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Pharmacological studies on the sedative and hypnotic effect of Kava kava and Passiflora extracts combination.

Abstract

Kava kava extract, Passiflora extract and a combination of both extracts, administered to mice, caused a significant decrease of the amphetamine-induced hypermotility and significant prolongation of sleeping phase induced by subcutaneous injection of barbiturates. Due to a synergism of both extracts, simultaneously administered the pharmacologically registered effect in both in vivo experiments was found to be superior over the sum of the single separately administered extracts.

[c] 2004 Published by Elsevier GmbH.

Keywords: Passiflora incarnata; Kava kava extracts; Sedative and hypnotic effects; Pharmacological synergism

**********

Introduction

Kava and Passiflora extracts have been used for a long time as pharmaceutical preparations with a sedative, hypnotic effect, and the synergism which is achieved with concomitant administration of the two plant drugs is known from the literature.

An extensive literature exists on the sedative effect of kava; the chemical (Smith, 1983; Smith et al., 1984; Klohs et al., 1959) and pharmacological (Haensel, 1959, 1964; Meyer, 1962, 1979; Kretzschmar and Meyer, 1969; Jamieson et al., 1989; Jamieson and Duffield, 1990a, b) properties of its components have been described.

Scientific studies on the effects of the active substances both on the central nervous system and on the peripheral nervous system have been carried out. In this connection, evidence of the sedative, anxiolytic, and muscle relaxant effect with mild antipsychotic effects has been provided (Jamieson et al., 1989; Meyer and Kretzschmar, 1969).

A direct effect on the muscular contractility and a local anesthetic effect have also been observed (Jamieson et al., 1989). A number of clinical studies have shown that the active substances of the kava plant promote physiological sleep, exert an anxiolytic effect, and lead to an improvement of psychovegetative and psychosomatic symptoms (Singh, 1983; Dona et al., 1986; Warnecke et al., 1986).

Recently, controlled clinical studies were carried out in which the therapeutic effect of kava on anxiety states was demonstrated (Kinzler et al., 1991). Clinical studies confirming the psychotherapeutic effect of kava (Volz and Kieser, 1997) and the available literature were reviewed in 1999 and in 2000; the clinical studies were carried out also in comparison with synthetically produced anxiolytic drugs. Additionally, the clinical efficacy of Kava extracts was also confirmed by a clinical study (Mittmann et al., 2000). There are also numerous scientific studies concerning extracts from Passiflora incarnata (Pittler and Ernst, 2000; Della Loggia et al., 1981; Sopranzi et al., 1990).

As early as 1981, Della Loggia et al., investigated the sedative effect of P. incarnata in comparison with other drugs and concluded from their studies that these P. incarnata extracts show potentiated anxiolytic properties in combination with other plant extracts (chamomile, valerian, hawthorn, Jamaican dogwood, belladonna, and henbane) with a less potent hypnotic component. The synergism of the pharmacological effect of passiflora was shown for combinations with other plant extracts.

Passiflora also showed a sedative, anxiolytic effect in rats without exerting negative effects on weight, rectally measured body temperature, pain sensitivity, motor coordination ability, and normal electocerebral activity (Della Loggia et al., 1981).

Recently, the sedative and anxiolytic effect of P. incarnata extracts and their most important efficacious principles was confirmed (Sopranzi et al., 1990).

For carrying out our experimental studies, we were provided with the following substances from Harras Pharma, Munich, Germany:

(1) Kava soft extract from root and rhizome (extract medium ethanol 96% v/v) standardized to 50 mg kavalactones HPLC in 100 mg extract/inert substance macrogol 3000 ~single dose 100 mg extract = 50 mg kavalactones.
 Method: HPLC determination (normal phase) against desmethoxy-yangonin,
 dihydrokawain, yangonin, kawain, dihydromethysticin, methysticin as
 reference substances (test specification no. 151) Company Gehrlicher
 GmbH.


(2) P. incarnata soft extract from herb 8:1 as native extract (extract medium ethanol 70% v/v) standardized to 4% m/m flavonoids HPLC ~single dose 250 mg native extract (corresponding to 2.0 g Herba Passiflorae).
 Method: HPLC determination (reversed phase) against apegenin as
 reference substance and calculated as apegenin.
 Test specification no. 381 Company Gehrlicher GmbH.
 Separation column: LiChrospher 100, RP-18.5 [micro]m; 250 X 4.6 mm.
 Flow: 1.2 ml/min; application value: 20[micro]l; detection: 340 nm.
 Eluent A: Acetonitril/water = 55/345 (m/m); pH = 2.8.
 Eluent B: Acetonitril/water = 120/180 (m/m); pH = 2.8.
 Gradient: 13.5 min long 100% A, from 13.5 to 16.5 min to 100% B,
 afterwards 7 min equilibration to 100% A.


(3) Combination of the kava and passiflora soft extracts (100 mg kava soft extract ~50 mg Kavalacton +250 mg passiflora soft extract = 350 mg combined soft extract) ~single dose 350 mg.

In the following sections, the extracts from kava, passiflora, and the combination will be referred to with the abbreviations K, P, and KP, respectively.

The following studies were carried out with these substances:

(A) Effect on amphetamine-induced hypermotility.

(B) Prolongation of the barbiturate-induced sleeping time.

All experimental studies described in the present report were carried out with the extracts provided by the company; analytic reports for batch numbers V1462000 (Kava), 7039 (Passiflora), and V1562000 (Kava and Passiflora) were available for these extracts. The analytic reports as well as portions of the extracts used were, as stipulated, stored in our Department.

Material and methods

General experimental conditions/good laboratory practice

The studies were carried out in accordance with the guidelines of good laboratory practice (GLP) applied in our laboratory.

All tests were supervised by a scientific employee with a doctorate; the staff members responsible for the tests were qualified for this job by their training and they were informed about the aim of the studies.

A person who did not belong to the study group monitored the correct application of the procedure and following of the experimental plan.

Until the time of the experiments, the experimental animals were kept in cages under a room temperature that was kept constant by an air-conditioning system. The animals were kept in Makrolon cages with automatic drinkers.

Each cage was provided with a label on which the experimental group was specified in a clearly readable way. Before the experiments were carried out, the cages and other equipment were thoroughly cleaned and the litter was changed at the required intervals.

Origin, room conditions, and feeding of the experimental animals

Origin

Male Swiss mice from the breeding colony of Charles River, Calco (Como, Italy) were used.

Feeding

The experimental animals were fed Altromin feed in the form of pellets and allowed to drink ad lib.

Housing

The animals were housed in cages containing four or five animals each in an air-conditioned environment (22[+ or -]2 [degrees]C) with a humidity of 60[+ or -]10% and artificial lighting with a light-dark cycle of 12:12 h.

Extracts

Extract: Kava kava e rhiz. et radice spissum standardized to 50 mg kavalactones HPLC in 100 mg extract/inert substance macrogol 3000 (Ph. Eur.) (desmethoxy-yangonin, dihydrokawain, yangonin, kawain, dihydromethysticin, and methysticin):
 Botanical name: Piper methysticum G. Forster.
 Extracted part of the plant: roots and rhizomes.
 Extracting medium: ethanol 96% v/v Ph. Eur./
 100 mg kava extract = 1 dose ~50 mg kavalactones.


Extract: Passiflorae e herb. spissum 8:1 (native extract) standardized to 4% m/m flavonoids HPLC:
 Botanical name: P. incarnata L.
 Extracted part of the plant: Herba.
 Extracting medium: Ethanol 70% v/v DAB 250 mg
 native extract = 1 dose corresponding 2 g Herba.


Extract: Kava/Passiflora spissum conc. (combination) consisting of 100 mg kava soft extract ~50 mg kavalactones HPLC and 250 mg passiflora soft extract 8:1 350 mg extract combination = 1 dose.

Pharmacological experiments

Results

Effect on amphetamine-induced hypermotility

A total of 40 mice with a body weight of 20-25 g were subdivided into four groups (10 animals/group). The extracts were administered at the following doses: kava extract (K) at a dose of 100 mg/kg (~50 mg kavalactones), passiflora extract (P) at a dose of 250 mg/kg, and the combination of the two extracts (KP) at a dose of 350 mg/kg (100 + 250 mg/kg). The above-mentioned doses were dissolved in macrogol 400 so that a quantity of liquid of 10 ml/kg was administered via a stomach tube. The same quantity of vehicle liquid was also administered via stomach tube to the control group. The amphetamine dose (amphetamine sulfate from Sigma Tau, Rome, Italy) of 5 mg/kg was administered subcutaneously in physiological saline to all animals 1 h after the stomach tube administration of the extracts and immediately before the measurement of spontaneous motility.

The activity of the animals was measured with an "activity cage" from U. Basile, Milan, Italy. The floor of these cages consists of metal bars that are insulated from one another; the movement of the animals triggers off impulses which are recorded by an electronic counter. The hypermotility produced by amphetamines was monitored over a period of 2 h; the activity was recorded at 30-min intervals.

The data for the individual animals are presented in Tables 1-4, and Fig. 1 shows the means. Based on the results, it can be seen that there was a clear increase in the mean motility in the control group. The groups treated exclusively with K or P showed a significant reduction of the motility compared with the control group. The decrease was far greater in the group simultaneously treated with both pharmaceutical preparations. When the percent decrease was calculated with reference to the control values (i.e. the values of the group that was treated only with amphetamine), the results showed a reduction of 47% in the group treated with K and 39% in the group treated with P 2 h after the injection of the amphetamine. The highest percentage for the reduction of hypermotility was achieved by the concomitant administration of both extracts.

In this case, the reduction was 83% compared to the control values.

The motility values of the groups treated with K, P, or KP were significantly different from those of the control group.

In our study, the results clearly showed the sedative characteristics of the stomach tube-administered kava extract and passiflora extract as well as the synergistic effect of both components for the tested dosage ratio.

Statistical methods

Effect on amphetamine-induced hypermotility

Comparison of motility values/step impulses (counts) at 30 min, 60 min, 90 min, 120 min in four groups (control, kava extract, passiflora extract, both kava + - passiflora extract).
 Method used: ANOVA-repeated measures.
 Four levels of within-subject factor (four times repeating).
 Four levels of between-subject factor (groups).
 Null hypothesis--equality of four groups was
 rejected with high significance p < 0,0005.
 Scheffe's method was used to compare control vs.
 kava, control vs. passiflora and control vs. kava + -
 passiflora in particular times (30, 60, 90, and
 120 min).
 Results in Tables 2-4.


Prolongation of the barbiturate-induced sleeping time

For this experiment, a total of 40 mice with an average weight of 20-25 g were used; they were subdivided into four groups (n = 10 animals/group).

Pentobarbital sodium dissolved in physiological saline was subcutaneously administered at a dose of 35 mg/kg body weight. Ninety minutes before the barbiturate injection, one group received only 10 ml/kg of the vehicle liquid (group C) via a stomach tube and the other three groups were administered the same quantity of vehicle liquid containing 100 mg/kg (corresponding to 50 mg kavalactones) of kava extract (group K), 250 mg/kg of passiflora extract (group P), or both extracts at the above-mentioned doses (combination product) (group K + P) in the same way. The sleep duration was measured based on the loss and regaining of the righting reflex. In Table 5, the individual data for all animals are presented, and Fig. 2 shows the means. It can be concluded from the results that the mean sleep duration of the control group (i.e. the animals that received no pharmacological treatment) was 17.8 min, while the sleep duration was prolonged by 45.5% and 53.4% in the groups which were administered a dose of 100 mg/kg kava extract or 250 mg/kg passiflora extract, respectively, via a stomach tube 90 min before the barbiturate injection. When both extracts were administered simultaneously, a prolongation of the sleep duration by 91.6% was achieved. This provides evidence of the hyperadditive synergism of the effects of the two extracts combined.

[FIGURE 1 OMITTED]

Sleep duration

Comparison of four groups:
 Method used: one-way ANOVA.
 Multiple comparisons--Sheffe.
 The null hypothesis--all groups are equal--is rejected with high
 significance p < 0.0005.

 Multiple comparisons (Sheffe):

C vs. K * p = 0.016
C vs. P * p = 0.018
C vs. KP *** p < 0.0005
K vs. P NS
K vs. KP * p = 0.013
P vs. KP * p = 0.012


[FIGURE 2 OMITTED]

Discussion

This conclusion is also confirmed in the relevant literature. For example, it should be recalled that it was already demonstrated in 1981 (Della Loggia et al.) that the passiflora extracts suitable for long-term therapy mentioned showed "specific anxiolytic effects" and the combination with other plant extracts led to great potentiation of the anxiolytic (at low doses) and sedative (at high doses) effects. According to Della Loggia et al., the therapeutic response for the combination with various plant extracts was "greater than for the individually administered monoextracts".

Also the publication of Williamson (2001) describes in a review synergistic effects--positive as well as negative--of phyto-extracts in relation to the single substances contained. Examples of hypericum, kava and gingko are interpreted. As a rule a stronger pharmacological effect of the active substance is observed in relation to the single substances.

Our study results with kava and passiflora confirm the results of Della Loggia et al., which provided evidence of a synergism of the extracts from passiflora and other plant extracts like chamomile, valerian, hawthorn, belladonna, etc., whereas our studies showed that there is a synergistic interaction between the extracts from passiflora and kava. These pharmacologically received results in our tests with passiflora and kava extracts have relevance for the clinical application as the synergistic effect of the combination stands also for a lower dosage of the single substances in the therapeutic application.

The quantitatively assessed effect in the pharmacological test shows an approximately 50% higher efficacy of the combination passiflora/kava in comparison with the single substances. In case of the barbiturate sleeping time the effect of the combination is as well approximately 50% higher compared with the single substances.
Table 1. Amphetamine-induced hypermotility in mice

Experimental Motility values/step impulses (counts) at
animals number 30 min 60 min 90 min

 1 2653 4373 8676
 2 3729 6736 4939
 3 4328 5111 7773
 4 3713 4127 9026
 5 1750 6185 10,112
 6 3480 3476 8344
 7 5437 4598 6381
 8 2348 6113 6134
 9 3363 5551 7350
10 3302 7934 9994
Mean 3410.3 5420.4 7872.9
Standard error [+ or -]327 [+ or -]428 [+ or -]536

Experimental Motility values/step impulses (counts) at
animals number 120 min

 1 12,115
 2 8436
 3 13,339
 4 13,447
 5 10,731
 6 8449
 7 9478
 8 8634
 9 9919
10 7990
Mean 10,253.8
Standard error [+ or -]653

Note: The control group (n = 10) was only treated with the vehicle
liquid macrogol 400 (10 ml/kg) administered via stomach tube 2 h before
subcutaneous administration of amphetamine sulfate (5 mg/kg).

Table 2. Amphetamine-induced hypermotility in mice

Experimental Motility values/step impulses (counts) at
animals number 30 min 60 min 90 min

 1 879 2449 4912
 2 1130 4730 5673
 3 1867 5429 3844
 4 3410 2870 3778
 5 2316 3112 4821
 6 2843 2836 5050
 7 1115 4331 5133
 8 1826 2896 6541
 9 1534 4887 2600
10 2813 4437 3002
Mean 1973.3 3797.7 4535.4
Standard error [+ or -]269 [+ or -]338 [+ or -]385
Compared with ** * ***
control group

Experimental Motility values/step impulses (counts) at
animals number 120 min

 1 5437
 2 6778
 3 8436
 4 5112
 5 5031
 6 4986
 7 4800
 8 7099
 9 5829
10 8134
Mean 6164.2
Standard error [+ or -]429
Compared with ***
control group

Note: The group (n = 10) was treated with 100 mg/kg kava extract
corresponding to 50 mg kavalactones in 10 ml/kg of the vehicle liquid
macrogol 400 administered via stomach tube 2 h before subcutaneous
administration of amphetamine sulfate (5 mg/kg).
*p < 0.05, **p < 0.01, and ***p < 0.001.

Table 3. Amphetamine-induced hypermotility in mice

Experimental Motility values/step impulses (counts) at
animals number 30 min 60 min 90 min

 1 2834 4733 8166
 2 3012 4422 7434
 3 1632 2748 6229
 4 1837 2637 5437
 5 1005 5035 3962
 6 2878 3713 4873
 7 3046 4117 8310
 8 2138 2054 6772
 9 2115 2733 3845
10 2691 3939 5046
Mean 2318.8 3613.1 6007.4
Standard error [+ or -]217 [+ or -]320 [+ or -]517
Compared with * ** *
control group

Experimental Motility values/step impulses (counts) at
animals number 120 min

 1 9120
 2 7839
 3 6224
 4 5736
 5 8330
 6 9211
 7 6347
 8 7004
 9 9122
10 6147
Mean 7508
Standard error [+ or -]436
Compared with **
control group

Note: The group (n = 10) was treated with 250 mg/kg passiflora solid
extract in 10 ml/kg of the vehicle liquid macrogol 400 administered via
stomach tube 2 h before subcutaneous administration of amphetamine
sulfate (5 mg/kg).
*p < 0.05, **p < 0.01.

Table 4. Amphetamine-induced hypermotility in mice

Experimental Motility values/step impulses (counts) at
animals number 30 min 60 min 90 min

 1 732 2122 3386
 2 847 1243 1829
 3 1233 1003 2831
 4 1627 940 1894
 5 639 1237 1637
 6 786 1115 2448
 7 999 2083 2826
 8 1050 1640 4093
 9 1335 1658 3031
10 1329 903 2314
Mean 1057.7 1394.4 2628.9
Standard error [+ or -]100 [+ or -]144 [+ or -]242
Compared with *** *** ***
control group

Experimental Motility values/step impulses (counts) at
animals number 120 min

 1 2284
 2 3126
 3 3237
 4 1870
 5 1925
 6 2627
 7 1044
 8 2200
 9 1521
10 1500
Mean 2133.4
Standard error [+ or -]225
Compared with ***
control group

Note: The group (n = 10) was treated with the combination kava extract
(100 mg/kg) corresponding to 50 mg kavalactones and passiflora native
extract (250 mg/kg) in 10 ml/kg of the vehicle liquid macrogol 400
administered via stomach tube 2 h before subcutaneous administration of
amphetamine sulfate (5 mg/kg).
***p < 0.001.

Table 5. Prolongation of the barbiturate-induced sleep in mice

Experimental
animals number C K P K + P

 1 16.7 28.4 23.9 41.6
 2 14.2 29.7 31.4 34.8
 3 15.4 26.4 28.4 24.1
 4 18.3 27.3 27.2 31.9
 5 27.2 27.9 25.8 42.5
 6 18.1 28.4 13.6 41.2
 7 17.9 25.3 28.4 44.7
 8 14.3 24.2 27.4 28.2
 9 20.4 18.7 24.3 24.3
10 15.3 22.4 27.1 28.1
Mean 17.8 25.9 25.8 34.1
SEM 1.2 1.1 1.5 2.5
Compared with * * ***
control group

Note: All groups of 10 experimental animals each received 35 mg/kg of
subcutaneously injected pentobarbital sodium (Sigma-Tau, Rome). One hour
before the injection, the groups were administered via a stomach tube 10
ml/kg of pure vehicle liquid (group C), vehicle liquid containing 100
mg/kg of kava extract (group K), vehicle liquid containing 250 mg/kg of
passiflora extract (group P), or vehicle liquid containing 100 mg/kg of
kava extract and 250 mg/kg of passiflora extract (group K + P). In the
table above, the individual values, means, and standard errors are
presented.
*p < 0.05 and ***p < 0.001.


Received 15 September 2003; accepted 5 March 2004

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Mittmann, V., Schmidt, M., Vrastyakova, J., 2000. Akut anxiolytische Wirksamkeit von Kava spissum Extrakt und Benzodiazepinen als Pramedikation bei chirurgischen Eingriffen, Ergebnisse einer randomisierten, referenzkontrollierten Studie. J. Pharmacol. Ther. 9, 99-108.

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Volz, H.P., Kieser, M., 1997. Kava kava extract WS 1490 versus placebo in anxiety disorders. A randomized, placebo-controlled, 25-week outpatient trial. Pharmacopsychiatry 30, 1-5.

Warnecke, G., Gerster, G., Jager, H., 1986. Anxiolyse mit einem Phyto-Tranquilizer in der Frauenheilkunde. Med. Welt 37, 1379-1383.

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A. Capasso (a), L. Sorrentino (b,*)

(a) 1st Department of Pharmaceutical Sciences, University of Salerno, Italy

(b) Department of Experimental Pharmacology, University of Napoli-Federico II, Via Domenico Montesano 45, 80131 Napoli, Italy

*Corresponding author. Fax: + 39 081 678 403.

E-mail address: sorrent@cds.unina.it (L. Sorrentino).
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Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Date:Jan 1, 2005
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