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Journal of Psychopharmacology
http://jop.sagepub.com/content/early/2014/09/12/0269881114550355
The online version of this article can be found at:
DOI: 10.1177/0269881114550355
published online 18 September 2014J Psychopharmacol Crippa
Mateus M Bergamaschi, Antonio Carlos dos Santos, Antonio Lucio Teixeira, Jaime EC Hallak and José Alexandre S
Marcos Hortes N Chagas, Antonio W Zuardi, Vitor Tumas, Márcio Alexandre Pena-Pereira, Emmanuelle T Sobreira,
double-blind trial
Effects of cannabidiol in the treatment of patients with Parkinson's disease: An exploratory
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DOI: 10.1177/0269881114550355
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Introduction
Cannabidiol (CBD) is one of the main components of Cannabis
sativa, but it is not involved in its psychomimetic effects.
Pharmacological studies on CBD have shown that the substance
has a wide spectrum of action with different effects on different
systems (Zuardi, 2008). The neuroprotective properties of CBD
have been under increasing scientific scrutiny in the context of
neurodegenerative diseases including Huntington’s disease,
Alzheimer’s disease and Parkinson’s disease (PD) (Iuvone et al.,
2009). Two investigations using animal models of PD have
been conducted to date to assess the neuroprotective effects of
CBD. In the first one, Lastres-Becker et al. (2005) showed that
the administration of CBD counteracted neurodegeneration
caused by the injection of 6-hydroxy-dopamine in the medial
prosencephalic bundle, an effect that could be related to the
modulation of glial cells and to antioxidant effects (Lastres-
Becker et al., 2005). In the next year, Garcia-Arencibia et al.
(2007) tested many cannabinoid compounds following the
lesion of dopaminergic neurons in the substantia nigra with
6-hydroxy-dopamine and found that the acute administration of
CBD seemed to have a neuroprotective action; nonetheless, the
administration of CBD one week after the lesion had no signifi-
cant effects (Garcia-Arencibia et al., 2007). This study also
pointed to a possible antioxidant effect with the upregulation of
mRNA of the enzyme Cu-Zn-superoxide dismutase following
the administration of CBD.
Despite the promising findings in animal models of PD, few
clinical trials have assessed the neuroprotective effects of CBD in
humans. An investigation with Cannabis users measured
N-acetylaspartate to creatine ratios (NAA/Cr) in the brain through
magnetic resonance spectroscopy (H1-MRS) to assess the neuro-
toxic and neuroprotective effects of cannabinoids present in the
drug and found a positive correlation between CBD and NAA/Cr
in the globus pallidus and putamen (r = 0.66; p = 0.004) (Hermann
et al., 2007). Furthermore, only one clinical trial has assessed the
Effects of cannabidiol in the treatment
of patients with Parkinson’s disease:
An exploratory double-blind trial
Marcos Hortes N Chagas1,2,3, Antonio W Zuardi1,2, Vitor Tumas1,
Márcio Alexandre Pena-Pereira1, Emmanuelle T Sobreira1, Mateus M
Bergamaschi1,2, Antonio Carlos dos Santos1,2, Antonio Lucio Teixeira4,
Jaime EC Hallak1,2 and José Alexandre S Crippa1,2
Abstract
Introduction: Parkinson’s disease (PD) has a progressive course and is characterized by the degeneration of dopaminergic neurons. Although no
neuroprotective treatments for PD have been found to date, the endocannabinoid system has emerged as a promising target.
Methods: From a sample of 119 patients consecutively evaluated in a specialized movement disorders outpatient clinic, we selected 21 PD patients
without dementia or comorbid psychiatric conditions. Participants were assigned to three groups of seven subjects each who were treated with placebo,
cannabidiol (CBD) 75 mg/day or CBD 300 mg/day. One week before the trial and in the last week of treatment participants were assessed in respect
to (i) motor and general symptoms score (UPDRS); (ii) well-being and quality of life (PDQ-39); and (iii) possible neuroprotective effects (BDNF and
H1-MRS).
Results: We found no statistically significant differences in UPDRS scores, plasma BDNF levels or H1-MRS measures. However, the groups treated with
placebo and CBD 300 mg/day had significantly different mean total scores in the PDQ-39 (p = 0.05).
Conclusions: Our findings point to a possible effect of CBD in improving quality of life measures in PD patients with no psychiatric comorbidities;
however, studies with larger samples and specific objectives are required before definitive conclusions can be drawn.
Keywords
Parkinson’s disease, cannabidiol, cannabis, treatment
1Department of Neuroscience and Behavior, Faculty of Medicine of
Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
2INCT Translational Medicine (CNPq), São Paulo, Brazil
3Barretos School of Health Sciences – Dr. Paulo Prata, Barretos, Brazil
4Laboratório Interdisciplinar de Investigação Médica, Universidade
Federal de Minas Gerais, Belo Horizonte, Brazil
Corresponding author:
Marcos Hortes N Chagas, Hospital das Clínicas da FMRP-USP- Terceiro
Andar; Av. Bandeirantes, 3900; 14048-900-Ribeirão Preto, SP, Brazil.
Email: mchagas@fmrp.usp.br; mchagas@facisb.edu.br
550355JOP0010.1177/0269881114550355Journal of PsychopharmacologyChagas et al.
research-article2014
Short report
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2 Journal of Psychopharmacology
therapeutic use and neuroprotective effect of CBD in PD patients
to date. Zuardi et al. (2009) conducted an open label study involv-
ing six patients with psychosis associated to PD and administered
CBD at doses ranging from 150 mg in the first week to 400 mg in
the fourth and last week of treatment according to the patients’
clinical response. There was a significant improvement in psycho-
sis and also in the total scores of a scale that measures general
symptoms of PD (Unified Parkinson’s disease rating scale –
UPDRS) (Zuardi et al., 2009). These results, together with the
findings from animal models of PD, point to the relevance of
additional clinical trials with CBD in PD patients.
Thus, we designed a clinical trial to assess the effects of CBD
in PD globally, including neurological assessments of motor and
functional symptoms, a psychiatric assessment and complemen-
tary tests (brain-derived neurotrophic factor plasma levels and
H1-MRS).
Method
Sample
Participants were selected from an initial sample of 119 patients
followed at the Movement Disorders Outpatient Clinic of the
Ribeirão Preto Medical School University Hospital who were
assessed by a neurologist, a psychiatrist and a neuropsychologist
over a period of 24 months. The inclusion criteria for the clinical
trial were: diagnosis of idiopathic PD, age above 45 years, use of
stable doses of anti-Parkinson medication for at least 30 days
before the trial and a score between 1 and 3 in the Hoehn and Yahr
scale. Exclusion criteria consisted of the presence of atypical
Parkinsonism, any previous or current psychiatric disorder, demen-
tia diagnosis according to the Diagnostic and Statistical Manual of
Mental Disorders (DSM-IV) criteria, relevant clinical comorbidity
and previous use of cannabis. According to these criteria, we
selected 23 patients to be included in the trial. Two patients refused
to participate while the remaining patients were divided into three
groups with seven participants each and matched according to age,
gender, PD duration and total score in the UPDRS (Figure 1).
The project was approved by the Local Ethics Committee
under process number HCRP 8990/2011 and the volunteers
signed an informed consent form to participate.
Study design
During a period of one week, the participants underwent psychiat-
ric and neurological assessments. After this baseline assessment,
the patients were randomly assigned to three groups in accordance
with the matching variables described above. Both the partici-
pants and investigators were blind in respect to the group each
subject belonged to for the whole period of the study. Patients
received placebo or doses of CBD (75 mg/day or 300 mg/day) for
6 weeks, in the last of which the baseline assessment was repeated.
Blood samples for plasma BDNF quantification and H1-MRS
scans were also performed in the last week of the trial.
CBD preparation
CBD was provided in powdered form with 99.9% purity by
THC-Pharma (Frankfurt, Germany). The drug was dissolved in
corn oil and placed in gelatin capsules containing 75 mg or 300
mg and stored in dark glass flasks at the Laboratory of Clinical
Psychopharmacology of the Ribeirão Preto Medical School.
Placebo consisted of capsules containing corn oil only. CBD and
placebo were supplied in identical capsules. The patients were
instructed to take the medication at night under the supervision of
relatives/caretakers.
Assessment instruments
The following scales were used: (i) UPDRS to assess PD symp-
toms; (ii) Parkinson’s Disease Questionnaire – 39 (PDQ-39) to
assess functioning and well-being; and (iii) Udvalg for kliniske
undersøgelser (UKU) side effect rating scale to evaluate possible
adverse effects of CBD.
The UPDRS (Fahn et al., 1987) consists of 42 items that
assess symptoms, signs and daily life activities of patients by
means of clinical observation and patient reports. The scale has
four parts: mentation, behavior and mood (Part I); activities of
daily living (Part II); motor exam (Part III); and complications of
therapy (Part IV).
The PDQ-39 (Jenkinson et al., 1995) is a questionnaire that
assesses functioning and well-being in PD patients, covering
characteristics that are specific to PD. Scores range between 0
and 100 and the questionnaire has good reliability and validity in
relation to other measures of quality of life (Fitzpatrick et al.,
1997; Jenkinson et al., 1997). The PDQ-39 can be divided into
eight factors: mobility, activities of daily living (ADL), emo-
tional well-being, stigma, social support, cognition, communica-
tion and bodily discomfort. The score in each factor is calculated
through the sum of the scores of each item corresponding to the
factor divided by the number of items and multiplied by 4. The
Patients without lifetime
psychiatric or dementia diagnoses
considered eligible for inclusion
N=23
Patients with PD consecutively
evaluated in the period between
February 2010 and November
2011
N=119
Patients who consented to
participate
N=21
Two patients refused to participate
Placebo
N=7
CBD 75mg
N=7
CBD 300mg
N=7
Figure 1. Flowchart describing the inclusion of patients from the
Movement Disorders Outpatient Clinic in the double-blind, placebo
controlled trial.
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Chagas et al. 3
result is then multiplied by 100 so that each factor has a score
ranging between 0 and 100.
Lastly, the UKU (Lingjaerde et al., 1987) is a detailed instru-
ment for the assessment of adverse medication effects including
psychic, neurologic, autonomic and other manifestations. Each
item is rated between 0 (absent) and 3 (severe). The rater has the
additional possibility of recording causal relations between medi-
cations and relevant clinical events and interference with the
patient’s daily life.
Complementary tests
BDNF. Approximately 10 ml of blood were collected in the base-
line week through venipuncture into tubes with sodium heparin.
The samples were then centrifuged twice for 10 minutes at 4oC
and plasma was stored at –74oC. Plasma BDNF levels were mea-
sured by ELISA according to the manufacturer’s instructions
(DuoSet, R&D Systems, Minneapolis, MN, USA) with concen-
trations described in pg/mL.
H1-MRS. Proton magnetic resonance scans were made at the
Center of Imaging Sciences and Medical Physics of the Ribeirão
Preto Medical School University Hospital by an experienced
technician. The scans were made using a Philips Achieva X-series
unit with a 3 T superconducting magnet (high field), 25 mT gra-
dient coils and a comercially-available circular-polarized head
coil. The different software used in the acquisition were provided
by the manufacturer together with the equipment.
Spectroscopy data were acquired using a single voxel (CSI
hybrid), point-resolved spectroscopy (PRESS) sequence and pre-
saturation for water supression with a MOIST sequence. The
bilateral basal ganglia (putamen) were defined as the volume of
interest (VDI). Echo time was short for the putamen (35 ms).
Post-processing included the application of a smooth Gaussian
filter and Fourier transformation.
Spectroscopy data were processed using software installed in
an auxiliary console of the acquisition equipment. The resonance
intensities of individual spectra were determined by the calcula-
tion of the integral of areas under the peaks of chemical disloca-
tion graphs.
Statistical analysis
We used one-factor ANOVA to compare the three groups when
variables had a normal distribution. When normality tests for the
whole sample or for specific groups did not indicate a normal
distribution, we used the Kruskal-Wallis test. Normality require-
ments for data distribution were confirmed using the Shapiro-
Wilk test. The groups were matched in respect to gender, age and
total UPDRS score. To analyze group differences in UPDRS and
PDQ-39 scores, we calculated the variations between baseline
and final (6 weeks) values and ran an ANOVA or Kruskal-Wallis
test according to the data distribuition. When the null hypothesis
was rejected, we used Bonferroni post-hoc tests to determine dif-
ferences across groups.
Results
Table 1 presents the clinical and demographic data of the three
groups, which were matched according to gender, age and total
UPDRS scores.
In respect to the UPDRS, we found no statistically significant
differences between mean score variations in the three groups.
However, in regard to the PDQ-39, we found significant differ-
ences between the total score of the placebo and CBD 300 mg/
day groups (p=0.05). The scores in factors “ADL” and “stigma”
also had statistically significant differences between groups tak-
ing placebo and CBD 300 mg/day (p=0.02) and CBD 75 mg/day
and 300 mg/day (p=0.04). Variations between baseline and final
mean scores in the UPDRS, PDQ-39, BDNF and NAA/Cr are
shown in Table 2.
There were no differences between the groups treated with
CBD and placebo in respect to BDNF levels at baseline and after
6 weeks, nor in the different measures using H1-MRS (NAA/
Cre). Also, no significant side effects were recorded in any of the
groups assessed with the UKU or through verbal reports.
Discussion
The endocannabinoid system has recently been implicated in the
neurobiology of PD, with possible neuroprotective effects. We
found significant improvements in measures of functioning and
well-being of PD patients treated with CBD 300 mg/day com-
pared to a group that received placebo. Despite this, we found no
differences across groups in what concerns the other measures,
including motor score as assessed with the UPDRS (Part III).
Quality of life is an important measure in clinical trials
because it refers to a number of areas related to personal well-
being. It is known that many therapies are able to improve the
core symptoms of a given disease without corresponding
Table 1. Clinical and demographic data of patients in each group at baseline.
Mean (SD) (min–max) CBD 75 mg/day CBD 300 mg/day Placebo ANOVA (F; p) or
Kruskal-Wallis test (p)
Gender (M/F) 5/2 5/2 5/2
Age (years) 65.86 (±10.59) (51–82) 63.43 (±6.48) (53–71) 67.29 (±7.23) (57–75) F2.18=0.387; p=0.685
Age at PD onset (years) 57.71 (±13.52) (37–79) 56.57 (±8.56) (46–68) 57.43 (±7.72) (50–69) F2.18=0.024; p=0.977
UPDRS total (on state) 30.39 (±11.91) (14–49) 38.86 (±13.99) (17–62) 40.17 (±11.20) (21–50) F2.18=1.245; p=0.313
PDQ-39 47.14 (±23.63) (11–69) 47.29 (±26.27) (10–86) 23.83 (±6.43) (18–33) F2.18=2.514; p=0.111
PD duration (years) 8.14 (±5.64) (2–15) 6.86 (±3.72) (3–12) 9.86 (±4.71) (5–17) F2.18=0.702; p=0.509
Education (years)a8.14 (±6.20) 10.71 (±7.18) 5.71 (±3.59) p=0.337
aNonparametric distribution.
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4 Journal of Psychopharmacology
improvements in quality of life. The PDQ-39 is a self-report
instrument that assesses several dimensions of PD providing a
detailed picture of the disease with little influence of symptom
oscillations throughout the day, especially in what refers to
treatment with levodopa. The score reduction in the PDQ-39
seen in the group of patients treated with CBD 300 mg com-
pared to the mean variation of the placebo group seems to be
mostly related with the ‘daily life activities’ factor (p<0.05) but
the relationship with ‘emotional well-being’ and ‘mobility’ fac-
tors also tended to be statistically significant.
Although we excluded patients with comorbid psychiatric
disorders, basal symptoms with no clinical significance or related
to the impairments of the disorder could be present and be some-
how connected with the observed improvement in emotional
well-being. A study on Cannabis and PD showed that the use of
the drug could be associated with subjective reports of emotional
well-being, even in the absence of significant improvement in
motor symptoms (Venderova et al., 2004). Recently, another
study revealed significant improvement in specific motor symp-
toms after treatment with Cannabis (Lotan et al., 2014). In addi-
tion, CBD’s possible anxiolytic (Bergamaschi et al., 2011; Crippa
et al., 2009), antidepressant (Saito et al., 2010; Zanelati et al.,
2010), antipsychotic (Zuardi et al., 1991; 1995) and sedative
(Chagas et al., 2013; 2014; Monti, 1977) properties could explain
the reports of improvements in emotional well-being, daily life
activities and, hence, quality of life, as a result of its action in the
non-motor symptoms of PD. It should be noted that the main
active component of Cannabis is Δ9-tetrahydrocannabinol
(THC), which was not investigated in this clinical trial.
Nonetheless, there is evidence of the effects of THC and Cannabis
in clinical trials (Lotan et al., 2014) and in animal models of PD
(van Vliet et al., 2008).
The mechanism of action of CBD, in general and particularly
in PD, remains unknown despite increasing efforts to explain it.
CBD acts in a number of sites and its action as a neuroprotective
agent is based on the following effects: local anti-inflammatory
properties, reduction of oxidative stress, attenuation of glial cell
activation and normalization of glutamate homeostasis
(Fernandez-Ruiz et al., 2013). It is noteworthy that the neuropro-
tective effect of CBD seems to be independent from its action on
the CB1 and CB2 receptors ( Garcia-Arencibia et al., 2007;
Lastres-Becker et al., 2005).
Despite the possible neuroprotective action of CBD, we
found no statistically significant differences across groups in
respect to UPDRS scores. Unfortunately the sample enrolled in
the study was too small, which restricts the reach of our analyses
and does not allow for definitive conclusions. Also, most partici-
pants were in the early stages of the disease, which hampers the
observation of broad variations, as these patients tend to have
low baseline scores. On the other hand, the inclusion of patients
with longer disease duration could also pose a problem to the
evaluation and the observation of positive effects due to
increased damage in the substantia nigra in the later phases of
the disease. Finally, although all UPDRS measures were made
during the on stage and in the morning, some items measured by
the scale may vary during the day and from day to day, which
does not necessarily mean improvement or worsening of the dis-
ease (Siderowf et al., 2002).
The neuroprotective effects of CBD are not easily measured
in humans and, although they have been reported in animal mod-
els, we failed to find such effects with the measures used here.
We hypothesized that the administration of CBD could increase
BDNF levels and the ratios of metabolites NAA and Cr as meas-
ured with H1-MRS, which are related to neuronal viability. Some
Table 2. Variations in the scores of UPDRS, PDQ-39, BDNF levels and NAA/Cr between baseline and final assessment.
Placebo CBD 75 mg/day CBD 300 mg/day ANOVA (F; p) or Kruskal-
Wallis test (p)
Variation/Baseline-
Final (DP)
Variation/Baseline-
Final (DP)
Variation/Baseline-Final
(DP)
UPDRS total on 3.83 (±6.85) 3.00 (±5.97) 6.57 (±5.83) F=0.631; p=0.544
UPDRS part I 0.17 (±0.75) 0.86 (±1.07) 0.29 (±1.38) F=0.737; p=0.493
UPDRS part IIa2.50 (±4.18) –1.29 (±3.45) 2.85 (±4.14) p=0.146
UPDRS part IIIa2.17 (±8.23) 3.85 (±5.37) 3.00 (±5.16) p=0.675
UPDRS part IV –1.00 (±2.19) –0.43 (±1.99) 0.43 (±2.64) F=0.644; p=0.538
PDQ-39 total 6.50 (±8.48)b10.00 (±12.15) 25.57 (±16.30)bF=4.142; p=0.034
Mobility 4.17 (±9.70) 5.71 (±12.89) 19.64 (±17.22) F=2.574; p=0.106
ADL –0.69 (±6.68)b16.07 (±16.21) 21.43 (±13.91)bF=4.847; p=0.022
Emotional well-being 2.78 (±13.09) 5.36 (±10.12) 17.85 (±11.21) F=3.339; p=0.060
Stigmaa3.13 (±5.23) –4.46 (±16.42)b15.18 (±14.37)bp=0.038
Social supporta0.00 (±10.54) 2.38 (±12.47) 5.95 (±12.47) p=0.694
Cognitiona13.57 (±30.72) 14.29 (±21.56) 7.14 (±4.31) p=0.332
Communication 0.00 (±11.79) 0.00 (±23.57) 9.52 (±14.77) F=0.657; p=0.531
Physical discomfort 13.89 (±15.52) 5.95 (±25.78) 23.81 (±18.28) F=1.323; p=0.292
BDNF levels –1,385.25 (±6,814.65) 822,67 (±7,884.29) –3,522.97 (±18,993.18) F=0.158; p=0.855
H1-MRS
NAA/Cre righta0.11 (0.18) 0.11 (0.18) 0.10 (0.18) p=0.875
NAA/Cre left 0.19 (0.18) –0.01 (0.07) 0.07 (0.22) F=1.890; p=0.183
aNonparametric distribution; bp<0.05, Bonferroni’s post hoc test.
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Chagas et al. 5
limitations should also be noted including those related to H1-
MRS and BDNF measures: the 6-week period might have been
insufficient for the occurrence of detectable changes in spectros-
copy measures linked to neuronal viability, added to the fact that
this measure has not been explored in depth in PD. Probably, a
longer treatment period should be tested before definitive conclu-
sions are drawn. Also, BDNF levels have large inter-individual
variations, which increases standard deviations and may hinder
the occurrence of differences in small samples.
Nowadays, most drugs used in the treatment of PD act in
the dopaminergic system and little is known about the role of
other neurotransmitter systems in the disease. The endocan-
nabinoid system seems to be an important target of investiga-
tion, mostly because of its action in those considered as the
non-motor symptoms of PD and of reports of its possible neu-
roprotective effects.
Conclusions
This study points to a possible effect of CBD in improving meas-
ures related to the quality of life of PD patients without psychiat-
ric comorbidities. We found no statistically significant differences
concerning the motor symptoms of PD; however, studies involv-
ing larger samples and with systematic assessment of specific
symptoms of PD are necessary in order to provide stronger con-
clusions regarding the action of CBD in PD.
Acknowledgements
A.W.Z., J.A.C and J.E.H. have the US patent of Cannabidiol derivatives.
A.W.Z., J.E.H., A.L.T., A.C.S and J.A.C. are recipients of a Conselho
Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil)
fellowships award. M.M.B. is a post-doctoral fellow of Fundação de
Amparo à Pesquisa de São Paulo.
Conflict of interest
The authors declare that there is no conflict of interest.
Funding
This research received no specific grant from any funding agency in the
public, commercial, or not-for-profit sectors.
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