Kava in the Treatment of Generalized Anxiety Disorder: A Double-Blind, Randomized, Placebo-Controlled Study
Kava (Piper methysticum) is a plant-based medicine, which has been previously shown to reduce anxiety. To date, however, no placebo-controlled trial assessing kava in the treatment of generalized anxiety disorder (GAD) has been completed. A total of 75 participants with GAD and no comorbid mood disorder were enrolled in a 6-week double-blind trial of an aqueous extract of kava (120/240 mg of kavalactones per day depending on response) versus placebo. γ-Aminobutyric acid (GABA) and noradrenaline transporter polymorphisms were also analyzed as potential pharmacogenetic markers of response. Reduction in anxiety was measured using the Hamilton Anxiety Rating Scale (HAMA) as the primary outcome. Intention-to-treat analysis was performed on 58 participants who met inclusion criteria after an initial 1 week placebo run-in phase. Results revealed a significant reduction in anxiety for the kava group compared with the placebo group with a moderate effect size (P = 0.046, Cohen d = 0.62). Among participants with moderate to severe Diagnostic and Statistical Manual of Mental Disorders–diagnosed GAD, this effect was larger (P = 0.02; d = 0.82). At conclusion of the controlled phase, 26% of the kava group were classified as remitted (HAMA ≤ 7) compared with 6% of the placebo group (P = 0.04). Within the kava group, GABA transporter polymorphisms rs2601126 (P = 0.021) and rs2697153 (P = 0.046) were associated with HAMA reduction. Kava was well tolerated, and aside from more headaches reported in the kava group (P = 0.05), no other significant differences between groups occurred for any other adverse effects, nor for liver function tests. Standardized kava may be a moderately effective short-term option for the treatment of GAD. Furthermore, specific GABA transporter polymorphisms appear to potentially modify anxiolytic response to kava.
Extracts of kava (Piper methysticum) induce acute anxiolytic-like behavioral changes in mice.
Kava has been used for centuries by Pacific Islanders for its tranquilizing and sedative effects. Recent clinical trials suggest that kava has therapeutic value for the treatment of anxiety. Demonstration of kava's anxiolytic effects in animals under controlled conditions would provide additional support for its clinical potential as an anxiolytic and would facilitate investigation of its mechanism(s) of action.
This study systematically characterized the acute dosage-dependent anxiolytic and sedative effects of kava extract in well established quantitative murine behavioral assays and compared kava- and diazepam-induced behavioral changes.
Various doses of an ethanolic extract of kava root or diazepam were administered intraperitoneally to BALB/cByJ inbred mice. Behavioral changes were measured in the mirrored chamber avoidance assay and elevated plus-maze assay. Reduced latency to enter and increased time spent in a normally avoided environment operationally defined anxiolysis. Sedation was defined by a significant decrease in locomotor activity in a circular arena.
Kava extract produced statistically significant dose-dependent anxiolytic-like behavioral changes in both assays of anxiolysis. ED(50) values for kava-induced increases in time spent inside the mirrored chamber and on the open arms of the plus maze were 125 mg/kg and 88 mg/kg, respectively. Kava extract also caused a profound decrease in locomotor activity (ED(50) of 172 mg/kg). Flumazenil, a competitive benzodiazepine receptor antagonist, blocked both the anxiolytic and sedative effects of diazepam, but had no effect on kava's behavioral actions.
Kava extracts produce significant murine anxiolytic-like behavioral changes and sedation that are not mediated through the benzodiazepine binding site on the GABA(A) receptor complex.
St. John's Wort Versus Placebo in Social Phobia: Results From a Placebo-Controlled Pilot Study
Recognition of social anxiety disorder (social phobia) as a common and disabling condition has led to new advances in its pharmacotherapy. Limitations with selective seroton reuptake inhibitors (side effects) and behavior therapy (scarcity of trained therapists), coupled with the tendency for patients with the disorder to self-medicate with alternative treatments, have led to the interest in Saint John's wort (SJW) (Hypericum perforatum) for this disorder. Although the literature is mixed, SJW has demonstrated efficacy in several double-blind depression trials, and some open-label studies with anxiety disorders. There is pharmacokinetic evidence for the serotonergic, domaminergic, and GABAminergic activity of hypericum, all of which are implicated in social anxiety disorder. This study was designed to generate pilot data to examine the potential efficacy of SJW in generalized social anxiety disorder. Forty subjects were randomized to 12 weeks of treatment with a flexible dose (600-1800 mg) of SJW (n = 20) or placebo (n = 20). Subjects with comorbid depression (clinician HAMD > 16) were excluded. Results found no significant difference between mean change on the Liebowitz Social Anxiety Scale with SJW (11.4) and placebo (13.2), P = 0.27, effect size = −0.09. Post-hoc analyses found larger effects sizes associated with increased baseline severity, omitting patients with variable scores (±30%) during the first week, and use of self-report HAMD scores for exclusion. Results of the study fail to provide evidence for the efficacy of SJW in social phobia. The impact of methodologic improvements on signal detection, while suggestive of improvement, remains to be established.
Effects of a Standardized Bacopa monnieri Extract on Cognitive Performance, Anxiety, and Depression in the Elderly: A Randomized, Double-Blind, Placebo-Controlled Trial
Objectives: Study aims were to evaluate effects of Bacopa monnieri whole plant standardized dry extract on cognitive function and affect and its safety and tolerability in healthy elderly study participants.
Design: The study was a randomized, double-blind, placebo-controlled clinical trial with a placebo run-in of 6 weeks and a treatment period of 12 weeks.
Setting/location: Volunteers were recruited from the community to a clinic in Portland, Oregon by public notification.
Subjects: Fifty-four (54) participants, 65 or older (mean 73.5 years), without clinical signs of dementia, were recruited and randomized to Bacopa or placebo. Forty-eight (48) completed the study with 24 in each group.
Interventions: Standardized B. monnieri extract 300 mg/day or a similar placebo tablet orally for 12 weeks.
Outcome measures: The primary outcome variable was the delayed recall score from the Rey Auditory Verbal Learning Test (AVLT). Other cognitive measures were the Stroop Task assessing the ability to ignore irrelevant information, the Divided Attention Task (DAT), and the Wechsler Adult Intelligence Scale (WAIS) letter-digit test of immediate working memory. Affective measures were the State-Trait Anxiety Inventory, Center for Epidemiologic Studies Depression scale (CESD)-10 depression scale, and the Profile of Mood States. Vital signs were also monitored.
Results: Controlling for baseline cognitive deficit using the Blessed Orientation–Memory–Concentration test, Bacopa participants had enhanced AVLT delayed word recall memory scores relative to placebo. Stroop results were similarly significant, with the Bacopa group improving and the placebo group unchanged. CESD-10 depression scores, combined state plus trait anxiety scores, and heart rate decreased over time for the Bacopa group but increased for the placebo group. No effects were found on the DAT, WAIS digit task, mood, or blood pressure. The dose was well tolerated with few adverse events (Bacopa n = 9, placebo n = 10), primarily stomach upset.
Herbal Insomnia Medications that Target GABAergic Systems: A Review of the Psychopharmacological Evidence
Honokiol and magnolol are two major bioactive constituents of M. officinalis bark which proved to be efficient in sedative and hypnotic. Honokiol increased pentobarbital-induced sleep duration in a dose-dependent manner, and treatment with honokiol (20 or 50 μM) increased the [Cl-] concentration to 36.9 or 43.9 mM in primary cultured cerebellar neurons. Additional treatment of primary cultured cerebellar granule cells showed selective GABAA receptor α-subunit expression increase, on the other hand, chronic honokiol treatment did not affect GAD abundance.
Chronic Caffeine (8mg/kg) Alters the Density of Adenosine, Adrenergic , Cholinergic, GABA, and Serotonin Receptors and Calcium Channe ls in Mouse Brain
1. Chronic ingestion of caffeine by male NIH strain mice alters the density of a variety of central receptors.
2. The density of cortical A1 adenosine receptors is increased by 20%, while the density of striatal A2A adenosine receptors is unaltered.
3. The densities of cortical β1 and cerebellar β2 adrenergic receptors are reduced by ca. 25% , while the densities of cortical α1 and α2 adrenergic receptors are not significantly altered. Densities of striatal D1 and D2 dopaminergic receptors are unaltered. The densities of cortical 5 HT1 and 5 HT2 serotonergic receptors are increased by 26–30%. Densities of cortical muscarinic and nicotinic receptors are increased by 40–50%. The density of cortical benzodiazepine-binding sites associated with GABAA receptors is increased by 65%, and the affinity appears slightly decreased. The density of cortical MK-801 sites associated with NMDA-glutaminergic receptors appear unaltered.
4. The density of cortical nitrendipine-binding sites associated with calcium channels is increased by 18%.
5. The results indicate that chronic ingestion of caffeine equivalent to about 100 mg/kg/day in mice causes a wide range of biochemical alterations in the central nervous system.
Ginseng and ginkgo, inhibit GABAB and GABAA.
Interactions of ginsenosides with ligand-bindings of GABAA and GABAB receptors
1. Total saponin fraction decreased the affinity of specific [3H]muscimol binding without changes in Bmax. Ginsenoside Rb1 Rb2, Rc, Re, Rf and Rg1 inhibited the specific [3H]muscimol binding to the high-affinity site.
2. Total saponin fraction increased the affinity of specific [3H]flunitrazepam binding. Ginsenoside Re and Rf enhanced specific [3H]flunitrazepam binding.
3. Total saponin fraction decreased the affinity of specific [35S]TBPS binding without changes in Bmax. Ginsenosides did not affect specific or non-specific [35S]TBPS binding.
4. Total saponin fraction decreased the affinity of specific [3H]baclofen binding without changes in Bmax. Ginsenoside Rc inhibited specific [3H]baclofen binding.
Baclofen, an agonist at peripheral GABAB receptors, induces antinociception via activation of TEA-sensitive potassium channels
Crocus sativus L (Saffron).: A comprehensive review
Effect on sexual behavior
The aphrodisiac activities of C. sativus stigma aqueous extract and its constituents, safranal and crocin, were evaluated in male rats. The aqueous extract (80, 160, and 320 mg/kg body wt.), crocin (100, 200, and 400 mg/kg body wt.), safranal (0.1, 0.2, and 0.4 ml/kg), sildenafil (60 mg/kg body wt., as a positive control), and saline were administered intraperitoneally to male rats. Mounting frequency (MF), mount latency (ML), intromission latency (IL), and ejaculation latency (EL) were the factors evaluated during the sexual behavior study. Crocin, at all doses, and the extract, especially at doses 160 and 320 mg/kg body wt., increased MF, IF, and EF behaviors and reduced EL, IL, and ML parameters. Safranal did not show aphrodisiac effects. This study exhibited an aphrodisiac activity of saffron aqueous extract and its constituent crocin.[28]
Anxiolytic activity
This study was designed to investigate in rodents whether or not crocins possess anxiolytic properties. For this aim, the light\dark test was selected. Either crocins, at a dose which did not influence animals’ motor activity (50 mg/kg), or diazepam (1.5 mg/kg), increased the latency to enter the dark compartment and prolonged the time spent in the lit chamber in the rats. Conversely, lower doses of crocins (15-30 mg/kg) did not substantially modify animals’ behavior. The present results indicate that treatment with these active constituents of C. sativus L. induces anxiolytic-like effects in the rat.[29]
Relaxant property
To study the mechanism(s) of the relaxant effects of C. sativus (Iridaceae), the stimulatory effect of aqueous-ethanolic extracts of this plant and one of its constituent, safranal, was examined on β-adrenoreceptors in tracheal chains of guinea pigs. The β2-adrenergic stimulatory was tested by performing the cumulative concentration-response curves of isoprenaline-induced relaxation of pre-contracted isolated guinea pig tracheal chains. The studied solutions included two concentrations of aqueous ethanolic extracts from C. sativus (0.1 and 0.2 g%), safranal (1.25 and 2.5 μg), 10 nM propranalol, and saline. The study was done in two different conditions including non-incubated (group 1, n = 9) and incubated tissues with 1 μM chlorpheniramine (group 2, n = 6). The results showed clear leftward shifts in isoprenaline curves obtained in the presence of only higher concentration of the extract in group 1 and its both concentrations in group 2 compared with that of saline. The EC50 (the effective concentration of isoprenaline, causing 50% of maximum response) obtained in the presence of both concentrations of the extract (0.17 ± 0.06 and 0.12 ± 0.02) and safranal (0.22 ± 0.05 and 0.22 ± 0.05) in group 1 and only in the presence of two concentrations of the extract (1.16 ± 0.31 and 0.68 ± 0.21) in group two was significantly lower compared to saline. The maximum responses obtained in the presence of both concentrations of the extract and safranal in group 1 were significantly lower than that of saline. The results indicated a relatively potent stimulatory effect of the extract from C. sativus on β2-adrenoreceptors, which is partially due to its constituent, safranal. A possible inhibitory effect of the plant on histamine (H1) receptors was also suggested.[30]
Effect on depression
The efficacy of petal of C. sativus was assessed in the treatment of mild-to-moderate depression in a 6-week double-blind, placebo-controlled and randomized trial. Forty adult outpatients who met the Diagnostic and Statistical Manual (DSM) of Mental Disorders, fourth edition for major depression based on the structural clinical interview for DSM IV, participated in the trial. In this double-blind, placebo-controlled and randomized trial, patients were randomly assigned to receive capsule of petal of C. sativus 30 mg/day (b.d.) (Group 1) and capsule of placebo (b.d.) (Group 2) for a 6-week study. At 6 weeks, petal of C. sativus produced a significantly better outcome on Hamilton Depression Rating Scale than placebo (d.f. = 1, F = 16.87, P<0.001). There were no significant differences in the two groups in terms of observed side-effects. The results of this study indicate the efficacy of petal of C. sativus in the treatment of mild-to-moderate depression.[31] In further preliminary work, saffron was compared to the drug fluoxetine; it was found that the saffron performed as well as the drug in the treatment of depression.[13] In addition, in a recent pre-clinical study, it has been reported that petal of C. sativus, the part of this herb that is very cheap compared to stigma of C. sativus (saffron), has antidepressant effect.[11]
Effect on learning behavior and long-term potentiation
The saffron extract and two of its main ingredients, crocin and crocetin, improved memory and learning skills in ethanol-induced learning behavior impairments in mice and rats. Oral administration of saffron may be useful in the treatment of neurodegenerative disorders and related memory impairment.[8,32]
Assessment of cognitive function following magnesium therapy in the traumatically injured brain.
Many studies have examined the preclinical efficacy of Mg2+ therapy in models of traumatic brain injury. However, more of these studies have examined sensorimotor and motor performance than cognitive performance following injury. The present paper reviews the use of Mg2+ therapy to facilitate cognitive recovery in several models of cortical injury in the rodent. The first study examined the ability of daily injections of MgCl2 (1 or 2 mmol) to impair acquisition of a reference memory task in the Morris Water Maze. Additional studies examined the ability of MgCl2 to improve cognitive function following bilateral anterior medial cortex ablations, bilateral frontal cortex contusions, and unilateral frontal contusions. The results from these studies indicate that MgCl2 therapy is biologically active and readily crosses the blood-brain barrier because daily injections of MgCl2 impaired learning of a reference memory task in intact rats. Mg2+ therapy for brain injury revealed that administration of post-injury MgCl2 effectively improved recovery of cognitive deficits following injury. These results suggest that Mg2+ therapy is effective in facilitating cognitive recovery of function following brain injury; however, there are task and dose-dependent aspects to this recovery.
Exercise Holds Immediate Benefits for Affect and Cognition in Younger and Older Adults
The positive impact of physical activity on cognition during adulthood: a review of underlying mechanisms, evidence and recommendations.
Area and I came up with a few natural alpha blockers, which could help situational anxiety, similar to beta blockers:
http://www.longecity...e-8#entry744569
Edited by gamesguru, 23 September 2015 - 02:58 AM.
