Kava-Kava extract LI 150 is as effective as Opipramol and Buspirone in Generalised Anxiety Disorder--an 8-week randomized, double-blind multi-centre clinical trial in 129 out-patients.

OBJECTIVE: An 8-week randomized, reference-controlled, double-blind, multi-centre clinical trial investigated Kava-Kava LI 150 in Generalized Anxiety Disorder (GAD; ICD-10: F41.1). METHOD: 129 out-patients received either 400 mg Kava LI 150, 10 mg Buspirone or 100 mg Opipramol daily for 8 weeks. At week 9, subjects were seen to check for symptoms of withdrawal or relapse. Primary outcome measures comprised the HAMA scale and the proportion of responders at week 8. Secondary measures were the Boerner Anxiety Scale (BOEAS), SAS, CGI, a self-rating scale for well-being (Bf-S), a sleep questionnaire (SF-B), a quality-of-life questionnaire (AL) and global judgements by investigator and patients. RESULTS: In 127 patients (ITT) no significant differences could be observed regarding all efficacy and safety measures. About 75% of patients were classified as responders (50% reduction of HAMA score) in each treatment group, about 60% achieved full remission. CONCLUSION: Kava-Kava LI150 is well tolerated and as effective as Buspirone and Opipramol in the acute treatment of out-patients suffering from GAD.

St. John's wort (Hypericum perforatum)--is it safe during breastfeeding?

Both doctors and patients often treat postnatal depression with herbal preparations derived from St. John's wort. Because these preparations are available to patients as "natural" over-the-counter drugs for depression, they are popularly assumed to be safe. However, no systematic information exists regarding treatment of postnatal depression, infant's safety or pharmacokinetics of hypericum constituents in human breast milk or infant plasma. A mother with post-natal depression was admitted at our service. Her pharmacist had recommended taking a St. John's wort preparation three times a day (Jarsin 300, Lichtwer Pharma AG, Berlin, Germany). Four breast-milk samples (fore and hind milk) during an 18-hour period were analyzed to measure concentration of hypericin and hyperforin. Only hyperforin is excreted into breast milk at a low level, hyperforin and hypericin (two major active components) were below the lower limit of quantification (BLQ: below lower limit of quantification, LQ hypericin: 0.20 ng/ml, LQ hyperforin: 0.50 ng/ml) in this infant's plasma. No side effects were seen in the mother or infant. Before recommending St John's wort for the treatment of depression to women who breastfeed, long-term studies of outcome in infants are needed.

Acute and chronic actions of a dry methanolic extract of Hypericum perforatum and a hyperforin-rich extract on dopaminergic and serotonergic neurones in rat nucleus accumbens.

Dry hydroalcoholic extract of Hypericum perforatum L. is effective in the treatment of mild-to-moderate depression. Neither the mechanism of action nor the component or components of the extract responsible are known to date. In several in vitro and ex vivo models, the extract and hyperforin, one of its active components, cause changes similar to those of tricyclic antidepressants. Little is known about effects on a complex neuronal system relevant to antidepressant actions such as the mesolimbic system in the brain. In animal models of depression, the levels of dopamine were reduced in the nucleus accumbens, which is an important part of the mesolimbic system. These and other deficits were compensated by imipramine. We investigated the actions of the methanolic Hypericum extract LI 160 and a hyperforin-rich research extract in the shell region of the nucleus accumbens under in vivo conditions after acute administration, and after application repeated fourteen times. Both extracts induced an increase of dopamine (DA) and 5-hydroxytryptamine (5-HT) levels measured by in vivo microdialysis. The dose-response curve followed an inverse U-shape. Repeated application caused a rapid tolerance of DA but not of 5-HT neurones. Similar changes were observed after acute and repeated applications of imipramine. Several lines of evidence have suggested other active components in the Hypericum extract. The potency of hyperforin surpassed that of imipramine in the acute release of both DA and 5-HT by the nucleus accumbens. The effect of hyperforin correlated well with the inhibiting potency on high-affinity DA and 5-HT uptake. The missing effect of relatively high doses on DA and 5-HT levels as found in dose-response experiments may be explained by self-inhibition caused by the activation of autosomal receptors and by the inhibition by GABA. The inhibition of neuronal GABA transport occurs at somewhat higher concentrations of hyperforin. In conclusion, the findings demonstrate an imipramine-like effect of methanolic Hypericum extract LI 160 and of hyperforin on mesolimbic, dopaminergic and serotonergic neurones in acute and chronic experiments, which probably contributes to the antidepressant action of the medication. The methanolic Hypericum extract contains active compounds other than hyperforin.

Qualitative and quantitative olfactometric evaluation of different concentrations of ethanol peppermint oil solutions.

Selection of an adequate placebo is a major problem in clinical trials of Euminz(R) (10% peppermint oil/ethanol) which is used topically for the treatment of tension-type headache. This randomized, controlled, double-blind, cross-over study was performed to investigate whether there are qualitative differences between 10%, 1%, 0.5%, 0.1%, and 0% peppermint oil. Forty-one healthy subjects participated (age range 21-28 years); they rated both intensity, and hedonic tone of the stimuli. Verbal descriptions were combined to multiple response sets (MRS). In addition, the trigeminal impact of odorants was determined. Intensity ratings and MRS "menthol like" and "alcohol/solvent" changed with stimulus concentration. However, intensity had no significant effect on hedonics, trigeminal impact, or the number of descriptive items used. When MRS "menthol like" and "alcohol/solvent" were analysed after being weighted with intensity ratings, changes in relation to stimulus concentration were lost. Thus, the differences between the five concentrations of peppermint oil were--to their largest part--due to changes in stimulus intensity. Considering the large day-to-day variability of olfactory sensitivity the present data support the hypothesis that the odour quality of 10% peppermint oil cannot be discriminated from the odour of 0.1%, 0.5%, or 1% peppermint oil when tested on separate days.

Acute effects of LI 160 (extract of Hypericum perforatum, St John's wort) and two of its constituents on neuroendocrine responses in the rat.

Extracts of Hypericum perforatum (St John's wort), such as LI 160, which are effective antidepressants have several active constituents. Their mode of action in depression, however, is unclear. In the present investigation, we assessed the effect of equivalent doses of LI 160 and two of its components, hypericin and hyperforin on serotonin (5-HT) and dopamine (DA)-mediated neuroendocrine responses in the rat. LI 160, hypericin and hyperforin significantly and equivalently increased plasma corticosterone. This effect was blocked by ketanserin but not WAY-100635, suggesting mediation via 5-HT2 receptors. LI 160 also lowered plasma prolactin and prevented the increase in plasma prolactin following haloperidol administration. Hyperforin had a similar but somewhat less pronounced effect. We conclude that LI 160, hypericin and hyperforin all increase 5-HT-mediated corticosterone release while LI 160 enhances DA-mediated inhibition of prolactin release. Hyperforin may contribute to the facilitatory effect of LI 160 on DA function, but hypericin does not.

Effects of a methanolic extract and a hyperforin-enriched CO2 extract of St. John's Wort (Hypericum perforatum) on intracerebral field potentials in the freely moving rat (Tele-Stereo-EEG).

Two extracts of St. John's Wort (Hypericum perforatum) were investigated in the animal model "Tele-Stereo-EEG" which consisted of continuous recording of intracerebral field potentials in the freely moving rat. One was a CO2 extract for research purposes containing 30.14% hyperforin, a phloroglucine derivative known to occur within the reproductive parts of the plant, and lacking other major constituents like naphtodianthrones and flavonoids according to HPLC fingerprint. The other extract was the methanolic extract LI 160S (4.67% hyperforin). The dosage schedule was elaborated for the application of identical amounts of hyperforin in both extracts in each dosing group. Both extracts produced nearly identical patterns of electrical power changes during the first two hours of recording. These changes mainly consisted of reproducible power increases within the alpha1 band of the striatum. Comparison with earlier data obtained by identical protocols revealed that the early action was very similar to that following the application of serotonin reuptake inhibitors, thus matching biochemical in vitro data previously reported. These changes might be due to the presence of hyperforin. Only LI 160S developed a late action not seen with the CO2 extract, consisting in increases in delta activity. This late action of LI 160S matched data obtained by analysis of the action of NMDA-antagonists like MK 801 or memantine. Again, these results support previously reported biochemical findings of the interaction of hypericum extract with the glutamatergic system. In all probability, this action stems from substances only present in LI 160S, not in the CO2 extract. Which of the components contained within hypericum extracts are responsible for the clinical efficacy of St. John's wort in depression remains to be determined.

5-HT brain function in affective disorder: d,l-fenfluramine-induced hormone release and clinical outcome in long-term lithium/carbamazepine prophylaxis.

Prolactin (PRL) and Cortisol (CORT) responses to d,l-fenfluramine (FEN) challenge (60 mg) were examined in patients with affective disorders on two occasions under euthymic conditions: drug-free before admission to prophylactic treatment and after about 9 months of medication with lithium or carbamazepine. Response to treatment was assessed by a complex algorithm using continuous ratings in outpatient clinic over a period of 2 years. In general, treatment resulted in a delayed and diminished CORT release (n.s.); subgroup analysis revealed an attenuated CORT response (P < 0.05) in responders, whereas nonresponders showed no change in CORT secretion pattern except an enhanced CORT baseline value (P < 0.05). Cross-sectional comparison of responders with nonresponders under medication yielded a trend for greater CORT stimulation in nonresponders. This result was not affected by FEN/NorFEN or lithium/carbamazepine serum levels, baseline CORT values, age, sex, diagnostic distribution, number of appointments to the outpatient clinic or duration of medication at the time of FEN test session. Before onset of prophylactic medication responders and nonresponders could not be discriminated significantly regarding stimulated hormone release, probably due to the small sample size (n = 17). CORT response to FEN was increased in drugfree unipolar patients compared to bipolar (P < 0.05) and to schizoaffective patients (P < 0.1). In accordance with its well-documented presynaptic 5-HT-agonistic action lithium medication resulted in a significantly greater increase in CORT release than carbamazepine (P < 0.05). Evaluation of PRL stimulation showed patterns of secretion quite similar to those of CORT, without reaching statistical significance in most cases. Perhaps due to methodological differences in assessing treatment response, these data do not confirm former results, which supposed an enhanced 5-HT net activity in long-term prophylactic lithium treatment. Because of high interindividual variances of hormone parameters, the FEN-test procedure is not a useful tool for the prediction of therapeutical outcome in terms of clinical routine use. Relations of stimulated hormone response as a marker of central serotoninergic activity and clinical outcome are discussed.