Posted 31 January 2012 - 09:28 AM

SECTION 1 – WHAT YOU SHOULD NOT TAKE:

definitely

possibly

DEFINITELY TO BE AVOIDED:

1) GABA RECEPTOR AGONISTS:

STRONGLY

IMPORTANT NOTE: Please kindly note that I am NOT stating that GABA RECEPTOR AGONISTS have no valuable medicinal use, nor am I suggesting that they should NEVER be taken in any circumstance. The topic of this thread is TREATING ANXIETY SAFELY & EFFECTIVELY, and by 'ANXIETY' we are talking about ANXIETY-RELATED MEDICAL CONDITIONS (e.g. Generalised Anxiety Disorder (GAD), Panic Disorder etc.); and as such, treatment entails administration of whatever substance for prolonged periods, namely the medium to long term .

Any GABA RECEPTOR AGONIST (whether PHARMACEUTICAL or NUTRACEUTICAL) will induce down regulation of the GABA receptors when administered for prolonged periods (i.e. for the medium to long-term). Hence, administration of GABA RECEPTOR AGONISTS for prolonged periods is ill advised. This is exactly the same reason why administration of OPIOID RECEPTOR AGONISTS (e.g. Morphine, Codeine, Oxycodone etc.) for prolonged periods is NOT recommended.

Therefore, it is strongly recommended that GABA RECEPTOR AGONISTS are not used for treating ANXIETY.

GABA RECEPTOR AGONISTS do have useful safe application in circumstances where the usage is restricted to short-term use only.

Some substances which are a GABA RECEPTOR AGONIST also have a number of other useful physiological beneficial effects that you might wish to benefit from (e.g. ASHWAGANDHA); in such instances it is recommended that the substance be CYCLED ON AND OFF, such that each 'ON' period is limited to the short-term use only, and an appropriate 'OFF' washout time period is employed that allows status to fully return to baseline.

i) BENZODIAZEPINES: Alprazolam; Bretazenil; Bromazepam; Brotizolam; Chlordiazepoxide; Cinolazepam; Clonazepam; Clorazepate;

Clotiazepam; Cloxazolam; Delorazepam; Diazepam; Estazolam; Etizolam; Flunitrazepam; Flurazepam; Flutoprazepam; Halazepam; Ketazolam; Loprazolam; Lorazepam; Lormetazepam; Medazepam; Midazolam; Nimetazepam; Nitrazepam; Nordazepam; Oxazepam; Phenazepam; Pinazepam; Prazepam; Premazepam; Quazepam; Temazepam; Tetrazepam; Triazolam

ii) NONBENZODIAZEPINES: Abecarnil; Alpidem; Divaplon; Eszopiclone; Fasiplon; Gedocarnil; Indiplon; Lorediplon; Necopidem; Ocinaplon; Pagoclone; Panadiplon; Pazinaclone; Pipequaline; Saripidem; Suproclone; Suriclone; Taniplon; Zaleplon; Zolpidem;

Zopiclone

(Thank you to NUPI for mentioning these)

iii) VALERIAN (VALERIANA OFFICINALIS)

iv) KAVA KAVA (PIPER METHYSTICUM)

v) PHENIBUT



vi) PICAMILON



vii) GABA



viii) GOTU KOLA (CENTELLA ASIATICA)



ix) TAURINE



x) ASHWAGHANDHA (WITHANIA SOMNIFERA)

xi) CALIFORNIA POPPY (ESCHSCHOLZIA CALIFORNICA)

xii) SKULLCAP (SCUTELLARIA LATERIFLORA)

xiii) CHAMOMILE (MATRICARIA CHAMOMILLA)

xiv) ALCOHOL

xv) GHB / GBL

xvi) NEFIRACETAM

2) GABA REUPTAKE INHIBITORS:

will also induce down-regulation of the GABA RECEPTORS with prolonged usage, and hence it is recommended to avoid prolonged usage for the medium or long-term.

The following is a summary of some (but not all) GABA REUPTAKE INHIBITORS which by definition should be AVOIDED if seeking to treat or prevent ANXIETY related disorders:

i

) PASSION FLOWER (PASSIFLORA INCARNATA)

ii) TIAGABINE (BRAND NAME: GABITRIL)

3) CANNABIS

NOT

( Thanks goes to HOOTER for reminding me of this )

4) CAFFEINE

5) OPIOID RECEPTOR AGONISTS

( T hank you to NUPI for suggesting these )

STRONGLY

i) OPIUM ALKALOIDS: Morphine; Codeine

ii) SEMI-SYNTHETIC DERIVATIVES: Heroin (Diamorphine / Diacetylmorphine); Dihydrocodeine; Hydrocodone; Hydromorphone; Nicomorphine;

Oxycodone; Oxymorphone

iii) SYNTHETIC DERIVATIVES: Alfentanil; Allylprodine; Alphamethylfentanyl; Bezitramide; Buprenorphine; Butorphanol; Carfentanyl; Dextromoramide; Dextropropoxyphene; Dezocine; Difenoxin; Dihydroetorphine; Diphenoxylate; Dipipanone; Etorphine; Fentanyl; Ketobemidone; Levomethadyl Acetate (LAAM); Levomethorphan; Levorphanol; Methadone; MPPP; Nalbuphine; Ohmefentanyl; Pentazocine; PEPAP; Pethidine (meperidine); Phenazocine; Piritramide; Prodine; Propoxyphene; Remifentanil; Sufentanil

iv) OTHERS: Lefetamine, Meptazinol, Tilidine, Tramadol, Tapentadol

POSSIBLY TO BE AVOIDED:

6) BETA-ALANINE

7) LEMON BALM (MELISSA OFFICINALIS)

8) HOPS (HUMULUS LUPULUS)

9) NIACINAMIDE / NICOTINAMIDE

VALERIAN (VALERIANA OFFICINALIS):

Valerenic acid [from Valerian]

inhibits GABA(A) receptors :

Chun-Su Yuan, MD PhD

Sangeeta Mehendale, MD PhD

Yingping Xiao, PhD

Han H. Aung, MD

Jing-Tian Xie, MD and

Michael K. Ang-Lee, MD

*Department of Anesthesia & Critical Care,

Tang Center for Herbal Medicine Research, and

Committee on Clinical Pharmacology and Pharmacogenomics, Pritzker School of Medicine, University of Chicago, Chicago, Illinois

valerian acts via gamma-aminobutyric acid (GABA)ergic mechanisms. Previous studies showed binding of valerian extract to GABA receptors

,

A

50

A

Then we showed that valerian extract 3 mg/mL induced a 29.6% ± 5.1% inhibition with an IC 50 of 240 ± 18.7 μg/mL, whereas 100 μM valerenic acid induced a 22.2% ± 3.4% inhibition with an IC 50 of 23 ± 2.6 μM (both P < 0.01).

the pharmacological effects of valerian extract and valerenic acid are mediated through modulation of GABA A receptor

We also observed that the inhibitory activity of both valerian extract and valerenic acid was induced via GABA A

B

Previous studies showed the binding of valerian extract to GABA A receptors

A

The GABA agonistic activity of valerian and its positive modulation of GABA A receptors could partly explain valerian’s antianxiety and sedative effects.

The dose-dependent inhibition of discharge frequency in muscimol-sensitive neurons by valerian extract suggests a GABA A agonistic activity. This activity could be mediated either by direct receptor action or by increasing the availability of GABA. It has been shown that valerian extract, aqueous or hydroalcoholic, contained GABA and other amino acids that could displace labeled muscimol, suggesting that specific constituents of valerian extract can directly bind to GABA A receptors. The GABA content of valerian extract could also be responsible for the stimulated release and reuptake of GABA. This could be an indirect mechanism of GABA agonistic activity of valerian extract…

the pharmacological effects of valerian extract and valerenic acid are mediated through GABAergic activity. This is also supported by a case report in which valerian withdrawal mimicked an acute benzodiazepine withdrawal syndrome

KAVA KAVA (PIPER METHYSTICUM):

The pharmacological properties of kava are

binding to gamma-aminobutyric acid (GABA) type A receptors

,

In the past few years, about 35 cases of severe liver toxicity associated with kava intake have been reported in Europe and the US. However, a direct causal relationship with kava use has been difficult to establish in the majority of the cases, and there is insufficient evidence to implicate kava as the responsible agent. Nevertheless, until further research clarifies any causality, kava should be used with caution.

leaf and root extracts of the Hawaiian kava (Piper methysticum Forst.) cultivars, Mahakea, Nene, Purple Moi and PNG, were tested on binding affinities to CNS receptors including GABAA (GABA and benzodiazepine binding site),

The most potent binding inhibition was observed for leaf extracts to GABAA receptors (GABA binding site)

our investigation indicates that the GABAA ,

receptors might be involved in the pharmacological action of kava extracts .

GOTU KOLA (CENTELLA ASIATICA)

SEE ATTACHED FILE: "Ancient-Modern Concordance in Ayurvedic Plants" ; N.B. You will need to SCROLL DOWN to the bottom of this post to find the attached file .

TAURINE:

GABAA receptors were down regulated with chronic administration of taurine.

"We have discovered that taurine is a strong activator of what are known as GABA receptors

It seems that taurine shares these receptors."

brain.

"We found that taurine is extraordinarily active on this population of GABA receptors

in

says.

"It came as a bit of a surprise that the same receptor was used by both taurine and GABA. Nevertheless, finding taurine's receptor has been like discovering the 'missing link' in taurine biology."

ASHWAGHANDHA (WITHANIA SOMNIFERA):

Ashwagandha

showed high affinity for both GABAA and GABAB receptors.

These results show that mWS affects the neuronal activities by mediating the GABA(A) receptor, which suggests that WS contains an ingredient with possible GABAmimetic activity .

The results suggested that the anticonvulsant effect of W. somnifera against PTZ seizure threshold paradigm involved the GABAAergic modulation .

These results suggest that the W. somnifera extract contains an ingredient which has a GABA-mimetic activity .

CALIFORNIA POPPY ( ESCHSCHOLZIA CALIFORNICA)

appeared to possess an affinity for the benzodiazepine [GABAA] receptor: thus, flumazenil, an antagonist of these receptors, suppressed the sedative and anxiolytic effects of the extract .

SKULLCAP (SCUTELLARIA LATERIFLORA)

The identification and quantification of the flavonoid, baicalin in a 50% EtOH extract (40 mg/g) and its aglycone baicalein in a 95% EtOH extract (33 mg/g), as well as the amino acids GABA in H2O and EtOH extracts (approximately 1.6 mg/g)

These compounds may play a role in anxiolytic activity since baicalin and baicalein are known to bind to the benzodiazepine site of the GABAA receptor and since GABA is the main inhibitory neurotransmitter .

Benzodiazepines, for example, have been linked to muscle weakness, amnesia, headaches, vertigo, urinary retention, slurred speech and gastrointestinal disturbances. They may lead to tolerance and physical and psychological dependence, and are considered to be dangerous to use long–term (BNF, 2008)

One important study (Liao et al, 1998) indicated oroxylin A, baicalein and wogonin, which are flavonoids found in S. lateriflora, had weak affinities for the benzodiazepine site of GABAA receptors

In another study Hui et al (2000) tested the capacity of baicalin, baicalein, scutellarein and wogonin to bind to the benzodiazepine site of the GABAA receptor in homogenised rat brain. Affinity to the benzodiazepine site for scutellarein was moderate and weak for baicalin. Contrary to results of the earlier study (Liao et al, 1998), the binding affinities of wogonin and baicalein [to the benzodiazepine receptors] were strong. The authors suggested the discrepancy may be due to differences in species and assay models used (Hui et al, 2000). The ability of the skullcap flavonoids to bind to the benzodiazepine site of the GABAA receptor suggests an anxiolytic effect for S. lateriflora…

CHAMOMILE (MATRICARIA CHAMOMILLA)

short-term

Benzodiazepine-like compounds and GABA in flower heads of Matricaria chamomilla.

Apigenin, a component of Matricaria recutita [and Matricaria chamomilla ] flowers, is a central benzodiazepine receptors-ligand with anxiolytic effects.

The results reported in this paper demonstrate that apigenin is a ligand for the central benzodiazepine receptors exerting anxiolytic and slight sedative effects

50

50

50

Matricaria recutita (German chamomile) and Humulus lupulus (hops) showed significant inhibition of GAD activity (0.11-0.65mg/mL).

NEFIRACETAM

No affinity for the alpha 1-, alpha 2-, beta-, muscarinic, 5-hydroxytryptamine-, dopamine, adenosine-A1-, mu-opiate, gamma-aminobutyric acid (GABA) ( except for nefiracetam (GABAA) ), benzodiazepine and glutamate receptors has been found.

PASSION FLOWER (PASSIFLORA INCARNATA)

Planta Med.

Anxiolytic activity of a phytochemically characterized Passiflora incarnata extract is mediated via the GABAergic system .

Following oral administration, the extract exerted an anxiolytic effect that was comparable to diazepam

and exhibited a U-shaped dose-response curve .

This study is the first demonstration of the IN VIVO, GABA-mediated anxiolytic activity of an HPLC- characterized extract of Passiflora incarnata

Phytother Res.

Modulation of the γ-aminobutyric acid (GABA) system by Passiflora incarnata L.

The extract inhibited [(3) H]-GABA uptake

but had no effect on GABA release and GABA transaminase activity . Passiflora incarnata inhibited concentration dependently the binding

to GABA(A) -receptors and

to GABA(B) -receptors

Passiflora could be classified as an antagonist of the GABA(B) receptor. In contrast, the ethanol- and the benzodiazepine-site of the GABA(A) -receptor were not affected by this extract. In conclusion, the first evidence was shown that numerous pharmacological effects of Passiflora incarnata are mediated via modulation of the GABA system including affinity to GABA(A) and GABA(B) receptors, and effects on GABA uptake.

The active principles of

passionflower might increase the inhibitory activity of benzodiazepines binding to the GABA receptors ,

BETA-ALANINE

rotransmitter.

Beta-alanine is structurally intermediate between alpha-amino acid (glycine, glutamate) and gamma-amino acid (GABA) neurotransmitters.

In

excitability.

beta-Alanine has 5 recognized receptor sites:

glycine

sensitive);

GABA-A receptor; GABA-C receptor ;

and

neocortex,

unique beta-alaninergic neurons with no GABAergic properties remain unidentified, and it is impossible to discriminate between beta-alaninergic and GABAergic properties in the CNS .

Nevertheless,

LEMON BALM (MELISSA OFFICINALIS)

short-term

The methanol extract was identified as a potent in vitro inhibitor of rat brain GABA transaminase (GABA-T)

50

50

The aqueous extract of Melissa officinalis (lemon balm) exhibited the greatest inhibition of GABA-T activity (IC 50 = 0.35mg/mL).

HOPS (HUMULUS LUPULUS)

absolutely safe’

short-term

Recent in vitro experiments on sedative activity indicated activity on the melatonin receptor .

The data suggest that potential sleep-inducing effects of hops extract are possibly centrally mediated through activation of melatonin receptors .

Other in vitro and in vivo research points towards involvement of the GABA- A receptor.

2

Another study examined the effects of beer, hop oils, and fragrance components on the GABA- A response using the Xenopus oocyte expression system and an electrophysiological method. The 2 hops oils alpha-humulene and mycrene caused only a small potentiation of the GABA- A receptor response. However, these compounds did not work as agonists. More pronounced were the effects of fragrances, which caused a potentiation of the GABA- A receptor response.

Effects of

hop on ionotropic gamma-aminobutyric acid receptors.

extract of the beer, hop (Humulus lupulus L.) oil, and myrcenol potentiated the GABA(A) receptor response elicited by GABA .

50

50

50

Humulus lupulus

(hops) showed significant inhibition of GAD activity (0.11-0.65mg/mL).

NIACINAMIDE

STUDIES INDICATING THAT NIACINAMIDE IS NEUROTOXIC :

gamma-Aminobutyric acid (GABA) modulation of triazolam and nicotinamide binding to benzodiazepine (BDZ) receptors in vitro was compared with the neurotoxicity and anticonvulsant activity of these two drugs in vivo.

nicotinamide [niacinamide] exhibited neurotoxicity

nicotinamide [niacinamide] potentiates 3, 4-methylenedioxymethamphetamine-induced serotonin neurotoxicity .

the long-term 5-HT deficits induced by MDMA were potentiated by nicotinamide [niacinamide] in all the brain regions examined.

STUDIES INDICATING THAT NIACINAMIDE IS NOT (OR IS A VERY WEAK) GABA RECEPTOR AGONIST:

binding studies showed that nicotinamide

have only low affinities for the benzodiazepine binding site. These results suggest that while nicotinamide may exert some neuronal depressant and anxiolytic activity, its site of action appears not to be associated with the benzodiazepine receptor site .

It was shown that nicotinamide and NAD inhibit the specific binding of [3H]flunitrazepam to benzdiazepine receptors without causing a direct influence of gamma-aminobutyric acid (GABA) receptors.

STUDIES INDICATING THAT NIACINAMIDE IS A GABA RECEPTOR AGONIST:

Nicotinamide is a brain constituent with benzodiazepine-like actions .

Pharmacological effects of nicotinamide. Probable endogenous ligand of benzodiazepine receptors .

its benzodiazepine-like effects ,

Additional reasons for niacinamide’s effectiveness likely have to do with its benzodiazepine-like effects .

In a recent case report by this author, a review of the literature was undertaken to determine the biological mechanism for niacinamide’s anxiolytic effects.

Its therapeutic effects are probably not related to it acting as a ligand for the benzodiazepine receptor, although it acts centrally and might have a weak binding affinity for the benzodiazepine receptor .

Both the benzodiazepines and niacinamide exert similar anxiolytic effects through the modulation of neurotransmitters commonly unbalanced in anxiety.

Another biochemical reason for niacinamide’s anxiolytic effects might have to do with the vital role that it has upon the synthesis of serotonin.

Taking pharmacological doses of niacinamide (or any other form of vitamin B3) would increase the production of serotonin ,

Niacinamide’s therapeutic ability to increase serotonin production might explain why it was successful in reducing the anxiety symptoms

The final biochemical reason for niacinamide’s favourable effect might have to do with its ability to modulate the metabolismof blood lactate (lactic acid)…

The most common side effect with niacinamide is sedation,43 but dry mouth and nausea have been the most common side effects... There has been one case report linking large pharmacological doses of niacinamide (9 g per day) to hepatic [liver] toxicity.

The interaction of nicotinamide

with central benzodiazepine receptor antagonist Ro 15-1788 and GABA-ergic system antagonist bicuculline were studied

Like in diazepam, the anxiolytic effects of benzodiazepines and nicotinamide was prevented by bicuculline and Ro 15-1788 .

This study indicates that NIACINAMIDE is a GABA RECEPTOR AGONIST

TAPERING-DOWN OF GABA RECEPTOR AGONISTS:

strongly advised

do not quit cold turkey

equivalent

ONCE YOU HAVE WEANED YOURSELF DOWN AND HAVE STOPPED TAKING THE BENZOS YOU SHOULD AVOID ALL GABA RECEPTOR AGONISTS. PERIOD.

SECTION 2 - WHAT IS SAFE AND EFFECTIVE TO TAKE:

SUMMARY OF SAFE & EFFECTIVE ANXIOLYTICS:

IMPORTANT NOTE! Before personally trying any of the items contained within the following list you should take the time to read and throughly familiarize yourself with the respective item's possible SIDE EFFECTS, INTERACTIONS and CONTRAINDICATIONS; and also what is the recommended DOSAGE for you .

N.B. I have not listed all such information d ue to not wishing to overly clutter this posting (which is already longer than many medical texts).

The following is a list ( in no particular order ) of ANXIOLYTICS which are NOT GABA RECEPTOR AGONISTS and/or regarding which there is conclusive substantiated evidence supporting their safety and efficacy in treating ANXIETY:

1) GARUM ARMORICUM (brands: STABILIUM; ADAPTON)



2) MAGNESIUM



3) BACOPA MONNIERI

4) RHODIOLA ROSEA

5) RELORA (MAGNOLIA OFFICINALIS and PHELLODENDRON AMURENSE)

(Thank you to AMPA-OMEGA for mentioning this!)

6) THEANINE



7) LOW DOSE NALTREXONE (LDN)

AND POSSIBLY:

The following is a list of ANXIOLYTICS which are NOT GABA RECEPTOR AGONISTS and/or regarding which there is an indicative but not wholly conclusive substantiated evidence supporting both their SAFETY and EFFICACY in treating ANXIETY:

8) AFOBAZOLE

9) TIANEPTINE

10) ESCITALOPRAM

11)

PIRACETAM ( at 9.8 - 24g total daily dosage )

12) ANIRACETAM

13) PROPRANOLOL

14) CLONIDINE

(Thanks goes to STEVE_86 for mentioning this!)

15) INOSITOL (MYO-INOSITOL)

(Thank you to BRAINFOGGED for suggesting this!)

GARUM ARMORICUM

very

The mechanism of action of these micro polypeptides is to either act as precursors to or mimic ENDORPHINS and ENCEPHALINS.

very small

The Effectiveness of Garum Armoricum in Reducing Anxiety

The administration of Garum Armoricum resulted in a statistically significant difference in mean anxiety test scores.

The reduction in anxiety test scores of subjects taking Garum Armoricum was statistically significant during the second and third weeks. This effect continued through the washout week when neither Garum Armoricum nor placebo was administered. Reduction of anxiety test scores for subjects taking placebo were not statistically different from the initial scores.

Anxiolytic and antidepressant-like effects of Garum Armoricum, a blue ling fish protein autolysate

Messaoudi M

Bisson JF

The anxiolytic- and antidepressant-like effects of GARUM ARMORICUM, a protein autolysate from the blue ling fish, were studied

These results indicate the potential anxiolytic and antidepressant-like properties of GARUM ARMORICUM in the absence of any change in cerebral activation and dependence .

MAGNESIUM:

(SEE ATTACHED FILE: "Hippocampal NMDA receptors and anxiety - At the interface between cognition and emotion"; N.B. You will need to SCROLL DOWN to the bottom of this post to find the attached file )

and

MALATE

at least

BACOPA MONNIERI:

GABA(A) receptor subunits-GABA(Aalpha1), GABA(Aalpha5,) and GABA(Adelta)-was downregulated

Treatment with B. monnieri and bacoside A reversed these changes to near-control levels .

Treatment with B. monnieri and bacoside A prevents the occurrence of seizures thereby reducing the impairment of GABAergic activity ,

The degree of reversal by Bacopa was significant

The antiamnesic effects of Bacopa suggest likely a gamma-aminobutyric acid-benzodiazepine pathway possibly affecting long-term potentiation .

RHODIOLA ROSEA

induce

worsen

J Altern Complement Med.

A pilot study of Rhodiola rosea (Rhodax) for generalized anxiety disorder (GAD).

Bystritsky A

Kerwin L

Feusner JD

Rhodiola rosea is an herbal supplement that many in the general population in Russia and elsewhere in the world have used for decades to alleviate everyday anxiety ,

The goal of this pilot study was to evaluate whether R. rosea is effective in reducing symptoms of generalized anxiety disorder (GAD).

Significant improvement in GAD symptoms was found with R. rosea,

Panossian A

Wikman G

Sarris J

Rhodiola preparations exhibit adaptogenic effect including, neuroprotective, cardioprotectiv e, anti-fatigue, antidepressive, anxiolytic, nootropic, life-span increasing effects and CNS stimulating activity .

Encouraging results exist for the use of Rhodiola in mild to moderate depression, and generalized anxiety .

Lack of interaction with other drugs and adverse effects in the course of clinical trials make it potentially attractive for use as a safe medication. In conclusion, Rhodiola rosea has robust traditional and pharmacological evidence of use in fatigue, and emerging evidence supporting cognition and mood.

RELORA (MAGNOLIA OFFICINALIS and PHELLODENDRON AMURENSE)

MAGNOLIA OFFICINALIS and PHELLODENDRON AMURENSE, which provides safe and effective ANXOLYTIC effects via a CORTISOL REDUCTION mechanism of action.

I should mention that in my clinical practice, despite the brand's marketing information regarding RELORA, it does in fact appear to cause sedation in some (but not all) people which can be a 'deal-breaker' regards taking it for treating ANXIETY; however, there are many people who can take RELORA without any side effects whatsoever, whom find it a helpful adjunct in treating ANXIETY.

See the following:

Nutr J.

This study measured the effects of a proprietary blend of extracts of Magnolia officinalis and Phellodendron amurense (Relora) on anxiety, stress and sleep in healthy premenopausal women.

This pilot study indicates that Relora may offer some relief for premenopausal women experiencing mild transitory anxiety.

THEANINE:

L-theanine relieves

positive, activation, and

anxiety symptoms

an 8-week, randomized, double-blind, placebo-controlled, 2-center study .

L-theanine was found to be a safe and well-tolerated medication.

L-theanine augmentation

can ameliorate

positive, activation, and

anxiety symptoms

Further long-term studies of L-theanine are needed to substantiate the clinically significant benefits of L-theanine augmentation .

L-theanine increases brain serotonin, dopamine, GABA levels and has micromolar affinities for AMPA, Kainate and NMDA receptors. In addition has been shown to exert neuroprotective effects in animal models possibly through its antagonistic effects on group 1 metabotrophic glutamate receptors .

The purpose of the study was to investigate the anxiolytic effects of L-theanine and its potential interaction with the GABAA receptor

The data suggest that L-theanine does not produce anxiolysis by modulation of the GABAA receptor ;

Ingestion of the nonproteinic amino acid theanine (5-N-ethylglutamine) has been shown to increase oscillatory brain activity in the so-called alpha band (8-14 Hz)

This increase of attention-related anticipatory alpha over the right parieto-occipital scalp suggests that theanine may have a specific effect on the brain's attention circuitry. We conclude that theanine has clear psychoactive properties ,

AFOBAZOLE

XICOLOGY

Effects of Afobazole on the Content of Neurotransmitter Amino Acids

in the

EDITED FROM FULL TEXT:

The objective of this study was to investigate delayed effects of afobazole on the levels of neurotransmitter amino acids in brain structures…

GABA level was significantly decreased in the striatum

After afobazole administration, GABA level improved and reached the control values recorded

Afobazole administration resulted in restitution of striatal GABA content, which approached the control values; this should promote recovery of neuroprotective systems related to inhibitory influences…

Afobazole administration

resulted in more substantial increase in taurine level in the striatum. Agonistic interaction between afobazole and σ1-receptors, possibly underlies this phenomenon…

Thus, the increase in taurine level alongside with GABA can be regarded as components of recovery therapy…

Our findings led us to a conclusion that afobazole administered

in a dose of 10 mg/kg to the animals 40 min after modeling of global ischemia

restored the impaired balance of excitatory and inhibitory amino acids in the striatum, normalized their content to control values, and activates endogenous taurine-dependent neuroprotection system…

Anxiolytic agent afobazole

restores impaired balance of excitatory and inhibitory amino acids

normalizes their content to control levels, and activates endogenous taurine-dependent system of neuroprotection.

^ According to this study AFOBAZOLE interacts with the sigma-1 (s1), melatonin-1 (MT1), and melatonin-2 (MT2) receptors, and acts as a reversible monoamine oxidase A (MAO-A) inhibitor .

^ Reinforces AFOBAZOLE 's sigma-1 activity which appears to be its main mechanism of action .

^ This study shows (or says I mean) that AFOBAZOLE is an agonist at sigma-1 .

^ In addition to its anxiolytic effects, AFOBAZOLE has antidepressant effects comparable to amitriptyline in the rodent Porsolt and Nomura swim tests (whatever those are, I'm assuming they're similar to the forced swim test (FST)).

^ AFOBAZOLE increases BDNF expression in the hippocampus and reverses the deficits in BDNF levels induced by stress, further markers of antidepressant efficacy.

TIANEPTINE

TRICYCLIC ANTIDEPRESSANTS (TCAs)

The effects of tianeptine

on 35% CO2 provoked panic in panic disorder .

Schruers K

Griez E

Tianeptine is an antidepressant with 5-HT reuptake enhancing properties (i.e. the opposite pharmacological profile to that of SSRIs). Therefore, no effect would be expected in panic disorder. The aim of the present study was to compare the effect of tianeptine with that of paroxetine, a selective 5-HT reuptake inhibitor with demonstrated efficacy in panic disorder

Tianeptine, as well as paroxetine, showed a significant reduction in vulnerability to the 35% CO(2) panic challenge. In spite of their opposite influence on 5-HT uptake, both tianeptine and paroxetine appeared to reduce the reaction to the panic challenge. These results raise questions about the necessity of 5-HT uptake for the therapeutic efficacy of anti-panic drugs.

In summary, tianeptine is a well-described antidepressant with effective actions against stress-induced sequelae of the nervous system. It is as effective as SSRIs in treating depression, produces fewer adverse side effects and reduces anxious symptoms associated with depression without the need for concomitant anxiolytic therapy. It is therefore relevant to note that tianeptine ameliorates symptoms in people with post-traumatic stress disorder (PTSD )

in addition to its effectiveness as a treatment in mood disorders, it potentially has broader applications, as in the treatment of anxiety .

ESCITALOPRAM

IMPORTANT NOTE:

very much

a dosage of 5mg in most cases is effective in providing a significant ANXIOLYTIC ANTIDEPRESSANT therapeutic effect without side effects

Therefore, if you wish to try ESCITALOPRAM I would strongly recommend limiting the dosage to 5mg.

Effects of escitalopram on anxiety symptoms

Spadone C

Global analysis of three studies comparing citalopram and escitalopram with a placebo in depressive disorders allowed specific investigation of the activity of these molecules upon the anxiety

The results for the two active molecules demonstrate significant superiority in comparison with the placebo. Furthermore, in the case of escitalopram, this improvement appeared significant as of the first week of treatment (p<0.05); by the end of the second week of treatment, the degree of significance was even more pronounced (p<0.001). The tolerability profile of these two active substances was very good. These studies thus demonstrate the efficacy of escitalopram against anxiety symptoms

Efficacy and tolerability of escitalopram in anxiety disorders: a review.

Escitalopram is the most selective SSRI available. Beyond its well-established efficacy in depression with or without anxiety, preclinical studies have demonstrated that escitalopram has a broad spectrum of anxiolytic activity.

This review focuses on the therapeutic use and the tolerability issues of escitalopram in the treatment of adult patients with panic disorder, generalized anxiety disorder (GAD), social anxiety disorder, and obsessive-compulsive disorder (OCD),

On the whole, numerous clinical data indicate that escitalopram, 10-20 mg/d, is an effective and well-tolerated first-line treatment option for the management of panic disorder, GAD, social anxiety and OCD.

Escitalopram for persistent symptoms of generalized anxiety disorder

after CBT: a pilot study.

Schneier FR

,

Belzer KD

,

Kishon R

,

Amsel L

,

Simpson HB

.

This study explored acceptability and efficacy of escitalopram for persons with persistent GAD symptoms

During escitalopram treatment, patients evidenced trends toward further improvement in GAD, depression, and quality of life .

Escitalopram may benefit GAD patients

Hum Psychopharmacol.

How long should a trial of escitalopram treatment be in patients with major depressive disorder, generalised anxiety disorder or social anxiety disorder?

An exploration of the randomised controlled trial database.

Baldwin DS

,

Stein DJ

,

Dolberg OT

,

Bandelow B

.

The pattern of response in these RCTs suggests that in patients with MDD, GAD or SAD in wider clinical practice, a [treatment] period of at least 4 weeks [with Escitalopram] is worthwhile before considering further intervention.

PROPRANOLOL

POSITIVE STUDIES:

Biochem Pharmacol.

Increased activity of the GABAergic system

after chronic propranolol treatment

Prolonged administration of propranolol increased GABA content, synthesis and turnover rate in the hypothalamus and the pons-medulla .

Our results indicate that propranolol increases GABAergic system activity. Therefore, we conclude that down-regulation of the GABAergic system in hypertension may be compensated by the regulatory action of propranolol.

Liebowitz MR

New uses are still being discovered for a number of psychotropic agents that have been available for some time.

the use of propranolol for anxiety disorders and for uncontrollable violent outbursts ;

Van Winter JT

Stickler GB

Imipramine hydrochloride, propranolol hydrochloride, phenelzine sulfate, and alprazolam are often useful in the treatment of panic attacks ,

Propranolol did not affect the drop-out rate or the incidence of withdrawal symptoms but significantly reduced their severity in patients completing the study .

Compr Psychiatry.

Imipramine versus propranolol for the treatment of panic attacks: a pilot study .

Munjack DJ

Rebal R

Shaner R

Staples F

Braun R

Leonard M

Thirty-eight patients agreed to participate in a preliminary crossover trial comparing imipramine to propranolol for the treatment of panic disorder and agoraphobia with panic attacks .

Approximately half of the patients lost their panic attacks completely, both on imipramine and propranolol .

BOTH POSITIVE & NEGATIVE STUDIES:

Heiser JF

Defrancisco D

The authors report on the effects of propranolol, a beta-adrenergic blocking agent, on 10 patients with pathological panic states. Propranolol was effective in treating acute pathological panic, but modest doses of the drug administered for brief periods of time did not alleviate chronic panic attacks associated with agoraphobia. The drug suppressed panic associated with depressive syndromes but did not affect the depression and had no clear effect on anticipatory anxiety .

NEGATIVE STUDIES:

Panic attacks and phobic symptoms responded to diazepam, but not to propranolol .

Munjack DJ

Crocker B

Cabe D

Brown R

Usigli R

Zulueta A

McManus M

McDowell D

Palmer R

Leonard M

Fifty-five patients completed a 5-week double-blind study comparing alprazolam, propranolol, and placebo in the treatment of panic disorder and agoraphobia with panic attacks .

The results generally support the efficacy of alprazolam, but not propranolol, in the treatment of panic disorder and agoraphobia with panic attacks .

INOSITOL (MYO-INOSITOL)

ANXIOGENIC

Therefore, taking into consideration all of the above information, I have added INOSITOL to the ‘ POSSIBLY SAFE & EFFECTIVE TO TAKE’ LIST for treating ANXIETY.

Unlike most antidepressant drugs, Inositol [Myo-Inositol] does not have a clear target in the synapse and was not demonstrated to alter monoamine levels in the brain.

The present data indicates that the antidepressant effect of Inositol [Myo-Inositol] may involve 5-HT(2) receptors .

Myo-inositol reduces serotonin (5-HT2) receptor

desensitization .

Myo-inositol also eliminated 5-HT induced heterologous desensitization

High dose mI [Myo-Inositol] has also been shown to be clinically effective in the treatment of obsessive-compulsive disorder, as well as panic and depression, although its mechanism of action remains elusive.

mI [Myo-Inositol] reduces 5HT2A-R function

In addition mI [Myo-Inositol] ,

[b] also reduces mAChR function. [/b]

The data provide novel information on understanding the mechanism of action of mI [Myo-Inositol] in depression and related anxiety disorders

[b] Controlled trials of inositol [Myo-Inositol] [/b] [b]in psychiatry.[/b]

[b] twenty-one patients with panic disorder with or without agoraphobia completed a double-blind, placebo-controlled, four week, random-assignment crossover treatment trial of Inositol [Myo-Inositol] 12 g per day. [/b] [b] Frequency and severity of panic attacks and severity of agoraphobia declined significantly with Inositol [Myo-Inositol] compared to placebo. [/b] [b] Side-effects were minimal. [/b]

[b] Inositol [Myo-Inositol] is reported to reverse desensitization of serotonin receptors [/b], [b] thirteen patients with OCD completed a double-blind controlled crossover trial of 18 g Inositol [Myo-Inositol] or placebo for six weeks each. Inositol [Myo-Inositol] significantly reduced scores of OCD symptoms compared with placebo. [/b]

[b] We studied oral Inositol [Myo-Inositol] in children with ADDH [Attention Deficit Disorder with Hyperactivity] in a double-blind, crossover, placebo-controlled manner. [/b]

[b] Results show a trend for aggravation of the syndrome with myo-inositol as compared to placebo. [/b]

[b] These results suggest that Inositol [Myo-Inositol] has therapeutic effects in the spectrum of illness responsive to serotonin selective re-uptake inhibitors, including depression, panic and OCD, and is not beneficial in schizophrenia, Alzheimer's, ADDH [Attention Deficit Disorder with Hyperactivity], autism or ECT-induced cognitive impairment. [/b]

[b] Inositol [Myo-Inositol] treatment of obsessive-compulsive disorder. [/b]

[b] 18 g/day of inositol [Myo-Inositol] [/b]

[b] The authors conclude that inositol [Myo-Inositol] is effective in depression, panic, and obsessive-compulsive disorder [/b]

[b] Double-blind, placebo-controlled, crossover trial of Inositol [Myo-Inositol] treatment for panic disorder. [/b]

[b] The frequency and severity of panic attacks and the severity of agoraphobia declined significantly more after Inositol [Myo-Inositol] than after placebo administration. Side effects were minimal. [/b]

[b] Double-blind, controlled, crossover trial of inositol [/b][b] [Myo-Inositol] [/b][b] versus fluvoxamine for the treatment of panic disorder. [/b]

[b] patients completed 1 month of inositol [/b][b] [Myo-Inositol] [/b][b] up to 18 g/day [/b]

[b] In the first month, inositol [/b][b] [Myo-Inositol] [/b][b] reduced the number of panic attacks per week (mean and SD) by 4.0 (2) [/b]

[b] Inositol [/b][b] [Myo-Inositol] [/b][b] treatment of post-traumatic stress disorder. [/b]

[b] Several antidepressants and antipanic medications were reported to have some effect on post-traumatic stress disorder (PTSD; Katz et al., 1995). We therefore carried out a study of Inositol [Myo-Inositol] in PTSD. [/b]

[b] No significant difference was found between Inositol [Myo-Inositol] and placebo for the improvement score (difference between baseline and four weeks) mean and S.D. for the overall IES score [/b]

[b] for the avoidance subscale [/b]

[b] or for the intrusion subscale [/b]

[b] we did not find any significant differences between the improvement score for Inositol [Myo-Inositol] and placebo on the Hamilton Depression Scale [/b]

[b] or for the Hamilton Anxiety Scale [/b]

[b] For the five patients at the Beer-Sheva clinic we found a significant difference on the depression subscale of the SCL-90 [/b]

[b] but no difference on the anxiety subscale [/b]

[b] This preliminary double-blind crossover study showed no effect of Inositol [Myo-Inositol] on PTSD core symptoms [/b]

[b] The results from the present study are in line with several other studies that did not find any effect of pharmacological treatment on intrusion and avoidance in PTSD [/b]

[b] Myo-inositol [/b][b] has no beneficial effect on premenstrual dysphoric disorder. [/b]

[b] No beneficial effect was demonstrated for inositol [/b][b] [Myo-Inositol] [/b][b] over placebo. [/b]

[b]The ABOVE study indicates that MYO-INOSITOL is INEFFECTIVE in treating PREMENSTRUAL DYSPHORIC DISORDER (PMDD); whereas the BELOW study indicates that MYO-INOSITOL is EFFECTIVE in treating PREMENSTRUAL DYSPHORIC DISORDER (PMDD); hence, there currently is conflicting evidence regards MYO-INOSITOL’s efficacy in treating PMDD.[/b]

[b] Myo-inositol [/b][b] in the treatment of premenstrual dysphoric disorder. [/b]

[b] Several studies have proposed a selective serotonin reuptake inhibitor-like role for myo-inositol, likely due to the fact that myo-inositol is the second messenger of serotonin [/b].

[b] Our results showed a significant improvement [/b]

[b] we were able to clearly prove the efficacy of myo-inositol in PMDD [premenstrual dysphoric disorder]. [/b]

[b] The anxiolytic effect of chronic inositol [/b][b] [Myo-Inositol] [/b][b] depends on the baseline level of anxiety. [/b]

[b] Clinical trials indicate that inositol [/b][b] [Myo-Inositol] [/b][b] may be effective in the treatment of patients with depression, panic disorder and obsessive compulsive disorder (OCD) [/b]

[b] This spectrum of clinical action parallels that of serotonin selective reuptake inhibitors (SSRIs), but inositol [/b][b] [Myo-Inositol] [/b][b] is a precursor in the phosphatidylinositol cycle, a second messenger system distal to the receptor for 5HT-2. [/b]

[b] The reduction in anxiety-like behaviors appears to be related to baseline levels [/b]

[b] Clinical controlled trials of inositol [/b][b] [Myo-Inositol] [/b][b] in patients with depression, panic disorder, and OCD were small, and positive psychoactive effects in animals clearly strengthen the case for further clinical trials and potential for general therapeutic use in humans [/b].

[b] The overall improvement in scores on the Hamilton Depression Rating Scale was significantly greater for inositol [/b][b] [Myo-Inositol] [/b][b] than for placebo at week 4. No changes were noted in hematology or in kidney or liver function. [/b]

[b] Although inositol [/b][b] [Myo-Inositol] [/b] [b] had a significant antidepressant effect in this study, replication is crucial. [/b]

[b] Four trials were identified, with a total of 141 participants. These were short term trials of double-blind design. The trials did not show clear evidence of a therapeutic benefit [/b],

[b] It is currently unclear whether or not inositol [/b][b] [Myo-Inositol] [/b][b] is of benefit in the treatment of depression. [/b]

[b] Unlike most antidepressant drugs, inositol [/b][b] [Myo-Inositol] [/b] [b] does not have a clear target in the synapse and was not demonstrated to alter monoamine levels in the brain. [/b]

[b] The present data indicates that the antidepressant effect of inositol [/b][b] [Myo-Inositol] [/b][b] may involve 5-HT(2) receptors. It is thus possible that the effects of reuptake antidepressant drugs and the effects of inositol [/b][b] [Myo-Inositol] [/b] [b] may have a common final pathway. [/b]

Int Clin Psychopharmacol 2000 Jul;15(4):244.

[b] Ten OCD patients who had failed to respond to current and previous trials of serotonin reuptake inhibitors participated in open-label trial of inositol [Myo-Inositol] (18 gm/day) [corrected] augmentation for 6 weeks. [/b]

[b] The majority of patients (n = 7) did not respond to treatment with inositol [Myo-Inositol] augmentation [/b]

[b] Unfortunately, inositol [Myo-Inositol] augmentation of a SRI did not lead to significant improvement in the majority of such cases. [/b]

Since treating ANXIETY and/or BENZODIAZEPINE WITHDRAWAL seems to be a reoccurring topic I thought it best to post this as a new topic, such that it can be linked to from other threads or read in its own right.Because this is going to comprise quite a bit of information I have done my best to organize matters, starting with WHAT YOU SHOULD NOT TAKE and then leading onto WHAT IS SAFE AND EFFECTIVE TO TAKEadvise that you AVOID any and all things where the mechanism of action is that of GABA RECEPTOR AGONISM; which induce down-regulation of the GABA receptors leading to TOLERANCE as well as REBOUND AND WITHDRAWAL upon their cessation of prolonged use.The following is a summary of some (but not all) GABA RECEPTOR AGONISTS which by definition should be AVOIDED if seeking to treat or prevent ANXIETY related disorders:The NONBENZODIAZEPINES (a.k.a. BENZODIAZEPINE-LIKE DRUGS) possess similar pharmacological effects to the BENZODIAZEPINES, in spite of having dissimilar organic chemical structures.NONBENZODIAZEPINES, like the BENZODIAZEPINES, are GABA RECEPTOR AGONISTS; and hence should also be AVOIDED if seeking to treat or prevent ANXIETY related disorders.GABA REUPTAKE INHIBITORSThe combination of THC and other MIXED CANNABINOIDS contained within CANNABIS stimulates a short-term spiking of GABA, but is followed by a subsequent LOWERING OF OVERALL GABA LEVEL; and hence overtime can CAUSE or EXACERBATE ANXIETY.There is some interesting recent research (and a growing number of annecdotal user reports) however that has indicated that PURE CANNABIDIOL might possibly be an effective ANXIOLYTIC, whereas the THC and/or some of the other MIXED CANNABINOIDS may be the cause of the long-term reduction in overall GABA levels, which can be avoided by ensuring that only the PURE CANNABIDIOL is administeredInhibits GABA production.advise that you also AVOID any and all things where the mechanism of action is that of OPIOID RECEPTOR AGONISM; which induce down-regulation of the OPIOID receptors leading to TOLERANCE as well as REBOUND AND WITHDRAWAL upon their cessation of prolonged use.The following is a summary of some (but not all) OPIOID RECEPTOR AGONISTS which by definition should be AVOIDED if seeking to treat or prevent ANXIETY related disorders:SEE THE FOLLOWING:Khom S, Baburin I, Timin E, Hohaus A, Trauner G, Kopp B, Hering S.Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.Valerian is a commonly used herbal medicinal product for the treatment of anxiety and insomnia. Here we report the stimulation of chloride currents through GABA(A) receptors (I(GABA)) by valerenic acid (VA), a constituent of Valerian. To analyse the molecular basis of VA action, we expressed GABA(A) receptors with 13 different subunit compositions in Xenopus oocytes and measured I(GABA) using the two-microelectrode voltage-clamp technique. We report a subtype-dependent stimulation of I(GABA) by VA. Only channels incorporating beta(2) or beta(3) subunits were stimulated by VA. Replacing beta(2/3) by beta(1) drastically reduced the sensitivity of the resulting GABA(A) channels. The stimulatory effect of VA on alpha(1)beta(2) receptors was substantially reduced by the point mutation beta(2N265S) (known to inhibit loreclezole action). Mutating the corresponding residue of beta(1) (beta(1S290N)) induced VA sensitivity in alpha(1)beta(1S290N) comparable to alpha(1)beta(2) receptors. Modulation of I(GABA) was not significantly dependent on incorporation of alpha(1), alpha(2), alpha(3) or alpha(5) subunits. VA displayed a significantly lower efficiency on channels incorporating alpha(4) subunits. I(GABA) modulation by VA was not gamma subunit dependent and not inhibited by flumazenil (1 microM). VA shifted the GABA concentration-effect curve towards lower GABA concentrations and elicited substantial currents through GABA(A) channels at > or = 30 microM. At higher concentrations (> or = 100 microM), VA and acetoxy-VA inhibit I(GABA). A possible open channel block mechanism is discussed. In summary, VA was identified as a subunit specific allosteric modulator of GABA(A) receptors that is likely to interact with the loreclezole binding pocket.PMID:17585957------------------------------------------------------------------------------------------------------------------------Author AffiliationsValerian is a medicinal herb that produces anxiolytic and sedative effects. It was suggested thatbut the functional effect of the binding has not been demonstrated. In this study we evaluated the GABAergic effect of valerian extract and one of its major constituents, valerenic acid, on brainstem neuronal activity in an in vitro neonatal rat brainstem preparation. We first observed that muscimol, a GABAreceptor agonist, decreased the firing rate in most brainstem neurons in a concentration-related fashion; 30 μM produced a 38.9% ± 3.0% (mean ± se) inhibition compared with control values (P < 0.01; 50% inhibitory concentration [IC], 2.0 ± 0.1 μM). This effect was antagonized by bicuculline (10 μM), a GABAantagonist.Bicuculline antagonized the inhibitory effects of both the valerian extract and valerenic acid. In addition, pretreatment with valerian extract or valerenic acid decreased the brainstem inhibitory effects produced by muscimol (both P < 0.05), suggesting that these compounds play an important role in the regulation of GABAergic activity. Data from this study suggest thatfunction. Thus, valerian may potentiate the sedative effects of anesthetics and other medications that act on GABA receptors, and presurgical valerian use may cause a valerian-anesthetic interaction……In this study, we demonstrated that treatment with valerian extract or valerenic acid caused an inhibitory effect on muscimol-sensitive NTS neurons in an in vitro brainstem preparation., but not GABA, receptors.in rat cortical membrane preparation. We observed the neuropharmacological effect of GABAactivity in our experiment.…Our data suggest thatCNS Drugs 2002;16(11):731-43.Singh YN, Singh NN.College of Pharmacy, South Dakota State University, Brookings, South Dakota 57007, USA. yadhu_singh@sdstate.eduAnxiety disorders are among the most common psychiatric disorders that affect all age groups of the general population. Currently, the preferred treatment is with pharmacological drugs that have antidepressant or anti-anxiety properties. However, these agents have numerous and often serious adverse effects, including sedation, impaired cognition, ataxia, aggression, sexual dysfunction, tolerance and dependence. Withdrawal reactions on termination after long-term administration are also a major limiting factor in the use of these agents. Herbal remedies, including kava (Piper methysticum), have been shown to be effective as alternative treatments, at least in mild to moderate cases of anxiety. Kava is a social and ceremonial herb from the South Pacific. It is available in the west as an over-the-counter preparation. Its biological effects, due to a mixture of compounds called kavalactones, are reported to include sedative, anxiolytic, antistress, analgesic, local anaesthetic, anticonvulsant and neuroprotective properties.postulated to include blockade of voltage-gated sodium ion channels, enhanced liganddiminished excitatory neurotransmitter release due to calcium ion channel blockade, reduced neuronal reuptake of noradrenaline (norepinephrine), reversible inhibition of monoamine oxidase B and suppression of the synthesis of the eicosanoid thromboxane A(2), which antagonises GABA(A) receptor function. Clinical studies have shown that kava and kavalactones are effective in the treatment of anxiety at subclinical and clinical levels, anxiety associated with menopause and anxiety due to various medical conditions. Until recently, the adverse effects attributed to kava use were considered mild or negligible, except for the occurrence of a skin lesion. This disorder, called kava dermopathy, occurs only with prolonged use of large amounts of kava and is reversible on reduced intake or cessation. Rare cases of interactions have occurred with pharmaceutical drugs that share one or more mechanisms of action with the kavalactones.PMID: 12383029-----------------------------------------------------------------------------------------------------------------------Planta Med. 2001 Jun;67(4):306-11.Dinh LD, Simmen U, Bueter KB, Bueter B, Lundstrom K, Schaffner W.Institute of Pharmaceutical Biology, University of Basel, Witterswil, Switzerland.Methanolicdopamine D2, opioid (mu and delta), serotonin (5-HT6 and 5-HT7) and histamine (H1 and H2). HPLC analysis was carried out in order to determine the amount of the main kavalactones kavain, 7,8-dihydrokavain, methysticin, 7,8-dihydromethysticin, yangonin and 5,6-demethoxyyangonin.with IC50 values of approximately 3 micrograms/ml, whereas root extracts were less active with IC50 values ranging from 5 micrograms/ml (Nene) to 87 micrograms/ml (Mahakea). Since the leaf extracts generally contained lower amounts of the kavalactones than the root extracts, there might exist additional substances responsible for these activities. Leaf extracts also inhibited binding to dopamine D2, opioid (mu and delta) and histamine (H1 and H2) receptors more potently than the corresponding root extracts with IC50 values ranging from 1 to 100 micrograms/ml vs. > or = 100 micrograms/l, respectively. Significant differences in the potential of binding inhibition were also observed between cultivars. Binding to serotonin (5-HT6 and 5-HT7) and benzodiazepine receptors was only weakly inhibited by both root and leaf extracts of all four cultivars. In conclusion,dopamine D2, opioid (mu and delta) and histamine (H1 and H2)Since the cultivars contained similar amounts of kavalactones, while their pharmacological activities differed markedly, other constituents may play a role in the observed activities. Additionally, leaves generally exhibited more potent binding inhibition than roots, therefore leaf of P. methysticum might be an interesting subject for further pharmacological studies.PMID: 11458444GOTU KOLA (CENTELLA ASIATICA) is also a GABA RECEPTOR AGONIST and hence should be AVOIDED.TAURINE is also a GABA RECEPTOR AGONIST so I would steer well clear of it.See the following:J Biomed Sci. 2010 Aug 24;17 Suppl 1:S14.L'Amoreaux WJ, Marsillo A, El Idrissi A.SourceDepartment of Biology, College of Staten Island, 2800 Victory Blvd, Staten Island, NY 10314, USA. William.Lamoreaux@csi.cuny.eduAbstractBACKGROUND:Taurine is one of the most abundant free amino acids especially in excitable tissues, with wide physiological actions. Chronic supplementation of taurine in drinking water to mice increases brain excitability mainly through alterations in the inhibitory GABAergic system. These changes include elevated expression level of glutamic acid decarboxylase (GAD) and increased levels of GABA. Additionally we reported thatHere, we investigated pharmacologically the functional significance of decreased / or change in subunit composition of the GABAA receptors by determining the threshold for picrotoxin-induced seizures. Picrotoxin, an antagonist of GABAA receptors that blocks the channels while in the open state, binds within the pore of the channel between the beta2 and beta3 subunits. These are the same subunits to which GABA and presumably taurine binds.METHODS:Two-month-old male FVB/NJ mice were subcutaneously injected with picrotoxin (5 mg kg-1) and observed for a) latency until seizures began, b) duration of seizures, and c) frequency of seizures. For taurine treatment, mice were either fed taurine in drinking water (0.05%) or injected (43 mg/kg) 15 min prior to picrotoxin injection.RESULTS:We found that taurine-fed mice are resistant to picrotoxin-induced seizures when compared to age-matched controls, as measured by increased latency to seizure, decreased occurrence of seizures and reduced mortality rate. In the picrotoxin-treated animals, latency and duration were significantly shorter than in taurine-treated animas. Injection of taurine 15 min before picrotoxin significantly delayed seizure onset, as did chronic administration of taurine in the diet. Further, taurine treatment significantly increased survival rates compared to the picrotoxin-treated mice.CONCLUSIONS:We suggest that the elevated threshold for picrotoxin-induced seizures in taurine-fed mice is due to the reduced binding sites available for picrotoxin binding due to the reduced expression of the beta subunits of the GABAA receptor. The delayed effects of picrotoxin after acute taurine injection may indicate that the two molecules are competing for the same binding site on the GABAA receptor. Thus, taurine-fed mice have a functional alteration in the GABAergic system. These include: increased GAD expression, increased GABA levels, and changes in subunit composition of the GABAA receptors. Such a finding is relevant in conditions where agonists of GABAA receptors, such as anesthetics, are administered.PMID: 20804588----------------------------------------------------------------------------------------------------------------------------------------------Medical News T. 2010 Jan 18Scientists Close In On Taurine's Activity In The BrainDr. Minerva Yue, Dr. Angelo Keramidas, Dr. Peter A. Goldstein, Dr. Dev Chandra, Dr. Gregg E. HomanicsSource: U.S. National Institutes of Health (NIH)Taurine is one of the most plentiful amino acids in the human brain, but neuroscientists are still puzzled by just how brain cells put it to use. Now, a team of researchers at Weill Cornell Medical College in New York City has uncovered a prime site of activity for the molecule, bringing them closer to solving that mystery.in a regulatory area of the brain called the thalamus," says study senior author Dr. Neil L. Harrison, professor of pharmacology and pharmacology in anesthesiology at Weill Cornell Medical College. "We had discovered these receptors two years ago and showed that they interact with a neurotransmitter called gamma-aminobutyric acid (GABA) -- the brain's key inhibitory transmitter -- that is also involved in brain development.The finding is a surprise and opens the door to a better understanding of taurine's impact on the brain, the researchers report in this month's issue of the Journal of Neuroscience.And while the amino acid is made naturally by the body, it's also a much-touted ingredient in so-called "energy drinks" such as Red Bull. "Its inclusion in these supplements is a little puzzling, because our research would suggest that instead of being a pick-me-up, the taurine actually would have more of a sedative effect on the brain," Dr. Harrison says.Still, the prime focus of the new study was simply to find a site for the neurological activity of taurine; such a site has been missing despite many years of study."Scientists have long questioned whether taurine might act on an as-yet-undiscovered receptor of its own," notes lead researcher Dr. Fan Jia, postdoctoral scientist in the Department of Anesthesiology. "But after some recent work in our lab, we ended up zeroing in on this population of GABA receptors in the thalamus."The thalamus, located deep in the brain's center, is involved in what neuroscientists call "behavioral state control," helping to regulate transitions between sleep and wakefulness, for example. "It's like a railway junction, controlling information traffic between the brainstem, the senses and the executive functions in the cortex," Dr. Harrison explains. "When you're sleeping, the thalamus is discharging slowly and isolates the cortex from sensory input. But when you're awake, the thalamus allows information from the sensory system to activate the cortex."Investigating further, the researchers exposed thin slices of thalamic tissue from the brains of mice to concentrations of taurine that were similar to what might be found in the humanthe thalamus," Dr. HarrisonOf course, the question of what taurine actually does in the brain remains unanswered for now. "Unraveling that mystery is the prime goal of that research, and that's where we're headed next." Dr. Harrison says.There's already one leading theory: "GABA is important for forging new cell-to-cell connections within the developing brain, and because taurine shares a receptor with GABA, it, too, may play a role in neurological development," the researcher speculates.And what about the energy-drink connection? "Remarkably little is known about the effects of energy drinks on the brain. We can't even be sure how much of the taurine in the drink actually reaches the brain!" Dr. Harrison says. "Assuming that some of it does get absorbed, the taurine -- which, if anything, seems to have a sedating effect on the brain -- may actually play a role in the 'crash' people often report after drinking these highly caffeinated beverages. People have speculated that the post-Red Bull low was simply a caffeine rebound effect, but it might also be due to the taurine content."Environmental Health Perspectives * Volume 107, Number 10, October 1999Sukh DevUniversity of Delhi, B.R.A. Centre for Biomedical Research, Delhi, India(root) is another important antiaging plant. We have investigated this plant in some detail because its extractReceptor-binding assay-guided fractionation of the crude methanol extract resulted in a butanol fraction with retention of GABAB receptor activity [concentration that inhibits 50% (IC50) - 47 pg/mL] and an aqueous fraction that retained both GABAA (IC50 - 0.37 pg/mL) and GABAB (IC50 - 15.8 pg/mL) affinities.-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Phytother Res. 2010 Aug;24(8):1147-50.Bhattarai JP, Ah Park S, Han SK.Department of Oral Physiology and BK21 program, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Jeonju, 561-756, Republic of Korea.The effect of the methanol extract of Withania somnifera (mWS) on the gonadotropin releasing hormone (GnRH) neuron was examined in juvenile mice using the whole cell patch clamp technique. GnRH neurons are the fundamental regulators of the pulsatile release of GnRH needed for puberty and fertility. GnRH neurons were depolarized by bath application of the mWS (400 ng/microl) under the condition of a high Cl(-) pipette solution in current clamp mode. In voltage clamp mode, mWS induced reproducible inward currents (31.7 +/- 5.51 pA, n = 14). The mWS-induced inward currents persisted in the presence of tetrodotoxin (TTX, 0.5 microM), but were suppressed by bicuculline methiodide (BMI, 20 microM), a GABA(A) receptor antagonist.PMID: 20044800-----------------------------------------------------------------------------------------------------------------------Indian J Exp Biol. 2008 Jun;46(6):465-9.Kulkarni SK, Akula KK, Dhir A.Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160 014, India. skpu@yahoo.comWithania somnifera (ashwagandha) is a widely used herb in the Ayurvedic system of medicine. The objective of the present study was to elucidate the effect of W. somnifera root extract (Ws) alone or in combination with exogenous gamma-amino butyric acid (GABA), a GABA receptor agonist or with diazepam, a GABA receptor modulator against pentylenetetrazol (PTZ, iv) seizure threshold in mice. Minimal dose of PTZ (iv, mg/kg) needed to induce different phases (myoclonic jerks, generalized clonus and tonic extension) of convulsions were recorded as an index of seizure threshold. Ws (100 or 200 mg/kg, po) increased the PTZ seizure threshold for the onset of tonic extension phase whereas a lower dose (50 mg/kg, po) did not show any effect on the seizure threshold. Co-administration of a sub-effective dose of Ws (50 mg/kg, po) with a sub-protective dose of either GABA (25 mg/kg, ip) or diazepam (0.5 mg/kg, ip) increased the seizure threshold.PMID: 18697606-------------------------------------------------------------------------------------------------------------Indian J Med Res. 1991 Aug;94:312-5.Mehta AK, Binkley P, Gandhi SS, Ticku MKDepartment of Pharmacology, University of Texas Health Science Center.A methanolic extract of W. somnifera root inhibited the specific binding of [3H]GABA and [35S]TBPS, and enhanced the binding of [3H]flunitrazepam to their putative receptor sites. The extract (5 micrograms) inhibited [3H]GABA binding by 20 +/- 6 per cent whereas a concentration of 1 mg of the extract produced 100 per cent inhibition. The extract (5-100 micrograms) produced 20 +/- 4 to 91 +/- 16 per cent enhancement of [3H]flunitrazepam binding. In functional studies using 36Cl-influx assay in mammalian spinal cord neurons, W. somnifera root extract increased 36Cl-influx in the absence of GABA. This effect on 36Cl-influx was blocked by bicuculline and picrotoxin; and enhanced by diazepam.PMID: 1660034Phytother Res. 2001 Aug;15(5):377-81.Rolland A, Fleurentin J, Lanhers MC, Misslin R, Mortier F.Laboratoire de Pharmacognosie, E.B.S.E., Université de Metz, Campus Bridoux, 1 rue des Récollets, F-57000 Metz, France.An aqueous alcohol extract of Eschscholzia californica (Ec) has been evaluated for benzodiazepine, neuroleptic, antidepressant, antihistaminic and analgesic properties, in order to complete the study of the sedative and anxiolytic effects previously demonstrated. The plant extract did not protect mice against the convulsant effects of pentylenetetrazol, and did not cause muscle relaxant effects butThe Ec extract induced peripheral analgesic effects in mice but did not possess antidepressant, neuroleptic or antihistaminic effects.PMID: 11507727Phytomedicine. 2003 Nov;10(8):640-9.Awad R, Arnason JT, Trudeau V, Bergeron C, Budzinski JW, Foster BC, Merali Z.Ottawa-Carleton Institute of Biology, University of Ottawa, Ottawa, Canada.The phytochemistry and biological activity of Scutellaria lateriflora L. (American skullcap) which has been traditionally used as a sedative and to treat various nervous disorders such as anxiety was studied. In vivo animal behaviour trials were performed to test anxiolytic effects in rats orally administered S. laterifolia extracts. Significant increases in the number of entries into the center of an "open-field arena"; number of unprotected head dips, number of entries and the length of time spent on the open arms of the Elevated Plus-Maze were found.and glutamine in a H2O extract (31 mg/g), was performed using HPLC.PMID: 14692724----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------British Journal of Wel. 2010 Jun;1(4):25-30Brock C., Whitehouse J., Tewfik I., Towell T.School of Life Sciences, University of Westminster, United Kingdom.Many orthodox anxiolytic treatments can have unwanted side effects.American skullcap (Scutellaria laterifl ora) (Figure 1) is one of the most commonly used herbs by western medical herbalists, particularly for anxiety and related conditions (Bergner, 2002–2003)…Due to its potential sedative action (Greenfi eld and Davis, 2004), it may be advisable to refrain from using S. lateriflora in combination with other sedatives, such as alcohol and benzodiazepines. It is not possible to comment on the safety of its use in pregnancy…Benzodiazepines are allosteric ligands for the GABAA receptor, a chloride channel that is gated by GABA. They bind to the benzodiazepine site of the GABAA receptor, thus increasing the affinity of the inhibitory neurotransmitter GABA for the GABA site of the GABAA receptor. This decreases the likelihood of action potentials by excitatory neurotransmitters (Rabow et al, 1995).in mouse cerebral cortex in vitro.CHAMOMILE’s mechanism of action in relation to its ANXIOLYTIC effects appears to involve both GABA RECEPTOR AGONISM and weak GABA TRANSAMINASE INHIBITION; and as such, prolonged usage will to an extent induce a down-regulation of the GABA RECEPTORS.Therefore, prolonged usage of CHAMOMILE for the medium to long-term should be avoided; and usage should be restricted tousage and/or CYCLING ON/OFF.See the following:Phytotherapy Res. 1996;10:177–179.Avallone, R.; Zanoli, P.; Corsi, L.; Cannazza, G.; Baraldi, M.Department of Pharmaceutical Sciences, Modena University, Via Campi 183, 41110 Modena (Italy)-----------------------------------------------------------------------------------------------------------------------------------------Planta Med. 1995 Jun;61(3):213-6.Viola H, Wasowski C, Levi de Stein M, Wolfman C, Silveira R, Dajas F, Medina JH, Paladini AC.Instituto de Biología Celular, Facultad de Medicina, Buenos Aires, Argentina.The dried flower heads of Matricaria recutita L. (Asteraceae) are used in folk medicine to prepare a spasmolytic and sedative tea. Our fractionation of the aqueous extract of this plant led to the detection of several fractions with significant affinity for the central benzodiazepine receptor and to the isolation and identification of 5,7,4'-trihydroxyflavone (apigenin) in one of them. Apigenin competitively inhibited the binding of flunitrazepam with a Ki of 4 microM and had no effect on muscarinic receptors, alpha 1-adrenoceptors, and on the binding of muscimol to GABAA receptors. Apigenin had a clear anxiolytic activity in mice in the elevated plusmaze without evidencing sedation or muscle relaxant effects at doses similar to those used for classical benzodiazepines and no anticonvulsant action was detected. However, a 10-fold increase in dosage produced a mild sedative effect since a 26% reduction in ambulatory locomotor activity and a 35% decrement in hole-board parameters were evident.but not being anticonvulsant or myorelaxant.PMID: 7617761-----------------------------------------------------------------------------------------------------------------------------------------Canadian Journal of Physiology and Pharmacology, Volume 85, Number 9, September 2007 , pp. 933-942(10)Awad, R.; Levac, D.; Cybulska, P.; Merali, Z.; Trudeau, V.L.; Arnason, J.T.NRC Research Press.In Canada, the use of botanical natural health products (NHPs) for anxiety disorders is on the rise, and a critical evaluation of their safety and efficacy is required. The purpose of this study was to determine whether commercially available botanicals directly affect the primary brain enzymes responsible for γ-aminobutyric acid (GABA) metabolism. Anxiolytic plants may interact with either glutamic acid decarboxylase (GAD) or GABA transaminase (GABA-T) and ultimately influence brain GABA levels and neurotransmission. Two in vitro rat brain homogenate assays were developed to determine the inhibitory concentrations (IC) of aqueous and ethanolic plant extracts. Approximately 70% of all extracts that were tested showed little or no inhibitory effect (ICvalues greater than 1mg/mL) and are therefore unlikely to affect GABA metabolism as tested. The aqueous extract of Melissa officinalis (lemon balm) exhibited the greatest inhibition of GABA-T activity (IC= 0.35mg/mL). Extracts from Centella asiatica (gotu kola) and Valeriana officinalis (valerian) stimulated GAD activity by over 40% at a dose of 1mg/mL. On the other hand, bothSeveral of these species may therefore warrant further pharmacological investigation. The relation between enzyme activity and possible in vivo mode of action is discussed.Brain Res Brain Res Rev. 1994 May;19(2):180-222.Gouliaev AH, Senning A.Department of Chemistry, Aarhus University, Denmark.Nearly three decades have now passed since the discovery of the piracetam-like nootropics, compounds which exhibit cognition-enhancing properties, but for which no commonly accepted mechanism of action has been established. This review covers clinical, pharmacokinetic, biochemical and behavioural results presented in the literature from 1965 through 1992 (407 references) of piracetam, oxiracetam, pramiracetam, etiracetam, nefiracetam, aniracetam and rolziracetam and their structural analogues. The piracetam-like nootropics are capable of achieving reversal of amnesia induced by, e.g., scopolamine, electroconvulsive shock and hypoxia. Protection against barbiturate intoxication is observed and some benefit in clinical studies with patients suffering from mild to moderate degrees of dementia has been demonstrated.The racetams possess a very low toxicity and lack serious side effects. Increased turnover of different neurotransmitters has been observed as well as other biochemical findings, e.g., inhibition of enzymes such as prolylendopeptidase. So far, no generally accepted mechanism of action has, however, emerged. We believe that the effect of the racetams is due to a potentiation of already present neurotransmission and that much evidence points in the direction of a modulated ion flux by, e.g., potentiated calcium influx through non-L-type voltage-dependent calcium channels, potentiated sodium influx through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor gated channels or voltage-dependent channels or decreases in potassium efflux. Effects on carrier mediated ion transport are also possible.PMID: 80616862008 Dec;74(15):1769-73. Epub 2008 Nov 12.Grundmann O, Wang J, McGregor GP, Butterweck V.College of Pharmacy, Department of Pharmaceutics, University of Florida, FL, USAThe purpose of this research was to assess the anxiolytic properties of a phytochemically characterized commercial extract from Passiflora incarnata (PI; Passifloraceae) in the elevated plus maze test in mice. Using an HPLC method, the flavonoids homoorientin, orientin, vitexin, and isovitexin were identified as major compounds.(1.5 mg/kg) at a dose of 375 mg/kgIn addition, antagonism studies using the GABA (A)/benzodiazepine receptor antagonist flumazenil and the 5-HT (1A)-receptor antagonist WAY-100 635 were conducted. The active dose was effectively antagonized by flumazenil, but not by WAY-100 635.PMID: 19006051-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------2011 Jun;25(6):838-43. doi: 10.1002/ptr.3352. Epub 2010 Nov 19.Appel K, Rose T, Fiebich B, Kammler T, Hoffmann C, Weiss G.VivaCell Biotechnology GmbH, Denzlingen, Germany.Passiflora incarnata L. (Passifloraceae) is important in herbal medicine for treating anxiety or nervousness, Generalized Anxiety Disorder (GAD), symptoms of opiate withdrawal, insomnia, neuralgia, convulsion, spasmodic asthma, ADHD, palpitations, cardiac rhythm abnormalities, hypertension, sexual dysfunction and menopause. However, the mechanism of action is still under discussion. Despite gaps in our understanding of neurophysiological processes, it is increasingly being recognized that dysfunction of the GABA system is implicated in many neuropsychiatric conditions, including anxiety and depressive disorders. Therefore, the in vitro effects of a dry extract of Passiflora incarnata (sole active ingredient in Pascoflair® 425 mg) on the GABA system were investigated.into rat cortical synaptosomesof [(3) H]- SR95531of [(3) H]-CGP 54626. Using the [(35) S]-GTPγS binding assayPMID: 21089181--------------------------------------------------------------------------------------------------------------------------------Phytother Res. 2009 Dec;23(12):1795-6.Carrasco MC, Vallejo JR, Pardo-de-Santayana M, Peral D, Martín MA, Altimiras J.Consultorio Local Nuestra Sra. de la Soledad de Guadiana del Caudillo, Centro de Salud Pueblonuevo del Guadiana (Badajoz), Travesía de la Constitución s/n. 06184 Pueblonuevo del Guadiana, (Badajoz), Spain.There is an increasing interest in the health risks related to the use of herbal remedies. Although most consumers think that phytomedicines are safe and without side effects, interactions between complementary alternative and conventional medicines are being described. The aim of this clinical case report is to highlight the importance of the safe use of herbal remedies by providing a clinical interaction study between pharmaceutical medicines and herbal medicinal products. The case of a patient self-medicated with Valeriana officinalis L. and Passiflora incarnata L. while he was on lorazepam treatment is described. Handshaking, dizziness, throbbing and muscular fatigue were reported within the 32 h before clinical diagnosis. The analysis of family medical history ruled out essential tremor, Parkinson's disease, Wilson's disease and other symptom-related pathologies. His medical history revealed a generalized anxiety disorder and medicinal plant consumption but no neurological disorder. Appropriate physical examination was carried out. An additive or synergistic effect is suspected to have produced these symptoms.Valerian andcausing severe secondary effects. Due to the increase in herbal product self-medication, the use of herbal remedies should be registered while taking the personal clinical history. Multidisciplinary teams should be created to raise studies on medicinal plants with impact on medical praxis.PMID: 19441067It does appear that BETA-ALANINE is also a GABA RECEPTOR AGONIST - see this study for example:Neurochem Int. 2010 Oct;57(3):177-88. Epub 2010 Jun 9.Tiedje KE, Stevens K, Barnes S, Weaver DF.Department of Chemistry, Dalhousie University, B3H 4J3 Halifax, Canada.This review discusses the role of beta-alanine as a neugeneral, beta-alanine satisfies a number of the prerequisite classical criteria for being a neurotransmitter: beta-alanine occurs naturally in the CNS, is released by electrical stimulation through a Ca(2+) dependent process, has binding sites, and inhibits neuronalco-agonist site on the NMDA complex (strychnine-insensitive); glycine receptor site (strychnineblockade of GAT protein-mediated glial GABA uptake. Although beta-alanine binding has been identified throughout the hippocampus, limbic structures, anda variety of data suggest that beta-alanine should be considered as a small molecule neurotransmitter and should join the ranks of the other amino acid neurotransmitters. These realizations open the door for a more comprehensive evaluation of beta-alanine's neurochemistry and for its exploitation as a platform for drug design.PMID: 20540981LEMON BALM’s primary mechanism of action in relation to its ANXIOLYTIC effects appears (somewhat uniquely) to be that of a GABA TRANSAMINASE INHIBITOR.GABA TRANSAMINASE is an enzyme which breaks down GABA within the brain, and hence inhibition of this enzyme induces an INCREASE in GABA LEVELS, which with prolonged usage theoretically will induce a down-regulation of the GABA RECEPTORS.Therefore, it could be considered that if one wanted to be ‘absolutely safe’, prolonged usage of LEMON BALM for the medium to long-term should be avoided for exactly the same reasons as GABA RECEPTOR AGONISTS and GABA REUPTAKE INHIBITORS; and hence usage should be restricted tousage only and/or CYCLING ON/OFF.However, to put things into perspective, LEMON BALM’S GABA TRANSAMINASE INHIBITION effects are relatively weak. Furthermore, it is by no means LEMON BALM’s only mechanism of action. As such, LEMON BALM’s physiological effects are somewhat complex.Consequently, after weighing up all the evidence I have placed LEMON BALM onto the ‘POSSIBLY TO AVOID’ list; and I feel the need to repeat that if one wanted to be ‘absolutely safe’ one can take LEMON BALM completely safely by CYCLING it ON and OFF.See the following:Phytother Res. 2009 Aug;23(8):1075-81.Awad R, Muhammad A, Durst T, Trudeau VL, Arnason JT.Centre for Advanced Research in Environmental Genomics (CAREG), Department of Biology, University of Ottawa, Ottawa, Ontario, Canada.A novel pharmacological mechanism of action for the anxiolytic botanical Melissa officinalis L. (lemon balm) is reported., an enzyme target in the therapy of anxiety, epilepsy and related neurological disorders. Bioassay-guided fractionation led to the identification and isolation of rosmarinic acid (RA) and the triterpenoids, ursolic acid (UA) and oleanolic acid (OA) as active principles. Phytochemical characterization of the crude extract determined RA as the major compound responsible for activity (40% inhibition at 100 microg/mL) since it represented approximately 1.5% of the dry mass of the leaves. Synergistic effects may also play a role.PMID: 19165747-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Canadian Journal of Physiology and Pharmacology, Volume 85, Number 9, September 2007 , pp. 933-942(10)Awad, R.; Levac, D.; Cybulska, P.; Merali, Z.; Trudeau, V.L.; Arnason, J.T.NRC Research Press.In Canada, the use of botanical natural health products (NHPs) for anxiety disorders is on the rise, and a critical evaluation of their safety and efficacy is required. The purpose of this study was to determine whether commercially available botanicals directly affect the primary brain enzymes responsible for γ-aminobutyric acid (GABA) metabolism. Anxiolytic plants may interact with either glutamic acid decarboxylase (GAD) or GABA transaminase (GABA-T) and ultimately influence brain GABA levels and neurotransmission. Two in vitro rat brain homogenate assays were developed to determine the inhibitory concentrations (IC) of aqueous and ethanolic plant extracts. Approximately 70% of all extracts that were tested showed little or no inhibitory effect (ICvalues greater than 1mg/mL) and are therefore unlikely to affect GABA metabolism as tested.Extracts from Centella asiatica (gotu kola) and Valeriana officinalis (valerian) stimulated GAD activity by over 40% at a dose of 1mg/mL. On the other hand, both Matricaria recutita (German chamomile) and Humulus lupulus (hops) showed significant inhibition of GAD activity (0.11-0.65mg/mL). Several of these species may therefore warrant further pharmacological investigation. The relation between enzyme activity and possible in vivo mode of action is discussed.HOPS’ mechanism of action in relation to its ANXIOLYTIC effects appears to be that of MELATONIN RECEPTOR AGONIST (like AFOBAZOLE) and weak GABA TRANSAMINASE INHIBITION (like LEMON BALM and CHAMOMILE).Since GABA TRANSAMINASE INHIBITION induces an INCREASE in GABA LEVELS, prolonged usage theoretically will to an extent induce a down-regulation of the GABA RECEPTORS.However, to put things into perspective, it is important to note that HOP’S GABA TRANSAMINASE INHIBITION effects are WEAK (much weaker in fact than that of LEMON BALM); and as such the potential for down-regulation of the GABA RECEPTORS is small.Consequently, after weighing up all the evidence I have placed HOPS onto the ‘POSSIBLY TO AVOID’ list.If one wanted to be ‘, prolonged usage of HOPS for the medium to long-term should be avoided; and usage should be restricted tousage only and/or CYCLING ON/OFF.See the following:HerbalGram. 2010; 87: 44-57Uwe Koetter, Martin BiendlAmerican Botanical CouncilMelatonin, a hormone secreted by the pineal gland in humans, through binding to its receptor, is responsible for maintaining the diurnal circadian rhythm in vertebrates.Hops extracts had significant hypothermic effects in vivo in male mice analog melatonin. This effect was antagonized with the competitive melatonin receptor antagonist luzindole.The fraction containing beta-acids of a lipophilic COhops extract was investigated in a benzodiazepine receptor-binding assay. Hops beta-acids affected the plateau of the GABA currents dose dependently without mediating this effect via the benzodiazepine receptor.In mice, the sedating activity of hops could be attributed to alpha-bitter acids as the most active constituents. Beta-bitter acids and the volatile oil contributed to the activity in ethanolic and carbon dioxide extracts of hops. Spontaneous locomotor activity was reduced, ketamine-induced sleeping time increased, and body temperature was reduced, thus confirming a central sedating effect.Most promising are the results from Butterweck et al. (2007), as they provide direction for future isolation and structure elucidation work. With the mode of action potentially linked to melatonin, structural analog substances or precursors may now be identified in hops.-----------------------------------------------------------------------------------------------------------------------------------------J Agric Food Chem. 2006 Apr 5;54(7):2514-9.beer andAoshima H, Takeda K, Okita Y, Hossain SJ, Koda H, Kiso Y.Department of Physics, Biology and Informatics, Faculty of Science, Yamaguchi University, Yoshida, Yamaguchi 753-8512, Japan.Beer induced the response of the ionotropic gamma-aminobutyric acid receptors (GABA(A) receptors) expressed in Xenopus oocytes, indicating the presence of gamma-aminobutyric acid (GABA)-like activity. Furthermore, the pentaneThe GABA(A) receptor responses were also potentiated by the addition of aliphatic esters, most of which are reported to be present in beer flavor. Aliphatic esters showed the tendency to decrease in the potentiation of the GABA(A) receptor response with an increase in their carbon chain length. When myrcenol was injected to mice prior to intraperitoneal administration of pentobarbital, the pentobarbital-induced sleeping time of mice increased additionally. Therefore, the beer contained not only GABA-like activity but also the modulator(s) of the GABA(A) receptor response.PMID: 16569037-----------------------------------------------------------------------------------------------------------------------------------------Canadian Journal of Physiology and Pharmacology, Volume 85, Number 9, September 2007 , pp. 933-942(10)Awad, R.; Levac, D.; Cybulska, P.; Merali, Z.; Trudeau, V.L.; Arnason, J.T.NRC Research Press.In Canada, the use of botanical natural health products (NHPs) for anxiety disorders is on the rise, and a critical evaluation of their safety and efficacy is required. The purpose of this study was to determine whether commercially available botanicals directly affect the primary brain enzymes responsible for γ-aminobutyric acid (GABA) metabolism. Anxiolytic plants may interact with either glutamic acid decarboxylase (GAD) or GABA transaminase (GABA-T) and ultimately influence brain GABA levels and neurotransmission. Two in vitro rat brain homogenate assays were developed to determine the inhibitory concentrations (IC) of aqueous and ethanolic plant extracts. Approximately 70% of all extracts that were tested showed little or no inhibitory effect (ICvalues greater than 1mg/mL) and are therefore unlikely to affect GABA metabolism as tested. The aqueous extract of Melissa officinalis (lemon balm) exhibited the greatest inhibition of GABA-T activity (IC= 0.35mg/mL). Extracts from Centella asiatica (gotu kola) and Valeriana officinalis (valerian) stimulated GAD activity by over 40% at a dose of 1mg/mL. On the other hand, both Matricaria recutita (German chamomile) andSeveral of these species may therefore warrant further pharmacological investigation. The relation between enzyme activity and possible in vivo mode of action is discussed.I have added NIACINAMIDE to the ‘POSSIBLY TO AVOID’ list, for four reasons, namely:1) There is evidence that NIACINAMIDE is NEUROTOXIC when taken at the high doses that produce its ANXIOLYTIC effects2) There is evidence that to some extent NIACINAMIDE exerts at least part of its ANXIOLYTIC effects via the GABA PATHWAY / RECEPTORS; however, there currently is conflicting information regards the full extent that NIACINAMIDE influences the GABA RECEPTORS, in that whilst some studies indicate that NIACINAMIDE is very much a GABA RECEPTOR AGONIST, others indicate that NIACINAMIDE is either NOT a GABA RECEPTOR AGONIST or is a very weak one.3) There is an ever increasing amount of evidence that indicates taking MEGA DOSES / OVER-DOSES of VITAMINS is ill advised and may present a variety of HEALTH RISKS when taken for the long-term; this applies to NIACINAMIDE, which is a form of VITAMIN B3.4) NIACINAMIDE when taken at the high doses that produce its ANXIOLYTIC effects has a number of potential SIDE EFFECTS, which includes (but is not limited to): DRY MOUTH, NAUSEA, SEDATION, and HEPATIC (LIVER) TOXICITY (N.B. this specifically is DOSAGE DEPENDANT).Neurosci Lett. 1985 Mar 15;54(2-3):173-7.Chweh AY, Swinyard EA, Wolf HH.GABA had no significant effect on the inhibitory potency of triazolam in [3H]flunitrazepam receptor binding, whereas GABA decreased the inhibitory potency of nicotinamide. When administered to mice, both triazolam andby the rotorod test and anticonvulsant activity by the pentylenetetrazol seizure threshold test. This suggests that GABA modulation of the receptor binding of a BDZ ligand in vitro is not a reliable predictor of the pharmacologic activity of the ligand.PMID: 2859562----------------------------------------------------------------------------------------------------------------------------------------------J Neurochem. 2000 Sep;75(3):982-90.Hervías I, Lasheras B, Aguirre N.Department of Pharmacology, University of Navarra Medical School, Pamplona, Spain.Neurotoxicity induced by different substituted amphetamines has been associated with the exhaustion of intracellular energy stores. Accordingly, we examined the influence of 2-deoxy-D-glucose (2-DG), a competitive inhibitor of glucose uptake and metabolism, and nicotinamide, an agent that improves energy metabolism, on 3, 4-methylenedioxymethamphetamine (MDMA)-induced 5-hydroxytryptamine (5-HT; serotonin) deficits. Administration of MDMA (15 mg/kg i.p.) produced a significant hyperthermia, whereas 2-DG caused a profound hypothermia that lasted throughout the experiment. When MDMA was given to 2-DG-treated rats, an immediate but transient hyperthermia occurred and was followed by a return to hypothermia. 2-DG had no effect on 5-HT concentrations in the frontal cortex, hippocampus, and striatum but prevented the neurotoxicity induced by MDMA. When rats were injected with 2-DG/MDMA and were warmed to prevent hypothermia, the protection afforded by 2-DG was abolished. Nicotinamide had no effect on body temperature of the rats, and the hyperthermia induced by the nicotinamide/MDMA treatment was similar to that of the saline/MDMA-treated rats. However,Finally, no change on ATP concentrations in the frontal cortex, hippocampus, and striatum was observed up to 3 h after a single dose of MDMA. These results suggest that an altered energy metabolism is not the main cause of the neurotoxic effects induced by MDMA.PMID: 10936179----------------------------------------------------------------------------------------------------------------------------------------------Br J Pharmacol. 1985 March; 84(3): 689–696.J. M. Bold, C. R. Gardner, and R. J. WalkerThe actions of nicotinamide and inosine were investigated on rat cerebellar Purkinje cells using ionophoretic and extracellular recording techniques. Ionophoretic application of nicotinamide or inosine showed that they were potent inhibitors of Purkinje cell firing. This inhibition differed from that induced by benzodiazepines in that it was not reversed by the GABA antagonists bicuculline methiodide and picrotoxin. RO 15-1788, the specific benzodiazepine antagonist, did not reverse the effects of nicotinamide. Chlordiazepoxide has been shown to increase significantly social interaction between pairs of male rats and this increase can be reversed by RO 15-1788, 20 mg kg-1 i.p. Nicotinamide also caused a small increase in social interaction but this effect was not reversed by the benzodiazepine antagonist. Inosine did not increase social interaction. [3H]-flunitrazepamand inosineSimilarly, inosine exerts a neuronal depressant effect dissimilar from that of benzodiazepines.----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Biokhimiia. 1989 Mar;54(3):381-6.].[Article in Russian]Fomenko AI, Stepanenko SP, Donchenko GV, Khalmuradov AG.The GABA-benzdiazepine complex was separated by solubilization with 0.5% lubrol PX. The solubilized preparations contain the binding sites for [3H]flunitrazepam alone (Kd = 5.9 nm). The Kd value for the membrane-bound benzdiazepine receptor is 2.9 nM. NAD inhibited the specific binding of [3H]flunitrazepam to the solubilized membrane preparation when used at concentrations by several orders of magnitude lower than that of nicotinamide. Using gel filtration on Sepharose 6B-CL, the molecular mass of the soluble benzdiazepine receptor protein was determined.PMID: 2546611-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Nature. 1979 Apr 5;278(5704):563-5.Möhler H, Polc P, Cumin R, Pieri L, Kettler R.PMID: 155222-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Ann Ist Super Sanita. 1982;18(1):95-8.Voronina TA.PMID: 6303184-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------J Orthomolecular Medicine 2005; 20(3): 167-178Prousky J EThe purpose of this report is to highlight the potential of niacinamide for the treatment of anxiety disorders. Three patientswere prescribed large pharmacological doses of niacinamide (2,000-2,500 mg per day). Each of the patients had considerable relief from their anxiety when regularly using niacinamide.. Adverse effects did not occur with these doses, but nausea and vomiting can occur when doses as high as 6,000 mg per day are used. These positive case reports suggest that niacinamide might be helpful for the treatment of anxiety disorders. However, definitive proof requires properly conducted randomized controlled trials to assess niacinamide’s actual therapeutic effects and adverse effects profile.In a previous review of the literature by Hoffer, both niacin and niacinamide were shown to have some sedative activity, and were able to potentiate the action of sedatives, anticonvulsant medications and certain tranquilizers.2414 Table 2 (p.174) summarizes this data.25-30 It appears that niacinamide has therapeutic effects comparable to the benzodiazepines.For example, in a patient with anorexia nervosa an insufficient supply of vitamin B3 or protein resulted in reduced urinary levels of the serotonin breakdown product, 5-hydroxy-indolacetic acid (5-HIAA).32 The authors of this report postulated that a deficiency of vitamin B3 reduced the feedback inhibition upon the kynurenine pathway, resulting in more tryptophan being diverted to the kynurenine pathway, making less substrate available for the synthesis of serotonin. By contrast, the use of pharmacological doses of vitamin B3 can increase the production of serotonin.33 In a rat study, the administration of 20 mg of niacin resulted in increased levels of 5-HIAA and decreased levels of anthurenic acid via the kynurenine pathway.34by diverting more tryptophan to become substrate for serotonin synthesis.of the three patients.In terms of proper dosing, most patients require a minimum of 2,000-4,500 mg per day to achieve therapeutic results…----------------------------------------------------------------------------------------------------------------------------------------------Biull Eksp Biol Med. 1986 Mar;101(3):329-31.[Article in Russian]Akhundov RA, Rozhanets VV, Voronina TA, Val'dman AV.and its electron structural analogs (NMF and AzN compounds)in a conflicting situation test. NMF and AzN behaved as the agonists of GABA-benzodiazepine receptor complex.The given compounds were shown to be more active, than nicotinamide.PMID: 2869801IF you are currently addicted to a GABA RECEPTOR AGONIST (e.g. BENZODIAZEPINES), then it isthat yousince this can in fact be potentially harmful and dangerous; in which case, you should follow a TAPERING-DOWN PROTOCOL; and you should switch to using anGABA RECEPTOR AGONIST WITH A SHORT HALF-LIFE (such as a short-acting BENZODIAZEPINE, e.g. MIDAZOLAM) and use that for the tapering-down process.Usage of herbal extracts for which the full extent of the interaction with the GABA receptors is unknown is NOT advised for use in the tapering-down process.GARUM ARMORICUM is a natural protein autolysate extract of the Blue Ling fish (Molva dypterygia) that functions as a safe and effective ANXIOYLTIC ANTIDEPRESSANT.GARUM ARMORICUM should NOT be confused with FISH OIL. Whilst both GARUM ARMORICUM and FISH OIL are both derived from fish, their respective compositions and physiological effects aredifferent.GARUM ARMORICUM’s primary active constituent is a very high percentage concentration of micro polypeptides, the majority of which comprise polypeptide chains with a molecular weight (size) of less than 700 Daltons, and which are similar to the hypophysiotropic hypothalamic peptides and to certain neurotransmitters.GARUM ARMORICUM also contains aquantity of EPA and DHA; however, this is NOT considered to be responsible for its respective physiological effects.The ANXIOLYTIC properties of GARUM ARMORICUM were first tested by Yalacta Laboratories in France in 1978 where it was found to be quite effective in treating patients that suffered from CHRONIC ANXIETY. And later scientists at California Polytechnic State University performed clinical trials which found that GARUM ARMORICUM was also useful in treating ANXIETY.See the following:Dorman T, et al. Journal of Advancement in Medicine, Vol.8(3):193-200, 1995.Anxiety has been classified as a psychiatric symptom and as such merits treatment. On the other hand it is a common sense observation that mild degrees of anxiety are a normal accompaniment of modern living. This has been reflected in the psychiatric literature, where the frequency of "undiagnosed" anxiety in a primary care setting has been lamented. The management of anxiety with pharmacologic means has been studied extensively and a consensus exists that there is a problem with habituation when using typical drug therapy. Additionally, there is uncertainty regarding how to combine medicinal management for anxiety and depression. There is, therefore, an emerging recognition that further approaches need to be sought.Two open small studies reported on the benefit of a product prepared from controlled enzymatic autolysis of the viscera of a certain | species of deep sea fish, Garum Armoricum, found off the | coast of Brittany, in weakness and fatigue patients with acute anxiety. The current study set out to review the possible benefit of this product in free-floating anxiety of otherwise healthy college students under the stress of final examinations, in a controlled experiment, while maintaining vigilance for possible side effects.Neither difference due to the week of treatment nor the order (Garum Armoricum first vs. placebo first), nor any interaction was statistically significant. Due to an unanticipated lingering anxiolytic effect of Garum Armoricum in the group who received it first (beyond the one week washout allowed in the initial design), their placebo scores were omitted from the placebo analysis.------------------------------------------------------------------------------------------------------------------------Curr Top Nutraceutical Res. 2008 Aug;6(3):115-23, Nejdi A,, Rozan P, Javelot H, Lalonde R.in male Wistar rats using the conditioned defensive burying (CDB) and the forced swimming (FST) tests, respectively. In the CDB, all doses of Garum Armoricum (25,50 and 100 mg/kg, PO) decreased the global score of anxiety and the latency of the first approach towards the probe after shock, in a similar way to diazepam (DZP) at the dose of 3 mg/kg, PO. But unlike DZP, the latency before touching again the probe after shock was not significantly reduced by GARUM ARMORICUM. In the FST the two higher doses of GARUM ARMORICUM (15 and 45 mg/kg PO) reduced immobility time in a similar way to imipramine (IMI) at the dose of 20 mg/hg, PO. But unlike IMI, GARUM ARMORICUM did not reduce open-field activity and, unlike DZA did not cause a place preference to develop.These psychotropic properties of GARUM ARMORICUM may be due to the synergistic action of its active constituents.MAGNESIUM is unlikely be a 'magic bullet' regards treating ANXIETY but can most certainly be a highly useful adjunct, through its mechanism of action as an NMDA RECEPTOR ANTAGONISTMAGNESIUM SULPHATE at a dosage of 1 GRAM elemental Magnesium adminstered via INTRAMUSCULAR INJECTION