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CC BY-NC-ND 4.0 · Sleep Sci 2025; 18(03): e365-e368
DOI: 10.1055/s-0045-1809993
Case Report

Insomnia Improved by Intravenous Mesenchymal Stem Cell Transplant: A Case Report

Authors

  • Takahiro Honda Pazili 

    Regenerative Medicine, Department of Cell Therapy, Japan Tokyo Stem Cell Transplant Research Institute, Cyuou-ku, Tokyo, Japan

Funding Source This study received no funding.
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Abstract

While several therapeutic options for insomnia are currently available, they often require long-term use and come with certain disadvantages. Given insomnia's significant impact on health overall, more effective treatments are warranted. Here, we report two patients with moderate to severe insomnia whose symptoms significantly improved following the intravenous administration of ex vivo-expanded bone marrow-derived mesenchymal stem cells (MSC).

The cases were 50-year-old and 38-year-old men with mild diabetes. They both developed insomnia several years ago and suffered from it despite taking some medications. We cultured their bone-marrow-derived MSCs and intravenously administered 1,5 × 108 cells to each patient. After the treatment, the insomnia of both patients was drastically improved, while diabetes itself showed only mild improvement. Notably, their improvements were associated with an increase in plasma interleukin-4 levels. This is the first case report demonstrating the therapeutic effects of MSCs on insomnia.


 

Keywords

insomnia - mesenchymal stem cells - cell transplantation - interleukin-4

Introduction

Insomnia is a sleep disorder marked by trouble falling asleep, remaining asleep, or combining both. Generally, it is diagnosed when people experience sleep difficulties at least three nights a week and is considered chronic when it lasts for at least three months.[1] Insomnia affects between 10% to 30% of the adult population, while the prevalence can be higher in certain groups, especially for elderly people. Insomnia can lead to various daytime impairments, such as tiredness, trouble focusing, mood swings, and reduced productivity at work or school.[2] Mainly, two types of insomnia exist, namely primary insomnia and secondary insomnia. The first one isn't linked directly to any other medical condition or issue. The second one is caused by other underlying health problems such as stress, anxiety, depression, medications, or medical conditions like asthma, chronic pain, or diabetes.[2] [3] Despite its significant impacts on overall health outcomes, the etiology and pathophysiology of insomnia are poorly understood. Sleep itself is mainly controlled by brain neural circuits, including the suprachiasmatic nucleus of the hypothalamus.[4] In addition, recent studies indicate that peripheral tissues are also involved in sleep regulation through sleep-immune crosstalk.[5] Treatments for insomnia are generally divided into non-medication treatments, including cognitive behavioral therapy, and pharmacologic therapies, depending on its severity and underlying causes. Pharmacologic treatments include benzodiazepine receptor agonists, selective histamine H1 antagonists, melatonin receptor agonists, and orexin antagonists. However, their adverse effects and some demerits have prohibited the wide and long-term application of these treatments.[6]

Stem cell therapy, including bone marrow-derived mesenchymal stem cells (MSC), has attracted significant attention for treating various diseases, including neurological, cardiovascular, autoimmune, and metabolic diseases like diabetes. However, few studies have been reported to indicate the therapeutic effects of the stem cell on insomnia. MSCs are structured postnatal stem cells that can self-renew and maintain a wide range of differentiation potentials, including those involved in sleep regulation.[7] [8] [9] MSCs also have immunomodulating roles by affecting several immune cells and their secreted factors, including cytokines such as interleukin-4.[10] [11] [12] These immunomodulatory properties of MSCs would benefit several diseases related to inflammation.[10] Thus, accumulated evidence suggests that MSCs could have therapeutic potential for insomnia independent of disease comorbidities. Herein, I report on two patients whose insomnia was successfully treated by intravenous administration of ex vivo-expanded MSCs.


 

Case Presentation

The first case was a 50-year-old man. Two years ago, he contracted COVID-19 and was admitted to the ICU of another hospital, in which his cardiopulmonary function was maintained by extracorporeal membrane oxygenation (ECMO) for two weeks. After the incident, he developed insomnia. He took Quetiapine, Brotizolam, and Zolpidem to control his insomnia. He had mild diabetes without any treatment history (HbA1c = 6.8%). The second case was a 38-year-old man. He suffered from insomnia for more than 10 years. He had atopic dermatitis, and borderline diabetes without any treatment history (HbA1c = 7.0%). They were not taking any medications, including corticosteroids.

We performed MSC treatment by the methodology we previously described.[13] After thoroughly explaining the potential benefits and risks of the treatment, written informed consent was obtained from the patients. Under local anesthesia, 60 ml of bone marrow aspirate (BMA) was collected from the patient's ilium. The BMA was sent to Kohjin Bio Ltd. (Saitama, Japan), a licensed laboratory for cell culture intended for clinical use. Following good manufacturing practices, the laboratory purified and expanded the MSCs over a month, limiting the number of passages to three. After confirming cell viability and the expression of surface markers CD73, CD90, and CD105, the cells were frozen and transported back to our clinic. The cells were thawed at 37°C and 1.5 × 108 cells were intravenously administered in 200 ml of saline. No adverse events were observed during or after the treatment, and the patients remained stable until they left the clinic.

Six months after the treatment, these patients came to the clinic for the follow-up. While diabetic conditions were mildly attenuated (HbA1c: 6.0% for the first patient and 6.3% for the second patient), the symptoms of insomnia were drastically improved in both patients. The Athens Insomnia Scale (AIS), a reliable self-report questionnaire consisting of eight items,[14] was improved from 16 (severe insomnia) to 0 (no insomnia) for the first patient and from 14 (moderate insomnia) to 2 (no insomnia) for the second patient. Interestingly, the plasma levels of interleukin-4, which were measured by CLEIA (chemiluminescent enzyme immunoassay) at SRL, Inc. (Tokyo, Japan), were increased after the treatment (230 pg/ml before the treatment vs. 390 pg/ml after the treatment for the first patient; 6.5 pg/ml before the treatment vs. 25.5 pg/ml after the treatment for the second patient). They were highly satisfied with the treatment.


 

Discussion

Few studies are reporting the therapeutic effects of stem cells on insomnia. Indeed, when we searched “insomnia and stem cell” in the PubMed database, there were no such clinical reports except for ones that reported sleep problems in cancer patients received with hematopoietic cell transplantation.[15] [16] However, such problems appear to be caused by irradiation, rather than stem cell transplantation itself.[17] As far as I know, there are no clinical studies reporting insomnia by stem cell treatments without irradiation as a combination therapy. Thus, to the best of my knowledge, this study, for the first time, showed the therapeutic effects of stem cells for insomnia.

We observed a drastic improvement in AIS score by the MSCs treatments in the current two patients despite very mild improvements in diabetic conditions. The degree of improvement of the AIS score (14 ± 2.8) should have a significant impact when considering that even the new orexin receptor antagonist, Lemborexant, improved the AIS score by less than 10 in the clinical trial.[18] Also, it is noteworthy that the current patients do not show any adverse events generally associated with sleep medications, such as drowsiness, attention deficits, and falls. While we did not measure other objective psychological or physiological scores, AIS has been shown to be associated with daytime drowsiness, depressive symptoms, and a decline in overall quality of life.[14] Most importantly, the current patients were well satisfied with the effects of MSC treatments.

While we observed that plasma levels of IL-4 were increased after the MSC treatment, IL-4 is often considered to be an anti-inflammatory and beneficial cytokine.[19] Moreover, several studies have shown that inflammation or inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) could play a significant role in causing insomnia.[20] Also, people with chronic inflammatory conditions, such as rheumatoid arthritis, inflammatory bowel disease, and chronic obstructive pulmonary disease (COPD), often experience higher rates of insomnia.[2] [3] [5] Notably, MSCs have immunomodulating properties that would benefit several inflammation-related diseases.[10] The immunomodulating effect of MSCs is reflected in T-cell properties, in which they cause T(H)1 cells to decrease interferon-gamma (IFN-gamma) while affecting the T(H)2 cells to increase secretion of IL-4.[11] Interestingly, one cellular study indicated that the anti-inflammatory effects of MSCs were mediated through the stimulation of IL-4.[12] Moreover, several studies indicate that IL-4 could enhance the function of MSCs in cellular differentiation, regeneration, and tissue remodeling.[21] [22] [23] While the exact role of IL-4 in insomnia is indeed unknown, if inflammation is mainly involved in causing insomnia in the current patients, an increase in IL-4 levels might contribute to the therapeutic effects of MSCs. Further studies analyzing other anti-inflammatory or proinflammatory biomarkers would provide additional insights into the mechanism of how MSC transplantation improved insomnia in the current cases.

Several studies indicate that sleep deprivation can negatively impact stem cell function, potentially impairing their ability to repair and regenerate tissues.[24] Additionally, there's accumulated evidence that stem cells play an important role in regulating sleep. Certain types of stem cells in the brain, such as neural stem cells, may influence sleep patterns and circadian rhythms.[9] Of note, MSCs not only can differentiate such neural stem cells but also can support their function through immunomodulation of cellular environments as well as via the release of trophic factors.[7] [8] These results indicate that sleep disorders and loss of stem cell function influence each other, likely forming a vicious cycle, in which transplantation of ex-vivo expanded MSCs might be an ideal therapeutic strategy for breaking such a vicious cycle.

There are some limitations in this study. First, we could not rule out that the drastic improvements from insomnia were mediated by the attenuation of the diabetic condition, although the changes in the diabetic marker HbA1c were very mild. Diabetes itself is tightly linked to proinflammatory status, which is a promising target for MSCs, and an increase of IL-4 might also be beneficial for diabetes through anti-inflammatory properties.[10] [25] [26] Thus, it might be difficult to clearly distinguish the effects of MSCs on insomnia independently of diabetes. Second, the etiology of insomnia in these cases was not diagnosed. While around 85% of insomnia is caused by other underlying health issues, known as secondary insomnia,[2] [3] the possibility of primary insomnia could not be ruled out for the current cases. Depending on etiology, the roles of inflammation or cytokines in insomnia should be different. Thus, more thorough examinations before and after the treatment would be necessary to understand the therapeutic effects of MSCs on insomnia.


 

Conclusion

In this case report, we observed two patients whose insomnia was drastically improved following intravenous administration of MSCs. To our knowledge, this is the first study documenting the therapeutic effects of MSCs on insomnia. Anti-inflammatory effects through stimulating IL-4 might be a key to understanding the therapeutic effects of MSCs on insomnia.


 

 

Conflicts of Interest

The author declares that there are no conflicts of interest.

Acknowledgments

I would like to thank the patients, and all other people related to this work.

Ethical Declaration

This case study was conducted in accordance with the Helsinki Declaration. The ethics committee in Japan Tokyo Stem Cell Transplant Research Institute, consisting of experts in several areas including stem cell research, stem cell treatment, law in medicine and human rights, approved this stem cell treatment, and the approval number is A005.


Data Availability

The data of the clinical record of this patient are available from the author upon request.



Address for correspondence

Takahiro Honda Pazili

Publication History

Received: 08 September 2024

Accepted: 19 May 2025

Article published online:
16 September 2025

© 2025. Brazilian Sleep Academy. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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