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8 AUTHORS, INCLUDING:
Geke A H van den Elsen
8 PUBLICATIONS 9 CITATIONS
19 PUBLICATIONS 38 CITATIONS
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Tetrahydrocannabinol for
neuropsychiatric symptoms in dementia
A randomized controlled trial
Correspondence to
Dr. van den Elsen:
geke.vandenelsen@radboudumc.nl
ABSTRACT
Objective: To study the efficacy and safety of low-dose oral tetrahydrocannabinol (THC) in the
treatment of dementia-related neuropsychiatric symptoms (NPS).
Classification of evidence: This study provides Class I evidence that for patients with dementiarelated NPS, low-dose THC does not significantly reduce NPS at 21 days, though it is welltolerated. Neurology 2015;84:19
GLOSSARY
AD 5 Alzheimer disease; AE 5 adverse event; CCGIC 5 Caregiver Clinical Global Impression of Change; CI 5 confidence
interval; CMAI 5 Cohen-Mansfield Agitation Inventory; NPI 5 Neuropsychiatric Inventory; NPS 5 neuropsychiatric symptoms; PAL WMS-R 5 Paired Associate Learning Wechsler Memory ScaleRevised; QoL-AD 5 Quality of LifeAlzheimers
Disease Scale; RCT 5 randomized controlled trial; THC 5 D-9-tetrahydrocannabinol.
Most patients with dementia will experience neuropsychiatric symptoms (NPS) over the course
of their disease.1 While nonpharmacologic interventions are preferred, data on their efficacy
remains limited and the interventions are not easily applicable in clinical practice.2 Pharmacologic treatment is challenging, as currently available medications have important drawbacks
concerning the benefit-to-risk ratio.36 This implicates a serious health care problem, as 62%
of community-dwelling patients and up to 80% of nursing home residents have clinically
relevant symptoms.7,8 Structured analgesic treatment has recently been demonstrated to be
beneficial for dementia-related NPS and in particular agitation.9 D-9-Tetrahydrocannabinol
(THC), the main constituent of cannabis, has both psychoactive and analgesic properties,10,11
and might therefore serve as an alternative pharmacologic treatment. Indeed, some preliminary
Supplemental data
at Neurology.org
*These authors contributed equally to this work as last authors.
From the Departments of Geriatric Medicine/Radboudumc Alzheimer Centre (G.A.H.v.d.E., A.I.A.A., M.A.v.d.M., M.G.M.O.R.), Pharmacology
and Toxicology (A.I.A.A., C.K.), Psychiatry (R.-J.V.), Internal Medicine (C.K.), and Health Evidence (T.F.), Radboud university medical center,
Nijmegen; the Department of Elderly (A.I.A.A.), Vincent van Gogh Institute, Venray; the Department of Clinical Pharmacy (C.K.), CanisiusWilhelmina Hospital, Nijmegen, the Netherlands; and the Department of Psychiatry and Behavioral Sciences (P.B.R.), John Hopkins University
School of Medicine, Baltimore, MD.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
2015 American Academy of Neurology
Study design. This was a randomized, double-blind, placebocontrolled, multicenter, phase II trial. Potential participants
2
Neurology 84
June 9, 2015
Figure
THC 5 tetrahydrocannabinol.
per center and minimized22 for NPI score, dementia severity, sex,
and current opioid use. Treatment allocation was strictly
concealed from participants, caregivers, investigators, and all
other personnel directly involved in the study and was not
made available until study completion and database lock.
June 9, 2015
Table 1
Men, n (%)
25 (50.0)
11 (45.8)
14 (53.8)
78.4 (7.4)
79.0 (8.0)
78.0 (7.0)
Community dwelling
24 (48.0)
13 (54.2)
11 (42.3)
13 (26.0)
4 (16.7)
9 (34.6)
13 (26.0)
7 (29.2)
6 (23.1)
25.0 (3.5)
25.0 (3.8)
25.0 (3.4)
Nursing home
BMI, kg/m2, mean (SD)a
Ethnicity, n (%)
Caucasian
50 (100.0)
24 (100.0)
26 (100.0)
Other
0 (0.0)
0 (0.0)
0 (0.0)
3.8 (1.6)
3.8 (1.6)
3.8 (1.6)
Alzheimer
34 (68.0)
16 (66.7)
18 (69.2)
Vascular
7 (14.0)
3 (12.5)
4 (15.4)
Mixed
9 (18.0)
5 (20.8)
4 (15.4)
11 (22.0)
5 (20.8)
6 (23.1)
19 (38.0)
9 (37.5)
10 (38.5)
20 (40.0)
10 (41.7)
10 (38.5)
14.8 (6.7)
15.9 (6.7)
14.0 (6.8)
Vascular disorders
21 (42.0)
12 (50.0)
9 (34.6)
19 (38.0)
11 (45.8)
8 (30.8)
Gastrointestinal disorders
18 (36.0)
7 (29.2)
11 (42.3)
Musculoskeletal disorders
17 (34.0)
8 (33.3)
9 (34.6)
15 (30.0)
7 (29.2)
8 (30.8)
Psychiatric disorders
14 (28.0)
7 (29.2)
7 (26.9)
Other
24 (48.0)
22 (91.7)
20 (76.9)
Antipsychotics
10 (20.0)
7 (29.2)
3 (11.5)
Antidepressants
20 (40.0)
9 (37.5)
11 (42.3)
Benzodiazepines
21 (42.0)
8 (33.3)
13 (50.0)
Anticonvulsants
0 (0.0)
0 (0.0)
1 (3.8)
Cholinesterase inhibitors
8 (16.0)
5 (20.8)
3 (11.5)
Memantine
3 (6.0)
2 (8.3)
1 (3.8)
Melatonin
13 (26.0)
5 (20.8)
8 (30.8)
Acetaminophen
15 (30.0)
5 (20.8)
10 (38.5)
NSAIDs
2 (4.0)
1 (4.2)
1 (3.8)
Opioids
2 (4.0)
1 (4.2)
1 (3.8)
23 (46.0)
8 (33.3)
15 (57.7)
Abbreviations: BMI 5 body mass index; CDR 5 Clinical Dementia Rating; MMSE 5 MiniMental State Examination; NSAID 5 nonsteroidal anti-inflammatory drugs; THC 5 D-9tetrahydrocannabinol.
a
3 missing for THC, 4 missing for placebo.
Neurology 84
screening, baseline, and day 21, and ECG and biochemistry and
hematology blood samples, assessed at screening and day 21. The
Paired Associate Learning Wechsler Memory ScaleRevised (PAL
WMS-R)28 was used for assessment of possible effects of THC on
episodic memory function (baseline and day 21).
June 9, 2015
In total, 54 patients
were assessed for eligibility, of whom 50 were randomized and received study medication (THC, n 5
24; placebo, n 5 26) (figure). Patient characteristics
are presented in table 1. Overall, 47 patients (94%)
completed the study, while 3 patients discontinued
participation due to the occurrence of AEs (n 5 2)
and withdrawal of informed consent (n 5 1).
June 9, 2015
Table 2
THC
No.
Placebo
Baseline
24
37.4 (13.7)
26
35.6 (13.0)
Day 14
19
31.0 (11.3)
23
26.1 (16.9)
Day 21
23
27.8 (13.1)
24
23.9 (16.8)
Baseline
24
5.7 (3.8)
26
6.2 (4.3)
Day 14
19
4.1 (4.7)
23
5.0 (3.9)
Day 21
23
4.5 (4.1)
24
4.4 (4.3)
24
4.5 (4.6)
26
5.2 (4.1)
Day 14
19
4.9 (4.0)
23
4.3 (4.2)
Day 21
23
3.6 (3.9)
24
3.7 (4.3)
Baseline
24
58.8 (18.5)
26
61.6 (16.4)
Day 21
23
56.5 (17.5)
24
53.7 (18.3)
Baseline
24
13.8 (5.1)
25
13.3 (5.3)
Day 21
22
13.3 (5.0)
24
12.0 (5.5)
Baseline
24
28.3 (4.9)
24
29.6 (5.2)
Day 21
21
27.5 (4.6)
22
29.1 (5.0)
Day 14
20
3.7 (1.0)
25
3.4 (1.2)
Day 21
22
3.5 (1.3)
24
3.2 (1.4)
Baseline
23
69.8 (11.4)
24
74.5 (12.5)
Day 21
22
66.3 (8.6)
24
71.6 (8.0)
Baseline
23
138.6 (21.2)
24
143.1 (15.9)
Day 21
22
143.7 (16.8)
24
141.3 (20.9)
Baseline
23
77.5 (8.0)
24
82.0 (10.4)
Day 21
22
76.9 (7.1)
24
78.2 (9.3)
Baseline
22
71.0 (14.3)
22
70.9 (13.8)
Day 21
20
70.4 (13.8)
22
71.1 (12.9)
Primary outcomes
NPI total score
Secondary outcomes
CMAI
Barthel Index
QoL-AD
CCGIC
Safety assessments
Heart rate, bpm
Weight, kg
Abbreviations: CCGIC 5 Caregivers Clinical Global Impression of Change; CI 5 confidence interval; CMAI 5 Cohen-Mansfield Agitation Inventory; NPI 5
Neuropsychiatric Inventory; QoL-AD 5 Quality of LifeAlzheimers Disease Scale; THC 5 D-9-tetrahydrocannabinol.
Group numbers are means (SDs). Estimates of overall mean differences over days 14 and 21 are based on linear mixed model analysis for repeated
measures with correction for (subscale) NPI score at baseline, center, Clinical Dementia Rating stage, sex, current opioid use, week, and using a random
intercept. A negative mean difference favors THC for NPI (range 0144), CMAI (range 29203), and CCGIC (range 17). A positive mean difference favors
THC for Barthel Index (range 020) and QoL-AD (range 1352).
a
7-point scale: 1, marked improvement; 2, moderate improvement; 3, minimal improvement; 4, unchanged; 5, minimal worsening; 6, moderate worsening; 7,
marked worsening.
Neurology 84
June 9, 2015
Table 3
THC (n 5 24)
Placebo (n 5 26)
16 (66.7)
14 (53.8)
0 (0.0)
0 (0.0)
10 (41.7)
13 (50.0)
Dizziness
4 (16.7)
4 (15.4)
Somnolence
2 (8.3)
4 (15.4)
Aphasia
1 (4.2)
1 (3.8)
Bradykinesia
0 (0.0)
1 (3.8)
Miosis
0 (0.0)
1 (3.8)
Muscle spams
0 (0.0)
1 (3.8)
Sensory loss
0 (0.0)
1 (3.8)
Headache
1 (4.2)
0 (0.0)
Muscular weakness
1 (4.2)
0 (0.0)
Balance disorder
1 (4.2)
0 (0.0)
Psychiatric disorders
7 (29.2)
4 (15.4)
Cognitive disorder
3 (12.5)
1 (3.8)
Restlessness
2 (8.3)
1 (3.8)
Agitation
0 (0.0)
1 (3.8)
Euphoric mood
0 (0.0)
1 (3.8)
Apraxia
1 (4.2)
0 (0.0)
Delirium
1 (4.2)
0 (0.0)
Investigations
1 (4.2)
6 (23.1)
Gamma-glutamyltransferase increased
1 (4.2)
2 (7.7)
0 (0.0)
2 (7.7)
0 (0.0)
1 (3.8)
0 (0.0)
1 (3.8)
4 (16.7)
2 (7.7)
Nausea
2 (8.3)
1 (3.8)
Diarrhea
0 (0.0)
1 (3.8)
1 (4.2)
0 (0.0)
1 (4.2)
0 (0.0)
2 (8.3)
3 (11.5)
Fatigue
2 (8.3)
2 (7.7)
Malaise
0 (0.0)
1 (3.8)
1 (4.2)
3 (11.5)
1 (4.2)
3 (11.5)
Gastrointestinal disorders
General disorders
4 (16.7)
0 (0.0)
Pneumonia
2 (8.3)
0 (0.0)
1 (4.2)
0 (0.0)
Nasopharyngitis
1 (4.2)
0 (0.0)
Cardiac disorders
1 (4.2)
2 (7.7)
Chest pain
0 (0.0)
1 (3.8)
Syncope
0 (0.0)
1 (3.8)
Presyncope
1 (4.2)
0 (0.0)
3 (12.5)
0 (0.0)
1 (4.2)
0 (0.0)
Musculoskeletal disorders
Back pain
Continued
personnel (together called the Hawthorne or instudy effect36). To correct for this substantial
placebo response within individual patients, it
might be worthwhile to implement an individually
randomized crossover design in future studies.
Despite the fact that we studied a vulnerable
patient population, the attrition level was low
(6%) and adherence high (98%100%). This
suggests a highly motivated group of participants
and caregivers, in combination with the occurrence
of only mild AEs. This study has some limitations.
Most importantly, we failed to enroll the planned
number of patients, despite comprehensive
recruitment efforts throughout various health care
settings. Rigorous national regulations on medical
cannabinoids hindered implementation of the
study in the participating clinics. Additionally,
fewer than expected patients visiting the clinics
had clinically relevant NPS as well as pain.
Omitting the latter inclusion criterion significantly
stimulated the recruitment. Despite this
underenrollment, the conditional power of 5%
emphasizes that it was very unlikely that exposure
of more participants to the study interventions and
assessments would have influenced our conclusion.
Contrary to the current RCT, previous studies all
reported positive effects of oral THC (2.57 mg
daily) in patients with dementia.12,13,21,37 However,
important methodologic factors significantly limit the
robustness of these findings: inclusion of small number
of patients (n 5 2 and n 5 15) and uncontrolled or
retrospective study designs. In a previous randomized
trial, we studied dosages up to 3 mg THC daily, and
did not observe a significant reduction in NPS, nor any
relevant AEs or effects on vital functions or mobility
(unpublished data, 2014). Therefore, we used a dosage
of 4.5 mg THC daily in this study.
Recent developments regarding the extended
legalization of marijuana for medical purposes in
over 30 US states has stimulated the discussion of
the therapeutic potential and safety profile of cannabinoids for various indications.38,39 Momentarily,
effective and safe treatments for NPS in patients
with dementia are lacking.40 Several pharmacotherapeutic options have been explored, such as acetylcholinesterase inhibitors and antidepressants,33,34
but they often have a suboptimal benefit-risk profile.
For example, while high-dose citalopram appears to
effectively reduce agitation and overall behavioral
disturbances, significant cardiac AEs limit its usefulness in this vulnerable population.34 Our current
trial indicates that 4.5 mg THC daily can be safely
administered to patients with dementia. The observation that there was no biological signal of AEs
suggests that the dosage was too low, as a psychoactive drug is rarely effective without showing any side
Neurology 84
June 9, 2015
Table 3
DISCLOSURE
Continued
THC (n 5 24)
Placebo (n 5 26)
Neck pain
1 (4.2)
0 (0.0)
Pain in extremity
1 (4.2)
0 (0.0)
Eye disorders
0 (0.0)
2 (7.7)
Dry eyes
0 (0.0)
1 (3.8)
Eye hemorrhage
0 (0.0)
1 (3.8)
0 (0.0)
2 (7.7)
Renal impairment
0 (0.0)
1 (3.8)
Urge incontinence
0 (0.0)
1 (3.8)
Skin disorders
2 (8.3)
0 (0.0)
Intertrigo
1 (4.2)
0 (0.0)
1 (4.2)
0 (0.0)
0 (0.0)
1 (3.8)
0 (0.0)
1 (3.8)
1 (4.2)
0 (0.0)
1 (4.2)
0 (0.0)
0 (0.0)
1 (3.8)
0 (0.0)
1 (3.8)
ACKNOWLEDGMENT
The authors thank the staff of the Department of Geriatric Medicine,
Jeroen Bosch Ziekenhuis, s Hertogenbosch; Vitalis WoonZorg Groep,
Eindhoven; Liemerije, Zevenaar; Stichting LuciVer, Wijchen; Department
of Elderly Care, GGNet, Apeldoorn; GGZ Breburg, Tilburg; and Hulp bij
Dementie, Venray, for the recruitment of potential participants; the nursing home staff of Vincent van Gogh Institute, Liemerije, Vitalis WoonZorg Groep, and Stichting LuciVer; and their research assistants for their
assistance in outcome assessments.
STUDY FUNDING
Funded by the European Regional Development Fund and the Province
of Gelderland. The Investigation Medical Product was provided by Echo
Pharmaceuticals, Weesp, the Netherlands, which did not provide financial support for the study and had no role in study design, collection,
analysis or interpretation of data, or writing the report.
8
Neurology 84
G. van den Elsen was supported by a grant from the European Regional
Development Fund for the conduct of the study. A. Ahmed, R. Verkes,
and C. Kramers report no disclosures relevant to the manuscript.
T. Feuth was supported by a grant from the European Regional Development Fund for the conduct of the study. P. Rosenberg reports no disclosures relevant to the manuscript. M. van der Marck was supported by
a grant from the European Regional Development Fund for the conduct
of the study. M. Olde Rikkert reports no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
June 9, 2015
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Neurology 84
June 9, 2015
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