nutrients

Review
Neuroimmunological Effect of Vitamin D on Neuropsychiatric
Long COVID Syndrome: A Review
Ting-Bin Chen 1 , Ching-Mao Chang 2,3,4 , Cheng-Chia Yang 5 , I-Ju Tsai 6 , Cheng-Yu Wei 7,8, * ,
Hao-Wen Yang 9, * and Chun-Pai Yang 6,10,11,12, *

1 Department of Neurology, Neurological Institute, Taichung Veterans General Hospital,

Taichung 407219, Taiwan; [email protected]
2 Center for Traditional Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; [email protected]
3 Faculty of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan
4 Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan
5 Department of Healthcare Administration, Asia University, Taichung 41354, Taiwan; [email protected]
6 Department of Medical Research, Kuang Tien General Hospital, Taichung 433, Taiwan;
[email protected]
7 Department of Exercise and Health Promotion, College of Kinesiology and Health,
Chinese Culture University, Taipei 11114, Taiwan
8 Department of Neurology, Chang Bing Show Chwan Memorial Hospital, Changhua 50544, Taiwan
9 Department of Family Medicine, Kuang Tien General Hospital, Taichung 433, Taiwan
10 Department of Neurology, Kuang Tien General Hospital, Taichung 433, Taiwan
11 Department of Nutrition, HungKuang University, Taichung 433, Taiwan
12 Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
* Correspondence: [email protected] (C.-Y.W.); [email protected] (H.-W.Y.);
[email protected] (C.-P.Y.); Tel.: +886-4-2665-1900 (H.-W.Y. & C.-P.Y.);
Fax: +886-4-2688-5599 (H.-W.Y. & C.-P.Y.)

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent
of the coronavirus disease 2019 (COVID-19). COVID-19 is now recognized as a multiorgan dis-
ease with a broad spectrum of manifestations. A substantial proportion of individuals who have
Citation: Chen, T.-B.; Chang, C.-M.;
recovered from COVID-19 are experiencing persistent, prolonged, and often incapacitating seque-
Yang, C.-C.; Tsai, I.-J.; Wei, C.-Y.; lae, collectively referred to as long COVID. To date, definitive diagnostic criteria for long COVID
Yang, H.-W.; Yang, C.-P. diagnosis remain elusive. An emerging public health threat is neuropsychiatric long COVID, encom-
Neuroimmunological Effect of passing a broad range of manifestations, such as sleep disturbance, anxiety, depression, brain fog,
Vitamin D on Neuropsychiatric Long and fatigue. Although the precise mechanisms underlying the neuropsychiatric complications of
COVID Syndrome: A Review. long COVID are presently not fully elucidated, neural cytolytic effects, neuroinflammation, cerebral
Nutrients 2023, 15, 3802. https:// microvascular compromise, breakdown of the blood–brain barrier (BBB), thrombosis, hypoxia, neu-
doi.org/10.3390/nu15173802
rotransmitter dysregulation, and provoked neurodegeneration are pathophysiologically linked to
Academic Editor: Herbert long-term neuropsychiatric consequences, in addition to systemic hyperinflammation and maladap-
Ryan Marini tation of the renin–angiotensin–aldosterone system. Vitamin D, a fat-soluble secosteroid, is a potent
immunomodulatory hormone with potential beneficial effects on anti-inflammatory responses, neuro-
Received: 3 August 2023
protection, monoamine neurotransmission, BBB integrity, vasculometabolic functions, gut microbiota,
Revised: 26 August 2023
Accepted: 28 August 2023
and telomere stability in different phases of SARS-CoV-2 infection, acting through both genomic
Published: 30 August 2023 and nongenomic pathways. Here, we provide an up-to-date review of the potential mechanisms
and pathophysiology of neuropsychiatric long COVID syndrome and the plausible neurological
contributions of vitamin D in mitigating the effects of long COVID.

Copyright: © 2023 by the authors. Keywords: long COVID; vitamin D; neuroimmunological effect
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
1. Introduction
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a type of betacoron-
4.0/).
avirus, is the causative agent of coronavirus disease 2019 (COVID-19). It predominantly

Nutrients 2023, 15, 3802. https://doi.org/10.3390/nu15173802 https://www.mdpi.com/journal/nutrients

Nutrients 2023, 15, 3802 2 of 17

leads to respiratory-related symptoms, with the majority of infected people being either
asymptomatic or experiencing self-limiting disease progression. The remaining cases mani-
fest as either mild or severe [1]. SARS-CoV-2 enters host cells by binding its spike protein
to the angiotensin-converting enzyme 2 (ACE2), a cell surface protein widely expressed in
the respiratory and gastrointestinal tissues. This interaction leads to direct virus-mediated
cytopathological damage, disruption of the renin–aldosterone–angiotensin system (RAAS)
as a result of ACE2 pathway maladaptation, endothelial damage, platelet activation, hy-
percoagulability, and an excessive immune response, which drive hyperinflammation and
hypercytokinemia, ultimately leading to organ injury through aberrant innate and acquired
immune responses [2–7].
Following the initial critical stage, the inflammatory response gradually subsides, the
damaged organs gradually recover, and some of the damaged organs progress to the fibro-
sis and chronic stage. This chronic phase includes conditions such as chronic critical illness,
persistent inflammation, immunosuppression, and catabolism syndrome [3]. Numerous
patients across different age groups continue to experience incapacitating symptoms similar
to the multiorgan damage observed in the acute phase of infection, regardless of whether
their initial infection was severe, mild, or even asymptomatic. These symptoms persist
over an extended period after recovery [8–10]. Long COVID encompasses a constellation
of new, returning, or ongoing symptoms lasting more than 4 weeks after acute infection
with SARS-CoV-2, which cannot be explained by an alternative diagnosis. The National
Institutes of Health introduced the concept of postacute sequelae of SARS-CoV-2 infec-
tion, which involves a broad spectrum of symptoms persisting well beyond the recovery
phase of the initial COVID-19 stage, encompassing various clinical syndromes, including
postintensive care syndrome, chronic fatigue syndrome, postacute COVID-19 syndrome
(i.e., signs and symptoms persisting between 4 and 12 weeks from the date of onset), and
post-COVID-19 syndrome (i.e., signs and symptoms persisting beyond 12 weeks from date
of onset) [11–13].
A wide range of persistent multisystem dysfunctions constituting the long COVID syn-
drome have been identified across studies [14,15]. Accurately distinguishing the sequelae
of acute COVID-19 from the symptoms derived from the hospitalization itself, deterioration
of preexisting chronic diseases, adverse effects of medications, or the emergence of new
conditions triggered by the initial COVID-19 infection is clinically important. Moreover, dif-
ferentiating between lingering symptoms of the acute disease and newly arising symptoms
subsequent to the resolution of the acute phase can identify potential drivers of diseases or
dysfunctions. Furthermore, as the number of COVID-19 hospitalized patients continues to
decline, the neurological manifestations of long COVID predominantly affect the younger
demographic of nonhospitalized patients, thereby causing a substantial socioeconomic
impact [16].
The potential pathophysiological mechanisms underlying long COVID syndrome
include pathological inflammation (e.g., occult viral persistence and systemic or tissue-
localized immune dysregulation), induced autoreactive immunity (e.g., antibodies against
the ACE2 receptor, hypocretin receptor, interferon, neutrophils, connective tissues, cyclic
citrullinated peptides, and cell nuclei), reactivation of human herpesviruses (e.g., Epstein–
Barr virus), changes in the gut microbiome, endothelial dysfunction, and activation of
coagulation processes [12,17–21]. Long COVID syndrome is a complex heterogeneous
multisystem disorder presenting a wide spectrum of clinical features (both pulmonary and
extrapulmonary). These manifestations include respiratory, cardiovascular, hematologic,
and neuropsychiatric symptoms either alone or in combination [22,23]. Common clinical
symptoms of this syndrome are sleep disturbances, fatigue, dyspnea, brain fogginess, mem-
ory impairment, headaches, loss of smell or taste, cough, depression, anxiety, palpitations,
dizziness, myalgia, and arthralgia [10,24–26].
Vitamin D consists of a group of structurally related secosteroids, including cholecalcif-
erol, ergocalciferol, 25-hydroxyvitamin D (25(OH)D, calcidiol), and 1,25-dihydroxyvitamin
D (1,25(OH)2D, calcitriol). Vitamin D plays a key role not only in bone metabolism but
Nutrients 2023, 15, 3802 3 of 17

also in the body’s defense against contagious agents such as bacteria, viruses, parasites,
and fungi [27]. This immunomodulatory function is mediated by the vitamin D receptor
(VDR) and the activating enzyme 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1) in
immune cells through the modulation of proinflammatory cytokines (e.g., IL-6, TNF-alpha,
and interferon-gamma), Th1 lymphocyte response, microbicidal activity of phagocytes,
and release of antimicrobial peptides. Vitamin D is believed to counteract or prevent detri-
mental hyperimmune states resulting from acute COVID-19 and as severe consequences of
COVID-19, such as acute respiratory distress syndrome, microvascular thrombosis, and
cytokine storm, with hyperinflammation as an underlying basis for all of these condi-
tions [28,29]. The overall pathophysiology of neuropsychiatric long COVID syndrome is
complex and encompasses persistent systemic inflammation and cytokine storm. In addi-
tion to its role in immune and inflammatory modulation during acute COVID-19, vitamin
D is implicated in the downregulation of the RAAS and improvement of disrupted glucose
homoeostasis, the coagulation cascade, and cardiovascular health [28–33]. Notably, vitamin
D deficiency or insufficiency is widespread among COVID-19 patients and is associated
with increased mortality and adverse outcomes in acute COVID-19. This is because vitamin
D deficiency contributes to the state of hyperinflammation and may exacerbate preexisting
metabolic and cardiovascular diseases [34–39]. Consequently, vitamin D has been proposed
as one of the crucial components in the treatment of acute COVID-19 infection [40–43].
Although vitamin D deficiency or insufficiency is prevalent in COVID-19 survivors [44,45],
studies investigating its association with neuropsychiatric long COVID syndrome are
limited. The primary objective of the present study was to provide a comprehensive
overview of the promising neuroimmunological mechanisms of vitamin D for long-term
neuropsychiatric consequences and to provide an updated review of this topic.

2. Neuropsychiatric Symptoms of Long COVID

Neurological and psychiatric symptoms are observed in >35% of individuals with
acute COVID-19 [46–49]. These individuals present various manifestations involving the
central nervous system (CNS), peripheral nervous system (PNS), neuromuscular junctions,
and skeletal muscles. Initial symptoms include sleep disturbances, headaches, chemosen-
sory impairment, and myalgia [47,50,51]. The multifactorial and complicated pathogenic
mechanisms of SARS-CoV-2, which exhibit neurotropic properties, contribute to the wide
spectrum of neuropsychiatric manifestations during acute COVID-19. These can arise either
through direct cytolytic effects or as a result of secondary hyperinflammatory reactions
(indirect effects). The virus can invade the nervous system through leukocyte migration
across the BBB, infection of the vascular endothelium, retrograde axonal transport through
the cranial nerves, and transsynaptic viral spread, thereby causing direct cytopathic injuries
in neurons and glial cells and neurotransmitter imbalance [52,53]. Moreover, SARS-CoV-2
infection may functionally divert the bioenergetic capacity of infected cells to support
viral replication, thereby disrupting mitochondrial homeostasis, impairing mitophagy, and
compromising neuronal function [54–56]. Once the virus gains entry into the nervous
system, it binds to ACE2, which is highly expressed in the substantia nigra, thalamus,
choroid plexus, olfactory bulb, ventricles, middle temporal gyrus, posterior cingulate
cortex, and brainstem. ACE2 is present in both neuronal and nonneuronal cell types (as-
trocytes, oligodendrocytes, pericytes, and endothelial cells) [57–59]. This interaction of
the virus with ACE2 promotes neuroinflammation, hypercoagulation, microhemorrhages,
disruption of the BBB, endothelitis or microvasculitis, generation of reactive species, and
hypoxia [53,60,61]. Neuropsychiatric impairment may occur through two main pathways:
(1) brain damage resulting from cytolytic effects, macro- and micro-hypoxic/ischemic
injuries, neuroinflammation, and BBB dysfunction and (2) systemic toxic-metabolic dys-
function secondary to diffuse alveolar and interstitial inflammatory exudation, multiorgan
dysfunction, sepsis/septic shock, systemic hyperinflammation, hypercoagulation, throm-
boembolism, endocrine or electrolyte imbalance, and effects of pharmacological agents [53].
Numerous studies on the neuropsychiatric consequences of COVID-19 have demonstrated
Nutrients 2023, 15, 3802 4 of 17

that certain significant changes in the cerebrospinal fluid and plasma biomarkers and
brain images may serve as diagnostic and prognostic tools during the acute infection
phase [62–65].
Neuropsychiatric long COVID syndrome encompasses various presentations of com-
promised integrative neurological functions that regulate key cognitive and affective pro-
cesses in the CNS in COVID-19 survivors [66]. Of these survivors, an estimated 31–69%
experience long COVID symptoms after initial recovery from SARS-CoV-2 infection [67].
Among the long COVID symptoms, fatigue (37–47%), sleep disorders (e.g., insomnia and
excessive sleepiness) (31%), myalgia (25%), headaches (15–18%), chemosensory impairment
(7–14%), cognitive dysfunction (22–32%) (e.g., brain fog, memory impairment, and atten-
tion disorder), anxiety (23%), depression (17%), and autonomic dysfunction are common
neuropsychiatric manifestations, some of which substantially increase in prevalence over
time and exert adverse effects on patients’ quality of life and ability to work [68–71]. As new
evidence continually emerges, the spectrum of clinical characteristics of neuropsychiatric
long COVID syndrome continues to broaden. In contrast to the overlapping pathogenetic
mechanisms implicated in the neurological manifestations of acute COVID-19, the underly-
ing biological causes of neuropsychiatric long COVID sequelae remain poorly delineated to
date. The proposed pathophysiological mechanisms are mainly inferred on the basis of the
pathophysiology of acute COVID-19. Persistent symptoms may result from a combination
of neurobiological and psychological factors.
The overall pathophysiology of neuropsychiatric long COVID syndrome is complex
and involves a combination of factors such as persistent systemic inflammation/cytokine
storm [70], SARS-CoV-2 neurotropism [60], prolonged neuroinflammation [70,72], BBB dis-
ruption [70,73,74], generation of autoantibodies [70], microvasculitis [73,74], prolonged en-
dothelial and platelet activation [73,74], enhanced thrombin generation [73], hypoxia [73,74],
dysregulation of neurotransmitters [72], amyloid aggregation [75], tau phosphorylation [76],
protein misfolding [75], and neuronal death [75], in addition to prolonged systemic inflam-
mation and maladaptative changes in the RAAS [70,77,78]. Moreover, chronic activation of
the extended autonomic system (including neuroendocrine and neuroimmune systems)
and the hypothalamus–pituitary–adrenal axis, physical deconditioning, psychological chal-
lenges (e.g., posttraumatic stress and fear of infecting others or stigmatization), and social
and financial effects contribute, in part, to the persistence of psychiatric problems in the
long term [72,79]. Furthermore, specific gut microbiome profiles are associated with the
persistence of long COVID, suggesting that dysbiosis and disruptions in the brain–gut
axis might play a vital role in the development of long COVID [80]. Moreover, persistent
SARS-CoV-2 infection can lead to the following: (1) mitochondrial dysfunction, causing
increased oxidative stress and ultimately resulting in the loss of mitochondrial integrity and
cell death; (2) binding of viral proteins to mitochondrial complexes, disrupting mitochon-
drial function and causing the immune cells to continually overreact; and (3) epigenetic
alterations (e.g., reduced telomere length and changes in DNA methylation) [81,82]. Fur-
thermore, female sex, respiratory symptoms at the onset of infection, severity of acute
COVID-19, admission to the intensive care unit, presence of comorbidities, history of men-
tal disease, and elevated levels of inflammatory markers are associated with an increased
risk of chronic neuropsychiatric manifestations [83,84].
Processes such as hippocampal and cortical atrophy, hypoxic changes, and small vessel
disease are relevant neurological processes that emerge as secondary to neuroinflamma-
tion, oxidative stress, BBB breakdown, disrupted proteostasis, and autophagic dysfunction
during COVID-19 [60,75,85–89]. Notably, an increasing body of research has indicated
that SARS-CoV-2 infection can initiate or accelerate neurodegeneration in surviving pa-
tients through the activation of the inflammasome, mislocalization of the tau protein from
the axons to soma, hyperphosphorylation of tau, and impaired clearance and pathologi-
cal accumulation of amyloid and tau proteins, ultimately leading to neuronal death [90].
The consequences of these neuropathological processes may manifest over the long term
through changes in brain images. These changes include findings such as white matter
Nutrients 2023, 15, 3802 5 of 17

lesions evident on magnetic resonance imaging (MRI), disruptions in the microstructural

and functional integrity of the brain observed on diffusion tensor imaging, hyperactivation
in specific brain regions such as the piriform cortex and anterior cingulate gyrus observed
on functional MRI, hypometabolism in the frontal cortex detected through fluorodeoxyglu-
cose positron emission tomography, reduced cerebral perfusion detected through single
photon emission computed tomography, widespread cerebral hypoperfusion observed on
arterial spin labeling MRI, and alterations in cortical excitability and activity of neurotrans-
mitters. Furthermore, blood biomarkers indicative of neural injury and neuroinflammation
contribute to understanding the scope of these neurological changes [91–97].
The scope and complexity of neuropsychiatric sequelae resulting from long COVID
may cause substantial morbidity and impose a substantial socioeconomic burden on pa-
tients, families, the healthcare system, and society at large. Because the prevalence of
neuropsychiatric symptoms appears to increase over time, a holistic and multidisciplinary
approach to their management becomes imperative. This approach can encompass various
components such as nutritional support, personalized and adapted physical and cardiopul-
monary rehabilitation, psychological support, and cognitive training. Such an approach is
crucial to promptly identify potentially life-limiting complications, mitigate the catastrophic
consequences of long COVID, and enhance both physical and mental well-being, ultimately
improving the overall quality of life of COVID-19 survivors.

3. Vitamin D and Its Neuroimmunological Roles

Vitamin D has gained increased attention in diverse areas of medical research because
of its multifaceted role extending beyond bone mineralization and calcium homeostasis.
The vitamin D endocrine system provides a wide range of skeletal and extra-skeletal func-
tions. Low vitamin D levels are believed to contribute to the development and progress of
autoimmunity, infectious diseases, diabetes mellitus, cardiometabolic disorders, obesity, can-
cer, gastrointestinal diseases, intestinal dysbiosis, stroke, dementia, and depression [98–103].
Vitamin D, a fat-soluble neuroactive prohormone, is increasingly recognized as not only a
marker of overall health but also a necessary neurosteroid and immunomodulator, exerting
pleiotropic effects on the neurological system. Vitamin D is mainly synthesized by the skin
(~80%) from 7-dihydrocholesterol following ultraviolet B exposure. Vitamin D becomes
biologically active in humans after undergoing sequential hydroxylation in the liver to
25(OH)D, which is catalyzed by CYP2R1 and CYP27A1, and then in the kidney to the
fully active metabolite 1,25(OH)2D, which is catalyzed by CYP27B1 [104]. In a smaller
proportion (~20%), vitamin D can also be obtained through dietary intake. Vitamin D
metabolites circulate within the bloodstream, typically bound to the vitamin D binding
protein (DBP). Among these metabolites, 25(OH)D is vital and is clinically assessed as an
indicator of an individual’s vitamin D level [105]. The concentration of 1,25(OH)2D in
the blood is strictly regulated through a feedback mechanism involving 1,25(OH)2D itself,
parathyroid hormone, calcium, fibroblast growth factor 23, and various cytokines [106].
Vitamin D and its metabolites have the ability to traverse the BBB, and they exert their
effects through both genomic and nongenomic pathways, contributing to their multidi-
rectional extra-skeletal benefits. Genomic responses are typically observable over several
hours to days, whereas nongenomic responses trigger the rapid activation of various
signaling cascades within 1–2 min and 15–45 min [107]. These actions stimulate the tran-
scription and expression of numerous target genes (regulating 3% of the human genome;
i.e., >900 genes) participating in numerous cellular processes related to cardiometabolic
functions, immune responses, neuroprotection, antioxidation, maintenance of mitochon-
drial integrity, and cellular proliferation and differentiation. These actions are facilitated by
the direct binding of vitamin D metabolites to a nuclear receptor (i.e., VDR), which forms a
heterodimer with the retinoid-X-receptor [99,104,108]. VDR and the enzymes involved in
vitamin D hydroxylation are widely expressed in various immune cells and brain tissues,
including dendritic cells, macrophages, lymphocytes, cerebral endothelial cells, pericytes,
neurons, astrocytes, and microglia distributed throughout the CNS, including areas such
Nutrients 2023, 15, 3802 6 of 17

as the cortex, limbic regions (amygdale, hippocampus, and hypothalamus), deep gray
matter (thalamus, basal ganglia, and nucleus accumbens), and the substantia nigra. This
widespread distribution highlights their critical roles in both immunological and neuro-
logical functions [99,104,108–110]. Furthermore, vitamin D metabolites can elicit rapid
nongenomic actions in a paracrine and autocrine manner by modulating the expression of
genes through a membrane-associated rapid-response steroid-binding protein (i.e., protein
disulfide isomerase A3, PDIA3). This mechanism not only contributes to the classical
genomic pathway but also enables cross-talk with various signaling pathways, modulating
inflammation, apoptosis, oxidative stress, and phosphorylation of cellular proteins, as
well as neuron excitability and other electrophysiological phenomena [111,112]. Notably,
the expression of PDIA3 in the brain, particularly in regions critical to neurocognitive
function, is orders of magnitude greater than its expression in the liver and kidneys [113].
The molecular mechanisms of vitamin D and its metabolites in genomic and nongenomic
pathways across large brain areas provide a foundation for understanding their crucial
neuropsychiatric functions. This understanding is supported by accumulating in vivo and
in vitro evidence indicating that the neurochemical and physiological actions of vitamin D
metabolites involve effects on neuroimmunomodulation, neuronal differentiation, neuronal
maturation, cellular proliferation, mitochondrial respiratory chain, redox balance, oxidative
phosphorylation, calcium signaling/homeostasis, neurotrophism, cerebral angiogenesis,
neural circuitry, neuroprotection, neurogenesis, synaptogenesis, synaptic plasticity, neuro-
transmission/neurotransmitter regulation, and amyloid clearance [99,100,114–116]. The
robust biological effects of vitamin D on CNS and PNS cells contribute to the protection
of the CNS from inflammation at the cellular level (including the BBB and glia). This
protection is achieved through multiple mechanisms including the secretion of cytokines
and growth factors, cell signaling, response to oxidative stress, regulation of BBB integrity,
and trafficking, as well as the support of myelination, axonal homogeneity in peripheral
nerves, and neuronal-cell differentiation [117,118].
The level of vitamin D is influenced by various factors, including the extent of sunlight
exposure (related to factors such as latitude, season, sedentary indoor lifestyles, sunscreen
use, sun avoidance, clothing habits, and home confinement/quarantine), air pollution,
personal factors (such as age, sex, ethnicity, body mass index, skin pigmentation, and medi-
cation use), underlying medical comorbidities (such as renal and hepatic insufficiency), and
genetic factors (nucleotidic polymorphisms of the genes DBP, NADSYN1/DHCR7, CYP2R1,
CYP24A1, and VDR) [108,119–123]. However, modifiable environmental or personal fac-
tors, instead of genetic variants, were found to be the main determinants of vitamin D
levels [122]. Severe vitamin D deficiency (serum 25(OH)D concentration <30 nmol/L)
requires correction. However, most guidelines recommend maintaining serum 25(OH)D
concentrations of >50 nmol/L for optimal skeletal health in older populations [124]. How-
ever, whether this range is suitable for preserving CNS integrity and neuropsychiatric
function remains unclear because both low and excessively high serum vitamin D levels are
associated with neurocognitive deficits in an inverse U-shaped manner [113]. Accumulat-
ing evidence from clinical, epidemiological, and basic science studies indicates that vitamin
D insufficiency is widespread across all age groups and even in healthy populations, irre-
spective of the geographical location or seasonal variation. Moreover, vitamin D deficiency
has been demonstrated to be mechanistically and clinically linked to the pathogenesis
of various neurological, psychiatric, and autoimmune disorders, such as cerebrovascular
diseases, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, depression, and
schizophrenia [98,101,103,104,108,124–127].
The inconsistent results in clinical interventional studies on the role of vitamin D
supplementation in the development or progress of autoimmune and neuropsychiatric
diseases can be attributed, in part, to various methodological factors, such as differences
in patient cohorts, varied doses of vitamin D administered, different study designs, and
bioanalytical determination methods used [108,124,128]. Although vitamin D deficiency
is a common risk factor, the origin of these disorders is complex. Whether vitamin D
Nutrients 2023, 15, 3802 7 of 17

deficiency is a causal factor influencing the etiology of these illnesses or is a consequence of

them, coupled with lifestyle changes and reduced sun exposure, remains debatable.
Apart from its recognized benefits for overall systemic health, such as its anti-infection
properties, its supporting role in mitochondrial function, cardiometabolic benefits, im-
munomodulatory effects, and anti-inflammatory effects, vitamin D exerts effects on im-
munomodulation or anti-inflammation, neuroprotection, regulation of monoamine neuro-
transmission, preservation of BBB integrity, vasculometabolic functions, modulation of gut
microbiota, and enhancement of telomere stability. These multifaceted roles highlight the
importance of vitamin D in maintaining normal brain functioning as well as preventing
and managing neuropsychiatric, neuroinflammatory, and neurodegenerative disorders.

3.1. Immunomodulation and Anti-Inflammation

Vitamin D is a well-known active regulator of both innate and adaptive immunity and
plays a crucial role in safeguarding the nervous system against invasive pathogens [129].
Regarding innate immunity, vitamin D enhances the synthesis of antimicrobial peptides
such as defensin beta 2 and cathelicidin in macrophages and monocytes. Additionally, it
promotes chemotaxis, autophagy, and phagolysosomal fusion in macrophages and natural
killer cells. Furthermore, vitamin D reinforces gut microbiota homeostasis and enhances
the physical barrier function of intestinal epithelial cells [103,130]. With respect to adaptive
immunity, vitamin D promotes an anti-inflammatory state by regulating T cells, B cells,
and antigen-presenting cells (dendritic cells and macrophages) through the suppression of
the activation of Th1 cells, inhibition of the production of proinflammatory cytokines, and
modulation of the activities of Th2 cells, T regulatory cells, and Th17 cells [101,103,130].
Overall, as a tolerogenic, anti-inflammatory cytokine, vitamin D not only aids the immune
system in dampening excessive or chronic reactions but also facilitates the rapid and
effective elimination of pathogens. The immune regulatory effects induced by vitamin D in
peripheral tissues may also extend protection to the CNS by locally reinforcing the BBB
and reducing glial activation in the brain parenchyma.
Vitamin D exerts anti-inflammatory effects on human microglia by inhibiting the pro-
duction of proinflammatory cytokines and facilitating differentiation of M2 macrophages and
the upregulation of the anti-inflammatory Toll-like receptor, thus inhibiting inflammation-
driven neural injury [123]. Moreover, it serves as a potent antioxidant during inflammatory
processes. It achieves this by enhancing defective autophagy and mitochondrial function
through the inhibition of the mTOR pathway. Vitamin D also reduces oxidative stress and
inflammatory responses by activating FoxO-dependent antioxidant pathways, inhibiting
NF-κB signaling, promoting reactive oxygen species-scavenging enzymes, downregulating
NADPH oxidase, and upregulating Nrf2 [123]. Vitamin D can be regarded as a pivotal
molecule for promoting cell survival. This is achieved by synchronizing calcium oscillatory
signaling in cells, regulating autophagy or apoptosis, and critically regulating the inflamma-
some during stress responses. Additionally, it promotes protein homeostasis and longevity
through stress response pathway genes such as skn-1, ire-1, and xbp-1 [131,132]. Further-
more, it downregulates the expression of adhesion molecules such as intercellular adhesion
molecule-1 and vascular cell adhesion molecule-1 in endothelial cells. This modulation
of adhesion molecules influences the BBB by controlling the migration of immune cells to
the CNS [117,133]. Collectively, neuroinflammation and oxidative stress play fundamental
roles in neural injury, BBB breakdown, and the progression of neurodegenerative processes.
These processes are key factors underlying a wide range of neurological, psychiatric, and
cardiovascular diseases, such as Alzheimer’s disease, Parkinson’s disease, multiple sclero-
sis, amyotrophic lateral sclerosis, and depression [101,134–136], rendering these processes
rational targets for new therapies even in individuals with sufficient vitamin D levels.

3.2. Neuroprotection
Vitamin D regulates neuronal differentiation and maturation, enhances neuronal
survival, and prevents neurotoxicity through the following mechanisms: (1) promotion
Nutrients 2023, 15, 3802 8 of 17

of the synthesis of essential neurotrophic factors, such as nerve growth factor, glial cell
line-derived neurotrophic factor, brain-derived neurotrophic factor, and neurotrophins;
(2) modulation of neuronal calcium homeostasis through the downregulation of L-type
voltage-sensitive calcium channels and synthesis of calcium-binding proteins, such as
calbindin, parvalbumin, and calretinin; (3) reduction of inducible nitric oxide synthase and
increases in glutathione, superoxide dismutase, and arginase-1, thereby protecting against
mitochondrial dysfunction; and (4) enhancement of the synthesis of other neurosteroids
such as estrogen and progesterone [112,117,137]. Additionally, it affects synaptic or neu-
ronal plasticity, axiogenesis or axonal growth, neuronal myelination, and the maintenance
of the cytoskeleton and cell transport of organelles through the regulation of numerous
proteins, such as drebrin, growth-associated protein-43, connexin 43, synapsin-1, neuro-
filament, tubulin, actin, microtubule-associated protein-2, glial fibrillary acidic protein,
creatine kinase b, kinesin, and dynactin [138,139]. Vitamin D may have beneficial effects
for neurodegenerative processes associated with Alzheimer’s disease. It can help atten-
uate the hyperphosphorylation of the tau protein, counteract neuronal death, mitigate
amyloid-induced cytotoxicity, and regulate amyloid homeostasis. It achieves this by (1) en-
hancing the clearance of amyloid plaques through increased phagocytosis by macrophages
and facilitating brain-to-blood efflux across the BBB, mediated by low-density lipoprotein
receptor related protein-1, and (2) reducing the amyloid production and increasing its
degradation by factors such as nicastrin, neprilysin, and secretases [140–145]. The conse-
quences of long-term deficiency or inefficient utilization of vitamin D can disrupt these
neuroprotective mechanisms, potentially rendering neurons more susceptible to aging
and neurodegeneration.

3.3. Monoamine Neurotransmission

Vitamin D actively regulates the genetic processes responsible for the synthesis of
acetylcholine, dopamine, serotonin, and gamma-aminobutyric acid, all of which modulate
a broad spectrum of neuropyschological functions, including mood, cognition, learning,
memory, reward processing, and sleep [146,147].

3.4. BBB Integrity

The functional and structural integrity of the BBB is crucial for maintaining the home-
ostasis of the brain microenvironment. This semipermeable membrane is essential for
regulating the influx and efflux of biological substances at the brain–blood interface, which
is fundamental for supporting the brain’s metabolic activity and neuronal function. Vi-
tamin D has potential benefits for neurovascular coupling and BBB function. Within the
neurovascular unit, various enzymes including CYP27A1, CYP27B1, and CYP24A1 are
expressed in astrocytes, endothelial cells, microglia, and oligodendrocytes, and CYP27B1
is abundantly expressed in neurons [148]. The VDR is primarily expressed in astrocytes,
whereas PDIA3 is abundantly expressed in all cerebral cell types [148]. Brain pericytes
lack the expression of CYP27B1 and are therefore unable to synthesize 1,25(OH)D. This
observation suggests that pericytes rely on paracrine or circulating 1,25(OH)D to maintain
neurovascular function [148]. Brain microvascular endothelial cells have a notable ability
to transform cholecalciferol into 25(OH)D. They also express VDR and PDIA3, contributing
to the regulation of BBB transporters (e.g., permeability-glycoprotein, multidrug resistance-
associated protein 1, and breast cancer resistance protein) and tight-junction proteins (e.g.,
occludin, claudin-5, and zonula occludens-1) [117,148]. Thus, vitamin D may play a vital
role in counteracting a deleterious cascade of injury processes and functional deficits that
result from compromised BBB integrity.

3.5. Vasculometabolic Functions

Vitamin D exerts various systemic cardiovascular effects through VDR-mediated mech-
anisms in cardiomyocytes and vascular endothelial cells as well as through the regulation of
the RAAS, adiposity, energy expenditure, and pancreatic cell activity [149]. In the genomic
Nutrients 2023, 15, 3802 9 of 17

pathway of cerebral endothelial cells, the expression of genes encoding stromal cell-derived
factor 1α, vascular endothelial growth factor, and nitric oxide synthase is upregulated,
contributing to vasodilation and anti-inflammation. Insulin-like growth factor 1 is involved
in the neuroprotection of axons and dendrites and thrombolysis through the activation
of plasminogen. The tight-junction proteins of the BBB ensure microvascular structural
integrity and microcirculatory function. Nerve growth factors are also influenced by this
genomic pathway [150]. Collectively, these beneficial genomic effects on vascular endothe-
lial cells result in reduction of thrombogenicity, reduction of vasoconstriction, inhibition of
oxidative/nitrative stress and atherogenesis, enhancement of endothelial repair, decrease
in foam cell formation, and improvement of vascular relaxation and dilatation [151]. Addi-
tionally, vitamin D plays a role in regulating matrix homeostasis through the modulation of
specific matrix metalloproteinases and tissue inhibitors of metalloproteinases, all of which
are critical in major cerebrovascular diseases, including atherosclerosis, arteriosclerosis,
and stroke [123]. By combining its vasculometabolic actions with the potent systemic and
neural immunomodulatory and antioxidant effects, vitamin D can positively modulate
cerebral vascular homeostasis and BBB function and prevent vascular dysfunction and
tissue injury as a result of systemic and local (neural) inflammation.

3.6. Gut Microbiota

The VDR plays a role in regulating the gut microbiome by suppressing inflamma-
tion, maintaining barrier function, promoting microbial homeostasis, and reducing insulin
resistance [152–154]. More than 90% of the body’s serotonin is synthesized in the gut,
predominantly by enterochromaffin cells. Disruption of the intestinal microbiota triggered
by inflammatory processes has been shown to directly compromise the synthesis of this
monoamine [155]. Vitamin D supplementation has been demonstrated to promote an
increase in serum serotonin levels in individuals with depression as well as in serum
dopamine levels in children with attention deficit/hyperactivity disorder [155]. Stud-
ies have suggested that vitamin D may serve as a key regulator in the gut–brain axis,
modulating gut microbiota and alleviating psychiatric symptoms such as depression and
anxiety [155,156]. Consequently, vitamin D deficiency leads to dysbiosis, a probable reason
for the increased vulnerability to inflammation-mediated illnesses.

3.7. Telomere Stability

Vitamin D has been demonstrated to be involved in telomere biology and genomic
stability through various pathways. It has the potential to preserve telomere length, inhibit
cellular aging, and mitigate telomere shortening through anti-inflammatory and anti-cell
proliferation mechanisms [157]. Significantly low levels of telomerase activity lead to the
development of shortened telomeres, which in turn triggers cell cycle arrest, ultimately
leading to cell senescence and apoptosis [157].

4. Vitamin D and Its Potential Benefits for Neuropsychiatric Long COVID Syndrome
The long-term impact of COVID-19 on survivors, including those with mild or no
symptoms, highlights the need to identify the pathophysiological mechanisms that con-
tribute to the development of long COVID syndrome. A large body of evidence supports
that vitamin D is required for maintaining normal immune function, combating pathogens,
and preventing autoimmune diseases. Until now, the association between vitamin D
and numerous neurocognitive and neuropsychiatric illnesses, such as neurodegenerative
diseases, stroke, autism, schizophrenia, depression, and attention deficit hyperactivity
disorder, has been extensively explored [137,158,159]. The profound effect of vitamin D
on neuroinflammatory and neurodegenerative processes within the CNS through both
genomic and nongenomic pathways has been demonstrated. The complex mechanisms
of its neuroprotective effects involve both VDR-mediated and nongenomic effects on
neurotrophin expression, mitigation of L-type calcium channel expression, mitigation of
oxidative stress, excitotoxicity, apoptosis, and promotion of neuroprotective and antiaging
Nutrients 2023, 15, 3802 10 of 17

processes through interference with multiple prosurvival signaling pathways. The ability
of vitamin D to attenuate neuroinflammation is noteworthy, as evidenced by the decreased
expression and release of proinflammatory cytokines and nitric oxide. In addition, through
critical mechanisms such as alleviation of defective autophagy and enhancement of mito-
chondrial function, immunomodulation, anti-inflammation responses, neuroprotection,
monoamine neurotransmission, maintenance of BBB integrity, vasculometabolic function,
regulation of the gut microbiota or gut–brain axis, and maintenance of telomere stability,
vitamin D potentially protects the brain from various pathophysiologies implicated in
neuropsychiatric long COVID syndrome. These include persistent neuroinflammation,
BBB breakdown, autoimmunity, thrombus formation, disrupted neurotransmission, and
neurodegeneration, as well as prolonged systemic inflammation and RAAS dysregulation.
The conflicting current clinical data regarding the effects of vitamin D intervention may be
attributed to inadequate dosing, variability in trial designs that hinders direct comparisons,
diverse routes of administrations employed, and insufficient consideration of the age- and
sex-related effects of vitamin D pharmacology. Nevertheless, vitamin D has emerged as
a strong candidate for modulating the wide range of neuropsychiatric symptoms and
pathophysiologies encountered in different stages of the long COVID syndrome.

5. Future Perspective
Gaining a deep understanding of the pathophysiology of neuropsychiatric long
COVID is essential to effectively evaluate and manage the consequences of this condi-
tion. Although robust and conclusive evidence derived from well-designed randomized
trials demonstrating the efficacy of regular daily vitamin D supplementation for mitigating
the full spectrum of neuropsychiatric symptoms in individuals who have recuperated
from COVID-19 is lacking, its overall favorable attributes across various domains (e.g.,
neurological, psychiatric, cardiovascular, and immune) might support the consideration of
vitamin D as a potential health supplement or an adjuvant treatment. This might be rele-
vant for maintaining both physical and mental well-being and managing neuropsychiatric
symptoms in both the acute and long COVID phases.
Long COVID syndrome encompasses a diverse range of symptoms, with wide varia-
tion among individuals. These symptoms often result from complex interactions between
various physiological and immunological processes, making it improbable for a single in-
tervention, such as vitamin D supplementation, to be universally effective for the treatment
of all aspects of this complex syndrome. Therefore, prior to strongly advocating for the
application of vitamin D as a stand-alone remedy or in conjunction with other therapeutic
agents for managing neuropsychiatric symptoms associated with long COVID syndrome,
several pivotal aspects must be elucidated. Critical considerations include determining the
optimal dosage, treatment duration, and ideal formulation or delivery method to ensure the
optimal absorption and efficacy of vitamin D. Striking a balance between treatment benefits
and potential risks, identifying specific target symptoms, identifying the patient group
that might benefit the most from this approach, and establishing methods for assessing
therapeutic responses are all challenging tasks and are still under investigation.

6. Conclusions
Long COVID continues to persist despite vaccination and booster doses, with highly
debilitating neuropsychiatric manifestations. This comprehensive review described the
pathophysiological mechanisms by which vitamin D may confer resistance against long
COVID based on the existing body of evidence. The literature strongly supports the
capacity of vitamin D to modulate both immune cells and neural cells through both
genomic and nongenomic pathways. Beyond its systemic health benefits (e.g., anti-infection
effects, metabolic benefits, immune regulation, and anti-inflammatory effects), the favorable
effects of vitamin D on neural immunomodulation/anti-inflammation, neuroprotection,
monoamine neurotransmission, BBB integrity, and vasculometabolic functions indicates
its indispensable role in preserving normal brain function as well as in preventing and
Nutrients 2023, 15, 3802 11 of 17

managing neuropsychiatric, neuroinflammatory, and neurodegenerative processes in long

COVID. Although these therapeutic roles of vitamin D in combating long COVID are
promising, this review may serve as a foundation for further exploration of its effect on
long COVID. Undoubtedly, additional epidemiological, experimental, and randomized
control trials are warranted to substantiate and translate these proposed effects in the
context of long COVID.

Author Contributions: T.-B.C., C.-M.C., C.-Y.W., H.-W.Y. and C.-P.Y. were responsible for the study
concept and design, modification of the study design, and review and interpretation of the data.
T.-B.C., C.-M.C. and C.-P.Y. were responsible for drafting the manuscript. C.-Y.W., H.-W.Y. and C.-P.Y.
made modifications to the study design and revised the manuscript. C.-C.Y., I.-J.T., C.-Y.W., H.-W.Y.
and C.-P.Y. contributed to the collection and analysis of data. T.-B.C., C.-M.C., C.-Y.W., H.-W.Y. and
C.-P.Y. contributed to interpretation of the data and revised the manuscript. All authors have read
and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare that they have no competing interest.

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