INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, VOL. 12: 913±919 (1997)

EFFECTS OF DRONABINOL ON ANOREXIA AND
DISTURBED BEHAVIOR IN PATIENTS WITH
ALZHEIMER'S DISEASE
1

LADISLAV VOLICER1 , MARILYN STELLY2, JUDITH MORRIS3 , JOSEPH McLAUGHLIN3 AND BEVERLY J. VOLICER2

E. N. Rogers Memorial Veterans Hospital, Geriatric Research Education Clinical Center, Bedford; Boston University
School of Medicine, Departments of Pharmacology and Psychiatry, Boston, USA
2
University of Massachusetts Lowell, School of Health Professions, Lowell, USA
3
E. N. Rogers Memorial Veterans Hospital, Dietetic and Pharmacy Services, Bedford, USA

SUMMARY
A placebo-controlled crossover design, with each treatment period lasting 6 weeks, was used to investigate eects ofdronabinol in 15 patients with a diagnosis of probable Alzheimer's disease who were refusing food. Eleven patientscompleted both study periods; one patient who died of a heart attack 2 weeks before the end of the study was also
included in the analysis. The study was terminated in 3 patients: one developed a grand mal seizure and 2 developed
serious intercurrent infections. Body weight of study subjects increased more during the dronabinol treatment
than during the placebo periods. Dronabinol treatment decreased severity of disturbed behavior and this eect
persisted during the placebo period in patients who received dronabinol ®rst. Adverse reactions observed morecommonly during the dronabinol treatment than during placebo periods included euphoria, somnolence andtiredness, but did not require discontinuation of therapy. These results indicate that dronabinol is a promising novel
therapeutic agent which may be useful not only for treatment of anorexia but also to improve disturbed behavior inpatients with Alzheimer's disease. # 1997 John Wiley & Sons, Ltd.
Int. J. Geriat. Psychiatry, 12, 913±919, 1997.
No. of Figures: 3. No. of Tables: 2. No. of References: 25.
KEY WORDS ÐAlzheimer's disease; anorexia; dronabinol; behavior

Anorexia is quite common in the cognitively intact
elderly (Morley et al., 1988). It has many causes
including social, physical and mental factors.
Physical changes associated with ageing which
could precipitate development of anorexia are
decreased taste and smell, decreased feeding drive
because of decreased eectiveness of endogenous
opioids, and increased satiety because of increased
sensitivity to the eect of cholecystokinin (Morley
et al., 1988). Abnormality of other neurotransmitters may also play a role, especially in demented
individuals. Brain levels of neuropeptide Y andnorepinephrine, which stimulate appetite, havebeen found to be reduced in patients sueringCorrespondence to: Dr L. Volicer, E. N. Rogers Memorial
Veterans Hospital (182B), 200 Springs Road, Bedford, MA
01730, USA.

Contract grant sponsors: Department of Veterans Aairs,
Roxane Laboratories, Inc.; UNIMED Pharmaceuticals, Inc.
CCC 0885±6230/97/090913±07$17.50# 1997 John Wiley & Sons, Ltd.

from dementia of the Alzheimer type (DAT)(Morley et al., 1988).
Dementia of the Alzheimer type leads to a
progressive loss of learned behaviors including theability to feed oneself, and some patients also startrefusing food during the course of the disease(Volicer et al., 1989). Several dierent factors
may contribute to the refusal of food by demented
individuals, including: dislike of hospital food,
failure to recognize edible objects as food(agnosia), or loss of sense of thirst and/or hunger(anorexia). Some patients develop food refusal
when they start choking on food or liquids and therefusal could be a consequence of dysphagia. Thiscan be corrected by diet modi®cations. Other
patients refuse food, even though swallowing is
unimpaired. This refusal may be a symptom of
depression, which is dicult to diagnose in thispatient population (Emery and Oxman, 1992).
Treatment with antidepressants improves foodReceived 18 September 1996
Accepted 16 March 1997

914

L. VOLICER ET AL.

intake even in patients with severe dementia(Volicer et al., 1994b). However, some patients do
not improve and are at risk for development ofmalnutrition. Therefore, additional therapeuticmodalities are needed to deal with this problem.
Smoking marijuana has been found to cause
appetite stimulation in normal humans (Struwe
et al., 1993). One of the main components
of marijuana, dronabinol, was associated withincreased food intake when used as an antiemetic
in cancer patients (Sallan et al., 1980). It also
improved appetite and sense of well-being, as wellas causing weight gain (Regelson et al., 1976). In apilot study of 10 AIDS patients, dronabinol
treatment was associated with weight gain andimprovement in mood or sense of well-being without euphoria (Gorter, 1991). In a double-blind
study of 12 AIDS patients, dronabinol treatment
increased % of body fat, decreased symptom
distress and tended to cause weight gain, increased
prealbumin and improved appetite scores (Struwe
et al., 1993). A multicenter trial (Beal et al., 1995),
including 139 AIDS patients, showed that dronabinol improved appetite and mood, and that
euphoria was the most common side-eect indronabinol-treated patients, occurring in 13% of
patients. Other side-eects occurred in less than
10% of patients and included dizziness, abnormal
thinking, sinusitis and somnolence.
The above studies indicate that dronabinol may
be eective in treatment of anorexia of demented
individuals even in the absence of nausea. However, nausea as a cause of anorexia in these
individuals cannot be excluded, since they areunable to complain about it, and some develop
periodic bouts of vomiting. Therefore, we investigated the eect of dronabinol on food refusal in
DAT patients. In addition, we also monitored theeect of dronabinol on disturbed behavior.
SUBJECTS AND METHODS
Subjects were 15 patients hospitalized on the
Dementia Study Unit, with the diagnosis of`probable' DAT made by a neurologist according
to DSM-III-R and NINCDS±ADRDA criteria(McKhann et al., 1984), who exhibited simple foodrefusal. Simple food refusal was characterized as
refusal of feeding by keeping the mouth shut,turning the head away, pushing away the spoon or
feeding hand, or by spitting food, in the absence ofchoking on food and/or liquids. Informed consent
INT. J. GERIAT. PSYCHIATRY. VOL. 12: 913±919 (1997)

was obtained from the guardians or the next-of-kin
of patients who did not have capacity to makehealth care decisions.
The patients were identi®ed by a survey ofnursing sta. They received physical examinationand laboratory examination including complete
blood count with dierential, liver function tests,
thyroid function tests including TSH, iron binding
capacity, albumin, BUN, creatinine and electrolytes. Patients who were choking on food or
liquids, had hypersensitivity to dronabinol orsesame oil or had signi®cant laboratory abnormalities were not eligible for the study.
The severity of dementia was measured by
the Mini-Mental State Examination (MMSE)(Folstein et al., 1975), Katz Activity of Daily
Living scale (Katz ADL) (Katz et al., 1963) and
Bedford Alzheimer Nursing ScaleÐSeverity(BANS-S) (Volicer et al., 1994a). The study used
a double-blind placebo-controlled crossover design
with each study period lasting 6 weeks. Dronabinol
or placebo was administered on a ®xed doseschedule, 2.5 mg capsule (Marionol, Roxane
Laboratories) or identical looking placebo capsule
every morning and noon. This administration
schedule was a modi®cation from that recommended for AIDS patients because DAT patientsusually eat most of their daily food during breakfast and lunch. Subjects were randomly assigned toplacebo ®rst or dronabinol ®rst groups. Possible
side-eects were determined every week by asking
the primary caregivers if the patient experienced
any of a list of possible symptoms.
Baseline measurements were taken the weekprior to randomization and treatment initiation.
Plasma albumin and lymphocyte count were also
obtained at the end of each treatment period. Body
weights, skin fold thickness, caloric intake andbehavior measures were obtained weekly for the
12-week duration of the trial. Repeated measureson these variables were therefore available for
6 weeks on dronabinol and 6 weeks on placebo
for each subject. Complete data were obtained for
11 subjects and for 10 weeks for the one subject
who died before the end of the study. For that
individual, who was assigned to the placebo for thelast 6 weeks of the study, values for the last 2 weeks
were estimated by taking the average of measures
for the previous 4 weeks.
Nutritional status was monitored by weekly
measurements of body weight and triceps skin foldthickness, and by measurement of plasma albumin
and lymphocyte count at the beginning and end of# 1997 John Wiley & Sons, Ltd.

EFFECTS OF DRONABINOL ON ANOREXIA AND DISTURBED BEHAVIOR IN PATIENTS

each study period. The caloric intake was calculated from the fraction of prescribed diet anddietary supplements consumed during 2 days eachweek. The diet was kept constant during the study.
Body mass index (BMI) was calculated from bodyweight and height measured either in a standing
position or by a knee caliper as weight (kg) divided
by height (m) squared.
The extent of disturbed behavior exhibited byeach patient was determined each week by interview with primary caregivers who were familiar
with patients' behavior and with rating scales. The
disturbed behavior was measured by the CohenMans®eld Agitation Inventory (CMAI) (CohenMans®eld et al., 1989), which is a widely used
instrument with good psychometric properties.
Twenty-nine items of this instrument are rated byfrequency (from 1  never to 7  constantly or
almost constantly) and by disruptiveness (from1  not at all to 5  extremely). For eachobservation period, the total score was calculated
by multiplying the frequency and disruptiveness of
individual items and adding the products. Patients'aect was measured using the Lawton ObservedAect ScaleÐPast (Lawton et al., 1996). This scaleconsists of six items, three measuring positive aect(pleasure, interest and contentment) and threenegative aect (anger, anxiety/fear and depression/sadness) on a ®ve-point scale (from 1  neverto 5  more than three times a day). The negativeand positive aect scores were calculated by adding
scores of the appropriate items.
Statistical analysis was performed using Statistix
4.1 (Analytic Software). Repeated measures
ANOVA for the 12 weeks of the study was done
to test for eects of order, time and treatment on
study variables. In this analysis, time and treatment
were repeated measures and order (dronabinol ®rst
vs placebo ®rst) was a non-repeated measure. The
repeated measures ANOVA was done for bodyweight, triceps skin fold thickness, caloric intake,disturbed behavior and negative and positive aect.
RESULTSOf the 15 patients enrolled in the study, 11 patientscompleted both study periods. One patient who
died of a heart attack 2 weeks before the end of
the study, while on placebo, was also included in
the analysis. The study was terminated in threepatients: one developed a grand mal seizure afterthe ®rst dronabinol dose and two developed serious# 1997 John Wiley & Sons, Ltd.

915

Table 1. Characteristics of study population
Characteristic

Mean+ SD

Range

Age (yr)
72:7+4:9
65±82
Gender
11 males, 1 female
Duration of DAT (yr)
7:0+4:1
2±16Duration of long-term care before
17:4+21:9
2.6±81.0
beginning of study (months)
Mini-Mental State Examination
4:0+7:4
0±20
score
Katz Activity of Daily Living
5:7+0:6
4±6
score
Bedford Alzheimer Nursing
17:5+3:0
13±22
ScaleÐSeverity score
22:6+2:5
16.9±26.2
Body mass index (kg/m2 )Plasma albumin (g/dl)
3:7+0:4
3.1±4.5
0.8±2.3
Lymphocyte count (thousand/mm3 ) 1:7+0:4
Note: The numbers are means+ SD.

intercurrent infections. Of the 12 patients includedin the analysis, six received placebo for 6 weeks
followed by dronabinol for 6 weeks, and six
received dronabinol for 6 weeks followed byplacebo for 6 weeks.
The subjects included in the analysis were all
65 years old or older and all but one were males(Table 1). Duration of DAT varied from 2 to
16 years and most patients had been in institutional
long-term care for many months before the onsetof the study. Most also suered from severe
dementia; the MMSE score was 0 in eight subjects.
Patients were also severely impaired in activities ofdaily living: nine were dependent in all six activities.
BANS-S score, which detects progression of thedisease even in the severe stage (Volicer et al.,1994a), indicated moderate to severe impairment.
The mean BMI was in a low normal range and only
one patient had BMI lower than 20. The mean
plasma albumin was in the normal range and nopatient had plasma albumin less than 3 g/dl. The
mean lymphocyte count was also in the normal
range and two patients had a count lower than
1200 cells/mm3 .
Body weight increased during the 12-week
study period, regardless of the order in which thetreatment was given (Fig. 1) F time  3:64,
df  5;143, p  0:006. The eect of dronabinol
on weight gain was greater for those who received
dronabinol ®rst than for those who received theplacebo ®rst F order  treatment  8:4 for interaction between order and treatment, df  1; 143,
p < 0:017. Patients on dronabinol gained 7:0+
1:5 lb and 2:3 +1:7 lb in the ®rst and second
INT. J. GERIAT. PSYCHIATRY. VOL. 12: 913±919 (1997)

916

L. VOLICER ET AL.

Fig. 1. Changes of the body mass index (BMI) during theplacebo and dronabinol phases of the study. The treatment was
switched after 6 weeks. For statistical analysis see text

period respectively, while patients on placebo
gained 4:6 + 1:3 lb and 1:7+ 2:3 lb. These bodyweight changes expressed as changes of the bodymass index are shown in Fig. 1. Triceps skin foldthickness also increased during the 12-week study
period F time  3:12, df  5; 143, p  0:016,
but was not aected by order or treatment. Caloric
intake did not change during the study period andwas similar in placebo 2200+ 128 kcal and2190 + 227 kcal and dronabinol 2219 +647 kcal
and 2299 + 227 kcal periods. Plasma albumin andlymphocyte counts did not change signi®cantly.
Disturbed behavior decreased during bothdronabinol treatment periods F order  treatment  2:78, df 1; 143, p  0:12 and thisdecrease in disturbed behavior persisted during
the placebo period following dronabinol treatment(Fig. 2). When the CMAI scores were expressed aspercentage of the baseline, there was a signi®cantorder  time interaction F  2:35 order  time,df  5; 143, p  0:05:Negative aect decreased during the 12-week
study period as shown in Fig. 3 F time  2:46,
df  5; 143, p  0:045 and it decreased morewhile patients were on dronabinol than during
the placebo periods F time  treatment  3:98,
df  5; 143, p  0:004: Further, the decrease wasgreater for those who received dronabinol ®rst
compared to those who received placebo ®rst
F order  time  5:45, df  5; 143, p < 0:0005:In contrast, positive aect remained similar during
both treatments and treatment periods.
Eleven of the patients were on a psychoactive medication before the beginning of thedronabinol study and were maintained on the same
INT. J. GERIAT. PSYCHIATRY. VOL. 12: 913±919 (1997)

Fig. 2. Changes of the Cohen-Mans®eld Agitation Inventory(CMAI) (14) score during the placebo and dronabinol phases ofthe study. For statistical analysis see text

Fig. 3. Changes of the negative aect score (15) during theplacebo and dronabinol phases of the study. For statisticalanalysis see text

medication during the study period. Four patientswere receiving regular doses of neuroleptics(perphenazine, thiothixene, haloperidol or thioridazine), four patients were receiving regular dosesof benzodiazepines (three lorazepam and one
alprazolam) and eight patients were receiving
regular doses of antidepressants. The antidepressants included sertraline (eight patients), trazodone(four patients) and desipramine (one patient). Threepatients were on both sertraline and trazodone, andone patient was switched from trazodone todoxepin. Antidepressant treatment was initiated atleast 4 weeks before the start of the study and themean duration of antidepressant treatment before
study initiation was 7 months. Eleven patients hadorders for psychoactive medications as needed(PRN). These included lorazepam in four patients# 1997 John Wiley & Sons, Ltd.

917

EFFECTS OF DRONABINOL ON ANOREXIA AND DISTURBED BEHAVIOR IN PATIENTSTable 2. Adverse reactions reported during the study
SymptomDronabinol

Patients

Weeks

Placebo

Patients

Weeks

N

%

N

%

N

%

N

%

Anxiety/nervousness
11
Emotional lability
11
Tiredness
9
Somnolence
8
Euphoria
7
Paranoid reaction
4
Hallucination
4
Depression
2
Ataxia2
Muscle pain2
Diarrhoea
2Flushing
1
Increased confusion1
Sweating
1
Increased speech diculty
Headache
1
Nightmares

92
92
75
67
58
33
33
16
16
16
16
8
8
8

37
32
25
29
31
16
11
4
6
7
3
2
2
2

53
46
36
41
44
23
16
6
8
10
4
3
3
3

12
10
5
4
5
5
5
2
2
1

100
83
42
33
42
42
42
16
16
8

43
36
15
12
16
18
16
4
3
3

61
51
21
17
23
26
23
6
4
4

8

1

1

2
2
1
1

16
16
8
8

2
2
1
1

3
3
1
1

1

8

1

1

Note: There were totals of 12 patients and 70 weeks of observation. In addition to the listed eects, one incidence of seizure in a
dronabinol-treated patient was observed.

and alprazolam, trazodone, doxepin, haloperidol,
perphenazine and thioridazine in one patient each.
The patients received these medications very rarely,
on average, 9.7 doses/6 weeks during placebo
administration and 7.2 doses/6 weeks during
dronabinol administration.
With the exception of a seizure which occurred in
one patient, no serious adverse reactions to dronabinol were detected. Some reactions, eg emotional
lability, anxiety/nervousness, hallucinations andparanoid reactions, were observed in most patients,
but were not associated with treatment. Morepatients exhibited tiredness, somnolence andeuphoria during the dronabinol treatment thanduring placebo periods (Table 2). The number ofweeks during which euphoria and somnolence wereobserved during the dronabinol therapy was alsomuch larger than the number of weeks during theplacebo periods. In no case was dronabinol treatment discontinued because of these side-eects.
DISCUSSION
Food refusal in DAT patients leads to considerable
stress among health care providers and families(Lo and Dornbrand, 1984) because of its emotional and ethical implications (Callahan, 1995).
Providing nourishment is one of the basic# 1997 John Wiley & Sons, Ltd.

components of care which is often seen asnecessary to maintain comfort of the patient. If
the problem is not openly discussed, the sta areforced to choose between allowing the patient todeteriorate physically because of inadequate intake
or forcing the patient to take nourishment against
his or her will. As a result, con¯icts arise withregard to the perceived obligation to keep thepatient alive, the desire not to cause pointlesssuering and respect for the patient's wishes(Norberg et al., 1980). Alternatively, tube feeding
is instituted, which deprives the patient of the tasteof food and contact with caregivers during thefeeding process, and may require restraining thepatient to prevent tube removal.
Antidepressant treatment is often eective indecreasing food refusal in patients with advanced
dementia (Volicer et al., 1994b). However, thepresent study indicates that weight gain could befurther promoted by administration of dronabinol
even in patients on antidepressant therapy. Body
weight actually increased in both patients who wereon dronabinol and placebo. This could have beencaused either by a delayed eect of antidepressantsor by more intensive feeding eorts. Since theantidepressants were started several weeks before
initiation of the study, it is unlikely that they caused
this weight gain. We felt that stopping antidepressant treatment would not be ethical in these
INT. J. GERIAT. PSYCHIATRY. VOL. 12: 913±919 (1997)

918

L. VOLICER ET AL.

nutritionally compromised patients. Changes in thepatient feeding practices may be a more likely
explanation of this general weight gain. Although
the study was double-blind, the sta knew theobjectives of the study and might have made more
intensive eorts to get the patients to eat.
Surprisingly, the caloric intake was similar
during the placebo and dronabinol periods. It is
possible that the weight gain was partly caused
by decreased agitation of the patients, which
could have decreased their caloric requirements.
Decreased agitation was observed using two scales:
CMAI and Observed aect Scale. The negative partof the Observed Aect Scale includes two items(anger and anxiety/fear) which are commonly
present in patients during agitated behaviors. The
third item, depression/sadness, was rarely observed,
as can be seen from Table 2. Thus both scales
measured similar disruptive behaviors. It is possiblethat this eect was partly due to somnolence, which
was twice as common in patients treated withdronabinol as in patients on placebo.
The possibility that the weight gain was partly
caused by decreased agitation is supported by the
restriction of the eect of dronabinol on bodyweight to the ®rst treatment period. Since the eectof dronabinol on disturbed behavior carried overto the following placebo period, there was nodierence in the disturbed behavior in the second
treatment period. This prolonged change in disturbed behavior could be due to a long-term eectof dronabinol. It has been reported that tetrahydrocannabinol metabolites are present in the urine aslong as 77 days after ingestion of marijuana (Elliset al., 1985). Dronabinol pharmacokinetics can be
described by a four-compartment model, withinitial half-life of 4 hours and terminal half-life of
25±36 hrs (Agurell et al., 1986). However, lowlevels of dronabinol metabolites have been detectedin the urine and feces for 2±5 weeks after initiationof a supervised abstinence (Dackis et al., 1982).
Dronabinol treatment did not change the positive aect (Lawton et al., 1996), although euphoria
as an adverse reaction was reported more frequently and in more patients during the dronabinol
treatment than during placebo periods. It is possible that the positive aect items represent more adegree of patient's engagement than patient's
mood (Lawton et al., 1995).
The main adverse reaction, possibly caused bydronabinol, was occurrence of a seizure in one
patient shortly after receiving the ®rst dose ofdronabinol. This seizure could have been caused by
INT. J. GERIAT. PSYCHIATRY. VOL. 12: 913±919 (1997)

dronabinol because it has been reported that
tetrahydrocannabinol lowers seizure thresholdin rats (Chiu et al., 1979). In a study involving
809 patients receiving dronabinol as an antiemetic,
two patients (0.24%) developed myoclonic jerking
and one patient (0.12%) developed grandmal seizures (Devine et al., 1987). However, it isimportant to note that recurrent seizures also
develop without any precipitating event in 20%
of patients with advanced DAT (Volicer et al.,1995). In the patient who developed a seizure afterthe ®rst dose of dronabinol, the seizure did notrecur despite the lack of anticonvulsant treatment,
but the follow-up was limited to 2 months because
the patient died of causes unrelated to participationin the study. Therefore, it is not clear if the seizure
observed in this study was caused by dronabinol orby progression of DAT. A larger trial of dronabinol in DAT patients is necessary to address
whether the incidence of seizures is increased
during dronabinol therapy. It is also possible thata lower dose than the one used in this study wouldbe eective and safer in this patient population.
Other possible side-eects included tiredness,
somnolence and euphoria, which were observed
more frequently and in more patients during
dronabinol treatment than during the placebo
period. These side-eects were not unexpectedconsidering the pharmacological pro®le of dronabinol, and were not severe enough to require
discontinuation of the study. In contrast, the study
indicates that dronabinol did not increase paranoid
reactions and hallucinations, although perception
distortions have been observed in previous trials(Devine et al., 1987). There was also no evidence
of increased confusion, ataxia and speech diculties which would impair cognitive or functional
abilities of Alzheimer patients.
Results of this study indicate that dronabinol
may be a useful addition to drugs used for management of patients with DAT and other dementias.
There are, however, several questions which need
to be further investigated. This study used a single®xed dose, which may not be optimal in this patient
population. The study was also not designed
speci®cally to investigate behavioral and aective
changes after dronabinol administration. Resultsof this further investigation are needed before theplace of dronabinol in the treatment of anorexia
and behavioral problems in DAT patients can beclearly delineated. None the less, these early results
are promising and a larger-scale study of dronabinol in patients with DAT is warranted.
# 1997 John Wiley & Sons, Ltd.

EFFECTS OF DRONABINOL ON ANOREXIA AND DISTURBED BEHAVIOR IN PATIENTSACKNOWLEDGEMENTS
The authors acknowledge with gratitude the contributions of nursing sta who provided important
clinical feedback. The study was supported by the
Department of Veterans Aairs, Roxane Laboratories, Inc., and the UNIMED Pharmaceuticals,
Inc.
The work was presented at the 5th International
Conference on Alzheimer's disease, July 24±29,
1996, Osaka, Japan.
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