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Publicly Available Published online by De Gruyter May 16, 2022

Oxytocin, the panacea for long-COVID? a review

Phuoc-Tan Diep, Mohammed Chaudry, Adam Dixon, Faisal Chaudry and Violet Kasabri ORCID logo

Abstract

Objectives

In this hypothesis paper we explore the underlying mechanisms for long-COVID and how the oxytocinergic neurones could be infected by SARS-CoV-2 leading to a reduction in plasma oxytocin (OXT). Furthermore, we aim to review the relevance of OXT and hypothalamic function in recovery from long-COVID symptoms and pathology, through exploring the pro-health effects of the OXT neuropeptide.

Methods

A review of published literature was surveyed using Google Scholar and PubMed.

Results

Numerous experimental data can be shown to correlate with OXT and long-COVID symptoms and conditions, thus providing strong circumstantial evidence to support our hypothesis. It is postulated that the reduction in plasma OXT due to acute and post-viral damage to the hypothalamus and oxytocinergic neurones contributes to the variable multi-system, remitting and relapsing nature of long-COVID. The intranasal route of OXT application was determined to be most appropriate and clinically relevant for the restoration of oxytocinergic function post COVID-19 infection.

Conclusions

We believe it is imperative to further investigate whether OXT alleviates the prolonged suffering of patients with long-COVID. Succinctly, OXT may be the much-needed post-pandemic panacea.

Highlights

  • – A comparison of long-COVID pathology with OXT therapeutic mechanisms was performed

  • – Following advances in neuroendocrinology and proposed use of OXT as an acute antiviral for COVID-19; we elaborate OXT mechanisms in treating long-COVID, via therapeutic relevance and methods of administration.

  • – Further demonstration of OXT levels for different demographic and susceptibility groups, acute levels in COVID-19 patients and periodic monitoring of OXT levels is warranted.

Introduction

The post-infection long term effects of COVID-19, “long-COVID” for short, is emerging as a post-viral, multi-system, remitting and relapsing illness similar in some respects to Chronic Fatigue Syndrome (CFS) and its variants. The global medical community is seeking effective drug treatments for both acute COVID-19 and for long-COVID. Principally FDA-approved drugs ivermectin, hydroxychloroquine and azithromycin –separately or in combinations- significantly improved COVID-19 outcomes via inhibiting the replication of SARS-CoV-2 [1a-h]. Moreover vitamin D [2], melatonin [3], and oxytocin (OXT) [4a–b] are proposed for acute COVID-19 therapy as the focus of this paper. Markedly proimmune and anti-inflammatory IV oxytocin infusion could counteract hyperinflammation in COVID-19 infected patients. Relatively recent data demonstrate the anabolic effect of oxytocin on bone micro-architecture. Conversely common side effects of oxytocin administration may include erythema at the site of injection, intensified contractions, more frequent contractions, nausea, vomiting, stomach pain, and loss of appetite. Serious adverse effects that require monitoring after oxytocin administration include cardiac arrhythmias, seizures, anaphylaxis, confusion, hallucinations, extreme increase in blood pressure, and blurred vision [4c,d].

The current pandemic of severe acute respiratory distress syndrome is attributed to the virus SARS-CoV-2; previous viral causes of severe acute respiratory distress syndrome include SARS-CoV and MERS-CoV [5]. The exact mechanism, by which SARS-CoV-2 putatively causes COVID-19, and all its multiple-system pathologies, is the source of unprecedented interest and research. The aetiopathogenic link between the virus SARS-CoV-2 and the disease COVID-19 has not been fully elucidated; there is much we do not know and therefore much we need to learn. It would be wise to move forward with humble scientific rigor and not presume what we cannot predict. Indeed, it is possible that COVID-19 may be an endpoint of a complex combination of genetic and epigenetic vulnerabilities [6] as well as physiological and environmentally induced vulnerabilities [7]. For example, some of the pathology and severity associated with COVID-19 and/or long-COVID may be due to reactivation of latent viruses such as Epstein–Barr virus [8] and cytomegalovirus (CMV) [9].

Hopefully hidden factors can be brought to light via an appropriate scientific method that incorporates sufficient data and unbiased critical analysis from multiple points of view [10]. What will truly be identified as a cause and what will be identified as merely an association needs to be made clear. We await the clarifying light of time. Meanwhile the COVID-19 pandemic has accelerated research and understanding of coronaviruses, and this may be one positive result that we can take from our time under its shadow. Whilst we analyze the present data and await future answers, we can explore the published scientific literature of the past for strong clues to help with this pandemic puzzle.

Viruses such as SARS-CoV [11], CMV [12] and the Human Immunodeficiency Virus (HIV) [13] are known to infect the hypothalamus. Also, viral infection can also down-regulate OXT receptor expression, thus providing key viral pathology enhancement mechanisms [14]. OXT is a potent nine peptide neurohormone produced primarily in the hypothalamus, where it is transported to the posterior pituitary gland and released into the systemic circulation. OXT has a broad range of pro-health and immune system enhancing effects throughout the entire body [15]. Some probiotic gut bacteria [16] are known to positively modulate OXT production via the vagus nerve. This pathway suggests a neuroendocrine based health enhancing opportunity involving OXT that could be applied to long-COVID patients and help reverse viral damage via neuroendocrine re-activation of the parasympathetic system. Our paper compares long-COVID pathology with OXT mechanisms in light of advances in neuroendocrinology and the proposed use of OXT as an acute antiviral for COVID-19 [4, 17], [18], [19]. We elaborate the literature of OXT mechanisms that may be implemented in treating long-COVID symptoms and conditions, and then discuss therapeutic relevance and methods of administration.

Long-COVID symptoms

Long-COVID pathologies may have always been with us, hiding under the surface, going by other names such as Chronic Fatigue Syndrome-like illnesses, idiopathic diseases and even psychiatric illnesses [20]; the overlap between long-COVID and some of these states make them indistinguishable from long-COVID. Also, it does seem that some factors associated with more severe COVID-19 such as old age and co-morbidities also increase the risk of long-COVID [21]. At present, globally defined diagnostic criteria for long-COVID have not been agreed upon. Indeed, the number of proposed symptoms and signs may be greater than 50 and the frequency of this diagnosis may be as high as 80% if broad and generous criteria are used (e.g. one symptom for a duration of two weeks) [22]. However, if stricter criteria for symptoms and duration are applied this may drop significantly to around 5% or lower [21].

It will be interesting to see, with hindsight, whether the current criteria are too broad and too generous to properly define long-COVID. For example CFS which has overlapping symptoms and signs has more rigid criteria as defined by the Centers for Disease Control and Prevention (CDC): “three symptoms and at least one of two additional manifestations”, “for six months” [23].

Some of the numerous symptoms and signs that have been attributed to long-COVID include, in brief and not exhaustively [21,22]: general fatigue, weakness, and sleep disorders; continuing headaches; protracted loss or change of smell and taste; psychiatric illnesses; inflammatory disorders such as myalgia; respiratory, cardiovascular, gastrointestinal, hepatic and renal dysfunction; and skin rashes.

The symptoms and conditions are legion and seem to be increasing as more data accumulates.

OXT vs. long-COVID symptoms and related disorders

OXT has beneficial mechanisms for treating disorders involving fatigue, weakness, and sleeplessness; symptoms seen in long-COVID. Brain inflammation due to mitochondrial, mast cell [24] and vagus nerve [25] dysfunction have been implicated as contributing factors behind CFS. OXT is known to mediate health enhancing effects via the vagus nerve [16]. It can inhibit mast cell degranulation in rats [26], and positively modulate both energy metabolism [27] and mitochondrial function [28]. OXT ameliorates weakness as it can regenerate muscle [29] and reduce age related declines in strength [30] in mice. OXT can induce release of the “sleep hormone” and potent anti-oxidant melatonin [31] in rats, probably via a breakdown product of OXT, melanocyte-inhibiting factor (MIF-1) [32]; it is reasonable to speculate that this mechanism is presently functional within humans.

OXT is neuroprotective and stimulates neurogenesis in rats and mice [33, 34]. In rats it can protect against diabetic neuropathy [35] and help recovery of damaged nerves [36]. OXT has a strong role in taste and smell, in both murine [37, 38] and human olfactory functions [39]. Stimulating neurogenesis even under stress [40] could affect the recovery of these senses after loss during acute COVID-19 infection. There is growing data to show the importance of OXT in depression and other areas of mental health [41]. It appears to have a role in anxiety and post traumatic stress [42] and has been highlighted as of great significance in terms of the psychological sequel of COVID-19, isolation and social distancing [43, 44].

OXT has numerous anti-inflammatory properties which may ameliorate the generalized inflammation seen in COVID-19 [4, 45, 46]. It has been shown that female patients suffering from fibromyalgia, a neuropathic pain disorder, have lower OXT levels [47]. OXT modulates pain and has been used as a treatment for headaches [48, 49]. OXT is known to have anti-pain and anti-nociceptive mechanisms [50], [51], [52] some of which may be through cannabinoid [53], opioid [53, 54] and vanilloid (capsaicin) [55] receptors.

Respiratory system damage is one of the major complications of COVID-19 and remains a risk for long-COVID sufferers. OXT can protect against lung inflammation [56] and damage [57]. OXT is known to increase nitric oxide [58, 59] which is present in the airways [60] and improves oxygenation [61], healing and repair [62] and has antiviral properties against SARS-CoV [63] therefore presumably against SARS-CoV-2.

OXT is considered a substantial cardiovascular hormone [64], associated with cardioprotective propensities and supportive mechanisms that combat obesity [65], atherosclerosis [66], inflammation and cardiac failure [67]. It has been highlighted as a potential cardioprotective agent for COVID-19 [68], and may serve well to ameliorate long-COVID cardiovascular symptoms.

OXT has been shown to be lower in children with recurrent abdominal pain [69]. Elevated levels of the neuropeptide improve symptoms of irritable bowel especially when associated with depression [70, 71] as well as reduce colonic inflammation [72, 73] and stress-aggravated colitis [74] in mice and rats, and could serve to reduce the gastrointestinal disturbances seen in long-COVID. OXT has been shown to rejuvenate the liver [29] and to protect the kidney from inflammation [75] in rats. It has been shown to modulate the stress responses in human skin cells [76] and to improve skin healing [77, 78] in rats. Mast cells are important in the development of skin rashes, and OXT has been shown to inhibit mast cell degranulation [26]. OXT has positive effects on stem cells [79] which may be of great help in overall recovery from COVID-19 and prevention of long-COVID.

In effect, this explicit interplay of therapeutic mechanisms could help treat acute COVID-19 and long-COVID. In addition, COVID-19 patients who have had prolonged periods in intensive care units may benefit from OXT’s potent therapeutic effects; as it improves muscle atrophy, post-traumatic stress, wound healing and possibly pressure ulcers [77, 78].

Hypothetical OXT dysregulation in COVID-19 and long-COVID

Previous research into viral infection of the hypothalamus and OXT neurons provides convincing data regarding the ability for viruses to affect OXT. An animal study has shown that the antiviral immune response is, at least in part, regulated by the hypothalamus-pituitary-adrenal axis [80]. Further, viral infection of the hypothalamus has been identified, including in SARS [11] HIV [13] and Zika virus [81]. A study reported that an HIV patient was shown to have CMV infection in the hypothalamus, expressing a reduction in vasopressin neurons leading to diabetes insipidus, and also a significant reduction in OXT neurones [12]. Hypopituitarism can be caused by viral infection and this has been identified for Hantaviruses [82, 83]. In terms of coronaviruses, SARS-CoV can infect hypothalamic neurons [11] and this can lead to hypothalamic dysfunction [84]. In addition to the reduction in OXT output, viral infection has also been shown to down regulate OXT receptors [14]. Another possible mechanism of OXT dysregulation is via vagus nerve dysfunction. The vagus nerve can be considered part of the OXT pathway and vagus nerve stimulation increases OXT [85]. In addition, the gut microbiome can increase OXT via the vagus nerve [16]. It has been proposed that chronic fatigue syndrome is due to vagus nerve infection [25] and indeed it has been shown that viral infection of the vagus nerve can occur [86, 87]. More specifically, it is plausible that the vagus nerve can be infected by SARS-CoV-2 [88].

Therefore, the mechanism of SARS-CoV-2 infection leading to long-COVID is hypothesized to be in the suggested order of consecutive events (Figure 1):

  1. SARS-CoV-2 infects the hypothalamus and specifically OXT neurons as both ACE2 and TMPRSS2 are most likely co-localized on OXT neurons [89].

  2. This will lead to cytopathic effects on the OXT neurons which will reduce their function or possibly lead to some degree of neuronal death.

  3. Therefore, OXT production will be reduced leading to decreased systemic plasma OXT levels.

  4. In addition, down-regulation of OXT receptors would lead to further OXT system dysfunction.

  5. Vagus nerve dysfunction will lead to an additional OXT dysfunction.

  6. This will most likely lead to a significant reduction in the potent protective and healing effects of OXT and subsequently exacerbate the effects of long-COVID.

Figure 1: 
Proposed routes of viral infection leading to oxytocin (OXT) and OXT receptor (OXTR) down-regulation.

Figure 1:

Proposed routes of viral infection leading to oxytocin (OXT) and OXT receptor (OXTR) down-regulation.

This seems plausible but there are some difficulties and limitations to the hypothetical mechanism for reduced OXT in COVID-19. At least seven come to mind.

First, proof of SARS-CoV-2 infection of the nervous system, as hypothesized above, needs to be acquired from sources such as post-mortems.

Second, measurement of plasma OXT is technically demanding [90]. In addition, OXT release is not stable and constant; it is pulsatile, being released approximately every half hour [91].

Third, OXT can stimulate vasopressin receptors and vice versa [92], therefore, assessment of OXT function needs to take into consideration vasopressin to some extent.

Fourth, OXT receptor function cannot be assessed by measuring the OXT peptide in the plasma, which means that even with normal or high levels of plasma OXT the pathway may still be dysfunctional.

Fifth, this does not take into account epigenetic influences on OXT function [93].

Sixth, OXT is produced and released from other tissues of the body such as muscle [94] and it is unknown how this affects overall OXT levels and function.

Seventh, and most importantly, to our knowledge, plasma OXT levels have not been directly measured in COVID-19 patients. However, Liu et al. investigated the association between the nasopharyngeal microbiome and metabolome in COVID-19 patients and identified down-regulation of the OXT signaling pathway; thus providing indirect but tantalizing evidence of reduced OXT levels [95].

Social isolation reduces OXT [43]. The pandemic has led to a significant disruption in normal social interaction [96]. If OXT is indeed a treatment for long-COVID then this has implications for social isolation measures. It may be that social isolation and thus reduced OXT levels, can be mitigated to some extent by actions that raise endogenous production of OXT, such as increasing aerobic capacity [97], singing [98], touch [99, 100], sex and bonding [101]. Interestingly, vitamin D probably up-regulates production of OXT and up-regulates the OXT receptor [102] and melatonin has been shown to increase nocturnal OXT release [103]. Maybe simple everyday actions such as getting sufficient sunlight (vitamin D) and sleep (melatonin) are part of the foundation for healthy OXT function, and by extrapolation, important for long-COVID recovery.

If there is incapacitated endogenous OXT output, then treatment with exogenous OXT may ameliorate the aforementioned ailments. It would be prudent to begin administration of OXT at low doses, on a gradually increasing scheme if required and if adverse effects are not evident. However, a limitation is that the half-life of OXT is in the range of minutes, up to approximately 30 min [4]. Another limitation is that the usual route, intravenous (IV) exogenous administration, would not be easily available at home. Acute high doses of exogenous OXT can cause unwanted cardiovascular effects [104] and can lead to down-regulation of the OXT receptor [105]. Higher than optimal levels of a hormone or a drug can have negative effects (endogenous or exogenous, natural or synthetic). Indeed, high levels of endogenous OXT can be released during stress responses [106] but chronic administration of exogenous OXT can also induce anxiety [107].

In addition, OXT does not cross the blood brain barrier passively [108], therefore IV exogenous administration is unlikely to reach the brain. This limits its positive effects on neuroinflammation and neuroprotection. Also, this reduces the possibility of stimulating endogenous central release of OXT [109].

Interestingly, avoiding the IV route may actually be advantageous as OXT is known to be pulsatile in its release and therefore intermittent administration, such as via intranasal spray, may be more effective. Intranasal OXT is well tolerated and has a good safety profile; however it is not heat-stable and requires refrigeration. A likely benefit is that this mode of delivery can reach the brain and can probably stimulate central release [109].

More recently a dry inhaler has been available which does not require refrigeration. Inhaled OXT is also unlikely to be able to cross the blood brain barrier. However, it would be able to reach the lungs directly which would be advantageous in reducing any ongoing lung pathology. Unfortunately, there is little data on the most effective dose of intranasal and inhaled OXT.

Conclusions

This paper has compared the symptoms of long-COVID with evidence of OXT’s use for these symptoms within other disorders. We have identified a potential mechanism for long-COVID that involves OXT dysfunction. The circumstantial evidence provided is broad and correlates with many areas of long-COVID symptoms and conditions. However, the evidence has its limitations; much of the data is experimental and based on animal models and thus have not been confirmed through formal clinical trials in humans. The following data is incomplete or missing from the literature, and there is need for further clinical research:

  1. OXT plasma levels for different demographic and susceptibility groups

  2. OXT plasma levels in acute COVID-19 patients

  3. Periodic monitoring of OXT plasma levels over days to weeks

It may be advantageous to focus treatment on patients with low OXT, identified through demographic and predisposing risk factors, and by direct measurement of plasma OXT. Raising OXT levels in the acute phase either by endogenous induction or exogenous administration may help mitigate the frequency and severity of long-COVID due to OXT’s multi-target protective mechanisms.

Ultimately, the “love hormone”, OXT, may be our great hope: it could be the post-pandemic panacea that has been hiding in plain sight.


Corresponding author: Violet Kasabri, PhD, MSc, BSc, School of Pharmacy, University of Jordan, Amman, Jordan, E-mail:

  1. Research funding: None declared.

  2. Author contribution: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: None included in this study.

  5. Ethical approval: The conducted research is not related to either human or animals.

References

1(a). Bryant, A, Lawrie, TA, Dowswell, T, Fordham, EJ, Mitchell, S, Hill, SR, et al.. Ivermectin for prevention and treatment of COVID-19 infection: a systematic review, meta-analysis, and trial sequential analysis to inform clinical guidelines. Am J Therapeut 2021;28:e434–e460, https://doi.org/10.1097/mjt.0000000000001442.Search in Google Scholar

(b) Caly, L, Druce, JD, Catton, MG, Jans, DA, Wagstaff, KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antivir Res 2020;178:104787, https://doi.org/10.1016/j.antiviral.2020.104787.Search in Google Scholar

(c) Rajter, JC, Sherman, MS, Fatteh, N, Vogel, F, Sack, J, Rajter, JJ. Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: the ivermectin in COVID nineteen study. Chest 2021;159:85–92, https://doi.org/10.1016/j.chest.2020.10.009.Search in Google Scholar

(d) Gautret, P, Lagier, JC, Parola, P, Hoang, VT, Meddeb, L, Mailhe, M, et al.. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020;56:105949, https://doi.org/10.1016/j.ijantimicag.2020.105949.Search in Google Scholar

(e) Calegari, J, Beverina, A, Tiraboschi, S, Gruppo di Autoformazione Metodologica (GrAM). Hydroxychloroquine and azithromycin as a treatment of COVID-19. Intern Emerg Med 2020;15:841–3.10.1007/s11739-020-02388-ySearch in Google Scholar PubMed PubMed Central

(f) Siddiqui, AJ, Jahan, S, Ashraf, SA, Alreshidi, M, Ashraf, MS, Patel, M, et al.. Current status and strategic possibilities on potential use of combinational drug therapy against COVID-19 caused by SARS-CoV-2. J Biomol Struct Dyn 2021;39:6828–41, https://doi.org/10.1080/07391102.2020.1802345.Search in Google Scholar

(g) Choudhary, R, Shama, AK. Potential use of hydroxychloroquine, ivermectin and azithromycin drugs in fighting COVID-19: trends, scope and relevance. New Microbes New Infect 2020;35:100684, https://doi.org/10.1016/j.nmni.2020.100684.Search in Google Scholar

(h) Cadegiani, FA, Goren, A, Wambier, CG, McCoy, J. Early COVID-19 therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in outpatient settings significantly improved COVID-19 outcomes compared to known outcomes in untreated patients. New Microbes New Infect 2021;43:100915, https://doi.org/10.1016/j.nmni.2021.100915.Search in Google Scholar

2. Vimaleswaran, KS, Forouhi, NG, Khunti, K. Vitamin D and COVID-19. BMJ 2021;372:n544, https://doi.org/10.1136/bmj.n544.Search in Google Scholar

3. Zhang, R, Wang, X, Ni, L, Di, X, Ma, B, Niu, S, et al.. COVID-19: melatonin as a potential adjuvant treatment. Life Sci 2020;250:117583, https://doi.org/10.1016/j.lfs.2020.117583.Search in Google Scholar

4(a). Buemann, B, Marazziti, D, Uvnäs-Moberg, K. Can intravenous oxytocin infusion counteract hyperinflammation in COVID-19 infected patients? World J Biol Psychiatr 2020;11:1–12, https://doi.org/10.1080/15622975.2020.1814408.Search in Google Scholar

(b) Imami, AS, O’Donovan, SM, Creeden, JF, Wu, X, Eby, H, McCullumsmith, CB, et al.. Oxytocin’s anti-inflammatory and proimmune functions in COVID-19: a transcriptomic signature-based approach. Physiol Genom 2020;52:401–7, https://doi.org/10.1152/physiolgenomics.00095.2020.Search in Google Scholar

(c) Simpson, KR. Considerations for active labor management with oxytocin: more may not be better. MCN Am J Matern/Child Nurs 2020;45:248, https://doi.org/10.1097/NMC.0000000000000639.Search in Google Scholar

(d) Breuil, V, Trojani, M-C, Ez-Zoubir, A. Oxytocin and bone: review and perspectives. Int J Mol Sci 2021;22:8551, https://doi.org/10.3390/ijms22168551.Search in Google Scholar

5. Zhu, Z, Lian, X, Su, X, Wu, W, Marraro, GA, Zeng, Y. From SARS and MERS to COVID-19: a brief summary and comparison of severe acute respiratory infections caused by three highly pathogenic human coronaviruses. Respir Res 2020;21:224, https://doi.org/10.1186/s12931-020-01479-w.Search in Google Scholar

6. Chlamydas, S, Papavassiliou, AG, Piperi, C. Epigenetic mechanisms regulating COVID-19 infection. Epigenetics 2021;16:263–70, https://doi.org/10.1080/15592294.2020.1796896.Search in Google Scholar

7. Marazziti, D, Cianconi, P, Mucci, F, Foresi, L, Chiarantini, I, Della Vecchia, A. Climate change, environment pollution, COVID-19 pandemic and mental health. Sci Total Environ 2021;773:145182, https://doi.org/10.1016/j.scitotenv.2021.145182.Search in Google Scholar

8. Chen, T, Song, J, Liu, H, Zheng, H, Chen, C. Positive Epstein–Barr virus detection in coronavirus disease 2019 (COVID-19) patients. Sci Rep 2021;11:10902, https://doi.org/10.1038/s41598-021-90351-y.Search in Google Scholar

9. Moss, P. The ancient and the new: is there an interaction between cytomegalovirus and SARS-CoV-2 infection? Immun Ageing 2020;17:14, https://doi.org/10.1186/s12979-020-00185-x.Search in Google Scholar

10. Dodd, LE, Freidlin, B, Korn, EL. Platform trials—beware the noncomparable Control group. N Engl J Med 2021;384:1572–3, https://doi.org/10.1056/nejmc2102446.Search in Google Scholar

11. Gu, J, Gong, E, Zhang, B, Zheng, J, Gao, Z, Zhong, Y, et al.. Multiple organ infection and the pathogenesis of SARS. J Exp Med 2005;202:415–24, https://doi.org/10.1084/jem.20050828.Search in Google Scholar

12. Moses, AM, Thomas, DG, Canfield, MC, Collins, GH. Central diabetes insipidus due to cytomegalovirus infection of the hypothalamus in a patient with acquired immunodeficiency syndrome: a clinical, pathological, and immunohistochemical case study. J Clin Endocrinol Metab 2003;88:51–4, https://doi.org/10.1210/jc.2002-020879.Search in Google Scholar

13. Chrousos, GP, Zapanti, ED. Hypothalamic-pituitary-adrenal axis in HIV infection and disease. Endocrinol Metab Clin N Am 2014;43:791–806, https://doi.org/10.1016/j.ecl.2014.06.002.Search in Google Scholar

14. Liu, Y, Conboy, I. Unexpected evolutionarily conserved rapid effects of viral infection on oxytocin receptor and TGF-β/pSmad3. Skeletal Muscle 2017;7:7, https://doi.org/10.1186/s13395-017-0125-y.Search in Google Scholar

15. Carter, C, Kenkel, W, Maclean, E, Wilson, S, Perkeybile, A, Yee, J, et al.. Is oxytocin “nature’s medicine”. Pharm Rev 2020;72:829–61, https://doi.org/10.1124/pr.120.019398.Search in Google Scholar

16. Erdman, S, Poutahidis, T. Probiotic ‘glow of health’: it’s more than skin deep. Benef Microbes 2014;5:109–19, https://doi.org/10.3920/bm2013.0042.Search in Google Scholar

17. Imami, AS, O’Donovan, SM, Creeden, JF, Wu, X, Eby, H, McCullumsmith, CB, et al.. Oxytocin’s anti-inflammatory and proimmune functions in COVID-19: a transcriptomic signature-based approach. Physiol Genom 2020;52:401–7, https://doi.org/10.1152/physiolgenomics.00095.2020.Search in Google Scholar

18. Diep, P-T, Talash, K, Kasabri, V. Hypothesis: oxytocin is a direct COVID-19 antiviral. Med Hypotheses 2020;145:110329, https://doi.org/10.1016/j.mehy.2020.110329.Search in Google Scholar

19. Tsegay, KB, Adeyemi, CM, Gniffke, EP, Sather, DN, Walker, JK, Smith, SEP. A repurposed drug screen identifies compounds that inhibit the binding of the COVID-19 spike protein to ACE2. Front Pharmacol 2021;12:685308, https://doi.org/10.3389/fphar.2021.685308.Search in Google Scholar

20. Bechter, K. Virus infection as a cause of inflammation in psychiatric disorders. Modern Trends Pharmacopsych 2013;28:49–60, https://doi.org/10.1159/000343967.Search in Google Scholar

21. Martimbianco, ALC, Pacheco, RL, Bagattini, ÂM, Riera, R. Frequency, signs and symptoms, and criteria adopted for long COVID-19: a systematic review. Int J Clin Pract 2021;75: e14357, https://doi.org/10.1111/ijcp.14357.Search in Google Scholar

22. Lopez-Leon, S, Wegman-Ostrosky, T, Perelman, C, Sepulveda, R, Rebolledo, PA, Cuapio, A, et al.. More than 50 long-term effects of COVID-19: a systematic review and meta-analysis. Sci Rep 2021;11:16144, https://doi.org/10.1038/s41598-021-95565-8.Search in Google Scholar

23. The Institute of Medicine (IOM). 2015 Diagnostic criteria. CDC (Center of Disease Control) Control and Prevention, National Center for Emerging and oonotic Infectious Diseases; 2021: 1–2 pp. Available from: https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/iom-2015-diagnostic-criteria.html [Accessed 12 Sep 2021].Search in Google Scholar

24. Hatziagelaki, E, Adamaki, M, Tsilioni, I, Dimitriadis, G, Theoharides, TC. Myalgic encephalomyelitis/chronic fatigue syndrome-metabolic disease or disturbed homeostasis due to focal inflammation in the hypothalamus? J Pharmacol Exp Therapeut 2018;367:155–67, https://doi.org/10.1124/jpet.118.250845.Search in Google Scholar

25. VanElzakker, MB. Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis. Med. Hypotheses 2013;81:414–23, https://doi.org/10.1016/j.mehy.2013.05.034.Search in Google Scholar

26. Gong, L, Li, J, Tang, Y, Han, T, Wei, C, Yu, X, et al.. The antinociception of oxytocin on colonic hypersensitivity in rats was mediated by inhibition of mast cell degranulation via Ca2+ NOS pathway. Sci Rep 2016;6:31452, https://doi.org/10.1038/srep31452.Search in Google Scholar

27. Chaves, VE, Tilelli, CQ, Brito, NA, Brito, MN. Role of oxytocin in energy metabolism. Peptides 2013;45:9–14, https://doi.org/10.1016/j.peptides.2013.04.010.Search in Google Scholar

28. Bordt, EA, Smith, CJ, Demarest, TG, Bilbo, SD, Kingsbury, MA. Mitochondria, oxytocin, and vasopressin: unfolding the inflammatory protein response. Neurotox Res 2019;36:239–56, https://doi.org/10.1007/s12640-018-9962-7.Search in Google Scholar

29. Mehdipour, M, Etienne, J, Chen, C-C, Gathwala, R, Rehman, M, Kato, C, et al.. Rejuvenation of brain, liver and muscle by simultaneous pharmacological modulation of two signaling determinants, that change in opposite directions with age. Aging [Albany NY] 2019;11:5628–45, https://doi.org/10.18632/aging.102148.Search in Google Scholar

30. Elabd, C, Cousin, W, Upadhyayula, P, Chen, RY, Chooljian, MS, Li, J, et al.. Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Nat Commun 2014;5:4082, https://doi.org/10.1038/ncomms5082.Search in Google Scholar

31. Simonneaux, V, Ouichou, A, Burbach, JPH, Pévet, P. Vasopressin and oxytocin modulation of melatonin secretion from rat pineal glands. Peptides 1990;11:1075–9, https://doi.org/10.1016/0196-9781(90)90133-p.Search in Google Scholar

32. Sandyk, R. MIF-induced augmentation of melatonin functions: possible relevance to mechanisms of action of MIF-1 in movement disorders. Int J Neurosci 1990;52:59–65, https://doi.org/10.3109/00207459008994244.Search in Google Scholar

33. Lin, Y-T, Chen, C-C, Huang, C-C, Nishimori, K, Hsu, K-S. Oxytocin stimulates hippocampal neurogenesis via oxytocin receptor expressed in CA3 pyramidal neurons. Nat Commun 2017;8:537, https://doi.org/10.1038/s41467-017-00675-5.Search in Google Scholar

34. Jafarzadeh, N, Javeri, A, Khaleghi, M, Taha, MF. Oxytocin improves proliferation and neural differentiation of adipose tissue-derived stem cells. Neurosci Lett 2014;564:105–10, https://doi.org/10.1016/j.neulet.2014.02.012.Search in Google Scholar

35. Erbas, O, Taşkıran, D, Oltulu, F, Yavaşoğlu, A, Bora, S, Bilge, O, et al.. Oxytocin provides protection against diabetic polyneuropathy in rats. Neurol Res 2017;39:45–53, https://doi.org/10.1080/01616412.2016.1249630.Search in Google Scholar

36. Gümüs, B, Kuyucu, E, Erbas, O, Kazimoglu, C, Oltulu, F, Bora, OA. Effect of oxytocin administration on nerve recovery in the rat sciatic nerve damage model. J Orthop Surg Res 2015;10:161, https://doi.org/10.1186/s13018-015-0301-x.Search in Google Scholar

37. Leng, G, Sabatier, N. Oxytocin – the sweet hormone? Trends Endocrinol Metabol 2017;28:365–76, https://doi.org/10.1016/j.tem.2017.02.007.Search in Google Scholar

38. Yu, G-Z, Kaba, H, Okutani, F, Takahashi, S, Higuchi, T. The olfactory bulb: a critical site of action for oxytocin in the induction of maternal behavior in the rat. Neuroscience 1996;72:1083–8, https://doi.org/10.1016/0306-4522(95)00600-1.Search in Google Scholar

39. Lee, MR, Wehring, HJ, McMahon, RP, Linthicum, J, Cascella, N, Liu, F, et al.. Effects of adjunctive intranasal oxytocin on olfactory identification and clinical symptoms in schizophrenia: results from a randomized double blind placebo controlled pilot study. Schizophr Res 2013;145:110–5, https://doi.org/10.1016/j.schres.2013.01.001.Search in Google Scholar

40. Leuner, B, Caponiti, JM, Gould, E. Oxytocin stimulates adult neurogenesis even under conditions of stress and elevated glucocorticoids. Hippocampus 2012;22:861–8, https://doi.org/10.1002/hipo.20947.Search in Google Scholar

41. Marazziti, D, Catena Dell’osso, M. The role of oxytocin in neuropsychiatric disorders. Curr Med Chem 2008;15:698–704, https://doi.org/10.2174/092986708783885291.Search in Google Scholar

42. Matsushita, H, Latt, HM, Koga, Y, Nishiki, T, Matsui, H. Oxytocin and stress: neural mechanisms, stress-related disorders, and therapeutic approaches. Neuroscience 2019;417:1–10, https://doi.org/10.1016/j.neuroscience.2019.07.046.Search in Google Scholar

43. Grinevich, V, Neumann, ID. Brain oxytocin: how puzzle stones from animal studies translate into psychiatry. Mol Psychiatr 2021;26:265–79, https://doi.org/10.1038/s41380-020-0802-9.Search in Google Scholar

44. Wang, L, Nabi, G, Zhang, T, Wu, Y, Li, D. Potential neurochemical and neuroendocrine effects of social distancing amidst the COVID-19 pandemic. Front Endocrinol 2020;11:582288, https://doi.org/10.3389/fendo.2020.582288.Search in Google Scholar

45. Soumier, A, Sirigu, A. Oxytocin as a potential defense against Covid-19? Med Hypotheses 2020;140:109785, https://doi.org/10.1016/j.mehy.2020.109785.Search in Google Scholar

46. Thakur, P, Shrivastava, R, Shrivastava, VK. Oxytocin as a potential adjuvant against COVID-19 infection. Endocr Metab Immune Disord – Drug Targets 2021;21:1155–62, https://doi.org/10.2174/1871530320666200910114259.Search in Google Scholar

47. Anderberg, UM, Uvnäs-Moberg, K. Plasma oxytocin levels in female fibromyalgia syndrome patients. Z Rheumatol 2000;59:373–9, https://doi.org/10.1007/s003930070045.Search in Google Scholar

48. Tzabazis, A, Mechanic, J, Miller, J, Klukinov, M, Pascual, C, Manering, N, et al.. Oxytocin receptor: expression in the trigeminal nociceptive system and potential role in the treatment of headache disorders. Cephalalgia 2016;36:943–50, https://doi.org/10.1177/0333102415618615.Search in Google Scholar

49. Wang, Y-L, Yuan, Y, Yang, J, Wang, C-H, Pan, Y-J, Lu, L, et al.. The interaction between the oxytocin and pain modulation in headache patients. Neuropeptides 2013;47:93–7, https://doi.org/10.1016/j.npep.2012.12.003.Search in Google Scholar

50. Goodin, BR, Ness, TJ, Robbins, MT. Oxytocin – a multifunctional analgesic for chronic deep tissue pain. Curr Pharmaceut Des 2015;21:906–13, https://doi.org/10.2174/1381612820666141027111843.Search in Google Scholar

51. Eliava, M, Melchior, M, Knobloch-Bollmann, HS, Wahis, J, da Silva Gouveia, M, Tang, Y, et al.. A new population of parvocellular oxytocin neurons controlling magnocellular neuron activity and inflammatory pain processing. Neuron 2016;89:1291–304, https://doi.org/10.1016/j.neuron.2016.01.041.Search in Google Scholar

52. Lussier, D, Cruz-Almeida, Y, Ebner, NC. Musculoskeletal pain and brain morphology: oxytocin’s potential as a treatment for chronic pain in aging. Front Aging Neurosci 2019;11:338, https://doi.org/10.3389/fnagi.2019.00338.Search in Google Scholar

53. Russo, R, D’Agostino, G, Mattace Raso, G, Avagliano, C, Cristiano, C, Meli, R, et al.. Central administration of oxytocin reduces hyperalgesia in mice: implication for cannabinoid and opioid systems. Peptides 2012;38:81–8, https://doi.org/10.1016/j.peptides.2012.08.005.Search in Google Scholar

54. Meguro, Y, Miyano, K, Hirayama, S, Yoshida, Y, Ishibashi, N, Ogino, T, et al.. Neuropeptide oxytocin enhances μ opioid receptor signaling as a positive allosteric modulator. J. Pharm.Sci. 2018;137:67–75, https://doi.org/10.1016/j.jphs.2018.04.002.Search in Google Scholar

55. Nersesyan, Y, Demirkhanyan, L, Cabezas-Bratesco, D, Oakes, V, Kusuda, R, Dawson, T, et al.. Oxytocin modulates nociception as an agonist of pain-sensing TRPV1. Cell Rep 2017;21:1681–91, https://doi.org/10.1016/j.celrep.2017.10.063.Search in Google Scholar

56. An, X, Sun, X, Hou, Y, Yang, X, Chen, H, Zhang, P, et al.. Protective effect of oxytocin on LPS-induced acute lung injury in mice. Sci Rep 2019;9:2836, https://doi.org/10.1038/s41598-019-39349-1.Search in Google Scholar

57. Lin, C-H, Tsai, C-C, Chen, T-H, Chang, C-P, Yang, H-H. Oxytocin maintains lung histological and functional integrity to confer protection in heat stroke. Sci Rep 2019;9:18390, https://doi.org/10.1038/s41598-019-54739-1.Search in Google Scholar

58. Danalache, BA, Paquin, J, Donghao, W, Grygorczyk, R, Moore, JC, Mummery, CL, et al.. Nitric oxide signaling in oxytocin-mediated cardiomyogenesis. Stem Cell 2007;25:679–88, https://doi.org/10.1634/stemcells.2005-0610.Search in Google Scholar

59. Melis, MR, Succu, S, Iannucci, U, Argiolas, A. Oxytocin increases nitric oxide production in the paraventricular nucleus of the hypothalamus of male rats: correlation with penile erection and yawning. Regul Pept 1997;69:105–11, https://doi.org/10.1016/s0167-0115(97)00002-5.Search in Google Scholar

60. Ricciardolo, FLM. Multiple roles of nitric oxide in the airways. Thorax 2003;58:175–82, https://doi.org/10.1136/thorax.58.2.175.Search in Google Scholar

61. Longobardo, A, Montanari, C, Shulman, R, Benhalim, S, Singer, M, Arulkumaran, N. Inhaled nitric oxide minimally improves oxygenation in COVID-19 related acute respiratory distress syndrome. Br J Anaesth 2021;126:e44–6, https://doi.org/10.1016/j.bja.2020.10.011.Search in Google Scholar

62. Luo, J, Chen, AF. Nitric oxide: a newly discovered function on wound healing. Acta Pharm Sin 2005;26:259–64, https://doi.org/10.1111/j.1745-7254.2005.00058.x.Search in Google Scholar

63. Åkerström, S, Mousavi-Jazi, M, Klingström, J, Leijon, M, Lundkvist, Å, Mirazimi, A. Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus. J Virol 2005;79:1966–9.10.1128/JVI.79.3.1966-1969.2005Search in Google Scholar PubMed PubMed Central

64. Gutkowska, J, Jankowski, M. Oxytocin revisited: it is also a cardiovascular hormone. J Am Soc. Hypert. 2008;2:318–25, https://doi.org/10.1016/j.jash.2008.04.004.Search in Google Scholar

65. Jankowski, M, Broderick, TL, Gutkowska, J. Oxytocin and cardioprotection in diabetes and obesity. BMC Endocr Disord 2016;16:34, https://doi.org/10.1186/s12902-016-0110-1.Search in Google Scholar

66. Wang, P, Wang, SC, Yang, H, Lv, C, Jia, S, Liu, X, et al.. Therapeutic potential of oxytocin in atherosclerotic cardiovascular disease: mechanisms and signaling pathways. Front Neurosci 2019;13:454, https://doi.org/10.3389/fnins.2019.00454.Search in Google Scholar

67. Habecker, BA. Oxytocin: a new therapeutic for heart failure? JACC (J Am Coll Cardiol): Basic Trans. Sci. 2020;5:498–500, https://doi.org/10.1016/j.jacbts.2020.03.011.Search in Google Scholar

68. Wang, SC, Wang, Y-F. Cardiovascular protective properties of oxytocin against COVID-19. Life Sci 2021;270:119130, https://doi.org/10.1016/j.lfs.2021.119130.Search in Google Scholar

69. Alfvén, G. Plasma oxytocin in children with recurrent abdominal pain. J Pediatr Gastroenterol Nutr 2004;38:513–7.10.1097/00005176-200405000-00010Search in Google Scholar PubMed

70. Gavril, R, Hritcu, L, Padurariu, M, Ciobica, A, Horhogea, C, Stefanescu, G, et al.. Preliminary study on the correlations between oxytocin levels and irritable bowel syndrome in patients with depression. Rev Chim (Bucharest) 2019;70:2204–6, https://doi.org/10.37358/rc.19.6.7305.Search in Google Scholar

71. Hritcu, L, Dumitru, IO, Padurariu, M, Ciobica, A, Spataru, MC, Spataru, C, et al.. The modulation of oxytocin and cortisol levels in major depression disorder and irritable bowel syndrome. Rev Chim (Bucharest) 2020;71:150–4, https://doi.org/10.37358/rc.20.1.7826.Search in Google Scholar

72. İşeri, SÖ, Şener, G, Sağlam, B, Gedik, N, Ercan, F, Yeğen, BÇ. Oxytocin ameliorates oxidative colonic inflammation by a neutrophil-dependent mechanism. Peptides 2005;26:483–91.10.1016/j.peptides.2004.10.005Search in Google Scholar PubMed

73. Tang, Y, Shi, Y, Gao, Y, Xu, X, Han, T, Li, J, et al.. Oxytocin system alleviates intestinal inflammation by regulating macrophages polarization in experimental colitis. Clin Sci [Lond] 2019;133:1977–92, https://doi.org/10.1042/cs20190756.Search in Google Scholar

74. Cetinel, S, Hancioğlu, S, Sener, E, Uner, C, Kiliç, M, Sener, G, et al.. Oxytocin treatment alleviates stress-aggravated colitis by a receptor-dependent mechanism. Regul Pept 2010;160:146–52, https://doi.org/10.1016/j.regpep.2009.11.011.Search in Google Scholar

75. Erbas, O, Anil Korkmaz, H, Oltulu, F, Aktug, H, Yavasoglu, A, Akman, L, et al.. Oxytocin alleviates cisplatin-induced renal damage in rats. Iran J Basic Med Sci 2014;17:747–52.Search in Google Scholar

76. Deing, V, Roggenkamp, D, Kühnl, J, Gruschka, A, Stäb, F, Wenck, H, et al.. Oxytocin modulates proliferation and stress responses of human skin cells: implications for atopic dermatitis. Exp Dermatol 2013;22:399–405, https://doi.org/10.1111/exd.12155.Search in Google Scholar

77. Petersson, M, Lundeberg, T, Sohlström, A, Wiberg, U, Uvnäs-Moberg, K. Oxytocin increases the survival of musculocutaneous flaps. Naunyn-Schmiedeberg’s Arch Pharmacol 1998;357:701–4, https://doi.org/10.1007/pl00005227.Search in Google Scholar

78. Xu, P-F, Fang, M-J, Jin, Y-Z, Wang, L-S, Lin, D-S. Effect of oxytocin on the survival of random skin flaps. Oncotarget 2017;8:92955–65, https://doi.org/10.18632/oncotarget.21696.Search in Google Scholar

79. Kim, YS, Kwon, JS, Hong, MH, Kang, WS, Jeong, H, Kang, H, et al.. Restoration of angiogenic capacity of diabetes-insulted mesenchymal stem cells by oxytocin. BMC Cell Biol 2013;14:38, https://doi.org/10.1186/1471-2121-14-38.Search in Google Scholar

80. Tong, J, Yu, Y, Zheng, L, Zhang, C, Tu, Y, Liu, Y, et al.. Hypothalamus-pituitary-adrenal axis involves in anti-viral ability through regulation of immune response in piglets infected by highly pathogenic porcine reproductive and respiratory syndrome virus. BMC Vet Res 2018;14:92, https://doi.org/10.1186/s12917-018-1414-3.Search in Google Scholar

81. Wu, Y-H, Cui, X-Y, Yang, W, Fan, D-Y, Liu, D, Wang, P-G, et al.. Zika virus infection in hypothalamus causes hormone deficiencies and leads to irreversible growth delay and memory impairment in mice. Cell Rep 2018;25:1537–47, https://doi.org/10.1016/j.celrep.2018.10.025.Search in Google Scholar

82. Ahn, HJ, Chung, J-H, Kim, D-M, Yoon, N-R, Kim, C-M. Hemorrhagic fever with renal syndrome accompanied by panhypopituitarism and central diabetes insipidus: a case report. J Neurovirol 2018;24:382–7, https://doi.org/10.1007/s13365-018-0624-6.Search in Google Scholar

83. Stojanovic, M, Pekic, S, Cvijovic, G, Miljic, D, Doknic, M, Nikolic-Djurovic, M, et al.. High risk of hypopituitarism in patients who recovered from hemorrhagic fever with renal syndrome. J Clin Endocrinol Metab 2008;93:2722–8, https://doi.org/10.1210/jc.2008-0311.Search in Google Scholar

84. Leow, MK, Kwek, DS, Ng, AW, Ong, K, Kaw, GJ, Lee, LS. Hypocortisolism in survivors of severe acute respiratory syndrome (SARS). Clin Endocrinol 2005;63:197–202, https://doi.org/10.1111/j.1365-2265.2005.02325.x.Search in Google Scholar

85. Stock, S, Uvnäs‐Moberg, K. Increased plasma levels of oxytocin in response to afferent electrical stimulation of the sciatic and vagal nerves and in response to touch and pinch in anaesthetized rats. Acta Physiol Scand 1988;132:29–34, https://doi.org/10.1111/j.1748-1716.1988.tb08294.x.Search in Google Scholar

86. Amin, MR, Koufman, JA. Vagal neuropathy after upper respiratory infection: a viral etiology? Am J Otolaryngol 2001;22:251–6, https://doi.org/10.1053/ajot.2001.24823.Search in Google Scholar

87. Bachor, E, Bonkowsky, V, Hacki, T. Herpes simplex virus type I reactivation as a cause of a unilateral temporary paralysis of the vagus nerve. Eur Arch Oto-Rhino-Laryngol 1996;253:297–300, https://doi.org/10.1007/BF00171147.Search in Google Scholar

88. Rangon, C-M, Krantic, S, Moyse, E, Fougère, B. The vagal autonomic pathway of COVID-19 at the crossroad of alzheimer’s disease and aging: a review of knowledge. J Alzheim. Dis Rep. 2020;4:537–51, https://doi.org/10.3233/adr-200273.Search in Google Scholar

89. Diep, P-T. Is there an underlying link between COVID-19, ACE2, oxytocin and vitamin D? Med Hypotheses 2021;146:110360, https://doi.org/10.1016/j.mehy.2020.110360.Search in Google Scholar

90. MacLean, EL, Wilson, SR, Martin, WL, Davis, JM, Nazarloo, HP, Carter, CS. Challenges for measuring oxytocin: the blind men and the elephant? Psychoneuroendocrinology 2019;107:225–31, https://doi.org/10.1016/j.psyneuen.2019.05.018.Search in Google Scholar

91. Baskaran, C, Plessow, F, Silva, L, Asanza, E, Marengi, D, Eddy, KT, et al.. Oxytocin secretion is pulsatile in men and is related to social-emotional functioning. Psychoneuroendocrinology 2017;85:28–34, https://doi.org/10.1016/j.psyneuen.2017.07.486.Search in Google Scholar

92. Carter, CS. The oxytocin–vasopressin pathway in the context of love and fear. Front Endocrinol 2017;8:356, https://doi.org/10.3389/fendo.2017.00356.Search in Google Scholar

93. Ellis, BJ, Horn, AJ, Carter, CS, van IJzendoorn, MH, Bakermans-Kranenburg, MJ. Developmental programming of oxytocin through variation in early-life stress: four meta-analyses and a theoretical reinterpretation. Clin Psychol Rev 2021;86:101985, https://doi.org/10.1016/j.cpr.2021.101985.Search in Google Scholar

94. Adamo, S, Pigna, E, Lugarà, R, Moresi, V, Coletti, D, Bouché, M. Skeletal muscle: a significant novel neurohypophyseal hormone-secreting organ. Front Physiol 2019;9:1885, https://doi.org/10.3389/fphys.2018.01885.Search in Google Scholar

95. Liu, J, Liu, S, Zhang, Z, Lee, X, Wu, W, Huang, Z, et al.. Association between the nasopharyngeal microbiome and metabolome in patients with COVID-19. Synth Syst Biotech 2021;6:135–43, https://doi.org/10.1016/j.synbio.2021.06.002.Search in Google Scholar

96. Kramer, P, Bressan, P. Infection threat shapes our social instincts. Behav Ecol Sociobiol 2021;75:4, https://doi.org/10.1007/s00265-021-02975-9.Search in Google Scholar

97. Amro, M, Mohamed, A, Alawna, M. Effects of increasing aerobic capacity on improving psychological problems seen in patients with COVID-19: a review. Eur Rev Med Pharmacol Sci 2021;25:2808–21, https://doi.org/10.26355/eurrev_202103_25443.Search in Google Scholar

98. Greenberg, DM, Decety, J, Gordon, I. The social neuroscience of music: understanding the social brain through human song. Am Psychol 2021;76:1172–85 https://doi.org/10.1037/amp0000819.Search in Google Scholar

99. Meijer, LL, Hasenack, B, Kamps, JCC, Mahon, A, Titone, G, Dijkerman, HC, et al.. Affective touch perception and longing for touch during the COVID-19 pandemic. Sci Rep 2022;12:3887–96.10.1038/s41598-022-07213-4Search in Google Scholar PubMed PubMed Central

100. Ionio, C, Ciuffo, G, Landoni, M. Parent–infant skin-to-skin contact and stress regulation: a systematic review of the literature. Int J Environ Res Publ Health 2021;18:4695, https://doi.org/10.3390/ijerph18094695.Search in Google Scholar

101. Lee, H-J, Macbeth, AH, Pagani, J, Young, WS. Oxytocin: the great facilitator of life. Prog Neurobiol 2009;88:127–51, https://doi.org/10.1016/j.pneurobio.2009.04.001.Search in Google Scholar

102. Patrick, RP, Ames, BN. Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. Faseb J 2014;28:2398–413, https://doi.org/10.1096/fj.13-246546.Search in Google Scholar

103. Forsling, ML, Wheeler, MJ, Williams, AJ. The effect of melatonin administration on pituitary hormone secretion in man. Clin Endocrinol 1999;51:637–42, https://doi.org/10.1046/j.1365-2265.1999.00820.x.Search in Google Scholar

104. Thomas, JS, Koh, SH, Cooper, GM. Haemodynamic effects of oxytocin given as i.v. bolus or infusion on women undergoing Caesarean section. Br J Anaesth 2007;98:116–9, https://doi.org/10.1093/bja/ael302.Search in Google Scholar

105. Phaneuf, S, Rodríguez Liñares, B, TambyRaja, RL, MacKenzie, IZ, López Bernal, A. Loss of myometrial oxytocin receptors during oxytocin-induced and oxytocin-augmented labor. J Reprod Fertil 2000;120:91–7, https://doi.org/10.1530/jrf.0.1200091.Search in Google Scholar

106. Tabak, BA, McCullough, ME, Szeto, A, Mendez, AJ, McCabe, PM. Oxytocin indexes relational distress following interpersonal harms in women. Psychoneuroendocrinology 2011;36:115–22, https://doi.org/10.1016/j.psyneuen.2010.07.004.Search in Google Scholar

107. Winter, J, Meyer, M, Berger, I, Peters, S, Royer, M, Bianchi, M, et al.. Chronic oxytocin-driven alternative splicing of CRFR2α induces anxiety. Mol Psychiatr 2021, https://doi.org/10.1038/s41380-021-01141-x.Search in Google Scholar

108. Yamamoto, Y, Higashida, H. RAGE regulates oxytocin transport into the brain. Commun Biol 2020;3:1–4, https://doi.org/10.1038/s42003-020-0799-2.Search in Google Scholar

109. Quintana, DS, Smerud, KT, Andreassen, OA, Djupesland, PG. Evidence for intranasal oxytocin delivery to the brain: recent advances and future perspectives. Ther Deliv 2018;9:515–25, https://doi.org/10.4155/tde-2018-0002.Search in Google Scholar

Received: 2021-04-13
Revised: 2021-12-11
Accepted: 2022-03-12
Published Online: 2022-05-16

© 2022 Walter de Gruyter GmbH, Berlin/Boston