In vivo Evidence for Therapeutic Properties of Cannabidiol (CBD) for Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a debilitating neurodegenerative disease that is affecting an increasing number of people. It is characterized by the accumulation of amyloid-β and tau hyperphosphorylation as well as neuroinflammation and oxidative stress. Current AD treatments do not stop or reverse the disease progression, highlighting the need for new, more effective therapeutics. Cannabidiol (CBD) is a non-psychoactive phytocannabinoid that has demonstrated neuroprotective, anti-inflammatory and antioxidant properties in vitro. Thus, it is investigated as a potential multifunctional treatment option for AD. Here, we summarize the current status quo of in vivo effects of CBD in established pharmacological and transgenic animal models for AD. The studies demonstrate the ability of CBD to reduce reactive gliosis and the neuroinflammatory response as well as to promote neurogenesis. Importantly, CBD also reverses and prevents the development of cognitive deficits in AD rodent models. Interestingly, combination therapies of CBD and Δ⁹-tetrahydrocannabinol (THC), the main active ingredient of cannabis sativa, show that CBD can antagonize the psychoactive effects associated with THC and possibly mediate greater therapeutic benefits than either phytocannabinoid alone. The studies provide “proof of principle” that CBD and possibly CBD-THC combinations are valid candidates for novel AD therapies. Further investigations should address the long-term potential of CBD and evaluate mechanisms involved in the therapeutic effects described.

Full text

MINI REVIEW
published: 03 February 2017
doi: 10.3389/fphar.2017.00020
Frontiers in Pharmacology | www.frontiersin.org 1February 2017 | Volume 8 | Article 20
Edited by:
Giuseppe Esposito,
Sapienza University of Rome, Italy
Reviewed by:
He-Hui Xie,
Shanghai Jiao Tong University, China
Ester Aso,
Bellvitge University Hospital, Spain
*Correspondence:
Tim Karl
t.karl@westernsydney.edu.au
Specialty section:
This article was submitted to
Ethnopharmacology,
a section of the journal
Frontiers in Pharmacology
Received: 12 October 2016
Accepted: 10 January 2017
Published: 03 February 2017
Citation:
Watt G and Karl T (2017) In vivo
Evidence for Therapeutic Properties of
Cannabidiol (CBD) for Alzheimer’s
Disease. Front. Pharmacol. 8:20.
doi: 10.3389/fphar.2017.00020
In vivo Evidence for Therapeutic
Properties of Cannabidiol (CBD) for
Alzheimer’s Disease
Georgia Watt 1and Tim Karl1, 2*
1Karl Group, Behavioural Neuroscience, Western Sydney University, Campbelltown, NSW, Australia, 2Neuroscience
Research Australia, Randwick, NSW, Australia
Alzheimer’s disease (AD) is a debilitating neurodegenerative disease that is affecting an
increasing number of people. It is characterized by the accumulation of amyloid-βand
tau hyperphosphorylation as well as neuroinflammation and oxidative stress. Current AD
treatments do not stop or reverse the disease progression, highlighting the need for new,
more effective therapeutics. Cannabidiol (CBD) is a non-psychoactive phytocannabinoid
that has demonstrated neuroprotective, anti-inflammatory and antioxidant properties
in vitro. Thus, it is investigated as a potential multifunctional treatment option for AD.
Here, we summarize the current status quo of in vivo effects of CBD in established
pharmacological and transgenic animal models for AD. The studies demonstrate the
ability of CBD to reduce reactive gliosis and the neuroinflammatory response as well as
to promote neurogenesis. Importantly, CBD also reverses and prevents the development
of cognitive deficits in AD rodent models. Interestingly, combination therapies of CBD
and 9
1-tetrahydrocannabinol (THC), the main active ingredient of cannabis sativa, show
that CBD can antagonize the psychoactive effects associated with THC and possibly
mediate greater therapeutic benefits than either phytocannabinoid alone. The studies
provide “proof of principle” that CBD and possibly CBD-THC combinations are valid
candidates for novel AD therapies. Further investigations should address the long-term
potential of CBD and evaluate mechanisms involved in the therapeutic effects described.
Keywords: Alzheimer’s disease, cannabidiol, 19-tetrahydrocannabinol, transgenic mouse model, therapy
THE PROBLEM
Alzheimer’s Disease (AD) is a debilitating neurodegenerative disease that is characterized by
cognitive decline. It is the most common form of dementia, accounting for over 60% of cases and
affecting over 33 million people worldwide (Wisniewski and Goni, 2014; Alzheimer’s Association,
2015). Unfortunately, as a result of the aging population, this number is expected to reach 115
million by the year 2050 (Wisniewski and Goni, 2014). AD typically begins with mild deficits
in short-term memory, learning, communication and spatial orientation. In the moderate stage
of the disease, the deficits begin to affect everyday life including eating, dressing and emotional
control (Alzheimer’s Association, 2015). In the late stages of the disease there is global disruption of
cognitive ability, with severe impairments in speech and facial recognition, all of which renders the
patients in need of 24-h care. As the disease progresses, patients become increasingly susceptible to
other illnesses as well (Alzheimer’s Association, 2015).

Watt and Karl Therapeutic Properties of Cannabidiol for Alzheimer’s Disease
THE ORIGIN
AD is classified into two types, late-onset sporadic AD (>95% of
cases) or early-onset familial AD (<5% cases) (Gotz and Ittner,
2008). Although, sporadic AD is the most common form, it
is much less understood than familial AD. Familial AD is also
known as the genetic form, as it results from autosomal dominant
mutations in the amyloid precursor protein (APP) gene or in
the presenilin 1 and 2 (PS1 and PS2) genes (Gotz and Ittner,
2008; Bettens et al., 2013). APP is the precursor molecule, which
is cleaved into amyloid-β(Aβ) peptides, while PS1 and PS2
encode the γ-secretase and β-secretase complexes that mediate
APP splicing (Bettens et al., 2013; Gotz and Ittner, 2008). After
APP splicing Aβcan exist in two forms, Aβ40 and Aβ42. Aβ42 is
thought to be the more toxic form of the protein as it aggregates
more readily than Aβ40 (Chapman et al., 2001). The cause of
sporadic AD is less clear and yet to be defined, however, recent
research indicates that it may result from a complex interaction
between several environmental factors and various susceptible
genes. Numerous genes have been reported as susceptible genes
for sporadic AD with the best-documented one being APOE
(Kamboh, 2004).
Although familial and sporadic AD differ in their cause, the
progression of the disease from this point onwards appears to
be the same. Both forms of AD exhibit a neurodegenerative
cascade that appears to be instigated by the accumulation
of Aβ(forming senile plaques) and hyperphosphorylated tau
[forming neurofibrillary tangles (NFTs)] (Chapman et al.,
2001). The cascade induces neuroinflammation and oxidative
stress, which creates a neurotoxic environment that potentiates
neurodegeneration and eventually leads to cognitive decline
(Hardy and Selkoe, 2002; Ahmed et al., 2015). Also, Aβ-induced
neurodegeneration elevates glutamate levels in the cerebral spinal
fluid of AD patients (Pomara et al., 1992) and cholinergic
neurons are lost in brain areas relevant for memory processing
(and accompanied by a decrease in acetylcholine) (Schliebs and
Arendt, 2011).
CURRENT TREATMENTS
Despite the increase in our understanding of disease mechanism,
the current approved AD treatments only provide limited
therapeutic benefits. There are four approved drugs available,
three are acetylcholinesterase inhibitors (rivistagmine, donepezil
and galantamine) and one is a N-methyl-D-aspartate (NMDA)
receptor antagonist (memantine) (Mangialasche et al., 2010).
Unfortunately, all of them have been associated with adverse
effects. Acetylcholinesterase inhibitors may cause nausea,
vomiting, diarrhea and weight loss (Kaduszkiewicz et al., 2005),
while memantine is known to cause hallucinations, dizziness
and fatigue (Herrmann et al., 2011). Furthermore, none of these
treatments prevent or reverse the progression of the disease
but rather they treat the disease symptoms with limited efficacy
(Salomone et al., 2012).
Current clinical trials to evaluate new AD treatments are
targeting various aspects of AD pathology, with a strong
focus on Aβ. Clinical trials have investigated both β- and γ-
secretase inhibitors, which play a crucial role in the formation
of pathological Aβ. Unfortunately, β-secretases are difficult to
target and γ-secretases have a wide range of functions resulting
in adverse side effects (e.g., impaired cognition and functionality,
gastrointestinal toxicity and increased incidence of skin cancer)
(Imbimbo and Giardina, 2011; Schenk et al., 2012). Active and
passive immunotherapies to target senile plaques and NFTs have
also been investigated. Aβimmunotherapies in mouse models
demonstrated potential as they increased microglial phagocytosis
of Aβand reduced cognitive decline. However, in phase II and III
clinical trials those therapies have demonstrated limited efficacy
or resulted in severe adverse effects (e.g., meningoenchephalitis)
(Mullane and Williams, 2013). A recent study investigating
an antibody based immunotherapy for Aβfound promising
results in phase I and phase II trials but this therapy is yet
to undergo phase III clinical trials (Sevigny et al., 2016). Tau
immunotherapies were effective in AD mouse models but have
provided limited success in clinical trials (McGeer et al., 2006;
Schenk et al., 2012; Mullane and Williams, 2013).
Epidemiological data have shown that non-steroidal anti-
inflammatory drugs (NSAIDs) are associated with a reduced
risk of AD (McGeer et al., 2006). Furthermore, animal
studies indicated that NSAID treatment could attenuate AD
pathogenesis, proposing that inhibiting neuroinflammation may
slow the progression of AD (Maccioni et al., 2009). However,
NSAIDs have also been associated with severe long-term adverse
effects (e.g., gastrointestinal problems) and have only shown
limited efficacy in reducing or preventing clinical symptoms
(McGeer et al., 2006; Rojo et al., 2008).
It is unlikely that any drug acting on a single pathway or
target will mitigate the complex pathoetiological cascade leading
to AD. Therefore, a multifunctional drug approach targeting a
number of AD pathologies simultaneously will provide better,
wider-ranging benefits than current therapeutic approaches (Van
der Schyf and Geldenhuys, 2011; Bedse et al., 2015). Importantly,
the endocannabinoid system has recently gained attention in AD
research as it is associated with regulating a variety of processes
related to AD, including oxidative stress (Marsicano et al., 2002),
glial cell activation (Germain et al., 2002) and clearance of
macromolecules (Bilkei-Gorzo, 2012).
CANNABIDIOL
The phytocannabinoid cannabidiol (CBD) is a prime candidate
for this new treatment strategy. CBD has been found in vitro to be
neuroprotective (Esposito et al., 2006b), to prevent hippocampal
and cortical neurodegeneration (Hamelink et al., 2005), to have
anti-inflammatory and antioxidant properties (Mukhopadhyay
et al., 2011), reduce tau hyperphosphorylation (Esposito et al.,
2006a) and to regulate microglial cell migration (Walter et al.,
2003; Martín-Moreno et al., 2011). Furthermore, CBD was shown
to protect against Aβmediated neurotoxicity and microglial-
activated neurotoxicity (Janefjord et al., 2014), to reduce Aβ
production by inducing APP ubiquination (Scuderi et al., 2014)
and to improve cell viability (Harvey et al., 2012) (summarized
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Watt and Karl Therapeutic Properties of Cannabidiol for Alzheimer’s Disease
in Table 1). These properties suggest that CBD is perfectly placed
to treat a number of pathologies typically found in AD. In the
following, we will outline in brief the endocannabinoid system
and the pharmacological profile of CBD before discussing recent
advances in the evaluation of the therapeutic properties of CBD
(and CBD-THC combinations) using in vivo AD rodent models.
The Endocannabinoid System and CBD
Pharmacology
The endocanabinoid system (eCBS) consists
of endocannabinoids [e.g., anandamide and 2-
arachiodonoylglycerol (2-AG)], enzymes required for their
synthesis and degradation [fatty acid amide hydrolase (FAAH),
monoglyceride lipase (MAGL), and diacylglycerol lipase
(DAGL)], and cannabinoid receptors [the best described being
cannabinoid receptors 1 and 2 (CB1and CB2)], (Di Marzo et al.,
2015). Post mortem analyses have found that several of these
components are altered in both composition and signaling in
AD postmortem brain tissue (Aso and Ferrer, 2015).
CBD has a complex interaction with the eCBS. It has
demonstrated low displacement at the CB1and CB2
receptors compared to other cannabinoids such as 19-
tetrahydrocannabinol (THC) (Thomas et al., 1998). CBD has
also been shown to have low affinity for both cannabinoid
receptors (Petitet et al., 1998) and has antagonistic properties
against the synthetic cannabinoid, CP 55 940, which is a potent
agonist at both CB1and CB2receptors. Interestingly, CBD
antagonizes CP 55, 940 at a much lower concentration than
it binds to the cannabinoid receptors, suggesting it may act
at a prejunctional site which is not the cannabinoid receptors
(Pertwee et al., 2002). CBD acts as an inverse agonist at the CB2
receptors, which may explain some of its anti-inflammatory
properties as inverse agonists at CB2receptors are able to inhibit
the migration of immune cells (Lunn et al., 2006). CBD has
also been found to act as an antagonist at the cannabinoid
G-protein receptors (GPR) GPR55 and GPR18 (Ryberg et al.,
2007; McHugh et al., 2010), as well as activate the putative
abnormal CBD receptor (Pertwee, 2008) and the vanilloid
receptor 1 (Bisogno et al., 2001). Finally, CBD interacts with
various neurotransmitter systems including glutamate receptors
[i.e., NMDA receptors, 2-amino-3-(4-butyl-3-hydroxyisoxazol-
5-yl)propionic acid (AMPA) receptors and kainite receptors] and
the serotonergic receptor, 5-HT1A (Russo et al., 2005). The wide
range of targets of CBD emphasizes its potential as a multimodal
drug for AD treatment.
CBD Effects in Pharmacological Rodent
Models of AD
The in vivo therapeutic potential of CBD in AD has not been
widely documented, however, there are a number of studies that
have reported the effect of CBD in pharmacological models of AD
(e.g., inoculation with fibrillar Aβ). These studies have described
anti-inflammatory and neuroprotective effects of CBD. The in
vivo anti-inflammatory effects of CBD were confirmed in a mouse
model of AD where the mice were intrahippocampally injected
with human Aβ42 and then treated daily with intraperitoneal
(i.p.) injections of CBD (2.5 or 10 mg/kg) for 7 days (Esposito
et al., 2007). The results from this study demonstrated that CBD
was able to dose-dependently inhibit glial fibrillary acidic protein
(GFAP) mRNA and protein expression. GFAP is the best known
marker of activated astrocytes and thought to be one of the main
features of reactive gliosis (Esposito et al., 2007). Therefore, these
results imply that CBD is able to reduce Aβ-induced reactive
gliosis. In addition, CBD reduced both iNOS and interleukin-1β
(IL-1β) protein expression and the related NO and IL-1βrelease
(Esposito et al., 2007). NO and IL-1βare a few of the many active
substances released by Aβ-stimulated microglia and therefore
have been identified as potential modulators of neuronal damage.
NO is a free radical and important in neuroinflammatory
and neurodegenerative conditions, which include accelerating
protein nitration and increasing tau hyperphosphorylation
(Esposito et al., 2007). IL-1βis involved in the cytokine cycle
responsible for neurodegeneration, the synthesis and processing
of APP, the activation of astrocytes and the overexpression of
iNOS and overproduction of NO (Esposito et al., 2007). Data
from in vitro studies suggest that CBD may be able to reduce
iNOS protein expression and NO release as a result of its ability
to rescue the Wnt/β-catenin pathway, which plays a role in tau
hyperphosphorylation (Esposito et al., 2006a). Finally, the ability
of CBD to attenuate reactive gliosis may result from CBD’s ability
to act as an inverse agonist at the cannabinoid receptor 2 (CB2),
which is thought to be involved in reactive gliosis (Walter and
Stella, 2004; Thomas et al., 2007).
The anti-inflammatory and neuroprotective effects of CBD
were further investigated in a rat model of AD-related
neuroinflammation. This study evaluated the involvement of the
peroxisome proliferator activated receptor (PPAR) receptors in
the therapeutic effects of CBD, as PPAR-γreceptors are increased
in AD patients (Esposito et al., 2011). Adult, male rats were
inoculated with human Aβ42 in the hippocampus and then
treated with CBD (10 mg/kg) either in the presence or in the
absence of a PPAR-γor PPAR-αreceptor antagonist for 15
days. CBD was able to dose-dependently decrease Aβ-induced
expression of iNOS, GFAP, S100 calcium binding protein B
(S100B) and p50 and p56 antibodies in rat astrocytes (Esposito
et al., 2011). iNOS and GFAP, as mentioned previously, are
key elements in reactive gliosis and therefore their reduction
demonstrates CBD’s anti-inflammatory properties. CBD’s ability
to reduce reactive gliosis is further emphasized by the inhibition
of S100B. S100B is an astroglial-derived neurotrophin that plays
a crucial role in the pro-inflammatory cytokine cycle and the
promotion of APP to cleave Aβ42. It is also involved in the
disruption of the Wnt/β-catenin pathway and therefore inhibits
tau hyperphosphorylation (Esposito et al., 2011). Furthermore,
the reduction of p50 and p56 expression indicates CBD’s ability
to inhibit NF-κB and therefore emphasizes the responsibility of
both PPAR-γand NF-κB in CBD’s anti-inflammatory properties
(Esposito et al., 2011). The therapeutic benefit of CBD was
blocked when co-administered with the PPAR-γantagonist (but
not the PPAR-αantagonist) (Esposito et al., 2011), suggesting
that CBD-induced anti-inflammatory properties are mediated
(at least partially) through the PPAR-γreceptor (Esposito et al.,
2011). Finally, the study found that CBD was able to restore CA1
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Watt and Karl Therapeutic Properties of Cannabidiol for Alzheimer’s Disease
TABLE 1 | Summary of the effects of CBD and CBD-THC combinations on AD models.
Effect of Cannabidiol on AD-like Pathology
Model Effect References
IN VITRO STUDIES USING CBD
PC12 Neuronal Cells Protected against Aβneurotoxicity and oxidative stress, increased cell survival
and decreased ROS production and lipid peroxidation
Iuvone et al., 2004
Inhibited tau hyperphosphorylation Esposito et al., 2006a
Prevented transcription of pro-inflammatory genes Esposito et al., 2006b
Glutamate Neuronal Toxicity Model Antioxidant properties Hampson et al., 1998
Primary Rat Microglia Increased microglial migration and prevented ATP-induced intracellular calcium
increase
Martín-Moreno et al., 2011
PC12 and SH-SY5Y Cells Improved cell viability after treatment with tert-butyl hydroperoxide treatment Harvey et al., 2012
SH-SY5Y Cells Protected against Aβneurotoxicity and microglial-activated neurotoxicity Janefjord et al., 2014
SH-SY5YAPP+Cells Induced APP ubiquination and subsequently Aβproduction and increased cell
survival by reducing apoptotic rate
Scuderi et al., 2014
IN VIVO STUDIES USING CBD
Mice inoculated with human Aβ42 peptide Attenuated Aβinduced neuroinflammatory responses by decreasing expression
of pro-inflammatory gene and mediators
Esposito et al., 2007
Reduced reactive gliosis Esposito et al., 2011
Mice intraventricularly injected with fibrillar AβDecreased microglial activation and reversed a spatial reference memory deficit
in the MWM
Martín-Moreno et al., 2011
APPxPS1 transgenic mice (mixed background) Reversed social and object recognition memory deficits in the CB task Cheng et al., 2014a
Prevented development of social recognition memory deficits. No effect on Aβ
load but subtle effects on inflammatory markers, cholesterol and dietary
phytosterol retention
Cheng et al., 2014b
IN VIVO STUDIES USING CBD-THC
Young APPxPS1 transgenic mice (mixed background) Improved memory deficits in the two-object recognition task and the active
avoidance task. Decreased soluble Aβ42 levels and changed plaque composition
and reduced astrogliosis, microgliosis and inflammatory related molecules
Aso et al., 2015
Aged APPxPS1 transgenic mice (mixed background) Restored cognition in the two object recognition task but had no effects on Aβ
load or related glial reactivity
Aso et al., 2016
Transgenic tauopathy mouse model Reduced Aβand tau deposition in the hippocampus and cerebral cortex,
increased autophagy, decreased gliosis, increased the ratio of reduced/oxidized
glutathione and reduced levels of iNOS
Casarejos et al., 2013
pyramidal neurons to a similar integrity to that of the control
rats. CBD also down-regulated gliosis and repaired neurogenesis
in the dentate gyrus (Esposito et al., 2011).
One study to date has investigated the effects of CBD on
cognition in a pharmacological model of AD. Three-month old
mice were intraventricularly injected with 2.5 µg of fibrillar Aβ.
They were then treated with 20 mg/kg CBD using daily i.p.
injections for 1 week and then 3 times/week for the following 2
weeks. The spatial learning of the mice was then assessed in the
Morris Water Maze (Martín-Moreno et al., 2011). CBD treatment
was able to reverse the cognitive deficits of Aβ-treated mice.
Interestingly, selective CB2agonists did not prevent the cognitive
deficit, indicating that CBD exerts this therapeutic effect via
other mechanisms (Martín-Moreno et al., 2011). CBD treatment
also prevented Aβ-induced IL-6 gene expression suggesting that
the behavioral benefits documented may be mediated by glial
activation modulation. However, CBD did not influence TNF-
αgene expression. In vitro results from this study supported
this finding as CBD treatment prevented the ATP-induced
intracellular calcium increase and promoted microglial activation
in cultured microglia (Martín-Moreno et al., 2011).
CBD Effects in Transgenic Mouse Models
of AD
Although pharmacological models of AD are useful in producing
AD-like symptoms, it is necessary to investigate the effects of
CBD in transgenic mouse models as they result from gene
mutations, which are seen in familial AD (e.g., APP,PS1, and PS2
gene mutations). Furthermore, based on the pharmacological
protocols used, some effects of CBD could be related to a direct
effect of the phytocannabinoid on exogenous Aβadministration
rather than the long-term effects of the accumulated Aβ. Initially,
two studies were conducted in our laboratories to elucidate the
remedial and preventative potential of chronic CBD treatment
in AD transgenic mice. To assess the remedial effects of CBD,
adult male APPxPS1 mice were treated for 3 weeks with CBD (20
mg/kg CBD, daily i.p. injections) post onset of cognitive deficits
and AD pathology (Cheng et al., 2014a). CBD treatment was
able to reverse cognitive deficits in object recognition memory
and social recognition memory without influencing anxiety
parameters (Cheng et al., 2014a).
In the preventative treatment study, male APPxPS1 mice at the
age of 2.5 months were treated for 8 months with either 20 mg/kg
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Watt and Karl Therapeutic Properties of Cannabidiol for Alzheimer’s Disease
CBD or vehicle pellets using a daily voluntary oral administration
protocol (Cheng et al., 2014b). This assessed the long-term effect
of CBD prior to “AD onset.” Long-term CBD treatment was
able to prevent the development of social recognition memory
deficits without affecting anxiety domains in AD transgenic mice
(Cheng et al., 2014b). These beneficial effects were not associated
with a reduction in Aβload or oxidative damage. There was also
no difference in hippocampal or cortical soluble and insoluble
levels of Aβ40 and Aβ42 in the AD transgenic mice regardless
of treatment. Furthermore, cortical lipid oxidation levels were
not altered by CBD treatment. However, the study did report
a complex interaction between CBD treatment, AD genotype
and cholesterol and phytosterol levels, suggesting they may be
involved in the mechanisms behind the beneficial effects of CBD.
There was also a subtle impact of CBD on inflammatory markers
of the brain (Cheng et al., 2014b). Further research will be
necessary to elucidate the potential mechanisms further, thereby
also considering other treatment designs (i.e., different ages at
treatment onset and CBD doses).
Recent research has indicated that a combination of CBD
and 19-tetrahydrocannabinol (THC) can avoid the detrimental
effects caused by THC-induced activation of the CB1receptors
(e.g., psychoactivity), and actually provide greater therapeutic
benefits than either phytocannabinoid alone. Importantly, there
is controversy about what the ratios of CBD:THC should
be used in order to antagonize detrimental THC effects. It
has been reported that a >10-fold higher dose of CBD was
necessary to prevent the unwanted side effects of THC. Other
research suggests that CBD may even modestly potentiate THC’s
psychoactive effects (Fadda et al., 2004; Klein et al., 2011).
Nevertheless, Sativex (GW pharmaceuticals, Salisbury, United
Kingdom), a combination therapy using a 1:1 ratio of CBD and
THC is approved as an anti-inflammatory drug treatment against
spasms in multiple sclerosis and does not appear to be associated
with any adverse THC effects, suggesting that CBD effectively
blocks those at the ratio chosen (Collin et al., 2010; Novotna et al.,
2011).
Three studies to date have evaluated the efficacy of a
combination of CBD and THC on AD-related processes in
vivo. The first study conducted by Casarejos et al. (2013)
investigated the effects of Sativex in a mouse model of tauopathy.
This mouse model was foremost a model of frontotemporal
dementia, parkinsonism and lower motor neuron disease. The
study found that Sativex decreased gliosis, increased the ratio
of reduced/oxidized glutathione and reduced the levels of iNOS
(Casarejos et al., 2013), thereby showing neuroprotective and
anti-oxidant properties. Importantly, Sativex reduced Aβand
tau deposition in the hippocampus and cerebral cortex as well
as increasing autophagy (Casarejos et al., 2013), thus implying,
that although the mouse model is not directly related to AD, the
therapeutic benefits are.
The second study conducted by Aso et al. (2015) compared
the effect of CBD, THC and a CBD-THC combination in the
APPxPS1 mouse model, in the early symptomatic phase (∼6
months). This study found that all treatments improved memory
deficits in the two-object recognition task but only the CBD-
THC combination prevented the learning deficit seen in the
active avoidance task. CBD-THC combination also decreased
soluble Aβ42 levels and changed plaque composition while
CBD and THC individually did not (Aso et al., 2015). Finally,
reduced astrogliosis, microgliosis and inflammatory related
molecules were more pronounced after treatment with the CBD-
THC combination than either phytocannabinoid individually
(Aso et al., 2015). This suggests that when CBD and THC
are combined there may be either a summative effect or an
interaction effect between the compounds, which potentiates
their therapeutic-like effects (Aso et al., 2015). In this context, it
should be mentioned, that although all treatments had cognition-
improving characteristics in the object recognition task, THC
alone had a detrimental effect on cognition in control mice,
highlighting the need to be cautious when considering THC as
a therapeutic. However, control mice treated with CBD-THC
combination did not show any cognitive deficits suggesting that
CBD may be able to antagonize the detrimental effects of THC
(Aso et al., 2015).
In a very recent follow-up study, Aso et al. also investigated
the effect of CBD-THC combination treatment on memory and
brain pathology in aged male APPxPS1 mice and littermate
controls (12 months) as well as non-aged controls, 3 months
old control mice (Aso et al., 2016). Compared to the non-
aged controls, vehicle-treated aged mice demonstrated impaired
cognition in the two-object recognition task. Interestingly, CBD-
THC combination restored the memory deficit of APPxPS1
but not WT control mice (Aso et al., 2016). In comparison to
their previous study testing younger APPxPS1 mice (Aso et al.,
2015), CBD-THC combination did not influence the Aβload
or the related glial reactivity in aged AD transgenic mice (Aso
et al., 2016)., However, the combination treatment normalized
synaptosome associated protein 25, glutamate receptors 2 and
3 and γ-aminobutyric acid receptor A subunit α1 expression,
implying that CBD-THC may exert its beneficial effects on
cognition via these mechanisms.
CONCLUSIONS
AD is a debilitating neurodegenerative disease that is becoming
increasingly common in today’s society. Unfortunately, there is
still no effective treatment that stops or reverses the disease
progression. The studies reviewed in this mini review provide
“proof of principle” for the therapeutic benefits CBD and possibly
CBD-THC combinations pose for AD therapy (summarized in
Table 1). However, further dose-dependent investigations into
transgenic mouse models of AD are necessary to understand
the full potential and the long-term effects of CBD. Importantly,
many of the discussed studies were conducted in mice aged
between 3 and 6 months, which is quite young considering AD
diagnosis is usually relatively late in the disease progression.
Furthermore, it is necessary to investigate the effects of CBD in
tauopathy mouse models specific to AD and in female mouse
models as all studies reviewed were conducted in male mice
only. Nevertheless, the studies discussed here provide promising
preliminary data and the translation of this preclinical work
into the clinical setting could be realized relatively quickly: CBD
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Watt and Karl Therapeutic Properties of Cannabidiol for Alzheimer’s Disease
is readily available, appears to only have limited side effects
(Bergamaschi et al., 2011) and is safe for human use (Leweke
et al., 2012).
AUTHOR CONTRIBUTIONS
TK and GW were both involved in the conceptualization,
reference search, and writing of this mini review.
ACKNOWLEDGMENTS
TK received a career development award (1045643) of the
National Health and Medical Research Council (NHMRC) and
is also supported by a NHMRC project grant (1102012), the
NHMRC Dementia Research Team Initiative (1095215) as well as
the Rebecca L. Cooper Limited Research Foundation. We thank
Jerry Tanda for critical comments on the manuscript.
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Conflict of Interest Statement: The authors declare that the research was
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