Biological bases for a possible effect of cannabidiol in
Nilson C. Ferreira-Junior,
Alline C. Campos,
Francisco S. Guimara
da R. Zimmermann,
Liberato Brum Junior,
Jaime E. Hallak,
Antonio W. Zuardi
Departamento de Farmacologia, Faculdade de Medicina de Ribeira
˜o Preto (FMRP), Universidade de Sa
˜o Paulo (USP), Ribeira
˜o Preto, SP,
Departamento de Morfologia Fisiologia e Patologia Ba
´sica, Faculdade de Odontologia de Ribeira
˜o Preto (FORP), USP, Ribeira
Prati Donaduzzi & Cia Ltda., Toledo, PR, Brazil.
Departamento de Neurocie
ˆncias e Cie
ˆncias do Comportamento, FMRP, USP,
˜o Preto, SP, Brazil.
Objective: Current pharmacotherapy of Parkinson’s disease (PD) is palliative and unable to modify
the progression of neurodegeneration. Treatments that can improve patients’ quality of life with fewer
side effects are needed, but not yet available. Cannabidiol (CBD), the major non-psychotomimetic
constituent of cannabis, has received considerable research attention in the last decade. In this
context, we aimed to critically review the literature on potential therapeutic effects of CBD in PD and
discuss clinical and preclinical evidence supporting the putative neuroprotective mechanisms of CBD.
Methods: We searched MEDLINE (via PubMed) for indexed articles published in English from
inception to 2019. The following keywords were used: cannabis; cannabidiol and neuroprotection;
endocannabinoids and basal ganglia; Parkinson’s animal models; Parkinson’s history; Parkinson’s and
Results: Few studies addressed the biological bases for the purported effects of CBD on PD. Six
preclinical studies showed neuroprotective effects, while three targeted the antidyskinetic effects of
CBD. Three human studies have tested CBD in patients with PD: an open-label study, a case series,
and a randomized controlled trial. These studies reported therapeutic effects of CBD on non-motor
Conclusions: Additional research is needed to elucidate the potential effectiveness of CBD in PD and
the underlying mechanisms involved.
Keywords: Cannabidiol; CBD; Parkinson; neurodegeneration; neuroprotection
Pathophysiology of Parkinson’s disease
In ‘‘An essay on the shaking palsy’’ (1817), James
Parkinson ﬁrst described a condition of insidious onset with
a progressive and disabling course characterized by resting
tremor, ﬂexed posture, and festinating gait.
later added extensive details to Parkinson’s observations,
identifying bradykinesia and rigidity as key symptoms of the
In 1895, Brissaud hypothesized that the sub-
stantia nigra (SN) was the main brain nucleus affected in
Parkinson’s disease (PD),
described protein aggregates in brain areas of PD patients,
including the globus pallidus, the dorsal nucleus of the
vagus, and the locus coeruleus.
Shortly thereafter, in 1919,
Tretiakoff validated Lewy’s hypothesis by describing the
protein aggregates observed in postmortem brain tissue of
PD patients, which he called Lewy bodies.
Pathologically, PD is characterized by early death of
dopaminergic neurons in the SN pars compacta (SNpc),
leading to dopamine deﬁciency within the basal ganglia
and a movement disorder consisting of the classic
parkinsonian motor symptoms. However, PD is also
associated with multiple non-motor symptoms, some of
which precede motor dysfunction by more than a decade.
The mainstay of PD management is symptomatic treat-
ment with drugs that increase brain dopamine concentra-
tions or directly stimulate dopamine receptors.
As noted above, PD begins years before clinical
diagnosis, involves multiple brain regions, and entails
motor and non-motor symptoms. It is a slow, progressive
neurodegenerative disorder of multifactorial etiology,
resulting from a combination of genetic and environmental
factors. For instance, although still controversial, smokers
are twice as likely to develop PD,
have a lower incidence of the disease,
between obesity and herbicide exposure seems to be a
risk factor for dopaminergic neurodegeneration.
genetic standpoint, studies have shown that mutations in
ˆnio W. Zuardi, Departamento de Neurocie
cias e Cie
ˆncias do Comportamento, Faculdade de Medicina de
˜o Preto, Universidade de Sa
˜o Paulo, Av. Bandeirantes, 3900,
CEP 14049-900, Ribeira
˜o Preto, SP, Brazil.
Submitted Feb 20 2019, accepted Apr 08 2019.
How to cite this article: Ferreira-Junior N, Campos AC, Guimara
FS, Del-Bel E, Zimmermann PMR, Brum Junior L, et al. Biological
bases for a possible effect of cannabidiol in Parkinson’s disease.
Braz J Psychiatry. 2019;00:000-000. http://dx.doi.org/10.1590/1516-
Brazilian Journal of Psychiatry. 2019 xxx–xxx;00(00):000–000
Brazilian Psychiatric Association
Revista Brasileira de Psiquiatria
CC-BY-NC | doi:10.1590/1516-4446-2019-0460
different genes – such as Parkin, PINK1,DJ-1,LRRK2,
GBA, and ATP13A2 – are implicated in several types of
parkinsonism as well as in PD.
Hereditary PD is
classiﬁed as either dominant or recessive; the majority of
genetically associated cases feature early (rarely, even
In the literature, the genetic factors associated with PD
have often been related to causal mechanisms such as
oxidative stress, glutamate excitotoxicity, mitochondrial
dysfunction, neuroinﬂammation, apoptosis, and increased
susceptibility of the dopaminergic neurons of the SNpc to
An important hypothesis proposes that
oxidative stress generates free radicals, such as dopa-
mine quinone, that can react with the cytoplasmic pro-
tein a-synuclein, producing protoﬁbrils that cannot be
degraded by the ubiquitin-proteasome system. These
protoﬁbrils accumulate and generate eosinophilic cyto-
plasmic inclusions (Lewy bodies), causing the death of
dopaminergic neurons in the nigrostriatal pathway.
Although the understanding of the pathophysiology of
PD has improved markedly since its initial characteriza-
tion, an effective pharmacological treatment to prevent or
slow the progression of dopaminergic neuronal degen-
eration has yet to be developed. The pharmacotherapy of
PD continues to be palliative, aiming to restore reduced
dopamine levels in the striatum.
The standard treat-
ment is based on (S)-2 amino-3-(3,4-dihydroxyphenyl)
propionic acid, also known as levodopa (L-DOPA).
L-DOPA is considered a safe and effective drug for
reducing the motor symptoms of PD, with only mild side
effects, such as nausea, vomiting, and postural hypoten-
However, the long-term efﬁcacy of L-DOPA is
limited by the development of disabling motor complica-
tions such as L-DOPA-induced dyskinesia, a set of abnormal
involuntary movements that include chorea, hemiballismus,
In this context, the search for more effective and
tolerable treatments is imperative. Preclinical research
provides opportunities for the discovery of new PD drugs,
and animal models that mimic some aspects of PD have
been used in an attempt to describe promising candidate
agents. We searched MEDLINE (via PubMed) for indexed
articles published in English from inception to 2019. The
following keywords were used: cannabis; cannabidiol and
neuroprotection; endocannabinoids and basal ganglia;
Parkinson’s animal models; Parkinson’s history; Parkin-
son’s and cannabidiol.
Animal models for the study of Parkinson’s
Neurotoxin-based models are useful to understand the
mechanisms underlying the neurobiology of PD and
the dopaminergic neuronal loss observed in PD, through
the use of neurotoxins such as dopamine analogs (e.g.,
6-hydroxydopamine [6-OHDA]), contaminants of synthetic
heroin (e.g., 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
[MPTP]), herbicides (e.g., rotenone), heavy metals (e.g.,
manganese and iron), and lipopolysaccharide (LPS).
The ﬁrst substance reported to cause lesions in the
nigrostriatal pathway in rats was 6-OHDA.
accumulates in the cytosol of neurons and promotes the
formation of hydrogen peroxide, other reactive oxygen
species, and quinines by auto-oxidation.
6-OHDA is a
hydrophilic compound and cannot cross the blood-brain
barrier. It is administered by direct injection into the SNpc,
medial forebrain bundle, or striatum, depending on the
objective of the researcher (rate and extent of injury).
Even though 6-OHDA has been the most common
model in preclinical research, it is non-selective for dopa-
mine transporters, and is commonly co-administered with
selective noradrenaline uptake blockers to prevent loss
of noradrenergic neurons.
Another disadvantage of
6-OHDA use relies on its inability to produce Lewy body-
MPTP is a neurotoxin that is converted into an
intermediate metabolite by the action of monoamine
oxidase B in glial cells, and then oxidized to 1-methyl-
MPP+has high afﬁnity
for the dopamine transporter, but lower afﬁnity for
norepinephrine and serotonin transporters.
minergic neurons, MPP+is sequestrated into synaptic
vesicles or concentrated within the mitochondria, where
it blocks the electron transport chain.
MPTP administration produces Lewy body-like inclu-
sions, and the susceptibility to MPTP-induced lesions
increases with age.
Rotenone is a pesticide that acts by blocking the
mitochondrial electron transport chain, mitosis, and cell
Chronic systemic exposure to rotenone in
rats causes many features of PD, including nigrostriatal
degeneration and Lewy body-like inclusions, but this
model is difﬁcult to replicate due to the high mortality
Another pesticide used to study PD is
paraquat, one of the most widely used herbicides in
It shares structural similarity to MPP+.
Paraquat generates Lewy body-like inclusions,
has low speciﬁcity for dopaminergic neurons and causes
variable cell death.
Paraquat has been used in conjunction with manga-
nese ethylene-bis-dithiocarbamate (maneb), a fungicide
which has been shown to potentiate the toxic effects
of paraquat and of MPTP.
Results have shown that
maneb may, on its own, decrease locomotor activity
and produce loss of neurons in the substantia nigra.
Chronic exposure to maneb produces signs of manga-
followed by a neurological syndrome
with cognitive, psychiatric, and movement abnormalities
that resemble some clinical features of PD.
appears to cross the blood-brain barrier and inhibit
mitochondrial complex III.
model can induce behavioral and motor impairments,
signiﬁcant dopamine-related degeneration, and altered
responsiveness to dopamine therapy. Conversely, multi-
ple variants of this animal model have been reported to
evoke neither formation of Lewy bodies nor non-motor
Moreover, some nonspeciﬁc and undesir-
able peripheral effects are reported, mainly in the lungs
(respiratory distress), which limits utilization of these
Braz J Psychiatry. 2019;00(00)
2Ferreira-Junior NC et al.
A large genome-analysis study has implicated 28 inde-
pendent variants across 24 loci in the pathogenesis of
Five genes associated with familial PD have
been extensively studied and used as genetic models of
PD in rodents: a-synuclein, PINK1, Parkin, DJ-1, and
Considering that the more prevalent forms
of PD involve several genes and alterations in many gene
monogenic models of PD would be expec-
ted to be less successful than toxin-induced models to
evoke loss in the dopaminergic nigrostriatal pathway.
However, genetic models are interesting tools to help to
recognize whether a mutant gene is associated with the
progression of PD in humans, verify the involvement of
unknown genes in the disease, and understand the more
common genetic mechanisms of PD.
Several studies have demonstrated the contribution
of genetic factors to PD development. A meta-analysis
evaluated the interaction between the diagnosis of PD
and risk factors. The strongest association with later
diagnosis of PD was found for patients having a ﬁrst-
degree or any relative with PD, suggesting an increased
risk of PD diagnosis in patients with a family history
Further convincing evidence for the contribution
of genetic factors to PD was provided by the discovery of
monogenic forms of the disease. The SNCA gene, which
encodes a-synuclein, was the ﬁrst to be associated with
Mutations in the LRRK2 and Parkin genes
have been associated with dominantly and recessively
inherited PD, respectively.
Currently, the most sig-
niﬁcant genetic risk factor for developing PD appears
to be a mutation in the GBA gene, which encodes
Endocannabinoids and basal ganglia
Preclinical studies have suggested that endocannabinoid
signaling plays an important role in basal ganglia
Endocannabinoids are neurotransmitters
derived from membrane phospholipids produced on
demand by enzymes expressed throughout the central
nervous system (CNS).
The main endogenous ligands
are anandamide (AEA) and 2-arachidonoylglycerol (2-
Endocannabinoids bind both to subtype 1 (CB
) cannabinoid receptors
AEA is synthesized
by N-acyl phosphatidylethanolamine phospholipase D
(NAPE-PLD) and degraded by fatty acid amide hydrolase
while 2-AG is synthesized by diacylglyce-
rol lipase (DGL) and degraded by monoacylglycerol
In the striatum, CB
is expressed at low levels in
glutamatergic terminals and at high levels in GABAergic
neurons in both D1 (substance P) and D2 (enkephalin)
spiny projection neurons.
The co-localization of CB
and GABAergic interneurons is controversial. Double-
labeling in situ hybridization revealed that neither soma-
tostatinergic nor cholinergic interneurons expressed CB
while GABAergic immunohistochemistry
showed high CB
immunoreactivity in the perikarya
and axons of parvalbuminergic interneurons, and low
levels in nitric oxide synthase (NOS)/somatostatin-
On the other hand, another study
showed that the highest expression of CB1 occurs in
calbindin interneurons, with less expression in parval-
found in calretinin or cholecystokinin neurons.
AEA synthesized in striatal postsynaptic GABAergic
neurons can act on glutamatergic presynaptic terminals,
decreasing glutamate release from cortical areas.
receptor stimulation is critical for long-term
depression (LTD) in corticostriatal synapses,
reducing glutamatergic synaptic effectiveness. Dopami-
nergic neurons do not express CB
endocannabinoid system can interact indirectly with
dopaminergic neurotransmission in the striatum, interfer-
ing with the control of voluntary movements.
tion of cannabinoid agonists to striatal slices produces
either no effect or a decrease in electrical stimulation-
evoked dopamine release,
while systemic adminis-
tration of a CB
agonist leads to inhibition of dopamine
release evoked by pulse-train stimulation of the medial
receptors in the striatum mediate motor deﬁcits
induced by cannabinoids.
The main psychoactive com-
ponent of cannabis, D9-tetrahydrocannabinol (THC), exerts
its effects in the CNS via activation of CB
Consistent with effects on basal-ganglia function, CB
activation by THC (or other cannabinoid agonists) alters
motor performance in a dose-dependent manner, ﬂuctuat-
ing from increased mobility
to inhibition of sponta-
irregular locomotion, or even immobility
On the other hand, CB
receptor activation dampens
amphetamine-induced hyperlocomotion, as well as the
rise in dopamine and glutamate release in the striatum.
receptors also decrease GABAergic input to
dopaminergic neurons of the SNpc, thus modulating the
ﬁring activity of these neurons.
Accordingly, it has been
accepted that the endocannabinoid system modiﬁes striatal
functioning and interferes with motor control.
Cannabidiol and neuroprotection
Unlike THC, which elicits subjective effects by binding at
receptors, cannabidiol (CBD), the main non-psycho-
tomimetic component of Cannabis sp., has low afﬁnity to
CBD was isolated by Adams
et al. in 1940
and its structure was identiﬁed 23 years
later by Mechoulam & Shvo.
The concentration of CBD
in cannabis is highly variable, depending on plant pheno-
type, cultivation conditions, and which part of the plant is
used to obtain the extract.
CBD exerts a variety of effects in laboratory animals
and humans, including sedative/hypnotic,
These actions do not seem to be
dependent on cannabinoid receptors.
Moreover, it is not
completely understood whether these effects are related
to CBD or to other organic compounds present in Cannabis
extracts, such as myrcene and other terpenoids.
Braz J Psychiatry. 2019;00(00)
Effectiveness and mechanisms of CBD in Parkinson 3
Therefore, more studies using pure CBD are needed to
conﬁrm the effects of CBD in animals and humans.
CBD binds to cannabinoid receptors only at micromolar
concentrations (X10 mM),
acting as a low-potency
agonist, inverse agonist, antagonist, or even as an allo-
steric modulator of the cannabinoid CB1 receptor.
Some CBD effects are antagonized by CB
suggesting this drug may exert
‘‘indirect agonism’’ at CB
receptors. Studies show that
CBD can increase AEA concentration by blocking the
AEA membrane transporter (AMT) or the FAAH enzyme,
which catalyzes AEA hydrolysis.
CBD also enhances
increases 2-AG levels,
Several studies have demonstrated the neuroprotective
properties of the CBD in different conditions, such as
newborn hypoxic-ischemic encephalopathy,
neonatal iron overload,
kainic acid-induced seizures.
The neuroprotective prop-
erties of CBD do not appear to depend on direct activation
but can be related to a reduction in
glutamate excitotoxicity and oxidative stress,
ulation/polarization of glial cells.
In spite of the involvement of CB
receptors in the
neuroprotective effect of CBD in a model of hypoxic-
ischemic in newborn mice,
the possibility of its direct
action at these receptors remains controversial.
also interacts with several other targets.
One of them
is a family of ionotropic receptors permeable to mono-
valent cations and calcium named transient receptor
potential vanilloid (TRPV).
At low concentrations (sub-
micromolar scale), CBD binds to equilibrative nucleoside
transporter (ENT), transient receptor potential melastatin
type 8 (TRPM8), serotonin 1A receptor (5-HT1A), glycine
receptors A1 and A3, and transient receptor potential
ankyrin type-1 (TRPA1).
On the other hand, at high
concentrations (micromolar scale), CBD activates TRPV2,
TRPV3, and TRPV4 receptors and peroxisome proliferator-
CBD is also an
antagonist of the orphan receptor GPR55
and it may
also increase intracellular calcium in physiological con-
ditions but decrease it under high neuronal excitability
Cannabidiol and Parkinson’s disease
Several in vitro experiments have demonstrated promis-
ing neuroprotective effects of CBD in PD models. In one
of these models, using PC12 and SH-SY5Y cells treated
with MPP+, CBD increased cell viability, differentiation,
and the expression of axonal (GAP-43) and synaptic
(synaptophysin and synapsin I) proteins. These neuro-
protective effects depended on the activation of tropo-
myosin receptor kinase A (TrkA) receptors.
protected SH-SY5Y cells against LPS- and b-amyloid-
induced decreases in cell viability, while increasing the
viability of SH-SY5Y cells incubated with conditioned media
derived from microglia previously activated with LPS.
In another study, CBD blunted ATP-induced increases in
intracellular calcium and LPS-evoked nitrite generation
in both N13 microglial cells and rat primary microglia.
The authors suggested that the reduction of microglial cell
activation promoted by CBD depends on both cannabinoid
and adenosine receptors.
In vivo studies, however, have produced conﬂicting
results. A neurotoxic model of PD using MPTP demon-
strated that administration of CBD (5 mg/kg) for 5 weeks
did not reduce motor deﬁcits or dopaminergic neuronal
loss in the nigrostriatal pathway.
On the other hand,
daily administration of CBD (3 mg/kg) for 14 days
decreased both dopamine depletion and tyrosine hydro-
xylase expression within the striatum of rats that received
These neuroprotective effects were asso-
ciated with an upregulation of mRNA levels of Cu
superoxide dismutase, a key enzyme necessary for the
endogenous control of oxidative stress.
Beyond these neuroprotective effects, one study
suggested a putative antidyskinetic effect of CBD in
hemiparkinsonian mice chronically treated with L-DOPA.
Of note, although CBD administration does not reduce
L-DOPA-induced dyskinesia, when combined with the
TRPV1 receptor antagonist capsazepine, a signiﬁcant
antidyskinetic effect was observed (capsazepine alone
also failed to decrease dyskinesia).
CBD also pre-
vented cataleptic behavior induced by repeated admin-
istration of reserpine
or haloperidol. In the latter case,
CBD also produced a reduction in c-Fos protein expres-
sion in the dorsal striatum via activation of 5-HT1A
An open-label pilot study conducted in PD patients
showed that oral doses of CBD ranging from 150-400
mg/day, combined with classic antiparkinsonian agents,
reduced psychotic symptoms evaluated by different
scales (the Brief Psychiatric Rating Scale [BPRS] and
the Parkinson Psychosis Questionnaire [PPQ]) with no
inﬂuence on cognitive and motor signs and no severe side
In a case series with four patients, CBD
reduced the frequency of events related to REM sleep
In a subsequent clinical trial, 300 mg/day of CBD
improved mobility, emotional well-being, cognition, com-
munication, and body discomfort compared to placebo.
The authors suggest that this effect might be related to
the anxiolytic, antidepressant, and antipsychotic proper-
ties of CBD.
these positive effects suggest it could be a promising
alternative for PD pharmacotherapy.
Therefore, double-blind, placebo-controlled, rando-
mized trials with larger samples of patients with PD are
needed to elucidate the possible effectiveness and
mechanisms involved in the therapeutic potential of
CBD in this movement disorder. This will also include the
putative effects of CBD in preventing L-DOPA-induced
severe side effects and preventing PD progression.
Additionally, studies conducted speciﬁcally to evaluate
the safety proﬁle of CBD in patients with PD (including
Braz J Psychiatry. 2019;00(00)
4Ferreira-Junior NC et al.
long-term safety), possible interactions with other anti-
parkinsonian drugs, and possible side effects, as well
as the therapeutic window for motor and non-motor PD
symptoms are also required.
This study was supported in part by grants from
`Pesquisa do Estado de Sa
Paulo (FAPESP; grant 2015/05551-0 awarded to ACC);
Conselho Nacional de Desenvolvimento Cientı
´gico (CNPq); Coordenac¸a
de Pessoal de Nı
´vel Superior (CAPES); Fundac¸a
Apoio ao Ensino, Pesquisa e Assiste
Hospital das Clı
´nicas, Faculdade de Medicina de
´cleo de Apoio a
`Pesquisa em Neurocie
(NAPNA), USP; and Instituto Nacional de Cie
Tecnologia Translacional em Medicina (INCT-TM;
FSG, JAC, and AWZ are recipients of CNPq 1A
productivity fellowships. ACC is recipient of CNPq 2
productivity fellowship. ED-B is recipient of CNPq
productivity fellowship. JAC has received travel support
from and is medical advisor of SCBD Centre; and has
received a grant from University Global Partnership
Network (UGPN) – ‘‘Global priorities in cannabinoid
research excellence.’’ JAC is member of the international
advisory board of The Australian Centre for Cannabinoid
Clinical and Research Excellence (ACRE), funded by the
National Health and Medical Research Council through
the Centre of Research Excellence).
JAC, FSG, and AWZ are co-inventors (Mechoulam R,
Crippa JA, Guimaraes FS, Zuardi A, Hallak, JE, and
Breuer A) of the patent ‘‘Fluorinated CBD compounds,
compositions and uses thereof. Pub. No.: WO/2014/
108899. International Application No.: PCT/IL2014/
050023’’ Def. US no. Reg. 62193296; July 29, 2015;
INPI on August 19, 2015 (BR1120150164927). Uni-
versidade de Sa
˜o Paulo has licensed the patent to
Phytecs Pharm (USP Resolution no. 15.1.130002.1.1).
USP has an agreement with Prati-Donaduzzi (Toledo,
Brazil) to ‘‘develop a pharmaceutical product containing
synthetic CBD and prove its safety and therapeutic
efﬁcacy in the treatment of epilepsy, schizophrenia,
Parkinson’s disease, and anxiety disorders.’’ The other
authors report no conﬂicts of interest.
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