Effects of cannabidiol on psychosocial stress, situational anxiety and nausea in a virtual reality environment: a protocol for a single-centre randomised clinical trial.

INTRODUCTION: The 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. METHODS: We 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 DISSEMINATION: The 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 NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12623000872639).

Profiling the chemical properties of Foeniculum vulgare Mill. and its flavonoids through comprehensive LC-MS/MS to evaluate their anti-motion sickness effect.

Foeniculum vulgare Mill. is a medicinal and food homologous plant, and it has various biological activities. Yet, no research has explored its anti-motion sickness effects. Chemical properties of fennel extracts (FvE) and flavonoids (Fvf) were analyzed based on UPLC-QTRAP-MS to elucidate its potential anti-motion sickness components in the present study. The mice models of motion sickness were stimulated by biaxial rotational acceleration. Behavioral experiments such as motion sickness index and open field test and the measurement of neurotransmitters were used to evaluate the efficacy of compounds on motion sickness. Results showed that FvE contains terpenes, alkaloids, flavonoids, etc. Eight flavonoids including quercetin-3ß-D-glucoside, rutin, hyperoside, quercetin, miquelianin, trifolin, isorhamnetin and kaempferol were identified in the purified Fvf. FvE and Fvf significantly reduced the motion sickness index of mice by 53.2% and 48.9%, respectively. Fvf also significantly alleviated the anxious behavior of mice after rotational stimulation. Among the eight flavonoids, isorhamnetin had the highest oral bioavailability and moderate drug-likeness index and thus speculated to be the bioactive compound in fennel for its anti-motion sickness effect. It reduced the release of 5-HT and Ach to alleviate the motion sickness response and improve the work completing ability of mice and nervous system dysfunction after rotational stimulation. This study provided in-depth understanding of the anti-motion sickness bioactive chemical properties of fennel and its flavonoids, which will contribute to the new development and utilization of fennel.

Calcitonin gene-related peptide receptor antagonism reduces motion sickness indicators in mouse migraine models.

BACKGROUND: Migraine and vestibular migraine are disorders associated with a heightened motion sensitivity that provoke symptoms of motion-induced nausea and motion sickness. VM affects ∼3% of adults in the USA and affects three-fold more women than men. Triptans (selective serotonin receptor agonists) relieve migraine pain but lack efficacy for vertigo. Murine models of photophobia and allodynia have used injections of calcitonin gene-related peptide (CGRP) or other migraine triggers, such as sodium nitroprusside (SNP), to induce migraine sensitivities in mice to touch and light. Yet, there is limited research on whether these triggers affect motion-induced nausea in mice, and whether migraine blockers can reduce these migraine symptoms. We hypothesized that systemic delivery of CGRP or SNP will increase motion sickness susceptibility and motion-induced nausea in mouse models, and that migraine blockers can block these changes induced by systemically delivered CGRP or SNP. METHODS: We investigated two measures of motion sickness assessment [motion sickness index (MSI) scoring and motion-induced thermoregulation] after intraperitoneal injections of either CGRP or SNP in C57BL/6J mice. The drugs olcegepant, sumatriptan and rizatriptan were used to assess the efficacy of migraine blockers. RESULTS: MSI measures were confounded by CGRP's effect on gastric distress. However, analysis of tail vasodilatations as a surrogate for motion-induced nausea was robust for both migraine triggers. Only olcegepant treatment rescued tail vasodilatations. CONCLUSIONS: These preclinical findings support the use of small molecule CGRP receptor antagonists for the treatment of motion-induced nausea of migraine, and show that triptan therapeutics are ineffective against motion-induced nausea of migraine.Trial Registration: Not Applicable.

Orexin-A attenuated motion sickness through modulating neural activity in hypothalamus nuclei.

BACKGROUND AND PURPOSE: We evaluated the hypothesis that central orexin application could counteract motion sickness responses through regulating neural activity in target brain areas. EXPERIMENTAL APPROACH: Thec effects of intracerebroventricular (i.c.v.) injection of orexin-A and SB-334867 (OX1 antagonist) on motion sickness-induced anorexia, nausea-like behaviour (conditioned gaping), hypoactivity and hypothermia were investigated in rats subjected to Ferris wheel-like rotation. Orexin-A responsive brain areas were identified using Fos immunolabelling and were verified via motion sickness responses after intranucleus injection of orexin-A, SB-334867 and TCS-OX2-29 (OX2 antagonist). The efficacy of intranasal application of orexin-A versus scopolamine on motion sickness symptoms in cats was also investigated. KEY RESULTS: Orexin-A (i.c.v.) dose-dependently attenuated motion sickness-related behavioural responses and hypothermia. Fos expression was inhibited in the ventral part of the dorsomedial hypothalamus (DMV) and the paraventricular nucleus (PVN), but was enhanced in the ventral part of the premammillary nucleus ventral part (PMV) by orexin-A (20 µg) in rotated animals. Motion sickness responses were differentially inhibited by orexin-A injection into the DMV (anorexia and hypoactivity), the PVN (conditioned gaping) and the PMV (hypothermia). SB-334867 and TCS-OX2-29 (i.c.v. and intranucleus injection) inhibited behavioural and thermal effects of orexin-A. Orexin-A (60 µg·kg-1) and scopolamine inhibited rotation-induced emesis and non-retching/vomiting symptoms, while orexin-A also attenuated anorexia with mild salivation in motion sickness cats. CONCLUSION AND IMPLICATIONS: Orexin-A might relieve motion sickness through acting on OX1 and OX2 receptors in various hypothalamus nuclei. Intranasal orexin-A could be a potential strategy against motion sickness.

Brown Slime Cap Mushroom (Chroogomphus rutilus, Agaricomycetes) Polysaccharide Resists Motion Sickness by Inhibiting the Activity of the Serotonin System in Mice.

Motion sickness (MS) is a disorder of the autonomic nervous system caused by abnormal exercise with symptoms such as nausea, vomiting and drowsiness. More than 90% of the human population has experienced different degrees of MS. At present, anticholinergics, antihistamines, and sympathomimetic drugs are used for treating MS, but these drugs generally have some adverse reactions and are not suitable for all people. Therefore, it is necessary to develop anti-MS drugs that have high efficiency and no adverse effects. Previous studies have found that Chroogomphus rutilus polysaccharide (CRP) is effective at preventing and treating MS in rats and mice. However, its mechanism of action is not clear. To clarify whether the CRP has anti-MS effects in mice, and to clarify its mechanism, we performed behavioral, biochemical, and morphological tests in a Kunming mouse model. Our results indicate that CRPs can significantly relieve the symptoms of MS, and their effect is equivalent to that of scopolamine, a commonly used anti-MS medicine. Our results indicate that CRPs may directly act on the gastrointestinal chromaffin cells to inhibit the synthesis and release of serotonin (5-hydroxytryptamine, or 5-HT) and thus reduce the signal from the gastrointestinal tract.

Anticholinergic Versus Antihistaminic Treatment for Simulator Sickness Prevention.

Flight simulators have an essential role in aircrew training. Occasionally, symptoms of motion sickness, defined as simulator sickness, develop during these sessions. Preventive methods for motion sickness have been investigated thoroughly; however, only a few studies have examined preventive treatments for simulator sickness. The aim of this study was to examine the efficacy of scopolamine (an anticholinergic drug) compared with cinnarizine (an antihistaminic drug) for helicopter simulator sickness prevention. A validated simulator sickness questionnaire (SSQ) score was used to determine the severity of simulator sickness symptoms in this study. Preliminary SSQ scores and SSQ scores after each sortie were calculated. Each participant was given scopolamine, cinnarizine, or a placebo in a double-blind randomized manner before the first sortie of each training day. Forty-one helicopter pilots participated in the trial. The average age was 30.5 ± 7.1 years. SSQ values significantly improved from an average of 73.30 in the preliminary SSQ questionnaire to an average of 30.92 after 2 hours following the administration of cinnarizine (P = .012, 95%CI 8.071-76.703). Scopolamine was found to be less effective than both cinnarizine and the placebo in the alleviation of simulator sickness symptoms. This study is the first to compare scopolamine with cinnarizine for simulator sickness prevention. Based on the results of this study, we recommend the use of cinnarizine over scopolamine for simulator sickness prevention.

Placebo effects on nausea and motion sickness are resistant to experimentally-induced stress.

Nausea often occurs in stressful situations, such as chemotherapy or surgery. Clinically relevant placebo effects in nausea have been demonstrated, but it remains unclear whether stress has an impact on these effects. The aim of this experimental study was to investigate the interplay between acute stress and placebo effects in nausea. 80 healthy female volunteers susceptible to motion sickness were randomly assigned to either the Maastricht Acute Stress Test or a non-stress control condition, and to either placebo treatment or no treatment. Nausea was induced by a virtual vection drum and behavioral, psychophysiological as well as humoral parameters were repeatedly assessed. Manipulation checks confirmed increased cortisol levels and negative emotions in the stressed groups. In the non-stressed groups, the placebo intervention improved nausea, symptoms of motion sickness, and gastric myoelectrical activity (normo-to-tachy (NTT) ratio). In the stressed groups, the beneficial effects of the placebo intervention on nausea and motion sickness remained unchanged, whereas no improvement of the gastric NTT ratio was observed. Results suggest that placebo effects on symptoms of nausea and motion sickness are resistant to experimentally-induced stress. Stress most likely interfered with the validity of the gastric NTT ratio to measure nausea and thus the gastric placebo effect.

Efficacy of Olanzapine in Addition to Standard Triplet Antiemetic Therapy for Cisplatin-Based Chemotherapy: A Secondary Analysis of the J-FORCE Randomized Clinical Trial.

Importance: It is unknown whether olanzapine combined with triplet antemetic therapy is effective for all patients undergoing highly emetogenic chemotherapy. A secondary analysis of randomized clinical trials using olanzapine may provide insight into the effectiveness of olanzapine for chemotherapy-induced nausea and vomiting (CINV), including cisplatin. Objective: To examine the add-on effect of olanzapine according to risk factors for CINV. Design, Setting, and Participants: This preplanned secondary analysis evaluated results of the J-FORCE trial, a large double-blind, placebo-controlled phase 3 randomized clinical trial conducted in Japan from February 9, 2017, to July 18, 2018. Participants were enrolled from 26 participating hospitals across Japan and included patients aged 20 to 75 years who had a malignant tumor and were cisplatin-naive. The efficacy analysis population of the J-FORCE trial was analyzed according to allocation adjustment factors (sex [male or female], age [≥55 years or <55 years], and cisplatin dose [≥70 mg/m2 or <70 mg/m2]) and patient-related risk factors (history of motion sickness, drinking habit [defined as alcoholic drinks consumption in excess of occasional drinking], and history of morning sickness during pregnancy). Statistical analysis was performed from February 18 to April 18, 2020. Interventions: Patients were randomized 1:1 to receive 5 mg of olanzapine or placebo combined with standard triplet antiemetic therapy. Main Outcomes and Measures: The primary end point was complete response (CR, defined as no vomiting and no use of rescue medication) in the delayed phase (24-120 hours after cisplatin-based chemotherapy administration). Secondary end points were CR, complete control, and total control in the acute, delayed, and overall phases for 6 CINV risk factors as well as time to treatment failure. The CR point estimates and 95% CIs of the differences between groups were calculated, and a Mantel-Haenszel test was performed. Results: Of the 705 patients (mean [SD] age, 63.0 [9.2] years; 471 males [66.8%]) included in the efficacy analysis population; 581 patients (82.4%) were 55 years or older, and 526 (74.6%) were treated with a cisplatin dose of 70 mg/m2 or more. Risk difference (RD) for a CR in the delayed phase was significantly greater in the olanzapine group than the placebo group in males (RD, 12.6% [95% CI, 5.0%-20.1%]; P = .001); in females (RD, 14.5% [95% CI, 2.2%-26.3%]; P = .02); in those 55 years or older (RD, 11.1% [95% CI, 3.9%-18.2%]; P = .003) or younger than 55 years (RD, 23.6% [95% CI, 7.3%-38.3%]; P = .005); for a cisplatin dose of 70 mg/m2 or more (RD, 13.5% [95% CI, 5.9%-21.0%]; P < .001); for those without a history of motion sickness (RD, 13.9% [95% CI, 6.9%-20.6%]; P < .001); for those with a drinking habit (RD, 14.9% [95% CI, 6.1%-23.4%]; P = .001) or without a drinking habit (RD, 12.0% [95% CI, 2.5%-21.3%]; P = .01); and for those with a history of morning sickness during pregnancy (RD, 27.2% [9.7%-42.6%]; P = .002). In other subgroups, a delayed CR was higher in the olanzapine group than the placebo group, although not significantly higher. Conclusions and Relevance: Results of this study suggest a benefit of using 5 mg of olanzapine plus triplet antiemetic therapy to counter CINV regardless of the presence or absence of risk factors. Trial Registration: University Hospital Medical Information Network Clinical Trials Registry Identifier: UMIN000024676.

The Vestibular Time Constant and Clinical Response to Antimotion Sickness Medication.

OBJECTIVE: The therapeutic effects of antimotion sickness medications involve suppression of several components along the vestibular system. Scopolamine-based medications have proved to be the most effective anti-seasickness agents. However, there is high variability in individual responses. The vestibular nuclei, in which the vestibular time constant is modulated, contain acetylcholine receptors which are affected by scopolamine. The hypothesis of the study was that successful seasickness prevention by scopolamine requires vestibular suppression to be reflected by the shortening of the vestibular time constant. DESIGN: Subjects were 30 naval crew members suffering from severe seasickness and were treated with oral scopolamine. The study participants were defined as responsive or non-responsive to the anti-seasickness medication according to the clinical outcome: successful response to scopolamine was defined as a reduction of seasickness severity from the highest score of 7 according to the Wiker scale to 4 or less. Scopolamine and placebo were assigned to each subject in a crossover, double-blind design. The horizontal semicircular canal time constant was evaluated by a computerized rotatory chair before, 1 and 2 hours after drug or placebo administration. RESULTS: The vestibular time constant was significantly shortened from 16.01 ± 3.43 seconds to 12.55 ± 2.40 seconds ( p < 0.001) in the scopolamine-responsive group but not in the nonresponsive group. In contrast, vestibular time constant values were 13.73 ± 4.08 and 12.89 ± 4.48 for baseline and 2 hours measurements, respectively. This change was not statistically significant. CONCLUSIONS: Reduction in the vestibular time constant after scopolamine administration can be used to predict whether motion sickness alleviation will occur. This will enable the administration of appropriate pharmaceutical treatment without the need for prior exposure to sea conditions.

Nutritional and Behavioral Countermeasures as Medication Approaches to Relieve Motion Sickness: A Comprehensive Review.

The mismatch in signals perceived by the vestibular and visual systems to the brain, also referred to as motion sickness syndrome, has been diagnosed as a challenging condition with no clear mechanism. Motion sickness causes undesirable symptoms during travel and in virtual environments that affect people negatively. Treatments are directed toward reducing conflicting sensory inputs, accelerating the process of adaptation, and controlling nausea and vomiting. The long-term use of current medications is often hindered by their various side effects. Hence, this review aims to identify non-pharmacological strategies that can be employed to reduce or prevent motion sickness in both real and virtual environments. Research suggests that activation of the parasympathetic nervous system using pleasant music and diaphragmatic breathing can help alleviate symptoms of motion sickness. Certain micronutrients such as hesperidin, menthol, vitamin C, and gingerol were shown to have a positive impact on alleviating motion sickness. However, the effects of macronutrients are more complex and can be influenced by factors such as the food matrix and composition. Herbal dietary formulations such as Tianxian and Tamzin were shown to be as effective as medications. Therefore, nutritional interventions along with behavioral countermeasures could be considered as inexpensive and simple approaches to mitigate motion sickness. Finally, we discussed possible mechanisms underlying these interventions, the most significant limitations, research gaps, and future research directions for motion sickness.

Risk factors associated with nausea and vomiting in children with cancer receiving chemotherapy.

INTRODUCTION: Despite treatment with antiemetic medications, nausea remains uncontrolled for many children receiving chemotherapy. One reason is that risk factors for nausea in children remain poorly explored. The purpose of this study was to identify risk factors for chemotherapy-induced nausea (CIN) in children. METHODS: Prospective, observational study including 101 children (median age 6.4 years, range 0.8-17.9) with cancer receiving moderately or highly emetogenic chemotherapy. Primary endpoints were complete control of acute and delayed CIN, defined as no nausea in the acute phase 0-24 h after chemotherapy and in the delayed phase starting after the acute phase and ending 5 days later. Multivariable analyses included age, sex, cancer type, susceptibility to motion sickness, chemotherapy duration, numbers of antiemetics, co-administration with opioids or tricyclic antidepressants, and previously uncontrolled nausea or vomiting. RESULTS: Acute CIN was associated with susceptibility to motion sickness (odds ratio [OR] 5.73, 95% confidence interval [CI] 1.36-33.7) and older age (OR 4.19, 95% CI 1.30-14.7), comparing age group 8-18 years with 0-3 years. Delayed CIN was associated with uncontrolled acute nausea or vomiting (OR 10.3, 95% CI 2.65-50.9), highly emetogenic chemotherapy (OR 8.26, 95% CI 1.17-76.8), and having a hematologic cancer type (OR 7.81, 95% CI 1.05-79.2). CONCLUSIONS: Susceptibility to motion sickness and age can influence the risk of acute CIN. More research is needed on how best to integrate risk information in preventive antiemetic strategies. Sufficient acute nausea and vomiting control are crucial to prevent delayed CIN.

Antihistamines for motion sickness.

BACKGROUND: Motion sickness is a syndrome that occurs as a result of passive body movement in response to actual motion, or the illusion of motion when exposed to virtual and moving visual environments. The most common symptoms are nausea and vomiting. Antihistamines have been used in the management of motion sickness for decades, however studies have shown conflicting results regarding their efficacy. OBJECTIVES: To assess the effectiveness of antihistamines in the prevention and treatment of motion sickness in adults and children. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials; Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 7 December 2021. SELECTION CRITERIA: Randomised controlled trials (RCTs) in susceptible adults and children in whom motion sickness was induced under natural conditions such as air, sea and land transportation. We also included studies in which motion sickness was induced under experimental conditions (analysed separately). Antihistamines were included regardless of class, route or dosage and compared to no treatment, placebo or any other pharmacological or non-pharmacological interventions. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1) the proportion of susceptible participants who did not experience any motion sickness symptoms; 2) the proportion of susceptible participants who experienced a reduction or resolution of existing symptoms. Secondary outcomes were 1) physiological measures (heart rate, core temperature and gastric tachyarrhythmia (electrogastrography)) and 2) adverse effects (sedation, impaired cognition, blurred vision). We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included nine RCTs (658 participants). Studies were conducted across seven countries, with an overall age range of 16 to 55 years. Motion sickness was induced naturally in six studies and experimentally in four studies (rotating chair). All the naturally induced studies only evaluated first-generation antihistamines (cinnarizine and dimenhydrinate). Risk of bias across the studies varied, with mostly low risk for random sequence generation and allocation concealment, and mostly high risk for selective reporting. Only the experimentally induced studies measured physiological parameters and only the naturally induced studies evaluated adverse effects. There were no studies that clearly assessed the paediatric population. Antihistamines versus placebo or no treatment Antihistamines are probably more effective than placebo at preventing motion sickness symptoms under natural conditions (symptoms prevented: 25% placebo; 40% antihistamines) (risk ratio (RR) 1.81, 95% confidence interval (CI) 1.23 to 2.66; 3 studies; 240 participants) (moderate-certainty). The evidence is very uncertain about the effect of antihistamines on preventing motion sickness under experimental conditions (standardised mean difference (SMD) 0.32, 95% CI -0.18 to 0.83; 2 studies; 62 participants) (very low-certainty). No studies reported results on the resolution of existing motion sickness symptoms. Antihistamines may result in little or no difference in gastric tachyarrhythmia under experimental conditions (mean difference (MD) -2.2, 95% CI -11.71 to 7.31; 1 study; 42 participants) (low-certainty). No studies reported results for any other physiological measures. When compared to placebo, antihistamines may be more likely to cause sedation (sedation: 44% placebo; 66% antihistamines) (RR 1.51, 95% CI 1.12 to 2.02; 2 studies; 190 participants) (low-certainty); they may result in little or no difference in blurred vision (blurred vision: 12.5% placebo; 14% antihistamines) (RR 1.14, 95% CI 0.53 to 2.48; 2 studies; 190 participants) (low-certainty); and they may result in little or no difference in terms of impaired cognition (impaired cognition: 33% placebo; 29% antihistamines) (RR 0.89, 95% CI 0.58 to 1.38; 2 studies; 190 participants) (low-certainty). Antihistamines versus scopolamine The evidence is very uncertain about the effect of antihistamines on preventing motion sickness under natural conditions when compared to scopolamine (symptoms prevented: 81% scopolamine; 71% antihistamines) (RR 0.89, 95% CI 0.68 to 1.16; 2 studies; 71 participants) (very low-certainty). No studies were performed under experimental conditions. No studies reported results on the resolution of existing motion sickness symptoms. The evidence is very uncertain about the effect of antihistamines on heart rate under natural conditions (narrative report, 1 study; 20 participants; "No difference in pulse frequency"; very low-certainty). No studies reported results for any other physiological measures. When compared to scopolamine, the evidence is very uncertain about the effect of antihistamines on sedation (sedation: 21% scopolamine; 30% antihistamines) (RR 0.82, 95% CI 0.07 to 9.25; 2 studies; 90 participants) (very low-certainty) and on blurred vision (narrative report: not a significant difference; 1 study; 51 participants; very low-certainty). No studies evaluated impaired cognition. Antihistamines versus antiemetics Antihistamines may result in little or no difference in the prevention of motion sickness under experimental conditions (MD -0.20, 95% CI -10.91 to 10.51; 1 study; 42 participants) (low-certainty). The evidence is of low certainty due to imprecision as the sample size is small and the confidence interval crosses the line of no effect. No studies assessed the effects of antihistamines versus antiemetics under natural conditions. No studies reported results on the resolution of existing motion sickness symptoms. Antihistamines may result in little or no difference in gastric tachyarrhythmia (MD 4.56, 95% CI -3.49 to 12.61; 1 study; 42 participants) (low-certainty). No studies reported results for any other physiological measures. No studies evaluated sedation, impaired cognition or blurred vision. One study reported physiological data for this outcome, evaluating gastric tachyarrhythmia specifically. Antihistamines may result in little or no difference in gastric tachyarrhythmia (MD 4.56, 95% CI -3.49 to 12.61; 1 study; 42 participants; low-certainty evidence). This evidence is of low certainty due to imprecision as the sample size is small and the confidence interval crosses the line of no effect. Antihistamines versus acupuncture The evidence is very uncertain about the effects of antihistamines on the prevention of motion sickness under experimental conditions when compared to acupuncture (RR 1.32, 95% CI 1.12 to 1.57; 1 study; 100 participants) (very low-certainty). This study did not assess the prevention of motion sickness under natural conditions, nor the resolution of existing motion sickness symptoms. There was no study performed under natural conditions. Physiological measures and adverse effects were not reported. AUTHORS' CONCLUSIONS: There is probably a reduction in the risk of developing motion sickness symptoms under naturally occurring conditions of motion when using first-generation antihistamines, in motion sickness-susceptible adults, compared to placebo. Antihistamines may be more likely to cause sedation when compared to placebo. No studies evaluated the treatment of existing motion sickness, and there are few data on the effect of antihistamines in children. The evidence for all other outcomes and comparisons (versus scopolamine, antiemetics and acupuncture) was of low or very low certainty and we are therefore uncertain about these effects of antihistamines.

Formulation and optimization of dimenhydrinate emulgels for topical delivery using response surface methodology.

Development of dimenhydrinate (DMN) emulgel formulation has been described in this work with enhanced permeation for transdermal delivery of DMN for effective management of motion sickness. Various DMN emulgel formulations were prepared using central composite design in response surface methodology. Propylene glycol and olive oil were used in varying ratios as permeation enhancers along-with carbopol-934 as gelling agent. Prepared formulations were evaluated by physico-chemical properties, stability and Fourier transform infrared spectroscopy (FTIR) studies. In-vitro drug release was studied using cellophane membrane. Formulation F2 showed maximum drug permeation following diffusion-based release mechanism and was used in further studies. Rat skin was used in Franz cell for ex-vivo studies to determine various permeation kinetic parameters. FTIR studies provided no evidence of chemical interaction between DMN and polymers used, whereas molecular docking revealed formation of a stable complex in the presence of aqueous environment with stable intermolecular binding and the complex was well hydrated. No evidence of skin irritation was observed in human volunteers following application of the optimized formulation. Histopathology data of the rat skin showed a decreased proliferation of the lymphocytes whereas monocytes were induced. In conclusion, combination of propylene glycol and olive oil was successfully employed for delivery of DMN through transdermal route with good permeability and prolonged release time that can be highly beneficial in treating motion sickness in unusual circumstances.

Influence of Inosine on Cerebral Hemodynamics in Space Motion Sickness in Experimental Animals.

BACKGROUND: Motion sickness occurs worldwide in healthy individuals regardless of age, ethnicity, or gender. It is an acute disorder; it can also present as a chronic disorder in some individuals. Motion sickness not only includes vomiting and nausea, but also includes other features such as pallor of varying degrees, cold sweating, headache, drowsiness, increased salivation, and cranial pain, which are severe. Some of the other assessment scales can interpret sickness on exposure to virtual or visual stimulation and while travelling in different types of transport. AIM: The aim of our research is to study the effect of the drug on the level of blood flow and vascular reactivity of cerebral vessels when simulating changes in the cerebral circulation in terrestrial conditions characteristic of hypogravity. METHODS: Chronic experiments were performed on non-anesthetized rabbits with large hemispheres, thalamus and hypothalamus were implanted with the needle-platinum electrodes 150 mm in diameter in the cortex, and local blood flow and vascular reactivity were recorded accordingly. Cerebrovascular disturbances were modeled using an MSAOP (motion sickness of animals in the anti-orthostatic position) with an inclined angle of 45° for 2 hours. Local blood flow (BF) was measured in ml/min/100g of tissue by the method of registration of hydrogen clearance. The vasodilator coefficient of reactivity (CrCO2) was calculated by the ratio of BF against the background of inhalation of a mixture of 7% CO2 with air to the initial BF; vasoconstrictor - in relation to BF on the background of inhalation of 100% O2 to the initial BF (CrO2). A series of experiments were carried out with different routes of drug administration: First, inosine was administered intravenously at a dose of 5 mg/kg immediately before the start of SMS modeling, same dose was administered 30 minutes before the start of exposure. As a control, we used the results of experimental animals under similar conditions without the administration of the drugs. RESULTS: Inosine has pronounced protective properties in cerebrovascular disorders on the background of space motion sickness (SMS) modeling, which is manifested by normalization of BF and restoration of compensatory reactions of cerebral vessels. In the mechanism of cerebroprotective action of inosine, it is able to correct the metabolic processes, which play an important role and help increase the compensatory capabilities and functional stability of the cerebrovascular system under gravitational influences. CONCLUSION: When using inosine orally, the effects are more pronounced than when administered intravenously, which should be taken into account when using it for the prevention of cerebrovascular disorders in extreme conditions.

Integrated metabolomics and network pharmacology approach to exploring the potential mechanism of tianxiang capsule for treating motion sickness.

ETHNOPHARMACOLOGICAL RELEVANCE: Motion sickness is a multi-system syndrome caused by abnormal spatial environmental sensory conflicts. Tianxiang Capsule (TXC) is a traditional Chinese medicine (TCM) formula for the prevention and treatment of motion sickness for years. However, the main active components of TXC and mechanism of its therapeutic effects on motion sickness are still unclear. AIM OF THE STUDY: The purpose of this work is to investigate the mechanism of TXC in preventing motion sickness based on serum metabolomics and network pharmacology. On the basis of the clear validation of the anti-motion sickness effect of TXC, we used the strategy of combined GC-MS metabolomics and network pharmacology to screen 60 differential metabolites regulated by TXC. MATERIALS AND METHODS: The rat models of motion sickness were stimulated by biaxial rotational acceleration, spontaneous activity was used to evaluate the efficacy of TXC on motion sickness. Serum metabolomics-based analysis was conducted to screen the differential metabolites related to motion sickness. Then, network pharmacology analysis was used to integrate the information of differential metabolites with target proteins and chemical components, and the "components-target protein-metabolite related protein-metabolite" network was constructed to explore the mechanism of the protective effect of TXC against motion sickness. RESULTS: The results of network integration analysis showed that the 50 TXC potential active ingredients mediated the differential expression of 49 metabolic biomarkers by targeting 25 target protein and regulated arachidonic acid metabolism, calcium signaling pathways, etc. In addition, we found that TXC can promote the secretion of insulin mediated by arachidonic acid pathway metabolites, regulate the levels of adrenaline and leptin, maintain blood glucose balance, and achieve the therapeutic effect of motion sickness. CONCLUSIONS: Our results indicated that the arachidonic acid metabolic pathway and related targets are the key ways for TXC to exert its efficacy, and its target protein and anti-motion sickness mechanism deserve further study. Our work proved that the integrated strategy of metabolomics and network pharmacology can well explain the "multi-component - multi-target" mechanism of complex TCM in vivo, which is a practical approach for the study of TCM formula.

Scopolamine Treatment and Adaptation to Airsickness.

BACKGROUND: Airsickness is a clinical syndrome manifesting in a variety of symptoms, particularly nausea and vomiting during flight. Studies of habituation to motion sickness in humans treated by scopolamine have produced conflicting results. The drug accelerated habituation, but a rebound effect on symptom severity was observed after its withdrawal. The purpose of the present study was to investigate whether scopolamine affects the adaptation process. We also evaluated the relationship between initial symptom severity and adaptation to airsickness.METHODS: Aviator cadets in the first two stages of their training were divided into two groups, treated and not treated by scopolamine. Airsickness severity was evaluated using both simulator sickness and motion sickness questionnaires, and drug administration was recorded.RESULTS: A statistically significant higher rate of adaptation was observed among the scopolamine-treated group compared with the nontreated group. On the simulator sickness questionnaire, rate of adaptation for the two groups was -0.21 ± 0.53 and -0.1 ± 0.17, respectively, and for the motion sickness questionnaire -2.34 ± 1.54 and -0.91 ± 1.41, respectively. Examination of a possible connection between initial symptom severity and adaptation rate failed to reveal a significant relationship.CONCLUSIONS: We recommend the use of oral scopolamine to accelerate habituation and find it a relatively safe short-term treatment for airsickness. Our results support the notion that scopolamine accelerates the natural adaptation process.Doron O, Samuel O, Karfunkel-Doron D, Tal D. Scopolamine treatment and adaptation to airsickness. Aerosp Med Hum Perform. 2020; 91(4):313-317.

Inner Ear Arginine Vasopressin-Vasopressin Receptor 2-Aquaporin 2 Signaling Pathway Is Involved in the Induction of Motion Sickness.

It has been identified that arginine vasopressin (AVP), vasopressin receptor 2(V2R), and the aquaporin 2 (AQP2) signaling pathway in the inner ear play important roles in hearing and balance functions through regulating the endolymph equilibrium; however, the contributions of this signaling pathway to the development of motion sickness are unclear. The present study was designed to investigate whether the activation of the AVP-V2R-AQP2 signaling pathway in the inner ear is involved in the induction of motion sickness and whether mozavaptan, a V2R antagonist, could reduce motion sickness. We found that both rotatory stimulus and intraperitoneal AVP injection induced conditioned taste aversion (a confirmed behavioral index for motion sickness) in rats and activated the AVP-V2R-AQP2 signaling pathway with a responsive V2R downregulation in the inner ears, and AVP perfusion in cultured epithelial cells from rat endolymphatic sacs induced similar changes in this pathway signaling. Vestibular training, V2R antagonist mozavaptan, or PKA inhibitor H89 blunted these changes in the V2R-AQP2 pathway signaling while reducing rotatory stimulus- or DDAVP (a V2R agonist)-induced motion sickness in rats and dogs. Therefore, our results suggest that activation of the inner ear AVP-V2R-AQP2 signaling pathway is potentially involved in the development of motion sickness; thus, mozavaptan targeting AVP V2Rs in the inner ear may provide us with a new application option to reduce motion sickness. SIGNIFICANCE STATEMENT: Motion sickness affects many people traveling or working. In the present study our results showed that activation of the inner ear arginine vasopressin-vaspopressin receptor 2 (V2R)-aquaporin 2 signaling pathway was potentially involved in the development of motion sickness and that blocking V2R with mozavaptan, a V2R antagonist, was much more effective in reducing motion sickness in both rat and dog; therefore, we demonstrated a new mechanism to underlie motion sickness and a new candidate drug to reduce motion sickness.

The effects of meclizine on motion sickness revisited.

AIMS: Antihistamines make up the first line of treatments against motion-sickness. Still, their efficacy and specific mechanism have come into question. The aim of this study was to investigate the effect of meclizine on motion-sensitivity. METHODS: This study was carried out as a triple-blinded randomized trial involving 12 healthy subjects who were exposed to (i) vestibular (VES), (ii) visual (VIS) and (iii) visual-vestibular (VIS+VES) stimulations in the roll plane. Subjects were divided into 2 groups by stratified randomization, receiving either meclizine or a placebo. Stimulations were carried out before, and after, drug administration, presented at 2 intensity levels of 14 and 28°/s2 . Eye movements were tracked, and torsional slow-phase velocities, amplitudes and nystagmus beats were retrieved. Subjects initially graded for their motion-sickness susceptibility. RESULTS: Susceptibility had no effect on intervention outcome. Despite large variations, repeated ANOVAS showed that meclizine led to a relative increase in torsional velocity compared to placebo during vestibular stimulation for both intensities: 2.36 (7.65) from -0.01 (4.17) during low intensities, and 2.61 (6.67) from -3.49 (4.76) during high. The visual-vestibular stimuli yielded a decrease during low acceleration, -0.40 (3.87) from 3.75 (5.62), but increased during high, 3.88 (6.51) from -3.88 (8.55). CONCLUSIONS: Meclizine had an inhibitory effect on eye movement reflexes for low accelerations during VIS+VES trials. This indicates that meclizine may not primarily work through sensory-specific mechanisms, but rather on a more central level. Practically, meclizine shows promise in targeting motion-sickness evoked by everyday activities, but its use may be counterproductive in high-acceleration environments.

Intranasal Scopolamine for Motion Sickness.

INTRODUCTION: Rapid onset, noninjection methods are required to provide "as needed" therapy for motion sickness. Intranasal scopolamine (IN SCOP) is attractive because it can be fast acting and work when gastric motility is slowed. Intranasal administration can provide a time to maximal concentration (Tmax) of drugs (e.g., naloxone and midazolam) of 30 min or less. We evaluated the efficacy, pharmacodynamics, and pharmacokinetics of IN SCOP in a placebo-controlled, randomized, double-blind, dose-ranging study, and compared pharmacokinetic outcomes against other published results.METHODS: There were 18 healthy adult volunteers (10 M, 8F) who received placebo, low dose (0.2 mg), and high dose (0.4 mg) IN SCOP intranasally using a pump device and a gel formulation. Participants rode in an off-vertical axis rotation (OVAR) chair 1.25 h after dose administration and completed neurocognitive tests to evaluate secondary drug impacts. Pharmacokinetics (PK) and pharmacodynamics (PD) were assessed in eight subjects. PK data were compared to results from previously published studies.RESULTS: Low and high dose IN SCOP increased chair time significantly compared to placebo. No significant sleepiness or cognitive impairment was seen, likely due to the small sample size. Tmax was long for both dosages (High dose 75.0 ± 49.4 min, Low dose 61.9 ± 37.1 min), compared to other intranasally administered drugs and some previous studies with IN SCOP. Average Tmax was not superior to previously published values for dose-matched (0.4-0.5 mg), orally-delivered SCOP.DISCUSSION: IN SCOP has potential as a rapid administration route for relieving MS symptoms, but more work is needed to identify optimal intranasal formulation and dispensing methods.KEYWORDS: Motion sickness, pharmacokinetics, scopolamine, intranasal administration.Stankovic AS, Alvarenga DL, Daniels VRC, Simmons RG, Buckey JC, Putcha L. Intranasal scopolamine for motion sickness. Aerosp Med Hum Perform. 2019; 90(11):917-924.