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Abstract

Ιntroduction: The behavioral and psychological symptoms of dementia (BPSD) are still among the most difficult symptoms in the management of dementia. It is estimated that BPSD affect up to 90% of all dementia subjects over the course of their illness, and is independently associated with poor outcomes, including distress among patients and caregivers, long-term hospitalization, early institutionalization, misuse of medication, and increased health care costs. Method: People with Dementia (PwD) and severe neuropsychiatric symptoms as assessed by the Greek version of Neuropsychiatric Inventory (NPI score >30) were recruited from the database of the Greek Association of Alzheimer’s disease and Related Disorders. Τhey were assigned to a prospective experimental study with cannabidiol (CBD) drops (KANNABIO CARE DROPS 3%®). The reassessment was performed either by a structured telephone interview or by clinical reassessment on site fifteen days after the initiation of the CBD administration. Results: The follow-up assessment showed improvement of the BPSD in 11 out of 17 of our patients, as was evaluated by the NPI (a decrease from a mean 65.54 to 19.73) in fifteen days after CBD initiation. These results were presented regardless of the underlying pathophysiology (Alzheimer’s, Frontotemporal, or Lewy Body Dementia). Conclusion: Our case series is one of the largest in the current literature regarding cannabinoids and BPSD. We suggest that CBD may be an effective and safe choice for managing the BPSD. Future clinical trials are needed to reassure these findings. Keywords: Cannabinoids; Dementia; Neurophychiatric symptoms; Cannabidiol; Behavioral and Psychological symptoms of Dementia (BPSD)
Ann Case Rep, an open access journal
ISSN: 2574-7754
1Volume 7; Issue 02
Case Series
Neuropsychiatric Symptoms in Dementia.
The Added Value of Cannabinoids. Are they
a Safe and Effective Choice? Case
Series with Cannabidiol 3%
Lydia Papadopoulou1, Foteini Alexandri1*, Anthoula Tsolaki2,3, Despina
Moraitou4, Anastasia Konsta5, Magda Tsolaki1-3
1Neurosciences and Neurodegenerative Diseases, Postgraduate Course, Medical School, Faculty of Health Sciences, Aristotle University
of Thessaloniki, Makedonia, Greece
2Alzheimer Hellas
3Department of Neurology, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, Makedonia, Greece
4School of Psychology, Aristotle University of Thessaloniki, Makedonia, Greece
5Department of Psychiatry, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, Makedonia, Greece
*Corresponding author: Foteini Alexandri, Neurosciences and Neurodegenerative Diseases, Postgraduate Course, Medical
School, Faculty of Health Sciences, Aristotle University of Thessaloniki, Makedonia, Greece
Citation: Papadopoulou L, Alexandri F, Tsolaki A, Moraitou D, Konsta A, et al. (2022) Neuropsychiatric Symptoms in Dementia.
The Added Value of Cannabinoids. Are they a Safe and Effective Choice? Case Series with Cannabidiol 3%. Ann Case Report 7:
799. DOI: 10.29011/2574-7754.100799
Received Date: 15 March, 2022; Accepted Date: 17 March, 2022; Published Date: 21 March 2022
Annals of Case Reports
Papadopoulou L, et al. Ann Case Rep: 7: 799.
www.doi.org/10.29011/2574-7754.100799
www.gavinpublishers.com
Abstract
Ιntroduction: The behavioral and psychological symptoms of dementia (BPSD) are still among the most difcult symptoms in
the management of dementia. It is estimated that BPSD affect up to 90% of all dementia subjects over the course of their illness,
and is independently associated with poor outcomes, including distress among patients and caregivers, long-term hospitalization,
early institutionalization, misuse of medication, and increased health care costs. Method: People with Dementia (PwD) and
severe neuropsychiatric symptoms as assessed by the Greek version of Neuropsychiatric Inventory (NPI score >30) were
recruited from the database of the Greek Association of Alzheimer’s disease and Related Disorders. Τhey were assigned to a
prospective experimental study with cannabidiol (CBD) drops (KANNABIO CARE DROPS 3%®). The reassessment was
performed either by a structured telephone interview or by clinical reassessment on site fteen days after the initiation of the
CBD administration. Results: The follow-up assessment showed improvement of the BPSD in 11 out of 17 of our patients,
as was evaluated by the NPI (a decrease from a mean 65.54 to 19.73) in fteen days after CBD initiation. These results were
presented regardless of the underlying pathophysiology (Alzheimer’s, Frontotemporal, or Lewy Body Dementia). Conclusion:
Our case series is one of the largest in the current literature regarding cannabinoids and BPSD. We suggest that CBD may be an
effective and safe choice for managing the BPSD. Future clinical trials are needed to reassure these ndings.
Citation: Papadopoulou L, Alexandri F, Tsolaki A, Moraitou D, Konsta A, et al. (2022) Neuropsychiatric Symptoms in Dementia. The Added Value of Can-
nabinoids. Are they a Safe and Effective Choice? Case Series with Cannabidiol 3%. Ann Case Report 7: 799. DOI: 10.29011/2574-7754.100799
2Volume 7; Issue 02
Ann Case Rep, an open access journal
ISSN: 2574-7754
Keywords: Cannabinoids; Dementia; Neurophychiatric
symptoms; Cannabidiol; Behavioral and Psychological symptoms
of Dementia (BPSD)
Introduction
Over 50 million people worldwide were living with dementia
in 2020. This number will almost double every 20 years, reaching
82 million in 2030 and 152 million in 2050 [1] (www.alzint.org).
Whilst there have been limited success of clinical trials and disease
modifying drugs, the behavioral and psychological symptoms of
dementia (BPSD) are still among the most difcult symptoms in
the management of PwD. BPSD includes emotional, perceptual,
and behavioral disturbances [2]. It is estimated that BPSD affects
over 90% of all dementia subjects over the course of their illness2,
and is independently associated with poor outcomes, including
distress among patients and caregivers, long-term hospitalization,
early institutionalization, misuse of medication, and increased
health care costs [3]. The prevalence of non-cognitive BPSD
in patients with Alzheimer’s Dementia (AD), which is the most
common form of Dementia, is 56–98% in the community and
up to 91–96% in hospitals or long-term care facilities [4]. BPSD
are caused by brain circuitry disruptions, which are theorized to
increase the PwD’s vulnerability to 3 categories of triggers: those
related to the (1) patient (e.g., pain, hunger, and infection), (2)
caregivers (e.g., competing priorities, unrealistic expectations,
and negative communications), and (3) environment (e.g.,
overstimulation and limited light exposure). Non-biological
determinants of BPSD identied that pre-morbid neuroticism, pre-
morbid post-traumatic stress disorder, and problematic caregiver
communication styles contribute to BPSD [2]. The experts’
opinion regarding the pharmaceutical management of BPSD
has not been altered signicantly during the last decades [5,6].
They recommend using an atypical antipsychotic for agitation
associated with delirium, psychosis, aggression, or anger. They
would also consider divalproex to manage anger with a risk of
physical aggression. Selective serotonin reuptake inhibitors were
recommended for the treatment of depression or anxiety in PwD.
Benzodiazepines or atypical antipsychotics were viewed as short-
term options for acute anxiety. Trazodone was recommended for
insomnia. Clinical experience has shown that BPSD with the above
pharmaceutical options are not always effectively controlled,
leaving the patient and his/her environment in an unbearable
distress, and leading to faster institutionalization. Therefore, their
use should be minimum, at low doses with slow titration [7]. It is
also suggested that they should be removed as fast as possible after
symptoms regulation with close monitoring [8]. Cannabinoids
have been shown to have neuroprotective properties, reduce
neuroinammation, and enhance neurogenesis [9,10]. Evidence
suggests that the utilization of marijuana products containing both
Δ9-tetrahydrocannbinol (THC) and cannabidiol (CBD) or CBD
alone have been effective and safe for use in older people with
agitation associated with dementia. Cannabinoids were shown
to be well tolerated, with few short-term side effects. This effect
differs from rst-line medications utilized for BPSD, which can
have unwanted side effects. However, the evidence is still weak
and further research regarding the safety, efcacy, and variability
of these products in older people is needed [11,12]. Our study
presents seventeen patients with severe BPSD, not well controlled
by common pharmaceutical choices that were assigned to the
clinical protocol with CBD 3% extract of industrial cannabis, as
a therapeutic approach. To our knowledge, this is the longest case
series published with CBD 3% Industrial Cannabis extract for
BPSD.
Methodology
This was a prospective experimental study. PwD from
different origins (Alzheimer’s, Lewy Body, Frontotemporal,
Parkinson’s Disease Dementia, and Down Syndrome) with severe
BPSD as assessed by the Greek version of Neuropsychiatric
Inventory (NPI score >30) were recruited from the database of the
Greek Association of Alzheimer’s Disease and Related Disorders
(GAADRD). After a detailed informative discussion with their
primary carer-givers and family members, they were assigned
to an open clinical trial with CBD drops (KANNABIO CARE
DROPS 3%®). The patient and the primary caregiver signed an
informed consent. The CBD botanical Extract product [containing
full spectrum organic hemp extract, premium organic extra
virgin olive oil, natural terpenes and 300mg CBD+CBDa (1mg
CBD+CBDa/drop), THC <0.2%] was supplied by the producer,
KANABIO Social Cooperative Enterprise (SCE) for free for
research purposes. The extract comes from biological cultures
of industrial cannabis in Volos, Greece, produced and vialed in
certied (ISO) laboratories in Greece and abroad. The patient
received one drop t.i.d. with gradual titration to a maximum
number of 10 drops daily (3 in the morning-3 in the afternoon-4
at night on the eighth day). The study protocol was approved by
the bioethics committee of the Greek Association of Alzheimer’s
Disease and Related Disorders (protocol no 61/14-10-2020). The
NPI reassessment was performed either by a trained psychologist
with a structured telephone interview or by clinical reassessment
on site fteen days from the CBD initiation.
Cases Patient #1
A 76-year-old woman with AD and main symptoms abberant
motor disturbances and appetite/eating changes visited the Day
Care Centre of the GAADRD. The most recent neuropsychological
assessment was on 12/10/2020 (MMSE: 5 HAMILTON:5, FRSSD
from her caregiver: 30, and the NPI on 20/11/2020 was 42). The
patient was treated with metformin 850mg, Levothyroxine 25mg,
Aniracetam 1500 mg, Clopidogrel 75mg q.d., Donepezil 5mg q.d.,
Memantine 10mg b.i.d., Folic acid 5mg q.d., hydroxocobalamin Inj
Citation: Papadopoulou L, Alexandri F, Tsolaki A, Moraitou D, Konsta A, et al. (2022) Neuropsychiatric Symptoms in Dementia. The Added Value of Can-
nabinoids. Are they a Safe and Effective Choice? Case Series with Cannabidiol 3%. Ann Case Report 7: 799. DOI: 10.29011/2574-7754.100799
3Volume 7; Issue 02
Ann Case Rep, an open access journal
ISSN: 2574-7754
IM and cholecalciferol 25.000IU/ week per os, with no signicant
effect on her behavioral symptoms. Non-pharmacological therapies
such as physical activity, music therapy, and reminiscence therapy
and psychoeducational intervention had modest effects on her
behavior. The patient initiated CBD 3 % on 20/11/2020 and they
titrated CBD to 10 drops/day according to protocol. The patient’s
daughter reported signicant improvement, especially of the
abberant motor disturbances. On 2/1/2021, the NPI was decreased
to 16. In particular, the patient was noted to have better orientation
inside the house, not going outside, and proper use of the toilet.
Patient #2
Α 78-year-old man with AD and main symptoms agitation,
depression, anxiety, irritability as well as nighttime sleep
disturbance visited the Day Care Centre of the GAADRD. The
most recent neuropsychological assessment was on 22/09/2020
(MMSΕ:20, HAM:1, FRSSD:7) and the NPI on 23/11/2020 was
36. His medical treatment consisted of Bromazepam 3mg q.d.,
Atorvastatin 20mg q.d., Irbesartan- hydrochlorothiazide 150/12,5
q.d., Hydroxyzine dihydrochloride 25mg q.d., cholecalciferol
25.000IU/ week, Donepezil 5mg q.d. He was previously treated
with paroxetine, but at his last examination, he had no depressive
symptoms. However, neither medications nor non-pharmacological
treatments had positive outcomes in the above BPSD. The patient
initiated CBD 3% on 23/11/2020 and they titrated the dose to 10
drops/day, according to protocol. The patient’s caregiver referred
to a signicant improvement, especially on anxiety and depression
symptoms, and the NPI was decreased signicantly from 36 to 7
on 2/12/2020.
Patient #3
Τhis is a 72-year-old man with Parkinson’s disease
Dementia (PDD) with main symptoms anxiety, apathy, irritability,
hallucinations-delusions and night time sleep disturbance. The
most recent neuropsychological assessment was on 9/9/2020
(MMSE: 22, HAM: 28, FRSSD from Caregiver: 16) and the
NPI on 26/11/20 was 48. His medical treatment at this point
consisted of Rivastigmine TTS 9.5mg/24h q.d., Memantine 10
b.i.d., Levodopa-Benserazide, Escitalopram 20 1x1, Folic acid 5,
pitavastatin 2mg q.d., Aspirin/Clopidogrel 100/75mg, Metoprolol,
Vortioxetine 5mg q.d. He was previously treated with olanzapine,
quetiapine, prazepam, trazodone, and venlafaxine in an effort to
ameliorate BPSD. He also participated in non- pharmacological
interventions. However, all these interventions did not reduce the
negative behavioral symptoms. The patient initiated CBD 3 %, on
23/11/2020 and they titrated the dose to 10 drops/day according
to protocol. Even though the patient’s primary caregiver reported
presence of hallucinations and delusions, they claimed a signicant
improvement in anxiety, apathy, irritability and nighttime sleep
disturbance, with a decrease of NPI from 48 to 34 on 15/12/2020.
Patient #4
An 86-year-old woman with Lewy Body Dementia (LBD)
and main BPSD symptoms agitation, depression, anxiety, irritability
as well as nighttime sleep disturbance visited the Day Care Centre
of the GAADRD. The most recent neuropsychological assessment
was on 21/09/2020 (MMSΕ: 14, HAMILTON: 12, FRSSD from her
caregiver: 17) and the NPI on 31/12/2020 was 64. The interventional
program comprised of pharmacological (Alprazolam 0.25mg
b.i.d., Rivastigmine TTS 9.5mg/24h q.d., Atorvastatin 20mg,
Metformin 850mg, Μemantine 10mg b.i.d., Sertraline 100mg q.d.,
Metoprolol, cholecalciferol 25.000IU/ week, hydroxocobalamin
inj IM, Amlodipine 5mg q.d., Hydroxyzine dihydrochloride 25mg
b.i.d) and non-pharmacological interventions. She was previously
treated with haloperidol, quetiapine, pipamperone, risperidone,
alprazolam, and sulpiride in an effort to ameliorate the BPSD.
However, all these interventions did not reduce the behavioral
symptoms. The patient initiated CBD 3 %, on 03/12/2020 and
they titrated the dose to 10 drops/day, according to protocol. On
5/1/2021, the NPI decreased from 64 to 28 and the patient was
calm on 10 drops/day.
Patient #5
A 75-year-old man with Frontotemporal Dementia (FTD)
and main BPSD symptoms agitation, delusions, anxiety, irritability
and abnormal abberant motor disturbances visited the Day Care
Centre of the GAADRD. The most recent neuropsychological
assessment was on 28/02/2020 (MMSΕ: 3, HAMILTON: 18,
FRSSD from his caregiver: 26) and the NPI on 28/12/2020 was
86. The patient was treated with Nebivolol 5mg q.d., Rivastigmine
TTS 13,3mg/24h, Magnesium-Potassium, hydroxocobalamin inj
IM, Quetiapine 25 t.i.p. He was previously treated with citalopram.
However, these medications had no positive outcomes. The patient
initiated on CBD 3% on 28/12/2020 and they titrated the dose to
10 drops/day, according to protocol. On 30/1/2021 the NPI was
remarkably decreased from 86 to 9. Apart from some mild abberant
motor disturbances, the patient’s primary caregiver reported
improvement, especially on the patient’s agitation, delusions/
hallucinations, anxiety, irritability and behavioral disinhibition.
Patient #6
A 73 -year-old man with severe AD and main symptoms
hallucinations-delusions, depression, nighttime sleep disturbance
and apathy visited the Day Care Centre of GAADRD. The
most recent neuropsychological assessment was on 31/07/2020
(MMSE:8, FuCAS:94, GDS:0, SAST:15, ΝPI:39, CDR:14, ADCS-
ADL:31, ROCFT:13). However, the NPI on 15/12/2020 was 57
and his family asked for help. His medical treatment consisted
of Quetiapine 25mg t.i.d., Memantine 20mg q.d. and Insulin for
Diabetes Mellitus. He was previously treated with citalopram,
venlafaxine, risperidone and mirtazapine. Neither the above
Citation: Papadopoulou L, Alexandri F, Tsolaki A, Moraitou D, Konsta A, et al. (2022) Neuropsychiatric Symptoms in Dementia. The Added Value of Can-
nabinoids. Are they a Safe and Effective Choice? Case Series with Cannabidiol 3%. Ann Case Report 7: 799. DOI: 10.29011/2574-7754.100799
4Volume 7; Issue 02
Ann Case Rep, an open access journal
ISSN: 2574-7754
medications nor common non- pharmacological interventions had
positive outcomes for his BPSD. The patient initiated on CBD 3%
on 5/1/2020 and they titrated the dose to 10 drops/day, according to
protocol. On 31/01/2021, the patient’s caregiver stated that he was
calmer and had an improvement in his sleep, with a considerable
decrease of NPI from 57 to 24.
Patient #7
A 78-year-old man with ΑD and main BPSD symptoms
hallucinations, agitation, anxiety, depression, disinhibition,
appetite/eating changes and night time sleep disturbance
visited the Day Care Centre of the GAADRD. The most recent
neuropsychological assessment was on 11/12/2020 (MMSE: 21,
HAM: 14, NPI: 18) and the NPI on 5/1/2021 was 92. His medical
treatment consisted of Metformin 850mg, Atorvastatin 20mg q.d.,
Bromazepam 3mg q.d., Hydroxyzine dihydrochloride 25mg t.i.d,
Homotaurine t.i.d., Donepezil 5mg, q.d., and Quetiapine 25mg
q.d. He also participated in non-pharmacological interventions.
He was previously treated with venlafaxine and amitriptyline-
perphenazine. However, all the above interventions did not reduce
the behavioral symptoms. The patient initiated on CBD 3 %, on
5/1/2020 and they titrated the dose to 10 drops/day, according to
protocol. The primary caregiver reported signicant improvement
in almost all the behavioral symptoms and the NPI was decreased
from 91 to 31 on 20/1/2021.
Patient #8
A 58-year-old man with FTD and main BPSD symptoms
agitation, depression and apathy visited the Day Care Centre of the
GAADRD. His neuropsychological assessment on 7/01/2021 was:
MMSE: 28, MoCA: 23, CDR: 3, FRSSD Caregiver: 14, FRSSD
Patient: 5 and the NPI on 07/01/2021 was 16, however with intense
agitation. The patient was treated with Memantine 10mg b.i.d,
Nebivolol 5mg q.d., Escitalopram 20mg q.d., Aniracetam, Sach
1500mg q.d., Hydroxyzine dihydrochloride 25mg q.d. and with
non-pharmacological interventions. He was previously treated
with citalopram, risperidone, and mirtazapine. Patient initiated
CBD 3 %, on 7/1/2021. They titrated the dose to 10 drops/day,
according to protocol. Τhe NPI on 30/1/2021 was 26 and the
primary caregiver reported a signicant improvement in patient’s
mood. However, the symptoms of apathy and the occasionally
present hallucinations-delusions remained unchanged.
Patient #9
A 75-year-old man with PDD and main BPSD symptoms
delusions, depression, anxiety, abberant motor disturbances and
nighttime sleep disturbance visited the Day Care Centre of the
GAADRD. The most recent neuropsychological assessment was
on 25/2/2020 (MMSE: 22, GDS: 2, FRSSD from his caregiver:
14) and the NPI on 5/1/2021 was 84. The medical treatment
contained Cholecalciferol 2000IU q.d., hydroxocobalamin inj
IM, Levodopa-Carvidopa-Entacapone occasionally, Rasagiline
1mg q.d., Sertraline 100mg q.d., Pravastatin/fenobrate 40/160mg
q.d. However, neither medications nor non-pharmacological
treatments had positive outcomes. The patient initiated on CBD
3% on 11/01/2021. They titrated the dose according to the
protocol. On 20/01/2021, the NPI decreased from 84 to 14. The
patient’s caregiver stated a general improvement, especially on the
patient’s sleep and abberant motor disturbances. Moreover, she
mentioned that patient’s pain was also reduced and thus reduced
the need for painkillers. However, because the patient would get
excessively sleepy during the day, the dose was decreased in the
morning hours.
Patient #10
A 94-year-old woman with AD and main BPSD symptoms
delusions, irritability, abberant motor disturbances, appetite/
eating changes and nighttime sleep disturbance visited the Day
Care Centre of the GAADRD. Her recent neuropsychological
assessment on 22/12/2020: MMSE: 15, HAMILTON: 32, FRSSD
from the caregiver: 22) and the NPI on 04/01/2021 was 58. The
patient was treated with Hydroxyzine dihydrochloride 25mg q.d.,
Citalopram 20mg q.d., Memantine 10 b.i.d., Betahistine 8mg
t.i.d., Folic Acid 5mg q.d., cholecalciferol 25.000IU/ week, Alpha-
tocopherol acetate 10mg q.d., glyceryl trinitrate q.d., Donepezil
10mg q.d., Diltiazem, Simvastatin 20mg q.d., Irbesartan 150mg
q.d. She was previously treated with mirtazapine and bromazepam.
She also participated in non-pharmacological interventions.
However, neither medications nor non-pharmacological treatments
had positive outcomes. The patient initiated on CBD 3% on
04/01/2021. They titrated the dose according to the protocol.
On 13/01/2021, the NPI was impressively decreased to 3 and
the caregiver mentioned great improvement in all the behavioral
symptoms. The patient was very calm, but sometimes she became
lethargic.
Patient #11
An 83-year-old woman with AD/ Depression and main
BPSD symptoms agitation, anxiety, irritability and nighttime sleep
disturbance visited the Day Care Centre of the GAADRD. Her
latest neuropsychological assessment was on 7/01/2021 (MMSE:
23, HAMILTON: 14, FRSSD from the caregiver: 7) and the NPI on
7/1/2021 was 46. Her medical treatment consisted of rivastigmine
2mg/ml syr. 3ml b.i.d., pramipexole 0.18mg t.i.d., empagliozin
10mg q.d., valsartan -hydrochlorothiazide el 150mg/12.5mg,
metoprolol 5mg q.d., rosuvastatin 5mg q.d., clopidogrel 75mf
q.d., glimepiride 4mg 1/2tb q.d., INN-insulin degludec/liraglutide
100U+ 3.6mg/ml q.d., Oxybutynin hydrochloride 5mg q.d.,
pantoprazole 40mg q.d., solifenacin 5mg q.d. She was previously
treated with Flunitrazepam, Sertraline and Hydroxyzine
dihydrochloride. She also participated in non-pharmacological
interventions. However, all the above interventions did not manage
Citation: Papadopoulou L, Alexandri F, Tsolaki A, Moraitou D, Konsta A, et al. (2022) Neuropsychiatric Symptoms in Dementia. The Added Value of Can-
nabinoids. Are they a Safe and Effective Choice? Case Series with Cannabidiol 3%. Ann Case Report 7: 799. DOI: 10.29011/2574-7754.100799
5Volume 7; Issue 02
Ann Case Rep, an open access journal
ISSN: 2574-7754
the behavioral symptoms. The patient initiated on CBD 3 %, on
07/01/2021. They titrated the dose according to the protocol. On
20/01/2021, the NPI was decreased from 46 to 16. The caregiver
mentioned the patient was very calm, stopped crying and her sleep
got better.
Patient #12
A 79-year-old woman with AD and main BPSD symptoms
agitation, irritability, apathy, appetite/eating changes and nighttime
sleep disturbance visited the Day Care Centre of the GAADRD.
Her latest neuropsychological assessment was on 22/12/2020
(MMSE: 0, HAMILTON: 13, FRSSD from her caregiver: 26 and
NPI: 33). Her medical treatment included Memantine 10mg bid and
Donepezil 10 mg qd. She was previously treated with Citalopram
and Hydroxyzine Dihydrochloride without any response. The
patient initiated CBD 3 %, on 30/12/2020. Unfortunately, they
stopped due to side effects. They stopped even after the second
attempt on 13/1/2021 because the patient became very aggressive
and anxious. The patient lives in an island far away from our Day
Center and her family had no opportunity to communicate with
us because of COVID-19 in order to understand what were the
problems with CBD.
Patient #13
A 60-year-old man with Dementia Down Syndrome
and epilepsy, with main symptoms hallucinations-delusions,
depression, anxiety, apathy, irritability and nighttime sleep
disturbance visited the Day Care Centre of the GAADRD. The most
recent neuropsychological assessment was on 3/10/2019 (MMSE:
0, HAMILTON: 12, FRSSD from his caregiver: 33) and the NPI
was 72 on 18/12/2020. The patient was treated with Hydroxyzine
dihydrochloride 25mg 1x3, Rosuvastatin 20mg qd, Rivastigmine
patch 9,5mg qd, Memantine 10mg b.i.d., Quetiapine 25mg q.d.,
Calcium gluconate q.d., Co Q10 q.d., Levothyroxine 75mg q.d.,
Risperidone 1mg q.d., Mirtazapin 30mg q.d., and Lamotrigine
100mg b.i.d. with no signicant effect on his behavioral symptoms.
He was previously treated also with paroxetine, alprazolam and
citalopram. The patient initiated CBD 3 %, on 18/12/2020. They
titrated the dose according to the protocol. The NPI on 5/1/2021
decreased from 72 to 12 with an improvement to his nighttime
sleep disturbance. However, as the dose increased to 10 drops
per day the patient has caregiver mentioned side effects such as
agitation and one epileptic seizure, so the administration stopped
on 12/1/2021.
Patient #14
Α 75-year-old woman with LBD and main BPSD symptoms,
delusions, anxiety, irritability, abberant motor disturbances
and appetite/eating changes visited the Day Care Centre of the
GAADRD. The most recent neuropsychological assessment was
on 09/12/2020 (MMSE: 17 HAM: 19, FRSSD from her caregiver:
27 and the NPI was 71). The patient was treated with Olmesartan
Medoxomil 20/12 q.d., Macrogol 13.3gr b.i.d., Vildagliptin-
Metformin 50/100 q.d., Rivastigmine TTS 9,5 mg q.d., Levodopa-
Benserazide (200+50mg) 1/2tb b.i.d, Citalopram 40mg q.d.,
Hydroxyzine dihydrochloride 25mg t.i.d. with no signicant effect
on her behavioral symptoms. The patient initiated CBD 3 %, on
09/12/2020. They titrated the dose according to the protocol only
for 4 days. On 08/01/2021, the NPI was 71 and the caregiver stated
that they did not notice any change in her behavior and they stopped
CBD after 4 days, on 13/1/2021. However, it has to be emphasized
that the patient did not have a 24/7 care- giver or family member
by her side and they did not follow the protocol.
Patient #15
Α 74-year-old woman with AD and main symptoms anxiety,
depression, sleep, appetite/eating changes and abberant motor
disturbances visited the Day Care Centre of the GAADRD. The
latest neuropsychological assessment was on 12/02/2020 (MMSE:
10, GDS: 1, NPI: 41, FRSSD from her caregeiver: 14) and the NPI
on 05/01/2021 was 54. The patient was treated with Alendronate
sodium trihydrate- Cholecalciferol 70 mg/ 140mcg, Calcium
carbonate 500mg, Atorvastatin-ezetimibe 10/40mg, Donepezil
5mg q.d., Memantine 10mg b.i.d., with no signicant effect
on his behavioral symptoms. She was previously treated with
bromazepam. The patient initiated on CBD 3 %, on 11/01/2021.
They titrated the dose according to the protocol. Τhe caregiver on
20/01/2021 stated that they did not notice considerable change in
her behavior as she was depressed and more anxious. The NPI was
52 and caregiver reported that they stopped CBD after 8 days, on
19/1/2021.
Patient #16
Α 94-year-old woman with LBD and main symptoms
anxiety, nighttime sleep disturbance, apathy, irritability and lifting
of suspensions visited the Day Care Centre of the GAADRD. The
latest neuropsychological assessment was on 30/10/2020 (MMSE:
17, HAM: 18, FRSSD from her caregiver: 26) and the NPI on
11/1/2021 was 69. The patient was treated with Paracetamol,
Rivastigmine 9.5/24h TTS, Hydroxyzine dihydrochloride 25mg
t.i.d., Diacerein, Folic Acid 5mg q.d., hydroxychloroquine 200mg
q.d., Omeprazole 20mg, cholecalciferol 25.000IU/ week, with
no signicant effect on her behavioral symptoms. The patient
was previously treated with mirtazapine, diazepam, olanzapine,
quetiapine, zolpidem in different periods in an effort to ameliorate
the BPSD. The patient initiated on CBD 3 %, on 11/1/2021. They
titrated the dose according to the protocol. Τhe caregiver on
20/01/2021 said that the patient was more anxious. In addition,
they noticed high blood pressure. She stopped CBD after 3 days
on 23/01.2021 due to the above side effects.
Citation: Papadopoulou L, Alexandri F, Tsolaki A, Moraitou D, Konsta A, et al. (2022) Neuropsychiatric Symptoms in Dementia. The Added Value of Can-
nabinoids. Are they a Safe and Effective Choice? Case Series with Cannabidiol 3%. Ann Case Report 7: 799. DOI: 10.29011/2574-7754.100799
6Volume 7; Issue 02
Ann Case Rep, an open access journal
ISSN: 2574-7754
Patient #17
A 64-year-old woman with FTD and main BPSD symptoms,
abbe, depression, apathy, as well as hallucinations-delusions
visited the Day Care Centre of the GAADRD. The most recent
neuropsychological assessment was on 19/10/20 (FuCAS: 119,
CDR: 16, ADCS-ADL: 9, FRSSD from her caregiver: 26) and
the NPI on 28/12/2020 was 57. Her medical treatment consisted
of Esomeprazole 40mg q.d., Pregabalin 150mg t.i.d., Trazodone
150mg q.d., Olanzapine 5mg q.d., biperiden b.i.d., Haloperidol
5mg b.i.d. She was also treated with levomepromazine previously.
However, the above treatments had no positive outcomes. The
patient initiated on CBD 3% on 31/12/2020. They titrated the
dose according to the protocol. The patient’s caregiver did not
notice a signicant important improvement and he stopped CBD
administration after 20 days, as he mentioned the patient was
disorganized. The NPI had a minimum decrease from 57 to 51 on
6/4/2021.
Discussion
To our knowledge, this is the largest case series regarding PwD
with different forms of dementia (9 AD, 3 LBD, 2 FTD and 2
PDD, 1 Down Syndrome) with severe BPSD (NPI score >30),
treated with CBD 3% extract of Industrial Cannabis. Our seventeen
patients were 9 females and 8 males, with a mean age of 80, 70
years. Eleven out of the seventeen had a positive outcome with an
average decrease of NPI from 65.54 to 19.73 in a very short time.
The feedback of the families was also positive in most of the cases.
We also observed a decrease of daily analgesic drug consumption
and a referred rigidity reduction/ mobility improvement of a
PDD patient. The most common adverse event was agitation and
in few cases somnolence which was improved by removing or
lowering the CBD dose. As described above, the least manageable
symptoms with CBD were the perceptual disturbances. The cases
that did not respond had various backgrounds (AD, LBD, FTD,
and Down syndrome), so we cannot conclude regarding the
underlying pathophysiology. Previous experimental studies with
cannabis products have also observed positive results regarding
the BPSD [13-15]. Few randomized controlled trials (RCTs)
have focused on medical cannabis for the older adult population.
Existing studies have small sample sizes (N <100) and indicate a
lack of high-quality evidence for the efcacy and safety of medical
cannabis for older adults [16], while only ve [17-21] have been
conducted with PwD. Three out of ve had the BPSD as primary
endpoints [17,18,21], and all of them used THC or its synthetic
analogue (nabilone). On the other hand, CBD has been used as
a treatment for psychiatric disorders and although available trials
reported potential therapeutic effects, there is still limited evidence
regarding the safety and efcacy of CBD for the treatment of
psychiatric disorders of PwD [22].
So, what is the underlying theory indicating this treatment
effect? Cannabis sativa L. has been used for decades for medical
purposes. However, its clinical use has been limited due to
the effects on the central nervous system and the possibility of
drug abuse and addiction [23]. The plant exudes two principal
components, Δ9- tetrahydrocannbinol (THC) and cannabidiol
(CBD). The structure and conguration of CBD was discovered
in the 60s and has gained particular attention due to the lack of
psychotropic activity, its antipsychotic, anxiolytic, antiseizure, as
well as anti- inammatory properties and its excellent tolerability
in humans. Cannabidiol exerts complex actions at multiple
receptors within the endocannabinoid system (ECS). The ECS
consists of cannabinoid receptors, endogenous ligands and
enzymes within the brain and immune system. The two principal
cannabinoid receptors are cannabinoid receptor type-1 (CB1) and
cannabinoid receptor type-2 (CB2), both distributed throughout
the brain with greater expression in the neocortex, basal ganglia,
and hippocampus. The CB1/CB2 receptor systems have a
mechanistic role in memory, appetite/eating changes, and stress
response. Cannabidiol acts as a non-competitive antagonist at CB1
receptors and an inverse agonist at CB2 receptors. Cannabidiol
inhibits the reuptake and enzymatic degradation of the endogenous
cannabinoid anandamide (N-arachidonoylethanolamine or AEA),
which has a well-established effect on neuronal/synaptic function.
Cannabidiol also exerts agonistic activity at the 5- HT1a receptors.
This action is hypothesized to mediate antidepressant, anxiolytic
and cognitive effects [13,24-26].
BPSD are a signicant problem in everyday clinical
practice due to the prevalence, severity of symptoms, burden on
the caregiver, and difculties in treatment. Many existing clinical
guides recommend the use of non-pharmacological methods as
the rst course of action, and that pharmacotherapy should be
used as a secondary option or when there is severe presentation
of symptoms. In practice, a range of drugs is used, although
most are antipsychotics [7]. Antipsychotics provide only modest
improvements and are associated with increased mortality [27].
There is no FDA- approved treatment for BPSD until today. There is
currently only one FDA-approved CBD (Epidiolex®) prescription
drug being used to treat two rare genetic epilepsy syndromes
[28] and Nabiximols (Sativex®) [29] is currently approved in
Europe and Canada for severe spasticity in MS. However, CBD
seems to have many off-label uses in neurological diseases such as
chronic pain, essential tremor, Parkinson’s disease, Anxiety related
disorders, trigeminal neuralgia, and epilepsy [28]. Moreover,
based on its pharmacology, cannabis components (THC±CBD)
may provide benets on brain tumors, brain injury, AD, chronic
traumatic encephalopathy and brain injury [30]. At this time,
recommendations for the routine use of CBD targeting BPSD
cannot be suggested. The evidence regarding CBD’s role in BPSD
will be investigated by ongoing and future Randomized Controlled
Citation: Papadopoulou L, Alexandri F, Tsolaki A, Moraitou D, Konsta A, et al. (2022) Neuropsychiatric Symptoms in Dementia. The Added Value of Can-
nabinoids. Are they a Safe and Effective Choice? Case Series with Cannabidiol 3%. Ann Case Report 7: 799. DOI: 10.29011/2574-7754.100799
7Volume 7; Issue 02
Ann Case Rep, an open access journal
ISSN: 2574-7754
studies [25]. There is limited evidence for use of CBD in dementia
with most of the research available in AD. However, the experience
from our patients indicate that CBD can be a treatment option in
BPSD, with the advantage of fast, at least short-term results, well
tolerated and cost-effective compared to the prescribed medical
Cannabis (Sativex®), which is currently available only to
patients with chronic pain due to cancer in Greece (off-label use).
Consent for publication
Written informed consent was obtained from all the subjects
and their caregivers for publication of this case report series. A
copy of the written consent is available for review by the Editor-
in-Chief of this journal.
Acknowledgements
To the Social Cooperative enterprise, (SCE) “KANABIO”
for the free disposal of the CBD extract, for research purposes.
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Introduction: Dementia is a very common disorder that affects people over 65 years old all over the world. Apart from the cognitive decline, Behavioral and Psychological Symptoms of Dementia (BPSD) are a crucial matter in dementia, because they affect up to 90% of the patients during the course of their illness. Irritability has been found to be a common BPSD and one of the most distressing behaviors for the caregivers. The aim of the current study was to explore the efficacy of a combination of non-pharmacological interventions to treat irritability. Methods: Sixty patients with different types and stages of dementia with irritability were participated in a cross-over RCT. Three non-pharmacological interventions were used; (a) Validation Therapy (VT)/Psycho-educational program, (b) Aromatherapy/massage and (c) Music Therapy (MT). The study assessed the three non-pharmacological interventions in order to find the most effective combination of the interventions. This study did not compare pharmacological and non-pharmacological treatments. The interventions lasted for five days. There was no drop-out rate. All patients were assessed at baseline using Mini Mental State of Examination (MMSE), Addenbrooke's Cognitive Examination Revised (ACE-R), Geriatric Depression Scale (GDS), Functional Rating Scale for symptoms in dementia (FRSSD), and Neuropsychiatric Inventory (NPI) (sub questions for irritability). Only NPI used for the assessment after each intervention. The analyses used categorical variables, Wilcoxon signed-rank test, Chi-square test and z value score. Results: The most effective combination of non-pharmacological interventions was Aromatherapy/massage (p = 0.003)-VT plus Psycho-educational program (p = 0.014) plus MT (p = 0.018). The same combination was the most effective for the caregivers' burden, too (p = 0.026). Conclusions: The above combination of non-pharmacological interventions can reduce irritability in patients with dementia and caregivers' burden.
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