




































The Therapeutic Potential of Synthetic and Natural Cannabinoids in Treating Alzheimer’s Disease - Front Page


Berkeley
Pharma Tech
Journal of Medicine

Correspondence 
nidhirkan@gmail.com

Keywords
Alzheimer's disease
Amyloid-beta
Cannabinoids
Tau Protein 
Hyperphosphorylation 
∆9-tetrahydrocannabinol

Submitted June 28, 2021 
Accepted July 6, 2021
Published December 17, 2021

Full Open Access

Creative Commons Attribution 
License 4.0

Abstract
Alzheimer’s disease (AD) is one of the most prevalent and debilitating neurodegenerative 
diseases in the world, highlighting the need for research on novel treatments and therapies. 
Previous studies have found that the body’s endocannabinoid system (ECS) interacts closely 
with its neural system, making it a potential avenue for the treatment of neurological 
disorders. One hallmark of AD is the accumulation of amyloid-beta (Aβ) in the brain and its 
potentially detrimental effects on cognitive function. Cannabis-based drugs have been 
observed to regulate Aβ modifications and inhibit AD progression. Furthermore, 
cannabinoids have been noted to reduce inflammation and neurotoxicity. Synthetic 
cannabinoids were able to rescue memory deficits and neurodegeneration, and reduce 
immunoreactivity. Similarly, natural cannabinoids like ∆9-tetrahydrocannabinol (THC) 
and cannabidiol (CBD) demonstrate therapeutic potential by interacting with the cholinergic 
system, and reversing the symptoms of AD. Although further research and testing are 
needed, it is evident that the use of cannabinoids shows promise for future treatment in AD 
patients. 

The Therapeutic Potential of  
Synthetic and Natural Cannabinoids 
in Treating Alzheimer’s Disease
By: Nidhi Kanchumarthi, Avigail Rockland, Thejaswini Vembar, Elaine Liu, Rithvik 
Kanaad, Erick Torres Hinojosa, Kira Tiv, Benjamin Chen, Shira Hao, Sri Guttikonda, and 
Ramiro Garza



I. Introduction
Previous studies have concluded that the endocannabinoid system (ECS) is
disrupted by many neurodegenerative disorders (Di Marzo et al., 2015;
Fagan, 2014; Paloczi et al., 2018). The goal of this paper is to
comprehensively review and outline the most recent data around the
pathophysiology of the ECS as it relates to Alzheimer’s Disease (AD), as
well as to investigate the e�cacy of natural and synthetic cannabinoids as a
therapeutic option. Even as medicine advances and life expectancy increases,
AD is still a prevalent issue.

With increased prevalence comes the need for new and e�ective therapies.
The endocannabinoid system shows promise, serving as both a
neuromodulator and immunomodulator. Cannabis sativa has been studied
for its potential neuroprotective qualities and its role in attenuating
nociception in several medical contexts, including cancer, psychiatric
disorders, and epilepsy. Its primary active components,
∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD), interact with the
endocannabinoid signaling system through the endocannabinoid CB1 and
CB2 receptors. Stimulation of these receptors by various agonists has also
successfully reduced the chronic neuroin�ammation associated with AD by
interfering with the di�erent neural pathways. Our goal has been to identify
the mechanisms by which the reduction in neuroin�ammation is
accomplished.

Accumulation of Aβ peptide and hyperphosphorylated tau protein in the
brain play an important role in the onset and progression of Alzheimer's
disease (AD) (Farkhondeh et al., 2020). However, recent research has
suggested that Aβ is no longer considered the primary cause, which was the
accepted belief for many years (Cubinkova et al., 2018). Nevertheless, the
ECS o�ers many therapeutic possibilities for targeting these Aβ deposits.
Many studies support the �nding that elevated levels of the
endocannabinoid 2AG, coupled with the modulation of the common
cannabinoid receptor CB2, could reduce Aβ plaque accumulation (Paloczi,
2018). While Aβ may not be the primary cause of AD, studies have shown
that these deposits are detrimental to healthy synapses (Shankar et al.,
2008), decreasing long-term potentiation and increasing long-term
depression. Sometimes, this neural damage is permanent, but the use of
cannabinoids to stimulate the ECS has shown some success in preventing
this kind of damage.

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Pathology of the cholinergic system is also associated with AD and thus has
been further investigated as a therapeutic target. Many cholinergic pathways
function in conscious awareness, attention, and working memory, which
are areas commonly found to be damaged or dysfunctional in those who
su�er from AD. Research by K.J. Thompson suggests that interacting
signals between the endocannabinoid and cholinergic systems may be a way
to improve cholinergic signaling and repair synaptic plasticity that is
damaged as a result of AD (Thompson et al., 2020). We then investigate the
inhibitory activity of various receptor agonists of the ECS, both natural and
synthetic. This section looks at CBD and THC as receptor agonists and
concludes that CBD plays a role in the inhibition of neural apoptosis while
THC is active in the inhibition of acetylcholinesterase (AChE), which
serves to improve the reduced cholinergic signalling associated with AD.
Both agonists seem to play a part in the reduction of Aβ build-up, but the
exact pathways still need to be elucidated.

Some of the most e�ective and well-researched synthetic agonists of the
ECS include Dronabinol, Nabilone, WIN55,212-2, and JWH-015.
Dronabinol and Nabilone were found to be particularly e�ective in treating
the neuropsychiatric symptoms (NPS) associated with AD, while the others
primarily function in reducing Aβ plaques and neuroin�ammation. Our
review presents published research that supports the e�cacy of both natural
and synthetic cannabinoids as a potential treatment for AD. This
introduces a potential bias, as studies which conclude positive results and
relationships are more likely to be published than those with negative
results. Nevertheless, this research highlights the potential bene�ts that
cannabinoid therapy could provide and recommends that it be studied
further.

II. Neural Pathway
A. Amyloidogenic Pathway
Accumulation of Aβ peptide and hyperphosphorylated tau protein in the
brain are the leading sources of the onset and progression of AD
(Farkhondeh et al., 2020). When amyloid precursor protein (APP) is
activated, it is cleaved by other proteins, which leads to the production of
small Aβ fragments. This induces an increased production and aggregation
of Aβ peptide in limbic and association cortices. As a result, the altered
neuronal homeostasis and oxidative injury provoke neuro�brillary tangle
formation. These tangles are a characteristic trait of AD brains and lead to

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neuronal loss and cognitive impairment (Hall et al., 2001; Nelson et al.,
2012).

Fig. 1: The process of neuro�brillary tangle formation induced by amyloid plaque buildup. As the
amyloid precursor protein (APP) is activated, amounts of Aβ are produced. This excess Aβ leads the
neuro�brillary tangle formation, as seen in AD a�ected patients.

CBD, a Cannabis derivative devoid of psychotropic e�ects, has been
shown to interfere with several Aβ-triggered neurodegenerative pathways
(Scuderi et al., 2014). Studies found that CBD led to the downregulation
of genes linked to AD, including genes coding for the kinases responsible
for tau phosphorylation and for the secretases involved in Aβ generation.
Pre-treatment with CBD prevented the expression of proteins potentially
involved in tau phosphorylation and Aβ production in gingiva-derived

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mesenchymal stem cells (GMSCs) (Libroet al., 2016). In one study, the
role of CBD was investigated as a modulating compound of APP
processing in SHSY5Y(APP+) neurons. In addition, the putative
involvement of PPARγ was explored as a candidate molecular site
responsible for CBD actions. The results indicated that CBD is capable of
inducing the ubiquitination —the degradation —of APP protein, leading
to a decrease in APP full length protein levels in SHSY5Y(APP+) and a
consequent decrease in Aβ production. CBD also promoted an increased
survival of SHSY5Y(APP+) neurons by reducing their long-term
apoptotic rate (Scuderi et al., 2014). In conclusion, research indicates that
cannabis-based drugs inhibited the progression of AD by regulating Aβ
modi�cations (Farkhondeh et al., 2020).

While the aggregation of Aβ plaques has been the leading hypothesis in the
onset ofAD for several years, recent research has suggested alternative
hypotheses. A number of drugs targeting Aβ, such as Aducanumab — an
antibody drug that binds to insoluble and soluble Aβ plaques to reduce its
levels in the brain — were successful in slowing the rate of cognitive
function decline in patients with mild AD, but not in treating the root
cause. One hypothesis suggests that AD is a synaptic disease. It has been
argued that synaptic impairment is an early event in neurodegenerative
processes during AD and that synaptic loss and failure corresponds with
cognitive decline in AD as well (Cubinkova et al., 2018). Recently, it was
shown that impaired synapses in AD brains released tau protein in response
to potassium chloride (KCl) stimulation, suggesting that it may be involved
in the progression of tau in the brain (Cubinkovaet al., 2018). In addition
to the synaptic hypothesis, some researchers believe that alpha-synuclein
acts as a pathogenic modulator in AD. Alpha-synuclein is a protein that
localizes to the nerve terminal and regulates neurotransmitter release in the
presynaptic neuron. It was found that levels of soluble alpha-synuclein are
about two-fold higher in the brains of AD patients than in control brains
and correlate better with cognitive impairment (Cubinkova et al.,2018),
suggesting that overexpression of the alpha-synuclein protein may play a
role in the onset of AD. Even in light of these alternative hypotheses, most
research focuses on the e�ects that cannabinoids have on the production of
Aβ plaques as a measure of treating AD.

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B. Endocannabinoid Signaling
The endocannabinoid system regulates brain function as well as immune
system activity, thus allowing it to serve as a therapeutic strategy for AD. Its
dual ability as a neuromodulator and immunomodulator is due to the
speci�c locations in which cannabinoid receptors type 1 (CB1) and type 2
(CB2) gather (Bonnet & Marchant, 2015). The components of the
endocannabinoid system primarily include two endocannabinoid signaling
molecules, 2-arachidonoyl glycerol (2AG) and anandamide (AEA), and
their G-protein coupled receptors, cannabinoid receptor type 1 and
cannabinoid receptor type 2 (Fagan & Campbell, 2014). The
endocannabinoid system works speci�cally in both the regulation of
neuroin�ammation as well as neurogenesis.Studies show that the
endocannabinoid system is able to reduce chronic neuroin�ammation, a
major mediator in neurodegeneration in Alzheimer’s patients. PPAR𝛾 is a
key component involved in the cannabinoid anti-in�ammatory e�ect. This
protein consists of a group of hormone receptors involved in gene
expression and in�ammation. The use of cannabinoids increases
PPAR𝛾transcriptional activity in adult rats, thus decreasing
neuroin�ammation (Fagan & Campbell, 2014).

Fig. 2: Illustration and description of CB1 & CB2 receptors, and the endocannabinoid signaling
molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2AG).

An elevation of the 2AG endocannabinoid signaling molecule, coupled
with a modulation of the CB2 speci�c cannabinoid receptor, could combat
aggregated Aβ neuritic plaques (Palocziet al., 2018). The cannabinoid
receptors play a vital role in allowing the formation of new neurons and
neuronal connections to sustain neuronal function. The proliferation of
neural precursor cells, both neural stem cells and neural progenitor cells, has
been proven to activate CB1 receptors; the proliferation of neural

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progenitor cells has been seen to activate both CB1 and CB2 receptors,
allowing the production and survival of new neurons (Fagan & Campbell,
2014). This activation of neurogenesis o�ers promising potential within the
endocannabinoid system in reducing brain atrophy in Alzheimer patients
(Fagan & Campbell, 2014).

A potential therapeutic component of the endocannabinoid system
involves the cannabinoid receptors CB1 and CB2. CB1 receptors, the most
abundant cannabinoid receptors,are mainly located in the neurons of the
central nervous system and work to regulate cognition and memory, motor
control, feeding, and pain perception — allowing the endocannabinoid
system to serve as a neuromodulator. Studies on CB1 receptors have yielded
inconsistent results,preventing a correlation between CB1 presence in AD
patients and in control patients from being observed (Ahmad et al., 2014).
A more recent study has indicated a reduction in the number of CB1
receptors in the frontal cortex while no change was observed in the
hippocampus. CB2 receptors, on the other hand, are expressed mostly in
immune cells and to some extent, in the peripheral system of the brain —
allowing the endocannabinoid system to serve as an immunomodulator. As
such, CB2 is highly involved in the research regarding the
neuroin�ammatory response associated with AD (Atakan, 2012). Within
the endocannabinoid system in an Alzheimer’s patient’s brain, studies
found an increase in CB2 receptor expression in microglia, phagocytic cells
in the brain and spinal cord. This increase correlates with Aβ levels and
plaque accumulation, suggesting that the activation of CB2 receptors plays
a role in stimulating Aβ removal (Talarico et al., 2019). The use of CB2
receptors has shown to be a promising medium for both a therapeutic
treatment and as a marker for the advancement of Alzheimer’s disease. In
addition, CB2 receptors have continuously been co-localized with Aβ
plaque buildup (Ahmad et al., 2016). Despite this, there have been �ndings
that demonstrated CB2 receptor concentration is highly expressed within
microglia cells surrounding senile plaques — extracellular deposits of Aβ —
within post-mortem brainsdiagnosed with AD (Aso & Ferrer, 2016).
Conversely, studies demonstrated that CB2 receptors may not be the most
accurate biomarker for tracking AD advancement, as they are also found on
neuronal cells. However, this does not necessarily eliminate them as targets
for treatment as they remain largely expressed within immune cells (Ahmad
et al., 2016). As such, the signi�cant presence of CB2 receptors in microglia
cells in brains of AD patients allows for selective activation(stimulating
certain CB2 receptors to decrease in�ammatory cell generation) in a�ected

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tissues,therefore decreasing the risk of harmful e�ects (Ramírez et al.,
2005).

Fig. 3: Illustration of the interaction between endocannabinoids and the cannabinoid receptors,
CB1 and CB2. Endocannabinoids from the postsynaptic neuron travel through the synaptic cleft to
the presynaptic neuron, thus attaching to the Cannabinoid Type 1 receptor. The binding of these
two molecules results in a suppression of neurotransmitters altering the neuronal �ring in the
postsynaptic cell, thus allowing it to work as a regulator.

One avenue of therapeutic treatment is the usage of CB2 activity against
in�ammation. Within microglia cells, CB2 receptors inhibit neurotoxicity
caused by microglia by substantially reducing the production of
pro-in�ammatory molecules and by manipulating macrophage
migration(Aso& Ferrer, 2016). "This was supported by experiments
utilizing receptor agonists within in vitro experiments containing di�erent
species of toxic Aβs, such as JWH-015, JWH-133, HU-308, WIN55,212-2,
and HU-210, which observed a reduction of in�ammatory molecules” (Aso
& Ferrer, 2016). It has been postulated that these CB2 receptor agonists aid
in inhibiting microglial activation through decreasing intracellular calcium
concentration (Martín-Moreno et al., 2011). In essence, the utilization and
subsequent exploitation of the endocannabinoid system provides an
essential medium for the therapeutic treatment of Alzheimer’s disease.

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The endocannabinoid system has shown to reduce in�ammatory response
through thePPARγ protein as well as facilitate neurogenesis through the
activation of both the cannabinoid receptors, when neural stem cells and
neural progenitor cells are proliferated. The self-renewal capability and
multipotency of stem cells is supported through the complex
microenvironment provided through the action of the endocannabinoid
system, speci�cally cannabinoid receptors CB1 and CB2 (Rodrigues et al.,
2019). The prospect of neural stem cells as regenerative therapies is very
promising, leading to a possible personalized and e�ective approach
(Rodrigueset al., 2019). Moreover, the various cannabinoid actions on
neural stem cells open paths of research to uncover the mechanisms
responsible behind cannabinoid e�ects. New avenues of research could
provide new knowledge, leading to the development of re�ned therapeutic
strategies to alleviate Alzheimer’s e�ects.

C. Synaptic Plasticity
Among the neural pathways negatively impacted by AD are those involved
in synaptic plasticity. The brain’s circuitry is heavily a�ected by numerous
daily activities ranging from learning new information to engaging in social
interactions. These exposures to the environment have the potential to
modify the brain’s neural organization and in�uence its activity. Synaptic
plasticity is the phenomenon that describes these changes in the neural
circuits’ structure and function, which result from modi�cations to
synaptic transmission. Although synaptic plasticity may allow a damaged
brain to restrengthen synaptic connections and reverse damage, AD is
known to impair this plasticity and leave permanent damage. Research has
demonstrated that Aβdeposition, a widely recognized hallmark of AD
pathophysiology, is detrimental to healthy synapses (Shankar et al., 2008).
Soluble dimeric Aβ assemblies were found to be strong inhibitors of
long-term potentiation —the strengthening of synaptic communication by
repeated stimulation (Shankar et al., 2008). The soluble Aβ assemblies were
also found to augment long-term depression causing a decrease in dendritic
spine density. Dendritic spine density has been found to strongly correlate
to the degree of dementia for patients with AD. Speci�cally,the research
showed that AD brain samples had a 47% decrease in spine density when
compared to a control (Shankar et al., 2008). The researchers localized
various receptors, includingN-methyl-D-aspartate receptors (NMDAR),
metabotropic glutamate receptors (mGluR), and nicotinic acetylcholine
receptors(nAChR) as among those impacted by Aβ and negatively a�ecting

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synaptic plasticity in diseased brains. Studies con�rmed that the
introduction of soluble Aβ dimers into rats interrupted their ability to
recall learned behaviors, further implicating Aβ as the primary culprit
responsible for impaired synapse remodeling and plasticity (Shankar et al.,
2008).

Fig. 4: In a research study conducted by Hughes and Herron, e�ects of long-term potentiation 
(LTP) of CBD was investigated in the hippocampus. Treatment of slices with CBD attenuated the 
Aβ-mediated de�cit in LTP. LTP was signi�cantly attenuated in the presence of Aβ1–42 (500nM)
(112.6±2.9%;n=23) compared to control (148.6±2.4%; n=59; AandC). B Application of CBD to 
slices 30 minutes prior to addition of Aβ attenuated theAβ-mediated de�cit in LTP (136.9±5.9%; 
n=15, p≤0.001) compared to Aβ alone. LTP in the presence of CBD and Aβ was similar to control 
(p>0.05).
Citation: Cannabidiol reverses de�cits in hippocampal LTP in a model of Alzheimer’s disease. (n.d.). 
NeurochemicalResearch. https://link.springer.com/article/10.1007/s11064-018-2513-z

Synaptic plasticity can be modulated through the interaction between CBD 
and the endocannabinoid system. While the exact mechanism must still be 
elucidated, it is clear that CBD in�uences and interacts with 
endocannabinoid receptors. Various studies have arrived at di�erent 
conclusions on the actions of CBD, some stating that there is no a�nity 
between CBD and the CB1/CB2 receptors (McPartland, 2007). Others 
state CBD binds as a weak antagonist (Thomas, 2007), and yet more that 
claim CBD functions as a negative allosteric modulator for the 
endocannabinoids 2-AG and delta-9-THC (Hughes et al., 2019). CBD 
enhances neuroprotection by di�erent signal transduction pathways that 
are controlled indirectly by cannabinoid receptors (Li et al., 2020). 
Similarly, CBD treatment enhanced synaptic transmission in mouse 
models, most likely acting in conjunction with CB1 and CB2 receptors to 
decrease neurotoxicity and cell death that was the result of Aβ deposits. 
CBD has shown its capability in reversing and preventing cognitive damage 
due to AD (Watt et al., 2017) and precluding the suppression of long-term

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https://link.springer.com/article/10.1007/s11064-018-2513-z


potentiation (Hughes et al., 2019). Therefore,modulation of the agonists
and antagonists which bind to CB1 and CB2 receptors, such as CBD, has
an e�ect on synaptic plasticity in the brain. AD-induced dysfunction of the
endocannabinoid receptors negatively in�uences synaptic plasticity.

Fig. 5: Illustration of synaptic plasticity and long-term potentiation. After repeated simulation and
long-term potentiation, there is an increase in the number of neurotransmitters in the presynaptic
neuron and an increase in the number of receptors in the postsynaptic neuron. This results in a
stronger response.

Pathology of the cholinergic system is also associated with AD. Many
cholinergic pathways are commonly found to be damaged or dysfunctional
in those who su�er from AD, impairing synaptic plasticity. AD has been
correlated with decreased cholinergic transmission, especially in the
hippocampus where new memories are formed. Studies have found
‘crosstalk’ — signals within one system that produce changes in another
system — between the cholinergic signaling and the endocannabinoid
signaling systems (Thompson et al., 2020). Past studies speci�cally
investigated this communication between the systems in AD. This research
found that α-7 nAChR are of particular concern because they are highly
expressed in the hippocampus and play a signi�cant role in the development
of memory and learning abilities (Thompson et al., 2020). Elevated levels of
α-7 nAChR have been found to disrupt normal signaling and negatively
impact synaptic plasticity (Thompson et al., 2020). Interestingly, Aβ
deposition also seems to increase in α-7 nAChR rich regions (Thompson et
al., 2020). While their research did not corroborate a de�nite ‘cross-talk’
between the ECS and α-7 nAChR speci�cally, they did �nd that α-5
nAChR and α-6 nAChR correlated to THC addiction and withdrawal
(Thompson et al., 2020), which are known to involve the pathways of the

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ECS. The researchers concluded that the ECS seemingly plays a role in
cholinergic signaling, although not speci�c to the α-7 nAChR.This research
suggests that indirect crosstalk between the endocannabinoid and
cholinergic systems and its modulation may be a way to improve cholinergic
signaling and repair synaptic plasticity that is damaged as a result of AD
(Thompson et al., 2020).

III. Receptor Agonists
A. Inhibitory Activity by Receptor Agonists
Many studies have investigated the variety of proposed therapeutic
treatments mediated by endocannabinoid receptor agonists, speci�cally the
inhibitory activity of receptor agonists in Alzheimer’s disease. One of the
primary focuses of cannabinoid receptor agonists is their ability to inhibit
neuroin�ammation, a speci�c characteristic signaled by the dysfunction of
microglia. Cannabinoid agonists increase endocannabinoid availability,
which allows activation of receptor agonists to prevent Aβ-induced
cognitive de�cits (Martín-Moreno et al., 2011). The synthetic cannabinoid,
WIN 5512-2, inhibits neuroin�ammation induced by Aβ through the CB1
and CB2 receptors. In primary cultures, a laboratory procedure in which
cell extracts are grown under controlled conditions, WIN5512-2’s
in�ammatory response speci�cally prevented cell death in astrocytes —
specialized glial cells that aid in a variety of neurological functions such as
water homeostasis and oxidative stress defense (Sofroniew, 2010). Mice
studies have e�ectively demonstrated this by reducing the levels of the
proin�ammatory molecules interleukin-1 beta (IL-1beta), TNF-alpha,
COX-2, and inducible nitric oxide synthase (iNOS) (Aguirre-Rueda, 2015)
within their system. Additionally, two proin�ammatory cytokines,
TNF-alpha and IL-6, were measured in the cerebral cortex of mice treated
with CBD and WIN5512-2 (Martín-Moreno et al., 2011). The initial 6-fold
increase of IL-6 from the Aβ was decreased by both cannabinoid agonists,
and WIN5512-2 partially reduced TNF-alpha gene expression
(Martín-Moreno et al., 2011). In a similar experiment, Aβ injected mice
subject to subchronic administration of WIN5512-2 or CBD showed
better performance in the Morris water maze task, an experiment in which a
mouse is placed within a circular pool of water and must escape from the
water onto a hidden platform whose location is discerned through the use
of spatial memory (Martín-Moreno et al., 2011).

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CBD is a CB2 receptor agonist that also prevents Aβ neurodegeneration by
reducing microglial activation responsible for the release of toxic molecules
like nitric oxide (NO) and proin�ammatory cytokines (Martín-Moreno et
al., 2011). By inhibiting calcium responses in glial cells, cannabinoid
agonists are similarly able to prevent microglial activation.

Fig. 6: Illustration of inhibitory activity by receptor agonists.

Additionally, CB1 receptor activation causes migration of the N13
(nitrogen-13) microglial cells and primary microglial cells
(Martín-Morenoetal., 2011). Migration is a cellular mechanism that
ultimately allows for the removal of deposit Aβ protein. In a study
conducted in Aβ injected mice, those that did not receive the CBD
treatment of WIN5512-2 showed signi�cant reduction in their ability to
reach a hidden platform (Martín-Moreno et al., 2011). Another strength

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pertaining to the inhibitory activity of receptor agonists is the suppression
of Aβ plaque buildup. Aspreviously mentioned, AD has been largely
characterized by its substantial aggregation of beta amyloid peptide clusters;
thus, focusing further investigation towards the wingless-related integration
site (Wnt) pathway as it becomes largely impacted due to aforementioned
clusters (Esposito, 2006). Normally, Wnt activation triggers the
“...inhibition of glycogen synthase kinase-3beta (GSK-3β), a
multifunctional phosphorylating serine/threonine kinase and relative
accumulation of [unphosphorylated] β-catenin in the cytoplasm”
(Esposito, 2006). This Aggregation allows for the expression of genes that
code for homeostasis and neuronal survival (Esposito, 2006). Within
neurons exposed to Aβ peptides, however, GSK-3ß is activated through
phosphorylation; therefore, Wnt signaling experienced signi�cant reduction
(Esposito, 2006). Furthermore, these phosphorylated GSK-3ß lead to the
neuro�brillary tangles and signi�cant tau protein hyperphosphorylation
witnessed in the brains of patients with AD (Esposito, 2006). CBD serves as
a rescue of the Wnt signaling pathway as it promptly reduces the
accumulation of phosphorylated GSK-3ß, consequently inhibiting the rise
of neuro�brillary tangles and tau protein hyperphosphorylation (Esposito,
2006). Furthermore, CBD indirectly inhibits neural apoptosis due to its
rescue of the Wnt signaling pathway (Esposito, 2006).

∆9-Tetrahydrocannabinol (THC) is another viable receptor agonist in
combating the advancement of Alzheimer’s disease via competitive
inhibition. THC, the active component of marijuana, competitively
inhibits acetylcholinesterase (AChE) in addition to preventing
acetylcholinesterase-induced Aβ plaque buildup (Eubanks, 2006). One
study, conducted by Eubanks et al., demonstrated through computational
modeling of THC-AChE interaction that THC binds to AChE in a critical
region involved in amyloid synthesis, ultimately serving an inhibitory
function (Eubanks, 2006). THC and analogous compounds were found to
augment acetylcholine levels by inhibiting Aβ aggregation and reducing
neurotransmitter degradation(Eubanks, 2006).This study proposes a
possible mechanism by which THC molecules directly impact the
pathogenesis of Alzheimer’s disease (Eubanks, 2006). Through focusing on
the cholinergic system, THC was found to be a promising receptor agonist
as its potential AChE inhibition might be implicated in AD treatment
(Campbell et al., 2007). Multiple drugs — donepezil, edrophonium,
galantamine, etc. — inhibit AChE for the purpose of increasing
acetylcholine (ACh) levels in the synapse and increasing cholinergic

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transmission. In an investigation of cannabinoids as potential inhibitors of
AChE, Δ-9-THC was found to be a competitive inhibitor for AChE, which
has the added e�ect of inhibiting Aβaggregation (AChE has been found to
accelerate the aggregation of Aβpeptides into complexes, increasing their
neurotoxicity) (Campbell et al., 2007).

Nonetheless, more research is needed in order to understand the e�cacies
of CBD and THC in the treatment of Alzheimer’s disease. As therapeutic
treatments for Alzheimer’s disease continue to be explored, CBD is a
promising candidate. A handful of studies show that THC is a more
e�ective inhibitor than CBD in regards to amyloid plaque buildup. While
the general consensus of the present community is built upon the e�ects of
cannabidiol, the e�cacy of ∆9-Tetrahydrocannabinol should also be
considered as a viable method of treatment for Alzheimer’s. It is nearly
impossible to ignore the therapeutic potential of receptor agonists within
the endocannabinoid system against the advancement of Alzheimer's
Disease.

B. Synthetic Cannabinoid Receptor Agonists
Synthetic cannabinoid receptor agonists target the degenerative e�ects of
Alzheimer’s through the CB1 and CB2 receptors of the ECS. These
receptor agonists can reduce the density of neuritic plaques by inhibiting
acetylcholinesterase activity, or increasing expression of neprilysin, an
enzyme in the Aβ degradation cascade (Fernández-Ruiz et al., 2015). The
syntheticcannabinoids also function as a treatment that blocks the
activation of the microglial clustercaused by the deposition of Aβ at the
senile plaque. This deposition is typically responsible for the prolonged
damaging e�ects of the disease, and the presence of cannabinoids alleviates
neurodegeneration (Ramírez et al., 2005).

Since these potential neuroprotective e�ects have been discovered, extensive
research is being dedicated towards studying the endocannabinoid system.
Researchers have already found That dysfunction of CB1 and CB2
receptors and in endocannabinoid signaling plays a speci�c role in the
pathophysiology of AD (Liu et al., 2015). One study investigated the
speci�c bene�ts that synthetic cannabinoids could have on neuropsychiatric
symptoms (NPS) associated with AD. The researchers studied two
synthetic analogs of Δ-9-THC, Dronabinol and Nabilone, and their
interactions with receptors in the ECS. Nabilone and Dronabinol were

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found to be more potent analogs to THC that act on both CB1 and CB2
receptors and reduced overall agitation in AD patients (Liu et al., 2015).
Participants receiving Nabilone experienced no adverse side e�ects. In the
Dronabinol study, the researchers measured disturbed behavior in study
participants using the Cohen-Mans�eld Agitation Inventory (CMAI), a
scale which systematically assesses patient agitation. They found that with
administration of the synthetic cannabinoid, disturbed behavior dropped
among the participants over the course of the 6-week test period (Liu et al.,
2015). Stimulation of the CB2 receptor by these synthetic cannabinoids
increases the removal of Aβ deposits by enhancing macrophage activity,
thus explaining the improvements in NPS seen in study participants.
Another studyinvestigating the e�cacy of Nabilone as a potential treatment
for the NPS of AD similarly found an overall decrease in agitation, and
sometimes aggression as well (Ruthirakuhan et al., 2019). The synthetic
cannabinoid receptor agonists WIN55,212-2 and
arachidonyl-2-chloroethylamide were also found to decrease aggressive
behavior associated with AD and reduce tau hyperphosphorylation and the
neuro�brillary tangles (Liu et al., 2015). WIN55,212-2 along with
JWH-133 were also found to assist in the removal of Aβ deposits, one of the
most common pathophysiology associated with Alzheimer’s.
WIN55,212-2’s ability to stimulate neurogenesis makes it a great contender
as a therapeutic agent. Although there are positive outcomes of such drugs
on reversing AD-related amnesia, they must be used with caution as there is
a risk of exacerbating the neurodegeneration associated with AD (Liu et al.,
2015).

Agonists that speci�cally target CB2 activate responses that reduce both
in�ammatory and Aβ plaque buildup. The CB2 agonist JWH-015 was used
to further investigate the function of CB2 with tests done on AD human
tissue. These tests demonstrated that JWH-015 was able to reduce plaque
buildup dramatically in THP-1 macrophage cells (Tolón et al., 2009).
However, the U373 astrocytoma cells, which are from the astrocytoma
cancer cell line in the human brain, were immune to the e�ects (Tolónet al.,
2009). Thus, the CB2 agonist induced plaque removal was only e�ective in
certain cells (the human macrophages). This �nding shows some limits of
CB2 agonist use in alleviating symptoms, while narrowing down a line of
cells to focus on. CB2 receptors' primary role in plaque removal, with in
vitro injection of the antagonist SR144528, showed partial reversal of the
JWH-015 Aβ removal (Tolón et al., 2009), which highlights other factors at
play in plaque reduction. These results indicate that JWH-015 can be used

Berkeley Pharma Tech Journal of Medicine | 16



as a speci�c target treatment for AD, however it is not the only option. CB2
receptor agonists have a preventative function in suppressing
neuroin�ammation (Ehrhart et al., 2005). Irregularly stimulated CD40
receptor expression by the signaling pathway IFN-γ is prominent in patients
with AD and is known to increase in�ammation (Ehrhart et al., 2005).
CD40 induction produces in�ammatory cytokines and is correlated with
the in�ammation and Aβ peptide increase in AD. Using the JWH-015
agonists, stimulation of CB2 diminishes IFN-γ-induced CD40 expression in
microglial cells (Ehrhart et al., 2005). This occurs by the intervention of the
JAK/STAT1pathway (Ehrhart et al., 2005), which is a pathway that is
involved with immune system response and ultimately decreases
IFN-γ-induced CD40 expression. There is further evidence to show
thatCB2 agonists have the potential to inhibit in�ammation. JWH-133, a
CB2 agonist, was found to rescue spatial memory de�cits in rats injected
with Okadaic acid (OKA), which induces spatial memory impairment and
neurodegeneration (Çakır et al., 2019). Rats injected with OKA were found
to have higher numbers of degenerative neurons in the cortex and
hippocampus, but the addition of JWH-133 ameliorated this damage
(Çakır et al., 2019). JWH-133 application was found to reduce the level of
immunoreactivity caused by OKA. Caspase-3, Aβ, and IL-1β
immunoreactivity were reduced in both the hippocampus and the cortex,
while TNF-αimmunoreactivity was reduced in only the hippocampus
(Çakır et al., 2019).

1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl) carbonyl) piperidine
(MDA7), a highly-selective CB2 agonist, was found to have a
neuroprotective e�ect in in vivo and in vitro models (Wu et al., 2012).
MDA7 administration in Aβ1–4-induced mice was found to lower
immunoreactivity in the hippocampus (Wu et al., 2012). The Morris water
maze test (Wu et al., 2012) showed MDA7 rescued amyloid �bril-impaired
performance. While progress has been made in the development of drugs
targeting these receptors, the ones currently available to patients come with
many unwanted side e�ects such as nausea, vomiting, and weight loss
(Wattet al., 2017). While there are bound to be side e�ects to most drugs,
synthetic cannabinoids o�er the added bene�t of producing e�ects similar
to that which natural Cannabis derivatives cause but without the
psychoactive side e�ects (Campbell et al., 2007). Due to the complexity of
AD and the pathology of many di�erent pathways involved, it is unlikely
that just one drug will su�ce to treat the progression of the disease. Rather,

Berkeley Pharma Tech Journal of Medicine | 17



it is more likely that multiple drugs will be needed to treat the multifaceted
symptoms of Alzheimer’s.

IV. Potential and E�ective Therapies
A. Natural Therapies
Cannabinoids possess great potential as e�ective natural therapies for AD.
Previous studies indicate that Cannabis use diminishes symptoms
associated with AD (Suryadevara et al., 2017). When administered in
patients with similar neurodegenerative conditions, Cannabis use is shown
to decrease pain and spasticity in people with multiple sclerosis, decrease
tremor, rigidity, and pain in people with Parkinson’s disease, and improve
the quality of life of amyotrophic lateral sclerosis (ALS) patients by
improving appetite and decreasing pain and spasticity (Suryadevara et al.,
2017). Interestingly, a large portion of the negative side e�ects from
Cannabis administration in these diseases is absent in Alzheimer’s patients
(Suryadevara et al., 2017). Cannabis has been used to alleviate pain and
muscular contractions to target the in�amed pathways of the brain in
Alzheimer’s patients. The perception of pain is atypical in that Alzheimer’s
patients are more prone to oxidative stress, which is an imbalance between
free radicals and the body’s ability to detoxify them. However, studies
demonstrate a positive relationship between stress reduction in dementia
and medical Cannabisuse (Aso et al., 2014). The anti-in�ammatory and
anti-neurotoxicity properties of cannabinoids help mediate the
neuroin�ammation caused by microglia activation, which is characteristic
of chronic pain in Alzheimer's patients. In addition, further studies have
shown that with the use of cannabinoids, Alzheimer’s patients have
experienced a decrease in altered cognitive ability (Aso et al., 2014).
Research indicates that a "coadministration of CBD and Δ9-THC” is
necessary in order to deliver the bene�cial elements of Cannabiswhile
attempting to reduce certain side e�ects of Δ9-THC in Alzheimer’spatients
(Giacoppo et al., 2014). CBD and THC, natural components in
cannabinoids, provide encouraging results for possible use in Alzheimer’s
patients. The phytocannabinoid component of Cannabis, a naturally
occurring component found in the trichomes of this plant, is seen to be
particularly bene�cial in the treatment of Alzheimer's Disease as it lacks
psychoactive properties and does not risk further cognitive impairment
damage in Alzheimer’s patients (Karlet al., 2017). In fact, Cannabis can can
actually help restore cognitive dysfunctions characteristic of Alzheimer’s
disease (Uddin et al., 2020). Cannabis is a promising agent with numerous

Berkeley Pharma Tech Journal of Medicine | 18



therapeutic properties that hinder the progression of AD, leading to the 
investigation of cannabidiol (CBD) therapies. Current CBD therapies are 
seen to bring “very modest symptomatic relief” (Karl et al., 2017). CBD 
treatment is described as being a preventative, multimodal drug strategy 
targeting the wide variety of symptoms, making it a viable candidate for AD 
therapy (Karl et al., 2017).

V. Conclusion
The features of AD, which consist of in�ammation (Atakan, 2012), 
amyloid-beta plaque buildup (Farkhondehet al., 2020), and neuro�brillary 
tangles (Hall et al., 2001; Nelson et al.,2012), lead to life-altering cognitive 
de�cits and other extensive e�ects that impact a signi�cant population of 
individuals. It is one of the most heavily researched diseases, yet there is still 
no method to stop its progression. Therefore, the injection of cannabinoids 
provides one promising revenue for scientists to counter the damage. The 
connection between AD and cannabinoids has been made apparent 
through many recent studies. Investigations into the e�cacy of the ECS as 
well as natural and synthetic cannabinoids have developed in regards to the 
treatment and management of AD and its varying pathologies. 
Cannabinoid agonists have presented researchers with neuroprotective 
qualities as well as the ability to manage the chronic psychiatric pathology 
associated with AD. This is due to the inherent physiology of the 
endocannabinoid system. ECS receptors exist both in the brain and parts of 
the immune system pathways, as a result, controlling its function through 
cannabinoid agonists and ECS ligands can serve both as a neuromodulator 
and an immunomodulator. Therapeutic use of the ECS and cannabinoids 
in relation to AD include elevated activation of endocannabinoid receptors 
to bolster neurogenesis and thus reduce the neurodegenerative e�ects of 
AD (Fagan & Campbell, 2014). This process occurs through the 
stimulation of CB1 receptors by the endocannabinoid signaling molecules 
and external agonists. CB2 receptors are mainly targeted for their 
anti-in�ammation properties (Tolón et al., 2009); their modulation using 
receptor agonists — such as JWH-015 (Tolón et al., 2009) and JWH-133 
(Çakır et al., 2019) — indicates a reduction of proin�ammatory 
molecules,which block proper neurofunction, that are normally present in 
AD. Endocannabinoid-speci�c agonists also inhibit the e�ects of AD by 
blocking harmful processes in the brain; these processes are microglia 
activation (Martín-Moreno et al., 2011), neuro�brillary tangles, and tau 
protein phosphorylation (Esposito, 2006). Experimentation with the

Berkeley Pharma Tech Journal of Medicine | 19



synthetic agonist has been seen to further suppress symptoms due to their
structural similarity to the natural cannabinoids and have even stronger
receptor activation. Mice study results identify the synthetic agonists
according to what they prevent in the AD injured brain: WIN55,212-2 is
correlated to nerve development (Liu et al., 2015), JWH-133 binds to CB2
to reduce rapid in�ammation (Çakır et al., 2019), and Dronabinol and
Nabilone treat mostly neuropsychiatric symptoms (Liu et al.,2015). In
dealing with the synapse, long term potentiation was regained in tests with
mice who had amyloid-beta plaque buildup in combination with CBD
dosages (Hughes et al., 2019). As The major �nding is the revival of neuron
activity, restoration of the cholinergic signaling system alleviates AND
e�ects (Thompson et al., 2020). While commonly used as a relief drug,
natural cannabinoids THC and CBD derived from the Cannabis Plant are
used in tandem to manage cognitive de�cits (Giacoppo et al., 2014). CBD
acts as a modulator to THC intoxication and together e�ectively reduces
oxidative stress and in�ammation associated with AD (Giacoppo etal.,
2014). While more studies and clinical trials are required before making any
de�nitive statements,the associations discovered thus far indicate necessary
future research and possible implementations of this form of therapy.

Berkeley Pharma Tech Journal of Medicine | 20



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