Since it is quite difficult to evaluate the data from 17 electrode positions in the presence of 6 frequency ranges (a total of 102 parameters) the mathematical tool of discriminant analysis was used to describe the action of the active drug in comparison to placebo for the recording condition eyes open. This method allows time-dependent evaluation of all changes with respect to the pre-drug condition. As can be seen in Figure all placebo values (labelled PL05 to PL4)-representing circadian rhythm dependent changes-group together with the two first recordings from active drug at 0. 5 to 1. 5 hours after administration (labelled Neu05 and Neu15). Depiction of the result of the effect of verum at 3 and 4 hours after administration in comparison to the effect of other synthetic reference drugs or plant-derived preparations tested earlier revealed clear effects for the active drug (labelled Neu3 and Neu4 in Figure ). Closest neighbours in space (representing the result of the first to third discriminant function) but with a different colour due to the result of the fourth to sixth discriminant function are Nutrifin-relax and L-Theanine. Another neighbour not too far away with the same colour is fluoxetine.
Figure 8 Discriminant Analysis of EEG source density data. Depiction of the result of linear discriminant analysis of EEG source density data for all four recording periods after administration of verum and placebo. Result from the first three discriminant functions (more ...)
This kind of analysis of the experimental series revealed that the preparation NEURAPAS®
balance modulated electric brain activity already after a single acute administration in a statistically significant manner in comparison to placebo. Three and four hours after the administration of verum, basic activity has changed to a considerable degree in comparison to placebo according to this analysis. The pattern of changes approached that seen after reference drugs or preparations like Nutrifin-relax, a plant-derived preparation marketed to cope with stress [9
]. Furthermore, fluoxetine, a chemical reference drug with clinically proven anti-depressive effects [17
] is projected within the documentation of the result of discriminant analysis more close than to a preparation of St. John's wort tested earlier under identical conditions (results not shown). Comparison with a previous study shows that the projection of Neurapas®
balance is close to that of ginkgo/ginseng. This vicinity of the projection of gingko/ginseng effects on electric activity of the brain suggests beneficial effects [18
], since clinically significant improvement in memory loss, concentration, fatigue, anxiety and depressed mood associated with ginkgo/ginseng has been reported in the literature [19
]. This suggests that NEURAPAS®
balance might unify anti-depressive and relaxing features as claimed by the design of the combination according to known effects of single extracts from St. John's wort, valerian, and passion flower (see reference under "background ").
Spectral power of frequencies, which predominantly were attenuated during performance of mental work in more centro-parietal areas of the brain, remain low 3 and 4 hours after administration of the active preparation in comparison to placebo (which led to an increase of spectral power rather than the decrease observed in the pre-drug condition!). This suggests that mental processing ability is relatively preserved 3-4 hours after administration of NEURAPAS® balance compared to the placebo condition, where increases of alpha and beta spectral power were observed presumably due to circadian rhythms and/or fatigue. Even if there was no difference in psychometric results, some higher values were noted with respect to the concentration performance test (CPT), where highest performance was recorded during the 3rd and 4th hour after administration, perhaps related to the relative constancy of EEG spectra.
For St. John's wort maximum effects after single dose administration have been observed between 4 and 6 hours after administration [20
]. This is in line with the current results, where no effects could be recognized before the 3rd hour after administration. Better cognitive functioning in the presence of one of the ingredients (St. John's wort) has been claimed on the basis of EEG recording by [21
]. But, due to the combination of three plant-derived extracts the effects cannot be attributed to one of them. However, it is important to note, that at least no interference with cognitive performance could be seen as reported repeatedly during the use of other synthetic preparations like benzodiazepines as anti-anxiety drugs or serotonin-reuptake inhibitors for treatment of depression [1
]. With respect to the rationale of combining the three extracts a more potent neuroactivity of the triple combination compared to Hypericum alone and the additive effects of Passiflora and Valeriana suggested a synergy between constituents of these herbal extracts as derived from in vitro experiments with multielectrode neurochips [22
]. This study indicated that the ingredients of NEURAPAS®
balance act on GABA and serotonin receptors. Involvement of the GABAergic transmission has also been claimed for one of the constituents of the triple combination (Passiflora incarnate) by in vivo trials by [23
] as well as in vitro experiments [24
EEG frequencies reflect the activity of particular neurotransmitter activities as discovered earlier in preclinical studies using recording from depth electrodes in freely moving rats. From these earlier preclinical experiments is became clear that alpha1 waves seem to be related to serotonergic transmission [25
] and that alpha2 waves seem to be related to the activity of dopamine [26
]. Based on these preclinical results one might interpret the data obtained with respect to NEURAPAS®
balance in a sense that ingredients contained within this extract combination activate serotonergic and dopaminergic transmission. These two transmitters are well known to be involved in depression and anxiety. Synthetic drugs acting at receptors of these two neurotransmitters are prescribed first line to treat these psychiatric conditions, especially serotonin-reuptake inhibitors for the treatment of depression. Some decreased values of alpha1 and alpha2 waves during the recording condition "eyes open" are therefore in line with the view that NEURAPAS®
balance activates these transmitter systems and initiates its action already after the first intake.
Finally, the question of combining different extracts must be tackled. According to literature changes of the EEG in the presence of for example valerian roots extract could not be shown, even at dosages as high as 300 or 600 mg [27
]. Also with respect to St. John's wort dosages as high as 900 mg had to be given in order to see changes of electrical activity [20
]. Positive results with an extract from passion-flower were obtained with a dose of 425 mg native extract (to be published). Thus, the relatively low amounts of the single extracts combined within NEURAPAS®
balance speak in favour of not only additive but potentiating effects of single ingredients from St. John's wort herb, valerian root, and passion flower herb in order to produce the electric profile of effects on the human brain as described above.