Capsaicin: A Potential Treatment to Improve Cerebrovascular Function and Cognition in Obesity and Ageing

Abstract

Impaired cognition is the primary symptom of dementia, which can lead to functional disability and reduced quality of life among an increasingly ageing population. Ageing is associated with increased oxidative stress, chronic low-grade systemic inflammation, and endothelial dysfunction, which reduces cerebrovascular function leading to cognitive decline. Chronic low-grade systemic inflammatory conditions, such as obesity, exacerbate this decline beyond normal ageing and predispose individuals to neurodegenerative diseases, such as dementia. Capsaicin, the major pungent molecule of chilli, has recently demonstrated improvements in cognition in animal models via activation of the transient receptor potential vanilloid channel 1 (TRPV1). Capsaicin-induced TRPV1 activation reduces adiposity, chronic low-grade systemic inflammation, and oxidative stress, as well as improves endothelial function, all of which are associated with cerebrovascular function and cognition. This review examines the current literature on capsaicin and Capsimax, a capsaicin supplement associated with reduced gastrointestinal irritation compared to capsaicin. Acute and chronic capsaicin treatment can improve cognition in animals. However, studies adequately assessing the effects of capsaicin on cerebrovascular function, and cognition in humans do not exist. Capsi-max may be a potentially safe therapeutic intervention for future clinical trials testing the effects of capsaicin on cerebrovascular function and cognition.

Full text

Citation: Thornton, T.; Mills, D.; Bliss,
E. Capsaicin: A Potential Treatment
to Improve Cerebrovascular Function
and Cognition in Obesity and Ageing.
Nutrients 2023,15, 1537. https://
doi.org/10.3390/nu15061537
Academic Editor: Yorito Hattori
Received: 23 February 2023
Revised: 17 March 2023
Accepted: 21 March 2023
Published: 22 March 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
nutrients
Review
Capsaicin: A Potential Treatment to Improve Cerebrovascular
Function and Cognition in Obesity and Ageing
Tammy Thornton 1, Dean Mills 1,2,3,4 and Edward Bliss 1,2,3,4,*
1School of Health and Medical Sciences, University of Southern Queensland, Ipswich, QLD 4305, Australia
2Respiratory and Exercise Physiology Research Group, School of Health and Medical Sciences, University of
Southern Queensland, Ipswich, QLD 4305, Australia
3Centre for Health Research, Institute for Resilient Regions, University of Southern Queensland,
Ipswich, QLD 4305, Australia
4Molecular Biomarkers Research Group, University of Southern Queensland,
Toowoomba, QLD 4350, Australia
*Correspondence: edward.bliss@usq.edu.au
Abstract:
Impaired cognition is the primary symptom of dementia, which can lead to functional
disability and reduced quality of life among an increasingly ageing population. Ageing is asso-
ciated with increased oxidative stress, chronic low-grade systemic inflammation, and endothelial
dysfunction, which reduces cerebrovascular function leading to cognitive decline. Chronic low-grade
systemic inflammatory conditions, such as obesity, exacerbate this decline beyond normal ageing
and predispose individuals to neurodegenerative diseases, such as dementia. Capsaicin, the major
pungent molecule of chilli, has recently demonstrated improvements in cognition in animal models
via activation of the transient receptor potential vanilloid channel 1 (TRPV1). Capsaicin-induced
TRPV1 activation reduces adiposity, chronic low-grade systemic inflammation, and oxidative stress,
as well as improves endothelial function, all of which are associated with cerebrovascular function
and cognition. This review examines the current literature on capsaicin and Capsimax, a capsaicin
supplement associated with reduced gastrointestinal irritation compared to capsaicin. Acute and
chronic capsaicin treatment can improve cognition in animals. However, studies adequately assessing
the effects of capsaicin on cerebrovascular function, and cognition in humans do not exist. Capsi-
max may be a potentially safe therapeutic intervention for future clinical trials testing the effects of
capsaicin on cerebrovascular function and cognition.
Keywords: capsaicin; cerebrovascular; cognition; obesity; ageing
1. Introduction
Dementia affects approximately 50 million people worldwide and is expected to rise to
130 million by 2050 [
1
]. Dementia is a major cause of functional disability, with a substantial
social and economic burden estimated to cost USD 2.8 trillion globally by 2030 [
1
–
3
]. The
primary symptom of dementia is impaired cognition, which is characterised by a reduction
in cognitive functions including memory, language, thinking, and/or judgment [
4
]. Reduc-
tions in these functions cause psychological changes that impact social relationships and
independence, which ultimately affect quality of life (QoL) (Figure 1)
[5,6]
. The reduced
cognition observed in dementia is typically preceded by a reduction in cerebrovascular
function [7,8].
Obesity and ageing lead to chronic low-grade systemic inflammation and oxidative
stress, which predisposes an individual to the development of dementia [
9
–
11
]. Obesity is
a current epidemic that affects two billion people worldwide and is defined as an excessive
accumulation of fat that may impair health [
12
]. The number of overweight and obese
people worldwide has tripled since 1975 [13–15]. Similarly, the proportion of people aged
Nutrients 2023,15, 1537. https://doi.org/10.3390/nu15061537 https://www.mdpi.com/journal/nutrients

Nutrients 2023,15, 1537 2 of 24
over 60 years will nearly double from 12% in 2015 to 22% in 2050, with people living longer
than previously [16].
Nutrients 2023, 15, x FOR PEER REVIEW 2 of 26
Figure 1. The outcomes of reduced cerebrovascular function leading to reduced quality of life.
Lowered cerebrovascular function influences cerebral hypoperfusion, which causes structural and
functional changes leading to reduced cognition. Reduction of cognition affects multiple regions of
the brain, which influence aspects that contribute to quality of life. This includes psychological,
physical, social, and occupational wellbeing. Lowered quality of life can reduce life expectancy [5].
Obesity and ageing lead to chronic low-grade systemic inflammation and oxidative
stress, which predisposes an individual to the development of dementia [9–11]. Obesity is
a current epidemic that affects two billion people worldwide and is defined as an
excessive accumulation of fat that may impair health [12]. The number of overweight and
obese people worldwide has tripled since 1975 [13–15]. Similarly, the proportion of people
aged over 60 years will nearly double from 12% in 2015 to 22% in 2050, with people living
longer than previously [16].
The current treatments for dementia are costly, have significant side effects, and tend
to target symptoms of cognitive decline in isolation. Further, there is also no clear evidence
that pharmaceuticals or cognitive training programs are effective in preventing or
stopping cognitive decline [17,18]. Prevention strategies such as cognitive training,
physical activity and dietary and lifestyle changes can also have low compliance,
particularly for those already suffering from cognitive decline [18,19]. Therefore, new
treatment strategies are urgently needed. Novel nutraceutical interventions hold promise
as complementary approaches to prevent cognitive decline [20]. Further, there is a need
for research on multi-functional treatments that address a variety of factors that can lead
to cognitive decline [18,21].
Capsaicin, a pungent molecule found in plants belonging to the Capsicum genus, has
been shown to have neuroprotective and anti-inflammatory properties in animal models
[22–25]. In animal studies, capsaicin decreases chronic low-grade systemic inflammation
and oxidative stress, which may ultimately improve cerebrovascular function and reduce
the symptoms of cognitive decline and dementia [10,26,27]. Therefore, the aims of this
review are to (1) provide a brief overview of cognition and cerebrovascular function; (2)
examine the mechanisms underlying how increased adiposity and ageing lead to reduced
cerebrovascular function and cognition; (3) examine how capsaicin attenuates the effects
of ageing and obesity on decreased cerebrovascular function and cognition; and (4)
provide a summary of potential health benefits associated with Capsimax, a capsaicin
supplement associated with reduced gastrointestinal irritation.
Figure 1.
The outcomes of reduced cerebrovascular function leading to reduced quality of life.
Lowered cerebrovascular function influences cerebral hypoperfusion, which causes structural and
functional changes leading to reduced cognition. Reduction of cognition affects multiple regions
of the brain, which influence aspects that contribute to quality of life. This includes psychological,
physical, social, and occupational wellbeing. Lowered quality of life can reduce life expectancy [
5
].
Abbreviations: ↑: increased; ↓: decreased.
The current treatments for dementia are costly, have significant side effects, and
tend to target symptoms of cognitive decline in isolation. Further, there is also no clear
evidence that pharmaceuticals or cognitive training programs are effective in preventing or
stopping cognitive decline [
17
,
18
]. Prevention strategies such as cognitive training, physical
activity and dietary and lifestyle changes can also have low compliance, particularly for
those already suffering from cognitive decline [
18
,
19
]. Therefore, new treatment strategies
are urgently needed. Novel nutraceutical interventions hold promise as complementary
approaches to prevent cognitive decline [
20
]. Further, there is a need for research on
multi-functional treatments that address a variety of factors that can lead to cognitive
decline [18,21].
Capsaicin, a pungent molecule found in plants belonging to the Capsicum genus, has
been shown to have neuroprotective and anti-inflammatory properties in animal mod-
els
[22–25]
. In animal studies, capsaicin decreases chronic low-grade systemic inflammation
and oxidative stress, which may ultimately improve cerebrovascular function and reduce
the symptoms of cognitive decline and dementia [
10
,
26
,
27
]. Therefore, the aims of this
review are to (1) provide a brief overview of cognition and cerebrovascular function; (2)
examine the mechanisms underlying how increased adiposity and ageing lead to reduced
cerebrovascular function and cognition; (3) examine how capsaicin attenuates the effects of
ageing and obesity on decreased cerebrovascular function and cognition; and (4) provide a
summary of potential health benefits associated with Capsimax, a capsaicin supplement
associated with reduced gastrointestinal irritation.
2. An Overview of Cognition and Cerebrovascular Function
Cognition, which is one of the brain’s primary functions, is the mental processing that
occurs when acquiring, encoding, adapting, and applying sensory experiences from the

Nutrients 2023,15, 1537 3 of 24
environment [
28
,
29
]. This encompasses perception, reasoning, awareness, and comprehen-
sion [
29
]. Cognition depends not only on the ability of the brain to acquire information via
sensory input but it also depends on the processing and integration of this information,
which guides behaviour and actions [
28
]. A reduction in these processes results in mood
and behavioural disturbances, social disruptions, loss of independence, and increased care,
ultimately leading to a lowered QoL [5,6,30].
The brain is one of the most metabolically active organs, consuming 15–20% of the
body’s nutrients and energy under resting conditions [
31
]. The brain cannot store nutri-
ents and oxygen and, therefore, requires a constant supply of these through the cerebral
blood flow (CBF) to function optimally and maintain its primary functions, particularly
cognition [32]. This supply is maintained by the function of the cerebrovasculature.
Cerebrovascular function describes the ability of the cerebrovasculature to perfuse
the brain with adequate blood (i.e., CBF) in response to physical and psychological stim-
uli [
33
,
34
]. This is achieved through neurovascular coupling (NVC) and cerebral autoregu-
lation [
33
]. These are the complex mechanisms that ensure a chemically stable environment
in response to increased neuronal metabolism and environmental, chemical and/or me-
chanical (i.e., physical) changes [
2
,
29
,
33
]. Changes in cerebral blood pressure, perfusion
pressure, vascular diameter, and blood viscosity all affect CBF [
29
,
35
,
36
]. Autoregulation
ensures that a constant mean arterial pressure of 50–160 mmHg is maintained in response
to chemical and/or mechanical stimuli [
33
,
34
]. This response is largely initiated by either
increased (vasodilatation) or decreased (vasoconstriction) nitric oxide (NO) metabolism,
which regulates the resistance applied globally to the cerebrovasculature [
32
,
37
]. Con-
versely, NVC is where neurons communicate with endothelial cells to release vasodilatory
mediators, such as NO, to maintain CBF locally during periods of increased neuronal
metabolism [37,38].
The primary contributing factor maintaining cerebrovascular function, and therefore
CBF, is endothelial function which is fundamental to cerebrovascular autoregulation and
NVC [
39
]. The upregulation of eNOS catalyses the synthesis and release of NO [
32
,
37
,
40
].
NO is released into vascular smooth muscle, causing rapid and sustained vasodilatation
and, therefore, increased blood flow [
37
]. Additionally, NO regulates inflammation and
oxidative stress via multiple pathways, thereby reducing chronic low-grade systemic
inflammation [
41
,
42
]. This is important because when NO production is reduced, it can
cause changes in CBF regulation, which leads to vascular insults [
10
,
29
,
43
]. This results in
reduced oxygen and nutrient delivery and structural and functional changes in the brain,
which precede cognitive decline and dementia [
10
,
29
,
43
]. This process is evidenced in
studies that have indicated cerebrovascular dysfunction is the second leading cause of
Alzheimer’s disease (AD) and the most common cause of vascular dementia, which are
arguably the two most prevalent forms of dementia [
7
]. It is therefore important to be able
to readily measure cerebrovascular function together with cognition.
3. Ageing and Obesity Are Risk Factors for Cerebrovascular Dysregulation
Ageing and increased adiposity have synergistic detrimental effects on endothelial
function, due to hormonal changes, chronic low-grade systemic inflammation and increased
reactive oxygen species (ROS) production (Figure 2) [
44
,
45
]. Uncoupling of eNOS creates
ROS instead of NO, causing oxidative stress which exacerbates endothelial dysfunction [
32
].
This results in impaired CBF, leading to hypoperfusion that causes structural and functional
changes in the brain which precede cognitive decline [
44
,
45
]. Endothelial NO is, therefore,
one of the most important signalling molecules for maintaining CBF through autoregulation
and NVC, and a potential target for preventing cerebrovascular and neurodegenerative
diseases [39,46].
3.1. Ageing
Life expectancy has increased compared to previous generations [
16
]. This is impor-
tant because ageing is the greatest predictor of cognitive decline, with the most significant

Nutrients 2023,15, 1537 4 of 24
impact on neurodegeneration [
44
,
47
,
48
]. Molecular and cellular damage accumulated over
time leads to structural and functional brain changes, impaired cognition, and neurode-
generation [
47
,
49
]. Ageing is also a key factor leading to endothelial dysfunction and
cerebrovascular dysregulation [42,50,51].
Ageing elevates circulating endothelial NO synthase (eNOS) inhibitors, such as asym-
metrical dimethylarginine and arginase, uncoupling eNOS and preventing the vital NO
synthesis cofactor, L-arginine, from being metabolised [
52
]. This, in turn, reduces NO
synthesis and bioavailability [
52
–
54
]. Conversely, insulin-like growth factor-1 (IGF-1)
and brain-derived neurotrophic factor (BDNF), which stimulate NO production are de-
creased with age [
32
,
55
]. Further, BDNF plays a role in neuron survival, growth and
maintenance [
56
]. IGF-1 is important for neurotransmitter synthesis and supports BDNF
production [57]. The reduction BDNF has therefore been associated with Alzheimer’s dis-
ease pathology [
58
]. Tetrahydrobiopterin (BH4) is an essential cofactor for NO production.
BH4 also decreases with age due to increased oxidation and decreased synthesis, as well
as age-related changes in metabolism, such as reduced folate and B12 absorption [
59
,
60
].
Decreased BH4 leads to eNOS uncoupling and production of ROS instead of NO produc-
tion [
61
]. Microglia are specialised immune cells in the brain which contribute to synaptic
plasticity [
62
]. Microglia assist with clearing misfolded proteins or damaged cells resulting
from neurodegeneration [
63
]. However, increased age causes impaired and prolonged
activation of microglia, which increases pro-inflammatory mediators and ROS, exacer-
bating neuronal damage [
64
–
66
]. Additionally, cytokines and low shear stress stimulate
the release of endothelins from endothelial cells, particularly ET-1, which is a powerful
vasoconstrictor [
67
]. The increase of ET-1 initiates increased expression of transcription
factors that promote inflammation, particularly nuclear factor kappa B (NF-
κ
B) [
68
]. NO
inhibits ET-1. Therefore, the reduction of NO due to increased ET-1 leads to an imbalanced
ET-1 and NO ratio [
69
]. This also leads to increased ROS and inflammation, resulting in
endothelial dysfunction [
32
,
70
]. Endothelial dysfunction causes decreased cerebrovascular
function and reduced CBF which precedes cognitive decline [
71
]. Further to the natural
progression of endothelial dysfunction seen with ageing, obesity exacerbates endothelial
dysfunction and has also been associated with the risk of dementia [72].
3.2. Obesity as a Risk Factor for Cognitive Decline
Obesity is a preventable and modifiable metabolic disease associated with chronic
low-grade systemic inflammation, increased oxidative stress and endothelial dysfunction,
which decreases CBF and promotes cognitive impairment (Figure 2) [
73
]. Increased adi-
pose tissue is the key feature of obesity [
74
]. Adipose tissue secretes over 600 signalling
molecules, called adipokines [
75
]. Increased adiposity reduces the production of anti-
inflammatory adipokines, such as adiponectin, and increases inflammatory adipokines,
such as leptin, therefore increasing inflammation [
76
]. Adiponectin is downregulated by in-
flammatory molecules, and oxidative stress, further promoting systemic inflammation [
77
].
Overexpression of inflammatory cytokines stimulates the attachment of leukocytes to the
endothelium. This results in increased vascular permeability, occlusions and inflammation,
thereby reducing eNOS function, systemic blood flow and CBF [
78
]. Therefore, increased
adiposity is a risk factor for cardiovascular disease, which correlates with reduced CBF,
hypoperfusion and cognitive decline [
11
,
79
]. A meta-analysis of seven observational stud-
ies demonstrated that obesity increased the risk of dementia between 32 and 45% due
to increased concentrations of inflammatory markers [
80
]. Therefore, dementia research
including populations with increased adiposity is required [
81
]. Nutraceuticals, such as cap-
saicin, have demonstrated promising effects in reducing the detrimental effects of adiposity
on endothelial dysfunction, adiposity itself, and cardiovascular disease [
82
,
83
]. In animal
models, capsaicin has been shown to reduce the release of obesity-related pro-inflammatory
cytokines IL-6, and tumour necrosis factor-
α
(TNF-
α
), therefore reducing inflammation,
improving eNOS function, NO synthesis, cerebrovascular function and cognition [
27
].
Although these results are clear in animal models, little research has been conducted on

Nutrients 2023,15, 1537 5 of 24
humans to determine the effects of capsaicin specifically on cerebrovascular function or
cognition.
Nutrients 2023, 15, x FOR PEER REVIEW 5 of 26
32 and 45% due to increased concentrations of inflammatory markers [80]. Therefore,
dementia research including populations with increased adiposity is required [81].
Nutraceuticals, such as capsaicin, have demonstrated promising effects in reducing the
detrimental effects of adiposity on endothelial dysfunction, adiposity itself, and
cardiovascular disease [82,83]. In animal models, capsaicin has been shown to reduce the
release of obesity-related pro-inflammatory cytokines IL-6, and tumour necrosis factor-α
(TNF-α), therefore reducing inflammation, improving eNOS function, NO synthesis,
cerebrovascular function and cognition [27]. Although these results are clear in animal
models, little research has been conducted on humans to determine the effects of capsaicin
specifically on cerebrovascular function or cognition.
Figure 2. The effect of ageing and obesity on endothelial dysfunction, leading to cognitive decline.
Obesity and ageing increase the production of inflammatory markers, including tumour necrosis
factor-alpha (TNF-α), and interleukin-6 (IL-6) and decrease anti-inflammatory mediators [66,76].
Increased reactive oxygen species (ROS) occurs in obesity and ageing, further promoting chronic
low-grade systemic inflammation [68,76,84]. Ageing also reduces the endothelial nitric oxide
Figure 2.
The effect of ageing and obesity on endothelial dysfunction, leading to cognitive decline.
Obesity and ageing increase the production of inflammatory markers, including tumour necrosis
factor-alpha (TNF-
α
), and interleukin-6 (IL-6) and decrease anti-inflammatory mediators [
66
,
76
].
Increased reactive oxygen species (ROS) occurs in obesity and ageing, further promoting chronic
low-grade systemic inflammation [
68
,
76
,
84
]. Ageing also reduces the endothelial nitric oxide syn-
thase (eNOS) cofactor, tetrahydrobiopterin (BH4), and increases asymmetrical dimethylarginine
(ADMA), which decreases nitric oxide (NO) synthesis and bioavailability [
68
]. Increased arginase
activity reduces L-arginine supply, thus also promoting the uncoupling of eNOS [
53
]. Increased
vasoconstrictors, such as endothelin-1 (ET-1), contribute further to increased vascular tone and
endothelial dysfunction [
67
]. Uncoupled eNOS creates further ROS instead of NO, exacerbating
endothelial dysfunction [
61
]. These mechanisms lead to low-grade systemic inflammation and ED,
leading to increased platelet aggregation, vascular tone and fatty plaques leading to cerebrovascular
dysfunction, thus reducing cerebral blood flow and cognition [
85
]. Abbreviations:
↑
: increased;
↓
:
decreased.

Nutrients 2023,15, 1537 6 of 24
4. Capsaicin
The capsaicinoids are the primary pungent molecule found in plants belonging to
the Capsicum genus, particularly chillies [
86
]. They are a group of phenolic compounds
characterised by a common vanilloid ring (Figure 3) [
87
]. Capsaicin, dihydrocapsaicin,
nordihydrocapsaicin, homocapsaicin and homodihydrocapsaicin all comprise the capsaici-
noids, with capsaicin being the most abundantly occurring of these [87,88]. Capsaicin has
been extensively studied for its multiple benefits as an anti-carcinogenic, anti-inflammatory,
antioxidant, and anti-obesity agent and for its use as a topical analgesic [
89
,
90
]. Table 1
summarises research studies that have investigated these effects.
When taken orally, capsaicin is passively absorbed in the stomach and jejunum [
26
,
87
].
Albumin transports capsaicin in the blood, and its vanilloid ring has a high affinity for
the transient receptor vanilloid 1 (TRPV1), a non-selective cation channel [
87
,
91
]. TRPV1
receptors are widely expressed in the body and are found to be concentrated in neural
tissue (peripheral and central) and the endothelium [
83
]. When capsaicin binds to TRPV1,
it causes a cation influx, activating numerous physiological pathways which are important
modulators of vasodilation and inflammation (Figure 4) [
92
–
94
]. In turn, downregulation
of these pro-inflammatory pathways and upregulation of anti-inflammatory pathways
promote the increased expression of eNOS and, therefore, increased NO production and
availability, counteracting the effects of endothelial dysfunction [93,95,96].
Table 1. Summary of studies outlining the effects of capsaicin on chronic disease states.
Disease State Main Findings Reference
Cardiovascular ↓Blood pressure [97]
Cancer Anti-proliferative [88]
Neuropathic pain ↓Painful neuropathy [98,99]
Adiposity and metabolic derangements
↑Energy expenditure
↑Fat oxidation
↑Thermogenesis
↑Glucose tolerance
↑Insulin sensitivity
↑Resting metabolic rate
↓Body mass
↓Total cholesterol
↓Triglycerides
↓Glucose
[83,100–104]
Abbreviations: ↑: increased; ↓: decreased.
Capsaicin: A Brief Overview of Its Role as Anti-Cardiometabolic Disease Treatment
Capsaicin’s action in reducing obesity, oxidative stress, and inflammation and improv-
ing cardiovascular function in animals has been previously described [83,86,105]. Obesity
increases blood triglycerides, free fatty acids and low-density lipoprotein (LDL), contribut-
ing to eNOS dysregulation, vascular remodelling, and atherosclerosis, which is the leading
cause of cardiovascular and cerebrovascular disease [83,93,106].
Capsaicin increases thermogenesis, energy expenditure and fat oxidation, all of which
assist in decreasing adiposity [
83
,
107
]. This is achieved by the activation of TRPV1 and
subsequent reduction of pro-inflammatory cytokines, such as TNF-
α
and IL-6, which are
increased with greater adiposity [
27
,
78
,
108
]. Ma et al. [
109
] found that dietary capsaicin
(0.1%) for 24 weeks in C57BL/6J mice activated TRPV1, inducing cytosolic calcium and
reduced lipid accumulation and atherosclerosis [
106
]. Wang, Y. et al. [
110
] cultured human
umbilical cord endothelial cells and treated them with capsaicin. Capsaicin increased NO,
and reduced cytokine production, monocyte adhesion, adhesion molecule expression and
activated NF-
κ
B, thereby reducing inflammation. TRPV1 activation with 1
µ
M capsaicin
rescued impaired macrophage autophagy induced by oxidised low-density lipoprotein,
activating AMPK signalling, inhibiting foam cell formation, and preventing atherosclerotic

Nutrients 2023,15, 1537 7 of 24
plaque formation [
106
]. Dai et al. [
111
] fed male apolipoprotein E knock-out mice 0.01%
capsaicin for 18 weeks alongside a high-fat diet or a high-fat diet with broad-spectrum
antibiotics. Capsaicin reduced serum lipopolysaccharide (an inflammatory mediator)
and low-density lipoprotein, as well as increased high-density lipoprotein. This was not
observed in the group fed capsaicin with concurrent antibiotics. The improvements resulted
in reduced intestinal inflammation and permeability, as well as improved endothelial
function, which led to a significant reduction in atherosclerotic lesions. This demonstrates
capsaicin’s ability to reduce adiposity and its associated inflammatory mediators, as well
as reducing cardiovascular-induced risk factors that can reduce cerebrovascular function
and cognition. This may also indicate capsaicin’s application as a resolution to other
inflammatory diseases such as autoimmune diseases, gastrointestinal disorders, and other
haemodynamic conditions, such as atherosclerosis.
Nutrients 2023, 15, x FOR PEER REVIEW 7 of 26
contributing to eNOS dysregulation, vascular remodelling, and atherosclerosis, which is
the leading cause of cardiovascular and cerebrovascular disease [83,93,106].
Capsaicin increases thermogenesis, energy expenditure and fat oxidation, all of
which assist in decreasing adiposity [83,107]. This is achieved by the activation of TRPV1
and subsequent reduction of pro-inflammatory cytokines, such as TNF-α and IL-6, which
are increased with greater adiposity [27,78,108]. Ma et al. [109] found that dietary
capsaicin (0.1%) for 24 weeks in C57BL/6J mice activated TRPV1, inducing cytosolic
calcium and reduced lipid accumulation and atherosclerosis [106]. Wang, Y. et al. [110]
cultured human umbilical cord endothelial cells and treated them with capsaicin.
Capsaicin increased NO, and reduced cytokine production, monocyte adhesion, adhesion
molecule expression and activated NF-ĸB, thereby reducing inflammation. TRPV1
activation with 1 µM capsaicin rescued impaired macrophage autophagy induced by
oxidised low-density lipoprotein, activating AMPK signalling, inhibiting foam cell
formation, and preventing atherosclerotic plaque formation [106]. Dai et al. [111] fed male
apolipoprotein E knock-out mice 0.01% capsaicin for 18 weeks alongside a high-fat diet or
a high-fat diet with broad-spectrum antibiotics. Capsaicin reduced serum
lipopolysaccharide (an inflammatory mediator) and low-density lipoprotein, as well as
increased high-density lipoprotein. This was not observed in the group fed capsaicin with
concurrent antibiotics. The improvements resulted in reduced intestinal inflammation
and permeability, as well as improved endothelial function, which led to a significant
reduction in atherosclerotic lesions. This demonstrates capsaicin’s ability to reduce
adiposity and its associated inflammatory mediators, as well as reducing cardiovascular-
induced risk factors that can reduce cerebrovascular function and cognition. This may also
indicate capsaicin’s application as a resolution to other inflammatory diseases such as
autoimmune diseases, gastrointestinal disorders, and other haemodynamic conditions,
such as atherosclerosis.
Figure 3. Capsaicin structure and function. Capsaicin and dihydrocapsaicin contribute the most to
the pungency of chilli and are found primarily in the fruit pod [86]. The capsaicinoids are
characterised by their common vanilloid ring (circled). Capsaicin consists of a trans configuration
with a double-bond and an even number of branched-chain fatty acid moieties [89]. The vanilloid
ring binds intracellularly to TRPV1 channels on cell membranes, causing an influx of extracellular
calcium into the cell and triggering numerous physiological pathways [82,94]. Capsaicin causes the
release of sensory neuropeptides such as calcitonin gene-related peptide (CGRP) [112]. CGRP is a
potent vasodilator that reduces reactive oxygen species (ROS) production by promoting increased
Figure 3.
Capsaicin structure and function. Capsaicin and dihydrocapsaicin contribute the most to
the pungency of chilli and are found primarily in the fruit pod [
86
]. The capsaicinoids are charac-
terised by their common vanilloid ring (circled). Capsaicin consists of a trans configuration with
a double-bond and an even number of branched-chain fatty acid moieties [
89
]. The vanilloid ring
binds intracellularly to TRPV1 channels on cell membranes, causing an influx of extracellular cal-
cium into the cell and triggering numerous physiological pathways [
82
,
94
]. Capsaicin causes the
release of sensory neuropeptides such as calcitonin gene-related peptide (CGRP) [
112
]. CGRP is a
potent vasodilator that reduces reactive oxygen species (ROS) production by promoting increased
endothelial nitric oxide synthase (eNOS) function and nitric oxide (NO) production [
94
,
112
]. Somato-
statin reduces pro-inflammatory cytokines, inducing anti-inflammatory and immunomodulatory
effects [
112
]. Phosphorylation of serine/threonine kinase 1 (Akt), mediates calcium-dependant pro-
tein kinase II (CaKMII), and increases phosphorylation of eNOS, thereby increasing NO production
and vasodilation [
93
,
113
]. Adenosine monophosphate-activated protein kinase (AMPK) increases
muscular uptake of glucose, thereby reducing adipose cytokine release, inducing anti-inflammatory
effects [
83
,
114
]. TRPV1 also regulates transcription of nuclear factor kappa B (NF-
κ
B), therefore
assisting modulation of cytokine transcription factors and reducing inflammation [
94
]. Abbreviations:
↑: increased; ↓: decreased.

Nutrients 2023,15, 1537 8 of 24
5. The Effects of Capsaicin on Cognition and Cerebrovascular Function
5.1. Cognition in Animal Studies
Capsaicin’s action in reducing obesity, oxidative stress, and inflammation and im-
proving cardiovascular function in animals has been previously described [
83
,
86
,
105
].
Obesity increases blood triglycerides, free fatty acids and low-density lipoprotein (LDL),
contributing to eNOS dysregulation, vascular remodelling, and atherosclerosis, which is
the leading cause of cardiovascular and cerebrovascular disease [83,93,106].
Tau proteins are concentrated in the central nervous system and are involved in
microtubule assembly [
115
]. Abnormal tau proteins can increase phosphorylation and
decrease microtubule binding, forming amyloid oligomers (such as amyloid-beta, A
β
) or
aggregated deposits, which impair brain function by reducing intra- and inter-neuronal
signalling, leading to cognitive decline [
116
]. Intraperitoneal administration of 1 mg/kg of
capsaicin for two weeks restored A
β
-induced memory deficits via improved hippocam-
pal synaptic function in C57BL/6 mice. This possibly occurred because it increased the
expression of the neuroprotective protein postsynaptic density protein 95 (PSD95), which
is often reduced with AD [
117
]. The increase in PSD95 improved spatial learning in adult
C57B1/6 mice, as its primary role is to maintain synaptic plasticity and promote inter-
neuronal signalling. Balleza-Tapia et al. [
24
] also found that hippocampal homogenate
with tissue-bath perfusion of capsaicin significantly reduced levels of A
β
and tau protein
via activation of TRPV1 in mice. Intraperitoneal administration of 1 mg/kg of capsaicin
in an AD mice model upregulated TRPV1, alleviated AD-type pathologies and improved
spatial learning and memory [
118
]. Shiri et al. [
23
] found that a 10 mg/kg single dose of
capsaicin given intraperitoneally improved cognitive performance via TRPV1 in rats, as
measured by passive avoidance learning tests. Pegorini et al. [
22
] found a single dose of
capsaicin between 0.2 and 0.6 mg/kg capsaicin, administered via sub-cutaneous injection,
was neuroprotective. The authors reported that capsaicin increased the survival rate of
CA1 neurons in the hippocampus seven days post-injection in male Mongolian gerbils.
However, low-dose capsaicin (0.1 mg/kg) did not affect cognition. Abdel-Salam et al. [
25
]
reported that either 25 mg or 50 mg/kg/day capsicum extract (1.2% capsaicin) given for
30 days
improved memory performance and increased central NO concentration, as well
as reduced markers of oxidative stress, inflammation and neurodegeneration in a rat model
of AD. They also reported that 50 mg/kg/day of capsicum extract reduced oxidative stress
and inflammation in non-AD rats compared to the control group.
Cholinesterase enzymatically breaks down acetylcholine, which is a powerful cholin-
ergic vasodilatory neurotransmitter that declines with ageing [
119
,
120
]. Cholinesterase is
increased in AD, further reducing acetylcholine. Therefore, cholinesterase inhibitors are a
current first-line treatment of AD pathologies [
121
,
122
]. Rajashri et al. [
123
] found 13 days of
dietary chilli oleoresin containing capsaicin (50 mg/kg; 1.9% w/w) given with scopolamine
(an anticholinergic), reduced acetylcholinesterase (AChE) by 50%. Scopolamine alone
decreased AchE, however, in the absence of a capsaicin only arm, it is unclear whether this
was a result of capsaicin promoting scopolamine’s actions. Viayna et al. [
124
] also reported
that capsaicin (2 mg/kg intraperitoneally, three times per week for four weeks), scaffolded
with the cholinesterase inhibitor huprine Y significantly reduced the A
β
42/A
β
40 ratio in
the hippocampus. The reduction in this ratio improved spatial learning and memory and
decreased neuroinflammation and hippocampal oxidative stress in APP/PS1 mice. Shalaby
et al. [
125
] reported that 47 days of intragastric infusion of capsaicin at a dose of 10 mg/kg
in mice significantly ameliorated A
β
1-42 peptide and tau proteins in the hippocampus,
abolishing behavioural impairments. A capsaicin-rich diet (0.01%, approximately 30 mg/kg
capsaicin) for six months improved spatial learning and memory consolidation in an AD
mice model [
27
]. This showed that chronic capsaicin intake reduced the total A
β
burden
by 32.3% and significantly attenuated tau hyperphosphorylation in both the neocortex and
hippocampus. Wang, J. et al. [
27
] also found that capsaicin significantly reduced proin-
flammatory cytokines IL-6 and TNF-
α
, and improved the expression of neuroprotective
post-synaptic proteins, such as PSD95, thereby ameliorating neuroinflammation.

Nutrients 2023,15, 1537 9 of 24
cAMP-response-element-binding-protein (CREB), a transcription factor critical in
maintaining spatial and long-term memory, is downregulated in AD [
126
]. Increased
phosphorylation of CREB is linked to the binding of calcitonin gene-related peptide
(CGRP), a potent vasodilator [
127
,
128
]. Intragastric administration of a single dose of
capsaicin (
10 mg/kg
) increased the expression of CREB [
129
]. Furthermore, 1 m/kg sub-
cutaneous administration of capsaicin for eight days increased CGRP tissue levels in the
hippocampus [
130
]. Therefore, capsaicin increased spatial memory and cognitive per-
formance [
129
,
130
]. This action was supported by Bashiri et al. [
131
], who found that
intrahippocampal capsaicin injections (0.05; 0.1; or 0.3
µ
g/rat) augmented mRNA ex-
pression of cyclic adenosine monophosphate (cAMP) and TRPV1 in the CA1 area of the
hippocampus, improving memory in rats with biliary cirrhosis.
Avraham et al. [
132
] found improvements in neurological scores and cognition up to
14 days following a single dose intraperitoneal injection of capsaicin (1.25
µ
g/kg) in female
Sabra mice with hepatic failure. Further, these effects were reversed with the application
of a TRPV1 antagonist, confirming that the observed effects of capsaicin were vanilloid
mediated [132].
Together these results demonstrate capsaicin’s ability to reduce oxidative stress and
inflammation centrally and systemically via TRPV1, thereby alleviating cognitive deficits in
animal models of disease. As these findings are all associated with reduced inflammation, it
is logical to conclude that the underlying mechanisms of ED could also influence cognitive
performance, and these findings could therefore translate to the human cerebrovasculature.
5.2. Cognition in Human Studies
Only one study assessed the effects of capsaicin on cognition. Liu et al. [
133
] as-
sessed the chilli pepper consumption of 338 community-dwelling people (>40 years old)
from Chongqing, China, using a self-reported food frequency questionnaire. Cognition
was measured using a Chinese version of the Mini-Mental State Examination (MMSE).
A capsaicin-rich diet was positively correlated with significantly higher MMSE scores.
However, those who consumed chilli daily were younger than those who self-reported
weekly chilli consumption. This was attributed to the social phenomenon that older people
preferred bland diets. Although limitations of this study also include the inability to quan-
tify self-reported chilli consumption, this demonstrates the possibility that capsaicin could
influence human brain health, and that further studies are required to test the effects of
chronic chilli consumption on cognition.
5.3. Cerebrovascular Function in Animals and Humans
Limited studies have investigated the effect of capsaicin on cerebrovascular function.
In vitro
studies of feline MCAs found vasodilation of pial arteries occurred with a lower
dose of capsaicin (5
×
10
−8
M) compared to high dose capsaicin (3
×
10
−7
M) which
had vasoconstrictive outcomes [
134
]. More recently, Marics et al. [
135
] tested the dural
application of capsaicin on meningeal blood flow
in vivo
, using a laser Doppler flowmeter
positioned over a branch of the middle meningeal artery of rats. CGRP release from the
meningeal afferents was elevated in response to both low (10
µ
M) and high (100
µ
M)
topical capsaicin application on the dura mater. Further, CGRP release was seen to be
higher in obese rats than in control rats [
135
]. This may be due to decreased CGRP receptor
sensitivity to CGRP (i.e., increased resistance of the CGRP receptor to CGRP) [
136
]. Xu
et al. [
137
] reported that six months of dietary capsaicin (0.01% for mice and 0.02% for rats)
increased the phosphorylation of eNOS in carotid arteries which was associated with the
activation of TRPV1. Marquez-Romero et al. [
138
] pipetted escalating capsaicin dosages
(33, 66, 99, 132, 165
µ
M) onto filtered paper. A single application was applied for 20 min to
the hemi-palate of 30 healthy undergraduate students and CBF was measured using TCD.
Capsaicin increased CBF, thus demonstrating its potential to elicit vasodilatation. Given
the link between CBF and cognition and the limited studies performed using capsaicin,
more studies are needed to determine the effects of capsaicin on cerebrovascular function.

Nutrients 2023,15, 1537 10 of 24
Recently, the synthetic capsaicin analogue, nitro-capsaicin, has been studied for its
effect on the brain structure and cognition [
139
]. Nitro-capsaicin substitutes the OCH
3
group on capsaicin with NO
2
and produces less gastro-intestinal irritation compared to
capsaicin [
139
,
140
]. Jamornwan et al. [
140
] found that nitro-capsaicin, in both vascular
damaged and control microglial cell cultures, suppressed microglial activation, decreasing
proinflammatory cytokines, such as TNF-
α
and IL-6, and enhanced anti-inflammatory fac-
tors, such as IL-4 and IL-10. Further, when mice with aberrant e4 apolipoprotein E (ApoE4)
genes were given 1 mg/kg/day intraperitoneal capsaicin for 1 month, it reversed impaired
lipid metabolism, microglial dysfunction, and other neuronal impairments induced by
mutant ApoE4 [
141
]. This demonstrates the potential of capsaicin and capsaicin analogues
to reduce chronic microglial activation, a risk factor of neurodegenerative disease and
cognitive decline.
6. Capsaicin Summary
Although capsaicin was first isolated in 1876 and has been extensively studied, it is
only in recent years that its benefits on endothelial function and cognition have become a
research focus. Research in animals demonstrates the beneficial effects of capsaicin as a
therapeutic agent in improving cognition (Figure 4). These findings suggest that capsaicin’s
intracellular binding to TRPV1 activates pathways that modulate inflammation (systemic
and neural), oxidative stress, and improve NO bioavailability. This was particularly
demonstrated in AD and obesity mice models. All studies with outcomes on A
β
showed
significant improvements in the A
β
or A
β
ratio in the hippocampus with various dosages
(1–50 mg/kg) and various dietary applications. Further, capsaicin can cross the blood–
brain barrier (BBB) and activate TRPV1, as well as increase its expression [
24
,
131
,
142
].
This capsaicin-induced activation decreases BBB permeability, consequently increasing its
integrity [
143
]. This has been directly related to significant memory and spatial learning
improvement in AD-type pathologies [
27
,
117
,
118
,
124
], and traumatic brain injury [
143
].
Due to this, capsaicin attenuates the progression of neurological disorders, such as dementia
in animals.
Despite the evidence that capsaicin can attenuate cognitive decline in animals, limited
human studies have been conducted. Further, no clinical studies have been completed that
test the effects of capsaicin on cerebrovascular function or cognition. This is summarised in
Table 2. This could be due to the technical difficulties associated with testing cerebrovascular
function [
43
]. This may also be due to the pungency of capsaicin which can cause side effects
of gastrointestinal irritation and discomfort with ingestion [
83
,
144
]. Pungency-related
issues with oral administration need to be overcome to test its effects on cerebrovascular
function and cognition in humans. Clinical trials assessing the effects of capsaicin on
neuroprotection would be beneficial [
26
]. Therefore, developing novel vehicles for capsaicin
delivery could see capsaicin being a suitable treatment option for the management of
chronic diseases.

Nutrients 2023,15, 1537 11 of 24
Table 2. Summary of studies that have investigated the effects of capsaicin on cognition and cerebrovascular function.
Reference Species and Characteristics Capsaicin Dosage/Application (Duration) Outcomes of Capsaicin Treatment
Effects of acute dose capsaicin on cognition in animals
[143] Adult male Sprague Dawley rats 125 mg/kg s.c. (3 days)
↓BBB permeability
↓vasogenic oedema formation
↓motor and cognitive deficit
↑free magnesium
[22]Ischaemia model
Male Mongolian gerbils 0.025, 0.05, 0.01, 0.2, 0.6 mg/kg s.c. ↑cognition
↑neuronal activity
[145] Young male Wistar rats 10 mg/kg i.G. ↑spatial memory
↑neuronal long-term potentiation
[132] Female Sabra mice 1.25 µg/kg i.p. (single dose) ↑cognitive function
↑neurological score
[130] C57BL/6 WT mice 1 mg/kg i.v. (8 days)
↑spatial learning
↑hippocampal CGRP
↑IGF-1 expression
[129] Sprague Dawley rats (Grade II, male) 10 mg/kg i.G. (single dose) ↑cognitive performance
↑hippocampal CREB
[23] Male Wistar mice 10 mg/kg i.p. (single dose) ↑cognitive performance
[24] P17-30 C57BL/6 (WT) and TRPV1 KO male mice Hippocampal slices (tissue bath) ↓Aβneuronal degradation
[131] Male Wistar rats 0.5, 0.3, 0.1 µg/rat (intrahippocampal injection)
↑memory
↑TRPV1
↑cAMP mRNA
[118] APP23/PS45 double transgenic AD mice 1 mg/kg i.p.(single dose)
↑spatial learning
↑memory
↑TRPV1 upregulation
↓hippocampal neurotic plaques
Effects of chronic dose capsaicin in animals
[117] Adult C57B1/6 mice 1 mg/kg/day i.p. (2 weeks)
↑spatial learning
↑memory
↑PSD95 expression
↓synapse loss

Nutrients 2023,15, 1537 12 of 24
Table 2. Cont.
Reference Species and Characteristics Capsaicin Dosage/Application (Duration) Outcomes of Capsaicin Treatment
[25] Adult male Sprague Dawley rats
AlCl3+ 25, 50 mg/kg/day i.p. capsicum extract
50 mg/kg/day i.p. capsicum extract
(1.2% capsaicin) (30 days)
↓neuro and systemic inflammation
↓oxidative stress
↓Aβ-peptide accumulation
↓cerebral cortex, substantia nigra and hippocampal
neurodegeneration
↑brain NO concentration and memory
[125] Adult albino mice 10 mg/kg i.G. (47 days)
↓behavioural impairments
↓Aβ1-42
↓tau proteins
[123] Male Wistar rats Scopolamine + 50 mg/kg oral chilli oleoresin (13 days)
↓Acetylcholinesterase (−50%)
↑locomotion activity
↓escape latency time
[141] Male, female C57BL/6J littermate ApoE4 mice 1 mg/kg i.p./day (1 month)
↓memory impairment
↓tau pathology
↓neuronal autophagy
↓microglial phagocytosis
[27]
APP/PS1 transgenic mice on C57BL/6 background
0.1% capsaicin-rich chow (approx. 30 mg/kg capsaicin)
(6 months)
↑memory
↑spatial learning
↓Aβplaque density
↓Aβvessel deposition
↓Aβ42, ↓Aβ40
↓hyperphosphorylation and tau
↓neuroinflammation
↓neurodegeneration
↓proinflammatory cytokines
↑synapse related proteins
[124]C47BL6/J mice;
APP/PSI mice 2 mg/kg, i.p. (4 weeks)
↑spatial learning
↑memory
↓Aβ42/Aβ40 ratio
↑basal synaptic activity
↓hippocampal oxidative stress
↓hippocampal Neuroinflammation

Nutrients 2023,15, 1537 13 of 24
Table 2. Cont.
Reference Species and Characteristics Capsaicin Dosage/Application (Duration) Outcomes of Capsaicin Treatment
Effect of capsaicin on animal cerebrovasculature
[134] Adult felines 10−7–10−5M (tissue bath) ↑vasodilation
[137]
C57BL/6J mice;
TRPV1 KO mice;
Wistar-Kyoto rats;
Stroke-prone, hypertensive male mice
chow + 0.01% dietary capsaicin
(0.01% mice; 0.02% rats)
(6 months)
↑phosphorylated eNOS
↑eNOS expression
Delayed stroke onset
TRPV1 function
↑cerebrovascular activity
[135] Male Sprague Dawley rats
100 nM (low dose), 10 µM (high dose)
(in vivo and dural application)
(20 weeks)
↑meningeal blood flow
↑CGRP release
Effect of capsaicin on human cerebrovasculature
[138]Healthy male adults (n = 30)
21 ±5 years old
33, 66, 99, 132, 165 µM dose escalation
Hemi-palate (20 min) ↑MCA velocity
Effect of capsaicin on cognition in humans
[133]Long-term community dwelling adults (n = 338)
≥40 years
Capsaicin dietary intake assessed by food frequency
questionnaire
↑cognition
Improved Aβ42/Aβ40 ratio
AlCl
3
: Aluminum Chloride; A
β
: beta-amyloid peptide; AD: Alzheimer’s disease; BBB: blood–brain barrier; cAMP: cyclic adenosine monophosphate; conc: concentration; CREB:
cAMP-response-element-binding-protein; eNOS: endothelial nitric oxide synthase; CGRP: Calcitonin gene-related peptide; i.G.: intragastric infusion; IGF-I: insulin-growth factor-1; i.p.:
intraperitoneally; i.v.: intravenously; KO: knockout; MCA: middle cerebral artery; N: number of participants; NO: nitric oxide; s.c.: subcutaneous injection; PSD95: postsynaptic density
protein-95; mRNA: messenger ribonucleic acid; N: number of participants; TRPV1: transient receptor potential vanilloid-1; WT: wild type; ↑: increased; ↓: decreased.

Nutrients 2023,15, 1537 14 of 24
Nutrients 2023, 15, x FOR PEER REVIEW 15 of 26
Figure 4. Schematic representation of the neuroprotective effects of capsaicin in animals. This figure
demonstrates the capacity of capsaicin to increase CBF, therefore increasing the delivery of nutrients
to the brain, a key factor in the prevention of cognitive decline and improved cognition [10,26,43].
Capsaicin decreases pro-inflammatory cytokines, including tumour necrosis factor-alpha (TNF-α),
interferon-gamma (IFN-γ) and interleukin-6 (IL-6), reducing inflammation [27,108]. Attenuation of
immunoreactive proteins, including postsynaptic density protein 95 (PSD95), synapsin-1 (SYN1),
synaptosomal-associated protein 25 (SNAP25) and antivesicle-associated membrane protein 1
(VAMP1), contribute to reducing hyperphosphorylation, neuroinflammation and
neurodegeneration [27]. Capsaicin also reduces the action of cyclo-oxygenase (COX-2), which
prevents atherosclerotic plaque formation [146,147]. These changes can lead to improved
endothelial function, CBF and, in turn, cognition [27,146]. Abbreviations: ↑: increased; ↓: decreased.
7. Capsimax
Capsimax is a readily available capsaicin supplement containing 2% capsaicinoids
[1.2–1.35% capsaicin, 0.6–0.8% dihydrocapsaicin, and 0.1–0.2% nordihydrocapsaicin])
from 15–25% Capsicum extract, 45–55% sucrose, and 30–35% cellulose gum coatings [148].
Capsimax prolongs release into the small intestine, which therefore overcomes pungency
and related issues associated with direct chilli or capsaicin application [148–151].
OmniActive Health Technologies dissolution studies indicate a range of 60–75% of the
total capsaicinoids content of Capsimax are released within four hours and are completely
released beyond six hours post-ingestion [149]. A pilot study by Deshpande et al. [148] of
incremental dose escalation 2, 4, 6, 8 and 10 mg of capsaicin (i.e., 100, 200, 300, 400 and 500
mg Capsimax) for seven days found all dosages tolerable and safe with no toxic effects
reported on vital signs, and metabolic, anthropometric and biochemical markers. As
Capsimax is a relatively new product to market, few studies have been performed,
Figure 4.
Schematic representation of the neuroprotective effects of capsaicin in animals. This figure
demonstrates the capacity of capsaicin to increase CBF, therefore increasing the delivery of nutrients
to the brain, a key factor in the prevention of cognitive decline and improved cognition [
10
,
26
,
43
].
Capsaicin decreases pro-inflammatory cytokines, including tumour necrosis factor-alpha (TNF-
α
), interferon-gamma (IFN-
γ
) and interleukin-6 (IL-6), reducing inflammation [
27
,
108
]. Attenua-
tion of immunoreactive proteins, including postsynaptic density protein 95 (PSD95), synapsin-1
(SYN1), synaptosomal-associated protein 25 (SNAP25) and antivesicle-associated membrane protein
1 (VAMP1), contribute to reducing hyperphosphorylation, neuroinflammation and neurodegenera-
tion [
27
]. Capsaicin also reduces the action of cyclo-oxygenase (COX-2), which prevents atheroscle-
rotic plaque formation [
146
,
147
]. These changes can lead to improved endothelial function, CBF and,
in turn, cognition [27,146]. Abbreviations: ↑: increased; ↓: decreased.
7. Capsimax
Capsimax is a readily available capsaicin supplement containing 2% capsaicinoids
[
1.2–1.35%
capsaicin, 0.6–0.8% dihydrocapsaicin, and 0.1–0.2% nordihydrocapsaicin]) from
15–25% Capsicum extract, 45–55% sucrose, and 30–35% cellulose gum coatings [
148
]. Cap-
simax prolongs release into the small intestine, which therefore overcomes pungency and
related issues associated with direct chilli or capsaicin application [
148
–
151
]. OmniActive

Nutrients 2023,15, 1537 15 of 24
Health Technologies dissolution studies indicate a range of 60–75% of the total capsaicinoids
content of Capsimax are released within four hours and are completely released beyond
six hours post-ingestion [
149
]. A pilot study by Deshpande et al. [
148
] of incremental dose
escalation 2, 4, 6, 8 and 10 mg of capsaicin (i.e., 100, 200, 300, 400 and 500 mg Capsimax) for
seven days found all dosages tolerable and safe with no toxic effects reported on vital signs,
and metabolic, anthropometric and biochemical markers. As Capsimax is a relatively new
product to market, few studies have been performed, particularly in brain health. Studies
have focused on obesity, potentially due to this being the reported outcome observed in
animal models.
Capsimax has been reported to be a safe and effective weight management strategy,
using a dose of 0.84 mg/kg for 52 days in obese C757BL/6J mice [
152
]. Mariwala et al. [
152
]
found that Capsimax increased thermogenesis and reduced lipogenesis by decreasing
biomarkers of adipogenesis, including peroxisome proliferator-activated receptor gamma
and fatty-acid binding protein 4. Oxidative stress and inflammation were decreased in male
Wistar rats supplemented with 10 mg/kg of Capsimax daily for eight weeks in combination
with either exercise [
108
], a low-fat high-sucrose, or high-fat diet [
153
]. This was primarily
achieved by reduced nuclear factor erythroid-related factor 2, an antioxidant transcription
factor, and NF-
κ
B. Sahin et al. [
153
] also reported that Capsimax increased phosphorylation
of eNOS in the aorta demonstrating potential for exploration of capsaicin to also improve
endothelial function through eNOS phosphorylation.
A single-dose crossover study by Bloomer et al. [149] found 100 mg Capsimax along-
side a protein-rich meal increased free fatty acid concentrations at 2 and 2.5 h and glycerol
at 4 h post-consumption in exercise-trained, non-smoking adults. Deng et al. [
154
] and
Rigamonti et al. [
155
] both completed single-dose, single-blinded cross-over studies using
100mg Capsimax. Both studies reported that Capsimax increased resting energy expendi-
ture +7.23% [154] and +16.44% [155] compared to placebo in males and females.
A double-blinded 12-week randomised control trial conducted by Rogers et al. [
156
]
and Urbina et al. [
157
], each separated groups using either 100 or 200 mg Capsimax or
placebo. After 12 weeks, Rogers et al. [
156
] found that 200 mg of Capsimax reduced fat mass
compared to placebo. In contrast, Urbina et al. [
157
] found no effect on body composition
but did report a reduction in waist-to-hip ratio with 100 mg Capsimax at six weeks. A
decrease in calorie consumption of 257 kcal per day and increased serum high-density
lipoprotein (HDL) was reported in participants given 200 mg Capsimax, compared to
100 mg Capsimax or placebo at 12 weeks. Similarly, a 12-week study comparing 200 mg
Capsimax or placebo alongside a calorie-restricted diet reported reductions in body weight,
BMI, waist circumference, and fat mass in overweight and obese women of reproductive
age [
150
]. This study reported a high dropout rate of 27%, which was due to the difficulties
of compliance with the prescribed restrictive diet rather than side effects of the intervention.
As restrictive diets can reduce adiposity [
158
], the outcomes found by Manca et al. [
150
]
could therefore be a result of the caloric restriction in this intervention, rather than Capsimax
supplementation.
These results are summarised in Table 3and indicate the potential for Capsimax to
reduce the oxidative stress and chronic low-grade systemic inflammation that is associated
with increased adiposity. As greater inflammation, oxidative stress and adiposity are all
factors that influence endothelial function, the reduction of these could lead to improved
endothelial function. This may have a flow on effect whereby increased endothelial func-
tion improves blood flow and, potentially, CBF and cognition. Although studies have
explored the ability of Capsimax to reduce adiposity, a significant risk factor associated
with cognitive decline, no clinical trials have been conducted testing the effects of Capsimax
on cerebrovascular function or cognition. Given the evidence that capsaicin can reduce
cognitive deficits in animal models, dementia research should aim to explore the effects of
Capsimax as a potential prevention of cognitive decline.

Nutrients 2023,15, 1537 16 of 24
Table 3. Review of Capsimax intervention studies.
Reference Study Design Species/Participants/Sex Study Duration Capsaicin Dosage Primary Outcome/s
Effects of Capsimax in animal studies
[152] Random allocation C57BL/6J male mice (n = 24) 52 days 0.84 mg/kg/day + high fat diet
↑thermogenesis
↓body mass
↓lipogenesis
[153] Random allocation Male Wistar rats (n = 42) 8 weeks 10 mg/kg/day ↓Inflammatory markers
↓body mass
[108] Random allocation Male albino Wistar rats (n = 28) 8 weeks 10 mg/kg/day
↑antioxidants
↓inflammation
↑time to exhaustion
Effects of Capsimax in human studies
[154] Single-blind, crossover Healthy adults (n = 40) 17F/23M 3 h 100 mg single dose ↑resting energy expenditure
[149]Double-blind, crossover,
randomised control trial
Healthy adults (n = 20)
10F/10M 3 h 100 mg single dose ↑free fatty acids
↑glycerol
[155]Single blind, crossover,
randomised control trial
Obese, hospitalised 15–34 years in
weight reduction program (n = 10)
4F/6M
6 h 100 mg single dose
↑resting energy expenditure
↑satiety
↓hunger
[148]Open-label, dose-finding,
adaptive study
Healthy overweight 25–55 years
women
(n = 12)
6 weeks 100 mg/day +100 mg/day weekly
escalating until 500 mg/day/week
Tolerable up to 500 mg/day
No adverse events
No dropouts
[150] Randomised control trial
Overweight or obese 18–51 years
women
(n = 61)
12 weeks 200 mg/day + diet restriction
↓fat mass
↓body mass
↓waist circumference
↑free fat mass
[156]Parallel double-blind,
randomised control trial
Heathy 18–56 years (n = 77)
47F; 30M 12 weeks 100 mg/day
200 mg/day
↓fat mass (−6.68%)
↓body mass (−5.91%)
[157]Double-blind, randomised
control trial Healthy adults (n = 77) 12 weeks 100 mg/day
200 mg/day
↓kJ intake
↓waist-to-hip ratio
↓appetite
↓HDL cholesterol
BMI: body mass index; eNOS: endothelial nitric oxide synthase; F: female; HDL: high-density lipoprotein; M: male; N: number of participants; ND: normal diet; NF-κB: nuclear factor
kappa-light-chain enhancer of activated B cells; ↑: increased; ↓: decreased.

Nutrients 2023,15, 1537 17 of 24
8. Summary
Dementia is a global health care challenge and is characterised by impaired cognition,
which leads to a reduced QoL. The brain relies on a constant CBF to preserve cognition.
NVC and autoregulation are the complex mechanisms that ensure homeostatic CBF during
increased neuronal metabolism and environmental and physical stimuli. If changes in CBF
are dysregulated, structural and functional changes occur in the brain, leading to cognitive
decline.
Ageing and obesity have synergistic detrimental effects on endothelial function due to
hormonal changes, oxidative stress and chronic low-grade systemic inflammation. This
causes an uncoupling of eNOS, reducing NO production and increasing oxidative stress,
resulting in endothelial dysfunction. Endothelial dysfunction is the main contributing factor
of cardiovascular disease, cerebrovascular dysfunction and reduced CBF, thus leading to
cognitive decline.
Capsaicin is a pungent molecule found abundantly in chillies and has demonstrated
beneficial effects on weight management, oxidative stress and chronic low-grade systemic
inflammation. Capsaicin-induced activation of TRPV1 can regulate inflammation and
oxidative stress by increasing NO production, thus improving endothelial function. Further,
this review indicated that acute and chronic capsaicin treatment attenuated AD-type
pathologies and improved cognition in animals. However, studies adequately assessing
the effects of capsaicin on cerebrovascular function, and cognition in humans do not exist.
Pungency-related side effects, such as gastrointestinal irritation, make determining the
effects of capsaicin in humans difficult to assess.
9. Conclusions
This review outlines how Capsimax, a capsaicin supplement, has been demonstrated
as a novel, safe and tolerable capsaicin supplement that reduces side effects such as gastroin-
testinal distress associated with capsaicin intake. Capsimax has been tested in both animals
and human clinical trials and reduced adiposity via increased thermogenesis and reduced
caloric consumption. Capsimax also reduced chronic low-grade systemic inflammation
and oxidative stress in animals, as well as improved endothelial function in rats, all of
which are hallmarks associated with cognitive decline beyond that of normal ageing.
This review provides justification for adopting Capsimax in clinical trials as an effec-
tive, non-pharmaceutical intervention to counteract the decline of cerebrovascular function
and cognition, particularly in obesity and ageing. Considering the lack of current preven-
tive strategies to counteract cognitive ageing, capsaicin may present a natural treatment to
counteract cognitive decline. Future prospective studies are required to see whether the
attenuation of cognitive decline by capsaicin can translate to reduced risk of disease such
as dementia and Alzheimer’s in humans.
Author Contributions:
E.B. and T.T. contributed to the review design. T.T. and E.B. conducted the
search and evaluation of the literature. T.T. designed the figures and tables, with E.B. and D.M.
critically evaluating all figures and tables. T.T. and E.B. wrote the text. D.M. and E.B. contributed to
the editing and revision of the text. All authors read and approved the final 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 no conflict of interest.

Nutrients 2023,15, 1537 18 of 24
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