapt to the virtual reality environment. Dropout criteria: ① subjects were unwilling to continue treatment and withdrew on their own; ② unable to complete treatment as prescribed for various reasons; ③ had missing data due to instrument failure.The study protocol was reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Xinxiang Medical University, and all study subjects were fully informed of the purpose of the study and signed the informed consent form. | PMC10726483 |
Research technique | PMC10726483 | |||
Measurement tools | A questionnaire was developed to collect general demographic information about the patient such as age, ethnicity, years of education, employment status, etc. as well as information on alcohol use including age of first drink, cumulative duration of use, duration of dependence, type of alcohol consumed, and dose of alcohol consumed etc.Visual analogue scale (VAS) [Physiological indicators were collected by multiparameter biofeedback (Infiniti3000A, Nanjing Vishee Medical Technology Co., Ltd.), including heart rate, skin conductance and respiratory signals before and during VR cue exposure. | PMC10726483 | ||
Procedure | ’ alcohol, alcohol-dependent, AD, alcohol dependence | ELECTROLYTE IMBALANCES | VR cue exposure procedure: The researcher first briefly introduced the experimental procedure to the patients, conducted a simple training for the patients, instructed the patients on the operation method of the VR handle, and instructed the patients to choose a comfortable position to sit on the chair. Alcohol was used to clean the patients’ skin. After the alcohol on the skin surface had evaporated, the BVP sensor was attached to the patients’ middle finger, the SC sensor was attached to the patients’ index finger and ring finger, and the respiratory sensor was attached to the patients’ chest or abdomen. After starting the procedure, the connection status was checked, and the patients were instructed to relax. If the connection status was good, heart rate, skin conductance and respiratory signals were collected for 2 min as baseline physiological index data, and then the patients were asked about alcohol craving by VAS as a baseline subjective assessment. The patients were then given a VR device and given enough time to adapt to the VR environment. After they had adapted, they began to watch the VR cue exposure video. At the same time, olfactory stimulation was provided by real alcohol. During the exposure procedure, a multiparameter biofeedback device was used to collect the patients’ heart rate, skin conductance and respiration, and then the patients’ alcohol craving was asked again by VAS.VR cue exposure was carried out in the hospital ward, and AD patients were permitted to stop the procedure at any time if they felt uncomfortable. After the conclusion of the VR cue exposure, participants were observed for about 10 min to ensure that they did not experience any significant discomfort. The sessions were conducted between 6:00 pm and 8:00 pm, as shown in Fig.
Flow chart of VR cue exposureTesting procedure: After completion of the acute withdrawal treatment, the alcohol-dependent patients were exposed to the above VR cue exposure (assessment), and the changes in VAS, heart rate, skin conductance, and respiration before and after exposure were recorded. Patients were randomly divided into the study group and the control group using the random number table method. The control group only received conventional clinical treatment for alcohol dependence, that is, benzodiazepines (such as oxazepam tablets) at the start of admission to control the acute withdrawal reaction, as well as high doses of group B and C vitamins, to correct water and electrolyte imbalances, and to improve liver function, and other symptomatic supportive treatments were given. The study group received conventional clinical treatment with the addition of VR cue exposure (treatment), 3 sessions per week (1 day apart) for 8 min. After treatment, a VR cue exposure (assessment) was conducted, and the changes in VAS, heart rate, skin conductance, and respiration before and after the exposure were recorded, as shown in Fig.
Flow chart of test procedure | PMC10726483 |
Statistical method | SPSS22.0 statistical software was used for data analysis, the Shapiro‒Wilk test was used for the normality test, and the measurement data conforming to the normal distribution were expressed as the mean ± standard deviation ( | PMC10726483 | ||
Results | PMC10726483 | |||
General information | A total of 44 patients completed the study, 23 patients in the study group and 21 patients in the control group. 6 patients in the study group were dropped, 4 patients were automatically dropped during the study and 2 patients had missing data due to instrument failure. 7 patients in the control group were dropped, 4 patients were automatically dropped during the study and 3 patients had missing data due to instrument failure.The mean age of the study group was 34.30 ± 5.23 years, the years of education was 9.00 (9.00, 12.00) years, the cumulative drinking time was 16.00 ± 5.74 years, the addiction time was 3.00 (2.00, 5.00) years, and the daily drinking amount was 210.00 (130.00, 260.00) g/day. The mean age of the control group was 35.90 ± 4.99 years, the years of education was 9.00 (9.00, 12.00) years, the cumulative drinking time was 16.24 ± 6.55 years, the addiction time was 3.00 (2.00, 5.50) years, and the daily drinking amount was 168.00 (104.00, 208.00) g/day. There were no significant differences in age, years of education, cumulative drinking time, addiction time or daily drinking amount between the two groups ( | PMC10726483 | ||
Comparison of VAS and physiological indicators before and after cue exposure before treatment | After VR cue exposure, the score of patients’ subjective psychological craving level 5.00 (2.00, 7.88) was significantly higher than that before exposure 2.00 (0.00, 3.75), the heart rate 87.67 ± 11.72 beats/min was significantly faster than that before exposure 83.64 ± 12.07 beats/min, the skin conductance 3.14 (1.42, 6.97) µΩ was significantly higher than that before exposure 2.68 (1.30, 6.02) µΩ, and the respiration 20.65 ± 2.84 times/min was significantly faster than that before exposure 20.04 ± 2.93 times/min ( | PMC10726483 | ||
Discussion | PMC10726483 | |||
Feasibility of the VR cue exposure scene | In this study, it was found that before treatment, the VAS score of patients after cue exposure was significantly higher than that before exposure, heart rate was significantly faster than that before exposure, skin conductance was significantly higher than that before exposure, and respiration was significantly faster than that before exposure. The results are consistent with previous studies (Bordnick et al. [ | PMC10726483 | ||
Effects of virtual reality-based cue exposure therapy | DISORDERS | Currently, studies in the field of substance use disorders have mainly evaluated the effectiveness of CET as follows [In this study, there were no significant differences in the changes in heart rate, skin conductance, and respiration before and after cue exposure before treatment ( | PMC10726483 | |
Deficiencies and prospects | alcohol-dependent, AD | However, there are some deficiencies in this study. First, the sample size of this study is small, and the study subjects are all male AD patients, resulting in the effect of VR cues exposed to induce and treat alcohol craving being gender different and not universal. Second, this study did not design a traditional CET as a control group, and it is impossible to compare whether the VR-CET is better than the traditional CET. Finally, the intervention duration and intervention period of this study were short, and long-term follow-up was not conducted to understand the long-term effectiveness of VR-CET.Future studies are still needed to further verify the relationship between heart rate, skin conductance, and respiration and craving. Future studies could also add aversion therapy or relaxation therapy after CET to increase the efficacy of the treatment. In addition, it is possible to monitor the patient’s blood pressure changes and use eye-tracking technology to track the participants’ gaze objects, gaze duration and other information to explore objective physiological indicators that can effectively reflect craving and help in the assessment and treatment of alcohol-dependent patients. | PMC10726483 | |
Acknowledgements | The authors would like to express appreciation to all the participants and researchers who made this work possible, with special thanks to the medical and nursing staff of the Department of Psychiatry V and the Psychological Counselling Centre of the Second Affiliated Hospital of Xinxiang Medical University for their help. | PMC10726483 | ||
Author Contributions | Junjun Zhang, Wenhui Li and Chuansheng Wang made substantial contributions to the conception and design of the work. Junjun Zhang, Ming Chen, Junli Yan, Chaojun Wang and Jiapeng Gu made substantial contributions to the data collection. Hongdu Deng and Dan Wang analyzed and interpreted the data. Junjun Zhang and Jiali Wang made substantial contributions in writing the manuscript. Chuansheng Wang contributed to the interpretation of the results and critical revision of the manuscript for important intellectual content and approved the final version of the manuscript. All authors have read and approved the final manuscript. | PMC10726483 | ||
Funding | Psychiatric | DISEASES | This work was supported by the Project of the Xinxiang Science and Technology Tackling Programme (GG2020037, GG2021032), the Open Project of Henan Provincial Clinical Medical Research Centre for Psychiatric and Mental Diseases (2021-zxkfkt-003), and the Open Project of Psychiatry and Neuroscience Discipline of Second Affiliated Hospital of Xinxiang Medical University (2022-xyefykfkt-003, 2022-xyefykfkt-006). | PMC10726483 |
Data Availability | The datasets generated and analysed during the current study are not publicly available due to patient privacy regulations but are available from the corresponding authors on reasonable request. | PMC10726483 | ||
Declarations | PMC10726483 | |||
Ethics approval and consent to participate | The study protocol was reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Xinxiang Medical University (XYEFYLL-Scientific research section-2021-06) on 24/02/2021 and was conducted in accordance with the Declaration of Helsinki and subsequent revisions. That is, all experiments were conducted in accordance with relevant guidelines and regulations. All participants were fully informed of the purpose of the study and signed the informed consent form. Patients were informed that their participation was voluntary, and that they had the right to withdraw from the study at any time with no negative effect on their treatment. The study protocol was also registered at the China Clinical Trial Registry on 26/02/2021 ( | PMC10726483 | ||
Consent for publication | Not applicable. | PMC10726483 | ||
Competing interests | The authors declare no competing interests. | PMC10726483 | ||
References | PMC10726483 | |||
Key Points | PMC9926328 | |||
Question | Δ9-THC | Are there acute pharmacokinetic or pharmacodynamic differences between oral ingestion of a Δ9-tetrahydrocannabinol (Δ9-THC)-dominant cannabis extract compared with a cannabidiol (CBD)-dominant extract at the same Δ9-THC dose (20 mg) in healthy adults who use cannabis infrequently? | PMC9926328 | |
Findings | Δ9-THC, impairment of cognitive and psychomotor ability | In this randomized clinical trial including 18 adult participants, ingestion of 20 mg Δ9-THC + 640 mg CBD resulted in stronger subjective drug effects, greater impairment of cognitive and psychomotor ability, and greater increase in heart rate relative to 20 mg Δ9-THC alone and placebo. These effects appear to be mediated by CBD inhibition of Δ9-THC and 11-OH-Δ9-THC metabolism. | PMC9926328 | |
Meaning | Δ9-THC | These findings suggest that high doses (>600 mg) of oral CBD can inhibit the metabolism of oral Δ9-THC, resulting in stronger drug effects compared with Δ9-THC in the absence of CBD. | PMC9926328 | |
Importance | Controlled clinical laboratory studies have shown that cannabidiol (CBD) can sometimes attenuate or exacerbate the effects of | PMC9926328 | ||
Objective | PD | To compare the PK and PD of orally administered | PMC9926328 | |
Design, Setting, and Participants | This randomized clinical trial was a within-participant, double-blind, crossover study conducted from January 2021 to March 2022 at the Johns Hopkins University Behavioral Pharmacology Research Unit, Baltimore, MD. Eighteen healthy adults completed 3 randomized outpatient experimental test sessions that were each separated by at least 1 week. | PMC9926328 | ||
Interventions | Brownies containing (1) no cannabis extract (ie, placebo); (2) | PMC9926328 | ||
Main Outcomes and Measures | Change-from-baseline plasma concentrations for | PMC9926328 | ||
Results | PD | The participant cohort of 18 adults included 11 males (61.1%) and 7 females (38.9%) with a mean (SD) age of 30 (7) years who had not used cannabis for at least 30 days prior to initiation of the study (mean [SD] day since last cannabis use, 86 [66] days). The CYP cocktail + placebo brownie and the CYP cocktail did not affect any PD assessments. Relative to CYP cocktail + | PMC9926328 | |
Conclusions and Relevance | In this randomized clinical trial of oral | PMC9926328 | ||
Trial Registration | clinicaltrials.gov Identifier: | PMC9926328 | ||
Introduction | PD, Δ9-THC, cognitive and psychomotor performance | SECONDARY | Globally, the reform of laws regulating cannabis products and their constituent chemical components has increased access to these products and decreased the stigma associated with their use. As of this writing, 37 US states and Washington, DC, have legalized the use of cannabis for recreational and/or medicinal purposes. Collectively, more than 5 million individuals in the US have registered as medicinal cannabis users, and approximately 50 million people in the US reported using cannabis in 2020.Δ9-Tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the 2 primary cannabinoids contained in cannabis products and are the most commonly purported constituents to have therapeutic benefits.Prior controlled Δ9-THC and CBD studies have predominantly used inhaled routes of administration, meaning much of the extant data regarding acute interactions between Δ9-THC and CBD may not translate to oral cannabis products (ie, edibles), which undergo first-pass metabolism in the intestine and liver before reaching the systemic circulation.The primary goal of this study was to evaluate potential cannabinoid-drug interactions with 5 established CYP probe drugs (ie, caffeine, losartan, omeprazole, dextromethorphan, and midazolam) administered as an oral CYP cocktail, and the secondary goal (and focus of the present manuscript) was to compare the PK and PD (ie, subjective drug effects, cognitive and psychomotor performance, and vital signs) of a cannabis extract high in Δ9-THC (20 mg) and containing no CBD with an extract high in CBD containing the same dose of Δ9-THC and a therapeutically-relevant dose of CBD (640 mg). | PMC9926328 |
Methods | This randomized clinical trial followed the Consolidated Standards of Reporting Trials ( | PMC9926328 | ||
Participants | allergies | ALLERGIES | Study volunteers were recruited via media advertisements and word-of-mouth communication. Inclusion criteria for the study were: (1) being 18 to 50 years of age; (2) having a body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) between 18 and 34; (3) past experience with cannabis; (4) no use of cannabis within 30 days prior to the first session; (5) negative urine drug test results for common drugs of abuse at screening and beginning of all sessions; (6) not pregnant or nursing; (7) report no allergies to cannabinoids or study drugs; and (8) in good health as determined via clinical chemistry blood testing (hematology and serology), medical history, and physical examination. | PMC9926328 |
Study Design and Procedures | This within-participant, double-blind crossover study was conducted from January 2021 to March 2022 at the Johns Hopkins Behavioral Pharmacology Research Unit. The trial protocol is available in | PMC9926328 | ||
Flow Diagram of Trial Participants | CBD indicates cannabidiol; THC, tetrahydrocannabinol.At the beginning of each session, participants arrived at approximately 7:30 | PMC9926328 | ||
Cannabis Extracts and Study Drugs | Two different whole-plant cannabis extracts were obtained from the NIDA Drug Supply Program. The Δ9-THC-dominant cannabis extract contained 70% Δ9-THC, 2.7% cannabigerol (CBG), 1.5% cannabinol (CBN), less than 1% tetrahydrocannabivarin (THCV), cannabichromene (CBC), and Δ8-THC, and no detectable CBD. The CBD-dominant cannabis extract contained 59.3% CBD, 2.1% CBC, 2.0% Δ9-THC, 1.1% CBG, and less than 1% CBN, THCV, and Δ8-THC. Both extracts were manufactured in accordance with cGMP regulations and were decarboxylated prior to use in the study. Extracts were suspended in an ethanol mixture to allow for precision with dosing, stability testing was conducted throughout the study, and sample brownies were made and tested periodically to ensure accuracy in target dosing. Placebo brownies were made with an approximately equal volume of ethanol added to the brownie mix; ethanol was allowed to dissipate from the batter prior to baking the brownies. Brownies were selected as the edible formulation based on our prior studies using this matrix to reliably deliver cannabis and be tolerated by healthy adults at the doses used. | PMC9926328 | ||
Outcome Measures | PD | BLOOD, DRUG EFFECT | A subjective drug effect questionnaire was administered, and vitals and blood were sampled at baseline and 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after CYP cocktail administration. A battery of PD assessments was completed at baseline and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours after CYP cocktail administration during each session.Blood was collected into 10-mL ethylenediaminetetraacetic acid-containing vacutainer tubes and spun at 1200 g at 4 °C for 10 minutes to obtain plasma. Plasma was stored at −80 °C and shipped frozen on dry ice to the Unadkat laboratory at the University of Washington for analysis of Δ9-THC, CBD, CYP probe drugs, and corresponding metabolites. Concentrations of Δ9-THC, 11-OH-Δ9-THC, and Δ9-THC-COOH were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) after employing a liquid-liquid extraction process.Subjective drug effects were assessed with the Drug Effect Questionnaire (DEQ), which has established sensitivity to the acute effects of THC and cannabis.Cognitive and psychomotor performance was assessed using 3 computerized tasks that have been shown to be sensitive to acute effects of THC and cannabis | PMC9926328 |
Statistical Analysis | PD, Δ9-THC | SECONDARY, DRUG EFFECT | A power analysis was conducted prior to the start of the study, which estimated that a total of 18 participants would provide 84% power to detect a 25% change in the primary outcome for this study (ie, losartan AUC), assuming 20% intra-individual variability, and a Type 1 error rate of .05. Power justification for the secondary outcomes (ie, the PD of the current report) was based on a meta-analysis comparing the statistical power of 13 drug effect assessments from 6 dose-effect studies, with 14 participants each, evaluating a range of abused drugs in our laboratory.The effect of the CYP cocktail was evaluated by comparing baseline scores to postbrownie and CYP cocktail administration scores during the placebo brownie session using a separate 1-way repeated-measures analysis of variance (ANOVA) with time (0-24 hours postbrownie and CYP cocktail administration) as the primary factor. PD outcomes of the cannabis extracts were evaluated using 2-way repeated-measures ANOVAs with the within-participant factors being brownie dose condition (CYP cocktail + placebo, CYP cocktail + Δ9-THC, and CYP cocktail + Δ9-THC + CBD) and time. Planned post-hoc (Tukey) tests were conducted for peak change from baseline scores on PD assessments between each brownie dose condition (ie, CYP cocktail + placebo vs CYP cocktail + Δ9-THC, CYP cocktail + placebo vs CYP cocktail + Δ9-THC + CBD, and CYP cocktail + Δ9-THC vs CYP cocktail + Δ9-THC + CBD). For all analyses, statistical significance was defined as an α error probability of less than .05. The threshold for statistical significance for the planned contrasts was set to | PMC9926328 |
Results | Thirty-six volunteers signed informed consent. Of the 22 randomized participants, 18 (11 [61.1%] males and 7 [38.9%] females) completed the study (For plasma C | PMC9926328 | ||
Mean Plasma Concentration vs Time Profiles for (A) Δ9-THC, (B) 11-OH-Δ9-THC, and (C) Δ9-THC-COOH | PD, Δ9-THC | Mean plasma concentration vs time profiles for (A) Δ9-THC, (B) 11-OH-Δ9-THC, and (C) Δ9-THC-COOH. Horizontal axes are not accurate time scales and represent the time points at which subjective drug effects were assessed following cannabis administration. Panels D, E, and F depict area under-the-curve ratios of 11-OH-Δ9-THC:Δ9-THC, Δ9-THC-COOH:Δ9-THC, and Δ9-THC-COOH:11-OH-Δ9-THC, respectively. Error bars indicate standard error of the means. The sample size was 18 for all outcomes. CBD indicates cannabidiol; CYP, cytochrome P450; Δ9-THC, Δ9-tetrahydrocannabinol; Δ9-THC-COOH, 11-nor-Δ9-tetrahydrocannabinol-carboxylic acid; 11-OH-Δ9-THC, 11-hydroxy-Δ9-tetrahydrocannabinol.No significant effects of time were observed in the placebo brownie condition, indicating the CYP cocktail was not associated with a significant change on any of the assessed PD outcomes. The main effects of dose, time, and dose × time interactions were observed across all outcomes within the 4 subjective drug rating categories (ie, general drug effects, positive, negative/adverse, and perceived degree of impairment) (eTable 2 in | PMC9926328 | |
Change From Baseline Mean Ratings for the Visual Analog Scale Items (A) Drug Effect, (B) Pleasant Drug Effect, and (C) Unpleasant Drug Effect From the Drug Effect Questionnaire Displayed Over Time | Scores ranged from 0 (not at all) to 100 (extremely). Error bars indicate standard error of the means. Horizontal axes are not accurate time scales and represent the time points at which subjective drug effects were assessed following cannabis administration. The sample size was 18 for all outcomes. CBD indicates cannabidiol; CYP, cytochrome P450; THC, tetrahydrocannabinol; VAS, visual analog score. | PMC9926328 | ||
Mean Peak Change From Baseline Values for Pharmacodynamic Measures | DRUG EFFECT | Abbreviations: CBD, cannabidiol; DAT, divided attention task; DEQ, drug effect questionnaire; DSST, digit symbol substitution task; PASAT, paced serial addition task; THC, tetrahydrocannabinol.No. = 18 for total sample.Significant difference from placebo (Significant difference between Δ-9-THC and Δ-9-THC/CBD (The main effects of time and a dose × time interaction was observed for the DSST, and main effects of dose and time and a dose × time interaction were observed for the PASAT and DAT ( | PMC9926328 | |
Change From Baseline Mean Total Correct on (A) the Digit Symbol Substitution Task (DSST) and (B) Paced Auditory Serial Addition Task (PASAT), the Average Distance From the Central Stimulus From the (C) Divided Attention Task (DAT), and the Beats Per Minute (BPM) for (D) Heart Rate | Lower scores indicate worse performance relative to baseline in Panels A and B. Higher scores indicate worse performance relative to baseline in Panel C. Error bars indicate standard error of the means. Horizontal axes are not accurate time scales and represent the time points at which subjective drug effects were assessed following cannabis administration. The sample size was 18 for all outcomes. CBD indicates cannabidiol; CYP, cytochrome P450; Δ9-THC, Δ9-tetrahydrocannabinol. | PMC9926328 | ||
Discussion | PD, Δ9-THC | Given the growing popularity of cannabis edibles and oral formulations for therapeutic and nontherapeutic use, controlled research characterizing the acute PK and PD of cannabis products that vary in chemical composition other than Δ9-THC is critical. Research is particularly needed to understand the association of CBD with Δ9-THC because there is a high degree of variability in CBD content across cannabis products, and products are marketed and used based on the content and ratios of Δ9-THC:CBD. However, much of the extant data on interactions between Δ9-THC and CBD are from studies that administered the cannabis product by inhalation or Δ9-THC and CBD intravenously.In contrast to some previous controlled studies evaluating the association of Δ9-THC or CBD alone,CBD has been shown to inhibit the cytochrome P450 enzymes (present in both the liver and intestine) which metabolize Δ9-THC and 11-OH-Δ9-THC, | PMC9926328 | |
Limitations | PD, Δ9-THC | ADVERSE EFFECTS | This study has limitations. First, a single dose of Δ9-THC (20 mg) and CBD (640 mg) was administered, and a CBD only condition was lacking. Future studies comparing multiple doses and ratios of Δ9-THC and CBD are needed to determine the generality of the observed associations, as well as the dose threshold for clinically significant alterations in PD outcomes. Second, the outcomes for Δ9-THC and Δ9-THC + CBD were assessed in the context of an oral CYP cocktail. Although no adverse effects were noted when the CYP cocktail was administered after the placebo brownie, the CYP cocktail may have contributed to the behavioral outcomes observed during the active cannabis conditions. Third, although the study included both males and females, the sample size of the present study was not powered to detect potential sex differences, which have been shown to influence acute cannabis effects. | PMC9926328 |
Conclusions | PD, Δ9-THC | ADVERSE EFFECTS | In this randomized clinical trial, plasma exposure to Δ9-THC, 11-OH-Δ9-THC, and Δ9-THC-COOH following ingestion of Δ9-THC + CBD was greater than that following ingestion of Δ9-THC and placebo. Consequently, participants experienced greater increases in subjective drug effects, impairment of cognitive and psychomotor performance, and HR. With legalized medicinal and nonmedicinal use of cannabis continually expanding, cannabis users and clinical or regulatory stakeholders must understand that differential chemical compositions other than Δ9-THC can significantly alter the PK and PD of cannabis products. High concentrations of CBD can inhibit Δ9-THC metabolism, which can increase the likelihood of acute adverse effects compared with the same dose of Δ9-THC in the absence of CBD. | PMC9926328 |
Background | death | DISEASES, ATHEROSCLEROSIS, CARDIOVASCULAR MORBIDITY | Diseases affecting the cardiovascular system are the most common cause of death worldwide. In addition to classical risk factors of atherosclerosis, long-term exposure to particulate matter with particles of size up to 10 µm (PM10) in the atmosphere has become an increasing focus of scientific attention in recent decades. This study analyses the associations of residential-associated air pollutants exposure with all-cause mortality and cardiovascular morbidity of older patients in a primary care setting. | PMC10318761 |
Methods | The “German Epidemiological Trial on Ankle Brachial Index” (getABI) is a prospective cohort study that started in 2001 and included 6,880 primary care patients with a follow-up of 7 years. The PM10 and nitrogen dioxide (NO | PMC10318761 | ||
Results | death | A total of 6,819 getABI patients were included in this analysis. 1,243 of them died during the study period. The hazard ratio (HR) (1.218, 95%-confidence-interval (CI) 0.949–1.562) for the risk of death from any cause was elevated by 22% per 10 µg/m | PMC10318761 | |
Conclusions | Our analysis renders some hints for the impact of air pollutants (PM10, NO | PMC10318761 | ||
Trial registration | DRKS00029733 | German Clinical Trials Register: DRKS00029733 (19/09/2022). | PMC10318761 | |
Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10318761 | ||
Introduction | death, cardiovascular disease, cardiovascular diseases, atherosclerosis, pulmonary diseases, peripheral artery disease, glucose tolerance disorders, deaths, coronary heart disease, coronary artery disease, Atherosclerotic | DISEASES, PERIPHERAL ARTERY DISEASE, ELEVATED CHOLESTEROL, CARDIOVASCULAR DISEASE, CARDIOVASCULAR DISEASES, OXIDATIVE STRESS, DISEASES, DIABETES MELLITUS, PULMONARY DISEASES, EVENTS, CARDIOVASCULAR MORBIDITY, CEREBROVASCULAR DISEASE, ELEVATED BLOOD PRESSURE, ATHEROSCLEROSIS, CORONARY HEART DISEASE, ARTERIAL HYPERTENSION, CORONARY ARTERY DISEASE, INFLAMMATORY RESPONSE | Diseases affecting the cardiovascular system are the most common cause of death worldwide. According to the World Health Organization (WHO), 17.9 million people died from cardiovascular diseases in 2016. Therefore, almost one in three deaths of the total number of people who died in 2016 (56.9 million deaths worldwide) was due to cardiovascular disease [The term cardiovascular disease encompasses several complex clinical pictures. These include coronary artery disease, cerebrovascular disease, and peripheral artery disease (PAD).Basically, atherosclerosis is assumed to be the cause of most cardiovascular diseases. Besides classic risk factors such as age, sex, nicotine consumption, diabetes mellitus, elevated cholesterol levels, and arterial hypertension, there may be other risk factors, which are not taken into account in everyday clinical practice. In particular, long-term exposure to particulate matter with particles of size up to 10 µm (PM10) from diesel soot, combustion reactions, and reactions of harmful gases in the atmosphere have become an increasing focus of scientific attention in recent decades [Several studies have documented that short-term as well as long-term exposure to PM10 have a significant effect on the incidence and outcome of coronary heart disease, cerebrovascular disease and pulmonary diseases [Although the exact effect of PM10 is still unknown, scientists suspect that an inflammatory response occurs in tissues exposed to particulate matter. Oxidative stress and the direct, damaging effects of PM10 cause further changes in the tissue. This process manifests itself in increased inflammatory markers in the serum, elevated blood pressure, glucose tolerance disorders, and reduced lung function. Atherosclerotic processes also advance more rapidly by exposure to PM10 [Since the beginning of 2005, upper limits for PM10 were established in the EU, meaning that the PM10 concentration must not exceed the daily limit of 50 µg/mAs an individual, it is almost impossible to protect oneself from the risk factor PM10 or to completely avoid its harmful effects. Reduced exposure to PM10 may prolong life expectancy up to 7 months, if the long-term PM10 concentration is reduced by 10 µg/mLong-term exposure to fine dust affects the incidence of certain diseases. For example, Hoffmann et al. [Furthermore, the ESCAPE study showed that the long-term exposure to PM10 is associated with an increased incidence of acute coronary events and that this relationship already exists below the EU limits [This study aims to corroborate the hypothesis that residence-associated PM10 exposure has an impact on all-cause mortality and cardiovascular morbidity using data of the German Epidemiological Trial on Ankle Brachial Index (getABI) cohort over a 7-year observation period [ | PMC10318761 |
Data and methods | PMC10318761 | |||
Study population | death, cardiovascular disease | EVENTS, CARDIOVASCULAR DISEASE | The getABI study is a prospective cohort study that started in 2001 and aimed to determine the association between the ankle brachial index (ABI) and cardiovascular events in primary care patients. 34 angiology specialists recruited primary care physicians from 344 practices all over Germany. In October 2001, at least 20 patients 65 years or older per general practitioner were recruited for the study. One exclusion criterion was a life expectancy of less than 6 months. A complete health status was obtained, which included a detailed medical history with special attention to cardiovascular disease as well as medical and socioeconomic risk factors. In addition, information on height, pulse status, heart rate, blood pressure, and ABI status was gathered. Followed-up visits took place after 1, 3, 5, and 7 years. In case of death, time of death and cause of death were determined with the help of the primary care physician and registration offices [ | PMC10318761 |
Air pollutants exposure and proximity to major road | The PM10 and NORegarding the proximity to major roads, geographers of the Ruhr University Bochum converted the places of residence of the getABI participants into Gauss-Krueger coordinates, and the distances to major roads were generated with the help of the "Functional Road Classes" from the StreetPro_EMEA program. Therein, all roads that fell under the three classes motorway, major road, and other major road (micodes 2001xxxx, 2002xxxx, and 2003xxxx, respectively) were considered together and referred to as major road in this work. A major road within a radius of ≤ 50 m to the residential address was considered an exposure to this potential risk factor. | PMC10318761 | ||
Definition of adjustment variables | PAD | PAD, EVENTS, DIABETES MELLITUS | Adjustment was performed in two a priori defined adjustment steps. Model 1 with adjustment for the variables age, sex, and one or more air pollutants formed the first step and is referred to as "basic adjustment" in the further course. Model 2 was labeled as "full adjustment" and additionally included the education status (International standard classification of eduction (ISCED)), smoking status, pack-years, body-mass-index, estimated glomerular filtration rate (eGFR), C-reactive protein (CRP), vitamin D, homocysteine, low-density lipoprotein (LDL), gamma-glutamyltransferase (GGT), arterial hypertension, diabetes mellitus, PAD, cardiovascular events prior to baseline, and intake of lipid-lowering, anticoagulant, antiplatelet, or digitalis medication.In order to investigate a possible effect of drug therapy on the impact of PM10 exposure, the intake of different drug groups was included in the analysis. Statins or fibrates were labeled as lipid-lowering medication. Anticoagulant medication was defined as the use of coumarin derivatives or heparin. Therapeutic use of acetylsalicylic acid, ticlopidine, clopidogrel, or dipyramidol was grouped under antiplatelet medication. The intake of digitalis was considered as a separate variable.The following seven interactions were pre-specified: each single air pollutant with PAD at baseline, NO | PMC10318761 |
Outcomes | apoplexy, death, PAD | MYOCARDIAL INFARCTION, EVENT, APOPLEXY, PAD, REGRESSION | The primary outcome in this analysis was death from any cause. Secondary, we investigated the impact of air pollutants and of proximity to major roads on the combined endpoint of death from any cause and cardio-vascular morbidity. The latter was defined as a new event of myocardial infarction, apoplexy, coronary or carotid revascularization.The third endpoint was defined as the time to the first occurrence of PAD not yet detected at baseline. This was defined as amputation, peripheral revascularization, or occurrence of necrosis/gangrene of the affected limb during the observation period. In addition, PAD was assumed, if the ABI fell below the threshold of 0.9 during the course of the study. Because the follow-up examinations were performed at fixed time points (1, 3, 5, and 7 years after baseline), and thus information for the time between the examination time points was missing, a progression curve was generated for the ABI by regression. If this curve had an intersection with the value 0.9 or if a new PAD symptom occurred, the event occurring first was used to calculate the event-free time to adequately reflect the incidence of PAD [ | PMC10318761 |
Statistical methods | ABI, PAD | REGRESSION, PAD, EVENTS, EVENT | Patients’ characteristics at baseline are also presented for subgroups defined by the quartiles of PM10 exposure in the study population.To investigate the relationship between the different exposure factors and mortality or incidence of PAD, survival times were modeled by Cox proportional hazards regression, briefly referred to as Cox regression. If multiple target events occurred in a patient during the analysis of the combined endpoint, only the event that occurred first was considered.Missing values rarely appeared (below 2%), on continuous variables such as CRP, eGFR, vitamin D, and ABI they were randomly supplemented with data from the sample. For categorical variables, missing values were assigned to the unexposed group.Effects were presented in the form of HR with associated 95% confidence intervals (CI). The effects of PM10 and NOThe significance level was set to 0.05. For interactions, the estimated HR and 95% CI on each level of the potentially modifying factor were provided. Corrections for multiple testing of hypotheses were not applied. | PMC10318761 |
Results | PMC10318761 | |||
Secondary Outcomes | PMC10318761 | |||
Discussion | This work found some hints for the impact of air pollutants (PM10, NO | PMC10318761 | ||
Particulate matter | stroke, death, hypertension | DIABETES MELLITUS, STROKE, HYPERTENSION, PAD | In 2019, the annual average PM10 value in Germany fell below 20 µg/mAn effect of long-term PM10 exposure on mortality, although lower than expected, cannot be dismissed. Several articles show a strong association of PM10 exposure with the incidence of stroke and an increase in the intima thickness of the carotid artery [Not only long-term PM exposure, but also acute increases in particulate matter concentration are associated with cardiovascular hospitalisation or death with an increase of 1.63% (95% CI 1.20-2.07) per 10 μg/mIt is possible that PM10 has an additive effect in combination with other cardiovascular risk factors such as hypertension or diabetes mellitus. Data on the association between PM10 and the incidence of PAD are incomplete, but the results of Hoffmann et al. [ | PMC10318761 |
Nitrogen dioxide | In 2019, an annual average value for traffic-related areas of 35 µg/mBy adjustment for PM10 and the distance to the nearest major road, the low effect of NO | PMC10318761 | ||
Distance to major road | REGRESSION | Several studies described a significant decrease in PM2.5, ultrafine particles, black carbon, and NOThe strength of our study lies in the cohort of unselected patients from all regions in Germany and the consideration of environmental pollutants, combining the influence of long-term background exposure and likely short-term peak exposure in the vicinity of heavy traffic. Our analysis faces some limitations. The used pollutant exposure refers to the start of the getABI trial. Trends in pollutant values before and after 2001 were ignored. The interpolated pollution data carries a regression to the mean effect, so the spread in values might be underestimated. No data on PM2.5 was considered. Thus, the data compilation has weaknesses, which might have influenced the results, but other options were not available. | PMC10318761 | |
Conclusions | Our analysis provides some hints for the impact of air pollutants (PM10, NO | PMC10318761 | ||
Acknowledgements | Not applicable. | PMC10318761 | ||
Authors’ contributions | HJT and MT were investigators of the study. DK, HJT, and UT did the conceptualization of this work. Data collection and data curation was done by RKM, HR, and MT. Methodology was developed by DK, RKM, UT and HR. MD conducted the formal analysis and wrote the original draft of the manuscript, which was edited by DK and HR. All authors reviewed the manuscript. | PMC10318761 | ||
Funding | Open Access funding enabled and organized by Projekt DEAL. | PMC10318761 | ||
Availability of data and materials | Request for sharing the trial data can be addressed to the corresponding author and will be considered on an individual basis by the authors. | PMC10318761 | ||
Declarations | PMC10318761 | |||
Ethics approval and consent to participate | The Ethics Committee of the Medical Faculty of the Ruhr University Bochum approved this research project on humans (registration no. 18–6363) on July 10, 2018. Informed consent was obtained from all patients and/or their legal guardian(s). All methods and examinations of this study were carried out in accordance with relevant guidelines and regulations. | PMC10318761 | ||
Consent for publication | Not applicable. | PMC10318761 | ||
Competing interests | The authors have no competing interests as defined by BMC, or other interests that might be perceived to influence the results and/or discussion reported in this paper. | PMC10318761 | ||
References | PMC10318761 | |||
Design, setting, participants | depression, MM, pain | Randomized, single-blinded, controlled study was conducted on 60 LE participants at university hospital. The active MM group (n = 30) received corticosteroid injection with DTFM and active Mill’s manipulation (MM) three sessions a week for 4 weeks and the sham MM group received corticosteroid injection with sham manipulation. The primary outcome was pain intensity, measured with the visual analog scale. The other outcome measures were percentage of injury measured by MRI and ultrasound, functional disability, handgrip strength, patient perception, kinesiophobia, depression status and quality of life which were measured at 4 weeks, 8weeks and at 6 months follow up. | PMC9925075 | |
Results | depression, injury, functional disability, pain | The between-group difference in pain intensity at 4 weeks was 1.6 (CI 95% 0.97 to 2.22), which shows improvement in the active group than sham group. The similar effects have been noted after 8 weeks and at 6 months 2.0 (CI 95% 1.66 to 2.33) follow up in pain intensity. Similar improvements were also found on percentage of injury, functional disability, handgrip strength, patient perception, kinesiophobia, depression status and quality of life (p = 0.001). | PMC9925075 | |
Conclusion | depression, injury, functional disability, pain | Corticosteroid injection with DTFM and Mill’s manipulation was superior to sham group for improving pain, percentage of injury, functional disability, handgrip strength, patient perception, kinesiophobia, depression status and quality of life in people with lateral epicondylalgia. | PMC9925075 | |
Data Availability | All relevant data are within the paper and its | PMC9925075 | ||
1. Introduction | inflammation, pain | RECURRENCE, INFLAMMATION, DISEASE, TENNIS ELBOW, LATERAL EPICONDYLITIS | Lateral epicondylalgia (LE), is a common musculoskeletal condition with clinical symptoms of pain and inflammation over the proximal attachment of the wrist extensor tendon of the humerus. It is frequently known as “lateral epicondylitis” or “tennis elbow” and maximum incidences occur between 30 and 65 years of the age [Recently, corticosteroid injections are discouraged by many physicians because of high recurrence rate [Along with the regular investigations, there is a need to find the radiological changes after corticosteroid injection with DTFM and Mill’s manipulation in lateral epicondylalgia. The advanced radio imaging techniques such as magnetic resonance imaging (MRI) and ultrasonography (US) are used to find the extent of disease, the associated problems and measure the degree of soft tissue injury [ | PMC9925075 |
2. Materials and methods | PMC9925075 | |||
2.1 Trial design | This trial was a prospectively registered, randomized, parallel group, sham controlled trial executed at department of physical therapy, college of applied medical sciences, Prince Sattam bin Abdulaziz University, Saudi Arabia. Participants were recruited between 1 | PMC9925075 | ||
2.2 Participants | fracture, psychiatric, pain | DISEASES | The participants were invited by sending personal email or mobile call and they were recruited from University hospital and King Khalid hospital, Al Kharj, Saudi Arabia by an orthopedic surgeon. They were informed about the harms and benefits of the research through an information form. Subjects who consented to participate in the study were selected for the study and the written informed consent was obtained from all subjects. Male, aged between 18 and 60 years, with a clinical diagnosis of chronic (> 2 months of pain) lateral epicondylalgia (M77.1 in ICD-10 –International classification of diseases), with pain intensity between 3 to 8 on the visual analog scale (VAS) were allowed to participate. Only male subjects were included in this study due to their responses to the interventions when compared to the female participants, which may alter the study reports. Participants with prior steroid injection therapy, associated neck or arm pain, severe musculoskeletal, neural, somatic and psychiatric conditions, waiting for surgery, having alcohol or drug abuse, involving in other weight training programs, and red flags to manipulation were excluded from the study. Participants with other soft tissue injuries, fracture at the limbs, deformities were also excluded from the study.The participants were randomized using computer generated randomization method and allocated into two groups: corticosteroid injection with DTFM and Mill’s manipulation–Active group (n = 30) and Sham group (n = 30) and the flow of study participants was shown in | PMC9925075 |
Flow chart showing the study details. | PMC9925075 | |||
2.3 Interventions | Following corticosteroid injection, the recommended physical therapy was given for 4 weeks, after which the participants were asked to exercise at home for another 4 weeks. The participants maintained an exercise log book during the study period. | PMC9925075 | ||
2.3.1 Corticosteroid injection | A physical examination was performed by an orthopedic surgeon before the administration of injection. 1 ml Triamcinolone Acetonide (10 mg/ml) (Kenacort- A 10) with 1 ml Lignocaine (1%) was administered into the most palpably tender point in the region of the lateral epicondyle [ | PMC9925075 | ||
2.3.2 Physical therapy | pain | A week after the injection the participants started with the physical therapy interventions. All participants received the respective physical therapy for 3 sessions per week for 4 weeks, each session lasted for 30 to 40 minutes.All the participants underwent baseline evaluation of variables before the administration of injection. To avoid intervention bias, a fixed physical therapy protocol was prepared on the basis of recent evidence with the objectives of ameliorating pain, increasing functional activity and soft tissue healing. A holistic approach consisting of physical modalities, exercise protocols and patient education were used to obtain these objectives. Participants in active MM group underwent deep transverse friction massage (DTFM) and Mill’s manipulation. Deep transverse friction massage (DTFM) is a specific type of connective tissue massage applied precisely to the soft tissues around the elbow. It is important that the depth of friction applied is tolerable to the patient. It was applied transversely to the specific tissue involved and applied for 5 minutes. This technique is applied to prepare the structures for the manipulation.For manipulation, the participant was asked to sit comfortably with proper backrest. The treating therapist stands behind the patient and grasp the patient’s arm under the crook of the elbow with the shoulder joint abducted to 90° and medially rotated. Therefore, the patient’s forearm is pronated. Place the thumb of other hand in the web space between the patient’s thumb and index finger and fully flex the patient’s wrist and pronate the forearm. Move the hand supporting the crook of the elbow on to the posterior surface of the elbow joint and, while maintaining full wrist flexion and pronation, extend the patient’s elbow until that all the slack has been taken up in the tendon. Apply a high velocity low amplitude thrust (HVLAT) by side flexing the body away from the arms and pushing downwards with the hand over the patient’s elbow. This procedure is conducted only once at each session because it is an uncomfortable procedure for the patient [Progressive resistance exercises (PRE) and home exercises were applied to both the treatment groups. The progressive resistance exercises were prescribed to the wrist joint with Thera-band based on the assessment of individual muscles, which was shown as an appendix-A ( | PMC9925075 | |
Appendix A–Theraband exercises. | PMC9925075 | |||
2.4 Outcome measures | PMC9925075 | |||
2.5 Sample size | pain | The sample size was calculated using a previous pilot study conducted in the department with primary outcome data of pain intensity measured with VAS scores. The | PMC9925075 | |
2.6 Blinding | BLIND | Due to the design and settings of the study, it is not possible to blind the treating therapist involved in the study. The participants and the therapist who is assessing the outcomes at baseline, after 4 weeks, 8 weeks and at 6 months were blinded. Subjects were instructed not to disclose the study procedures and treatment protocol with fellow subjects and the assessing therapist. | PMC9925075 | |
2.7 Statistical analysis | RECRUITMENT | The data analysis was performed by a statistician who did not participate in the recruitment, evaluation and treatment aspects of the study. The study homogeneity was analyzed using the Kolmogorov-Smirnov test. The data analysis was performed on an intention-to-treat basis. For the missing data, results obtained in the last available assessment of each participant were repeated. The time and group (4 × 2) of each outcome variable was analyzed with linear mixed model (LMM) analysis. The effects between the active and sham groups were analyzed by between group analysis and the intra group effects were analyzed by within group analysis for various intervals. The mean difference (MD) and 95% confidence interval (CI) were also calculated for each between-group comparison. The statistical analyses were processed using a commercial statistical software (IBM SPSS Statistics for Windows—version 20.0) and a level of significance of p≤0.05 was adopted for all tests. | PMC9925075 | |
3. Results | PMC9925075 | |||
3.1 Flow of participants through the study | Flow of study participants throughout the trial is depicted in | PMC9925075 |
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