Application of Chaihu-Guizhi-Longgu-Muli decoction combined with Liuwei Dihuang Pills in the treatment of menopausal insomnia and its effect on sleep quality.

To explore the application of Chaihu-Guizhi-Longgu-Muli decoction (CGLM) combined with Liuwei Dihuang Pills in the treatment of menopausal insomnia and its effect on sleep quality. The data of 120 menopausal insomnia patients admitted to our hospital from February 2019 to February 2020 were retrospectively analyzed and they were equally divided into the experimental group (n=60) and the control group (n=60) according to the order of admission. All patients were treated with Liuwei Dihuang Pills, and the experimental group was additionally given CGLM. The Pittsburgh Sleep Quality Index (PSQI), estrogen level, negative emotion score, quality of life score, serum ß-endorphin (ß-EP) level, serotonin level (5-HT) and treatment effective rate were compared between the two groups of patients. After treatment, the experimental group obtained markedly lower PSQI scores and negative emotion scores than the control group (P<0.001). The estrogen levels, ß-EP levels and 5-HT levels of the experimental group after treatment were significantly better than those of the control group (P<0.001). Higher quality of life scores and treatment effective rates were observed in the experimental group after treatment than the control group (P<0.001). CGLM combined with Liuwei Dihuang Pills can regulate the serum hormone levels of patients with menopausal insomnia, reduce negative emotions and improve sleep quality and quality of life, which merits clinical promotion.

Soporific effect of modified Suanzaoren Decoction on mice models of insomnia by regulating Orexin-A and HPA axis homeostasis.

AIM: Modified Suanzaoren Decoction (MSZRD) is obtained by improving Suanzaoren Decoction (SZRT), a traditional Chinese herbal prescription that has been used to treat insomnia for more than thousands of years. Our previous study showed that MSZRD can improve the gastrointestinal discomfort related insomnia by regulating Orexin-A. This study is the first study to evaluate the effects and possible mechanisms of MSZRD in mice with insomnia caused by p-chlorophenylalanine (PCPA) combined with multifactor random stimulation. METHODS: After 14 days of multifactor stimulation to ICR mice, a PCPA suspension (30 mg/mL) was injected intraperitoneally for two consecutive days to establish an insomnia model. Three different doses of MSZRD (3.6, 7.2, and 14.4 g/kg/day) were given to ICR mice for 24 days. The food intake and back temperature were measured, and behavioral tests and pentobarbital sodium-induced sleep tests were conducted. The levels of Orexin-A, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and adrenocortical hormones (CORT) in the serum and 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE) in hypothalamus were measured using enzyme-linked immunosorbent assay (ELISA) kits. The levels of γ-aminobutyric acid (GABA) and glutamic acid (Glu) were measured by high-performance liquid chromatography (HPLC). The expression of 5HT1A receptor (5-HTRIA) and orexin receptor 2 antibody (OX2R) was measured by Western blot (WB) and immunohistochemical staining (ICH). Hematoxylin and eosin (H&E) staining and Nissl staining were used to assess the histological changes in hypothalamus tissue. RESULTS: Of note, MSZRD can shorten the sleep latency of insomnia mice (P < 0.05, 0.01), prolonged the sleep duration of mice (P < 0.05, 0.01), and improve the circadian rhythm disorder relative to placebo-treated animals. Furthermore, MSZRD effectively increased the content of 5-HT and 5-HTR1A protein in the hypothalamus of insomnia mice (P < 0.05, 0.01), while downregulated the content of DA and NE (P < 0.05, 0.01). Importantly, serum GABA concentration was increased by treatment with MSZRD (P < 0.05), as reflected by a decreased Glu/GABA ratio (P < 0.05). Moreover, MSZRD decreased the levels of CORT, ACTH, and CRH related hormones in HPA axis (P < 0.05, 0.01). At the same time, MSZRD significantly downregulated the serum Orexin-A content in insomnia mice (P < 0.05), as well as hypothalamic OX2R expression (P < 0.05). In addition, MSZRD also improved the histopathological changes in hypothalamus in insomnia mice. CONCLUSION: MSZRD has sleep-improvement effect in mice model of insomnia. The mechanism may be that regulating the expression of Orexin-A affects the homeostasis of HPA axis and the release of related neurotransmitters in mice with insomnia.

Successful treatment of restless leg syndrome with the traditional herbal medicines Dangguijakyak-san and Shihogyeji-tang: A case report (CARE-compliant).

RATIONALE: Dopamine replacement is currently the standard treatment for restless leg syndrome (RLS); however, various adverse effects are associated with long-term therapy, and the benefits disappear upon discontinuation. To overcome these limitations, interest in traditional East Asian medicine has increased. PATIENT CONCERNS: A 72-year-old Asian woman originally admitted for an intracerebral hemorrhage presented with complaints of an unpleasant sensation throughout the body that appeared at night. DIAGNOSES: The patient was diagnosed with chronic persistent RLS based on the 2012 Revised International Restless Leg Syndrome Study Group Diagnostic Criteria. INTERVENTIONS: The patient was treated with extracts of the traditional herbal medicines Dangguijakyak-san (DS) and Shihogyeji-tang (ST). After 47 days of therapy, all herbal medicines were discontinued, and symptoms had not returned by the last follow-up 244 days after the initial treatment. OUTCOMES: One week after initiating herbal treatment with DS and ST, the RLS symptoms began to improve, and the total hours of sleep had increased from 2 to 9 hours by day 21, with a Korean version of the international restless legs scale score of 11 points. On day 36, ST was discontinued, given the continued improvement of symptoms. On day 47, symptoms had disappeared (Korean version of the international restless legs scale score: 0), and sleep disturbances caused by RLS had completely resolved. After day 47, DS was also discontinued. There were no adverse effects associated with the administration of DS and ST, and the symptoms had not recurred by the last follow-up on day 244. LESSONS: In this case, RLS related symptoms, which had been present for approximately 60 years, were improved using only the traditional herbal medicines DS and ST (without dopamine replacement), and no symptoms recurred for 244 days. This case suggests that if replacement therapy is difficult or not desired, herbal medicinal therapies may be an effective alternative. This also suggests that the effect of herbal medicine on RLS might be semi-permanent. Further investigations, including clinical trials, are needed to confirm these effects.

Study on the mechanism of regulating the hypothalamic cortical hormone releasing hormone/corticotropin releasing hormone type I receptor pathway by vibro-annular abdominal massage under the brain-intestine interaction in the treatment of insomnia.

BACKGROUND: Insomnia is a common disease associated with different nervous system stress response and endocrine disorders. It has been reported previously that abdominal vibration and ring massage therapy can significantly improve the symptoms of insomnia patients, enhance the activity of neurons. In addition, functional MRI (resting state brain functional magnetic resonance imaging [Rs_fMRI]) of the resting state brain test has proved that the functional connection between hypothalamus and parahippocampal gyrus could be significantly enhanced after abdominal massage treatment. It has been confirmed that there is possible involvement of brain-gut interaction effect in the treatment of insomnia, but there is a lack of research to elucidate the possible mechanisms of brain-gut interaction in the treatment of insomnia. The purpose of this study is to investigate the relationship between the hypothalamus and intestinal interaction in the treatment of insomnia by abdominal massage. METHODS AND DESIGN: A single blind randomized controlled trial will be conducted. Sixty chronic insomnia volunteers and 30 healthy volunteers will be recruited for this study. Sixty insomnia volunteers will be randomly divided into a drug group and a massage group, and 30 healthy volunteers will be assigned to the healthy group. The manipulation of the treatment group will be mainly carried out through abdominal rubbing and vibration massage, once a day, 30 min/time, 5 days for a course of treatment, and a total of 4 intervention courses will be carried out. Patients in the drug group will be given orally spleen-invigorating bolus, twice a day, 1 pill in the morning and 1 pill in the evening. The course of treatment will be carried for 5 days, and a total of 4 courses of treatment will be administered.The massage group will be compared with the healthy group and the drug group by Pittsburgh Sleep Index scale (PSQI), Hyperarousal scale (HAS), Hamilton Depression scale (HAMD), Fatigue scale-14 (FS-14), and Wechsler Adult Memory scale (WAIS) scales using to observe the sleep quality. Rs-fMRI will be used to observe various BOLD signals in the brain and compare the values of Reho, fALFF, and FC. MRS technology will be used to observe the contents of GABA and 5-HT in the hypothalamus. Additionally, the contents of cortical hormone releasing hormone (CRH), adrenocorticotropic hormone (ACTH), COR, GABA, NE, PGE2, and 5-HT in the serum will be also detected. The serum of each group will be taken for 1H nuclear magnetic resonance (1HNMR) metabolomics study to analyze the various common metabolites, differential metabolites, potential metabolic biomarkers, and metabolic pathways among the 3 groups. Finally, in combination with the brain functional imaging and brain spectrum, the potential mechanism of abdominal vibration and ring massage will be discussed. DISCUSSION: The results of this study will be used to possibly elaborate the various mechanisms of brain and intestine interaction in the treatment of insomnia by employing abdomen ring rubbing.

Acupuncture stimulation at HT7 as a non-pharmacological therapy for sleep disorder caused by caffeine administration in rats.

OBJECTIVES: Insomnia is one of the most common sleep disorders and is difficult to completely treat because of the undesirable side effects of hypnotics. The present study was designed to investigate the hypnotic effect of acupuncture stimulation at HT7 on caffeine-induced sleep disorders and locomotor activity in rats. We also evaluated neuronal activity changes in the arousal region of the basal forebrain. METHODS: Rats received intraperitoneal injections of caffeine, and then electroencephalogram power spectrum analysis and locomotor activity measurements were performed. Stimulation at HT7 was performed using a mechanical acupuncture instrument (MAI) before caffeine injection, and its effects on caffeine-induced changes in sleep architecture, locomotor activity and c-Fos expression were examined. RESULTS: Caffeine injection (7.5 mg/kg) produced a significant decrease in slow-wave sleep and an increase in wake time compared with saline injection. Caffeine injection also increased locomotor activity and c-Fos expression in the medial septum-vertical limb of the diagonal band of Broca (MS-VDB), one of the arousal regions of the basal forebrain. Stimulation at HT7 with the MAI alleviated the caffeine-induced sleep disturbance and the increase in locomotor activity. In addition, MAI treatment at HT7, compared with treatment at a location not corresponding to any traditional acupuncture point, reduced the caffeine-induced increase in c-Fos expression. CONCLUSION: These results indicate that the hypnotic effect of HT7 acupuncture stimulation on caffeine-induced insomnia was associated with suppression of neuronal activity in the basal forebrain.

Study on acupuncture improving insomnia comorbid with depression and anxiety based on rs-fMRI: A protocol for systematic review and meta-analysis.

BACKGROUND: Long term insomnia and low sleep quality often lead to depression, anxiety and other negative emotions, and often interact with each other. Many studies have confirmed the effectiveness of acupuncture in the treatment of insomnia comorbid with emotional disorders, but its specific mechanism needs to be further explored. Resting-state functional magnetic resonance (rsfMRI) is an important means to study the changes of brain activity. However, the results are inconsistent and lack of systematic evaluation and analysis. METHODS: Nine databases will be searched, including PubMed, EMBASE, EBSCOhost-medline, Web of Science, Cochrane Library, China National Knowledge Infrastructure, VIP Database and Wan-Fang Database, Chinese Biomedical Literature Database from inception to January 2021. And screening clinical registration platform related research, in order to obtain more relevant studies. The outcomes include the change of rs-fMRI, sleep quality, depression, and anxiety. Quality assessment of the included studies will be performed according to the Cochrane Risk of Bias tool. Evidence quality will be assessed by using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. RevMan software (Version 5.3) and stata13.1will be used for statistical analyses. Subgroup analysis will be performed if necessary. If the data is insufficient, qualitative synthesis will be conducted instead of quantitative synthesis. RESULTS: This study will analyze the effect of acupuncture on the brain activity changes, improvement of sleep quality and clinical symptoms of anxiety and depression with insomnia comorbid with emotional disorders. CONCLUSION: This study used meta-analysis method to explore the characteristics of acupuncture on brain activity changes in insomnia comorbid with emotional disorders, so as to provide effective evidence for clarifying its pathogenesis.

Effects of acupuncture versus cognitive behavioral therapy on brain-derived neurotrophic factor in cancer survivors with insomnia: an exploratory analysis.

INTRODUCTION: Decreased brain-derived neurotrophic factor (BDNF) is associated with poor sleep. This study examined the effects of acupuncture versus cognitive behavioral therapy for insomnia (CBT-I) on serum BDNF and sleep outcomes in cancer survivors with insomnia. METHODS: This was an exploratory analysis of a randomized clinical trial (n = 160) comparing acupuncture versus CBT-I for cancer survivors with insomnia. Interventions were delivered over 8 weeks. Outcomes were assessed at baseline and week 8. Serum BDNF was evaluated with enzyme-linked immunosorbent assay (ELISA). Sleep was evaluated with the insomnia severity index and consensus sleep diary. Pearson correlations between BDNF and sleep outcomes were calculated. Data analysis was limited to 87 survivors who provided serum samples. RESULTS: Among 87 survivors, the mean age was 61.9 (SD: 11.4) years, 51.7% were women, and 24.1% were non-White. Mean serum BDNF did not significantly increase in acupuncture (n = 50) or CBT-I (n = 37) groups. When analysis was restricted to patients with low baseline BDNF (i.e. levels below the sample median of 47.1 ng/mL), the acupuncture group (n = 22) demonstrated a significant 7.2 ng/mL increase in mean serum BDNF (P = 0.03), whereas the CBT-I group (n = 21) demonstrated a non-significant 2.9 ng/mL increase (P = 0.28). Serum BDNF was not significantly correlated with sleep outcomes (all P > 0.05). CONCLUSION: Among cancer survivors with insomnia and low baseline BDNF, acupuncture significantly increased serum BDNF levels; however, the clinical significance of this finding requires further investigation.Trial registration no. NCT02356575 (ClinicalTrials.gov).

Clinical evaluation of the pharmacological impact of ashwagandha root extract on sleep in healthy volunteers and insomnia patients: A double-blind, randomized, parallel-group, placebo-controlled study.

ETHNOPHARMACOLOGICAL RELEVANCE: Ashwagandha (Withania somnifera (L.) Dunal.) is long known for its sleep-inducing effects. Ashwagandha can be proposed as an alternative to the recommended present treatments for insomnia. This study aimed to evaluate the pharmacological effect of Ashwagandha root extract on sleep in healthy subjects and also in the subjects having insomnia. MATERIAL AND METHODS: We performed a randomized, parallel-group, stratified design, placebo-controlled study. A total of 80 eligible participants, 40 in Arm-A (healthy) and 40 in Arm-B (insomnia) were assigned to two groups, either Ashwagandha or placebo and studied for 8-weeks. The assessment was done based on the sleep parameters (Sleep Onset Latency, Total Sleep Time, Wake After Sleep Onset, Total time in bed, and Sleep Efficiency), Pittsburgh Sleep Quality Index and Hamilton Anxiety scale-A questionnaire, mental alertness on rising assessment, and sleep quality questionnaire. Safety and adverse events along with the concomitant medication were also assessed. RESULTS: In both healthy and insomnia subjects, there was a significant improvement in the sleep parameters in the Ashwagandha root extract supplemented group. The improvement was found more significant in insomnia subjects than healthy subjects. Repeat measure Analysis of variance (ANOVA) confirmed the significant improvement in SOL (p 0.013), HAM-A outcomes (p < 0.05), mental alertness (p 0.01), and sleep quality (p < 0.05) of the insomnia patients. A two-way ANOVA was used to confirm the outcomes that denoted sleep onset latency (p < 0.0001) and sleep efficiency (p < 0.0001) as the most improved parameters, followed by TST (p < 0.002) and WASO(p < 0.040). All these parameters (SOL, TST, WASO, TIB, SE, PSQI, HAM-A, Mental Alertness, and Sleep quality) were also statistically assessed for the significant improvement within the group both for the treatment, and the placebo groups in the healthy and the insomnia datasets. Obtained results suggest statistically significant (p < 0.0001) changes between the baseline values and the end of the study results except for the HAM-A and the mental alertness scoresn the healthy subject group. CONCLUSION: The present study confirms that Ashwagandha root extract can improve sleep quality and can help in managing insomnia. Ashwagandha root extract was well tolerated by all the participants irrespective of their health condition and age. Additional clinical trials are required to generalize the outcome.

Altered thalamic connectivity in insomnia disorder during wakefulness and sleep.

Insomnia disorder is the most common sleep disorder and has drawn increasing attention. Many studies have shown that hyperarousal plays a key role in the pathophysiology of insomnia disorder. However, the specific brain mechanisms underlying insomnia disorder remain unclear. To elucidate the neuropathophysiology of insomnia disorder, we investigated the brain functional networks of patients with insomnia disorder and healthy controls across the sleep-wake cycle. EEG-fMRI data from 33 patients with insomnia disorder and 31 well-matched healthy controls during wakefulness and nonrapid eye movement sleep, including N1, N2 and N3 stages, were analyzed. A medial and anterior thalamic region was selected as the seed considering its role in sleep-wake regulation. The functional connectivity between the thalamic seed and voxels across the brain was calculated. ANOVA with factors "group" and "stage" was performed on thalamus-based functional connectivity. Correlations between the misperception index and altered functional connectivity were explored. A group-by-stage interaction was observed at widespread cortical regions. Regarding the main effect of group, patients with insomnia disorder demonstrated decreased thalamic connectivity with the left amygdala, parahippocampal gyrus, putamen, pallidum and hippocampus across wakefulness and all three nonrapid eye movement sleep stages. The thalamic connectivity in the subcortical cluster and the right temporal cluster in N1 was significantly correlated with the misperception index. This study demonstrated the brain functional basis in insomnia disorder and illustrated its relationship with sleep misperception, shedding new light on the brain mechanisms of insomnia disorder and indicating potential therapeutic targets for its treatment.

Hypnotic Activity of Capparis spinosa Hydro-alcoholic Extract in Mice.

BACKGROUND: Sleep disorders are among the most common psychiatric and medical conditions. Herbal medicine appears to be effective in the treatment of sleep disorders which have been valued by many of publications and patents. OBJECTIVE: The present study aimed at investigating the hypnotic activity of the hydro-alcoholic extract of Capparis spinosa (HAE) in mice. METHODS: Three doses of HAE (30, 60 and 120 mg/kg) and three fractions of it, namely n-hexane fraction (NHF), water fraction (WF), and ethyl acetate fraction (EAF), were given in comparison with diazepam (3 mg/kg body weight i.p.) as a positive control and saline as a negative control. After 30 min, pentobarbital (30 mg/kg body weight i.p.) was administered. In addition, LD50 of HAE was examined and the cytotoxicity of HAE was assessed in l929 cells using the MTT assay. Moreover, for motorcoordination ability, 30 mins after administration of HAE, the rotarod test was performed. RESULTS: The results exhibited that the HAE and all the fractions significantly augmented pentobarbital induced sleeping time, which was comparable to that of induced by diazepam. The LD50 value was 2.4 g/kg. The extract did not induce any cytotoxic effects in L929 fibroblast cells. HAE did not affect the animals' performance on the rotarod test. CONCLUSION: Our finding suggests that the hydro-alcoholic extract of C. spinosa possesses a hypnotic potential that may require further scientific investigations.

Biological rhythms and chronotherapeutics in depression.

Depressive syndromes are frequent and heterogeneous brain conditions with more than 90% of patients suffering from sleep complaints. Better characterizing this "sleep" domain may allow to both better treat acute episodes with existing chronotherapeutics, but also to prevent the manifestation or recurrences of mood disorders. This work aims to i) review theoretical and fundamental data of chronotherapeutics, and ii) provide practical recommendations. Light therapy (LT) can be used as a first-line monotherapy of moderate to severe depression of all subtypes. LT can be also used as a combination with antidepressant to maximize patients' response rates, which has a clear superiority to antidepressant alone. Sleep deprivation (SD) is a rapid and powerful chronotherapeutic with antidepressant responses within hours in 45-60% of patients with unipolar or bipolar depression. Different strategies should be combined to stabilize the SD antidepressant effect, including concomitant medications, repeated SD, combination with sleep phase advance and/or LT (triple chronotherapy). Melatonin treatment is of interest in remitted patients with mood disorder to prevent relapses or recurrences, if a complaint of insomnia, poor sleep quality or phase delay syndrome is associated. During the acute phase, melatonin could be used as an adjuvant treatment for symptoms of insomnia associated with depression. The cognitive behavioral therapy for insomnia (CBT-I) can be recommend to treat insomnia during euthymic phases. The Interpersonal and social rhythm therapy (IPSRT) is indicated for the acute treatment of bipolar depression and for the prevention of mood episodes. Chronotherapeutics should always be associated with behavioral measures for healthy sleep.

Sedative and hypnotic effects of Perilla frutescens essential oil through GABAergic system pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine believes that depression syndrome has become one of the core pathogenesis of insomnia. The pharmacology of traditional Chinese medicine points out that Perilla frutescens has the effect of regulating Qi and relieving depression, promoting Qi circulation to relieve pain, so Perilla frutescens may have the potential therapeutic effect on insomnia. Related studies have reported the sedative and hypnotic effects of Perilla frutescens, but these studies have not yet explored the mechanism of sedative and hypnotic effects of Perilla frutescens essential oil (PFEO) through inhalation administration. AIM OF THE STUDY: The purpose of this study is to explore the underlying sedative and hypnotic mechanisms of PFEO through the GABAergic system pathways. MATERIALS AND METHODS: Established the PCPA insomnia model of mice, The open field test, pentobarbital-induced falling asleep rate, latency of sleeping time, and duration of sleeping time experiments were used to evaluate the behavior of mice, the enzyme-linked immunosorbent assay was used to analyze the content of 5-HT and GABA in hypothalamus and cerebral cortex. Immunohistochemical experiment, Western blot experiment and RT-PCR experiment were used to study the mechanism of PFEO through GABAergic pathway to regulate insomnia. The main volatile constituents of PFEO were analyzed by gas chromatography-mass spectrometry (GC-MS). RESULTS: The inhalation of PFEO has sedative and hypnotic effects, which reduce significantly the autonomic activity of PCPA insomnia mice, increase falling asleep rate, shorten latency of sleeping time, and prolong duration of sleeping time; the results of enzyme-linked immunosorbent assay show that PFEO increase the content of 5-HT and GABA in hypothalamus and cerebral cortex. The results showed that inhalation of PFEO increase the expression of GABAAα1 and GABAAα2 positive cells, increase the level of GABAAα1 and GABAAα2 protein and also increase the level of GABAAα1 mRNA and GABAAα2 mRNA in the hypothalamus and cerebral cortex. The highest content of PFEO is Perillaldehyde (54.37%), followed by 1,4-Cineole (7.42%), Acetaldehyde diethyl acetal (6.61%), D-Limonene (5.09%), Eucalyptol (4.94%), etc. CONCLUSION: The inhalation of PFEO has sedative and hypnotic effects, it is speculated that the mechanism of which may be the sedative and hypnotic effects through the GABAergic pathway.

Cannabinoids in the Treatment of Insomnia Disorder: A Systematic Review and Meta-Analysis.

BACKGROUND: Insomnia is associated with significant comorbidity, disability and impact on quality of life and, despite advances in pharmacotherapy and psychotherapy, remains a significant burden to society. Cannabinoids are gaining acceptance for use as medicines in the treatment of insomnia disorder. OBJECTIVE: We conducted a systematic review and meta-analysis to evaluate the efficacy of cannabinoids in the treatment of insomnia disorder. METHODS: We performed a systematic review of the PubMed, Cochrane Library, MEDLINE, and Cumulative Index to Nursing and Allied Health Literature Complete databases from inception to 5 December 2019, and again prior to data abstraction, for studies of cannabis-based products for the treatment of insomnia disorder in adults. Inclusion criteria were (1) clinical studies, (2) participants aged ≥ 18 years, (3) insomnia disorder either formally diagnosed against contemporaneous diagnostic criteria or quantified with validated instruments and (4) compared cannabis-based products with the standard of care, placebo or a sedative. No language restrictions were imposed. Non-primary research, animal studies and studies of cannabis-induced insomnia were excluded. Risk of bias was assessed using the RoB 2 tool for randomised controlled trials (RCTs) and Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) tool for non-randomized trials. Heterogeneity was assessed with the I2 statistic. RESULTS: A total of five studies (two RCTs and three non-randomised studies) with 219 study participants were included, of which three could be combined. The three non-randomised studies contributed data on the Pittsburgh Sleep Quality Index Questionnaire score, showing a favourable effect of cannabinoids at ≤ 4 weeks of follow-up (mean difference - 1.89 [95% confidence interval {CI} - 2.68 to - 1.10]; n = 176) and at 8 weeks of follow-up (mean difference - 2.41 [95% CI - 3.36 to - 1.46]; n = 166). One double-blind crossover RCT (n = 32) reported that, compared with amitriptyline, nabilone-a synthetic analogue to tetrahydrocannabinol (THC)-improved Insomnia Severity Index scores after 2 weeks of treatment (adjusted difference - 3.25 [95% CI - 5.26 to - 1.24]) and resulted in a more restful sleep as a sub-measure of the Leeds Sleep Evaluation Questionnaire (LSEQ) (difference 0.48 [95% CI 0.01-0.95]) but with no effect on overall sleep quality as measured by the LSEQ. In a single ascending-dose RCT (n = 9), THC reduced sleep-onset latency compared with placebo at 10 mg, 20 mg and 30 mg doses (mean difference - 43.00 min [95% CI - 82.76 to - 3.24], - 62.00 [95% CI - 103.60 to - 20.40] and - 54.00 [95% CI - 103.93 to - 4.07], respectively). All the included studies were assessed as poor quality, mainly due to small sample sizes, short treatment periods, uncertain clinical significance and high risk of bias. CONCLUSIONS: Few studies have examined the efficacy of cannabinoids in the treatment of insomnia disorder. Despite some possible signals for efficacy, the heterogeneity of participants, interventions, efficacy outcomes and results, and the high risk of bias across included trials, do not reliably inform evidence-based practice. This review highlights shortcomings in the existing literature, including lack of diagnostic clarity, poorly defined participant groups, non-standardised interventions and studies of inappropriate design, duration and power to detect clinically meaningful outcomes. Further research in the form of high-quality RCTs are required before drawing any conclusions about the efficacy of cannabinoids in the treatment of insomnia disorder. TRIAL REGISTRATION: PROSPERO registration number, CRD42020161043.

Impact of coronavirus disease 2019 (COVID-19) pandemic on patients with migraine: a web-based survey study.

BACKGROUND: Since the declaration COVID-19 as a pandemic, healthcare systems around the world have faced a huge challenge in managing patients with chronic diseases. Patients with migraine were specifically vulnerable to inadequate medical care. We aimed to investigate the "real-world" impact of COVID-19 pandemic on migraine patients, and to identify risk factors for poor outcome. METHODS: We administered an online, self-reported survey that included demographic, migraine-related, COVID-19-specific and overall psychosocial variables between July 15 and July 30, 2020. We recruited a sample of patients with migraine from headache clinic registry and via social media to complete an anonymous survey. Outcomes included demographic variables, change in migraine frequency and severity during the lockdown period, communication with treating physician, compliance to migraine treatment, difficulty in getting medications, medication overuse, symptoms of anxiety and/or depression, sleep and eating habits disturbance, screen time exposure, work during pandemic, use of traditional medicine, effect of Botox injection cancellation, and overall worries and concerns during pandemic. RESULTS: A total of 1018 patients completed the survey. Of the respondents, 859 (84.3%) were females; 733 (71.9%) were aged 20 to 40 years, 630 (61.8%) were married, and 466 (45.7%) reported working during the pandemic. In comparison to pre-pandemic period, 607 respondents (59.6%) reported increase in migraine frequency, 163 (16%) reported decrease in frequency, and 105 (10.3%) transformed to chronic migraine. Severity was reported to increase by 653 (64.1%) respondents. The majority of respondents; 626 (61.5%) did not communicate with their neurologists, 477 (46.9%) reported compliance to treatment, and 597 (58.7%) reported overuse of analgesics. Botox injections cancellation had a negative impact on 150 respondents (66.1%) from those receiving it. Forty-one respondents (4%) were infected with COVID-19; 26 (63.4%) reported worsening of their headaches amid infection period. Sleep disturbance was reported by 794 (78.1%) of respondents, and 809 (79.5%) reported having symptoms of anxiety and/or depression. CONCLUSIONS AND RELEVANCE: COVID-19 pandemic had an overall negative impact on patients with migraine. Several risk factors for poor outcome were identified. Long-term strategies should be validated and implemented to deliver quality care for patients with migraine, with emphasis on psychosocial well-being.

The role of Yoga in working from home during the COVID-19 global lockdown.

BACKGROUND: The COVID-19 pandemic has become a major cause of stress and anxiety worldwide. Due to the global lockdown, work, employment, businesses and the economic climate have been severely affected. It has generated stress among people from all sections of society, especially to workers who have been assigned to cater to healthcare service or those constrained to secure daily essential items. It is widely perceived that elderly or those affected by diabetes, hypertension and other cardiovascular diseases are prone to COVID-19. As per an ongoing survey, the initial data shows that the above-mentioned anxiety and stress cause insomnia, and has the considerable potential to weaken the immune system, the sole protection against the virus. OBJECTIVE: This study focuses on the need of Yoga practice at work places and at home during the global lockdown due to the COVID-19 pandemic. METHODS: Literature was searched using PubMed and Google Scholar for COVID-19-related stress and anxiety at work and society due to the worldwide lockdown. The predisposing comorbidities, viral mechanism of action and treatment regimen were also searched. Yoga-based intervention studies and online programs were also searched. RESULTS: As the lockdown cannot last forever and workplaces will have to be functional soon, there is an increased possibility of recurrent infection. Therefore, Yoga can provide the necessary tool for risk reduction, amelioration of stress and anxiety and strengthening of the immune function. The online platforms provide a good media for Yoga training at work places and homes. CONCLUSION: Due to social distancing norms, the availability of Yoga trainers has become restricted. Yoga practice is actively sought to achieve reduced anxiety and stress so that improved sleep may positively impact immunity. As a consequence, there is a spurt in social media, catering to daily online Yoga sessions which apparently prove useful in providing accessible means to achieve mental as well as physical well-being.

Traditional Chinese herbal bath therapy for insomnia: A protocol for systematic review.

INTRODUCTION: Insomnia is a major public health problem. Due to the side effects of pharmacological therapy, people are seeking to choose complementary and alternative therapies for insomnia disorder. Traditional Chinese herbal bath therapy is an important complementary therapy which combines advantages of Chinese herbs and bathing therapy. This protocol describes the methodology of a systematic review assessing the effectiveness and safety of traditional Chinese herbal bath therapy for insomnia. METHODS AND ANALYSIS: Reporting of this review will be adherent to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We will electronically search the following seven databases from inception to January 23, 2020: PubMed, Cochrane database (CENTRAL), EMBASE, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), VIP Database, and Wanfang Database. Parallel randomized controlled trials evaluating the effectiveness and safety of traditional Chinese herbal bath therapy for insomnia will be included. Study selection, data extraction and assessment of risk of bias will be performed independently by two researchers. The sleep quality will be assessed as the primary outcome. Global symptom improvement, anxiety and depression, and adverse events will be evaluated as secondary outcomes. The Cochrane's risk of bias tool will be utilized for assessing the methodological quality of included studies. Revman software (v.5.3) will be used for data synthesis and statistical analysis. Data will be synthesized by either fixed-effects or random-effects model according to a heterogeneity test. If it is not appropriate for a meta-analysis, a descriptive analysis will be conducted. GRADE system will be used to assess the quality of evidence. PROSPERO REGISTRATION NUMBER: CRD42020168507.

Effect of Suvorexant vs Placebo on Total Daytime Sleep Hours in Shift Workers: A Randomized Clinical Trial.

Importance: Many shift workers have difficulty sleeping during the daytime owing to an inappropriately timed circadian drive for wakefulness. Objective: To determine whether a dual hypocretin receptor antagonist would enable shift workers to have more daytime sleep. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial included 2 weeks of baseline data and 3 weeks of intervention data, from March 2016 to December 2018. Individuals were recruited through poster advertisements in the broader San Francisco Bay area in California. From an initial voluntary recruitment cohort of 38 shift workers, 19 individuals with self-reported difficulty sleeping during the daytime following night work shift were included. Data were analyzed from Janaury to March 2019. Interventions: 1 week of 10 mg suvorexant or placebo, titrated upward to 20 mg suvorexant or placebo for 2 additional weeks. Main Outcomes and Measures: Objective (ie, actigraphy) and subjective (ie, sleep logs) measures of sleep. Results: Among 19 participants who completed the study (mean [SD] age, 37.7 [11.1] years; 13 [68%] men), 8 participants (42%) were assigned to the suvorexant group and 11 participants (58%) were assigned to the placebo group. Compared with individuals in the placebo group, individuals in the suvorexant group increased their objective total sleep time by a mean (SE) of 1.04 (0.53) hours (P = .05) at the end of 1 week of 10-mg doses and by 2.16 (0.75) hours (P = .004) by the end of the 2 weeks of 20-mg doses. Subjective sleep was similarly improved as, compared with the placebo group, individuals in the suvorexant group increased their subjective total sleep time by a mean (SE) of 2.08 (0.47) hours (P < .001) at the end of 1 week of 10-mg doses and by 2.97 (0.56) hours (P < .001) by the end of the 2 weeks of 20-mg doses. Physician ratings of daytime sleep aligned with these measures, as there was no change in the placebo group and a much improved change in the suvorexant group. No adverse events were reported in the suvorexant group. Conclusions and Relevance: This pilot study found that the use of a dual hypocretin receptor antagonist in shift workers under real-world conditions resulted in more than 2 extra hours of daytime sleep per episode. Future research should confirm this pilot finding in a larger sample size and examine whether, over the long term, use of this medication has a concomitant improvement in medical and psychiatric health as well as workplace performance and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02491788.

Targeting Arousal and Sleep through Noninvasive Brain Stimulation to Improve Mental Health.

Arousal and sleep represent fundamental physiological domains, and alterations in the form of insomnia (difficulty falling or staying asleep) or hypersomnia (increased propensity for falling asleep or increased sleep duration) are prevalent clinical problems. Current first-line treatments include psychotherapy and pharmacotherapy. Despite significant success, a number of patients do not benefit sufficiently. Progress is limited by an incomplete understanding of the -neurobiology of insomnia and hypersomnia. This work summarizes current concepts of the regulation of arousal and sleep and its modulation through noninvasive brain stimulation (NIBS), including transcranial magnetic, current, and auditory stimulation. Particularly, we suggest: (1) characterization of patients with sleep problems - across diagnostic entities of mental disorders - based on specific alterations of sleep, including alterations of sleep slow waves, sleep spindles, cross-frequency coupling of brain oscillations, local sleep-wake regulation, and REM sleep and (2) targeting these with specific NIBS techniques. While evidence is accumulating that the modulation of specific alterations of sleep through NIBS is feasible, it remains to be tested whether this translates to clinically relevant effects and new treatment developments.