REVIEW
published: 13 March 2019
doi: 10.3389/fpsyt.2019.00115
The Therapeutic Potential of
Mangosteen Pericarp as an
Adjunctive Therapy for Bipolar
Disorder and Schizophrenia
Melanie M. Ashton 1,2,3*, Olivia M. Dean 1,2,4 , Adam J. Walker 1 , Chiara C. Bortolasci 5 ,
Chee H. Ng 3 , Malcolm Hopwood 6 , Brian H. Harvey 7 , Marisa Möller 7 , John J. McGrath 8,9,10 ,
Wolfgang Marx 1 , Alyna Turner 1,4 , Seetal Dodd 1,4,11 , James G. Scott 8,12,13 ,
Jon-Paul Khoo 1,12 , Ken Walder 5 , Jerome Sarris 3,14 and Michael Berk 1,2,4,11,15
1
Edited by:
Lourdes Martorell,
Institut Pere Mata, Spain
Reviewed by:
Polymnia Georgiou,
University of Maryland, Baltimore,
United States
Maria Donniacuo,
Second University of Naples, Italy
*Correspondence:
Melanie M. Ashton
m.ashton@deakin.edu.au
Specialty section:
This article was submitted to
Molecular Psychiatry,
a section of the journal
Frontiers in Psychiatry
Received: 31 August 2018
Accepted: 15 February 2019
Published: 13 March 2019
Citation:
Ashton MM, Dean OM, Walker AJ,
Bortolasci CC, Ng CH, Hopwood M,
Harvey BH, Möller M, McGrath JJ,
Marx W, Turner A, Dodd S, Scott JG,
Khoo J-P, Walder K, Sarris J and
Berk M (2019) The Therapeutic
Potential of Mangosteen Pericarp as
an Adjunctive Therapy for Bipolar
Disorder and Schizophrenia.
Front. Psychiatry 10:115.
doi: 10.3389/fpsyt.2019.00115
Frontiers in Psychiatry | www.frontiersin.org
IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia, 2 Florey
Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia, 3 Professorial Unit, The
Melbourne Clinic, Department of Psychiatry, University of Melbourne, Richmond, VIC, Australia, 4 Department of Psychiatry,
Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia, 5 Centre for Molecular and Medical Research,
School of Medicine, Deakin University, Geelong, VIC, Australia, 6 Professorial Psychiatry Unit, Albert Road Clinic, University of
Melbourne, Melbourne, VIC, Australia, 7 Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy
(Pharmacology), North West University, Potchefstroom, South Africa, 8 Queensland Centre for Mental Health Research, The
Park Centre for Mental Health, Wacol, QLD, Australia, 9 Queensland Brain Institute, University of Queensland, St. Lucia, QLD,
Australia, 10 National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark, 11 Centre of Youth Mental
Health, University of Melbourne, Parkville, VIC, Australia, 12 Faculty of Medicine, The University of Queensland, Herston, QLD,
Australia, 13 Metro North Mental Health, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia, 14 NICM Health
Research Institute, Western Sydney University, Westmead, NSW, Australia, 15 Orygen Youth Health Research Centre,
Parkville, VIC, Australia
New treatments are urgently needed for serious mental illnesses including bipolar
disorder and schizophrenia. This review proposes that Garcinia mangostana Linn.
(mangosteen) pericarp is a possible adjunctive therapeutic agent for these disorders.
Research to date demonstrates that neurobiological properties of the mangosteen
pericarp are well aligned with the current understanding of the pathophysiology of
bipolar disorder and schizophrenia. Mangosteen pericarp has antioxidant, putative
neuroprotective, anti-inflammatory, and putative mitochondrial enhancing properties,
with animal studies demonstrating favorable pharmacotherapeutic benefits with respect
to these disorders. This review summarizes evidence of its properties and supports the
case for future studies to assess the utility of mangosteen pericarp as an adjunctive
treatment option for mood and psychotic disorders.
Keywords: mangosteen pericarp, bipolar disorder, schizophrenia, psychiatry, oxidative stress, inflammation,
mitochondria
INTRODUCTION
Serious mental illness, generally defined as disorders with psychotic or high severity symptoms
(such as bipolar disorder and schizophrenia), contribute significantly toward disease burden
worldwide (1). Importantly, those living with serious mental illnesses often experience suboptimal
responses to conventional treatments (2, 3), and treatment options are limited (2, 4). The
developmental pipeline for conventional psychiatric medications, historically driven by large
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Therapeutic Potential of Mangosteen Pericarp
pharmaceutical companies, is dwindling (5, 6); as such,
the investigation of novel therapeutics is both warranted,
and needed. One promising avenue of research is in the
potential use of nutraceutical agents, as adjunctive therapies,
that target biological pathways known to be dysregulated in
neuropsychiatric disorders (7).
This narrative review explores the neurobiological properties
and therapeutic potential of an extract derived from the
pericarp of Garcinia mangostana Linn. (mangosteen) for serious
mental illness. Due to its bioactive components and the
parallels with the current understanding of the pathophysiology
of both schizophrenia and bipolar disorder, the mangosteen
pericarp may be or may contain a useful adjunctive therapeutic
agent for these disorders. The salient neurobiological targets
that overlap in serious mental illness include; oxidative
stress, neuroinflammation, neurogenesis and apoptosis, and
mitochondrial dysfunction. The potential therapeutic value of
mangosteen pericarp will be explored within the context of
these factors.
common monoamine theory (19), but instead mediate changes
through the biological processes outlined from here in.
Oxidative Stress
Altered oxidative biology in serious mental illness is indicated
by a reduction in antioxidant levels, including glutathione
and glutathione transferase (20, 21) and increased reactive
oxygen species (ROS) and reactive nitrogen species (RNS) (20).
There may also be a rise in oxidative stress markers such
as malondialdehyde (MDA) and thiobarbituric acidic reactive
substances (TBARS). Redox markers (20), including nitric oxide,
superoxide dismutase, catalase, and glutathione peroxidase are
altered in serious mental illness (20, 22, 23). It has been suggested
that the variability in redox markers may to some extent be due
to differences between early and late stages of the disorder (19).
The high levels of oxidative stress may, in part, originate in
mitochondria and are associated with mitochondrial dysfunction
(19). Aberrations in neurotransmitters such as glutamate are also
associated with altered redox state and this ties into changes
in monoamines seen in serious mental illness (13). Targeting
redox imbalance has been shown to be a useful therapeutic
pathway, exemplified by agents such as N-acetyl cysteine that
have conferred some benefits in schizophrenia and bipolar
disorder (20, 24–27).
BIPOLAR DISORDER AND
SCHIZOPHRENIA: SHARED PHYSIOLOGY
Major neuropsychiatric disorders appear to share much of
their basic neurobiology, suggesting that nutraceutical and
other agents may have broad utility. Schizophrenia and bipolar
disorder exhibit shared genetic and neurocognitive factors and
clinical symptoms (8, 9). Similarly, schizophrenia and bipolar
disorder have overlapping biological aberrations demonstrated
by the use of some drugs to treat both conditions (e.g., atypical
antipsychotics) (10).
Inflammation and Neurogenesis
In both schizophrenia and bipolar disorder, there is evidence
of raised inflammatory cytokines both in the central nervous
system and peripheral circulation (21, 28–32). The effects of
neuroinflammation include lowering mitochondrial energy
generation, increased free radicals and lipid peroxidation and
increased neuroexcitation which may lead to neurodegeneration
and apoptosis through raising intracellular calcium and
glutamate levels (21, 33, 34). Inflammation can also lead to
higher levels of NO being produced by inducible nitric oxide
synthase (iNOS) (35). A recent meta-analysis found that acute
illness in schizophrenia was associated with elevated levels
of the peripheral proinflammatory cytokines interleukin (IL)
6 and tumor necrosis factor alpha (TNF-α), and elevated
levels of cytokine receptor antagonist (IL-1Ra) and soluble
cytokine receptor (36). In chronically ill patients, peripheral
IL-6, IL-1β, and soluble cytokine receptor levels were persistently
elevated (36).
Serious mental illnesses are also associated with higher rates
of programmed cell death or apoptosis than healthy controls
(37, 38), with irregularities in apoptotic and metabolic markers
observed in schizophrenia (39). For example, evidence indicates
activated apoptotic programmed cell death pathways in the
anterior cingulate cortex and hippocampus of patients with
schizophrenia (40). Alterations in neurotrophins, which protect
against neuronal apoptosis, have been reported in bipolar
disorder. For example, brain derived neurotrophic factor, Bcell lymphoma 2 (bcl-2), and vascular endothelial growth factor
(VEGF) are decreased during acute phases of bipolar disorder
(both mania and depression) (21).
Mitogen-activated protein kinases (MAPK) regulate cell
survival and apoptosis via gene expression, cell proliferation,
Monoamine Disturbances
Monoamines play a critical role in the pathophysiology of bipolar
disorder and schizophrenia (11, 12). Glutamatergic dysregulation
has also been implicated in the pathophysiology of bipolar
disorder (13–15) and schizophrenia (16). Excess mesolimbic
dopaminergic activity is implicated in the pathophysiology
of psychosis (17). Serotonergic dysregulation has also been
implicated in bipolar disorder and schizophrenia including
alterations in 5-HT2A , 5-HT1A, and 5-HT1B receptors in
the prefrontal cortex and hippocampus (18). Some common
psychotropic medications target these pathways but are not
effective for everyone. Therefore, new therapies should aim to
address critical biological targets which are not addressed by this
Abbreviations: 3-NP, 3-nitropropionic acid; Bcl-2, B-cell lymphoma 2; COX-2,
Cyclooxygenase-2; CRP, C-reactive protein; DPPH, 11-diphenyl-2-picrylhydrazyl;
ENA, Epithelial Cell-Derived Neutrophil-Activating Protein; ERK, Extracellular
Signal-regulated Kinase; GPx, Glutathione peroxidase; GSH, Glutathione
peroxidase; H2 O2, Hydrogen peroxide; IBA-1, Ionized calcium binding adaptor
molecule 1; IL, Interleukin; iNOS, Inducible nitric oxide synthase; JNK, c-Jun
N-terminal; LPS, Lipopolysaccharide; MAPK, Mitogen-activated protein kinases;
MDA, Malondialdehyde; MIA, Maternal immune-activation; MTT, 3-(2,5dimethylthiazol-1-yl)2,5-; NF-kB, Nuclear factor kappa B; NO, Nitric oxide; NOS,
Nitric oxide synthase; NOX, NADPH-oxidase; PGE2 , Prostaglandin E2 ; ROS,
Reactive oxygen species; SOD, Superoxide dismutase; TBARS, Thiobarbituric
acidic reactive substances; TNF-α, Tumor necrosis factor; VEGF, Vascular
endothelial growth factor.
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Therapeutic Potential of Mangosteen Pericarp
corresponding to dysregulated energy metabolism (59, 60).
Medications targeting mitochondria, such as L-acetylcarnitine (61) and methylene blue (62, 63), have demonstrated
therapeutic utility as antidepressants, antipsychotics, and
mood stabilizers.
In bringing together the aforementioned relevant information
regarding the known pathophysiology of serious mental illness
and the known bioactivity of mangosteen pericarp, this review
sets the scene for exploring the potential use of mangosteen
pericarp for the treatment of serious mental illness. The wide
variety of pathophysiological targets discussed, likely combined,
may highlight one of the most important and still unsolved
problems in the development of psychotropic medications. New
developments targeting these pathways in combination, may
help to improve treatment response and fill the gap left by
conventional treatments.
cell survival, and death, and thus, are important for neuronal
plasticity (37). Other MAPKs, including p38 and c-Jun Nterminal (JNK), are also possible mediators of mitochondrialinduced apoptosis (41). Neuroleptic medications used in bipolar
disorder and schizophrenia (e.g., olanzapine and haloperidol) can
activate the MAPK pathway (42).
Heightened neuroinflammation, and indeed microglial
activation are associated with inhibition of neurogenesis
(43, 44). Some evidence suggests that altered neurogenesis,
particularly in the hippocampus, occurs in schizophrenia.
For example, a significant reduction in Ki67+ cells (a
marker for cell proliferation) was observed in post-mortem
hippocampal tissue of patients with schizophrenia (45, 46).
Altered postnatal neurogenesis in the striatum was also
proposed as an explanation for the dopaminergic deficits
commonly reported in schizophrenia (43), in addition to gross
hypodopaminergia in the frontal cortex, and hyperdopaminergia
in the striatum (16).
Adjunctive treatments targeting inflammation (and
consequently neuroprotection), for example celecoxib (COX-2
inhibitor) and minocycline (tetracyclic antibiotic), have shown
some efficacy in treating schizophrenia and bipolar disorder
[see Müller (47); Sommer et al. (48) for discussion]. Other
adjuncts with anti-inflammatory effects, including aspirin,
N-acetylcycteine, and estrogen modulating treatments were also
shown to have potential efficacy (48–51).
GARCINIA MANGOSTANA LINN.
(MANGOSTEEN) PERICARP
Garcinia mangostana Linn, more commonly known as
mangosteen, is a tropical fruit affectionately referred to as
the “Queen of the Fruits” (64, 65). The flesh of the fruit is
contained within a husk (pericarp). Mangosteen pericarp has
historically been used for its antimicrobial effects in South East
Asia to treat skin infections, wounds and dysentery (64). The
mangosteen pericarp contains at least 50 different bioactive
compounds including polyphenol-subclasses, xanthones and
catechins (64). Several of these compounds are reported in
this review, including α-mangostin, γ-mangostin, gartanin,
8-deoxygartanin, garciniafuran, garcinone C, and garcinone
D (66), 7-O-demethyl mangostanin (67), mangostenone F
(68, 69), and mangostenone G (69). Compared to the edible
aril part of the fruit, the pericarp contains 10 times more
phenolic compounds and 20 times more antioxidant activity
(70). It is noteworthy that xanthones are tricyclic compounds
and their biological activities might be associated with this
chemical structure (64). The most prominent xanthones in
the mangosteen pericarp are α-mangostin and γ-mangostin
(64). There have been many reports of the potential benefits of
xanthones of the mangosteen pericarp, including properties that
are antioxidant, anti-inflammatory and anti-apoptotic (64, 71).
The properties of mangosteen pericarp have been summarized
in Table 1.
To further illustrate the biomarkers and mechanistic pathways
mangosteen pericarp may have an effect on, Figure 1 provides
a summary of the molecular pathways implicated in oxidative
stress, inflammation and mitochondrial function and which may
be targeted by mangosteen pericarp.
Mitochondrial Dysfunction
Mitochondria are essential contributors to cellular energy
metabolism, synaptic transmission and neuronal growth and
are involved in oxidative stress and apoptotic pathways.
Overproduction of ROS can cause mitochondrial dysfunction
by damaging mitochondrial DNA and mitochondrial respiratory
chain (leading to a reduction in energy production). Lipid
peroxidation can also occur due to ROS and increase the
mitochondrial membrane permeability leading to a disruption
in Ca2+ homeostasis (52). Elevation in intracellular Ca2+
levels can cause neuronal degeneration and cell death and can
lead to the production of superoxide ion radicals, forming
a vicious cycle (52, 53). Differences in the size, shape, and
distribution of mitochondria has been reported in post-mortem
prefrontal cortex of participants with bipolar disorder compared
to healthy controls (54). There is a shift toward glycolysis
within the mitochondria which is associated with an impairment
of oxidative phosphorylation with lactate accumulation and
decreased energy production (55).
Accumulating evidence suggests that differences in
mitochondrial abundance, function, and morphology are
associated with the onset and pathophysiology of schizophrenia
(56, 57). Post-mortem studies of schizophrenia patients
have reported region-specific differences in mitochondrial
abundance, localization, size, and function across a number of
cell types and brain regions [see Roberts (58) for review].
There is also some evidence to suggest a link between
schizophrenia symptoms and mitochondrial pathology in
the periphery, for example altered microstructure as well as
a decreased density of mitochondria in blood lymphocytes,
Frontiers in Psychiatry | www.frontiersin.org
The Neuroreceptor Profile of Mangosteen
Pericarp Extract
Studies have demonstrated that α- and γ-mangostin have antihistaminergic properties and can selectively block serotonin type
2A (5-HT2A ) receptors in rabbit aorta, a pathway that is a
feature of some atypical antipsychotics (96, 97). Furthermore,
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Therapeutic Potential of Mangosteen Pericarp
TABLE 1 | Summary of neurobiological activity of Garcinia mangostana Linn. (mangosteen).
Paper
Mangosteen compound
Pathway/marker
Method
Interpretation
Marquez-Valadez et al.
(72)
α-mangostin
↓TBARs
↓ mitochondrial dysfunction
Rats received pro-oxidant
agents: ferrous sulfate,
quinolinic acid and 3-NP
(n = 60)
Antioxidant properties,
reduced mitochondrial
dysfunction
Marquez-Valadez et al.
(73)
α-mangostin CH2Cl2–MeOH
(dichloromethane) solution extraction
↓GSH
↓GPx
∼ Glutathione S-transferase
In vitro Rats administered
ferrous sulfate, or 3-NP, in
addition to α-mangostin and
compared to control of
only α-mangostin
Selective modulation of
GSH system,
antioxidant properties
Moongkarndi et al. (65)
α-mangostin Comparing ethyl acetate
vs. water extract
↓DPPH (↑ROS scavenging; water
extract only)
↓ cancer cell production
In vitro Breast cancer
(SKBR3) cells
Antioxidant properties
Lee et al. (74)
α-mangostin
↓Bcl-2
↑Bax
↓MAPk and ERK pathways,
↑apoptosis
In vitro—tongue carcinoma
cells
Yang et al. (67)
7-O-Demethyl mangostanin
↑apoptosis
In vitro Cancer cells
Shin-Yu et al. (75)
α-mangostin
↓TBARs
↑ GSH, GPx, glutathione reductase,
SOD, and catalase
In vitro. High fat diet with
mangosteen vs. High fat
diet without mangosteen
and compared to regular
diet control.
Antioxidant properties
Oberholzer et al. (76)
Mangosteen pericarp extract
↓ hippocampal lipid peroxidation
In vivo: Flinders sensitive line
rats, compared with
imipramine (tricyclic
antidepressant)
Antioxidant properties
Harvey et al. (77);
Lotter et al. (78)
Raw mangosteen pericarp (50 mg/kg)
↓IL-6 and TNF-α
↓ cortico-striatal lipid peroxidation
In vivo inflammatory rat
model of schizophrenia cf.
haloperidol
Antioxidant and
Anti-inflammatory
properties
Wang et al. (66)
α-Mangostin, 8-Deoxygartanin,
Gartanin, Garciniafuran, Garcinone C,
Garcinone D, and γ-Mangostin
↓β-amyloid build up
↓ DPPH ↑ROS scavenging (↓
oxidative stress)
↑neuroprotective properties
In vitro
Antioxidant and
Neuroprotective
properties
Catorce et al. (79)
α-Mangostin
↓IL-6 and COX-2
∼IL-β and TNF-α,
In vivo 18 mice with LPS
induced neuroinflammation.
Anti-inflammatory
properties
Gutierrez-Orozco et al.
(80)
α-mangostin
↓IL-8 and TNF-α
↑ TNF-α in monocyte-derived
macrophages cells
In vitro. LPS-induced
inflammation in human cells.
Anti-inflammatory
properties
Tewtrakul et al. (81)
Mangosteen pericarp
(ethanoic extract) α-mangostin
γ-mangostin
↓NO, PGE2 , TNF-α, IL-4
↓iNOS (α- and γ-mangostin)
↓ COX-2 (α-mangostin only)
In vitro. LPS-induced
inflammation in murine
RAW264.7 macrophage
cells.
Anti-inflammatory
properties
Chen et al. (82)
α- and γ-mangostin (ethyl acetate
extract)
↓NO, PGE2
↓ iNOS
∼ COX-2
In vitro. LPS-induced
inflammation in murine
RAW264.7 macrophage
cells.
Anti-inflammatory
properties
Cho et al. (68)
Mangostenone F
↓ NO, TNF-α, IL6 and IL-1β,
↓ iNOS
↓ NF-κB (via p65 and IκB-α)
↓ MAPK (vis AP-1)
In vitro. LPS-induced
inflammation in murine
RAW264.7 macrophage
cells.
Anti-inflammatory
properties
Bumrungpert et al. (83)
α- and γ-mangostin
↓IL-6, IL1β, interferon-γ and TNF-α
↓ MAPK, NF-κB
In vitro
Anti-inflammatory
properties
Hu et al. (84)
α-mangostin (1, 10, and 100 nM).
↓ IBA-1 and iNOS production
↓ H2 O2 (reduced ROS)
↑ Dopamine uptake
In vitro—wild-type
Sprague-Dawley rat cells
treated with α-synuclein
induced inflammation.
Anti-inflammatory
properties
Weecharangsan et al.
(85)
Mangosteen pericarp extracted by:
Water vs. 50% ethanol vs. 95%
ethanol vs. ethyl acetate
↓ DPPH free radical scavenging.
↓NG108-15
(water and 50% ethanol superior)
↓ H2 O2 Cell death
In vitro NG108-15 cells
treated with H2 O2
Neuroprotective and
antioxidant properties
(Continued)
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TABLE 1 | Continued
Paper
Mangosteen compound
Pathway/marker
Method
Interpretation
Janhom et al. (86)
α-mangostin
↓ apoptosis and ROS
↓Bax, Bax/Bcl-2, p53, and caspase 3
In vitro human SH-SY5Y
neuroblastoma cells in an
MPP+ Parkinson’s Disease
like state
Neuroprotective and
anti-apoptotic
properties
Phyu and Tangpong
(87)
Xanthones from aqueous extract of
mangosteen pericarp
↓acetylcholinesterase
↓MDA
N = 42 lead-poisoned mice
Antioxidant and
neuroprotective
properties
Sattayasai et al. (88)
Mangosteen pericarp extract
↓ROS
In vivo and In vitro memory
impaired mice
Antioxidant and
neuroprotective
properties
Wihastuti et al. (89)
Mangosteen pericarp extracted by
ethanol solution
↓ VEGFR-1, NF-κB
In vivo 20 male
rats-−5 groups:
Normal diet
High cholesterol diet
High cholesterol and
mangosteen pericarp 200
mg/kg
High cholesterol and
mangosteen pericarp 400
mg/kg
High cholesterol and
mangosteen pericarp
800 mg/kg
Neurogenesis,
anti-oxidative and
anti-inflammatory
properties
Huang et al. (90)
Mangosteen pericarp extract
∼ JNK, ERK
↓ROS, COX-2 and IL-6
↑GSH, brain derived neurotropic
factor, and serotonin
In vivo and In vitro: 3xTg-AD
mouse model of Alzheimer’s
Disease. Hippocampal cells
and serum.
Antioxidant and
neuroprotective
properties
Jariyapongskul et al.
(91)
α-mangostin
↓ VEGF, TNF-α, MDA, and fasting
glucose
In vivo: 56 type 2 diabetic
rats, retinal blood.
Neurogenesis,
anti-inflammatory,
antioxidant, and
anti-hyperglycemic
properties
Aisha et al. (92)
combination of α- and γ-mangostin
(81 and 16%, respectively)
↑caspases-3/7
↑MAPK, ERK and p52
In vitro: human colon cancer
cells
Activate mitochondrial
pathway of apoptosis
Tang et al. (93)
Commercially available Mangosteen
juice (Mangosteen PlusTM with
Essential Minerals® ), main xanthone:
β-mangostin
↓IL-1α ↓CRP
∼ IL-β and IL-2
Randomized, double-blind,
placebo-controlled trial
(n = 60)
Anti-inflammatory
properties
Xie et al. (94)
Mangosteen-based drink (Verve® )
↓Peroxyl radical scavenging capacity
(antioxidant activity)
↓CRP
∼ IL- 1α, IL- 1β, and IL- 2
Randomized, double-blind,
placebo-controlled trial
(n = 60)
Antioxidant and
anti-inflammatory
properties
Udani et al. (95)
Mangosteen juice from whole fruit,
combined with other fruit juices
(XanGo JuiceTM )
↓CRP (18 oz/day group only),
IL-12p70
↓ Body mass index (for 6oz group
only)
∼ENA-78 and lipid peroxidation
Randomized, double blind
placebo-controlled pilot of
obese participants (n = 40)
Anti-inflammatory
properties
↑ Bcl-2
3-NP, 3-nitropropionic acid; Bcl-2, B-cell lymphoma 2; COX-2, cyclooxygenase-2; CRP, C-reactive protein; DPPH, 1,1-diphenyl-2-picrylhydrazyl; ENA, epithelial Cell-Derived NeutrophilActivating Protein; ERK, extracellular Signal-regulated Kinase; GPx, glutathione peroxidase; GSH, glutathione peroxidase; H2 O2, hydrogen peroxide; IBA-1, ionized calcium binding
adaptor molecule 1; IL, interleukin; iNOS, inducible nitric oxide synthase; JNK, c-Jun N-terminal; LPS, lipopolysaccharide; MAPK, Mitogen-activated protein kinases; MDA,
malondialdehyde; NF-kB, nuclear factor kappa B; NO, nitric oxide; PGE2, prostaglandin E2 ; ROS, reactive oxygen species; SOD, superoxide dismutase; TBARS, thiobarbituric acidic
reactive substances; TNF-α, tumor necrosis factor; VEGF, vascular endothelial growth factor.
Antioxidant Properties of Mangosteen
Pericarp
α- and γ-mangostin have demonstrated some inhibitory effects
on cyclic adenosine monophosphate (cAMP) phosphodiesterase
(98, 99), a property shared with another putatively psychoactive
plant, sceletium tortuosum (100). Indeed, cyclic adenosine
monophosphate cAMP phosphodiesterase inhibitors, such as
rolipram, have antidepressant and anti-inflammatory activity
(101). Targeting these pathways is implicated in antidepressant
and antipsychotic treatments (97).
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Marquez-Valadez et al. (72) explored α-mangostin as a
treatment to reduce oxidative damage in homogenized rat brain
tissue (cerebellum removed) and synaptosomal P2 fractions,
in a model of neurotoxicity. Following administration of
various neurotoxins, viz. ferrous sulfate, quinolinic acid, and
3-nitropropionic acid (3-NP), administration of α-mangostin
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Therapeutic Potential of Mangosteen Pericarp
FIGURE 1 | Proposed neurobiology of bipolar disorder and schizophrenia and associated mechanisms of mangosteen pericarp (purple italics). These major
psychiatric disorders have been shown to have aberrations in oxidative biology, mitochondrial function and neurogenesis/apoptosis. The purple italicized text indicates
the points at which mangosteen pericarp has mechanistic actions that may benefit these disorders. Complexes I, II, II, and IV; CoQ, Coenzyme Q; C, cytochrome C;
Fe2+ , ferrous ion; GPx, glutathione peroxidase; GSH, reduced glutathione; GSSG, oxidized glutathione; H2 O, water; H2 O2, hydrogen peroxide; NADH, nicotinamide
adenine dinucleotide (phosphate); NO, nitric oxide; Nox, NADH, Reduced Nicotinamide adenine; O2, Superoxide anion; OH, Hydroxyl radical; ONOO, peroxynitrite;
SOD, Superoxide dismutase.
any of the groups. Due to the varying effects of α-mangostin
on redox activity, the authors concluded that α-mangostin was
selectively modulating the GSH system to preferentially raise
protective GSH levels, thereby highlighting a putative mechanism
for α-mangostin’s antioxidant properties.
Moongkarndi et al. (65) compared 25 µg/ml doses of purified
α-mangostin with mangosteen pericarp extracts using two
different solvents—ethyl acetate and water to explore the
bioactive components in SKBR3 cells, a breast cancer cell line.
The ethyl acetate-soluble extract, noted to contain low polar
constituents, appeared to inhibit cancer cell proliferation. The
purified α-mangostin and the water extract of mangosteen
pericarp that contains high polar constituents both demonstrated
antioxidant activity. In particular, the water-soluble extract
demonstrated the most pronounced free-radical scavenging
activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH). It was
concluded that purified α-mangostin showed superior activity
in reducing cytotoxicity, apoptosis, and antioxidative activity
in cancer cells, compared to the water extract. Previous cancer
studies have shown mangosteen pericarp to be pro-apoptotic in
certain laboratory conditions [e.g., Lee et al. (74) and Yang et al.
(67)]. Differences in tissue type (e.g., cancer cells), dosing and
other parameters complicate the interpretation of these studies
within the context of neurobiology. Similarly, biological agents
(25–500 uM) resulted in a reduction in toxin-induced oxidative
stress as measured by TBARs formation, with all doses
being effective. α-Mangostin also reduced quinolinic acid and
3-nitropropionic acid induced mitochondrial dysfunction as
assessed by 3-(2,5-dimethylthiazol-1-yl)2,5-diphenyltetrazolium
(MTT) reduction. It was concluded that α-mangostin was
effective as a broad-spectrum antioxidant.
Marquez-Valadez et al. (73) then examined α-mangostin
modulation of the GSH system and antioxidant properties in
rat brain tissue prepared as above (72). Rats (n = 4–5 per
group) received varying doses of α-mangostin (10, 25, and
50 µM) either alone or with ferrous sulfate or with 3-NP.
Synaptosomal fractions were analyzed for glutathione (GSH),
glutathione peroxidase GPx, and glutathione S-transferase (GST)
levels. All doses of α-mangostin reduced GSH levels compared to
controls when tested alone (no ferrous sulfate or 3-NP). In the
ferrous sulfate studies, α-mangostin at doses of 25 and 50 µM
returned GSH levels to control levels and were significantly
higher than that of the ferrous sulfate group. Similar results were
found with respect to GSH levels following 3-NP challenge for
all doses of α-mangostin. GPx activity was increased only in the
α-mangostin 25 and 50 µM doses compared to controls, but this
effect was lost when administered alongside ferrous sulfate. There
were no differences in glutathione S-transferase activity across
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and 100 µM). Release of PGE2 was significantly inhibited by
all compounds at all doses. Pro-inflammatory cytokine TNF-α
release was inhibited by mangosteen pericarp (10 and 30 µM)
and by α- and γ-mangostin (30 and 100 µM). All extracts
significantly inhibited release of IL-4 (10, 30, and 100 µM).
However, the inhibition of TNF-α and IL-4 were only of
moderate effect. Lastly, inducible iNOS and COX-2 expression
were inhibited by α-mangostin, with γ-mangostin only inhibiting
iNOS. Similar studies found an ethyl acetate extract of α- and
γ-mangostin inhibited LPS induced NO and PGE2 production
and iNOS (but not COX-2) expression in murine RAW264.7
cells (82). Therefore, the authors concluded that mangosteen
pericarp and, in particular, α- and γ-mangostin have potential
anti-inflammatory activity.
Cho et al. (68) also investigated the effects of the xanthone,
mangostenone F, an isolated compound of the mangosteen
pericarp, on LPS-induced inflammation in murine RAW264.7
macrophage cells. The RAW264.7 cells were pre-treated with
mangostenone F (0, 10, 20, 30, 40, 60, 80, and 100 µM) for
24 h. Mangostenone F significantly inhibited the production of
NO in a dose dependent manner by decreasing the expression
of iNOS. To explore the effects of mangostenone F on the
pro-inflammatory cytokines TNF-α, IL6, and IL-1β, the cells
were pre-treated at doses of 20, 40, and 60 µM. There was a
dose dependent reduction in all pro-inflammatory cytokines by
mangostenone F. There was also a dose dependent reduction in
NF-κB DNA binding activity, via p65 and IκB-α. Lastly, AP-1
reporter activity was inhibited by the mangostenone F, suggesting
suppression of the MAPK signaling pathway. Therefore, it
was suggested that the anti-inflammatory response was via
suppression of MAPK and NF-κB activation. In agreement
with afore-noted findings, an in vitro study in human cells
examined whether α- and γ-mangostin could reduce obesityassociated inflammation (83). The study found that the reduction
in inflammation was possibly due to the mangosteen pericarp
extract preventing MAPK and NF-κB activation which in turn
reduced levels of IL-6, IL-1β, interferon-γ and TNF-α (83).
A study investigating a cell culture model of Parkinson’s
disease included investigations of NO and iNOS response
to α-mangostin (84). There was a significant dose-dependent
reduction of iNOS by α-mangostin, showing the effects of
α-mangostin to reduce immunologically-induced NO release.
The authors also explored the NF-κB signaling pathway
via IκB-α and p65 in the cytosol and found α-mangostin
had a concentration dependent beneficial effect on these
pathways. Therefore, this may be a pathway for α-mangostin
reduction of pro-inflammatory cytokines and NO production.
In addition, they noted that ROS was significantly reduced
by α-mangostin in a dose dependent manner in microglial
cells, demonstrated by reduction of H2 O2 . The authors posited
that this may be due to α-mangostin targeting NADPHoxidase (NOX). Reduced dopamine uptake induced by αsynuclein was also increased by α-mangostin, with α-mangostin
significantly protecting dopamine neurons from apoptosis in
a dose-dependent manner. It was concluded that α-mangostin
has demonstrated capacity as a neuroprotective agent in
neurodegenerative disorders via microglial activation pathways
often have both beneficial and detrimental effects, dependent
on these factors. For example, in an environment of oxidative
stress, N-acetylcycteine has beneficial effects but can be toxic
(due to oversupply of cysteine) under conditions of normal redox
homeostasis (102).
Shin-Yu et al. (75) fed mangosteen pericarp extract (85% αmangostin; 25 mg/day) to rats in addition to a high-fat diet and
compared changes in oxidative stress and mitochondrial activity
among rats fed a high fat diet and a group on AIN-93M control
diet. Results showed significantly reduced liver TBARS levels in
mangosteen fed rats compared with the high-fat diet group (and
were similar levels to controls). The authors posited that the
reduction in oxidative stress and increased cellular protection
(measured by TBARS) could be due to mangosteen pericarpinduced increases in cellular oxidative defense mechanisms. All
antioxidant enzymes explored were significantly higher in the
mangosteen pericarp extract group than that described in the
high-fat diet group (i.e., GSH, GPx, glutathione reductase, SOD,
and catalase; CAT). This study also suggested the potential utility
of mangosteen pericarp in a population that has high co-morbid
obesity and metabolic disorders (30).
Anti-inflammatory Properties of
Mangosteen Pericarp
Catorce et al. (79) explored the anti-inflammatory properties
of α-mangostin in a murine model. They administered
lipopolysaccharide (LPS) to mice (n = 18) to induce
neuroinflammation. Results showed that oral gavage
administration of α-mangostin significantly inhibited the
LPS-induced increase in IL-6 in the brain. The levels of other
inflammatory cytokines studied (IL-1β and TNF-α) were not
affected by α-mangostin administration. This study further
demonstrated α-mangostin-associated reduction in the levels of
the inflammation-associated enzyme COX-2, in the brain.
The anti-inflammatory effects of α-mangostin have also
been observed in human cells challenged with LPS (80), where
α-mangostin was found to significantly reduce the release of
pro-inflammatory cytokines IL-8 and TNF-α. Interestingly,
these results were only true for THP-1 (monocyte-like
leukemia), HepG2 (hepatocellular carcinoma), and Caco-2
HTB-37 (colorectal adenocarcinoma with enterocyte-like
phenotype) cells, but not for other cell-lines such as monocytederived macrophages. These results suggest the effects of
α-mangostin may differ depending on cell type. In contrast, αmangostin stimulated the release of TNF-α in monocyte-derived
macrophages cells.
In a study by Tewtrakul et al. (81), an ethanolic extraction
of mangosteen pericarp and α- and γ-mangostin isolations were
administered to murine RAW264.7 macrophage cells to explore
the pathway of anti-inflammatory action of the compounds.
LPS was first used to produce an increase in inflammatory
molecules NO, prostaglandin E2 (PGE2 ), TNF-α, and IL-4, with
mangosteen pericarp and its isolates administered in different
concentrations (0, 0.3, 1, 3, 10, 30, and 100 µM). Release of
NO was significantly inhibited by α-mangostin (3, 10, 30, and
100 µM), and by γ-mangostin and mangosteen pericarp (10, 30,
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mg/kg) was most effective in terms of anti-oxidative and antiinflammatory activities.
Huang et al. (90) investigated the effects of a mangosteen
pericarp extract rich in xanthones and polyphenols in a 3xTg-AD
mouse model of Alzheimer’s Disease to explore neuroprotective
and anti-apoptotic properties. Mice received the mangosteen
pericarp extract in addition to a regular diet and were compared
to a control group fed only the regular diet. Analyses were
conducted both in vitro in hippocampal cells and in vivo with
respect to serum markers. In hippocampal cells, no differences
in JNK or ERK pathways were noted in the hippocampal cells,
although an increase in GSH levels was observed. However, the
results in serum showed a reduction in ROS, cyclooxygenase-2
(COX-2), and IL-6, as well as an increase in GSH and serotonin.
Lastly, mice treated with the mangosteen pericarp dietary
supplement presented with reduced cognitive impairment and
spatial memory retrieval deficit compared to untreated controls.
It was concluded the mangosteen pericarp extract demonstrated
antioxidative, anti-inflammatory and neuroprotective properties.
To test for anti-inflammatory, antioxidant, and antihyperglycemic properties of the mangosteen pericarp,
Jariyapongskul et al. (91) investigated the effects of α-mangostin
on inflammatory cytokines, oxidative stress markers, and
neurotrophins in the retina of streptozotocin-induced diabetic
mice. In an in vivo study, within 8 weeks of intraperitoneally
injecting rats with streptozotocin, α-mangostin was administered
via gavage to type-2 diabetic rats (n = 56). The treatment with
α-mangostin reduced ocular degeneration, a manifestation
that can occur in early stages of type 2 diabetes. The authors
found that α-mangostin treatment reduced levels of VEGF,
TNF-α, and MDA. Whilst α-mangostin significantly reduced
fasting glucose levels of the diabetic rats, there was no difference
between non-diabetic rats and control rats, suggesting a role in
glucose regulation. Whilst this study illustrates some promise as
a treatment option in type 2 diabetes, further research is needed
to determine if it may also be a preventative strategy for the
disorder and for the development of vascular abnormalities.
Due to the relationship between general medical conditions,
including metabolic disorders such as diabetes and bipolar
disorder and schizophrenia, this study highlights the potential
symbiosis of treating the disorders together (41).
of neuroinflammation and serves as an anti-inflammatory and
antioxidant agent.
Production of NO through iNOS and inflammatory process
have been implicated in both psychosis and depression (23,
103). It is relevant to note that diverse antidepressants
(104) and antipsychotics (105) target the NO system, while
selectively targeting the NO system has been implicated in
the antidepressant and antipsychotic actions of methylene
blue (62, 63).
Neuroprotective and Anti-apoptotic
Properties of Mangosteen Pericarp
Effective neuroprotective compounds will impede or stop the
progression of an illness (44). Neuroprotective compounds can
modulate antioxidant systems (85) and inflammatory systems
(44). Weecharangsan et al. (85) investigated the neuroprotective
properties of four mangosteen pericarp extractions: distilled
water, 50% ethanol, 95% ethanol or ethyl acetate. Each treatment
group was assessed for antioxidant activity through DPPH free
radical scavenging and for neuroprotective activity in NG10815 cells treated with hydrogen peroxide (H2 O2 ). Both the water
and 50% ethanol extracts dose-dependently exhibited superior
free radical-scavenging activities and inhibited H2 O2 -induced
cell death, compared to the other extracts.
Xanthones extracted from mangosteen pericarp (aqueous
extraction) were explored for neuroprotective properties in
lead-poisoned mice (87). Lead results in cognitive impairments
by inhibiting antioxidant function and increasing free radical
production. This is achieved by lead competitively inhibiting
calcium binding sites on acetylcholinesterase, leading to oxidative
damage. Xanthone treatment (administered orally, in drinking
water) had a significant dose-dependent effect on increasing
acetylcholinesterase activity in the blood and brain of lead-treated
mice. Oxidative stress in the mangosteen pericarp treatment
groups was significantly reduced as shown by MDA reduction.
Thus, the authors concluded that the xanthone component
of mangosteen pericarp has neuroprotective properties while
reducing cognitive impairment by inhibiting oxidative stress.
In addition to these results, depressive-like behavior in leadintoxicated mice as demonstrated using the forced swim test was
significantly reversed by the xanthone extract group compared to
control groups (87).
In an in vivo study by Wihastuti et al. (89), the effect of
mangosteen pericarp on neurogenesis was explored. Varying
doses (200, 400, and 800 mg/kg) of mangosteen pericarp
extracted by an ethanol solution were trialed via gavage in
rats fed a high-cholesterol diet (and compared to a normal
diet, negative control group and high-cholesterol diet, positive
control group). The VEGF receptor 1 and NF-κB were
measured. VEGF receptor 1 is expressed in inflammatory
cells including macrophages and monocytes. The protein
NF-κB responds to free radicals and is involved in the
production of cytokines and influences synaptic plasticity and
memory. Mangosteen pericarp extract significantly inhibited
the formation of VEGF receptor 1, and reduced NF-κB,
iNOS, H2 O2, and H1F1-α expression. The highest dose (800
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Mitochondrial Enhancing Properties of
Mangosteen Pericarp
Many of the biological targets for mangosteen pericarp and
its isolates involve the mitochondria. For example, when
mitochondrial dysfunction was induced in vitro via 3-NP,
increased oxidative stress was mitigated by α-mangostin (72, 73,
75). It was further suggested that α-mangostin may modulate
apoptosis associated with mitochondrial pathways (86). This
shows how complex and inter-related the mitochondrial,
oxidative stress, and inflammation pathways are, and suggests the
potential of treatments that can target these pathways.
To better inform the therapeutic potential of mangosteen
pericarp in psychiatry, we investigated other fields where
mangosteen pericarp has been shown to have relevant actions.
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Therapeutic Potential of Mangosteen Pericarp
correction of disordered brain monoamines as well as the
restoration of cellular damage brought on by oxidative stress
(76). Interestingly, disordered redox status is known to mediate
changes in brain monoamines (107) that in turn can drive
changes in behavior (108).
Cancer cells studies can demonstrate the relationship between
apoptosis and the mitochondria, relevant to psychiatry. Aisha
et al. (92) explored the anti-colon cancer effects of a combination
of α- and γ-mangostin (81 and 16%, respectively) through in
vitro and in vivo experiments. For the in vitro study, human
colon cancer cells were treated with the xanthone extract of
mangosteen pericarp and α-mangostin and compared to the
chemotherapy medication, cisplatin as a positive control. The
treatment with xanthones killed the cancer cells and did so at
a lower concentration than cisplatin. Their findings suggested
an action mediated by enhancing executioner caspases-3/7 and
by activating the initiator caspase-9 leading to apoptosis of
cancer cells. The authors postulated that mitochondria-mediated
cytotoxicity was involved. Apoptosis was further analyzed
through the upregulation of the MAPK/ERK and p53 pathways,
showing potent, selective, and dose dependent cytotoxicity due
to the enhancement and activation of mitochondrial pathways
of apoptosis.
This review outlines pathways implicated in oxidative
stress, inflammation and mitochondrial function. Importantly,
these pathways are also directly or indirectly linked to
monoamine release and/or function. As previously mentioned,
α-mangostin has a tricyclic structure (64) which is relevant
to existing medications (e.g., tricyclic antidepressants) which
block serotonin re-uptake. However, we believe that because
mangosteen has other important biological properties in addition
to potentially modulating monoamines, mangosteen pericarp
may be a novel and indeed highly efficacious adjunctive therapy.
Mangosteen Pericarp as an Antipsychotic
Concerning schizophrenia, preclinical findings in a maternal
immune-activation (MIA) rat model of schizophrenia found that
chronic oral dosing of haloperidol (2 mg/kg for 14 days) and
raw mangosteen pericarp (50 mg/kg for 14 days) were equally
effective in reversing MIA-induced deficits in sensorimotor
gating and depressive-like behavior, with haloperidol plus
mangosteen showing a more pronounced response (77, 78).
MIA-induced elevations in IL-6 and TNF-α levels and corticostriatal lipid peroxidation were reversed by haloperidol,
mangosteen, and haloperidol plus mangosteen. The authors
suggested that, at least in this model, depressive manifestations
are more responsive to mangosteen than sensorimotor gating
deficits, implicating promise in the management of mood-related
deficits in schizophrenia (77, 78).
Mangosteen Pericarp as a Treatment for
Neurodegenerative Disorders
The neuroprotective effects of α-mangostin were investigated in
a cellular model of Parkinson’s disease (86) by exposing human
SH-SY5Y neuroblastoma cells to 1-methyl-4-phenylpyridinium
(MPP+ ). α-mangostin was then administered for 24 h (doses 2.5,
5, 10, 20, and 40 µM). Doses of 20 and 40 µM α-mangostin
induced significant loss of cell viability and were excluded from
further experiments. All other doses of α-mangostin significantly
decreased ROS induced apoptosis in an MPP+ model designed
to trigger apoptosis. α-mangostin also significantly reduced
MPP+ induced Bax, Bax/Bcl-2, p53, and caspase-3 expression.
Therefore, the study suggests the ability of α-mangostin to reduce
apoptosis, potentially via mitochondrial pathways and reduction
of oxidative stress. Of interest, Parkinson’s disease has been
viewed as a biological parallel to bipolar disorder because of the
dopaminergic pathology and the cyclical nature of depression
which occurs in the on-off phenomenon in Parkinson’s disease
(11). In fact, novel methylene blue analogs which inhibit nitric
oxide synthase (NOS) and inhibit monoamine oxidase have been
synthesized to address such a comorbid condition by virtue of
their neuroprotective actions and restoration of mitochondrial
function (62).
In the study utilizing a Parkinson’s disease model, the
effects of α-mangostin on neuroinflammation via the microglial
activation pathway was investigated (84). In this study, wildtype Sprague-Dawley rat cells were treated with α-synuclein to
induce inflammation and then treated for 24 h with α-mangostin
at 1, 10, and 100 nM doses. Results showed a significant dose
dependent reduction in pro-inflammatory cytokines IL-6, IL1β, and TNF-α in the α-mangostin treated group. The 100 nM
dose of α-mangostin reduced microglial activation by inhibiting
production of a marker of ionized calcium binding adaptor
molecule 1(IBA-1), a microglial specific protein.
THERAPEUTIC POTENTIAL OF
MANGOSTEEN PERICARP
Mangosteen Pericarp as an Antidepressant
Recent preclinical evidence has demonstrated the antidepressant
and memory enhancing actions of mangosteen pericarp, together
with a suppression of hippocampal lipid peroxidation, in a
rodent model of depression (76). In this study, an extract of
mangosteen pericarp at an acute dose of 50 mg/kg administered
by oral gavage was found to be an effective antidepressant
in Flinder’s Sensitive Line rats (a model of depression). The
raw pericarp extract contained predominantly α- and γmangostin. A 14-day treatment regimen of mangosteen pericarp
extract (50 mg/kg per day) displayed sustained antidepressant
and pro-cognitive effects in the forced swim test and novel
object recognition test, respectively, while demonstrating parity
with the reference tricyclic antidepressant, imipramine (76).
Behavioral and regional brain monoamine assessments suggested
a more prominent serotonergic action for mangosteen pericarp
extract as opposed to the noradrenergic action of imipramine,
with both imipramine and mangosteen pericarp extract reversing
hippocampal lipid peroxidation in rats. Indeed, the hippocampus
is highly vulnerable to oxidative stress while being a key factor
in memory. Moreover, both memory and hippocampal structure
and function are compromised in patients with depression
(106). This work confirms the antidepressant activity of raw
mangosteen pericarp, while linking this therapeutic action to
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Therapeutic Potential of Mangosteen Pericarp
A randomized, placebo-controlled, double blind trial studied
the effects of 30 days of treatment with a commercially available
mangosteen juice (Mangosteen PlusTM with Essential Minerals R ;
mixed with vitamins A, B-6, C, D, E, selenium, folate, and
thiamine; 59 ml) on immunity in 60 healthy human participants
aged 40–60 years (93). Fructose liquid (59 ml) was used as a
placebo control. The most prominent bioactive substances in
the juice were β-mangostin and catechins. The mangosteen
juice group had significantly higher levels of inflammatory
cytokines IL-1α and IL-1b compared to placebo. To note, antiinflammatory medications are adept at reducing heightened
inflammation. If there is no inflammation in the system then
adding anti-inflammatories may be detrimental, or even toxic
(e.g., as with N-acetylcycteine (102). The mangosteen juice
group also reported a reduction in inflammatory biomarker Creactive protein (CRP) compared to baseline. There were no
significant group differences with respect to IL-1β and IL-2.
Interestingly, all participants in the mangosteen juice group selfreported an increase in subjective health status compared to the
placebo group.
A randomized, double-blind, placebo controlled clinical
trial explored antioxidant and anti-inflammatory biomarkers
in healthy adults who were administered a mangosteen-based
drink (94). Whilst mainly containing mangosteen, the drink also
included vitamins, green tea, aloe vera, and a caffeinated energy
blend. A total of 60 adult participants (30 men, 30 women) were
administered 245 ml of either the mangosteen-based drink or
placebo (fructose liquid) daily for 30 days together with preand post-administration blood analyses. After 30 days, results
showed significantly more antioxidant activity, as measured by
an increase in the peroxyl radical scavenging capacity, in the
mangosteen-based drink group compared to the placebo arm.
CRP levels significantly decreased in the mangosteen-based drink
group and were not changed in the placebo group. There was no
significant change in immunity markers IgA, IgG, IgM, C3, C4;
and no significant change in inflammatory markers IL- 1α, IL1β, and IL- 2 across groups and time points.
Udani et al. (95) conducted a randomized, double-blind,
controlled pilot study of commercially available mangosteen juice
(XanGo JuiceTM ), a whole fruit juice blended with other fruit
juices, in obese participants. A combination of fruit juices and
sucrose was used as a control. A total of 40 participants who
agreed to not change any current diet or exercise regimes and
ceased any anti-inflammatory agents completed the study, all
of whom were obese and had an elevated CRP score of ≥3.
This was a 4-arm study: control, 3, 6, or 9 oz XanGoTM juice
whereby participants drank the intervention or control juice
twice a day for 8 weeks. The combination juice used as a control
was added to each of the lower mangosteen doses so each total
individual serving volume was 9 oz liquid. As a result, participant
received total daily doses of XanGOTM juice at 6 oz, 12 oz
or 18 oz, or control juice. Results showed a non-significant
increase in CRP for the placebo group as well as a non-significant
decrease in CRP for all doses of the mangosteen juice. There
was a significant difference between changes in CRP across the
8 weeks in the control and the 18 oz/day group. Changes in
body mass index and body fat were only significantly reduced
Mangosteen pericarp has been investigated as a treatment
for Alzheimer’s disease (66). In one in vitro study, the
seven most common xanthones were isolated (α-mangostin, 8deoxygartanin, gartanin, garciniafuran, garcinone C, garcinone
D, and γ-mangostin) and assessed for their ability to inhibit βamyloid-related cell damage, as well as their metal chelating,
antioxidant and neuroprotective properties in an Alzheimer’s
Disease model (66). Results demonstrated that mangosteen
pericarp reduced β-amyloid build up and reduced glutamateinduced cell damage by scavenging ROS (assessed by DPPH). Of
the isolated xanthones, α-mangostin, gartanin, garcinone C, and
γ-mangostin showed the greatest antioxidant properties.
Similar protective effects of mangosteen pericarp extract were
explored in vitro and in vivo in mice in a study by Sattayasai et al.
(88). Mice were administered scopolamine to induce memory
impairments in an attempt to model the cognitive symptoms
of Alzheimer’s disease through central cholinergic muscarinic
receptor antagonism. Afflicted mice were administered either
mangosteen pericarp extract at 100 mg/kg via oral gavage or
water as a control. Results obtained using the Morris water maze
test for spatial memory and passive avoidance (fear) tests showed
mangosteen pericarp extract protected mice from the memory
degrading effects of scopolamine, leading to improved memory
retention. In the in vitro arm of the study, mangosteen pericarp
was protective against H2 O2 and polychlorinated biphenyl
induced oxidative stress in SK-N-SH (human blastoma cells)
cells pre-incubated with mangosteen pericarp extract as shown
by reduced ROS. This study demonstrated not only the antioxidative and neuroprotective properties of mangosteen pericarp
extract, but also its memory protecting capacity, and thus is
congruent with the in vivo depression model data described in
Flinder’s Sensitive Line rats by Oberholzer et al. (76).
CLINICAL TRIALS OF MANGOSTEEN
PERICARP
Mangosteen pericarp, as well as isolated compounds such as αmangostin, have been demonstrated in both animal and in vitro
studies to favorably modulate pathways relevant to mitochondrial
function, inflammation, and oxidative stress. However, clinical
trials are required to confirm whether these properties are
clinically relevant. The following sections will provide an
overview of the existing clinical trial data and its relevance
to psychiatry, in particular bipolar disorder and schizophrenia.
The behavioral effects of mangosteen pericarp are summarized
in Table 2.
Use of Mangosteen Pericarp in General
Health
Mangosteen pericarp has been investigated in general medicine.
Given these data are predominantly in healthy individuals,
caution needs to be taken regarding the specific applicability
to psychiatric disorders. However, to provide a comprehensive
overview of the potential mechanisms by which mangosteen
pericarp may be beneficial for psychiatric disorders these data
have been included in this review.
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TABLE 2 | Summary of behavioral evidence for Garcinia mangostana Linn. (mangosteen).
Paper
Mangosteen compound
Outcome
Method
Oberholzer et al. (76)
Mangosteen pericarp extract
↓ Depressive-like behaviors,
↑ Recognition memory
In vivo: Flinders sensitive line rats,
compared with imipramine (tricyclic
antidepressant)
Harvey et al. (77);
Lotter et al. (78)
Raw mangosteen pericarp (50 mg/kg)
↓ Depressive-like behaviors
In vivo inflammatory rat model of
schizophrenia cf. haloperidol
Phyu et al. (87)
Xanthones from aqueous extract of
mangosteen pericarp
↓ Depressive-like behaviors
In vivo lead-poisoned mice (n = 42)
Sattayasai et al. (88)
Mangosteen pericarp extract
↑ Memory
In vivo and In vitro memory impaired
mice
Huang et al. (90)
Mangosteen pericarp extract
↓ Cognitive impairment and spatial memory
recall
In vivo and In vitro: 3xTg-AD mouse
model of Alzheimer’s Disease.
Hippocampal cells and serum.
Chang et al. (109)
Mangosteen-based juice blend (containing
305 mg of α-mangostin and 278 mg of
hydroxycitric acid)
∼ Physical fatigue, heart rate,
↓ Mental fatigue
Randomized, double-blind,
placebo-controlled trial healthy adults
(n = 12)
Watanabe et al. (110)
Mangosteen pericarp (40% α- and
γ-mangostin)
↓ Insulin levels and insulin resistance
∼ Glucose levels, weight loss, waist
circumference, body composition, LDL, HDL,
triglycerides
Randomized controlled pilot study
(n = 20)
Kudiganti et al. (111)
Meratrim (Sphaeranthus indicus flower and
mangosteen pericarp at 3:1 ratio)
↓ Total mood disturbance
Randomized, double-blind,
placebo-controlled trial in healthy
overweight subjects (n = 60)
Laupu (112)
1,000 mg/day Mangosteen pericarp
↓ Depressive-like behaviors, positive and
negative symptoms of schizophrenia,
↑ Life satisfaction and general functioning
Randomized, double-blind,
placebo-controlled trial in
schizophrenia/schizoaffective
population (n = 80)
in the 6 oz/day group compared to placebo. There were no
significant differences between groups for lipid peroxidation and
Epithelial Cell-Derived Neutrophil-Activating Protein (ENA)-78.
There was a significant reduction of IL-12p70 levels across time
in all active groups.
Due to the association between ROS and fatigue during
exercise, Chang et al. (109) trialed mangosteen in 12 healthy
adults. Participants were randomized to receive an acute dose of
either a mangosteen juice blend or a diluted drink that replaced
50% mangosteen juice with water. There was no significant
difference in time to exhaustion or other measures of physical
performance (e.g., heart rate).
Mangosteen pericarp has been trialed in a combination
treatment for weight loss in two human trials (111, 113) and
mangosteen pericarp alone in one insulin resistance study (110)
and all showed some promising results. In a population of
obese female adults with insulin resistance (but not diabetes)
mangosteen pericarp was trialed as a treatment for insulin
resistance, reducing inflammatory markers and participant
weight in a 26-week randomized controlled pilot study (110).
All participants in the study (n = 20) received a lifestyle
intervention delivered by a dietician focusing on physical
activity and caloric restriction. Participants were randomized to
receive either 400 mg/day mangosteen pericarp (40% α- and
γ-mangostin) in addition to the intervention or no additional
study medication. Participants in the mangosteen pericarp group
showed significantly reduced insulin levels and demonstrated
reduced insulin resistance. However, there were no significant
Frontiers in Psychiatry | www.frontiersin.org
differences in body fat percentage, waist circumference, or
weight loss between participants in the mangosteen pericarp
arm and control arm. There were no significant differences
in glucose markers or in cholesterol markers and triglycerides
levels when comparing the mangosteen pericarp and control
groups. This study would have benefited from a placebo
control to include blinding and reduce placebo response from
the mangosteen administration. Given the lack of placebo,
small sample size and female only sample, results from this
study are cautiously interpreted as showing some efficacy in
reducing insulin and insulin resistance and appears to be
well tolerated.
These trials provide preliminary clinical evidence to suggest
that mangosteen juice and mangosteen pericarp extract can alter
inflammatory markers in vivo. However, due to most studies
providing mangosteen in combination with other bioactive
compounds, further trials are required to determine the effect
of mangosteen pericarp or mangosteen juice as a standalone
intervention for inflammation. Furthermore, the small sample
sizes and predominately healthy populations included in these
studies suggest that they may be underpowered.
It has been highlighted that the anti-inflammatory and
antioxidant properties of varying extracts of mangosteen pericarp
can also help to reduce co-morbid metabolic disorders common
in those with bipolar disorder (114). Shandiz et al. (114) discussed
this in their review on the metabolic effects of mangosteen
pericarp extract in vitro and in vivo. Their review concluded that
the reduction in metabolic disorders may occur by inhibiting
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Ashton et al.
Therapeutic Potential of Mangosteen Pericarp
Safety Profile of Mangosteen Pericarp
inflammatory cytokines, reducing body weight and fat storage,
and altering glucose metabolism.
Whilst current clinical evidence is limited, several studies
demonstrate that mangosteen pericarp appears to have a good
safety profile and is well-tolerated. In animal models, mangosteen
pericarp has been shown to reduce blood glucose levels,
suggesting it could be used as a treatment for diabetes mellitus
and that consumption of mangosteen pericarp may need to
be supervised in patients undergoing insulin therapy (91, 115).
In the insulin resistance study (110), gastrointestinal upset
were the only reported adverse events and this occurred across
both groups.
Suthammarak et al. (116) investigated the safety and
antioxidant effects of mangosteen pericarp. Participants
were orally administered polar (water-soluble) fractions of
mangosteen pericarp in capsule form for 24 weeks. For the
first three months, participants weighing under 55 kg received
a 220 mg dose and those over 55 kg received 280 mg. After 3
months, all participants had their doses doubled. Participants
were monitored at weeks 0, 1, 4, 12, 16, and 24. The study
was limited by the lack of a placebo control group and a small
sample size (n = 11) making it difficult to relate the emergence
of adverse events to an association with the mangosteen
pericarp. In addition, a small dose of mangosteen pericarp was
used. Nevertheless, no major adverse events or medical issues
were reported.
In a pilot study of 1,000 mg mangosteen pericarp for the
adjunctive treatment of schizophrenia, there was no significant
difference of reported adverse events between the placebo and the
active groups (112). Only 2 adverse events were reported in this
study (viz. headache and thoughts of self-harm). However, given
the nature of the population, it is probable that adverse events
could have been under-reported.
No adverse events were reported in a placebo-controlled
randomized control trial of mangosteen juice in adults aged
40–60 years (93). Nor were there any adverse events in a
similar study with a mangosteen-based drink (Verve R ) (94).
The mangosteen-based drink study also showed no significant
difference compared to the placebo group for weight, body mass
index, heart rate or blood pressure (94). Another mangosteen
juice study again had no side effects reported and no clinically
significant changes in electrocardiograms (95). In a study of 400
mg/day capsules of Meratrim for weight loss (n = 60), there
was no significant difference in adverse events or liver, heart,
kidney, or metabolic function, compared to the placebo group
(113). This safety profile held true for another study of Meratrim
at 800 mg/day (111). Interestingly, mangosteen pericarp has also
been associated with increased renoprotection due to reduction
in inflammation and oxidative and/or nitrosative stress (117).
Hence, the current evidence suggests that mangosteen pericarp
is well-tolerated with no known side effects. However, given the
limited evidence base, particularly within clinical populations
and those with polypharmacy, future trials are required to
evaluate the long-term safety of this intervention across a
range of doses and treatment durations. This is especially true
when considering that the clinical application for mangosteen
will be adjunctive to conventional treatments. With the recent
study in animals suggesting increased serotonergic activity in
Use of Mangosteen Pericarp in Mental
Health
In the study by Chang et al. (109) where the effect of mangosteen
juice was explored in a small placebo-controlled trial for exercise
fatigue in healthy adults, self-reported mood, and fatigue were
assessed as a secondary outcome using the Profile of Mood
States. There were no significant differences between depression
scores of the mangosteen juice vs. placebo groups at any
time point. Whilst both groups had an increase in fatigue
following the exercise, those who received mangosteen had
significantly less mental fatigue (measured on the Profile of Mood
States scale) compared to the control intervention. Both groups
also reported improvements in vigor and fatigue compared to
baseline (109).
Mental health was assessed as a secondary outcome in
a randomized controlled trial of a combination herbal
treatment containing mangosteen pericarp (Meratrim R )
in a healthy overweight human sample (111). The primary
outcomes of the study were reduction in weight, body
mass index, waist, and hip size which were all significantly
improved in the Meratrim R group compared to placebo.
Participants (n = 60) were randomized to receive 400 mg,
twice a day Meratrim (combination of Sphaeranthus
indicus flower and mangosteen pericarp extract in a
3:1 ratio) or placebo. Participants receiving Meratrim
reported reduced mood disturbances as measured by the
Short form of the Profile of Mood States when compared
to placebo.
In a double-blind placebo-controlled randomized trial,
adjunctive mangosteen pericarp (1,000 mg) was investigated in
participants with schizophrenia receiving second generation
antipsychotic treatment (n = 80) (112). The mangosteen
pericarp group performed significantly better than the placebo
group across all outcomes including the primary outcome,
the Positive and Negative Syndrome Scale and secondary
outcomes including Montgomery Åsberg Depression Rating
Scale, positive, negative, and general subscales of the Positive
and Negative Syndrome Scale, Clinical Global Impression
Severity and Improvement, Self-rated Life Satisfaction Scale,
and Global Assessment of Functioning. Therefore, the study
concluded there was a significant reduction in symptoms
of depression and symptomatology of schizophrenia and
schizoaffective disorder. The study was limited due to its
small sample size, and while symptoms of depression were
a secondary outcome, participants on average had mild
depression at baseline as measured by the Montgomery Åsberg
Depression Rating Scale. To date, this is the only study
which directly assesses the potential of mangosteen pericarp
at treating a serious mental illness. Due to the small sample
size combined with promising results, this study provides
significant impetus for further research of mangosteen pericarp
for the treatment of bipolar disorder, schizophrenia, and other
psychiatric disorders.
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Ashton et al.
Therapeutic Potential of Mangosteen Pericarp
and pro-cognitive effects in the Flinders Sensitive Line rat,
a genetic animal model of depression (76). In addition, a
reduction of hippocampal lipid peroxidation and correction of
disordered regional brain monoamines and sensorimotor gating
and depressive-like symptoms were reduced in an inflammatory
rat model of schizophrenia (77, 78). Future directions could
directly trial mangosteen pericarp as an adjunctive antidepressant
in human trials for major depressive disorder and bipolar
disorder. There are no animal studies utilizing the effects of
mangosteen pericarp in a bipolar disorder model, however, due
to the psychosis overlap with schizophrenia models, and the
depressive phase of the illness, symbiotic benefits may be inferred.
There is a need to demonstrate these findings from animal
models in human studies. There are currently two studies directly
trialing the effect of mangosteen pericarp on schizophrenia
(118) (Trial registry ID: ACTRN12616000859482) and bipolar
depression (119) (Trial registry ID: ACTRN12616000028404),
both in adult populations.
mangosteen pericarp-treated depressed rats (76), and given the
unknown interactions of mangosteen pericarp with conventional
serotonergic agents, the possibility of drug-drug interactions
should be considered.
Use of Mangosteen Pericarp as an
Adjunctive Treatment for Serious Mental
Disorders
In summary, this review has summarized a number of properties
of the mangosteen pericarp that could target known aberrations
in bipolar disorder and schizophrenia. In terms of biological
processes, bipolar disorder, and schizophrenia share heightened
oxidative stress including an increase in ROS, RNS, TBARS, and
MDA which may be modulated by the glutamatergic system.
Mangosteen pericarp in animal models reduces ROS, TBARS,
MDA, and has demonstrated effects on the glutamatergic system.
Inflammation is present in bipolar disorder and schizophrenia
indexed by inflammatory cytokines IL-6, IL-1Ra, IL-1β TNFα, and also by NO production via iNOS, superoxide dismutase
catalase, and glutathione peroxidase. Our review collates results
showing mangosteen pericarp can also have an effect on IL6, IL-1β TNF- α, NO, catalase, and glutathione peroxidase,
in addition to IL-2, IL-8, COX-2, and NF-κB. Alterations in
apoptosis and neurogenesis are demonstrated by changes in
Ki67+ cells as well as relevant markers including VEGF, bcl-2,
MAPK, and JNK. Mangosteen pericarp has demonstrated effects
on VEGF, bcl-2, and MAPK. However, there were no significant
demonstrated effects of mangosteen pericarp on JNK. Lastly,
the mitochondrial disturbances observed in bipolar disorder
and schizophrenia may be targeted by mangosteen via the
mitochondrial pathway to apoptosis. In addition to the biological
pathways, mangosteen pericarp has demonstrated potential in
reducing depression which is a key phase in bipolar disorder and
in negative symptoms of schizophrenia. However, future research
is required to observe the efficacy of mangosteen pericarp across
the scope of the disorders and in human participants.
CONCLUSION
The evidence of the bioactivity and neurobiology of mangosteen
pericarp is rapidly emerging. Mangosteen pericarp has produced
promising results in animals, and has been demonstrated to have
antioxidant, anti-inflammatory, anti-apoptotic, neuroprotective,
and mitochondrial enhancing properties. Taken together,
the theoretical biological rationale of psychiatric disorders,
bioactivity of mangosteen pericarp extract and the available
preclinical data, support the therapeutic potential as an
adjunctive psychiatric treatment. As the clinical evidence base
for mangosteen pericarp as an adjunctive psychiatric treatment
is scarce, future research requires human clinical trials to explore
the risks and benefits of treatment and assess the potential for
translation into clinical care.
AUTHOR CONTRIBUTIONS
Initial planning of the paper was conducted by MA, OD, and MB.
MA conducted the literature search and wrote the first draft. MA,
CB, and AW created the descriptive figure. OD, AW, CB, CN,
MH, BH, MM, JM, WM, AT, SD, JGS, J-PK, KW, JS, and MB
contributed to and edited drafts of the paper.
FUTURE DIRECTIONS
Mangosteen pericarp is a potential adjunctive treatment option in
bipolar disorder and schizophrenia. Given only one randomized
controlled trial has been completed in the field (112), future
work could target the limitations of research such as the
small sample sizes, lack of comparable outcomes, and nonstandardization in the extraction process. Currently, a range of
mangosteen pericarp extracts have been utilized which are either
whole compound or isolated components (such as α- and γmangostin). Further research must be undertaken to discern the
optimal dosing and extraction of the bioactive components, if
separate, or if the bioactivity comes from a combination of the
components working together in the compound. Mangosteen
pericarp has been posited for use in neurodegenerative disorders
such as Alzheimer’s (66, 88, 90) and Parkinson’s disease (84, 86).
In animal models, mangosteen pericarp has been trialed for
cognitive decline (87) and memory impairments (88). More
recently, mangosteen pericarp displayed marked antidepressant
Frontiers in Psychiatry | www.frontiersin.org
ACKNOWLEDGMENTS
The authors would like to acknowledge the NHMRC Project
Grant Scheme (APP1121510) for supporting this review. MA
would further like to acknowledge the support of Australian
Rotary Health/Ian Parker Bipolar Research Fund PhD
scholarship and the ASBDD/Lundbeck PhD neuroscience
scholarship. OD is supported by a NHMRC R.D. Wright
Biomedical Research Fellowship (APP1145634). AW is
supported by a Trisno Family Fellowship. CB is supported
by an Alfred Deakin Postdoctoral Research Fellowship. BH
declares that the work referred to in this manuscript has been
funded by Deakin University and the South African National
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Ashton et al.
Therapeutic Potential of Mangosteen Pericarp
Research Foundation (grant number 77323). The NRF grantholder acknowledges that opinions, findings and conclusions
or recommendations expressed in any publication generated
by NRF supported research are those of the authors, and that
the NRF accepts no liability whatsoever in this regard. JM is
supported by a NHMRC John Cade Fellowship (APP1056929)
and Niels Bohr Professorship from the Danish National Research
Foundation. JGS is supported by a National Health and Medical
Research Council Practitioner Fellowship Grant APP1105807
and employed by The Queensland Center for Mental Health
Research which receives core funding from the Queensland
Health. JS is funded by an NHMRC Clinical Research Fellowship
APP1125000. MB is supported by NHMRC Senior Principal
Research Fellowship (APP1059660 and APP1156072).
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Therapeutic Potential of Mangosteen Pericarp
support from NIH, Simons Autism Foundation, Cancer Council of Victoria, CRC
for Mental Health, Stanley Medical Research Foundation, MBF, NHMRC, Beyond
Blue, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly,
GlaxoSmithKline, Organon, Novartis, Mayne Pharma, and Servier. OD is a R.D.
Wright Biomedical Research Fellow and has received grant support from the Brain
and Behavior Foundation, Simons Autism Foundation, Stanley Medical Research
Institute, Deakin University, Lilly, NHMRC and Australasian Society for Bipolar
and Depressive Disorders (ASBDD)/Servier. CN had served as a consultant for
Grunbiotics, Lundbeck, Servier, Janssen-Cilag, Wyeth and Eli Lilly, received
research grant support from Wyeth and Lundbeck, and speaker honoraria from
Servier, Lundbeck, Bristol-Myers Squibb, Organon, Eli Lilly, GlaxoSmithKline,
Janssen- Cilag, Astra-Zenaca, Wyeth, and Pfizer. MH has received grant support
from ISSCR, Servier, US DOD and Bionomics, has been a speaker for JanssenCilag, Lundbeck, and Servier, and has been a consultant for AstraZeneca, Eli
Lilly, Janssen-Cilag, Lundbeck, and, Servier. SD has received grant support from
the Stanley Medical Research Institute, NHMRC, Beyond Blue, ARHRF, Simons
Foundation, Geelong Medical Research Foundation, Harry Windsor Foundation,
Fondation FondaMental, Eli Lilly, Glaxo SmithKline, Organon, Mayne Pharma
and Servier, speaker’s fees from Eli Lilly, advisory board fees from Eli Lilly
and Novartis and conference travel support from Servier. BH has participated
in advisory boards and received honoraria from Servier, R and has received
research funding from Deakin University, Servier R and Lundbeck, R and has
received funding from Deakin University to specifically undertake mangosteenrelated research in animal models. AT has received grants/research support
from NHMRC, AMP Foundation, Schizophrenia Fellowship of NSW, the
National Stroke Foundation, and the Hunter Medical Research Institute. JS has
received either presentation honoraria, travel support, clinical trial grants, book
royalties, or independent consultancy payments from: Integria Healthcare &
MediHerb, Pfizer, Scius Health, Key Pharmaceuticals, Taki Mai, FIT-BioCeuticals,
Blackmores, Soho-Flordis, Healthworld, HealthEd, HealthMasters, Kantar
Consulting, Research Reviews, Elsevier, Chaminade University, International
Society for Affective Disorders, Complementary Medicines Australia, SPRIM,
Terry White Chemists, ANS, Society for Medicinal Plant and Natural Product
Research, Sanofi-Aventis, Omega-3 Centre, the National Health and Medical
Research Council, CR Roper Fellowship. J-PK has received research support,
travel and educational support, consultancy payments, and/or presentation
honoraria from Alkermes, AstraZeneca; Bionomics, Bristol-Myers Squibb; Eli
Lilly; GlaxoSmithKline; Janssen; Lundbeck; Pfizer; Sanofi-Aventis; Servier; and
Wyeth. MB has received Grant/Research Support from the NIH, Cooperative
Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley
Medical Research Foundation, MBF, NHMRC, Beyond Blue, Rotary Health, Meat
and Livestock Board, Astra Zeneca, Woolworths, Avant and the Harry Windsor
Foundation, book royalties from Oxford University Press, Cambridge University
Press, Springer Nature and Allen and Unwin, has been a speaker for Astra Zeneca,
Lundbeck, Merck and Servier and served as a consultant to Allergan, Astra Zeneca,
Bioadvantex, Bionomics, Collaborative Medicinal Development, Grunbiotics,
Janssen Cilag, LivaNova, Lundbeck, Merck, Mylan, Otsuka, and Servier. MB is
a co-inventor on two provisional patents regarding the use of NAC and related
compounds for psychiatric indications, assigned to the Mental Health Research
Institute.
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8-0114
The remaining authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as a potential
conflict of interest.
Copyright © 2019 Ashton, Dean, Walker, Bortolasci, Ng, Hopwood, Harvey,
Möller, McGrath, Marx, Turner, Dodd, Scott, Khoo, Walder, Sarris and
Berk. This is an open-access article distributed under the terms of the
Creative Commons Attribution License (CC BY). The use, distribution or
reproduction in other forums is permitted, provided the original author(s)
and the copyright owner(s) are credited and that the original publication in
this journal is cited, in accordance with accepted academic practice. No use,
distribution or reproduction is permitted which does not comply with these
terms.
Conflict of Interest Statement: MB is a co-inventor on a patent application
regarding the use of mangosteen and related compounds for psychiatric
indications, assigned to Deakin University. MA has received grant/research
support from Deakin University, Australasian Society for Bipolar Depressive
Disorders, Lundbeck, Australian Rotary Health, Ian Parker Bipolar Research
Fund, and Cooperative Research Center for Mental Health. MB has received grant
Frontiers in Psychiatry | www.frontiersin.org
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