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\begin{document}

\title{A literature review on the therapeutic applicability of cannabidiol in
epilepsy, multiple sclerosis and Parkinson's disease}



\author[1]{Maria de Fátima dos Santos Sampaio}%
\author[1]{Yara Bezerra de Paiva}%
\author[2]{Tuane Bazanella Sampaio}%
\author[3]{Messias Gonzaga Pereira}%
\author[1]{Norberto Cysne Coimbra}%
\affil[1]{Universidade de Sao Paulo Faculdade de Medicina de Ribeirao Preto}%
\affil[2]{Universidade Federal de Santa Maria}%
\affil[3]{Universidade Estadual do Norte Fluminense Darcy Ribeiro}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Neurodegenerative diseases have complex etiologies, however,
neuroinflammation and oxidative stress are important markers in this
pathogenesis and, in this sense, cannabinoids, especially CBD, have been
identified as potential therapeutics for playing a neuroprotective role.
Studies have demonstrated the neuroprotective effect of cannabinoids and
derivatives of \emph{Cannabis sativa} L in diseases of the central
nervous system due to their interaction with the endocannabinoid system
through receptors and other molecular targets. The aim of this review
was to provide an overview of the endocannabinoid system and a summary
of the clinical and preclinical findings of the therapeutic use of
cannabinoids in epilepsy, multiple sclerosis and Parkinson's disease,
pointing out interactions with molecular targets and the potential for
neuroprotection of CBD. Electronic searches were carried out in
international databases, including studies that presented consistent
data on this subject. Significant therapeutic effects of CBD were shown
for epilepsy and Parkinson's disease, while nabiximols contributed to
the reduction of spasticity, being a frequent option for the treatment
of multiple sclerosis. Although much has been projected on the
therapeutic potential of cannabinoids for neurological disorders, there
is a long way to go in the search for strong scientific evidence of
their pharmacological effectiveness.%
\end{abstract}%



\sloppy


\textbf{A literature review on the therapeutic applicability of
cannabidiol in epilepsy, multiple sclerosis and Parkinson's disease}

Maria de F\selectlanguage{ngerman}átima dos Santos Sampaio\textsuperscript{a,b}, Yara Bezerra de
Paiva\textsuperscript{a}, Tuane Bazanella Sampaio\textsuperscript{c},
Messias Gonzaga Pereira\textsuperscript{b}, Norberto Cysne
Coimbra\textsuperscript{a}

\textsuperscript{a}Laboratory of Neuroanatomy and Neuropsychobiology,
Department of Pharmacology, Ribeirão Preto Medical School of the
University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão
Preto, 14049-900, São Paulo, Brasil

\textsuperscript{b}Universidade Estadual do Norte Fluminense Darcy
Ribeiro (UENF), Centro de Ciências e Tecnologias Agropecuárias (CCTA),
Av. Alberto Lamego, 2000, Campos dos Goytacazes, 28013-602, Rio de
Janeiro, Brasil.

\textsuperscript{c} Programa de Pós-graduação em Farmacologia, Centro de
Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS,
97105-900, Brasil.

\textbf{Corresponding authors:}

Prof. Dr. Norberto Cysne Coimbra (nccoimbr@fmrp.br), Laboratory of
Neuroanatomy and Neuropsychobiology, Department of Pharmacology,
Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP),
Av. Bandeirantes, 3900, Ribeirão Preto, 14049-900, São Paulo, Brazil.

Maria de Fátima dos Santos Sampaio (mfss.sampaio@gmail.com), D.Sc.

Yara Bezerra de Paiva (ybpaiva@alumni.usp.br), D.Sc.

Tuane Bazanella Sampaio (tuanebs@gmail.com), Ph.D.

Messias Gonzaga Pereira (messias@uenf.br), Ph.D.

Norberto Cysne Coimbra (nccoimbr@fmrp.br), M.D., M.Sc., Sc.D.

\textbf{Abstract}

Neurodegenerative diseases have complex etiologies, however,
neuroinflammation and oxidative stress are important markers in this
pathogenesis and, in this sense, cannabinoids, especially CBD, have been
identified as potential therapeutics for playing a neuroprotective role.
Studies have demonstrated the neuroprotective effect of cannabinoids and
derivatives of \emph{Cannabis sativa} L in diseases of the central
nervous system due to their interaction with the endocannabinoid system
through receptors and other molecular targets. The aim of this review
was to provide an overview of the endocannabinoid system and a summary
of the clinical and preclinical findings of the therapeutic use of
cannabinoids in epilepsy, multiple sclerosis and Parkinson's disease,
pointing out interactions with molecular targets and the potential for
neuroprotection of CBD. Electronic searches were carried out in
international databases, including studies that presented consistent
data on this subject. Significant therapeutic effects of CBD were shown
for epilepsy and Parkinson's disease, while nabiximols contributed to
the reduction of spasticity, being a frequent option for the treatment
of multiple sclerosis. Although much has been projected on the
therapeutic potential of cannabinoids for neurological disorders, there
is a long way to go in the search for strong scientific evidence of
their pharmacological effectiveness.

\textbf{Keywords:} Cannabinoids, endocannabinoid system; epilepsy,
multiple sclerosis, Parkinson's disease.

\textbf{Introduction}

\emph{Cannabis sativa} L. (Magnoliopsida; Cannabaceae) popularly known
as hemp, marijuana, cannabis, weed, among other names is a species
belonging to the Cannabaceae family {[}1-6{]}. All over the
world,\emph{Cannabis sativa} L. is an ancient and traditional plant in
several cultures, which has been passing through generations, from
antiquity to the present day. Although at the beginning of the 20th
century it was established as an illegal drug, even with a reduced
consumption, it was considered the most consumed recreational drug in
the world. Its presence among humans is highlighted in religious rites,
for food, psychoactive and especially medicinal use {[}7, 8{]}.

The constituents of \emph{C. sativa} are formed by nitrogen compounds,
amino acids, hydrocarbons, terpenes, and sugars responsible for the
toxicological and pharmacological effects {[}9{]}. However, it is widely
known that the two main ingredients in \emph{Cannabis} are \selectlanguage{greek}Δ\selectlanguage{english}9
-tetrahidrocanabinol (THC) and Cannabidiol (CBD) {[}10{]}, CBD being the
most abundant phytocannabinoid that does not present psychoactive
properties, which has shown benefits to human health, mainly due to its
molecular interaction with the endocannabinoid system (ES) {[}11{]} .

After discovering cannabinoid receptors, mammals were shown to produce
endogenous agonists for these receptors (the endocannabinoids), such as
anandamide, also known as N-arachidonoylethanolamine (AEA) and
2-arachidonoyl-glycerol (2-AG) {[}6, 12{]}. Endocannabinoids are
involved in food intake, analgesia, cancer, and addiction {[}13{]}, but
until the discovery of the ES, the receptor identified as ``cannabinoid
receptor 1 (CB1)'' was a ``receptor coupled to G'' protein without a
previously known ligand. The high affinity of THC for the CB1 receptor
has increased knowledge about the ES {[}5{]}. However, the second
cannabinoid receptor (CB2) has low psychoactive activity compared to the
CB1 receptor {[}2-5, 14{]}. As for CBD, studies have shown that it
develops an allosteric binding activity between CB1 and CB2 receptors
and that it presents other potential therapeutic targets such as
transient receptor potential vanilloid (TRPV), o peroxisome
proliferator-actived receptor \selectlanguage{greek}γ \selectlanguage{english}(PPAR\selectlanguage{greek}γ\selectlanguage{english}), o G protein-coupled receptor 55
(GPR55), receptors 5-hydroxytryptamine (5-HT), \selectlanguage{greek}γ-\selectlanguage{english}Aminobutyric acid type
A (GABA\textsubscript{A}) e transient receptor potential cation channel
subfamily M (melastatin) member 8 (TRPM8). While the CB2 receptor is
mostly found in cells of the immune system, the CB2 receptor is highly
common in the central nervous system (CNS), mainly in brain areas
{[}15{]}.

In this way, CBD has been identified as a potent anti-inflammatory and
antioxidant that, interacting directly or indirectly with CB1 and CB2
receptors and other molecular targets, mediates neuroprotection. In this
sense, it has been investigated as a potential therapy for
neurodegenerative diseases {[}16{]}, considering that throughout the
world, due to the increase in people's life expectancy, these diseases
have been worrying because they gradually lead to functional loss of
motor and /or cognitive and produce high economic and social impacts
{[}16-19{]}.

There are several suggestions about the pathogenesis of
neurodegenerative diseases, including the idea that the entire brain
begins to be invaded by abnormal protein aggregates that are the result
of an abnormal conformation of the peptides \selectlanguage{greek}β-\selectlanguage{english}amyloid, \selectlanguage{greek}α-\selectlanguage{english}synuclein and
tau {[}16, 18, 20, 21{]}. It is considered that Parkinson's disease, a
neurodegenerative disease that generally affects the elderly, presents
aggregates of \selectlanguage{greek}α-\selectlanguage{english}synuclein as a triggering factor for neurotoxicity and,
consequently, neuronal death. In this process, microglia are activated
leading to the production of pro-inflammatory cytokines and mediators of
oxidative stress, resulting in the death of dopaminergic neurons in the
white matter {[}22-25{]}.

Also recognized as a neurodegenerative disease, multiple sclerosis
affects around 2.8 million people worldwide, including children. It is a
very prevalent chronic inflammatory disease of the CNS, with a complex
and multifactorial etiology {[}26, 27{]}. In multiple sclerosis, there
is no consensus that white matter lesions are of inflammatory or
neurodegenerative origin, considering that in the early stages of the
disease inflammation is rarely observed, thus suggesting that there is a
direct involvement of lymphocytes in tissue damage or indirect
involvement through the activation of microglia {[}27, 28{]}. CBD and
THC formulas, in a 1:1 ratio, have been used to treat neuropathic pain
and spasticity in multiple sclerosis considering, according to Russo and
Guy {[}29{]} that beneficial therapeutic effects are increased when
these phytocannabinoids are combined in a single product. In this sense,
CBD has been seen as responsible for reducing the adverse effects of THC
{[}16{]}.

CBD has been indicated for pediatric epileptic disorders, refractory to
medications, and its clinical use was authorized in 2018 by the Food and
Drug Administration (FDA). It is known that epileptic disorders are
triggered by an imbalance in the excitatory and inhibitory
neurotransmission system {[}30{]}. On the other hand, epilepsy has
currently been recognized as comorbidity in neurodegenerative diseases,
consequently increasing longevity. Seeking to control epilepsy in the
elderly, for example, would result in the reduction of cognitive
deficits, the prevention of mortality from injuries arising from
seizures and even from falls, which are frequent in this case {[}19{]}.
Thus, alone or as an adjuvant, in the near future, CBD may extend its
clinical use to secondary neurodegenerative disorders {[}16{]}.

It is known that cannabis has promoted the modulation of several
pathophysiological phenomena due to the interaction between the ES and
different preparations, natural (phytocannabinoids) or synthetic
(cannabinoids) {[}31-34{]}. Thus, this review aimed to provide an
overview of the ES and a summary of the clinical and preclinical
findings of the therapeutic use of cannabinoids in epilepsy, multiple
sclerosis and Parkinson's disease, pointing out the interactions between
them and molecular targets. We sought to show the great potential for
neuroprotection of CBD and its promise in primary neurodegenerative
diseases and secondary to other CNS complications, such as epilepsy.

\textbf{1.4 The endocannabinoid system}

\textbf{1.4.1 The complexity of the endocannabinoid system - the
``endocannabinoidome''}

With the advancement of studies, ES has proven to be increasingly
complex, since in addition to endocannabinoids of a lipophilic nature,
with AEA and 2-AG acting as ligands for CB1 and CB2 receptors, it
maintains a relationship with several other mediators such as N-
acylethanolamines and 2-acylglycerols, primary amides, lipoamino acids
and N-acyl neurotransmitters, with SE-specific enzymes and metabolic
enzymes such as fatty acid amide hydrolase (FAAH), N-acyl-phosphatidyl
ethanolamine-specific phospholipase (NAPE-PLD), monoacylglycerol lipase
(MAGL), DAGL (sn-1-diacylglycerol lipase) and diacylglycerol lipase \selectlanguage{greek}β
\selectlanguage{english}(DAGL\selectlanguage{greek}β\selectlanguage{english}) and other receptors such as peroxisome proliferator-actived
receptor \selectlanguage{greek}α \selectlanguage{english}(PPAR\selectlanguage{greek}α\selectlanguage{english}), G protein-coupled receptor 118 (GPR118), G
protein-coupled receptor 119 (GPR119), GPR55, TRPV1, PPAR\selectlanguage{greek}γ, \selectlanguage{english}T-type Ca2+
channels (Cav3.2), TRPM8, 5-HT1A and GABA\textsubscript{A}. In this
sense, the therapeutic targeting of anabolic or catabolic
endocannabinoid enzymes has been hampered by the promiscuity of this
system, which interacts with several neuromediators, such as endogenous
opioids and GABA, forming a broad alternative network of metabolic
pathways and processes {[}10, 35-37{]}. Therefore, just as the terms
transcriptome, proteome and metabolome emerged, the term
``endocannabinoidome'' has been used {[}36, 38-41{]}.

It must be considered that alternative synthesis routes, both for AEA
and for 2-AG, have been reported. In the case of AEA, those cited as
alternative pathways to ''transacylation-phosphodiesterase'' are
FLC-like/protein tyrosine phosphatase N22 (PTPN22) {[}42-44{]},
phospholipase A2/lyso-FLD {[}43, 45{]} and alpha-beta
hydrolase-4/glycerophosphodiesterase GDE1 (Abh4/GDE1) {[}46{]}.
Furthermore, anandamide can interact with several molecular targets,
including the activation of postsynaptic TRPV1 channels at an
intracellular site {[}47{]}. Such activation may inhibit diacylglycerol
lipase \selectlanguage{greek}α \selectlanguage{english}(DAGL\selectlanguage{greek}α\selectlanguage{english}), resulting in a decrease in 2-AG production, thus
constituting a regulatory feedback mechanism {[}43{]}.

Regarding the synthesis of 2-AG, according to Kano et al. {[}48{]} other
pathways have been proposed including sequential reactions by
phospholipase A1 (PLA1) and lysoPI-specific PLC, the conversion of
2-arachidonoyl lysophosphatidic acid into 2 -AG by phosphatase, and the
formation of 2-arachidonoyl phosphatidic acid by
1-acyl-2-arachidonoylglycerol.

Both AEA and 2-AG were able to interact with other targets such as GPR55
{[}43{]}. As well as reactions involving the arachidonate cascade
enzymes, cyclooxygenase-2 (COX-2), originating
prostaglandins-ethanolamides (prostamides) and lipoxygenase-12 and -15
(LOX-12-15), also including cytochrome p450 oxygenase enzymes have been
mentioned by some authors as exhibiting a catabolic potential for both
endocannabinoids {[}43, 48, 49{]}.

In this context, we briefly illustrate in fig. 1 the complexity of the
ES.

\textbf{Fig. 1.} The complexity of the ES

\textbf{1.4.2 Additional ligands and receptors of the endocannabinoid
system}

In addition to CB1 and CB2, the ES may include additional ligands and
receptors capable of binding to other pharmacological targets. The most
studied of the receptors involved in this system are TRPV1,
5HT\textsubscript{1A}, PPAR\selectlanguage{greek}γ \selectlanguage{english}and PPAR\selectlanguage{greek}α, \selectlanguage{english}although some works have
addressed the role of two GPRs, GPR55 and G protein-coupled receptor 18
(GPR18) {[}50-55{]}.

TRPV1 is a cation-permeable ion channel activated by heat, acidic pH,
and capsaicin (the pungent compound in the pepper \emph{Capsicum
frutescens} pepper). It is a ''vanilloid channel'' or ''transient
receptor potential cationic channel, subfamily V, member 1'' {[}56{]},
located in the GABAergic and glutamatergic terminals and in the
perikarya of neurons in the hippocampus and cerebellum, being identified
as an important target that may represent a potential treatment for some
diseases {[}36, 57-60{]}. In models of epilepsy, for example, TRPV1 is
believed to increase the excitability of central neurons. In this case,
studies have shown that from a double blockade of FAAH/TRPV1 there was a
mediation of the excitatory effects of anadamide. This strategy induced
an increase in AEA, levels, selectively activating the CB1 receptor and
inhibiting neuronal activity {[}56, 61, 62{]}.

In short, TRPV1 has been identified as a receptor with high affinity for
endogenous AEA having an opposite action to the CB1 receptor {[}47{]},
since while the binding of anandamide to the CB1 receptor inhibits
neuronal activity, activation of TRPV1 depolarizes neurons and promotes
neuronal activity. release of neurotransmitters {[}50, 63-65{]}.

As for 5HT\textsubscript{1A}, they are serotonin receptors coupled to a
Gi/o protein and have been related to cannabinoids, including
neuroprotective effects {[}66{]}. These receptors are considered
autosomal and are located on presynaptic membranes and are also found
postsynaptically in various areas of the brain {[}67{]}. From an\emph{in
vivo} study, the hypothesis emerged that 5HT\textsubscript{1A}was a
mediator that facilitated the neurotransmission of CBD, thus being an
agonist of these cannabinoid receptors {[}68{]}. However, according to
Campos et al {[}69{]} this agonist action was not corroborated in other
subsequent studies, thus presenting the idea that
5HT\textsubscript{1A}-mediated effects of CBD would be caused by
allosteric interactions with the receptor binding site and/or
interference with intracellular pathways.

The antiaversive pharmacological effects of CBD were observed when CBD
was injected systemically and in different areas of the brain, such as
the dorsal periaqueductal gray matter, the medial hypothalamus and the
medial prefrontal cortex, and in different animal models, including
threat stress of predator {[}70-75{]}. Based on these and other
findings, CBD has been proposed as a positive allosteric modulator for
the 5HT\textsubscript{1A} receptor {[}76-78{]}.

In addition to TRPV1 and 5HT\textsubscript{1A} receptors, investigations
with PPAR\selectlanguage{greek}γ \selectlanguage{english}and PPAR\selectlanguage{greek}α \selectlanguage{english}have been presented in the literature. It is known
that PPAR\selectlanguage{greek}α \selectlanguage{english}and PPAR\selectlanguage{greek}γ, \selectlanguage{english}an important class of nuclear hormone receptors
(PPARs), are additional targets of endocannabinoids {[}79, 80{]}.
Although the data are more significant for some cannabinoids, such as
N-oleoylethanolamine (OEA) and N-palmitoylethanolamine (PEA),
neuroprotection, anti-inflammatory and analgesic effects have been
considered mediated, in part, by their activation to PPARs. However,
there are a myriad of factors influencing interactions between
cannabinoids and PPARs that need to be elucidated {[}81-83{]}.

Interestingly, PEA (a compound related to cannabinoids) is currently
used to treat pain and inflammation. Like other cannabinoid-related
molecules, PEA has a very complex mechanism of action, which includes
direct and/or indirect interaction with CB1, TRPV1, PPAR, GPR55 and
GPR18, among other receptors {[}84{]}. It is known that GPR119, another
putative receptor identified, can bind to PEA and also OEA compounds
{[}85{]}.

The list of non-cannabinoid receptors has been advancing. GPR18 and
GPR55 have been presented as targets of various phytocannabinoids,
synthetic cannabinoids and endocannabinoids {[}86-89{]}. Both are
related to the modulation of several pathways of signaling of various
metabolic disorders, being located mainly dispersed in the central and
peripheral systems of the body, such as the brain and vascular system
{[}90{]}.

Moreover, GPR18 interact directly or indirectly with cannabinoids and
seem to play an important role in inflammation, acting in the control of
immune system activities, such as migration and apoptosis of leukocytes,
and also in reducing intraocular pressure in mice. Its expression was
evidenced in testes, spleen, peripheral blood leukocytes and lymph nodes
{[}88{]}.

Regarding GPR55, it has been shown to act in the nervous system, being a
therapeutic target for Parkinson's disease {[}91-93{]}, Alzheimer's
disease (Medina-Vera et al, 2020), epilepsy (Gaston et al, 2016; Kaplan
et al., 2017), in memory and spatial learning {[}94{]}. Furthermore,
that it exerts antiproliferative effects through inhibition of protein
kinase B (PKB) and extracellular signal-regulated kinase (ERK) in which
CBD acts as a GPR55 antagonist {[}90{]}, as well as, that PEA has high
affinity for GPR55 as a full agonist {[}95{]}. Several interaction
actions between endocannabinoids and GPR55 in the CNS have been studied
recently, but many mechanisms need to be elucidated in order to obtain
scientific evidence {[}15, 95{]}.

An \emph{in vitro} and \emph{in vivo} study analyzed the affinity of
eight compounds, namely, THC, [?]9-tetrahydrocannabinolic acid (THCA), [?]9-
tetrahydrocannabivarin (THCV), CBD, cannabidiolic acid (CBDA),
cannabidivarin (CBDV), canabigerol (CBG) and cannabichromene (CBC), with
CB1 and CB2 receptors. The results demonstrated that many of these
phytocannabinoids have a partial agonist activity on CB1 and/or CB2
receptors, and in vivo the interaction of phytocannabinoids often occurs
with CB1 receptors {[}96{]}.

\textbf{1.5 Therapeutic applications in diseases of the nervous system}

\textbf{1.5.1 Epilepsy}

For cases of intractable seizures such as Dravet syndrome,
Lennox-Gastaut syndrome and tuberous sclerosis complex, the use of CBD
(branded as Epidiolex) was approved in 2018 and 2019 by FDA and the
European Medicines Agency, respectively.

Epilepsy is a neurological disorder that affects people of all ages; it
is a chronic disorder of the brain characterized by convulsive crises
with events of hyperactivation and synchronization of groups of neurons
that lead to motor, sensory, autonomic, and behavioral alterations
{[}97{]}. Roughly 50 million people worldwide have epilepsy, making it
one of the most common neurological disorders in the world, and
approximately 30\% of patients are affected by treatment-resistant
epilepsy due to the failure of common antiepileptic therapies {[}98,
99{]}.

With the advance in the understanding of neurotransmitter systems in
recent years, it has been accepted that the break in the balance between
excitatory and inhibitory neurotransmitter systems may underlie the
triggering of epileptic disorders. However, a precise relationship
between such neural systems and the characteristics of epileptiform
syndromes has not yet been established {[}30{]}.

Many epilepsy induction models have been used to study the antiepileptic
properties of CBD {[}100-104{]}. Broadly, both antiepileptogenic effects
with CB1 and CB2 receptor agonists and pro-epileptogenic effects using
blockers of these receptors in temporal lobe models of epilepsy have
been observed {[}62, 105-107{]}.

In fact, there is evidence that the ES participates in seizure control
mechanisms in developing animals through the CB1 receptor {[}108{]}. In
preclinical seizure models, the anticonvulsant effect has been related
to a pharmacological increase in endocannabinoid levels, and AEA and
2-AG are released after neuronal hyperexcitability to combat glutamate
excitotoxicity during seizures {[}36, 107, 109, 110{]}. Nonetheless,
according to Schlicker and Kathmann {[}111{]} and Alger {[}112{]}, many
axon terminals of the CNS express CB1 receptors with the function of
inhibiting the release of excitatory and inhibitory neurotransmitters.

A recent review by Bilbao and Spanagel {[}113{]} showed that CBD has a
significant therapeutic effect (high grade) for epilepsy. Regarding the
effects of CBD in epilepsy, it is not yet clear how it exerts its action
(a summary of this mechanism was shown in figure 2). However, it has
been proposed that the anticonvulsant action of CBD is exerted through
several mechanisms independently of CB1 receptors {[}114{]}, instead
including the effects on 5-HT\textsubscript{1A} receptors, vanilloid
TRPV1 receptors, N-metil D-Aspartat receptors (NMDA), GPR55 receptors,
Ca\textsuperscript{++} flux regulation, increased adenosine signaling,
and interaction with GABAergic receptors {[}36, 101, 103, 115-122{]}. In
addition to the anticonvulsant potential of CBD {[}103, 123{]}, a
neuroprotective effect has been proposed, restoring hippocampal
interneuron functions in a temporal lobe epilepsy model {[}124-126{]}.

\textbf{Fig. 2} . Diagram of interactions and therapeutic effects of CBD
in epilepsy

It is noteworthy that other compounds derived from Cannabis are being
studied, with emphasis on CBDV, which has shown anticonvulsant results,
and future analyses may better identify its potential for epilepsy
treatment {[}116, 127, 128{]}. In summary, several well-designed trials
have shown the effectiveness of cannabinoids in controlling epileptic
seizures (Table 1). This review presents some studies using CBD,
preferably randomized, double-blind, placebo-controlled clinical trials.
Serious adverse effects are relatively rare, with somnolence, decreased
appetite, and diarrhea being common. However, the use of concomitant
medications such as clobazam and sodium valproate has been associated
with somnolence and elevated liver enzymes {[}99, 129, 130{]}.

Currently, CBD can be considered a reasonable treatment for several
types of refractory epilepsy, with a favorable profile of adverse events
and prolonged and sustained efficacy. However, it is necessary to be
careful that these results, which have been demonstrating safety and
efficacy, do not extrapolate to other formulations that lack rigorous
standards of production and purity; nevertheless, there is more to learn
and less to fear with CBD as a treatment for epilepsy {[}129{]}.

\textbf{Table 1.} Preclinical and clinical evidence using Cannabis
derivatives in epilepsy models and patients.

It is important to consider that in addition to pediatric epilepsies,
people over 65 years of age can be diagnosed with epilepsy
(cryptogenic), underlying seizures resulting mainly from
neurodegenerative diseases and also from traumatic brain injury,
cerebrovascular diseases and brain tumors. Therefore, in the context of
neurodegenerative diseases, epilepsy has been highlighted, including in
the search for evaluative procedures for early diagnosis and
intervention in elderly people with initial seizures.{[}19{]}.

\textbf{1.5.2 Multiple sclerosis}

Multiple sclerosis is a chronic, progressive, autoimmune disease caused
by inflammation, demyelination, gliosis, and neurodegeneration
{[}131{]}. It manifests itself clinically through sensory, motor, and
psychological symptoms, and via neurological aspects. The most common
signs are fatigue (40\%), optic neuritis (22\%), paresthesia (21\%),
diplopia (12\%), vertigo (5\%), and bladder dysfunction (5\%). However,
other symptoms include cognitive impairment, ataxic gait, spasticity,
depression, and internuclear ophthalmoplegia. The region of the CNS that
is affected will determine how multiple sclerosis manifests itself, as
well as the frequency, severity, progression of the disease's
incapacitation, and the sequelae of the relapses {[}132{]}. In young
adults between 20 and 40 years of age, it appears as the main cause of
disability and has a higher incidence in women (2.3:1) {[}133{]}.

Regarding the pathophysiology, self-reactive leukocytes cross the
blood-brain barrier and form active plaques formed by perivascular and
parenchymal infiltrates of macrophages, B lymphocytes, and T
lymphocytes, which destroy the myelin sheath. The acute inflammatory
phase is characterized by partial remyelination by oligodendrocytes in
the affected axons {[}134{]}. Infiltration of T lymphocytes in the CNS
accompanied by oligodendrocyte destruction and axonal damage marks the
arrival of the progressive phase of the disease. After the demyelinating
event, impulse transmission in the affected axons occurs at 5 to 10\% of
normal speed. In addition, demyelinated axons generate spontaneous
electrical discharges known as Lhermitte's sign {[}135{]}.

Treatment aims to reduce the occurrence of new outbreaks, slow the
progression of neurological damage, and delay the progressive phase of
multiple sclerosis, mainly seeking to partially prevent axon destruction
arising from the autoimmune inflammatory process. In this sense, CBD use
in animal models and patients with multiple sclerosis has been reported
(Table 2), with indications for spasticity, pain, relaxation, sleep,
anxiety, and tremor {[}136{]}. Patients with multiple sclerosis have
shown alterations in the expression of CB1 and CB2 receptors and,
therefore, therapies with cannabis derivatives have been proposed {[}36,
126{]}.

\textbf{Table 2.} Preclinical and clinical evidence using Cannabis
derivatives in multiple sclerosis models and patients.

Nabiximols have been frequently prescribed as a spray solution for
buccal spraying, consisting of THC:CBD (1:1) and trade names
Sativex/Mevatyl when prepared synthetically {[}136-141{]}. An oral
solution that can also be prescribed is dronabinol, being a synthetic
enantiomer of THC, under the trade names Marinol/Syndros {[}142{]}.

Recently, improvements in spasticity and pain linked to multiple
sclerosis have been associated with the use of nabiximols. However,
despite indicating to be a promising therapy, with good tolerability and
safety, nabiximois and dronabinol were not able to significantly improve
the symptoms of multiple sclerosis {[}113, 126, 143-146{]}. Thus, there
is no consensus regarding the possible molecular and cellular mechanisms
related to the treatment with these cannabinoids, mainly, how they act
to reduce neuroinflammation.

With regard to better elucidating the interaction between THC + CBD and
neuroinflammation in experimental autoimmune encephalomyelitis (EAE)
models, the work by Al-Ghezi et al. {[}147{]} investigated the mechanism
by which the THC + CBD combination (10 mg/kg each) suppressed
neuroinflammation and showed that these effects were mediated by CB1 and
CB2 receptors, since in mice deficient in CB1 and CB2 this effect was
reversed, with no reduction in the inflammatory process. In addition,
treated animals showed a decrease in the levels of CD4 + T cells
infiltrated in the brain and pro-inflammatory molecules (IL-17, INF-\selectlanguage{greek}γ,
\selectlanguage{english}TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-1\selectlanguage{greek}β, \selectlanguage{english}IL-6 and TBX21) and on the other hand , an increase in
anti-inflammatory phenotype molecules such as FoxP3, STAT5b, IL-4, IL-10
and TGF-\selectlanguage{greek}β. \selectlanguage{english}We also investigated epigenetic mechanisms through miRNA
microarray analysis of brain-derived CD4 + T cells, transfection
involving miR-21 and use of Mir21 - / - mice. It was suggested in this
study that the combination of THC + CBD suppresses neuroinflammation and
attenuates the clinical development of EAE and that this effect is
associated with changes in the miRNA profile in cells that infiltrate
the brain. In figure 3, a diagram showing interactions and effects of
THC:CBD in multiple sclerosis.

Finally, in multiple sclerosis, among other mechanisms, interactions
between cannabinoids and receptors need to be better explored, in
particular, the pharmacological activation of the CB2 receptor since it
has a strong involvement with neuroinflammation, remyelination and
neuronal survival.

\textbf{Fig. 3.} Diagram of interactions and therapeutic effects of
THC:CBD in multiple sclerosis



\textbf{1.5.3 Parkinson's disease}

Parkinson's disease is the second most prevalent neurodegenerative
disease, affecting 5\% of the population over 85 years of age.
Furthermore, its global burden has more than doubled, making it the
fastest growing neurodegenerative disease. Genetic causes also
contribute to the etiology of Parkinson's disease, but in smaller
proportions, estimated at 5\% of all people with the disease. It is
known that the combination of these genetic and environmental factors
increases the risk of the disease {[}150{]}.

Symptomatically, it is characterized by motor and non-motor symptoms,
which are generally underdiagnosed and untreated {[}149{]}; being
diagnosed only with the development of motor impairment (e.g. tremor,
rigidity and bradykinesia). However, motor features are strongly linked
to dopaminergic damage in the nigrostriatal pathway, which occurs only
in the intermediate stages of the disease {[}148{]}. Staging is based on
the appearance of \selectlanguage{greek}α-\selectlanguage{english}synuclein aggregates, and it can take 20 years for
motor disorders to appear, highlighting the involvement of other
neurotransmission systems and their relationship with early non-motor
symptoms, such as mild olfactory and cognitive impairment and depression
{[}149, 151{]}.

Parkinson's disease onset is tightly related to \selectlanguage{greek}α-\selectlanguage{english}synuclein
overexpression and/or modification, a protein involved in the synaptic
vesicle release. In turn, misfolded \selectlanguage{greek}α-\selectlanguage{english}synuclein forms aggregates called
Lewy bodies {[}152{]}. Due to an impaired synaptic function, several
cellular and physiological mechanisms are affected, resulting in
neuroinflammation, oxidative stress, reduced trophic support, and
excitotoxicity {[}153{]}. Since endocannabinoids regulate synaptic and
motor functions through cannabinoid receptors CB1 and CB2, this system
is also impacted by striatal rearrangement after dopamine depletion
{[}154-156{]}.

In fact, people with Parkinson's disease have higher AEA levels and
altered cannabinoid expression {[}156-158{]}. Regarding the CB1
receptor, brain MRI studies demonstrated greater expression in the
mesolimbic and mesocortical regions {[}158, 159{]}. In contrast, the
availability of CB1 and CB2 receptors decreased in the substantia nigra
{[}157, 158{]}; furthermore, the CB1 receptor appears to be involved in
the action of 3,4-dihydroxy-L-phenylalanine (L-DOPA), preventing motor
fluctuations that are commonly observed in therapy {[}160{]}, and the
CB2 receptor is increased in glial cells in post-mortem tissues
{[}161{]}.

Based on exposure, pharmacological modulation of the ES may be an
interesting approach for Parkinson's disease management. In vitro and in
vivo studies on THC effects on Parkinson's disease models have revealed
neuroprotective effects that are likely mediated by the CB1 receptor
{[}162-165{]}. Furthermore, PPAR\selectlanguage{greek}γ \selectlanguage{english}appears to play a crucial role,
mediating the downregulation of the CB1 receptor and the restoration of
mitochondrial content {[}162, 166, 167{]}.

Recently, in a meta-analysis, it was shown that treatment with CBD
promoted a significant improvement in parkinsonian symptoms, however,
these benefits were not seen in therapy with nabilone {[}113{]}. Thus,
modulation between cannabinoid receptors and TRPV may be associated with
these results {[}126, 168, 169{]}.

Beneficial effects of CBD in Parkinson's disease models suggest CB2 but
not CB1 receptor involvement {[}170, 171{]}. CBD treatment showed
neuroprotective effects on the nigrostriatal pathway {[}163, 170, 172,
173{]}, \emph{in vitro} data suggest that CBD's neuroprotective action
is linked to tropomyosin receptor kinase A activation {[}174{]}. Lastly,
Gugliandolo et al. {[}171{]} reported that the antiapoptotic effect of
CBD is mediated by ERK and Akt/mTOR pathways, while ERK activation
seemed to be modulated by TRPV1 and CB2 receptors. Finally, recently,
Wang et al {[}175{]} demonstrated anti-apoptotic effects of dopaminergic
neurons and neuroinflammation in which CBD repressed the expression of
the inflammasome pathway NLRP3/caspase-1/IL-1\selectlanguage{greek}β, \selectlanguage{english}upregulated Bcl-2 and
downregulated Bax and Caspase-3, corroborating its neuroprotective and
anti-apoptotic role.

Besides THC and CBD, other cannabis derivatives displayed therapeutic
potential in preclinical investigations. There is evidence that THCA, 7
(Z)-methyl p-hydroxycinnamate (ZMHC), Beta-caryophyllene (BCP), and THCV
have neuroprotective effects in Parkinson's disease models {[}165, 172,
173, 176{]}. Moreover, BCP chronic treatment demonstrated antioxidant
and anti-inflammatory effects mediated by the CB2 receptor in a
Parkinson's disease model induced by rotenone {[}176, 177{]}. In turn,
THCV inhibits motor impairment, glutamatergic changes, and microglial
activation induced by6-hydroxydopamine (6-OHDA){[}172{]}.

In summary, the scientific evidence on therapeutic cannabis use and its
derivatives in Parkinson's disease are inconsistent and of poor quality,
hindering concrete conclusions of its efficacy to be made. Based on the
scientific evidence presented in this review, the therapeutic potential
of phytocannabinoids in Parkinson's disease is illustrated in figure 4
and the studies shown in table 3.

\textbf{Fig. 4.} Diagram of interactions and therapeutic potential of
phytocannabinoids in Parkinson's disease.

\textbf{Table 3.} Preclinical and clinical evidence using Cannabis
derivatives in in Parkinson's disease models and patients

\textbf{2. Conclusion}

In this context of medicinal cannabis as a therapy for diseases of the
nervous system, especially neurodegenerative diseases, the highlights
have been the cannabinoids, THC and CBD. Several strategies, involving
preclinical and clinical research, have reinforced the role of CBD in
neuroinflammation, neuroprotection and anti-apoptotic, antiepileptic, as
presented in this review. But, evidence on the molecular, cellular and
behavioral mechanisms resulting from its interaction with a complex
expanded endocannabinoid system requires further studies, particularly
in epilepsy, multiple sclerosis, Parkinson's disease, diseases addressed
in this review.

Significant therapeutic effects of CBD have been observed for epilepsy
and Parkinson's disease, while nabiximois has been a frequent option for
the treatment of multiple sclerosis and has been evaluated as a drug
that contributes to the reduction of spasticity {[}113{]}. Its role as a
CB2 receptor inverse agonist, AEA reuptake inhibitor and non-competitive
negative allosteric modulator of the CB1 receptor is known {[}178{]},
but a possible action of CBD in neutralizing the effects of THC has been
discussed and it is expected that such interaction mechanisms will be
addressed in future studies. In general, in some diseases CBD has shown
promising therapeutic benefits, but it is necessary to wait for the
evidence to come from more randomized, double-blind, placebo-controlled
studies that reach diverse populations.

Much research still needs to be done, requiring preclinical studies that
mimic the pathological conditions and double-blind, randomized,
placebo-controlled clinical trials so that robust data allow conclusions
based on scientific evidence.

\textbf{Abbreviations}

2-AG, 2-arachidonoyl-glycerol; 5-HT\textsubscript{1A,} serotoninergic
receptors of the 5-HT\textsubscript{1A} type; AEA, anandamide; BCP,
\selectlanguage{greek}β-\selectlanguage{english}caryophyllene; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor
2; CBC, cannabichromene; CBD, cannabidiol; CBDA, cannabidiolic acid;
CBDV, cannabidivarin; CBG, canabigerol; CNS, Central nervous system; D;
DAGL\selectlanguage{greek}α, \selectlanguage{english}diacylglycerol lipase \selectlanguage{greek}α; \selectlanguage{english}DAGL, sn-1-diacylglycerol lipase; DAGL\selectlanguage{greek}β,
\selectlanguage{english}diacylglycerol lipase \selectlanguage{greek}β; \selectlanguage{english}EAE, Experimental autoimmune encephalomyelitis;
ERK, protein extracellular signal-regulated kinase; ES, endocannabinoid
system; FAAH, fatty acid amide hydrolase; FDA, Food and Drug
Administration; FoxP3, Forkhead box P3; GABA\textsubscript{A},
\selectlanguage{greek}γ-\selectlanguage{english}Aminobutyric acid type A;~ GPCRs, orphan G protein-coupled receptors;
GPR118; G protein-coupled receptor 118; GPR119; G protein-coupled
receptor 119; GPR18; G protein-coupled receptor 18; GPR55, G
protein-coupled receptor 55; IL-10, Interleukin-10; IL-17,
Interleukin-17; IL-1\selectlanguage{greek}β, \selectlanguage{english}Interleukin 1 beta; IL-4, Interleukin-4; IL-6,
Interleukin-6; INF-\selectlanguage{greek}γ, \selectlanguage{english}Interferon gamma; MAGL, monoacylglycerol lipase;
miRNA, MicroRNA; MS, Multiple sclerosis; NAPE-PLD, N-acyl-phosphatidyl
ethanolamine-specific phospholipase; OEA, N-oleoylethanolamine; PEA,
N-palmitoylethanolamine; PPAR\selectlanguage{greek}α, \selectlanguage{english}peroxisome proliferator-actived receptor
\selectlanguage{greek}α; \selectlanguage{english}PPAR\selectlanguage{greek}γ, \selectlanguage{english}peroxisome proliferator-actived receptor \selectlanguage{greek}γ; \selectlanguage{english}STAT5b, signal
transducer and activator of transcription 5B; TBX21; T-box transcription
factor 21; TGF-\selectlanguage{greek}β, \selectlanguage{english}Transforming growth factor beta; THC,
\selectlanguage{greek}Δ\selectlanguage{english}\textsuperscript{9} -tetrahidrocanabinol;~ THCA,
[?]9-tetrahydrocannabinolic acid; THCV, [?]\textsuperscript{9}-
tetrahydrocannabivarin; TNF-\selectlanguage{greek}α, \selectlanguage{english}Tumor necrosis factor alpha; TRPM8,
transient receptor potential cation channel subfamily M (melastatin)
member 8; TRPV1, transient receptor potential vanilloid 1.

\textbf{Author's contributions}

Maria de F\selectlanguage{ngerman}átima dos Santos Sampaio: writing, reviewing and figures
design. Yara Bezerra de Paiva and Tuane Bazanella Sampaio: writing.
Messias Gonzaga Pereira: writing and revised. Norberto Cysne Coimbra:
writing, revised and supervised. All authors have read and approved the
final version of the manuscript.



\textbf{Declaration of competing interest}

The authors declare no conflict of interest.

\textbf{Acknowledgments}

This work was supported by the Fundação de Amparo à Pesquisa do Estado
de São Paulo (FAPESP) (Research Grant 2020/15050-7), Fundação de Apoio
ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade
de Medicina de Ribeirão Preto da Universidade de São Paulo (FAEPA)
(Research Grant 374/2022), and Pro-Rectory of the University of São
Paulo (USP) Research Grant (NAP-USP-NuPNE; process
IaPq2012-156-USP-12.1.25440.01.6). M. de Fátima dos Santos Sampaio is a
postdoctoral researcher supported by CNPq (PDJ grant 155489/2018-6).
N.C. Coimbra is a researcher from CNPq (PQ1A-level grants 301905/2010-0
and 301341/2015-0; PQ2-level grant 302605/2021-5). Each organisation had
no further role in the study design; the collection, analysis, and
interpretation of the data; the writing of the report; or the decision
to submit the paper for publication. All figures in the manuscript were
created with BioRender.com.

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\textbf{Tables}

\textbf{Table 1.} Preclinical and clinical evidence using Cannabis
derivatives in epilepsy models and patients.

\textbf{Table 2.} Preclinical and clinical evidence using Cannabis
derivatives in multiple sclerosis models and patients.

\textbf{Table 3.} Preclinical and clinical evidence using Cannabis
derivatives in in Parkinson's disease models and patients

\textbf{Legends}

\textbf{Fig. 1.} The complexity of the endocannabinoid system. Diagram
showing the components of the expanded endocannabinoid system including
the biosynthesis and degradation of endocannabinoids in the CNS. In
response to demand, AEA and 2-AG are produced, which can cross the
synaptic cleft and activate presynaptic CB1 receptors resulting in
neurotransmitter inhibition. Biosynthesis and inactivation of AEA
endocannabinoids in postsynaptic neurons is done by FAAH and NAPE-PLD. O
2-AG is hydrolyzed in presynaptic neurons by MAGL, also by enzymes DAGL\selectlanguage{greek}α
\selectlanguage{english}and DAGL\selectlanguage{greek}β. \selectlanguage{english}Note the complexity of the endocannabinoid system that
interacts with several neuromediators, receptors and new molecular
targets. 2-AcGs; 2-acylglycerols; 2-AG, 2-arachidonoyl-glycerol;
5-HT\textsubscript{1A,} serotoninergic receptors of the
5-HT\textsubscript{1A} type; AA, arachidonic acid; Abh4,
alpha-betahydrolase-4; AEA, anandamide; CB1, cannabinoid receptor 1;
CB2, cannabinoid receptor 2; COX-2, cyclooxygenase-2; DAGL,
sn-1-diacylglycerol lipase; ETA, ethanolamide;~ FAAH, fatty acid amide
hydrolase; GLY, glycerol; GPRs, G protein-coupled receptors; Lyso PLC,
lysoPI-specific PLC; LOX, lipoxygenase; MAGL, monoacylglycerol lipase;
NAES; N-acylethanolamines; NAPE-PLD, N-acyl-phosphatidyl
ethanolamine-specific phospholipase D; PLA1, phospholipase A1; PPAR\selectlanguage{greek}γ,
\selectlanguage{english}peroxisome proliferator-actived receptor \selectlanguage{greek}γ; \selectlanguage{english}PTPN22, protein tyrosine
phosphatase nonreceptor type 22; TRPV1, transient receptor potential
vanilloid 1. (Created with BioRender.com).

\textbf{Fig. 2} . Diagram of interactions and therapeutic effects of CBD
in epilepsy.

2-AG, 2-arachidonoyl-glycerol; 5-HT\textsubscript{1A,} serotoninergic
receptors of the 5-HT\textsubscript{1A} type; AEA, anandamide; CB1,
cannabinoid receptor 1; CBD, cannabidiol; GPR55, G protein-coupled
receptor 55; TRPV1, transient receptor potential vanilloid 1. (Created
with BioRender.com).

\textbf{Fig. 3.} Diagram of interactions and therapeutic effects of
THC:CBD in multiple sclerosis. A perivascular and parenchymal infiltrate
of macrophages, B lymphocytes and T lymphocytes is observed in MS, which
cross the blood-brain barrier and destroy the myelin sheath, followed by
partial remyelination by oligodendrocytes (acute inflammatory phase)
than by infiltration of T lymphocytes, oligodendrocyte destruction and
axonal injury will progress to the progressive phase of the disease.
Combined THC:CBD therapy has demonstrated pharmacological activation of
the CB2 receptor strongly associated with suppression of
neuroinflammation and induction of remyelination processes and neuronal
survival. Furthermore, the decrease in astrocyte activity leading to
inhibition of the neuroinflammatory process was also notable. CBD,
cannabidiol; CB1, cannabinoid receptor 1; MS; multiple sclerosis; THC,
\selectlanguage{greek}Δ\selectlanguage{english}\textsuperscript{9}-tetrahidrocanabinol. (Created with BioRender.com).

\textbf{Fig. 4.} Diagram of interactions and therapeutic potential of
phytocannabinoids in Parkinson's disease. PD is characterized by
dopaminergic damage to the nigrostriatal pathway, dopamine depletion,
excitocicity, accumulation of \selectlanguage{greek}α-\selectlanguage{english}synuclein and Lewy bodies, reduced
trophic support and oxidative stress in the brain region.
Cannabis-derived products have been used for the treatment of PD, such
as: THC and THCV which have shown neuroprotective effects. In the case
of THC, possibly mediated by the CB1 receptor, being also associated
with PPAR\selectlanguage{greek}γ, \selectlanguage{english}in the negative regulation of the CB1 receptor and the
restoration of mitochondrial content. THCV is mediated by the CB1
receptor. CBD has been linked to CB2 and TRPV receptors showing
neuroprotective, anti-apoptotic, neuroinflammatory and antioxidant
effects. CB2 receptor-mediated anti-inflammatory and antioxidant effects
have been demonstrated by BCP. 2-AG, 2-arachidonoyl-glycerol; AEA,
anandamide; BCP, \selectlanguage{greek}β-\selectlanguage{english}caryophyllene; CB1, cannabinoid receptor 1; CB2,
cannabinoid receptor 2; CBD, cannabidiol; FAAH, fatty acid amide
hydrolase; NAPE-PLD, N-acyl-phosphatidyl ethanolamine-specific
phospholipase D; PD, Parkinson's disease; PPAR\selectlanguage{greek}γ, \selectlanguage{english}peroxisome
proliferator-actived receptor \selectlanguage{greek}γ; \selectlanguage{english}THC,
\selectlanguage{greek}Δ\selectlanguage{english}\textsuperscript{9}-tetrahidrocanabinol;~ THCV,
\selectlanguage{greek}Δ\selectlanguage{english}9-tetrahydrocannabivarin; TRPV1, transient receptor potential vanilloid
1. (Created with BioRender.com).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4/Figure-4}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`Table 1 (Epilepsy).doc`  available at \url{https://authorea.com/users/673796/articles/672479-a-literature-review-on-the-therapeutic-applicability-of-cannabidiol-in-epilepsy-multiple-sclerosis-and-parkinson-s-disease}

\textbf{Hosted file}

\verb`Table 2 (Multiple sclerosis).doc`  available at \url{https://authorea.com/users/673796/articles/672479-a-literature-review-on-the-therapeutic-applicability-of-cannabidiol-in-epilepsy-multiple-sclerosis-and-parkinson-s-disease}

\textbf{Hosted file}

\verb`Table 3 (Parkinson's disease).doc`  available at \url{https://authorea.com/users/673796/articles/672479-a-literature-review-on-the-therapeutic-applicability-of-cannabidiol-in-epilepsy-multiple-sclerosis-and-parkinson-s-disease}

\selectlanguage{english}
\FloatBarrier
\end{document}

