Passionflower in the treatment of generalized anxiety: A pilot double-blind randomized controlled trial with oxazepam

Abstract

Objective: Passionflower (Passiflora incarnata) is a folk remedy for anxiety. A double-blind randomized trial compared the efficacy of Passiflora incarnata extract with oxazepam in the treatment of generalized anxiety disorder.
Methods: The study was performed on 36 out-patients diagnosed with GAD using DSM IV criteria. Patients were allocated in a random fashion: 18 to the Passiflora extract 45 drops/day plus placebo tablet group, and 18 to oxazepam 30 mg/day plus placebo drops for a 4-week trial.
Results: Passiflora extract and oxazepam were effective in the treatment of generalized anxiety disorder. No significant difference was observed between the two protocols at the end of trial. Oxazepam showed a rapid onset of action. On the other hand, significantly more problems relating to impairment of job performance were encountered with subjects on oxazepam.
Conclusion: The results suggest that Passiflora extract is an effective drug for the management of generalized anxiety disorder, and the low incidence of impairment of job performance with Passiflora extract compared to oxazepam is an advantage. A large-scale trial is justified.

Full text

Passion¯ower in the treatment of generalized anxiety:
a pilot double-blind randomized controlled trial
with oxazepam
S. Akhondzadeh*PhD, H. R. Naghavi* MD, M. Vazirian* MD,
A. ShayeganpourPharmD,H.RashidiPharmD and M. KhaniMSc
*Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, South Kargar Avenue, Tehran and
Institute of Medicinal Plants, Jehad-E-Daneshgahi, Tehran, Iran
SUMMARY
Objective: Passion¯ower (Passi¯ora incarnata)
is a folk remedy for anxiety. A double-blind
randomized trial compared the ef®cacy of Passi-
¯ora incarnata extract with oxazepam in the
treatment of generalized anxiety disorder.
Methods: The study was performed on 36 out-
patients diagnosed with GAD using DSM IV
criteria. Patients were allocated in a random
fashion: 18 to the Passi¯ora extract 45 drops/day
plus placebo tablet group, and 18 to oxazepam
30 mg/day plus placebo drops for a 4-week trial.
Results: Passi¯ora extract and oxazepam were
effective in the treatment of generalized anxiety
disorder. No signi®cant difference was observed
between the two protocols at the end of trial.
Oxazepam showed a rapid onset of action. On the
other hand, signi®cantly more problems relating
to impairment of job performance were encoun-
tered with subjects on oxazepam.
Conclusion: The results suggest that Passi¯ora
extract is an effective drug for the management of
generalized anxiety disorder, and the low inci-
dence of impairment of job performance with
Passi¯ora extract compared to oxazepam is an
advantage. A large-scale trial is justi®ed.
Keywords: herbal medicines, Passi¯ora incarnata,
RCT, traditional medicine
INTRODUCTION
Generalized Anxiety Disorder (GAD) is the most
common anxiety disorder but is generally less
severe than panic disorder. GAD is probably the
disorder most often found with a coexisting mental
disorder, usually another anxiety disorder or a
mood disorder (1). The ratio of women to men is
about 2 : 1. The cause of GAD is not known. The
primary symptoms of GAD are anxiety, motor
tension, autonomic hyperactivity and cognitive
vigilance (1). DSM IV (2) employs the following
criteria for GAD: excessive anxiety and worry,
occurring more days than not for at least 6 months,
about a number of events or activities that are
dif®cult to control. Autonomic symptoms are no
longer required for diagnosis. The principal
neurotransmitter systems thought to modify anxi-
ety are the gamma-aminobutyric acid (GABA)
system, and the noradrenergic, serotonergic,
dopaminergic and histaminergic system (3, 4).
GABA is an important and abundant inhibitory
transmitter in the mammalian nervous system.
Three types of GABA receptor may be distin-
guished on the basis of their pharmacological
properties and the physiological consequences of
their activation: GABA
A
, GABA
B
and GABA
C
.
GABA
A
receptors can be allosterically regulated by
a diverse range of both naturally occurring and
synthetic compounds (5±10). These substances
include the barbiturates and benzodiazepines,
which have important sedative, anxiolytic and
anticonvulsant uses (11±16). The most effective
treatment of patients with GAD is probably one
that combines psychotherapeutic, pharmacothera-
peutic and supportive approaches. Because of the
long-term nature of the disorder, a treatment plan
must be carefully thought out. The two major
drugs to be considered for the treatment of GAD
are buspirone and the benzodiazepines (3, 4).
Benzodiazepines are the drugs most frequently
prescribed for the treatment of anxiety disorders.
Received 13 June 2001, Accepted 24 July 2001
Correspondence: Dr Shahin Akhondzadeh PhD, No. 29, 39th
Street, Gisha Street, Tehran 14479, Iran. E-mail: s.akhond@
neda.net
Journal of Clinical Pharmacy and Therapeutics (2001) 26, 363±367
Ó2001 Blackwell Science Ltd 363

They act through the benzodiazepines-GABA
receptor, where they inhibit neuronal activity by
increasing the chloride ion in¯ux into neurones.
This includes hyperpolarization of the nerve cell, a
condition that leads to decreased responsiveness to
incoming stimuli (17, 18).
Several problems are associated with the use of
benzodiazepines (BZDs) in GAD. About 25±30%of
all patients fail to respond, and tolerance and
dependence may occur. Some patients also experi-
ence impaired alertness while taking the drugs. In
addition, there are several reports that indicate
cognitive impairment induced by benzodiazepines
(19±25). The cessation of use of benzodiazepines
can induce a withdrawal syndrome, characterized
by psychological symptoms of anxiety, such as
apprehension and irritability. Physiological symp-
toms of anxiety include tremor and palpitation,
and perceptual disturbances include hypersensiv-
ity to light, sounds, touch or motion. Only one-
third of patients who have GAD seek psychiatric
treatment (19±25). Many patients go to general
practitioners, internists and cardiologists but they
also use herbal medicines like Passi¯ora.
Passion¯ower (Passi¯ora incarnata) is a woody,
hairy, climbing vine and is reputed to have seda-
tive/anxiolytic properties and has been used
widely as an ingredient of herbal remedies, chie¯y
in the form of a liquid tincture. The commission E
approved the internal use of passion¯ower for
nervous restlessness, and the British Herbal
Compendium indicates its use for sleep disorders,
restlessness, nervous stress and anxiety (26±29). In
our continuing study of traditional medicines with
neurotropic effects, we evaluated the use of this
plant for its anxiolytic effect in a double-blind,
randomized and parallel group trial, comparing it,
at a ®xed daily doses of 45 drops extract of Passi-
¯ora incarnata (Passipay
TM
, Iran Darouk), with
oxazepam 30 mg/day.
METHODS
Outpatients in group 1 received ®xed daily doses
of Passi¯ora extract 45 drops/day plus placebo
tablet (group 1), whereas those in group 2 received
oxazepam 30 mg/day plus Passi¯ora drop (group
2) for a period of 4 weeks. Thirty-six outpatients
(20 women and 16 men) aged between 19 and
47 years of age, who satis®ed the DSM IV (2) for a
diagnosis of GAD (duration of illness of 6 months)
and had a score of 14 or more on the Hamilton
Anxiety Rating Scale (HAM-A) were recruited.
Patients were excluded if screening showed a his-
tory of a serious suicide attempt or current acute
suicidal ideation, an unexpected recent panic attack
or full DSM IV panic disorder within the previous
6 months, a life-time diagnosis of DSM IV mania,
psychosis, paranoia or dementia, or if there was a
concurrent or recent diagnosis of substance abuse,
drug psychosis, obsessive-compulsive disorder,
hypomania or major depression. Pregnant and
lactating women were also excluded. Prior to the
study, the patients were free from all psychotropic
medication for a minimum of 7 days. After giving
informed consent, patients were randomly allo-
cated to the two treatment groups. Four subjects
dropped out of the trial due to non-compliance
(two from each group), leaving 32 subjects who met
the DSM IV criteria for GAD and completed the
trial. Patients were assessed by a psychiatrist at
baseline and 4, 7, 14, 21 and 28 days after the
medication started. The principal measure of the
outcome was the HAM-A score. The rater used
standardized instructions in the use of HAM-A.
The mean decrease in HAM-A score from baseline
was used as the main outcome measure of
response.
Statistical analysis
Repeated measures analysis of variance (
ANOVA
)
with a two-tailed post-hoc Tukey mean comparison
test was performed on the change in HAM-A
scores from baseline. To compare the outcome of
two groups in the same week, an unpaired two-
sided Student's t-test was used. Results are
presented as mean  SEM Differences were
considered signi®cant when P<0á05. To compare
the demographic data and the frequency of side-
effects between the two groups, Pearson Chi square
test was performed.
RESULTS
Ef®cacy
The mean  SEM scores for the two groups of
patients are shown in Fig. 1. There were no signi®-
cant differences between the two groups on day 0
Ó2001 Blackwell Science Ltd, Journal of Clinical Pharmacy and Therapeutics,26, 363±367
364 S. Akhondzadeh et al.

(baseline) on the HAM-A (t0á1563, d.f. 30,
P0á8769). A repeated measures
ANOVA
showed a
signi®cant effect of treatment on the GAD scores. In
both groups post-hoc comparisons of the baseline
GAD scores with the scores at week 4 by means of the
Tukey procedure revealed a signi®cant reduction
from baseline (P<0á001). However, post-hoc testing
revealed a signi®cant reduction from baseline from
day 4 in oxazepam group and from day 7 in the
Passi¯ora group. At days 4, 7 and 14 the mean
HAM-A scores for the Passi¯ora placebo group were
higher than the oxazepam group. The differences
between the two treatments were signi®cant at day 4
(t2á842, d.f. 30, P0á008). However, after day 4
the differences were no longer signi®cant.
Clinical complications and side-effects
A number of probable side-effects were studied
(Table 1). Although impairment of job performance
was observed more often in the oxazepam group,
there were no signi®cant differences between the
two treatments in terms of total side-effects pro®le
(P0á831, NS; Table 1).
DISCUSSION
Anxiety is a common reaction to a signi®cant life
stress. It is characterized by fear and apprehension
that may or may not be associated with a clearly
identi®able stimulus (30±32). BZDs are considered
as ®rst line in the pharmacotherapy of anxiety (33).
They were hailed as a breakthrough because they
have fewer of the drawbacks of prior sedative-
hypnotics and are effective in a range of disorders
(20). However, BZDs have been the subject of
debate that tends to centre on issues related to
overuse, misuse and abuse (15). The realization
that BZDs have a narrow safety margin between
Trial (Days)
-5 0 5 10 15 20 25 30
Hamilton Anxiety Score
0
5
10
15
20
25
ns
ns
**
ns
ns
ns
***
***
***
***
***
***
***
***
***
ns
Oxazepam Tablet + Placebo Drop
Passiflora Drop + Placebo Tablet
Fig. 1. Mean  SEM scores of two protocols on Hamilton
anxiety score. ns = non-signi®cant.
Table 1. Clinical complication and side-effects
Passi¯ora drop + placebo tablet Placebo drop + oxazepam tablet
Complications None Mild Moderate Severe
Severe,
Disabling None Mild Moderate Severe
Severe,
Disabling P
Dizziness 9 3 4 0 0 8 3 4 1 0 0á787
Drowsiness 10 6 0 0 0 9 5 2 0 0 0á342
Confusion 12 4 0 0 0 12 3 1 0 0 0á565
Slurred speech 16 0 0 0 0 16 0 0 0 0 None
Ataxia 14 1 1 0 0 12 3 1 0 0 0á562
Hypore¯exia 16 0 0 0 0 15 0 1 0 0 0á310
Respiratory
depression
16 0 0 0 0 13 1 2 0 0 0á191
Dyspenea 16 0 0 0 0 14 0 2 0 0 0á144
Allergic reaction 14 1 1 0 0 13 2 1 0 0 0á831
Aggression 16 0 0 0 0 16 0 0 0 0 None
Disinhibition 16 0 0 0 0 16 0 0 0 0 None
Impairment of job
performance
85 3 0 0 43 2 6 1 0á049*
*Signi®cantly more problems relating to impairment of job performance were encountered with patients on oxazepam.
Ó2001 Blackwell Science Ltd, Journal of Clinical Pharmacy and Therapeutics,26, 363±367
Passion¯ower in the treatment of general anxiety 365

the anxiolytic effect and the untoward side-effects
has prompted many researchers to evaluate new
compounds in the hope that safer alternative drugs
will be discovered (20). Among these alternative
drugs, medicinal plants such as Passi¯ora have a
special place. To the best of our knowledge, the
present study is the ®rst double-blind controlled
trial of Passi¯ora in the treatment of GAD (27±29).
Our main overall ®nding was that Passi¯ora extract
and oxazepam are effective in the treatment of
GAD. No signi®cant difference in ef®cacy was
observed between the two treatments. Neverthe-
less, in the oxazepam group, but not the Passi¯ora
group, signi®cant effects were observed by day 4.
This indicates a rapid onset of action for BZDs. On
the other hand, the substantially lower incidence of
impairment of job performance could be an
important advantage of Passi¯ora extract. However,
it should be emphasized that there was no signi®-
cant difference between the two treatments in
terms of the overall frequency of side-effects. We
conclude that Passi¯ora extract is potentially a
signi®cant improvement over benzodiazepines in
the management of GAD, particularly when drug-
induced impairment of job performance is to be
avoided. A large-scale trial is justi®ed.
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Passion¯ower in the treatment of general anxiety 367