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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 H(1)-MRS). Results: We found no statistically significant differences in UPDRS scores, plasma BDNF levels or H(1)-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.
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Journal of Psychopharmacology
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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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... Among all the clinical trials that have been conducted thus far investigating the usefulness of CBD in PD patients (four studies) concluded that no improvement was noted regarding the effect of CBD on the severity of motor symptoms, as evaluated by the Unified Parkinson Disease Rating scale (UPDRS) [84,86,88,89]. The details of each study are summarized in Table 1. ...
... The non-motor PD symptoms mentioned above (psychosis, anxiety, depression, sleep disturbance, and pain) are associated with PD patients' quality of life (QOL). These symptoms are significant predictors of declining QOL [84,117]. However, few studies have examined the impact of pharmacological therapies on PD patients' QOL, and the results are inconclusive. ...
... The first study in 2004 with Cannador ® (2.5 mg Δ9-THC + 1.25 mg CBD) revealed no positive effect on quality of life. However, in 2014, Chagas et al. conducted an explorative, randomized double-blind, placebo-controlled study for 6 weeks in 21 PD patients and concluded that CBD (300 mg) significantly improved QOL [84,89]. Conversely, a recent study concluded that even doses of 75 or 300 mg CBD had no significant effect on quality of life as a secondary outcome [86]. ...
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Background Parkinson’s disease (PD) is primarily known as a motor disorder; however, its debilitating non-motor symptoms have a significant impact on patients’ quality of life. The current standard treatment, l-DOPA, is used to relieve motor symptoms, but prolonged use is often associated with severe side effects. This creates an urgent need for effective alternatives targeting both motor and non-motor symptoms. Objectives Over the past decade, Cannabis sativa and its cannabinoids have been widely studied across various health conditions. Among these compounds, cannabidiol (CBD), a non-psychoactive component, is garnering growing interest due to its multi-targeted pleiotropic properties. This work aims to provide a comprehensive overview of CBD’s efficacy in PD. Methods This review compiles data on both motor and non-motor symptoms of PD, integrating results from preclinical animal studies and available clinical trials. Results Preclinical research has demonstrated promising results regarding CBD’s potential benefits in PD; however, the total number of clinical trials is limited (with only seven studies to date), making it difficult to draw definitive conclusions on its efficacy. Conclusions While preclinical findings suggest that CBD may have therapeutic potential in PD, the limited number of clinical trials highlights the need for further research. This review emphasizes the gaps that need to be addressed in future studies to fully understand CBD’s role in treating both motor and non-motor symptoms of PD.
... Due to the ability of CBD to modulate the endogenous cannabinoid system, there has been an increasing interest in CBD as a potential alternative treatment for several brain disorders defined by neuronal loss and/or damage. As such, the literature search on neuroprotective effects of CBD mostly provided results regarding animal models of neurodegenerative diseases, such as Alzheimer's (reviewed by [171]), Huntington's [172,173], and Parkinson's disease ( [174,175]; reviewed by [171,176]) as well as in experimental animal models of hypoxic-ischemia [177] and encephalopathy [178,179] or studies with patients with the above-mentioned diseases [110,[180][181][182] reviewed in [183,184]. In addition, various in vitro studies assessed CBD effects after induction of damage mimicking various neurological diseases, some of them suggesting that CBD is able to prevent a number of the cellular and molecular alterations associated with neurological damage [185,186]. ...
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Background: Cannabidiol (CBD) is a cannabinoid present in the hemp plant (Cannabis sativa L.). Non-medicinal CBD oils with typically 5–40% CBD are advertised for various alleged positive health effects. While such foodstuffs containing cannabinoids are covered by the Novel Food Regulation in the European Union (EU), none of these products have yet been authorized. Nevertheless, they continue to be available on the European market. Methods: The Permanent Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG) reviewed the currently available data on adverse and potential beneficial effects of CBD in the dose range relevant for foods. Results: Increased liver enzyme activities were observed in healthy volunteers following administration of 4.3 mg CBD/kg bw/day and higher for 3–4 weeks. As lower doses were not tested, a no observed adverse effect level (NOAEL) could not be derived, and the dose of 4.3 mg/kg bw/day was identified as the lowest observed adverse effect level (LOAEL). Based on the CBD content and dose recommendations of CBD products on the market, the SKLM considered several exposure scenarios and concluded that the LOAEL for liver toxicity may be easily reached, e.g., via consumption of 30 drops of an oil containing 20% CBD, or even exceeded. A critical evaluation of the available data on potential beneficial health effects of CBD in the dose range at or below the LOAEL of 4.3 mg/kg bw/day revealed no scientific evidence that would substantiate health claims, e.g., in relation to physical performance, the cardiovascular, immune, and nervous system, anxiety, relaxation, stress, sleep, pain, or menstrual health. Conclusions: The SKLM concluded that consumption of CBD-containing foods/food supplements may not provide substantiated health benefits and may even pose a health risk to consumers.
... Costa et al., 2022;Crippa et al., 2019;Almeida et al., 2018;Deuel et al., 2020;Erga et al., 2022;Ferreira-Junior et al., 2020;Figura et al., 2022;Fraguas-Sánchez et al., 2018;Kolongowski et al., 2021;Lacroix et al., 2022;Mainka et al., 2018;Mechoulam et al., 2016;Oikonomou et al., 2022;Ortiz et al., 2022;Owusu et al., 2020;O'Sullivan et al., 2021;Paes-Colli et al., 2022;Patel et al., 2019;Pérez-Olives et al., 2021;Peres et al., 2018;Pisanti et al., 2017;Russo, 2018;Stasiłowicz et al., 2021;Suryadevara et al., 2017;Urbi et al., 2021;Velayudhan et al., 2021;Viana et al., 2022;White, 2019;Yan et al., 2021). Alguns estudos afirmam que houve melhora na cognição e na comunicação com doses diárias de 300mg de CDB (Chagas et al., 2014a;Díaz Rodríguez et al., 2023;Dash et al., 2020;Ferreira-Júnior et al., 2020;Kim et al., 2022). Outros destacam que doses orais de 150 a 400mg de CBD não alteraram o desfecho nos sintomas cognitivos, mas também não causaram uma piora do estado prévio (Ferreira-Junior et al., 2020); assim como a nabilona . ...
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Objetivo: Mapear e analisar as evidências disponíveis na literatura existente acerca da efetividade e segurança do uso da Cannabis sativa no tratamento dos Sintomas Não-Motores (SNM) da Doença de Parkinson (DP). Metodologia: Trata-se de uma revisão de escopo, com busca realizada nas bases de dados BVS Direct, EBSCO, Embase, PubMed e Scopus, sem limite temporal ou de idioma. Este processo foi norteado pela pergunta de pesquisa “Quais são as evidências da efetividade e segurança do uso terapêutico de Cannabis sativa no tratamento dos sintomas não-motores em pacientes com Doença de Parkinson?”. Resultados: Dos 2193 artigos encontrados, 90 estudos foram considerados elegíveis. Os estudos indicaram que a Cannabis sativa possui potencial para tratar diversos SNM, com melhora significativa da dor e distúrbios do sono, bem como melhora em manifestações neuropsiquiátricas e da qualidade de vida. As taxas de efeitos colaterais tendem a ser baixas e geralmente são classificados como leves e bem tolerados. No entanto, os resultados variam dependendo da dose utilizada, forma de administração do produto e composto canabinoide utilizado, sendo necessário mais estudos para avaliar a sua efetividade e segurança. Conclusão: O uso da Cannabis sativa pode melhorar os SNM, com potencial para impactar positivamente a qualidade de vida dos portadores de DP. Entretanto, mais estudos são necessários para garantir a efetividade e segurança dessa terapia complementar.
... Cannabidiol (CBD) is an approved treatment for childhood epilepsies [1] and a promising candidate treatment for psychosis, Parkinson's disease, anxiety, addiction, and insomnia [2][3][4][5][6][7][8][9]. It has a relatively benign adverse effect profile and is highly accepted by patients compared to existing psychiatric treatments [10,11]. ...
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Background: Cannabidiol (CBD) is an approved treatment for childhood epilepsies and a candidate treatment for several other CNS disorders. However, it has poor oral bioavailability. We investigated the effect of a novel lipid formulation on its absorption in humans and on its tissue distribution in mice. Methods: In a double-blind crossover study in fasting healthy volunteers, we compared the pharmacokinetics of a single dose of 1000 mg of CBD in the lipid formulation and in a powder formulation (ClinicalTrials.gov: NCT05032807). In a second study, male CD1 mice were administered CBD in either the lipid formulation or dissolved in water, via oral gavage (n = 1 per timepoint). The tissue distribution of CBD was assessed using matrix-assisted laser desorption/ionization mass spectrometric imaging. Results: Plasma exposure (AUC0–48) of CBD was nine times greater for the lipid formulation than the powder formulation (611.1 ng·h/mL [coefficient of variation {CV%}: 104.6] and 66.8 ng·h/mL [CV%: 50.7], respectively). With the powder formulation, the AUC0–48 was related to the concentration of specific gastrointestinal bacteria and bile acids. These associations were attenuated with the lipid formulation. In the animal study, after treatment with the lipid formulation, measurable concentrations of CBD were identified in all organs. For the aqueous formulation, tissue concentrations of CBD were below the limit of quantification. Conclusions: Administering oral CBD in a lipid formulation was associated with an increase in its gastrointestinal absorption, as well as an attenuation of the relationship between its absorption and features of the gut microbiome.
Chapter
Cannabis-based medicine (CBM) is used in a wide variety of different neurological disorders. While the use of CBM in the treatment of pain, AIDS wasting, loss of appetite, and spasticity is well established, CBM application in movement disorders and neurodegenerative disorders is still an emerging topic. The purpose of this chapter is to summarize current evidence behind the use of CBM in selected neurological diseases, mainly movement and neurodegenerative disorders. The best evidence for efficacy of CBM is for Tourette syndrome resulting in an improvement of tics and psychiatric comorbidities. In this indication, delta-9-tetrahydrocannabinol (THC)-containing CBMs are recommended. There is limited evidence that CBMs are also effective in Parkinson’s disease in which they may improve tremor, but also non-motor symptoms such as pain and sleeping problems. With respect to other neurodegenerative diseases, there is limited evidence that CBMs may improve behavioral symptoms in Huntington’s disease. In addition, it has been speculated that CBMs may have neuroprotective effects, but this has not yet been confirmed in the clinical setting.
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Introdução: O canabidiol (CBD), componente não psicoativo da Cannabis sativa, tem demonstrado potencial terapêutico em condições neurológicas devido às suas propriedades anticonvulsivantes e neuroprotetoras. Este estudo revisou sistematicamente a literatura sobre as indicações do CBD na neurologia. Objetivo: Analisar evidências sobre o uso do CBD em doenças neurológicas, seus mecanismos de ação, eficácia clínica e segurança. Metodologia: Realizou-se uma revisão qualitativa nas bases PubMed, SciELO, LILACS e Google Acadêmico, abrangendo publicações de 2008 a 2023. Utilizaram-se descritores relacionados ao CBD e neurologia, selecionando 30 estudos relevantes para análise detalhada. Resultados e Discussão: O CBD mostrou eficácia como terapia adjuvante em epilepsias refratárias, reduzindo crises convulsivas nas síndromes de Dravet e Lennox-Gastaut. Na doença de Parkinson, melhorou a qualidade de vida sem agravar sintomas motores. Na esclerose múltipla, embora mais estudado em combinação com THC, o CBD isolado apresenta potencial neuroprotetor e imunomodulador. Em transtornos do espectro do autismo, evidenciou melhorias comportamentais. Seus mecanismos de ação envolvem múltiplas vias neuroquímicas, incluindo modulação de receptores serotoninérgicos e vaniloides. O perfil de segurança é favorável, mas há risco de interações medicamentosas. Considerações Finais: O CBD é uma alternativa promissora na neurologia, porém enfrenta limitações como estudos com amostras pequenas e falta de padronização de doses. Questões legais e regulatórias impactam o acesso ao tratamento. Pesquisas futuras devem determinar doses ideais, avaliar a segurança a longo prazo e aprofundar a compreensão dos mecanismos de ação para integrar o CBD eficazmente na prática clínica.
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For millennia, Cannabis sativa has served diverse roles, from medicinal applications to recreational use. Despite its extensive historical use, only a fraction of its components have been explored until recent times. The therapeutic potential of Cannabis and its constituents has garnered attention, with suggestions for treating various conditions such as Parkinson's disease, epilepsy, Alzheimer's disease, and other Neurological disorders. Recent research, particularly on animal experimental models, has unveiled the neuroprotective properties of cannabis. This neuroprotective effect is orchestrated through numerous G protein-coupled receptors (GPCRs) and the two cannabinoid receptors, CB1 and CB2. While the capacity of cannabinoids to safeguard neurons is evident, a significant challenge lies in determining the optimal cannabinoid receptor agonist and its application in clinical trials. The intricate interplay of cannabinoids with the endocannabinoid system, involving CB1 and CB2 receptors, underscores the need for precise understanding and targeted approaches. Unravelling the molecular intricacies of this interaction is vital to harness the therapeutic potential of cannabinoids effectively. As the exploration of cannabis components accelerates, there is a growing awareness of the need for nuanced strategies in utilizing cannabinoid receptor agonists in clinical settings. The evolving landscape of cannabis research presents exciting possibilities for developing targeted interventions that capitalize on the neuroprotective benefits of cannabinoids while navigating the complexities of receptor specificity and clinical applicability.
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Cannabis sativa is known for producing over 120 distinct phytocannabinoids, with Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) being the most prominent, primarily in their acidic forms. Beyond Δ9-THC and CBD, a wide array of lesser-known phytocannabinoids, along with terpenes, flavonoids, and alkaloids, demonstrate diverse pharmacological activities, interacting with the endocannabinoid system (eCB) and other biological pathways. These compounds, characterized by phenolic structures and hydroxyl groups, possess lipophilic properties, allowing them to cross the blood–brain barrier (BBB) effectively. Notably, their antioxidant, anti-inflammatory, and neuro-modulatory effects position them as promising agents in treating neurodegenerative disorders. While research has extensively examined the neuropsychiatric and neuroprotective effects of Δ9-THC, other minor phytocannabinoids remain underexplored. Due to the well-established neuroprotective potential of CBD, there is growing interest in the therapeutic benefits of non-psychotropic minor phytocannabinoids (NMPs) in brain disorders. This review highlights the emerging research on these lesser-known compounds and their neuroprotective potential. It offers insights into their therapeutic applications across various major neurological conditions.
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O Canabidiol (CBD), um composto não psicoativo derivado da planta Cannabis sativa, tem emergido como uma terapia promissora para doenças neurodegenerativas, como a Doença de Alzheimer (DA), Doença de Parkinson (DP) e Esclerose Lateral Amiotrófica (ELA), devido às suas propriedades anti-inflamatórias, antioxidantes e neuroprotetoras. Esta metanálise investigou a eficácia e segurança do CBD no tratamento dessas doenças, analisando 15 estudos clínicos e pré-clínicos, totalizando 1.280 participantes. Os resultados indicam que o CBD proporciona melhora significativa em desfechos como cognição (DMP = 0,36; IC 95%: 0,12–0,60; p = 0,003) e redução da agitação em pacientes com Alzheimer, além de melhorias nos sintomas não motores da Doença de Parkinson, como ansiedade (DMP = -0,41; IC 95%: -0,65–-0,17; p < 0,001) e qualidade do sono (DMP = 0,35; IC 95%: 0,14–0,56; p = 0,001). Em pacientes com ELA, o CBD reduziu significativamente a espasticidade (DMP = -0,29; IC 95%: -0,50–-0,08; p = 0,006) e a dor neuropática (DMP = -0,34; IC 95%: -0,54–-0,14; p = 0,001). Em termos de segurança, o CBD foi bem tolerado, com efeitos adversos leves, como fadiga e diarreia, sendo os mais comuns. No entanto, os efeitos do CBD sobre a progressão das doenças neurodegenerativas, especialmente DA e ELA, ainda são inconclusivos. A metanálise conclui que o CBD pode ser uma terapia adjuvante eficaz em doenças neurodegenerativas, especialmente no manejo de sintomas não motores e comportamentais, porém, mais estudos de longo prazo e com amostras maiores são necessários para validar esses achados.
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The use of cannabis as a therapeutic agent for various medical conditions has been well documented. However, clinical trials in patients with Parkinson disease (PD) have yielded conflicting results. The aim of the present open-label observational study was to assess the clinical effect of cannabis on motor and non-motor symptoms of PD. Twenty-two patients with PD attending the motor disorder clinic of a tertiary medical center in 2011 to 2012 were evaluated at baseline and 30 minutes after smoking cannabis using the following battery: Unified Parkinson Disease Rating Scale, visual analog scale, present pain intensity scale, Short-Form McGill Pain Questionnaire, as well as Medical Cannabis Survey National Drug and Alcohol Research Center Questionnaire. Mean (SD) total score on the motor Unified Parkinson Disease Rating Scale score improved significantly from 33.1 (13.8) at baseline to 23.2 (10.5) after cannabis consumption (t = 5.9; P < 0.001). Analysis of specific motor symptoms revealed significant improvement after treatment in tremor (P < 0.001), rigidity (P = 0.004), and bradykinesia (P < 0.001). There was also significant improvement of sleep and pain scores. No significant adverse effects of the drug were observed. The study suggests that cannabis might have a place in the therapeutic armamentarium of PD. Larger, controlled studies are needed to verify the results.
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Unlabelled: Cannabidiol (CBD) is one of the main components of Cannabis sativa and has a wide spectrum of action, including effects in the sleep-wake cycle. Objective: The objective of this paper is to assess the effects on sleep of acute systemic administration of CBD. Method: Adult male Wistar rats were randomly distributed into four groups that received intraperitoneal injections of CBD 2.5 mg/kg, CBD 10 mg/kg, CBD 40 mg/kg or vehicle (n=seven animals/group). Sleep recordings were made during light and dark periods for four days: two days of baseline recording, one day of drug administration (test), and one day after drug (post-test). Results: During the light period of the test day, the total percentage of sleep significantly increased in the groups treated with 10 and 40 mg/kg of CBD compared to placebo. REM sleep latency increased in the group injected with CBD 40 mg/kg and was significantly decreased with the dose of 10 mg/kg on the post-test day. There was an increase in the time of SWS in the group treated with CBD 40 mg/kg, although this result did not reach statistical significance. Conclusion: The systemic acute administration of CBD appears to increase total sleep time, in addition to increasing sleep latency in the light period of the day of administration.
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What is known and objective: Cannabidiol (CBD) is the main non-psychotropic component of the Cannabis sativa plant. REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of muscle atonia during REM sleep associated with nightmares and active behaviour during dreaming. We have described the effects of CBD in RBD symptoms in patients with Parkinson's disease. Cases summary: Four patients treated with CBD had prompt and substantial reduction in the frequency of RBD-related events without side effects. What is new and conclusion: This case series indicates that CBD is able to control the symptoms of RBD.
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Objectives: to briefly outline the development and validation of the Parkinson's Disease Questionnaire (PDQ-39) and then to provide evidence for the use of the measure as either a profile of health status scores or a single index figure. Design: the PDQ-39 was administered in two surveys: a postal survey of patients registered with local branches of the Parkinson's Disease Society of Great Britain (n = 405) and a survey of patients attending neurology clinics for treatment for Parkinson's disease (n = 146). Data from the eight dimensions of the PDQ-39 were factor-analysed. This produced a single factor on the data from both surveys. Outcome measures: the eight dimensions of the PDQ-39 and the new single index score—the Parkins's disease summary index (PDSI), together with clinical assessments (the Columbia rating scale and the Hoehn and Yahr staging score). Results: in the postal survey 227 patients returned questionnaires (58.2%). All 146 patients approached in the clinic sample agreed to take part. Higher-order principal-components factor analysis was undertaken on the eight dimensions of the PDQ-39 and produced one factor on both datasets. Consequently it was decided that the scores of the eight domains could be summed to produce a single index figure. The psychometric properties of this index were explored using reliability tests and tests of construct validity. The newly derived single index was found to be both internally reliable and valid. Discussion: data from the PDQ-39 can be presented either in profile form or as a single index figure. The profile should be of value in studies aimed at determining the impact of treatment regimes upon particular aspects of functioning and well-being in patients with Parkinson's disease, while the PDSI will provide a summary score of the impact of the illness on functioning and well-being and will be of use in the evaluation of the overall effect of different treatments. Furthermore, the PDSI reduces the number of statistical comparisons and hence the role of chance when exploring data from the PDQ-39.
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An anonymous questionnaire sent to all patients attending the Prague Movement Disorder Centre revealed that 25% of 339 respondents had taken cannabis and 45.9% of these described some form of benefit. © 2004 Movement Disorder Society
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Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, antioxidant, antiemetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and antioxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with Δ(9) -tetrahydrocannabinol is already under clinical evaluation in patients with Huntington's disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ(9) -tetrahydrocannabinol, i.e. CB(1) and CB(2) receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB(2) receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.