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1May 2019 | Volume 10 | Article 363
REVIEW
doi: 10.3389/fpsyt.2019.00363
published: 23 May 2019
Frontiers in Psychiatry | www.frontiersin.org
Edited by:
Lourdes Martorell,
Institut Pere Mata,
Spain
Reviewed by:
Hiromasa Funato,
Toho University,
Japan
Yuri Zilberter,
INSERM U1106 Institut de
Neurosciences des Systèmes,
France
Zoltan Sarnyai,
James Cook University,
Australia
*Correspondence:
Csilla Ari
csari2000@yahoo.com
Specialty section:
This article was submitted to
Molecular Psychiatry,
a section of the journal
Frontiers in Psychiatry
Received: 21 August 2018
Accepted: 10 May 2019
Published: 23 May 2019
Citation:
KovácsZ, D’AgostinoDP,
DiamondD, KindyMS, RogersC
and AriC (2019) Therapeutic
Potential of Exogenous Ketone
Supplement Induced Ketosis in the
Treatment of Psychiatric Disorders:
Review of Current Literature.
Front. Psychiatry 10:363.
doi: 10.3389/fpsyt.2019.00363
Therapeutic Potential of Exogenous
Ketone Supplement Induced Ketosis
in the Treatment of Psychiatric
Disorders: Review of Current
Literature
Zsolt Kovács 1, Dominic P. D’Agostino 2,3, David Diamond 2,4, Mark S. Kindy 5,6,7,
Christopher Rogers 2 and Csilla Ari 4*
1 Savaria Department of Biology, ELTE Eötvös Loránd University, Savaria University Centre, Szombathely, Hungary,
2 Department of Molecular Pharmacology and Physiology, Laboratory of Metabolic Medicine, Morsani College of Medicine,
University of South Florida, Tampa, FL, United States, 3 Institute for Human and Machine Cognition, Ocala, FL, UnitedStates,
4 Department of Psychology, Hyperbaric Neuroscience Research Laboratory, University of South Florida, Tampa, FL, UnitedStates,
5 Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, United States,
6 James A. Haley VA Medical Center, Tampa, FL, United States, 7 Shriners Hospital for Children, Tampa, FL, United States
Globally, psychiatric disorders, such as anxiety disorder, bipolar disorder, schizophrenia,
depression, autism spectrum disorder, and attention-deficit/hyperactivity disorder (ADHD)
are becoming more prevalent. Although the exact pathological alterations are not yet clear,
recent studies have demonstrated that widespread changes of very complex metabolic
pathways may partially underlie the pathophysiology of many psychiatric diseases. Thus,
more attention should be directed to metabolic-based therapeutic interventions in the
treatment of psychiatric disorders. Emerging evidence from numerous studies suggests that
administration of exogenous ketone supplements, such as ketone salts or ketone esters,
generates rapid and sustained nutritional ketosis and metabolic changes, which may evoke
potential therapeutic effects in cases of central nervous system (CNS) disorders, including
psychiatric diseases. Therefore, the aim of this review is to summarize the current information
on ketone supplementation as a potential therapeutic tool for psychiatric disorders. Ketone
supplementation elevates blood levels of the ketone bodies: D-β-hydroxybutyrate (βHB),
acetoacetate (AcAc), and acetone. These compounds, either directly or indirectly, beneficially
affect the mitochondria, glycolysis, neurotransmitter levels, activity of free fatty acid receptor
3 (FFAR3), hydroxycarboxylic acid receptor 2 (HCAR2), and histone deacetylase, as well as
functioning of NOD-like receptor pyrin domain 3 (NLRP3) inflammasome and mitochondrial
uncoupling protein (UCP) expression. The result of downstream cellular and molecular
changes is a reduction in the pathophysiology associated with various psychiatric disorders.
Abbreviations: A1R and A2AR, dierent types of adenosine receptors; AcAc, acetoacetate; ADHD, attention-decit/hyperactivity
disorder; BBB, blood–brain barrier; βHB, D-beta-hydroxybutyrate (R-3-hydroxybutyrate); β-OHBD, βHB dehydrogenase; CNS,
central nervous system; COX-2, cyclooxygenase-2; FFAR3, free fatty acid receptor 3; HCAR2, hydroxycarboxylic acid receptor 2; HPA,
hypothalamic-pituitary-adrenal; HMG-CoA, hydroxymethylglutaryl-CoA; HMGL, hydroxymethylglutaryl-CoA-lyase; HMGS,
hydroxymethylglutaryl-CoA-synthase; KE, ketone ester; KS, ketone salt; IL-1β, interleukin-1β; MCT, medium chain triglyceride;
NLRP3, NOD-like receptor pyrin domain 3; ROS, reactive oxygen species; SCOT: succinyl-CoA:3-ketoacid CoA transferase;
SSRI, selective serotonin reuptake inhibitor; UCP, uncoupling proteins; WAG/Rij, Wistar Albino Glaxo/Rijswijk.
Ketone Supplement Induced Ketosis in PsychiatryKovács et al.
2May 2019 | Volume 10 | Article 363Frontiers in Psychiatry | www.frontiersin.org
We conclude that supplement-induced nutritional ketosis leads to metabolic changes and
improvements, for example, in mitochondrial function and inflammatory processes, and
suggest that development of specific adjunctive ketogenic protocols for psychiatric diseases
should be actively pursued.
Keywords: psychiatric diseases, exogenous ketone supplements, ketosis, mitochondrial dysfunction, inflammation
INTRODUCTION
With an increasing global prevalence, psychiatric disorders can
present as serious medical conditions composed of emotional,
cognitive, social, behavioral, and functional impairments (1).
Lifetime onset of major
depressive disorders in the general
population is up to 11–16% (2, 3), with bipolar disorder present
in 1% (4, 5), schizophrenia in 1% (6, 7), and anxiety disorder in
5–31% (1). In relation to attention-decit/hyperactivity disorder
(ADHD), worldwide prevalence of this disease in children/
adolescence and adults is about 5.3% and 2.5%, respectively (8, 9),
while about 1 in 68 children were diagnosed with autism in the
United States in 2012 (10). It has been demonstrated that not only
genetic factors but also environmental factors (e.g., infections, early
traumas, and drugs), age, sociodemographic factors (e.g., ethnicity
and socioeconomic status), and a complex interplay between these
factors have a role in the pathophysiology of dierent psychiatric
diseases, such as anxiety disorder (1, 11), bipolar disorder (5),
schizophrenia (6, 12), major depressive disorder (2, 13, 14),
autism spectrum disorder (15), and ADHD (16). Close association
between dierent psychiatric disorders, such as anxiety disorder
and major depressive disorder, has been demonstrated (5, 17–21).
However, while symptoms, characteristics, and classication
of different psychiatric disorders are adequately described
(1, 5, 7, 15, 16, 22), the pathophysiology of psychiatric diseases
is not yet fully understood. Nevertheless, recent studies have
demonstrated that the disturbance in the monoaminergic (23–
26) and other neurotransmitter systems (e.g., glutamatergic,
purinergic, and GABAergic) (27–34), in addition to widespread
changes of very complex and connected metabolic pathways,
may partially explain the general condition. For example, it has
been suggested that mitochondrial dysfunction could play a
major role (35). Mitochondrial dysfunction may decrease energy/
ATP production, impair calcium homeostasis, increase levels
of reactive oxygen species (ROS), and alter apoptotic pathways,
inammatory processes, neurotransmission, synaptic plasticity,
and neuronal activity and connectivity (35, 36). Moreover, changes
in hypothalamic–pituitary–adrenal (HPA) axis activity were
also demonstrated in patients with psychiatric diseases, in which
alterations may inuence mitochondrial functions: a chronic
increase in glucocorticoid levels may decrease mitochondrial
energy production (35, 37). Membrane lipid dysregulation may
aect the levels of pro-inammatory cytokines, as well as the
function of mitochondria, ion channels, and neurotransmitter
systems implicated in the pathophysiology of psychiatric diseases
(38, 39). In addition, changes in membrane fatty acid composition
may alter the function of dierent cell-surface receptors, ion pumps,
and special enzymes, such as 5’-nucleotidase, adenylate cyclase, and
Na+/K+-ATPase (38, 40). Increased activity of the inammatory
system and redox pathways may enhance oxidative and nitrosative
stress, mitochondrial dysfunction, neurodegeneration and
neuronal death, production of pro-inammatory cytokines, and
activity of the HPA axis, whereas it may decrease neurogenesis
and serotonin levels (35, 37). In addition, functional brain imaging
studies demonstrated abnormalities in regional cerebral glucose
metabolism in the prefrontal cortex in patients with mood disorders,
providing evidence of persistent hypometabolism, particularly in
the frontal gyrus, in depressed patients (41). Recent transcriptomic,
proteomic, and metabolomics studies have also highlighted an
abnormal cerebral glucose and energy metabolism as one of the
potential pathophysiological mechanisms of schizophrenia, raising
the possibility that a metabolically based intervention might have
therapeutic value in the management of the disease (42).
Consequently, different metabolic changes and their
downstream eects may generate complex, interlinked molecular
and cellular processes, which may lead to dierent psychiatric
diseases. It can be concluded that alterations in multiple interactive
metabolic pathways and their eects on dierent physiological
processes may largely underlie the pathophysiology in patients
with psychiatric diseases. Indeed, if defective metabolism is the
cause of such pathologies, then utilization of therapies designed to
address deciencies of metabolism (known as metabolic therapies)
would be a rational approach for the treatment of these diseases.
In a process known as ketogenesis, the ketone bodies [D-β-
hydroxybutyrate (βHB), acetoacetate (AcAc), and acetone] are
catabolized under normal physiological conditions by the liver
from fatty acids as a source of fuel (43–45). Higher levels of
ketones are produced during starvation, fasting, and neonatal
development (46, 47). Moreover, although most of βHB, which
is used as an energy source in the brain, is synthesized by the
liver, ketone body synthesis and release by astrocytes have also
been demonstrated (48, 49). Ketone bodies can transport to
the bloodstream from the liver, cross the blood–brain barrier
(BBB), enter brain cells through monocarboxylic transporters,
convert to acetyl CoA in the mitochondria, and enter the Krebs
cycle (43–44, 45, 50). rough this process, ketosis (increased
ketone body levels in the blood) provides energy by metabolism
of ketone bodies to acetyl-CoA and synthesis of ATP for cells
in the central nervous system (CNS) (43, 51, 52). It has been
demonstrated in animal—and/or human studies—that ketogenic
diets and supplements may have metabolism-based therapeutic
potential in the treatment of several diseases, such as Alzheimer’s
disease (53–57), Parkinson’s disease (54, 58–60), glucose
transporter type 1-deciency syndrome (61–63), amyotrophic
lateral sclerosis (60, 64), cancer (44, 58, 65, 66), epilepsy
(54, 67, 68), schizophrenia (42, 69–74), anxiety (55, 75–77),
autism spectrum disorder (78–81), and depression (69, 77, 82).
Ketone Supplement Induced Ketosis in PsychiatryKovács et al.
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Ketogenic diets are high-fat, adequate protein and very
low carbohydrate diets that may have an alleviating role on
psychiatric diseases (69, 73), likely through bioenergetics, ketone
metabolism, and signaling, as well as their eects on, for example,
neuronal activity, neurotransmitter balance, and inammatory
processes (43, 52, 83–91). Strict patient compliance to the KD
is the primary factor in achieving therapeutic ketosis, and this is
oen dicult or impossible in the psychiatric population (69).
erefore, the administration of exogenous ketone supplements
including medium chain triglycerides (MCTs), ketone salt (KS),
ketone ester (KE), and their combination with MCT oil (e.g.,
KSMCT) presents a strategy to circumvent dietary restriction
to rapidly induce and sustain nutritional ketosis (65, 75, 84,92).
Ketone bodies not only enhance cell energy metabolism through
anaplerotic eects but also suppress oxidative stress, decrease
inammatory processes, and regulate functions of ion channels
and neurotransmitter systems (45, 93, 94)—all processes
implicated in the pathophysiology of psychiatric diseases (1, 5, 6,
15, 16, 22). erefore, the rationale exists for the use of exogenous
ketone supplementation, which induces a nutritional ketotic state
similar to that derived from the ketogenic diet and may mimic the
eects of ketogenic diet on several CNS diseases through ketone
body-evoked metabolic and signaling alterations (54, 55, 67, 75,
95–99) and epigenetic eects (100).
In contrast to diabetic ketosis, which can induce pathological
levels of blood βHB (ranging >25 mM) and potentially lead to
life-threatening acidosis, nutritional ketosis elevates blood βHB
from the normal range (0.1–0.2 mM) to a safe and—in many
cases—therapeutic range (1–7 mM: therapeutic ketosis) (44, 54,
101). While rigorous adherence to ketogenic diets is typically
dicult to follow and requires clear medical guidance and
strong motivation, consumption of exogenous ketogenic agents
eectively induces ketosis with little diculty (65, 75, 84, 92,
102). Moreover, prolonged consumption of ketogenic diets may
generate side eects, such as weight loss, alteration of mentation,
growth retardation, nephrolithiasis, nausea, constipation,
gastritis, hyperlipidemia, hypoglycemia, hyperuricemia, and
ulcerative colitis (44, 69, 103, 104). Consequently, developing
a safer alternative method using ketone body precursors and
exogenous ketone supplements, such as KSs or KEs, to circumvent
dietary restriction is appealing.
Recent research has demonstrated that it is possible to rapidly
increase and maintain blood levels of ketone bodies in a dose-
dependent manner in both animals and humans (54, 84, 99) for
the treatment of several CNS diseases (55, 64, 67, 75). us, it is
possible that exogenous ketone supplementation-induced ketosis
may be an eective therapeutic tool against psychiatric diseases.
Indeed, exogenous ketone supplements have a modulatory
inuence on behavior and anxiolytic eect in animal studies
(55, 75, 83). Moreover, in contrast to ketogenic diets, exogenous
ketone supplements are relatively well-tolerated and can be
formulated and titrated to minimize or avoid side eects (56, 65,
75, 84, 99, 105, 106).
ere is limited evidence to support the benecial eects
of exogenous ketone supplements in psychiatric diseases at
the moment [e.g., Refs. (55, 75, 76)], but the use of exogenous
ketone supplements may be a viable alternative or adjuvant to
pharmacotherapy in the treatment of these disorders. Consequently,
in the following major section, we provide a short overview of
the metabolism of exogenous ketone supplements, which results
in rapid and safe mild therapeutic ketosis and, as a consequence,
may be an alternative method to ketogenic diets for the treatment
of psychiatric disorders. In the next major sections, therapeutic
potential of exogenous ketone supplements in the treatment of
each psychiatric disease is summarized. is is followed by a brief
conclusions section with perspective and future outlook.
METABOLISM OF EXOGENOUS KETONE
SUPPLEMENTS: GENERATION OF
THERAPEUTIC KETOSIS
Under typical (high carbohydrate) diet conditions, glycogen-
derived glucose is the main energy source of brain cells (43,
107). However, ketogenic diets, starvation, and fasting result
in an increased reliance of the brain on fat-derived ketones for
fuel (43, 44, 108). Free fatty acids are converted into acyl-CoA
in the liver cells, and subsequently, acyl-CoA is metabolized to
acetyl-CoA by mitochondrial β-oxidation (Figure 1A). Acetyl-
CoA may generate energy (via Krebs cycle: tricarboxylic acid
cycle/TCA cycle) or it gets converted into ketone bodies (43–
44, 45, 50). As hepatocytes are not able to utilize the high levels
of acetyl-CoA derived from ketogenic diet-, starvation-, and
fasting-evoked increase in fatty acids, under these conditions,
a large portion of acetyl-CoA can be converted to ketone
bodies (44, 45, 107). Two acetyl-CoA molecules fuse into
one acetoacetyl-CoA molecule by acetoacetyl-CoA-thiolase.
Subsequently, hydroxymethylglutaryl-CoA-synthase (HMGS)
condenses the third acetyl-CoA molecule with acetoacetyl-
CoA to form hydroxymethylglutaryl-CoA (HMG-CoA)
(this process, catalyzed by HMGS, is the rate-limiting step of
ketogenesis) (43–44, 45, 50). AcAc is liberated from HMG-CoA
by hydroxymethylglutaryl-CoA-lyase (HMGL). AcAc may
reduce to βHB by a NADH molecule in a βHB dehydrogenase
(β-OHBD) catalyzed reaction, or, in lesser amounts, a part of
AcAc may metabolize to acetone by the spontaneous, non-
enzymatic decarboxylation of AcAc (43–44, 45, 50). e
major circulating water-soluble ketone body is βHB (44, 50).
AcAc is a chemically unstable molecule, and acetone is a very
volatile compound (eliminated mainly via respiration from
the lungs) (44, 50). As the metabolic enzyme succinyl-CoA:3-
ketoacid CoA transferase (SCOT) is not expressed in the liver,
hepatocytes are not able to consume ketone bodies as an energy
substrate (45, 50, 52); thus, AcAc and βHB can exit the liver,
enter the bloodstream, and be distributed to various tissues,
including the brain, aer transport through monocarboxylate
transporters (43–44, 45, 50). In the mitochondria of brain cells,
ketone bodies are converted back to acetyl-CoA (Figure 1A)
(43–44, 45, 50). As the rst step of this metabolic pathway,
βHB oxidizes to AcAc by NAD+ and β-OHBD. AcAc is then
metabolized to acetoacetyl-CoA, which converts to two acetyl-
CoA molecules (by SCOT and acetoacetyl-CoA-thiolase,
respectively). Finally, acetyl-CoA molecules enter the Krebs
cycle as an energy source for ATP synthesis (43–44, 45, 50).
Ketone Supplement Induced Ketosis in PsychiatryKovács et al.
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FIGURE 1 | Mitochondrial ketone body metabolism: ketogenesis in liver cells (hepatocytes) and ketolysis in brain cells (neuron) (A). Main βHB-evoked metabolic
effects and their consequences, which may evoke alleviating effects on different psychiatric diseases (B) (see text for more detailed putative mechanisms by
which βHB may evoke alleviating effects on psychiatric diseases). Abbreviations: A, acetone; A1R and A2AR, different types of adenosine receptors; AcAc,
acetoacetate; ATP, adenosine triphosphate; BBB, blood–brain barrier; βHB, D-beta-hydroxybutyrate (R-3-hydroxybutyrate); β-OHBD, βHB dehydrogenase; COX-2,
cyclooxygenase-2; ETC, electron transport chain; GABA, gamma-aminobutyric acid; HMGL, hydroxymethylglutaryl-CoA-lyase; HMGS, hydroxymethylglutaryl-CoA-
synthase; IL-1β, interleukin-1β; NADH/FADH2, nicotinamide adenine dinucleotide/flavin adenine dinucleotide; NLRP3, NOD-like receptor pyrin domain 3; NMDAR,
N-methyl-D-aspartate receptor; SCOT, succinyl-CoA:3-ketoacid CoA transferase; thiolase, acetoacetyl-CoA-thiolase; UCP, uncoupling proteins.
Ketone Supplement Induced Ketosis in PsychiatryKovács et al.
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While a ketogenic diet could potentially confer numerous
benets to patients suering from psychiatric disorders,
compliance to the diet would likely be low. Reasons include the
lack of knowledge, support, palatability, and dierent adverse
eects such as gastrointestinal side eects (69, 103, 104).
Most importantly, ketogenic diets must continuously restrict
carbohydrates (typically 20 g/day) to sustain ketogenesis through
elevated long-chain fatty acid oxidation (109). Nevertheless,
the production of ketone bodies from KSs or KEs (e.g., by liver
alcohol dehydrogenase and/or hydrolysis in the small intestine)
is not inhibited by carbohydrates; thus, ketone supplements may
be usable while maintaining a normal diet (105) to generate
therapeutic ketosis.
Aer consumption or gavage administration, KEs are fully
hydrolyzed in the small intestine by esterases, which can be
transported to the systemic bloodstream, and converted to
1,3-butanediol. Following this, 1,3-butanediol is metabolized
to AcAc and βHB in the liver by alcohol and aldehyde
dehydrogenase (106, 110, 111). Moreover, MCTs/MCT oils
are hydrolyzed to medium chain fatty acids (e.g., decanoic and
octanoic acid) by lipases in the gastrointestinal tract, which are
metabolized to ketone bodies in the liver (112). us, similar to
ketogenic diets, metabolism of exogenous ketone supplements
may result in increased levels of blood ketone bodies, which may
serve the energy needs of brain cells (Figure 1A). For example,
KS supplementation signicantly increased the mitochondrial
activity of both β-OHBD and acetoacetyl-CoA-thiolase in the
brain of rats (83), and oral administration of exogenous ketone
supplements is able to evoke and maintain rapid and safe mild
ketosis in both animals and human (54, 64, 65, 75, 84, 92, 99,
101, 106, 108).
Unfortunately, MCTs are oen not well tolerated because of
their gastrointestinal side eects (e.g., diarrhea, dyspepsia, and
atulence) and supplementation of MCTs generates relatively low
levels of ketone bodies in the blood (113). Oral administration of
KEs fully metabolizes to βHB and AcAc and, as a consequence,
more eectively increases ketone body levels compared to MCTs
(56). KEs, such as (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate
and R,S-1,3-butanediol AcAc diester, are well-tolerated, safe,
and ecient ketogenic agents in both animals and humans
(56, 99, 105, 106). Moreover, it was demonstrated that a proper
dose of KS alone (99) or in combination with other exogenous
ketone supplements, such as KE and MCT (KEKS and KSMCT,
respectively), may be a safe and ecacious way to achieve ketosis
(65, 75, 84, 99). us, exogenous ketone supplements may be an
eective alternative to ketogenic diets for therapeutic ketosis.
THERAPEUTIC POTENTIAL OF
EXOGENOUS KETONE SUPPLEMENTS
IN THE TREATMENT OF PSYCHIATRIC
DISEASES
Although there has been remarkable progress in our knowledge
on the biological eects and mechanisms of action of exogenous
ketone supplements, their exact mechanisms on CNS diseases are
largely unknown. It has been demonstrated that an increase in
ketone body/βHB concentration may modulate neurotransmitter
balance and release (43, 52, 85), decrease hyperexcitability, reduce
ring rates of neurons (43, 84, 86), decrease neuroinammation
(43, 91), enhance brain energy metabolism (43, 50, 83, 84, 87),
and provide neuroprotective eects (43, 45, 84, 88, 90), which
together may protect dierent physiological processes under
pathological conditions resulting in CNS diseases, such as
psychiatric disorders (35–36, 37, 58, 69). us, it is possible that
exogenous ketone supplement-evoked ketosis (65, 75, 84) and
its signicant metabolic eects, as well as their consequences,
may have both preventive and therapeutic potential as a
metabolic-based therapy in patients with psychiatric diseases
(Figure 1B). In spite of the several metabolic alterations, the
mechanism of action of exogenous ketone supplement-evoked
ketosis on dierent psychiatric diseases was not investigated
comprehensively. As a result, we have only limited results in
relation to exact links between alleviating eects of ketone
supplement-generated ketosis and pathological changes in
psychiatric diseases. Nevertheless, both recent literature results on
basic pathomechanisms of psychiatric diseases and mechanisms
of therapeutic eects of exogenous ketone supplement-evoked
ketosis strongly support the hypothesis that exogenous ketone
supplement-evoked ketosis may modulate the background
pathophysiological processes of psychiatric diseases. Indeed,
an MCT diet caused anxiolytic eects (76) and βHB decreased
anxiety-related and depressive behaviors in rats and mice (114,
115). It has also been demonstrated that sub-chronic (7 days)
oral administration of exogenous ketone supplements, such as
KE, KS, and KSMCT, evoked an anxiolytic eect in normal rats
(Sprague–Dawley/SPD rats) and diseased rats (Wistar Albino
Glaxo/Rijswijk rats: WAG/Rij rats; a rat model of human absence
epilepsy) on elevated plus maze (EPM) test in correlation with
increased levels of βHB (75, 95). Elevated ketone body levels
were demonstrated in schizophrenic patients, suggesting that
the energy supply of brain shis from glucose towards ketone
bodies in this disease (116). Based on correlation between βHB
plasma levels and symptoms it was suggested that βHB may have
a protective eect on executive functions in patients treated with
schizophrenia (117). Other studies presented cases of patients
with chronic schizoaective disorders where the KD begin
helping with mood and psychotic symptoms within 1 month or
lead to remission of psychotic symptoms (73, 74). It has also been
suggested that plasma level of βHB is associated with severity of
depression in human and that βHB-evoked antidepressant-like
eects may be in relation to its inhibitory eect on NOD-like
receptor pyrin domain 3 (NLRP3)-induced neuro-inammatory
processes. e authors also suggested that modication of βHB
levels by diet may be a novel therapeutic target for the treatment
of mood disorders, such as depression (115, 118). In addition,
ketosis (induction of βHB) may be the primary mediator of the
therapeutic eect of the ketogenic diet and exogenous ketone
supplements on dierent CNS diseases. From this viewpoint, the
eect of exogenous ketone supplements mimics the ketogenic
diet (43, 44, 51, 52, 54, 58, 72, 94, 96, 101, 119). us, ketogenic
diet-evoked eects on psychiatric diseases may result (at least
partly) from benecial metabolic eects of βHB, for example,
Ketone Supplement Induced Ketosis in PsychiatryKovács et al.
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on mitochondrial functions, neuronal activity, neurotransmitter
release, and inammatory processes (43, 50, 52, 86, 91). Indeed,
administration of a ketogenic diet not only increased the ketone
body level but also was associated with improvements in anxiety
disorder (75, 77), bipolar disorder (120), schizophrenia (42, 70,
73, 74, 121), depression (77, 122), autism spectrum disorder
(78, 80, 123), and ADHD (124, 125) in animal models and/or
humans, suggesting the benecial eects of exogenous ketone
supplement-induced ketosis on psychiatric diseases (Figure 1B).
However, thorough investigation of signaling pathways by
which exogenous ketone supplement-evoked ketosis exerts
benecial eects on psychiatric diseases is needed. In the
following subsection, we provide an overview of the main putative
basic mechanisms, by which ketone supplement-evoked ketosis
may alleviate dierent pathophysiological processes involved in
psychiatric disorders.
Ketosis-Generated Effects on
Mitochondrial Functions, Neurotransmitter
Systems, Inflammatory Processes, and
Their Consequences: Putative Alleviating
Influences on Psychiatric Diseases
It has been demonstrated that ketone bodies serve as
alternative fuel for brain cells when the glucose supply is
insufficient: ketone bodies improve mitochondrial respiration
and enhance mitochondrial ATP synthesis (Figure 1B) (47,
126). Increased mitochondrial ATP production may promote
the repolarization of neuronal membrane after stimulation
by means of Na+/K+ ATPase and may modulate the
neurotransmitter levels (119). In addition, βHB may inhibit
vesicular glutamate transporters (127). This effect, together
with increased ATP production, decreases glutamate loading
to vesicles and glutamate release and, as a consequence,
suppresses neuronal excitability (68, 119, 127).
It was recently demonstrated that βHB inhibits the activity
of N-type Ca2+ channels in sympathetic nerve terminals and
may decrease the release of noradrenaline via activation of its
G-protein-coupled receptor free fatty acid receptor 3 (FFAR3)
(128). Increased levels of ketone bodies, such as βHB, may
evoke other changes in metabolic pathways, such as inhibition
of glycolysis (43). An inhibition of glycolysis may result in
decreased levels of cytosolic ATP and, as a consequence,
increased activity of ATP-sensitive potassium (KATP) channels
generating hyperpolarization of neuronal membrane and
decrease in neuronal activity (43, 129). As it was demonstrated,
ketosis not only decreases glutamate release and extracellular
glutamate levels and enhances the GABAergic eects by means
of increased GABA levels and GABAA receptor activity (43, 68)
but also increases adenosine levels (130) and may modulate
metabolism of monoamines (Figure 1B). For example, increased
levels of noradrenaline in mice brain (131) and decreased
levels of metabolites of monoamine dopamine and serotonin
(homovanillic acid/HVA and 5-hydroxyindole acetic acid/5-
HIAA, respectively) in the human cerebrospinal uid (132)
were demonstrated under a ketotic state. Increased levels of
extracellular adenosine lead to increased activity of adenosine
receptors and may decrease hyperexcitability via A1Rs, increase
hyperpolarization of neuronal membrane, and decrease neuronal
activity (133, 134). In addition, adenosine decreases the energy
demand of brain tissue (e.g., via A1R and A2AR) (135), modulates
immune system functions (e.g., activation of A2AR decreases the
inammation-induced cytokine production from microglial
cells) (136), and has a neuroprotective eect (e.g., evokes a
decrease in oxidative stress and attenuates the harmful inuence
of ROS on brain cells via A1R) (137, 138).
β-Hydroxybutyrate may exert its eects on numerous
targets, including oxidative stress mediators (e.g., by inhibition
of histone deacetylases and increased activity of antioxidant
enzymes) and metabolic rate (e.g., increased NAD+–NAD+/
NADH ratio) directly and/or indirectly via its G-protein-
coupled receptors, such as hydroxycarboxylic acid receptor
2 (HCAR2, also known as PUMA-G or GPR109 receptor)
(45, 90, 139, 140). As an endogenous ligand, βHB activates
the HCAR2 receptor expressed on, for example, microglial
cells (141). HCAR2 mediates the inhibitory eects of βHB on
neurodegeneration, microglial activation, and inammatory
processes [e.g., decreases the expression/level of interleukins,
such as interleukin-1β (IL-1β), and lipopolysaccharide/LPS-
induced increase in cyclooxygenase-2/COX-2 activity and
interleukin levels] (141–143) (Figure 1B). NOD-like receptor
pyrin domain 3 inammasome is a multiprotein complex, which
may evoke cleavage of pro-IL-1β to its active form (IL-1β) for
secretion by caspase-1 (144, 145). It was demonstrated that βHB
decreases inammatory processes likely through inhibition
of NLRP3: βHB decreased not only the expression of NLRP3
and caspase-1 but also the level/release of proinammatory
cytokines, such as IL-1β (91, 146).
In general, oxidative stress damages proteins, lipids, and
nucleic acids. One putative downstream eect of this damage is
the opening of the mitochondrial permeability transition (mPT)
pore and, as a consequence, activation of the apoptotic cascade
processes pursuant to release of cytochrome c to the cytoplasm
(147). It was demonstrated that increased production of ROS may
activate mPT pore (97, 147). Ketone bodies decreased oxidative
stress and ROS formation by enhancing complex I (NADH
dehydrogenase)-driven mitochondrial respiration (140). It has
also been demonstrated that KE increased both ketone body
levels and expression of mitochondrial uncoupling proteins
(UCPs; e.g., UCP 4 and UCP 5 in rat brain), which can decrease
the production of ROS (50, 148) (Figure 1B). In addition, it
was suggested that βHB not only prevents neuronal loss but
also preserves synaptic function: βHB mitigates eects, which
may evoke cell death/apoptosis (e.g., glutamate excitotoxicity,
enhanced ROS production, impaired mitochondrial energetic
functions, pathogenic mutations on mitochondrial DNA, and
activation of mPT pore) (44, 97, 119, 149), and βHB may restore
impairment of hippocampal long-term potentiation (150).
e changes induced by ketosis may lead to enhanced brain
energy metabolism, promotion of repolarization of neuronal
membrane, neuronal hyperpolarization, decreased hyperexcitability
and neuronal ring, modulation of neurotransmitter release/
balance, neuroprotective eects, and decreased inammatory
processes (Figure 1B). Downstream eects may include increased
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GABA and ATP/adenosine levels, decreased levels of glutamate
and IL-1β, and reductions in neuronal excitability and ROS
formation. Based on these putative alleviating eects, which may
have therapeutic potential in the treatment of dierent psychiatric
diseases, this subsection is followed by a brief overview of the main
pathological changes in dierent psychiatric diseases, which may
be modulated or improved by ketosis-evoked benecial eects
and their consequences. Currently, we lack detailed information
for understanding the exact mechanisms by which ketosis evokes
benecial eects on psychiatric disorders. However, we can be
reasonably condent that the alleviating eects of exogenous
ketone supplements on these disorders aect several interacting
factors, including mitochondrial function, neurotransmitter levels,
and inammatory processes.
Anxiety Disorders
An increasing body of evidence suggests that dysregulation of the
glutamatergic, serotonergic, purinergic, and GABAergic systems
plays a role in the pathophysiology of anxiety disorders (33, 34,
151–153). For example, inhibition of NMDA and AMPA receptors
by their antagonists (e.g., DL-2-amino-5-phosphonovaleric
acid/APV and 6-cyano-7-nitroquinoxaline-2,3-dione/CNQX,
respectively) fully or partially blocked the expression and/
or acquisition of fear conditioning (30, 154). Activation of the
serotonergic system (e.g., via increased levels of serotonin by
selective serotonin reuptake inhibitors/SSRIs and activation of
serotonin 5-HT1A receptors by buspirone or tandospirone) and
increased activity of adenosinergic system (e.g., via activation
of A1 type of adenosine receptors/A1R) have an anxiolytic eect
(34, 155). Moreover, enhanced GABAergic neurotransmission
evoked an anxiolytic eect, whereas decreased GABAergic
transmission generated anxiogenic responses in animals (151,
153, 156). Altered functions are present in many regions,
including the extended amygdala, ventromedial prefrontal
cortex, hippocampus, hypothalamus, and the midbrain, and
changed connections between these areas are implicated in the
pathophysiology of anxiety disorders (157–159). Specic changes,
such as underactivation (e.g., in ventromedial prefrontal cortex),
overactivaton (e.g., in amygdala), and decient functional
connectivity (e.g., between hippocampus and amygdala), have
also been demonstrated (157, 158, 160, 161). Changes in gray
matter volume (e.g., in the right orbitofrontal cortex, amygdala,
and hippocampus) (160, 162, 163), as well as dysfunction or
hyperactivation of HPA axis and inammatory system (e.g.,
increased level of proinammatory cytokines) (14, 164), may
have a role in pathophysiology of anxiety disorders. It was also
demonstrated that mitochondrial dysfunctions and oxidative
stress may be key factors in the emergence of anxiety disorders
(165, 166).
Schizophrenia
It has been demonstrated that alterations in the neurotransmitter
systems governed by GABA, glutamate, and the monoamines
are involved in the development of schizophrenia (7, 23, 27, 32,
167–169). For example, in the prefrontal cortex, which partially
mediates the negative symptoms of schizophrenia, low serotonin
and dopamine levels were detected (7, 23). Cognitive symptoms
may be linked with decreased level of GABA and serotonin
(e.g., in the dorsolateral prefrontal cortex) (7, 170). Moreover,
decrease in serotonin level was demonstrated in amygdala,
which may lead to aggressive symptoms (7). It was concluded
that, among others, hypofunction of the inhibitory GABAergic
interneurons and changes in activity of implicated brain areas
(e.g., because of decreased activity of inhibitory eects and
imbalance between inhibitory/excitatory processes) have a
role in the pathophysiology of schizophrenia (7, 167). Another
recent study using an acute NMDA receptor hypofunction
model of schizophrenia showed that feeding C57BL/6 mice a
low carbohydrate/high-fat KD for 7 weeks prevented a variety of
behavioral abnormalities induced by pharmacological inhibition
of NMDA glutamate receptors (42). In the study, they found a
lack of correlation between the measured prepulse inhibition of
startle and body weight changes, providing evidence against the
role of calorie restriction in its mechanism of action (42). Case
studies on human patients with schizophrenia also supported the
ecacy of using KD to improve symptoms (73, 74). Reduction in
the volume of brain areas encompassing cortical gray and white
matter (e.g., in amygdala and hippocampus/sensorimotor and
dorsolateral prefrontal cortices) (171–173), gliosis (174), and
increased neuronal apoptosis (7, 175) were also demonstrated
in patients with schizophrenia. A great deal of evidence suggests
that microglial activation, oxidative stress (e.g., increase in
ROS activity), and mitochondrial dysfunction (e.g., changes in
activity of complex I and cytochrome-c-oxidase/IV of electron
transport chain) may also be involved in the pathophysiology of
schizophrenia (167, 176–178). Increased activation of HPA axis
by psychological stress, inammatory processes, and increased
level of cytokines (e.g., tumor necrosis factor alpha/TNF-α and
IL-1β), as well as enhanced levels of glutamate and dopamine
auto-oxidation, could lead to enhanced production of ROS and
subsequently neurodegeneration and apoptosis (7, 167, 178–180).
Major Depressive Disorder
Structural brain alterations, such as decreased volume and
cell number of brain areas (e.g., in hippocampus and several
cortical areas) (3, 181–183) and abnormalities in activation or
connectivity of brain structures and networks (e.g., chronic
hyperactivity of limbic centers and brainstem) (13, 22, 184–186),
may underlie the functional and behavioral changes observed
in depressed patients. It has been demonstrated that changes in
several components, including the glutamatergic system (e.g.,
increased glutamate level) (29), monoaminergic system (e.g.,
decrease in the level of serotonin, noradrenaline, and dopamine)
(3, 13, 24, 187, 188), GABAergic system (e.g., reduced plasma
and cerebrospinal uid GABA levels) (189, 190), and purinergic
system (e.g., overexpression of A2A type of adenosine receptors/
A2AR) (28) have a role in the pathophysiology of major
depressive disorder. Activation of microglia and astrocytes and
inammatory pathways (14, 164, 191, 192) may be associated
with major depressive disorder. For example, increased activation
and expression of NLRP3 inammasome and interleukins (e.g.,
IL-1β) were revealed in both animal models and patients with
depression (13, 193, 194). Hyperactivity of HPA system was also
demonstrated (195). Neurodegeneration and neuronal death
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(e.g., through increased oxidative/nitrosative stress) and
alterations in mitochondrial functions (e.g., decreased ATP
production as well as enhanced apoptosis and oxidative stress)
(35, 177, 196) also play a role in the emergence of major
depressive disorder. It has been demonstrated that enhancement
of inammatory processes is associated with depression by
modulation of dierent neurotransmitter systems: for example,
inammatory cytokines (e.g., IL-1β) reduce synaptic availability
of monoamines and increase excitotoxicity (via extrasynaptic
NMDA receptors) by increasing levels of extracellular glutamate
(164, 197, 198). Moreover, cytokines may evoke decreased
motivation and anhedonia via dierent pathways (e.g., by
decreased release of dopamine in the basal ganglia) (164, 199).
Bipolar Disorder
It has been demonstrated that imbalance in monoaminergic
neurotransmitter system (e.g., serotonergic, dopaminergic,
and noradrenergic) (200–202), GABAergic system (e.g.,
decreased GABAergic transmission) (190), purinergic system
(e.g., increased level of uric acid and reduced adenosinergic
activity at A1Rs) (31), and glutamatergic system (e.g.,
increased glutamate levels and NMDA receptor activity) (29)
are associated with bipolar disorder. These alterations may
be associated with mitochondrial dysfunction (e.g., deficit in
activity of complexes I and IV), apoptosis, increase in ROS,
oxidative damage, hyperexcitability (5, 177, 203, 204), and,
as a consequence, decrease in glial cell or neuron number
and gray matter, as well as changes in connectivity between
implicated brain areas (e.g., hippocampus, prefrontal cortex,
and amygdala) (205–207). Changes in endocrine functions
(e.g., dysregulation of HPA axis) and inammatory processes
(e.g., increased proinflammatory cytokine levels, such
as IL-1β) were demonstrated in association with bipolar
disorder (203, 208).
Autism Spectrum Disorder
It has been demonstrated that agenesis of corpus callosum,
changes in brain volume, thinning of several brain cortical
areas (e.g., in the frontal parietal lobe), and decreased
functional connectivity between brain areas (e.g., within
frontal cortex) contribute to pathophysiology of autism
spectrum disorder (209–212). It was also demonstrated
that dysfunction in glutamatergic system (e.g., exaggerated
signaling) (213–215) and GABAergic system (e.g., decreased
GABA receptor expression and GABA-evoked inhibitory
effects) (215, 216) may have a role in the pathophysiology
of autism spectrum disorder by alterations in the excitation/
inhibition balance. In addition, decreased level of serotonin/
adenosine in implicated brain areas (e.g., medial frontal
cortex) have also been demonstrated/suggested in this disease
(25, 217–220). Impaired immune response, inammation, and
oxidative stress may be causative factors of autism spectrum
disorder (15, 221). In fact, recent studies suggest that autism
spectrum disorder is associated with inflammation (e.g.,
activation of glial cells and increased levels of cytokines)
(222–224), mitochondrial dysfunction, and oxidative stress
(e.g., increased ROS activity) (79, 225–227).
Attention Deficit/Hyperactivity Disorder
Reduction of brain volume and gray matter (e.g., in putamen
and caudate nucleus) and underactivation or hyperactivation
of dierent brain networks (e.g., in the frontoparietal and
ventral attention network and the somatomotor system) were
demonstrated in patients with ADHD (228, 229). Numerous
studies have shown that increased glutamatergic tone/glutamate
level (230), dopamine hypofunction (e.g., decreased stimulation-
evoked release of dopamine) (26), and changes in GABAergic
(e.g., decrease in GABA level) (230, 231), noradrenergic, and
serotonergic system (16, 232–235) in the implicated brain areas
may be causative factors of ADHD. Furthermore, increased
oxidative stress (e.g., enhanced production of ROS) was
demonstrated in a rat model of ADHD (236).
CONCLUSION
e eects of nutritional ketosis on CNS diseases, whether
through diet or supplementation, have not been fully investigated.
Consequently, only limited results have demonstrated the
existence of alleviating eects of exogenous ketone supplement
administration on animal models of psychiatric diseases and
patients with psychiatric disorders. Nevertheless, there are
several common pathophysiological metabolic alterations, such
as changes in neurotransmitter release, increased inammatory
processes, abnormal cerebral glucose metabolism, and decreased
mitochondrial-associated brain energy metabolism, which
may have a role in the emergence of psychiatric diseases.
Consequently, ketogenic interventions that can modulate a
broad array of metabolic and signaling changes underlying the
pathophysiology of psychiatric diseases may alleviate the onset
of symptoms.
Based on our review of the literature, we hypothesize that
utilizing exogenous ketone supplements alone or with ketogenic
diet, either as a primary or an adjunctive therapy for selected
psychiatric disorders, may potentially be an eective treatment.
us, adding ketone supplements as an additional agent to the
therapeutic regimen may alleviate symptoms of psychiatric
diseases via modulation of dierent metabolic routes implicated
in psychiatric disorders. erefore, detailed investigation of
exogenous ketone supplement-evoked direct and/or indirect
alterations in molecular pathways and signaling processes
associated with psychiatric diseases is needed.
e use of exogenous ketone supplements in psychiatric
diseases is only in its infancy. Nevertheless, our increasing
understanding of how exogenous ketone supplement-evoked
ketosis/βHB exerts its eects on CNS diseases, combining with
new results on pathophysiology of psychiatric diseases and their
complex interplay with each other, suggests that exogenous ketone
supplements may be ideal and eective adjuvants to drugs used
in the treatment of psychiatric diseases. us, because exogenous
ketone supplements modulate endogenous processes, their
administration is a safe method to promote disease-alleviating
eects without considerable risk, as well as minimal or no side
eects compared to pharmacological treatments. Consequently,
exogenous ketone supplements may help to both manage the
Ketone Supplement Induced Ketosis in PsychiatryKovács et al.
9May 2019 | Volume 10 | Article 363Frontiers in Psychiatry | www.frontiersin.org
side eects and increase the ecacy of drugs used in psychiatric
diseases, especially in cases of treatment resistance.
Future research should explore the eects of exogenous
ketones on the metabolic processes that underlie the diseases
leading to psychiatric disorders in order to restore abnormal
cerebral glucose and energy metabolism. Moreover, new studies
are needed to investigate the eects, therapeutic ecacy, and
exact mechanism(s) of action of exogenous ketone supplements
alone or in combination with a ketogenic diet not only on
animal models of psychiatric diseases, but also on patients
with dierent psychiatric disorders. Future studies are needed
to reveal which factors (e.g., age, sex, lifestyle, drugs, other
diseases, and so on) can modify the eects of exogenous ketone
supplements on psychiatric diseases; to develop new, more
eective, and safe ketone supplements, which can be used
in special ketogenic foods for treatment of CNS disorders,
including psychiatric diseases. ere is urgent need to develop
therapeutic strategies and broadly accepted protocols guiding
the administration of dierent types and combinations of
exogenous ketone supplements. As a result of new studies in
the near future, a better understanding of the pathophysiology
of dierent psychiatric diseases and the connections between
the underlying metabolic/signaling pathways may promote the
development of novel metabolism-based adjuvant therapies,
such as the administration of exogenous ketone supplements
against psychiatric diseases.
AUTHOR CONTRIBUTIONS
ZK contributed to the conception of the manuscript, comprehensive
search of the electronic databases, and writing of the manuscript.
DPD contributed to the writing of the manuscript. DD, MK, and
CR were in charge of revising the manuscript. CA was in charge of
writing and revising the manuscript.
ACKNOWLEDGMENTS
is work was supported by OTKA K124558 Research Grant (to
Zsolt Kovács) and ONR Grant N000141310062 and GLUT1D
Foundation Grant #6143113500 (to Dominic D`Agostino). We
thank Quest Nutrition LLC for supporting ongoing studies on
this topic (toCsilla Ari).
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Conict of Interest Statement: International Patent #PCT/US2014/031237,
University of South Florida, D.P. D’Agostino, S. Kesl, P. Arnold, “Compositions and
Methods for Producing Elevated and Sustained Ketosis.” Non-provisional patents:
#62289749, University of South Florida, C. Ari, D.P. D’Agostino, “Exogenous ketone
supplements for reducing anxiety-related behavior”; Ari, C., Arnold P., D’Agostino,
D.P. Technology Title: “Elevated blood ketone levels by ketogenic diet or exogenous
ketone supplements induced increased latency of anesthetic induction” USF Ref.
No. 16A018PR; Ari, C., Arnold P., D’Agostino, D.P. Technology Title: “Exogenous
ketone supplementation improved motor function in Sprague–Dawley rats.” USF
Ref. No: 16A019; Ari, C., Arnold P., D’Agostino, D.P. Technology Title: “Lowering
of blood glucose in exercising and non-exercising rats following administration of
exogenous ketones and ketone formulas.” USF Ref. No: 16A049; Ari, C., Arnold P.,
D’Agostino, D.P. Technology Title: “Ketone supplementation elevates blood ketone
level and improves motor function in GLUT1 deciency syndrome mice.” USF Ref.
No: 16B116 (provisional patent); Ari, C., Arnold P., D’Agostino, D.P. Technology
Title: “Neuroregeneration improved by ketone.” USF Ref. No: 16B128 (provisional
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to seizure by combinations of ketone supplements.” USF Ref. No: 16B138PR. D.P.
D’Agostino and C. Ari are co-owners of the company Ketone Technologies LLC,
providing scientic consulting and public speaking engagements about ketogenic
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