Effect of hydrogen–oxygen inhalation on sleep disorders and abnormal mood: a single-blind, randomized controlled trial

Abstract

Sleep disorders are associated with various chronic diseases. While hydrogen has anti-inflammatory, antioxidant, and antifibrotic effects and has potential applications in disease management, its impact on sleep disorders remains unclear. This single-blind, randomized controlled clinical trial from September 2022 to July 2023 at the Second Medical Center of the PLA General Hospital and the Affiliated Hospital of Chengde Medical College examined the effect of hydrogen–oxygen on sleep disorders. Sixty-six participants with sleep disorders were randomly divided into a control group and a hydrogen–oxygen group that received nasal gas inhalation for seven days. Sleep quality and mood were assessed using the Pittsburgh Sleep Quality Index, Self-Rating Depression Scale, and Self-Rating Anxiety Scale. An Actiwatch helped evaluate the effects of two kinds of gas inhalation on total sleep time, sleep efficiency, and the wake time of patients with sleep disorders. The control group showed no significant changes in sleep parameters during treatment, whereas the hydrogen–oxygen group showed significant improvements in total sleep time and sleep efficiency on days 3, 5, and 7 and significant reductions in wake time on days 3 and 7. Compared with those in the control group, the total sleep time was greater and the wake time was lower in the hydrogen–oxygen group. After 7 days, the scores of the Pittsburgh Sleep Quality Index and Self-Rating Depression Scale in the hydrogen–oxygen group were lower than those in the control group, whereas the Self-Rating Anxiety Scale scores did not differ significantly. Hydrogen–oxygen therapy effectively improved sleep disorders by reducing wake time, relieving psychological stress, and enhancing sleep quality. The study was registered in the Chinese Clinical Trial Registry (registration No. ChiCTR2400084103).

Introduction

Sleep disorders include difficulties in sleep initiation, reduced sleep duration, disruption of sleep integrity, and a decline in sleep quality, often leading to impaired daytime functioning. In adults, insomnia is frequently associated with worry and anxiety about prolonged wakefulness at night, insufficient sleep, or poor sleep quality.1,2,3 Both psychological and social–cultural factors, along with internal factors, affect sleep and awakening. Furthermore, it highlighted that insomnia was particularly prevalent among younger people and that teenagers, children, and older adults were also seriously impacted by sleep disorders. Subjective sleep quality and mood have a bidirectional correlation, suggesting that sleep quality is important for mood stability and that mood inversely affects sleep quality. In modern medicine, the “biopsychosocial model” suggests that sleep problems are inseparable from mental health status. There is a strong relationship between sleep and mood regulation. Sufficient sleep positively impacts emotional stability and regulation. Conversely, poor sleep can lead to memory decline and emotional anxiety and increase the risk of cardiovascular, cerebrovascular, and Alzheimer’s disease in older populations.4,5

Currently, cognitive behavioral therapy for insomnia (CBTi) is a safe and effective intervention for insomnia and sleep maintenance disorders. Its effectiveness is equal to or better than that of drug therapy. The benefits of the CBTi, which was originally used for chronic primary insomnia, also extend to short-term and secondary insomnia. CBTi requires guidance from an experienced clinician, although many hospitals lack psychiatrists with such expertise. Hence, refractory sleep disorders are frequently managed with drugs; however, even minimal doses of hypnotics should be used with caution in older patients or those with impaired liver function. Furthermore, drug treatments typically do not yield long-term benefits and may lead to dependence, with only a limited number of effective medications available that do not cause adverse side effects.6,7

The therapeutic effects of hydrogen have been widely reported. In 1975, Dole et al.8 reported the inhibitory effect of hydrogen on squamous cell carcinoma in mouse skin. Hydrogen therapy, recognized as an antioxidant treatment, is gradually gaining attention from the medical community. Ongoing research aims to identify the diseases for which hydrogen is effective, assess the efficacy of hydrogen absorption, and evaluate any potential side effects.9 Additionally, studies indicate that hydrogen-rich water can alter several behavioral markers of sleep stress but not slow wave activity.10 Therefore, we investigated the effects of hydrogen and oxygen inhalation therapy on sleep disorders and mood.

Methods

Subjects

This single-blind, randomized controlled clinical trial was conducted from September 2022 to September 2023 at the PLA General Hospital and the Affiliated Hospital of Chengde Medical University. The study was approved by the Ethics Committee of the Chengde Medical College Affiliated Hospital (approval No. CYFYLL2022314, approval date: October 19, 2022). Prior to the initiation of the trial, the participants signed an informed consent form. All components of the study followed the requirements of the Declaration of Helsinki. All procedures were conducted according to the national standards for laboratory care and use guidelines of the National Institutes of Health. The study was registered in the Chinese Clinical Trial Registry (Registration No. ChiCTR2400084103). The study was performed in accordance with the CONsolidated Standards Of Reporting Trials (CONSORT) guideline.11

Sixty-six participants with sleep disorders were recruited for the study and diagnosed according to the International Classification of Sleep Disorders, Third Edition.12,13 The criteria for chronic insomnia included persistent difficulty in sleeping; challenges in both falling asleep and staying asleep; early waking and impairment of daytime functioning due to nighttime insomnia; and fatigue, inattention, and mood disorders. These symptoms had to occur at least three times a week and to have persisted for a minimum of 3 months. Additionally, the symptoms could not be solely attributed to insufficient sleep or to an inappropriate sleep environment.14,15

Participants with sleep disorders were screened using the Pittsburgh Sleep Quality Index (PSQI), a self-assessment scale that evaluates the frequency of sleep problems and overall sleep quality over the previous month. This scale is suitable for evaluating sleep quality in patients with sleep and mental disorders, as well as for the general evaluation of sleep quality. The PSQI comprises 19 self-rating questions, each scored on a scale from 0 to 3, with higher scores indicating more severe sleep disorders. The total PSQI ranges from 0 to 21, with a score of ≥ 7 classified as indicative of low sleep quality in Chinese adults.16 This study enrolled participants with a PSQI score > 7.

Patients who declined to participate in the survey; had taken sleep or anti-anxiety medication; or had serious underlying disorders such as heart, liver, kidney or autoimmune diseases were excluded from the study.

A total of 66 participants with sleep disorders were randomly assigned to either the control group (n = 25) or the hydrogen–oxygen (n = 41) group. Only the researcher and data analyst were aware of the constituents of each group.

Intervention therapy

All participants were instructed to maintain their usual lifestyle and dietary habits. The control group was administered air, and the hydrogen–oxygen group was administered a mixture of hydrogen and oxygen (66.7% hydrogen and 33.3% oxygen). Hydrogen–oxygen mixed gas was generated from water using a hydrogen–oxygen meter with spray electrolysis (Small H D-HO-001; Jinkai Instrument Co., Dalian, China). By combining the advantages of traditional electrolysis technology and ionic membrane technology, this pure-water electrolysis device produces a gas mixture consisting of 66.6% hydrogen and 33.3% oxygen, with adjustable flow rates ranging from 20 to 60 mL/min. Each participant was given a nasal tube to inhale gas twice a day at a volume of 60 mL/min for 1 hour each time for 7 consecutive days. Inhalation was completed 2 hours before the patients went to bed.

The participants in both groups were assessed using the PSQI, Self-Rating Depression Scale (SDS), and Self-Rating Anxiety Scale (SAS) before and after 1, 3, 5, and 7 days of treatment. Changes in sleep quality and abnormal mood were also recorded. A Philips Actiwatch (Respironics, Murrysville, PA, USA) device was used to record the sleep efficiency, total sleep time and wake time during these periods.

Motor sleep state

The participants wore the Actiwatch from the beginning of the intervention until the end of the experiment on day 7 to allow for the monitoring of their exercise, rest, and sleep states. The Actiwatch is a convenient tool for evaluating insomnia.17,18 When a body-motion watch records alternating states of sleep and wakefulness, it indicates unstable sleep, whereas a continuous sleep pattern indicates stable sleep. During the trial, the participants were permitted to engage in their usual daily activities. Changes in total sleep time, sleep efficiency, and awakening time were analyzed and evaluated before and after treatment.

Statistical analysis

All the statistical analyses were conducted using SPSS Statistics for Windows, version 27.0 (IBM, Armonk, NY, USA). A normality test was conducted on the scale scoring data, with measurements conforming to a normal distribution expressed as the mean ± standard deviation. An independent-sample t-test was performed for comparisons between the two groups, and a paired t-test was used for comparisons before and after control. An analysis of variance was used to compare differences among the groups. The chi-square test was performed on the count data. All P values were two-sided, with a P value < 0.05 deemed statistically significant.

Results

The average age of the participants in the control group was 50.44 ± 12.27 (range 36–81) years, and the proportion of males was 36%. The average age of the participants in the hydrogen–oxygen group was 53.29 ± 15.47 (range 32–85) years, and the male proportion was 36.6%. No significant differences were observed in age or sex between the two groups (P > 0.05).

Changes in sleep disorder parameters

Sleep disorders showed significant improvement among participants in the hydrogen–oxygen group. Each participant underwent eight nocturnal sleep-monitoring sessions, during which they wore an Actiwatch to monitor their sleep status. Six participants reportedly lost their watches or experienced other data loss. To ensure accuracy, data from the remaining 60 participants, whose sleep states were fully recorded across all eight sessions, were analyzed.

There were no changes in sleep disorders within the control group before and after treatment. Specifically, no significant differences were observed in total sleep time, sleep efficiency, or awakening time when comparing measurements taken before treatment to those taken 1, 3, 5, and 7 days after treatment (P > 0.05).

The participants in the hydrogen–oxygen group exhibited significant improvements in awakening disturbances before and after treatment. Notably, total sleep time and sleep efficiency showed significant differences between pre-treatment values and those recorded 3, 5, and 7 days after treatment (P < 0.05). A significant difference was noted in the awakening time before treatment and 3 and 7 days after treatment (P < 0.05; Figure 1).

Figure 1.

Changes in total sleep time, sleep efficiency and wake time in patients with sleep disorders after hydrogen and oxygen inhalation.

(A‒C) Changes in total sleep time (A), sleep efficiency (B), and wake time (C) in the control group (n = 25) and hydrogen–oxygen group (n = 41). The data are expressed as the mean ± SD. *P < 0.05, ** P < 0.01 (t-test).

After 7 days of hydrogen–oxygen inhalation, the total sleep time increased, whereas the awakening time decreased significantly. However, there was no significant improvement in sleep efficiency between the hydrogen–oxygen group and the control group.

Changes in PSQI, SAS, and SDS scores

After 7 days of treatment, no significant changes from pretreatment values were observed for the PSQI, SAS, or SDS scores of participants in the control group (all P > 0.05). In contrast, participants in the hydrogen–oxygen group exhibited significant decreases in their PSQI, SAS, and SDS scores after 7 days of treatment compared with their pre-treatment scores (all P < 0.05). Significant differences were observed in the PSQI and SDS scores between the hydrogen–oxygen and control groups after treatment (both P < 0.05), although no significant differences were observed in the SAS scores (P > 0.05; Figure 2). These findings indicate that hydrogen–oxygen inhalation significantly improved the participants’ abnormal emotions, alleviating stress and depression; however, it did not significantly impact anxiety levels between the two groups.

Figure 2.

Changes in PSQI (A), SAS (B), and SDS scores (C) between the hydrogen‒oxygen group and the control group before and 7 days after treatment.

The data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ##P < 0.01. PSQI: Pittsburgh Sleep Quality Index; SAS: Self-Rating Anxiety Scale; SDS: Self-Rating Depression Scale.

Discussion

In this study, we evaluated the effectiveness of hydrogen–oxygen inhalation therapy in improving sleep quality and mood in individuals with sleep disorders. Our findings indicated that, compared with the control group, the hydrogen–oxygen group exhibited significant improvements in total sleep time, sleep efficiency, and wake time, highlighting the potential of hydrogen–oxygen inhalation therapy as a novel treatment for sleep disorders. The novelty and significance of our study lies in its exploration of the therapeutic benefits of hydrogen beyond its established anti-inflammatory effects. By focusing on sleep disorders and mood, our research introduces a new, non-pharmacological intervention with promising implications for personalized medicine.

Sleep disorders not only accelerate a decline in cognitive function but also induce and aggravate mental and behavioral symptoms, negatively impacting the mental health of caregivers and increasing the economic burden associated with these conditions on society. There appears to be a causal relationship between sleep disorders and Alzheimer’s disease, with sleep disorders manifesting at all stages of the disorder.19 Sleep disorders increase physiological stress20 and impair memory, attention, and executive function.21 There may be an interaction between sleep duration and chronic diseases, as well as comorbidities.22 A large proportion of people with sleep disorders also experience mental health issues. The causes of anxiety-induced sleep disorders are complex; for example, a study involving children with elevated anxiety symptoms found that higher levels of adaptation were associated with a greater incidence of sleep-related problems.23

Numerous pharmacological treatments can improve disorders related to sleep and wakefulness to a certain extent; however, these treatments are often accompanied by side effects. CBTi can improve sleep problems, such as initial insomnia, shallow sleep, and terminal insomnia. The short-term effects of CBTi are comparable to those of medication, while its benefits tend to persist longer than those achieved through pharmacotherapy. Despite these positive outcomes, many hospitals lack experienced psychiatrists, and treatment efficacy varies significantly based on patient adherence.

Low-dose hydrogen–oxygen inhalation for the treatment of sleep disorders is currently in the clinical trial stage, and the potential mechanism requires further in vivo confirmation. Hydrogen-rich water has been shown to improve the intestinal flora imbalance and brain energy metabolism, as well as to reduce inflammatory reactions, suggesting that hydrogen-rich water is an effective hydrogen donor that can treat Alzheimer’s disease.24 Patients with Alzheimer’s disease often experience sleep–awakening disorders early in the progression of the disease. Oxygen and hydrogen inhalation can reduce pathological damage in people suffering from sleep disturbances. Hydrogen–oxygen inhalation may also influence depression because insomnia is a common symptom. This therapy can relieve various diseases associated with inflammation and pain. In our study, we observed that hydrogen–oxygen inhalation significantly improved sleep arousal and mood abnormalities.

Hydrogen biology is a novel concept in health protection, with the potential to enhance research and expedite the benefits of this non-drug therapy for patients.25,26 Hydrogen, a new effective antioxidant and reducing gas, has been reported as a potential neuroprotective agent capable of selectively scavenging hydroxyl radicals and peroxynitrite ions during physiological processes.27 The most significant advantage of hydrogen is its lack of known side effects. According to the current literature, moderate inhalation of a hydrogen–oxygen mixture does not exhibit anesthetic effects. We hypothesize that this phenomenon may be attributed to the following reasons: (1) The mixed gas produced by the hydrogen‒oxygen atomizer contains a specific proportion of oxygen (33.3%), which ensures that inhaling this mixture does not lead to a decrease in the body’s oxygen concentration, thereby preventing suffocation or anesthetic effects. (2) Hydrogen is an inert gas that does not engage in chemical reactions within the body; thus, it does not impact the nervous system in the same manner as anesthetics. The proportional concentration has been applied in a number of clinical trials; has been used in the treatment of novel coronavirus infection, and has been included in the seventh edition of the novel coronavirus pneumonia diagnosis and treatment protocol. To date, no safety concerns have been reported.

Hydrogen therapy, an emerging therapeutic strategy, employs hydrogen molecules as therapeutic agents.28 The primary benefits of this therapy lie in the selective scavenging ability of hydrogen molecules. They can reshape the microenvironment of diabetic wounds, reduce inflammation, promote collagen accumulation and angiogenesis, and effectively accelerate the healing of chronic wounds.

Hydrogen–oxygen inhalation can significantly increase the levels of superoxide dismutase, an enzyme that scavenges free radicals. Therefore, hydrogen production is an innovative and promising therapeutic strategy.29 However, the low solubility and high dispersion of hydrogen molecules have constrained its therapeutic effects on many diseases. To improve the effectiveness of hydrogen therapy, it is critical to address existing challenges, including effective gas storage, targeted delivery, and controlled release.30

Sleep disorders may lead to sleep deficiency and inefficiency, subsequently leading to decreased work efficiency, impaired cognitive function, aggravated hypertension, myocardial ischemia, and reduced insulin sensitivity. However, the influences of these disorders remain unclear due to the limited understanding of many chronic sleep disorders.31,32 The serious consequences of sleep disorders warrant further attention and research. Sleep plays a crucial role in the processing and regulation of emotions. Insufficient sleep can lead to negative emotions, including irritability, anxiety, aggression, and mood swings. Furthermore, chronic anxiety can aggravate sleep disorders. Overall, sleep disorders may decrease through increased awareness, enhanced psychological support, and favorable environmental influences.33,34

This lack of significant improvement may be attributed to the limited treatment duration. The theoretical basis for choosing a 7-day cycle is that in the treatment of insomnia, it is usually recommended that patients adhere to a 7-day treatment cycle because the human body’s biological clock and sleep cycle have a certain regularity. Through continuous treatment and regulation for 7 days, one may facilitate the concomitant adjustment of the biological clock. We, therefore, speculate that sleep efficiency between the two groups would have differed significantly if the treatment period had been extended. However, this hypothesis requires further study.

This study has several limitations. First, the relatively small number of participants with sleep disorders limited subsample analyses stratified by age. Second, treatment outcomes were measured shortly after the initiation of treatment, especially on days one, three, five, and seven. Longer treatment periods, such as 2–4 weeks, may yield more pronounced changes in the efficiency of hydrogen–oxygen inhalation therapy among participants with sleep disorders. Unfortunately, given the limitations of funds and the reluctance of participants, we were unable to collect blood samples in this trial; however, we plan to pursue blood sampling in future studies. In the meantime, electroencephalographic monitoring will be carried out to address certain shortcomings of the design of this study. In any event, further research is required to confirm and elaborate on these preliminary findings.

The results of this study suggest that inhaling a low-dose mixture of hydrogen and oxygen can improve sleep quality and abnormal mood through its antioxidant properties. We conclude that this treatment represents a promising option for people with sleep disorders.

Data availability statement:

No additional data are available.