809 replies to this topic

[Daniel Cooper]

I'm surprised to see that Magnolia Officinalis is on the approved list since it appears to be a GABAA PAM or agnonist.   What is the explanation for that?

 

 

 

 

[Galaxyshock]

The retarded idea that anything GABA-affecting should be avoided needs to be removed to make people seek for actually working treatments for their anxiety. Herbal GABAergics basically never get you in trouble - I know of only one case report of a man taking mega-doses of valerian root for 10 years for sleep then running out and having insomnia and anxiety symptoms, rapidly improved with short course of benzos.

 

I remember someone reporting seizures from GABA-A damaging antibiotics and our scienceguy recommended some crap like magnesium and vitamin C. What the fuck.

[Daniel Cooper]

The retarded idea that anything GABA-affecting should be avoided needs to be removed to make people seek for actually working treatments for their anxiety. Herbal GABAergics basically never get you in trouble - I know of only one case report of a man taking mega-doses of valerian root for 10 years for sleep then running out and having insomnia and anxiety symptoms, rapidly improved with short course of benzos.

 

I remember someone reporting seizures from GABA-A damaging antibiotics and our scienceguy recommended some crap like magnesium and vitamin C. What the fuck.

 

I hear what you're saying.  I'm a little cautious about playing with gabaergics since I'm trying to heal from some damage from some long term z-drug use.  But, even in cases like that I think these herbs can be useful.

[Hannes2]

The warning on using Gaba-ergics is certainly a good one, but that strict and general avoidance does not strike me as reasonable. Without knowing much about how brain chemistry works, I can't imagine that introducing any sort and any dose of Gaba-ergics just leads to an equivalent downregulation of the system without any net win and benefit. I would guess that thresholds need to be crossed before the receptors fire without sufficient interruption and respond with long-term downregulation, so that enhancing GABA signaling might be possible to some extent with a more gentle approach than hitting with benzodiazepines and flooding with GABA agonists.

 

Like, supposedly meditation leads to an increase of GABA brain levels, but if this were just downregulating the receptors there would be no benefit from this as far as GABA signaling is concerned and people could experience withdrawel symptoms from ceasing meditation! 

Edited by Hannes2, 25 November 2017 - 08:45 AM.

[world33]

If anyone is suffering from Generalized Anxiety Disorder and the symptoms are worse in the morning due to higher cortisol (stress) levels I urge you to try:

• Phosphatidylserine (sunflower or soy derived) up to 600/800mg per day divided in two or three doses (higher dosages in the morning and lower in the evening when cortisol lowers naturally). 100mg (the standard dosage of many supplements out there) per day is too low and does not do much for me.
• EGCG
• Quercetin
• Glycyrrhizic Acid (found in licorice but not recommended because it has a side effect to increase blood pressure) 

They all reduce cortisol with different mechanisms of action. In particular EGCG, Quercetin and Glycyrrhizic acid are potent Inhibitors of Human 11β-hydroxysteroid Dehydrogenase Type 1  (HSD) the enzyme responsible to convert the inactive cortisone to the active hormone cortisol (the stress hormone). If you suffer from chronic or acute stress and think that it may play a role in your anxiety or depression I would seriously give it a try. Drinking decaffeinated green tea is good but it does not have the same potent effect of a EGCG supplement. Same thing apply to food containing quercetin (i.e. onions, apples etc.); a Quercetin supplement is much stronger.
Reducing cortisol levels has also many other important positive effects on so many levels including belly fat. An interesting reading is The Cortisol Connection which explains the role of HSD in cortisol levels and health-related effects.
My anxiety is a type of anxiety very strong in the morning and almost disappearing in the evening and it is therefore related to cortisol levels and/or glucocorticoid receptor sensitivity. Mifepristone, a glucocorticoid receptor antagonist drug used for abortion, is also something I want to try in the future. Some clinical trials have been carried out using that drug for several mental illnesses such as anxiety, bipolar disorder and PTSD. For anxiety see Antiglucocorticoid Therapy for Cognitive Impairment in Late-life Anxiety Disorders .

 

Under a genetic point of view the following Genes are currently associated with Generalized Anxiety Disorder according to Malacards.org; for each gene I provide a potential drug/supplement to treat the mutations:

1) HTR1A

Try HTR1A Agonists

Buspirone, Tandospirone

 

2) SLC6A4

Try SSRI
In particular Escitalopram

 

3) TSPO

Try TSPO agonists

Etifoxine

 

4) HTR2A

Try HTR2A Antagonists
?

 

5) SLC6A2

Try SSRI
In particular Escitalopram

 

6) MAOA

Too risky to act on this gene (?)

 

7) PSMD9

Not sure what could help for this gene.

 

8) HTR3A

Try 5-HT3 receptor antagonists

List at https://en.wikipedia...tor#Antagonists

 

9) TPH1

Try anything that increase serotonin (watch out for serotonin syndrome and do not mix them)

L-Tryptophan
5-HTP
SSRI 

 

10) CRHR1

Try CRHR1 antagonists

Antalarmin, Quercetin

 

11) RGS2

Not sure what could help for this gene

 

12) BDNF

Try BDNF enhancers

Excercise, SSRI, Lion's mane, NSI-189 (still under clinical investigation and potentially risky)

Others

 

13) DRD2

DRD2 agonists 

Cabergoline (not for long term due to potential receptors down-regulation)

 

The list above is just a draft and does not pretend to be exhaustive; I am sure there are plenty of drugs/supplements missing targeting each gene and exercise and a good diet potentially have a positive impact on many of them.

One or multiple mutations in one or more SNPs associated with the above genes could be the cause of your Generalized Anxiety Disorder.

If you do not have the time to take a genetic test with 23andme or, even better, a whole exome sequencing (which is much more comprehensive and unfortunately expensive than 23andme) with companies like Gene by Gene and interpret the results with third party services like livewello.com and selfhacked.com the best option is to go through a process of trial and error, under medical supervision, targeting each gene one at the time with the proper drug/supplement above or other you might find through your own research. It is not surprising that SSRI and moderate exercise might have a positive impact on many of the deficiencies caused by the gene mutations above.

[Daniel Cooper]

So what ever happened to ScienceGuy?  Was he run off?

 

If anyone knows where he is on the internet these days please PM me.

 

 

 

[Galaxyshock]

So what ever happened to ScienceGuy?  Was he run off?

 

If anyone knows where he is on the internet these days please PM me.

 

He drank a cup of chamomile tea and died from the withdrawals.

[world33]

To add to my post above on Generalized Anxiety Disorder associated with chronic stress and cortisol levels/sensitivity (higher anxiety in the morning) rhodiola rosea is also a supplement to consider (from 100 to 500mg in the morning on an empty stomach 20 mins before breakfast; it can be divided in two doses morning and early afternoon; dosage depending on your reaction and potency of the brand).

 

Not all rhodiola supplements on the market have the same effect.

 

According to this 2015 UK research "The authenticity and quality of Rhodiola rosea products" available at https://www.scienced...003189?via=ihub
 
Now Foods (#24, US) and Higher Nature (#10) / Vitano (#11) both manufactured from a German company called Dr. Willmar Schwabe GmbH are the supplements with the highest content of rosavins (PC1) and salidrosides (PC2) (see chart) among 40 products (see attached word document with the modified list including brand names of the best products) available in the UK market (see picture with basket of products)
 

 

 

Now Foods contains 500mg which might be too much for some. I suggest to open the capsule and start taking 1/3 (166mg) or half (250mg) to test the effect on you. Everyone is different and supplements have different effect accordingly. Sometime it is not just a question of right brand but also right dosage...

Attached Files

•  The authenticity and quality of Rhodiola rosea products.docx   22.03KB   4 downloads

Edited by world33, 30 January 2018 - 03:24 AM.

[Mind_Paralysis]

To add to my post above on Generalized Anxiety Disorder associated with chronic stress and cortisol levels/sensitivity (higher anxiety in the morning) rhodiola rosea is also a supplement to consider (from 100 to 500mg in the morning on an empty stomach 20 mins before breakfast; it can be divided in two doses morning and early afternoon; dosage depending on your reaction and potency of the brand).

 

Not all rhodiola supplements on the market have the same effect.

 

According to this 2015 UK research "The authenticity and quality of Rhodiola rosea products" available at https://www.scienced...003189?via=ihub
 
Now Foods (#24, US) and Higher Nature (#10) / Vitano (#11) both manufactured from a German company called Dr. Willmar Schwabe GmbH are the supplements with the highest content of rosavins (PC1) and salidrosides (PC2) (see chart) among 40 products (see attached word document with the modified list including brand names of the best products) available in the UK market (see picture with basket of products)
 

 

 

Now Foods contains 500mg which might be too much for some. I suggest to open the capsule and start taking 1/3 (166mg) or half (250mg) to test the effect on you. Everyone is different and supplements have different effect accordingly. Sometime it is not just a question of right brand but also right dosage...

 

Excellent data, mate. Something to consider though, in order to get the right dosage, is if, and how, one can test ones cortisol-levels daily? A test in the morning and a test in the evening would be the ideal, to really get some objective data on the effects.

 

Anybody know how one does that?

[prunk]

Scienceguys list of what to take and not to take is a good example of a meaningless list. It's just impossible to say in advance what works and what doesn't. Your mileage may truly vary.

[Josko]

If anyone is suffering from Generalized Anxiety Disorder and the symptoms are worse in the morning due to higher cortisol (stress) levels I urge you to try:

• Phosphatidylserine (sunflower or soy derived) up to 600/800mg per day divided in two or three doses (higher dosages in the morning and lower in the evening when cortisol lowers naturally). 100mg (the standard dosage of many supplements out there) per day is too low and does not do much for me.
• EGCG
• Quercetin
• Glycyrrhizic Acid (found in licorice but not recommended because it has a side effect to increase blood pressure) 

They all reduce cortisol with different mechanisms of action. In particular EGCG, Quercetin and Glycyrrhizic acid are potent Inhibitors of Human 11β-hydroxysteroid Dehydrogenase Type 1  (HSD) the enzyme responsible to convert the inactive cortisone to the active hormone cortisol (the stress hormone). If you suffer from chronic or acute stress and think that it may play a role in your anxiety or depression I would seriously give it a try. Drinking decaffeinated green tea is good but it does not have the same potent effect of a EGCG supplement. Same thing apply to food containing quercetin (i.e. onions, apples etc.); a Quercetin supplement is much stronger.
Reducing cortisol levels has also many other important positive effects on so many levels including belly fat. An interesting reading is The Cortisol Connection which explains the role of HSD in cortisol levels and health-related effects.
My anxiety is a type of anxiety very strong in the morning and almost disappearing in the evening and it is therefore related to cortisol levels and/or glucocorticoid receptor sensitivity. Mifepristone, a glucocorticoid receptor antagonist drug used for abortion, is also something I want to try in the future. Some clinical trials have been carried out using that drug for several mental illnesses such as anxiety, bipolar disorder and PTSD. For anxiety see Antiglucocorticoid Therapy for Cognitive Impairment in Late-life Anxiety Disorders .

 

Under a genetic point of view the following Genes are currently associated with Generalized Anxiety Disorder according to Malacards.org; for each gene I provide a potential drug/supplement to treat the mutations:

1) HTR1A

Try HTR1A Agonists

Buspirone, Tandospirone

 

2) SLC6A4

Try SSRI
In particular Escitalopram

 

3) TSPO

Try TSPO agonists

Etifoxine

 

4) HTR2A

Try HTR2A Antagonists
?

 

5) SLC6A2

Try SSRI
In particular Escitalopram

 

6) MAOA

Too risky to act on this gene (?)

 

7) PSMD9

Not sure what could help for this gene.

 

8) HTR3A

Try 5-HT3 receptor antagonists

List at https://en.wikipedia...tor#Antagonists

 

9) TPH1

Try anything that increase serotonin (watch out for serotonin syndrome and do not mix them)

L-Tryptophan
5-HTP
SSRI 

 

10) CRHR1

Try CRHR1 antagonists

Antalarmin, Quercetin

 

11) RGS2

Not sure what could help for this gene

 

12) BDNF

Try BDNF enhancers

Excercise, SSRI, Lion's mane, NSI-189 (still under clinical investigation and potentially risky)

Others

 

13) DRD2

DRD2 agonists 

Cabergoline (not for long term due to potential receptors down-regulation)

 

The list above is just a draft and does not pretend to be exhaustive; I am sure there are plenty of drugs/supplements missing targeting each gene and exercise and a good diet potentially have a positive impact on many of them.

One or multiple mutations in one or more SNPs associated with the above genes could be the cause of your Generalized Anxiety Disorder.

If you do not have the time to take a genetic test with 23andme or, even better, a whole exome sequencing (which is much more comprehensive and unfortunately expensive than 23andme) with companies like Gene by Gene and interpret the results with third party services like livewello.com and selfhacked.com the best option is to go through a process of trial and error, under medical supervision, targeting each gene one at the time with the proper drug/supplement above or other you might find through your own research. It is not surprising that SSRI and moderate exercise might have a positive impact on many of the deficiencies caused by the gene mutations above.

 

 

Hello,

Im new here. I suffer from social anxiety. After much reading, it seems that finding the right stack for your body is a really difficult task, and everybody reacts differently to the substances I find this genetic tests a good idea to try to cast some light upon the matter. Has anyone tried them?.

 

To world33, thank you for sharing all this info, until I saw your post I had not thought of the possibility of a genetic test: is the 23andme test good enough to find out about anxiety? (I see they speak on their webpage mainly about ancestors).

 

Any opinion about this one?

https://newlifegenet...s-anxiety-test/
 

Edited by Josko, 11 August 2018 - 09:47 PM.

[world33]

Hi Josko,

Personally I only took 23andme genetic test but it is very limited. The guys from Snpedia recommends genos.co for a Whole Exome Sequencing (499$ plus shipping out of the US).
I have not taken that yet because I am waiting to save a bit of money. When it comes to interpretation of the results Promethease (run by the same guys of Snpedia) accepts the raw data file generated by genos.co . Livewello.com should also accept their raw data file but selfdecode.com which is a quite powerful interpretation service is not supporting such an extensive file (only 23andme and ancestry I think).
So on one side you have the choice to go for a limited and cheaper test compatible with many interpretation tools and services and on the other side go for a whole Exome Sequencing where you get much more data and genes coverage at a higher cost.
If I were you with no issue of budget I would choose genos.co
When it comes to social anxiety Malacards shows no elite gene(s) responsible for it. Possibly it is a combination of genes or there is still no wide study which has found out the main culprits:
https://www.malacard...y#related_genes
You might try to search the clinvar database for keywords "social anxiety" and "genes" or "SNP" and see if there are more up-to-date results.
If I am not wrong malacards uses an algorythm and a search bot scanning several sources in order to retrieve, extract and publish their information. Algorythms and bots are never as good as humans to search, extract and organize information in my opinion so some studies might be missing from their listing.


What supplements have you tried?
Recently I have tried ashwagandha extract and it is working quite well for GAD (due to chronic stress in my case) I have to say.

world33

[world33]

By the way the SLC6A4 gene is listed as one of the potential culprits for SAD (source: https://insights.ovi...201706000-00003 ). If that applies to you SSRI, in particular lexapro, could help in that regard.
The other gene mentioned in that publication is the ANK3. In that case Sodium channel blockers might help. Kava has some potency as sodium channel blocker according to selfdecode https://www.selfhack..._Treats_Anxiety

Edited by world33, 22 August 2018 - 12:27 PM.

[Josko]

Hi Josko,

Personally I only took 23andme genetic test but it is very limited. The guys from Snpedia recommends genos.co for a Whole Exome Sequencing (499$ plus shipping out of the US).
I have not taken that yet because I am waiting to save a bit of money. When it comes to interpretation of the results Promethease (run by the same guys of Snpedia) accepts the raw data file generated by genos.co . Livewello.com should also accept their raw data file but selfdecode.com which is a quite powerful interpretation service is not supporting such an extensive file (only 23andme and ancestry I think).
So on one side you have the choice to go for a limited and cheaper test compatible with many interpretation tools and services and on the other side go for a whole Exome Sequencing where you get much more data and genes coverage at a higher cost.
If I were you with no issue of budget I would choose genos.co
When it comes to social anxiety Malacards shows no elite gene(s) responsible for it. Possibly it is a combination of genes or there is still no wide study which has found out the main culprits:
https://www.malacard...y#related_genes
You might try to search the clinvar database for keywords "social anxiety" and "genes" or "SNP" and see if there are more up-to-date results.
If I am not wrong malacards uses an algorythm and a search bot scanning several sources in order to retrieve, extract and publish their information. Algorythms and bots are never as good as humans to search, extract and organize information in my opinion so some studies might be missing from their listing.


What supplements have you tried?
Recently I have tried ashwagandha extract and it is working quite well for GAD (due to chronic stress in my case) I have to say.

world33

 

Thank you for the info I have to think which to go for. Although it seems to me that after all you will always be left with trying supplements and see which ones work for you, but it will always be better having as much info as possible thats for sure, I have to do one of them. I do know since many years ago that I have one mutation that gives me hemochromatosis which I am treated for.

I am trying Fish Oil (high in DHA), Multivitamins, intended more as long-term routine to improve general health.

L-Theanine with Lemon Balm for anxiety, noticing only mild effects so far.

And Magnesium at night which makes me fall asleep faster and also intended as long-term supplement.

 

I have also ordered Ashwagandha recently. I have some hopes on it as well. Jarrows KSM-66 300mg, same as on the Ashwa miracolous herb thread. I have read it can lowers Cortisol as well. (I also feel worse in the mornings)

Have in mind also all those KAVA, Inositol, Curcumin, maybe Fasoracetam.

 

I am trying also Phenibut for the hard days. Noticed effect at 500mg although not in stressful situations just yet. Will try next week again 500g-600g. I know you have to be careful with this. I intend to use it 1 day per week.

 

I guess for SAD, ideal situation would be to find 5 different nootropics that work for you for each day of the week, with weekends off, and those 5 affecting differently your brain so not developing any tolerance. No idea if that is even realistic or achieveable.

[XenMan]

This is the worst of the worst of Longecity.

Self diagnosis, supps based isolated parts of studies, and unqualified advice.

See a psychologist, psychiatrist, look at CBT and meditation.

Pharmaceuticals can help until you have behaviour and cogntive change.

Last post on this site, last straw for me.

[world33]

This is the worst of the worst of Longecity.

Self diagnosis, supps based isolated parts of studies, and unqualified advice.

See a psychologist, psychiatrist, look at CBT and meditation.

Pharmaceuticals can help until you have behaviour and cogntive change.

Last post on this site, last straw for me.

Tried psychologist and CBT and did nothing for me apart from emptying my wallet. When your morning anxiety is so strong that you continuously release adrenaline and/or cortisol for no reason whatsoever to the point that your brain go blank, and extreme brain fog and lack of concentration take over you and you just wish to fall asleep again and wake up in the evening when this awful condition slightly fades away there is no psychologist or CBT that can help you out. It may work for mild forms of anxieties but medications and supplements are the only way to go.
If you are not happy with adults sharing personal experiences and science based research papers you can go to another forum to leave your 2 cents judgmental comments. You will not be missed.

[goncal]

A naturopath told me its adrenal fatigue, i read might or could be hpa dysfunction or pysche. Basically actual part of thalamus brain not working right. there is alot info on that via web too, no therapies though. Im always short of breath too, especislly if I miss my meals or exert too much physically.
I havent slept well most of last month. Sleeping pills sometimes dont work. Tried lots of natural sedatives, they seem to work first few times, then no more.

U folks shud try a dozen of them, buy like 5 adaptogens and all safe sedatives on this forum, try rotate to avoid tolerance every 3 days...
What hurt me the most was losing my sleep. Just feel faint wen I take walks now and very very short of breath

Lungs are checked, doc doesnt wanna do anything.
Just try be positive, it get worse every time I stress or had panic episodes, msybe there not enough gaba? I felt alot better months ago. Mri has multiple brain lesions as well.
Just telling my story.

Edited by goncal, 07 November 2018 - 06:03 PM.

[Josko]

Well, after trying out some supplements for my anxiety my experiences so far:

 

Ashwaganda: It lowers my irritability and helps with well being, which is nice, but not so much for anxiety.

 

Kratom: Have tried red, green, white. Not noticing much. One big euphoria first time with green malay, but nevermore, and not what Im looking for.

 

CBD Oil: Seems to do something, but have noticed weird heart beat 1-2 seconds, 1-2 times the day I take it, so discontinuing for now.

L-Theanine/Lemon Balm/Tryptophan: Not much.

 

Phenibut: the only thing that really has been notiaceable. Very noticeable, no placebo, no blablabla. At super low dose, 500mg. Only using 1 time per week for now. The dont give a f*** feeling it gives is better than any euphoria for me. Downsides: the usual drinking a lot of water to maintain hydrated which is just inconvenient. And it seems to give sometimes a bit of internal itching/burning feeling at one knee, although not sure about it yet.

 

Still quite a few things to try out. I´ll see...

 

 

 

 

[fred899]

After having tried a lot of what's been recommended here, I have some conclusions:

• I built a tolerance to Theanine and had to quit it because it's not sustainable. I tried many other substances over the course of several years, but I either built tolerance to those, or they simply didn't work. 
• 1g+ of Vitamin B6 daily helped (careful though, work your way up and watch for signs of overconsumption) (I take pyridoxine for the most part, but pyridoxal phosphate should work identically
• Meditation helped the most, but was very hard to get started with. I used mostly Kelly McGonical's work
• The Wim Hof method (which I've only been trying for 2 weeks) helped a lot regarding brain fog and meditation, which in turn reduces anxiety. Don't know what it is? Do 3 rounds just after you wake up and before dinner. 

[goncal]

If you were mentally well before these problems, It cud be this, hpa axis dysfunction or brain lesions or adrenal insufficiency

This doesnt really change treatment...unless adrenal then get hormones. Same thing for hpa

Edited by goncal, 13 February 2019 - 07:59 PM.

[BarrelBoy]

I'd encourage anyone who is hyperfocused on pills and supplements as the only answer to curing what ails you to consider environmental and behavioral changes and that the cause of anxiety can vary a lot between people.

 

Here are some different causes of anxiety that have much more obvious "treatments" than taking some substance.

 

- Poor sleep quality. Especially due to sleep apnea or not enough sleep.

 

- Conscious/unconscious negative self-talk. Longterm beliefs about yourself being a failure or unworthy can hugely damaging.

 

- Failing to stick to social or personal commitments. Again, usually leading to negative self-talk/self-perception.

 

- Being in an environment that continually tells you that you aren't good enough or making you worried about making mistakes.

 

- Regularly taking other non-gabagineric substances, such as stimulants.

 

 

The list can go on but those are a few ideas. In the case of negative self-talk/beliefs, one very good place to start is simply writing down how you feel, every day. There are plenty of more structured writing programs you can look that will ask you to explore your past and especially your beliefs about the future - as it is commonly said that depression is regret about the past while anxiety is fear of the future. In this respect, the more you can live in the present the less you'll be drawn into sad and stressful states. If supplements help, by all means take them but this an extremely narrow treatment approach by itself.

[CarlSagan]

I'm surprised to see that Magnolia Officinalis is on the approved list since it appears to be a GABAA PAM or agnonist.   What is the explanation for that?

Not sure but looking into the whole "benzo like withdrawals" thing it doesn't seem like a concern with this at standard doses, different mechanisms at GABA A  benzos bind to their own receptor sites & this has different binding sites. most anecdotal reports online do not mention withdrawals after sustained magnolia bark use. I can't find any papers showing this in studies. only ones that show weeks of use were fine but not sure if there was follow up. I saw 1 report on reddit that mentioned panic attacks & withdrawals after 2 months, the same user posted 1 year later about taking magnolia bark for 6 months with no withdrawal symptoms.

https://www.reddit.c...web2x&context=3
 

So I think many people don't realize the complexities in these receptors and systems. They see GABA or GABA-A and assume they are more simple than they are in reality. Take magnolia bark for instance. Magnolol and honokiol are positive allosteric modulators of the GABA-A receptors, showing particularly high efficacy at δ-containing receptors. Benzodiazepines are also positive allosteric modulators, but have their own binding site between the α and γ subunit. So if you were to just see GABA-A and positive allosteric modulator, you might think magnolia bark and benzodiazepines act the same way, but they don't. The α1 containing GABA-A receptors have been shown to be crucial in the dependence seen in some GABAergic compounds. In fact, some pharma companies are developing non-dependence-forming alternatives by leveraging that knowledge. It also explains why benzos can form tolerance and dependence so quickly, where other compounds that are targeting the non-α1 binding sites don't. Admittedly, that's simplifying it down even more than reality. You have to get even more detailed to really get a full picture, like separating the α1β3γ2 subreceptor from the α1β3δ ones. However, the main idea is the same. Which specific receptors you are hitting, and how you are hitting them, is crucial to the dependence and withdrawal effects. That's to say nothing of GABA-B or other affinities, which all affect signaling cascades.

So remember that things are much more complex than they seem on the surface. I've personally used gotu kola, lemon balm, magnolia bark, etc. daily for longer periods, then stopped cold turkey without any issues. I get very strong rebound effects from benzos, though. There is a very clear difference. That's not saying that some people might not have issues.. Everyone is different, and I have seen people with strange reactions to all sorts of things. However, when talking about dependency and withdrawal, you are talking two totally different leagues with these botanical extracts and proper benzos.

 

(side note about dopamine - Magnolia bark lowers dopamine in the striatum and amygdala, but raises it in the hippocampus, thalamus and hypothalamus.)

https://www.reddit.c...web2x&context=3

 

 

4 weeks Relora showed efficacy with no adverse effects 250mg x2 daily 1.5% honokiol 0.1% berberine

https://www.ncbi.nlm...les/PMC3750820/

 

6 weeks 250mg x 3 well tolerated overall (lowered evening cortisol)

https://todayspracti...06_garrison.pdf
 

6 weeks 250mg x 3 well tolerated overall in women (showed efficacy for acute anxiety effect)

https://nutritionj.b...-2891-7-11#Tab1


^ I don't know if lack of adverse effects includes an extra time period after stopping in these. but if not i'd imagine they would have started to know about it by 6 weeks if there were benzo like sides & tolerance? which wasn't reported.   if concerned about this specifically could trial for a few weeks & see what happens after stopping before taking long term, but going by all this looks ok.   
BTW the magnolia bark part of Relora is fat soluable.

Mice treated with 1-10 mg kg(-1) diazepam, but not those treated with 0.1 - 2 mg kg(-1) honokiol, for 12 days showed withdrawal symptoms characterized by hyperactivity and running-fit when they were challenge-administered intraperitoneal flumazenil
https://europepmc.or...le/med/10197425

Edited by CarlSagan, 18 July 2021 - 09:58 AM.

[CarlSagan]

I'm surprised to see that Magnolia Officinalis is on the approved list since it appears to be a GABAA PAM or agnonist.   What is the explanation for that?

Not sure but looking into the whole "benzo like withdrawals" thing it doesn't seem like a concern with this at standard doses, different mechanisms at GABA A  benzos bind to their own receptor sites & this has different binding sites. most anecdotal reports online do not mention withdrawals after sustained magnolia bark use. I can't find any papers showing this in studies. only ones that show weeks of use were fine but not sure if there was follow up. I saw 1 report on reddit that mentioned panic attacks & withdrawals after 2 months, the same user posted 1 year later about taking magnolia bark for 6 months with no withdrawal symptoms.

https://www.reddit.c...web2x&context=3
 
So I think many people don't realize the complexities in these receptors and systems. They see GABA or GABA-A and assume they are more simple than they are in reality. Take magnolia bark for instance. Magnolol and honokiol are positive allosteric modulators of the GABA-A receptors, showing particularly high efficacy at δ-containing receptors. Benzodiazepines are also positive allosteric modulators, but have their own binding site between the α and γ subunit. So if you were to just see GABA-A and positive allosteric modulator, you might think magnolia bark and benzodiazepines act the same way, but they don't. The α1 containing GABA-A receptors have been shown to be crucial in the dependence seen in some GABAergic compounds. In fact, some pharma companies are developing non-dependence-forming alternatives by leveraging that knowledge. It also explains why benzos can form tolerance and dependence so quickly, where other compounds that are targeting the non-α1 binding sites don't. Admittedly, that's simplifying it down even more than reality. You have to get even more detailed to really get a full picture, like separating the α1β3γ2 subreceptor from the α1β3δ ones. However, the main idea is the same. Which specific receptors you are hitting, and how you are hitting them, is crucial to the dependence and withdrawal effects. That's to say nothing of GABA-B or other affinities, which all affect signaling cascades.
So remember that things are much more complex than they seem on the surface. I've personally used gotu kola, lemon balm, magnolia bark, etc. daily for longer periods, then stopped cold turkey without any issues. I get very strong rebound effects from benzos, though. There is a very clear difference. That's not saying that some people might not have issues.. Everyone is different, and I have seen people with strange reactions to all sorts of things. However, when talking about dependency and withdrawal, you are talking two totally different leagues with these botanical extracts and proper benzos.
 
(side note about dopamine - Magnolia bark lowers dopamine in the striatum and amygdala, but raises it in the hippocampus, thalamus and hypothalamus.)
https://www.reddit.c...web2x&context=3

 
 
Don't know about the combo but magnolia bark might even UPregulate GABA receptors
 
https://www.reddit.c...web2x&context=3
 
Magnolol and honokiol modulate the benzodiazepine receptor, but they do it very differently than a benzo does. They are very selective to the receptor subtypes they affect. Also, they lead to increases in the number of GABA binding sites and increase their binding affinity. So rather than down-regulation of the GABA sites like a benzo, you get up-regulation and increased binding of endogenous GABA. They also preferentially affect GABA receptors in the hippocampus, rather than the cortex and cerebellum. Benzos are actually REM sleep inhibitors. However, magnolia bark increases both REM and NREM sleep. So while benzos can make you fall asleep, they negatively affect sleep architecture. However, magnolia positively affects it. So while if we remove all complexity and specificity from the equation, it does look like magnolia bark is similar to a benzo, it is actually MUCH different in all the ways we want.
https://examine.com/...urotransmission
 
"20µM magnolol in vitro appears to enhance the density of GABAA receptors with an α type subunit, without affecting β nor γ type subunits or GAD65/67 (required for GABA synthesis).%5B32%5D This increase in the subunit has been noted elsewhere with 4-O-methylhonokiol (oral intake of 0.5mg/kg in mice) and diazepam.%5B10%5D
Magnolol appears to be able to increase the overall expression of GABAA receptors with alpha type subunits. This may be biologically relevant following oral ingestion"

 

https://www.research...btypes_in_vitro

As for subunit combinations, honokiol and magnolol have a more potent enhancing effect on alpha2 subunit containing combinations (with a maximum enhancement of 400-450% of control).

Edited by CarlSagan, 18 July 2021 - 11:14 AM.

[magta39]

Anyone have any opinions on apigenin?

[CarlSagan]

GABA aside honokiol in Magnolia bark may also lessen anxiety through normalizing a hyperactive HPA axis.  chronic stress reduces GR mRNA expression in the hippocampus as part of a negative feedback mechanism over time, and the hippocampus is involved in regulating HPA axis activity. honokiol might normalize this by increasing expression of GR in the hippocampus.   it also restored BDNF back to normal levels in depressed rats (connection with anti-depressants).

 

https://jin.imrpress...ype=PDF&id=4635

 

The mRNA expression of GR in the hippocampus of depressed rats returned to control (non-depressed) levels after treatment with honokiol.

These results indicate that honokiol can reduce HPA axis activity by regulating GC and GR mediated negative feedback to exert antidepressant effects in depressed rats. The hippocampus is a key regulatory center of HPA axis activity and the stress response, which can mediate the recovery from hyperactive HPA axis activity resulting from chronic stress (Belleau et al.,2019). There are two steroid hormone receptors in the hippocampus, GR and MR. MR has a strong affinity for GC, and its expression in the central nervous system is mainly concentrated in the marginal area. It maintains the basal level of cortisol in circulation when the body is in a normal state (Micale and Drago, 2018). GR has a much weaker affinity for GC than MR. GR contributes to the circadian secretion of cortisol and the regulation of stress-related cortisol secretion (Odeon et al., 2017). The hippocampus maintains HPA axis activity stability through the regulation of MR and the negative feedback mechanism mediated by GR and GC. The body exhibits HPA axis hyperactivity and secretes large amounts of glucocorticoids when it is subjected to chronic stress.

 

Furthermore, glucocorticoids will be maintained at high levels during chronic stress exposure. The high concentration of glucocorticoids repeatedly stimulates GRs, inducing GR dysfunction,

with deficits in the negative feedback mechanism. The result is ongoing HPA axis hyperactivity and damage to the hippocampus, inducing a maladaptive cycle (Bellavance and Rivest, 2014; Gądek-

Michalska et al., 2013). This process is considered to be the most substantial physiological and biochemical basis of stress-induced depression. In general, GR-mediated negative feedback regulation plays a vital role in maintaining the typical activity of the HPA axis. Repeated corticosterone injections can reduce GR mRNA expression in the hippocampus in rats, accompanied by HPA axis hyperactivity and depression-like behavior. However, these adverse effects of CORT are successfully treated with honokiol. This indicates that the antidepressant effects of honokiol are related to the restoration of GR mediated negative feedback.              

 

(Also found out Honokiol / Magnolol are potent anti-fungal compounds). https://sfamjournals...5X.2010.02900.x and anti cancer too.

Personal report on short usage, i didn't seem to get along well with Relora (stomach issues, woke up in the middle of the night hot & nauseous, repeated next day similar stomach issues and maybe higher body temp spike than usual. but it is hot here lately).

I think this was a problem with the other bark included in Relora alongside magnolia though, as I tried a low dose of high % magnolia bark extract yesterday & today and didn't notice the same sides. did not help get to sleep first night but maybe slight anxiety reduction for a bit. taking today I noticed a slight mood lift. will up dose a bit.

If this is good to go by http://www.itmonline...ts/magsafe.htm then traditional usage is 3-9 grams of bark as tea, and if typical honokiol content is 2% then that would be about 60mg - 180mg honokiol. toxicity studies in rats showed no toxicity at 240mg / kg of bark extract.

 

but who knows how this 60mg+ honokiol content relates to the amount in relora studies which showed some efficacy & impact on cortisol (when combined with the other bark though), hard to tell as they wouldn't disclose the magnolia content and compound %. "The product is standardized to “not less than 1.5% honokiol and 0.1% berberine." 

 

what does "not less" mean though? can it be 15% or 40% as long as its not under 1.5%? they took 250mg x3 a day, if its 50% magnolia that's 375mg. if 1.5% that's 5.6mg honokiol. if 15% that's 56mg honokiol.  don't want to skew things too much. so I will keep dose at or under the lower end of traditional use @ 60mg honokiol content just at night time.

Edited by CarlSagan, 22 July 2021 - 12:40 PM.

[CarlSagan]

An update on magnolia bark

 

I personally found it worked but gave me rebound anxiety the next mornings acutely & with a week or so of consecutive use when taken at night. i've seen people report not noticing any with continued use so guess it depends on the person like many things.

Overall I found it's useful situationally to get some acute relief from anxiety and a mood lift, when used spaced out once or twice a week during the daytime, but not back to back & in a smaller dose. no more than 1/4 of the swanson high dose 200mg extract. just under 1/4 works taken with fatty food.

 

--

 

I've been taking ND's nigella sativa 5% extract as it has anti-viral effects, got this as part of a covid / flu stack.

I found i've had decently lessened anxiety after taking this on empty stomach in mornings. surprising as i've tested it for sleep before and it definitely gave me nightmares taken before bed. but yeah seems taking this in the day has been beneficial. idk the mechanism but something worth looking in to. 

Edited by CarlSagan, 27 October 2021 - 01:40 PM.

[kurdishfella]

New (relative to research) research from the University of Cincinnati (UC) shows that elevated levels of sodium blunt the body's natural responses to stress by inhibiting stress hormones that would otherwise be activated in stressful situation

 

That's why I felt calmer from saline

Edited by kurdishfella, 20 December 2021 - 06:04 PM.

[liltokamak]

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 TAKE

SECTION 1 – WHAT YOU SHOULD NOT TAKE:

I have split the categorization into two; namely the items for which the evidence is wholly substantiated and conclusive, and hence should definitely be avoided; and secondly the items for the substantiated evidence is highly indicative but either conflicting or not wholly conclusive, and hence these items possibly should be avoided:

DEFINITELY TO BE AVOIDED:

1) GABA RECEPTOR AGONISTS:

I STRONGLY advise 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.

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.

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:

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)

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.

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:

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

N.B. This refers to CANNABIS in general and NOT PURE CANNABIDIOL

The 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 administered (Thanks goes to HOOTER for reminding me of this)

4) CAFFEINE

Inhibits GABA production.

5) OPIOID RECEPTOR AGONISTS (Thank you to NUPI for suggesting these)

I STRONGLY 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:

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

(N.B. I am sure that I have missed loads here and will try to revisit this list to make it more comprehensive as an when I have another free minute)

SEE THE FOLLOWING:

VALERIAN (VALERIANA OFFICINALIS):

Neuropharmacology. 2007 Jul;53(1):178-87. Epub 2007 May 13.

Valerenic acid [from Valerian] potentiates and inhibits GABA(A) receptors: molecular mechanism and subunit specificity.

Khom S, Baburin I, Timin E, Hohaus A, Trauner G, Kopp B, Hering S.

Source
Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.

Abstract
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

------------------------------------------------------------------------------------------------------------------------

The Gamma-Aminobutyric Acidergic Effects of Valerian and Valerenic Acid on Rat Brainstem Neuronal Activity [EDITED FULL TEXT]

• 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

Author Affiliations

• *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

Abstract
Valerian is a medicinal herb that produces anxiolytic and sedative effects. It was suggested that valerian acts via gamma-aminobutyric acid (GABA)ergic mechanisms. Previous studies showed binding of valerian extract to GABA receptors, but 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 GABA_A receptor 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 [IC₅₀], 2.0 ± 0.1 μM). This effect was antagonized by bicuculline (10 μM), a GABA_A antagonist. Then we showed that valerian extract 3 mg/mL induced a 29.6% ± 5.1% inhibition with an IC₅₀ of 240 ± 18.7 μg/mL, whereas 100 μM valerenic acid induced a 22.2% ± 3.4% inhibition with an IC₅₀ of 23 ± 2.6 μM (both P < 0.01). 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 that the pharmacological effects of valerian extract and valerenic acid are mediated through modulation of GABA_A receptor function. 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…

Discussion
…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. We also observed that the inhibitory activity of both valerian extract and valerenic acid was induced via GABA_A, but not GABA_B, receptors. Previous studies showed the binding of valerian extract to GABA_A receptors in rat cortical membrane preparation. We observed the neuropharmacological effect of GABA_A activity in our experiment. 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…
…Our data suggest that 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):

CNS Drugs 2002;16(11):731-43.

Therapeutic potential of kava in the treatment of anxiety disorders.

Singh YN, Singh NN.

Source
College of Pharmacy, South Dakota State University, Brookings, South Dakota 57007, USA. yadhu_singh@sdstate.edu

Abstract
Anxiety 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. The pharmacological properties of kava are postulated to include blockade of voltage-gated sodium ion channels, enhanced ligand binding to gamma-aminobutyric acid (GABA) type A receptors, diminished 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. 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.
PMID: 12383029

-----------------------------------------------------------------------------------------------------------------------

Planta Med. 2001 Jun;67(4):306-11.

Interaction of various Piper methysticum cultivars with CNS receptors in vitro.

Dinh LD, Simmen U, Bueter KB, Bueter B, Lundstrom K, Schaffner W.

Source
Institute of Pharmaceutical Biology, University of Basel, Witterswil, Switzerland.

Abstract
Methanolic 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), dopamine 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. The most potent binding inhibition was observed for leaf extracts to GABAA receptors (GABA binding site) 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, our investigation indicates that the GABAA, dopamine D2, opioid (mu and delta) and histamine (H1 and H2) receptors might be involved in the pharmacological action of kava extracts. 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: 11458444


GOTU KOLA (CENTELLA ASIATICA)

GOTU KOLA (CENTELLA ASIATICA) is also a GABA RECEPTOR AGONIST and hence should be AVOIDED.

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:

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.

Pharmacological characterization of GABAA receptors in taurine-fed mice.

L'Amoreaux WJ, Marsillo A, El Idrissi A.

Source
Department of Biology, College of Staten Island, 2800 Victory Blvd, Staten Island, NY 10314, USA. William.Lamoreaux@csi.cuny.edu

Abstract

BACKGROUND:
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 that GABAA receptors were down regulated with chronic administration of taurine. Here, 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

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Medical News T. 2010 Jan 18

Scientists Close In On Taurine's Activity In The Brain

Dr. Minerva Yue, Dr. Angelo Keramidas, Dr. Peter A. Goldstein, Dr. Dev Chandra, Dr. Gregg E. Homanics

Source: 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.

"We have discovered that taurine is a strong activator of what are known as GABA receptors 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. It seems that taurine shares these receptors."

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 human brain.

"We found that taurine is extraordinarily active on this population of GABA receptors in the thalamus," Dr. Harrison 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."

Of 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."


ASHWAGHANDHA (WITHANIA SOMNIFERA):

Environmental Health Perspectives * Volume 107, Number 10, October 1999

Ancient-Modern Concordance in Ayurvedic Plants: Some Examples

Sukh Dev

Source
University of Delhi, B.R.A. Centre for Biomedical Research, Delhi, India

Extract from Full Text
Ashwagandha (root) is another important antiaging plant. We have investigated this plant in some detail because its extract showed high affinity for both GABAA and GABAB receptors. Receptor-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.

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Phytother Res. 2010 Aug;24(8):1147-50.

The methanolic extract of Withania somnifera ACTS on GABAA receptors in gonadotropin releasing hormone (GnRH) neurons in mice.

Bhattarai JP, Ah Park S, Han SK.

Source
Department of Oral Physiology and BK21 program, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Jeonju, 561-756, Republic of Korea.

Abstract
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. 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.

PMID: 20044800

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Indian J Exp Biol. 2008 Jun;46(6):465-9.

Effect of Withania somnifera Dunal root extract against pentylenetetrazol seizure threshold in mice: possible involvement of GABAergic system.

Kulkarni SK, Akula KK, Dhir A.

Source
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160 014, India. skpu@yahoo.com

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

PMID: 18697606

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Indian J Med Res. 1991 Aug;94:312-5.

Pharmacological effects of Withania somnifera root extract on GABAA receptor complex.

Mehta AK, Binkley P, Gandhi SS, Ticku MK

Source
Department of Pharmacology, University of Texas Health Science Center.

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

PMID: 1660034


CALIFORNIA POPPY (ESCHSCHOLZIA CALIFORNICA)

Phytother Res. 2001 Aug;15(5):377-81.

Neurophysiological effects of an extract of Eschscholzia californica Cham. (Papaveraceae).

Rolland A, Fleurentin J, Lanhers MC, Misslin R, Mortier F.

Source
Laboratoire de Pharmacognosie, E.B.S.E., Université de Metz, Campus Bridoux, 1 rue des Récollets, F-57000 Metz, France.

Abstract
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 but 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. The Ec extract induced peripheral analgesic effects in mice but did not possess antidepressant, neuroleptic or antihistaminic effects.

PMID: 11507727


SKULLCAP (SCUTELLARIA LATERIFLORA)

Phytomedicine. 2003 Nov;10(8):640-9.

Phytochemical and biological analysis of skullcap (Scutellaria lateriflora L.): a medicinal plant with anxiolytic properties.

Awad R, Arnason JT, Trudeau V, Bergeron C, Budzinski JW, Foster BC, Merali Z.

Source
Ottawa-Carleton Institute of Biology, University of Ottawa, Ottawa, Canada.

Abstract
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. 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) and glutamine in a H2O extract (31 mg/g), was performed using HPLC. 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.

PMID: 14692724
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British Journal of Wel. 2010 Jun;1(4):25-30

American skullcap (Scutellaria lateriflora): an ancient remedy for today’s anxiety?

Brock C., Whitehouse J., Tewfik I., Towell T.

Source

School of Life Sciences, University of Westminster, United Kingdom.

Extract from Full Text

Many orthodox anxiolytic treatments can have unwanted side effects. 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)…

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). 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 mouse cerebral cortex in vitro. 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)

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 to short-term usage and/or CYCLING ON/OFF.

See the following:

Phytotherapy Res. 1996;10:177–179.

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

Avallone, R.; Zanoli, P.; Corsi, L.; Cannazza, G.; Baraldi, M.

Source
Department of Pharmaceutical Sciences, Modena University, Via Campi 183, 41110 Modena (Italy)

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Planta Med. 1995 Jun;61(3):213-6.

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

Viola H, Wasowski C, Levi de Stein M, Wolfman C, Silveira R, Dajas F, Medina JH, Paladini AC.

Source
Instituto de Biología Celular, Facultad de Medicina, Buenos Aires, Argentina.

Abstract
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. The results reported in this paper demonstrate that apigenin is a ligand for the central benzodiazepine receptors exerting anxiolytic and slight sedative effects but not being anticonvulsant or myorelaxant.

PMID: 7617761
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Canadian Journal of Physiology and Pharmacology, Volume 85, Number 9, September 2007 , pp. 933-942(10)

Effects of traditionally used anxiolytic botanicals on enzymes of the γ-aminobutyric acid (GABA) system

Awad, R.; Levac, D.; Cybulska, P.; Merali, Z.; Trudeau, V.L.; Arnason, J.T.

Source
NRC Research Press.

Abstract
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 (IC₅₀) of aqueous and ethanolic plant extracts. Approximately 70% of all extracts that were tested showed little or no inhibitory effect (IC₅₀ values 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 (IC₅₀ = 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) 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.


NEFIRACETAM

Brain Res Brain Res Rev. 1994 May;19(2):180-222.

Piracetam and other structurally related nootropics.

Gouliaev AH, Senning A.

Source
Department of Chemistry, Aarhus University, Denmark.

Abstract
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. 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. 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: 8061686


PASSION FLOWER (PASSIFLORA INCARNATA)

Planta Med. 2008 Dec;74(15):1769-73. Epub 2008 Nov 12.

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

Grundmann O, Wang J, McGregor GP, Butterweck V.

Source
College of Pharmacy, Department of Pharmaceutics, University of Florida, FL, USA

Abstract
The 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. Following oral administration, the extract exerted an anxiolytic effect that was comparable to diazepam (1.5 mg/kg) at a dose of 375 mg/kg and exhibited a U-shaped dose-response curve. In 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. This study is the first demonstration of the IN VIVO, GABA-mediated anxiolytic activity of an HPLC- characterized extract of Passiflora incarnata.

PMID: 19006051
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Phytother Res. 2011 Jun;25(6):838-43. doi: 10.1002/ptr.3352. Epub 2010 Nov 19.

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

Appel K, Rose T, Fiebich B, Kammler T, Hoffmann C, Weiss G.

Source
VivaCell Biotechnology GmbH, Denzlingen, Germany.

Abstract
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. The extract inhibited [(3) H]-GABA uptake into rat cortical synaptosomes but had no effect on GABA release and GABA transaminase activity. Passiflora incarnata inhibited concentration dependently the binding of [(3) H]- SR95531 to GABA(A) -receptors and of [(3) H]-CGP 54626 to GABA(B) -receptors. Using the [(35) S]-GTPγS binding assay 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.

PMID: 21089181
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Phytother Res. 2009 Dec;23(12):1795-6.

Interactions of Valeriana officinalis L. and Passiflora incarnata L. in a patient treated with lorazepam.

Carrasco MC, Vallejo JR, Pardo-de-Santayana M, Peral D, Martín MA, Altimiras J.

Source
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.

Abstract
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. The active principles of Valerian and passionflower might increase the inhibitory activity of benzodiazepines binding to the GABA receptors, causing 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: 19441067


BETA-ALANINE

It 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.

Beta-alanine as a small molecule neurotransmitter.

Tiedje KE, Stevens K, Barnes S, Weaver DF.

Source
Department of Chemistry, Dalhousie University, B3H 4J3 Halifax, Canada.

Abstract
This review discusses the role of beta-alanine as a neurotransmitter. Beta-alanine is structurally intermediate between alpha-amino acid (glycine, glutamate) and gamma-amino acid (GABA) neurotransmitters. In general, 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 neuronal excitability. beta-Alanine has 5 recognized receptor sites: glycine co-agonist site on the NMDA complex (strychnine-insensitive); glycine receptor site (strychnine sensitive); GABA-A receptor; GABA-C receptor; and blockade of GAT protein-mediated glial GABA uptake. Although beta-alanine binding has been identified throughout the hippocampus, limbic structures, 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, a 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: 20540981


LEMON BALM (MELISSA OFFICINALIS)

LEMON 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 to short-term usage 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.

Bioassay-guided fractionation of lemon balm (Melissa officinalis L.) using an in vitro measure of GABA transaminase activity.

Awad R, Muhammad A, Durst T, Trudeau VL, Arnason JT.

Source
Centre for Advanced Research in Environmental Genomics (CAREG), Department of Biology, University of Ottawa, Ottawa, Ontario, Canada.

Abstract
A novel pharmacological mechanism of action for the anxiolytic botanical Melissa officinalis L. (lemon balm) is reported. The methanol extract was identified as a potent in vitro inhibitor of rat brain GABA transaminase (GABA-T), 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
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Canadian Journal of Physiology and Pharmacology, Volume 85, Number 9, September 2007 , pp. 933-942(10)

Effects of traditionally used anxiolytic botanicals on enzymes of the γ-aminobutyric acid (GABA) system

Awad, R.; Levac, D.; Cybulska, P.; Merali, Z.; Trudeau, V.L.; Arnason, J.T.

Source
NRC Research Press.

Abstract
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 (IC₅₀) of aqueous and ethanolic plant extracts. Approximately 70% of all extracts that were tested showed little or no inhibitory effect (IC₅₀ values 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 (IC₅₀ = 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) 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 (HUMULUS LUPULUS)

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 ‘absolutely safe’, prolonged usage of HOPS for the medium to long-term should be avoided; and usage should be restricted to short-term usage only and/or CYCLING ON/OFF.

See the following:

HerbalGram. 2010; 87: 44-57

Hops (Humulus lupulus): A Review of its Historic and Medicinal Uses

Uwe Koetter, Martin Biendl

Source
American Botanical Council

Extract from Full Text
Recent in vitro experiments on sedative activity indicated activity on the melatonin receptor. Melatonin, 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 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. The fraction containing beta-acids of a lipophilic CO₂ hops 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.

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.

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.
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J Agric Food Chem. 2006 Apr 5;54(7):2514-9.

Effects of beer and hop on ionotropic gamma-aminobutyric acid receptors.

Aoshima H, Takeda K, Okita Y, Hossain SJ, Koda H, Kiso Y.

Source
Department of Physics, Biology and Informatics, Faculty of Science, Yamaguchi University, Yoshida, Yamaguchi 753-8512, Japan.

Abstract
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 pentane extract of the beer, hop (Humulus lupulus L.) oil, and myrcenol potentiated the GABA(A) receptor response elicited by GABA. The 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
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Canadian Journal of Physiology and Pharmacology, Volume 85, Number 9, September 2007 , pp. 933-942(10)

Effects of traditionally used anxiolytic botanicals on enzymes of the γ-aminobutyric acid (GABA) system

Awad, R.; Levac, D.; Cybulska, P.; Merali, Z.; Trudeau, V.L.; Arnason, J.T.

Source
NRC Research Press.

Abstract
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 (IC₅₀) of aqueous and ethanolic plant extracts. Approximately 70% of all extracts that were tested showed little or no inhibitory effect (IC₅₀ values 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 (IC₅₀ = 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) 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.


NIACINAMIDE

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 effects

2) 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).

STUDIES INDICATING THAT NIACINAMIDE IS NEUROTOXIC:

Neurosci Lett. 1985 Mar 15;54(2-3):173-7.

gamma-Aminobutyric acid modulation of benzodiazepine receptor binding in vitro does not predict the pharmacologic activity of all benzodiazepine receptor ligands.

Chweh AY, Swinyard EA, Wolf HH.

Abstract
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. 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 and nicotinamide [niacinamide] exhibited neurotoxicity by 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

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J Neurochem. 2000 Sep;75(3):982-90.

2-Deoxy-D-glucose prevents and nicotinamide [niacinamide] potentiates 3, 4-methylenedioxymethamphetamine-induced serotonin neurotoxicity.

Hervías I, Lasheras B, Aguirre N.

Source
Department of Pharmacology, University of Navarra Medical School, Pamplona, Spain.

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

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

Br J Pharmacol. 1985 March; 84(3): 689–696.

Central effects of nicotinamide and inosine which are not mediated through benzodiazepine receptors.

J. M. Bold, C. R. Gardner, and R. J. Walker

Abstract

The 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]-flunitrazepam binding studies showed that nicotinamide and inosine 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. Similarly, inosine exerts a neuronal depressant effect dissimilar from that of benzodiazepines.

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Biokhimiia. 1989 Mar;54(3):381-6.

[Solubilization of the central benzodiazepine receptor and study of its interaction with nicotinamide].
[Article in Russian]

Fomenko AI, Stepanenko SP, Donchenko GV, Khalmuradov AG.

Abstract
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. 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
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STUDIES INDICATING THAT NIACINAMIDE IS A GABA RECEPTOR AGONIST:

Nature. 1979 Apr 5;278(5704):563-5.

Nicotinamide is a brain constituent with benzodiazepine-like actions.

Möhler H, Polc P, Cumin R, Pieri L, Kettler R.

PMID: 155222

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Ann Ist Super Sanita. 1982;18(1):95-8.

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

Voronina TA.

PMID: 6303184
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J Orthomolecular Medicine 2005; 20(3): 167-178

Supplemental Niacinamide Mitigates Anxiety Symptoms: Three Case Reports

Prousky J E

Extract from Full Text

Abstract
The purpose of this report is to highlight the potential of niacinamide for the treatment of anxiety disorders. Three patients
were 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. The possible biochemical reasons for niacinamide’s effectiveness might be related to the correction of subclinical pellagra, the correction of an underlying vitamin B3 dependency disorder, its benzodiazepine-like effects, its ability to raise serotonin levels, or its ability to modify the metabolism of blood lactate (lactic acid). 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.

Benzodiazepine-like Properties
Additional reasons for niacinamide’s effectiveness likely have to do with its benzodiazepine-like effects. 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.24 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.14 Table 2 (p.174) summarizes this data.25-30 It appears that niacinamide has therapeutic effects comparable to the benzodiazepines. 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.

Serotonin Synthesis
Another biochemical reason for niacinamide’s anxiolytic effects might have to do with the vital role that it has upon the synthesis of serotonin. 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.34 Taking pharmacological doses of niacinamide (or any other form of vitamin B3) would increase the production of serotonin, by diverting more tryptophan to become substrate for serotonin synthesis. Niacinamide’s therapeutic ability to increase serotonin production might explain why it was successful in reducing the anxiety symptoms of the three patients.

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

Prescribing Instructions
In terms of proper dosing, most patients require a minimum of 2,000-4,500 mg per day to achieve therapeutic results…

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.

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Biull Eksp Biol Med. 1986 Mar;101(3):329-31.

[Mechanism of the tranquilizing action of electron structural analogs of nicotinamide].
[Article in Russian]

Akhundov RA, Rozhanets VV, Voronina TA, Val'dman AV.

Abstract
The interaction of nicotinamide and its electron structural analogs (NMF and AzN compounds) with central benzodiazepine receptor antagonist Ro 15-1788 and GABA-ergic system antagonist bicuculline were studied in a conflicting situation test. NMF and AzN behaved as the agonists of GABA-benzodiazepine receptor complex. Like in diazepam, the anxiolytic effects of benzodiazepines and nicotinamide was prevented by bicuculline and Ro 15-1788. The given compounds were shown to be more active, than nicotinamide.

PMID: 2869801

This study indicates that NIACINAMIDE is a GABA RECEPTOR AGONIST


TAPERING-DOWN OF GABA RECEPTOR AGONISTS:

IF you are currently addicted to a GABA RECEPTOR AGONIST (e.g. BENZODIAZEPINES), then it is strongly advised that you do not quit cold turkey since 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 an equivalent GABA 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.

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 due 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!)

(N.B. I will try to revisit this list to make it more comprehensive as an when I next have a free minute)


GARUM ARMORICUM

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 are very different.

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.

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

GARUM ARMORICUM also contains a very small quantity 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.

The Effectiveness of Garum Armoricum in Reducing Anxiety in College Students

Abstract:
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.
The administration of Garum Armoricum resulted in a statistically significant difference in mean anxiety test scores. 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. 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.
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Curr Top Nutraceutical Res. 2008 Aug;6(3):115-23

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

Messaoudi M, Nejdi A, Bisson JF, Rozan P, Javelot H, Lalonde R.

Abstract
The anxiolytic- and antidepressant-like effects of GARUM ARMORICUM, a protein autolysate from the blue ling fish, were studied 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 results indicate the potential anxiolytic and antidepressant-like properties of GARUM ARMORICUM in the absence of any change in cerebral activation and dependence. These psychotropic properties of GARUM ARMORICUM may be due to the synergistic action of its active constituents.


MAGNESIUM:

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 ANTAGONIST (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)

MAGNESIUM SULPHATE at a dosage of 1 GRAM elemental Magnesium adminstered via INTRAMUSCULAR INJECTION is the ideal; however, this is not easily accessible due MAGNESIUM SULPHATE FOR INJECTION being a PRESCRIPTION DRUG and due the need to self-administer an INTRAMUSCULAR INJECTION.

The next best thing is to administer MAGNESIUM via a combination of PER ORALLY and TRANSDERMALLY. In order to yield the optmimum therapeutic beneficial effects with regards to treating ANXIETY it is necessary to ensure that both the ADMINISTRATION METHODS and recommended DOSAGES are adhered to. For example, taking a low dose of MAGNESIUM per orally only is not likely to yield much (if any) therapeutic effect with regards to ANXIETY.

Firstly, it is recommended that 4 - 6.25 grams (= 640 - 1,000mg Mg) of MAGNESIUM MALATE be taken PER ORALLY. I would advise spliting the dosage into three, and if you are currently have problems with sleep due to the BENZODIAZEPINE withdrawal then taking a disproportionately higher amount immediately prior to bed will prove helpful in reduced SLEEP ONSET TIME and SLEEP QUALITY. For example, you might like to take 1 gram upon waking, 1 gram in the afternoon and 4.25 grams at bedtime.

The MALATE form of MAGNESIUM is recommended and is distinctly preferred over the CITRATE form; this is due to the following facts:

1) the MALATE will enhance energy production and feeling of wellbeing via enhancement of KREBS CYCLE function. The typical diet is already overlaiden with too much CITRATE and hence MORE CITRATE will if anything only serve to further imbalance the KREBS CYCLE function.

2) The CITRATE form is significantly more LAXATIVE than the MALATE form, which in itself is a reason to avoid it. The dosage regimen that I have recommended for the MAGNESIUM MALATE, namely 1 gram upon waking, 1 gram in the afternoon and 4.25 grams at bedtime, should not cause you to become 'too loose' so to speak; however, in the unlikely event that it does then a simple dosage adjustment will rectify matters.

Secondly, it is recommended that MAGNESIUM SULPHATE by adminstered transdermally, via 1 - 2 cups ESPOM SALTS (MAGNESIUM SULPHATE) added to a HOT bath in which you soak for at least 10 minutes daily, such that you will absorb the MAGNESIUM SULPHATE through your skin into your body transdermally.

You can purchase a bulk quantity (e.g. 25kg sack) of EPSOM SALTS (= MAGNESIUM SULPHATE) which is much more economical than buying small quantities.

This will have a significant anxiolytic and relaxing effect and combined with the PER ORAL MAGNESIUM MALATE should be highly useful in helping to treat ANXIETY (and also BENZODIAZEPINE withdrawal symptom).


BACOPA MONNIERI:

BACOPA MONNIERI in fact might prove very helpful, since this has been shown in studies firstly to NOT be a GABA RECEPTOR AGONIST, but has in fact be shown to upregulate down-regulated GABA receptors, which means it could prove highly useful in helping to treat recovery from GABA RECEPTOR AGONIST ADDICTION:

Epilepsy Behav. 2010 Apr;17(4):441-7. Epub 2010 Feb 11.

Behavioral deficit and decreased GABA receptor functional regulation in the cerebellum of epileptic rats: effect of Bacopa monnieri and bacoside A.

Mathew J, Peeyush Kumar T, Khan RS, Paulose CS.

Source
Department of Biotechnology, Molecular Neurobiology and Cell Biology Unit, Centre for Neuroscience, Cochin University of Science and Technology, Kerala, India.

Abstract
In the present study, the effects of Bacopa monnieri and its active component, bacoside A, on motor deficit and alterations of GABA receptor functional regulation in the cerebellum of epileptic rats were investigated. Scatchard analysis of [(3)H]GABA and [(3)H]bicuculline in the cerebellum of epileptic rats revealed a significant decrease in B(max) compared with control. Real-time polymerase chain reaction amplification of GABA(A) receptor subunits-GABA(Aalpha1), GABA(Aalpha5,) and GABA(Adelta)-was downregulated (P<0.001) in the cerebellum of epileptic rats compared with control rats. Epileptic rats exhibit deficits in radial arm and Y-maze performance. Treatment with B. monnieri and bacoside A reversed these changes to near-control levels. Our results suggest that changes in GABAergic activity, motor learning, and memory deficit are induced by the occurrence of repetitive seizures. Treatment with B. monnieri and bacoside A prevents the occurrence of seizures thereby reducing the impairment of GABAergic activity, motor learning, and memory deficit.
PMID: 20153260

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And specifically to reverse the effects of Diazepam on the benzodiazepine pathway:

Psychopharmacology (Berl) 2008 Sep;200(1):27-37. Epub 2008 Jan 13.

Bacopa monniera exerts antiamnesic effect on diazepam-induced anterograde amnesia in mice.

Prabhakar S, Saraf MK, Pandhi P, Anand A.

Source
Department of Neurology, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh, 160012, India.

Abstract

RATIONALE:

As Benzodiazepines are known to produce amnesia by involvement of the GABAergic system, we examined Bacopa monniera, an herb known for memory enhancement for reversal of memory deficits caused by diazepam.

OBJECTIVES:

The objective of the study was to study the effect of standardized extract of B. monniera on diazepam-induced amnesia in mice using Morris water maze.

MATERIALS AND METHODS:

We used the rota rod test as a screening measure for muscle incoordination followed by the Morris water maze scale to evaluate the effect of B. monniera on amnesia. The index of acquisition and retrieval was recorded with varying doses of Bacopa.

RESULTS:

The results revealed antiamnesic effects of B. monniera (120 mg kg(-1) oral) on diazepam (1.75 mg kg(-1) intraperitoneal)-induced amnesia. The degree of reversal by Bacopa was significant as it progressively reduced escape latency time when mice treated with diazepam were subjected to acquisition trials.

CONCLUSIONS:

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

PMID: 18193203


RHODIOLA ROSEA

RHODOLA ROSEA's primary mechanism of action appears to be threefold; firstly, that of MAO INHIBITION; secondly, that of INCREASING levels of ENDORPHINS and ENCEPHALINS; and thirdly, by INHIBITION of CORTISOL release, thereby lowering CORTISOL levels.

Whilst RHODOLA ROSEA is demonstrated to yield ANXIOLYTIC effects at appropriate dosages, it should be noted that TOO HIGH a dosage can in fact induce of worsen ANXIETY symptoms.

See the following:

J Altern Complement Med. 2008 Mar;14(2):175-80.

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

Bystritsky A, Kerwin L, Feusner JD.

Source
Department of Psychiatry, University of California, Los Angeles, CA, USA. abystritsky@mednet.ucla.edu

Abstract

BACKGROUND:
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, depression, and insomnia. Whether R. rosea is effective in reducing similar symptoms in clinical samples is unknown. The goal of this pilot study was to evaluate whether R. rosea is effective in reducing symptoms of generalized anxiety disorder (GAD).

METHOD:
Ten (10) participants with a DSM-IV diagnosis of GAD, recruited from the UCLA Anxiety Disorders Program and between the ages of 34 and 55, were enrolled in this study from November 2005 to May 2006. Participants received a total daily dose of 340 mg of R. rosea extract for 10 weeks. Assessments included the Hamilton Anxiety Rating Scale (HARS), the Four-Dimensional Anxiety and Depression Scale, and the Clinical Global Impressions of Severity/Improvement Scale.

RESULTS:
Individuals treated with R. rosea showed significant decreases in mean HARS scores at endpoint (t=3.27, p=0.01). Adverse events were generally mild or moderate in severity, the most common being dizziness and dry mouth.

CONCLUSIONS:
Significant improvement in GAD symptoms was found with R. rosea, with a reduction in HARS scores similar to that found in clinical trials. These preliminary findings warrant further exploration of treatment with R. rosea in clinical samples.

PMID: 18307390
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Phytomedicine. 2010 Jun;17(7):481-93. Epub 2010 Apr 7.

Rosenroot (Rhodiola rosea): traditional use, chemical composition, pharmacology and clinical efficacy.

Panossian A, Wikman G, Sarris J.

Source
Swedish Herbal Institute Research and Development, Askloster, Sweden. alexander.panossian@shi.se alexander.panossian@shi.se

Abstract
The aim of this review article was to summarize accumulated information related to chemical composition, pharmacological activity, traditional and official use of Rhodiola rosea L. in medicine. In total approximately 140 compounds were isolated from roots and rhizome - monoterpene alcohols and their glycosides, cyanogenic glycosides, aryl glycosides, phenylethanoids, phenylpropanoids and their glycosides, flavonoids, flavonlignans, proanthocyanidins and gallic acid derivatives. Studies on isolated organs, tissues, cells and enzymes have revealed that Rhodiola preparations exhibit adaptogenic effect including, neuroprotective, cardioprotectiv e, anti-fatigue, antidepressive, anxiolytic, nootropic, life-span increasing effects and CNS stimulating activity. A number of clinical trials demonstrate that repeated administration of R. rosea extract SHR-5 exerts an anti-fatigue effect that increases mental performance (particularly the ability to concentrate in healthy subjects), and reduces burnout in patients with fatigue syndrome. Encouraging results exist for the use of Rhodiola in mild to moderate depression, and generalized anxiety. Several mechanisms of action possibly contributing to the clinical effect have been identified for Rhodiola extracts. They include interactions with HPA-system (cortisol-reducing), protein kinases p-JNK, nitric oxide, and defense mechanism proteins (e.g. heat shock proteins Hsp 70 and FoxO/DAF-16). 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.

PMID: 20378318


RELORA (MAGNOLIA OFFICINALIS and PHELLODENDRON AMURENSE)

RELORA is a proprietory blend of two herbal extracts, namely 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. 2008 Apr 21;7:11.

Effect of a proprietary Magnolia and Phellodendron extract on stress levels in healthy women: a pilot, double-blind, placebo-controlled clinical trial.

Kalman DS, Feldman S, Feldman R, Schwartz HI, Krieger DR, Garrison R.

Source
Director, Nutrition, Miami Research Associates, Miami, FL, USA. dkalman@miamiresearch.com

Abstract

BACKGROUND:
Recent research has established correlations between stress, anxiety, insomnia and excess body weight and these correlations have significant implications for health. 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.

METHODS:
This randomized, parallel, placebo controlled clinical study was conducted with healthy, overweight (BMI 25 to 34.9), premenopausal female adults, between the ages of 20 and 50 years, who typically eat more in response to stressful situations and scores above the national mean for women on self-reporting anxiety. The intervention was Relora (250 mg capsules) or identical placebo 3 times daily for 6 weeks. Anxiety as measured by the Spielberger STATE-TRAIT questionnaires, salivary amylase and cortisol levels, Likert Scales/Visual Analog Scores for sleep quality and latency, appetite, and clinical markers of safety. The study was conducted by Miami Research Associates, a clinical research organization in Miami, FL.

RESULTS:
The intent-to-treat population consisted of 40 subjects with 26 participants completing the study. There were no significant adverse events. Relora was effective, in comparison to placebo, in reducing temporary, transitory anxiety as measured by the Spielberger STATE anxiety questionnaire. It was not effective in reducing long-standing feelings of anxiety or depression as measured using the Spielberger TRAIT questionnaire. Other assessments conducted in this study including salivary cortisol and amylase levels, appetite, body morphology and sleep quality/latency were not significantly changed by Relora in comparison to placebo.

CONCLUSION:
This pilot study indicates that Relora may offer some relief for premenopausal women experiencing mild transitory anxiety. There were no safety concerns or significant adverse events observed in this study.

PMID: 18426577


THEANINE:

THEANINE could be a highly useful ANXIOLYTIC, since it DOES NOT function as a GABA RECEPTOR AGONIST but UPREGULATES THE PRODUCTION OF GABA within the brain, functions as a GLUTAMATE RECEPTOR ANTAGONIST, and enhances ALPHA-WAVE production within the brain.

See the following studies:

J Clin Psychiatry. 2011 Jan;72(1):34-42. Epub 2010 Nov 30.

L-theanine relieves positive, activation, and anxiety symptoms in patients with schizophrenia and schizoaffective disorder: an 8-week, randomized, double-blind, placebo-controlled, 2-center study.

Ritsner MS, Miodownik C, Ratner Y, Shleifer T, Mar M, Pintov L, Lerner V.

Source
Department of Psychiatry, The Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.

Abstract

OBJECTIVE:
L-theanine is a unique amino acid present almost exclusively in the tea plant. It possesses neuroprotective, mood-enhancing, and relaxation properties. This is a first study designed to evaluate the efficacy and tolerability of L-theanine augmentation of antipsychotic treatment of patients with chronic schizophrenia and schizoaffective disorder.

METHOD:
60 patients with DSM-IV schizophrenia or schizoaffective disorder participated in an 8-week, double-blind, randomized, placebo-controlled study. 400 mg/d of L-theanine was added to ongoing antipsychotic treatment from February 2006 until October 2008. The outcome measures were the Positive and Negative Syndrome Scale (PANSS), the Hamilton Anxiety Rating Scale (HARS), the Cambridge Neuropsychological Test Automated Battery (CANTAB) for neurocognitive functioning, and additional measures of general functioning, side effects, and quality of life.

RESULTS:
40 patients completed the study protocol. Compared with placebo, L-theanine augmentation was associated with reduction of anxiety (P = .015; measured by the HARS scale) and positive (P = .009) and general psychopathology (P < .001) scores (measured by the PANSS 3-dimensional model). According to the 5-dimension model of psychopathology, L-theanine produced significant reductions on PANSS positive (P = .004) and activation factor (P = .006) scores compared to placebo. The effect sizes (Cohen d) for these differences ranged from modest to moderate (0.09-0.39). PANSS negative and CANTAB task scores, general functioning, side effect, and quality of life measures were not affected by L-theanine augmentation. L-theanine was found to be a safe and well-tolerated medication.

CONCLUSIONS:
L-theanine augmentation of antipsychotic therapy can ameliorate positive, activation, and anxiety symptoms in schizophrenia and schizoaffective disorder patients. Further long-term studies of L-theanine are needed to substantiate the clinically significant benefits of L-theanine augmentation.

PMID: 21208586
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J Herb Pharmacother 2006;6(2):21-30.

The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent.

Nathan PJ, Lu K, Gray M, Oliver C.

Source
Behavioural Neuroscience Laboratory, Department of Physiology, Monash Center for Brain and Behaviour, Monash University, Australia. Nathan@med.monash.edu.au

Abstract
L-theanine (N-ethyl-L-glutamine) or theanine is a major amino acid uniquely found in green tea. L-theanine has been historically reported as a relaxing agent, prompting scientific research on its pharmacology. Animal neurochemistry studies suggest that 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. Behavioural studies in animals suggest improvement in learning and memory. Overall, L-theanine displays a neuropharmacology suggestive of a possible neuroprotective and cognitive enhancing agent and warrants further investigation in animals and humans.

PMID: 17182482
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AANA J. 2009 Dec;77(6):445-9.

Anxiolytic effects of L-theanine--a component of green tea--when combined with midazolam, in the male Sprague-Dawley rat.

Heese T, Jenkinson J, Love C, Milam R, Perkins L, Adams C, McCall S, Ceremuga TE.

Source
US Army Graduate Program in Anesthesia Nursing, Carl R. Darnell Army Medical Center, Fort Hood, Texas, USA.

Abstract
The purpose of the study was to investigate the anxiolytic effects of L-theanine and its potential interaction with the GABAA receptor in Sprague-Dawley rats. L-theanine is a major component of green tea, which has traditionally been used as an herbal remedy in the treatment of many medical conditions, including anxiety. Herbals and supplements and their potential interactions perioperatively are a concern to anesthetists. Fifty-five rats were divided into 5 groups: control (saline); L-theanine (positive control); flumazenil (a known benzodiazepine receptor antagonist) and L-theanine; and midazolam and L-theanine. The behavioral component of anxiety was evaluated using the elevated plus-maze and calculated by the time spent in the open arm of the maze divided by total time in the maze. Data were analyzed using a 2-tailed multivariate analysis of variance and Sheffé posthoc test. The data suggest that L-theanine does not produce anxiolysis by modulation of the GABAA receptor; however, in combination with midazolam, a synergistic or additive effect was demonstrated by decreased anxiety and both fine and basic motor movements. These data may provide direction for further studies examining L-theanine and its effects on anxiety and motor activity.

PMID: 20108732
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Clin Neuropharmacol. 2007 Jan-Feb;30(1):25-38.

The deployment of intersensory selective attention: a high-density electrical mapping study of the effects of theanine.

Gomez-Ramirez M, Higgins BA, Rycroft JA, Owen GN, Mahoney J, Shpaner M, Foxe JJ.

Source
Program in Cognitive Neuroscience, Department of Psychology, The City College of the City University of New York, New York, NY, USA.

Abstract

OBJECTIVE:

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) during resting electroencephalographic recordings in humans. Independently, alpha band activity has been shown to be a key component in selective attentional processes. Here, we set out to assess whether theanine would cause modulation of anticipatory alpha activity during selective attentional deployments to stimuli in different sensory modalities, a paradigm in which robust alpha attention effects have previously been established.

METHODS:

Electrophysiological data from 168 scalp electrode channels were recorded while participants performed a standard intersensory attentional cuing task.

RESULTS:

As in previous studies, significantly greater alpha band activity was measured over parieto-occipital scalp for attentional deployments to the auditory modality than to the visual modality. Theanine ingestion resulted in a substantial overall decrease in background alpha levels relative to placebo while subjects were actively performing this demanding attention task. Despite this decrease in background alpha activity, attention-related alpha effects were significantly greater for the theanine condition.

CONCLUSION:

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, and that it represents a potentially interesting, naturally occurring compound for further study, as it relates to the brain's attentional system.
PMID: 17272967


AFOBAZOLE

AFOBAZOLE does not in fact appear to have ANY direct interaction with the GABA RECEPTORS at all.

AFOBAZOLE’s mechanism of action seems to be that of SIGMA AND MELATONIN RECEPTORS AGONIST and REVERSIBLE MAO-A INHIBITION.

With THERAPEUTIC EFFECTS including: Antidepressant, anxiolytic, and increases BDNF; with good tolerability profile; and no sedation, cognitive impairment or muscle relaxation, etc.

And with demonstrated efficacy in human clinical trials.

SEE THE FOLLOWING:

Bulletin of Experimental Biology and Medicine, Vol. 151, No. 5, September, 2011 PHARMACOLOGY AND TOXICOLOGY

Effects of Afobazole on the Content of Neurotransmitter Amino Acids in the Striatum in Global Transient Ischemia

V. S. Baykova, I. A. Kadnikov, M. V. Voronin, T. S. Ganshina, A. V. Gnezdilova, A. A. Gorbunov, P. C. Mirzoyan, and S. B. Seredenin

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 of ischemic rats. After afobazole administration, GABA level improved and reached the control values recorded in intact animals…

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 to ischemic animals 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 (10 mg/kg intraperitoneally) 24 h after ischemia restores impaired balance of excitatory and inhibitory amino acids in the striatum of mongrel rats, normalizes their content to control levels, and activates endogenous taurine-dependent system of neuroprotection.

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Neuroreceptor mechanisms of the afobazole effect (2009):
Quote:

The interaction of afobazole (5-ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihydrochloride) and its main metabolite M-11 (2-[2-(3-oxomorpholine-4-yl)-ethylthio]-5-ethoxy benzimidazole hydrochloride) with neuroreceptors was studied using the method of radioligand analysis. The binding of afobazole with s1 (Ki =5.9 x 10(-6) M), MTI (Ki =1.6 x 10(-5) M), and MT3 (Ki =9.7 x 10(-7) M) receptors, as well as with a regulatory site of MAO-A (Ki = 3.6 x 10(-6) M) was revealed. The binding of M-11 with MT3 receptors (Ki = 3.9 x 10(-7) M) was demonstrated. The translocation of s1 receptor from endoplasmatic reticulum to the external membrane was revealed by the confocal microscopy technique on the immmortalized hippocampal HT-22 cells under the condition of 30- and 60-min-long afobazole (10(-8) M) application. Afobazole was shown to inhibit MAO-A reversibly. These properties of afobazole are consistent with our previous findings of the anxiolytic and neuroprotective effects of this drug.
^ 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.


Interaction of Afobazole with sigma(1)-Receptors (2009):
Quote:

In vitro radioligand assay revealed interaction of afobazole with sigma(1)-receptors (Ki=5.9x10(-6)M). Translocation of sigma(1)-receptors from the endoplasmic reticulum to the outer membrane was demonstrated by confocal microscopy. Experiments were performed on the model of HT-22 immortalized hippocampal cells after incubation with afobazole in a concentration of 10(-8)M.
^ Reinforces AFOBAZOLE 's sigma-1 activity which appears to be its main mechanism of action.

Afobazole decreases motor side effects induced by haloperidol (2009):
Quote:

Experiments on mice showed that a single intraperitoneal administration of anxiolytic afobazole (10 mg/kg) increases the effect of haloperidol in the apomorphine-induced climbing test and does not influence the catalepsy caused by the neuroleptic agent. The daily dose of afobazole 10 mg/kg during a five-day preliminary test reduced the extrapyramidal effects of haloperidole on rats and mice without significant change of the apomorphine-induced climbing test results. The ability of afobazole to reduce extrapyramidal disturbances caused by haloperidol can be related to the agonist effect of afobazole with respect to sigma 1 receptors.
^ This study shows (or says I mean) that AFOBAZOLE is an agonist at sigma-1.

Antidepressant properties of afobazole in Porsolt and Nomura tests (2009):
Quote:

Anxiolytic afobazole was shown in the experiments on outbred rats to decrease the immobility in the Porsolt and Nomura swim tests. The degree of afobazole effect in a dose of 5 mg/kg (i.p.) is similar to that of the standard antidepressant amitriptyline administered in doses of 10 mg/kg. Data obtained are testifying to the antidepressant activity of afobazole.
^ 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)).

Selective anxiolytic afobazole increases the content of BDNF and NGF in cultured hippocampal HT-22 line neurons (2009):
Quote:

Experiments on immortalized hippocampal cell culture of mice showed that afobazole increases the NGF level in a final concentration of 10(-8) M and the BDNF level in final concentrations from 10(-8) to 10(-5) M.

Effects of afobazole on the BDNF content in brain structures of inbred mice with different phenotypes of emotional stress reaction (2006):
Quote:

Changes in the BDNF content in brain structures--hippocampus, hypothalamus, striatum, and frontal cortex--were determined in mice of different emotional-stress reaction phenotypes, which were subjected to emotional stress and treated by the selective anxiolytic afobazole. The changes were different in BALB/c and C57BL/6 mice. Afobazole exhibited a significant protector action against a decrease in the brain BDNF level caused by emotional stress in BALB/c mice.
^ AFOBAZOLE increases BDNF expression in the hippocampus and reverses the deficits in BDNF levels induced by stress, further markers of antidepressant efficacy.


TIANEPTINE

TIANEPTINE is an ANXIOLYTIC ANTIDEPRESSANT which does not share pharmacological properties with TRICYCLIC ANTIDEPRESSANTS (TCAs), MAO-INHIBITORS or SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs).

Early studies suggested that TIANEPTINE’s primary mechanism of action to be that of a SELECTIVE SEROTONIN REUPTAKE ENHANCER (SSRE), with opposing mechanism of action to that of a SEROTONIN REUPTAKE INHIBITOR (SSRI).

However, more recent research indicates that TIANEPTINE’s actions as an ANXIOLYTIC ANTIDEPRESSANT may be independent of modulating serotonin levels; but instead, its primary mechanism of action is to influence the expression of synaptic plasticity via the modulation of glutamatergic neurotransmission.

See the following:

J Psychopharmacol. 2004 Dec;18(4):553-8.

The effects of tianeptine or paroxetine on 35% CO2 provoked panic in panic disorder.

Schruers K, Griez E.

Source
Department of Psychiatry and Neuropsychology, Research Institute Brain and Behaviour, Maastricht University, 6200 AB Maastricht, The Netherlands. koen.schruers@pn.unimaas.nl

Abstract
Antidepressants that inhibit the reuptake of serotonin (5-HT) are particularly effective in the treatment of panic disorder. Evidence suggests that increased 5-HT availability is important for the anti-panic effect of serotonergic drugs and in maintaining the response to selective serotonin reuptake inhibitors (SSRIs). 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, on the vulnerability to a laboratory panic challenge in panic disorder patients. Twenty panic disorder patients were treated with either tianeptine or paroxetine for a period of 6 weeks, in a randomized, double-blind, separate group design. The reaction to a 35% CO(2) panic challenge was assessed at baseline and after treatment. Improvement on several clinical scales was also monitored. 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.

PMID: 15582922
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Curr Neuropharmacol. 2008 December; 6(4): 311–321.

Tianeptine: An Antidepressant with Memory-Protective Properties

Phillip R Zoladz, Collin R Park, Carmen Muñoz, Monika Fleshner, and David M Diamond

Sources:
1: Medical Research Service, VA Hospital, Tampa, Florida, USA
2: Department of Psychology, University of South Florida, Tampa, Florida, USA
3: Departments of Molecular Pharmacology & Physiology, University of South Florida, Tampa, Florida, USA
4: Center for Preclinical and Clinical Research on PTSD, University of South Florida, Tampa, Florida, USA
5: Institut de Recherches Internationales Servier, Courbevoie, France
6: Center for Neuroscience and Department of Integrative Physiology, University of Colorado, Boulder, Colorado, USA

EXTRACT FROM FULL TEXT

…More recent work has suggested that tianeptine’s antidepressant effects may be attributable to its normalization of the stress-induced alterations of glutamatergic neurotransmission. This finding resonates with accumulating evidence that has implicated abnormal glutamate activity in the pathogenesis of depression. Other research has shown that tianeptine has anticonvulsant properties, which are dependent upon adenosine receptor activation. Given the involvement of adenosine receptors in anxiolytic effects on behavior, tianeptine’s antidepressant effects could also involve modulation of adenosinergic neurotransmitter systems.

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) and in recent work has been shown to block the effects of intense stress on behavior and cardiovascular systems in an animal model of PTSD. Thus, the well-described antidepressant and memory protective properties of tianeptine indicate that, in addition to its effectiveness as a treatment in mood disorders, it potentially has broader applications, as in the treatment of anxiety.


ESCITALOPRAM

ESCITALOPRAM is an ANXIOLYTIC ANTIDEPRESSANT whose mechanism of action is that of a SELECTIVE SEROTONIN REUPTAKE INHIBITOR (SSRI).

ESCITALOPRAM is arguably the most effective and best tolerated (i.e. least potential for side effects) out of ALL the SSRIs currently available; this is most likely due to the fact that of all the SSRIs currently available ESCITALOPRAM has the highest affinity for the human serotonin transporter; i.e. it is the most selective SSRI yet developed.

IMPORTANT NOTE: Regarding dosage for ESCITALOPRAM, it should be noted that whilst ESCITALOPRAM is arguably the best tolerated (i.e. least potential for side effects) out of ALL the SSRIs currently available, this does NOT mean that it does not have the potential to induce side effects; however, clinical research and medical practice have demonstrated that ESCITALOPRAM's likelihood to induce side effects is very much dosage dependant, and that a dosage of 5mg in most cases is effective in providing a significant ANXIOLYTIC ANTIDEPRESSANT therapeutic effect without side effects; and that where side effects are experienced it is almost always as a dosage higher than 5mg (e.g. 10 - 20mg). Therefore, if you wish to try ESCITALOPRAM I would strongly recommend limiting the dosage to 5mg.

See the following:

Encephale. 2002 Sep-Oct;28(5 Pt 1):461-5.

Effects of escitalopram on anxiety symptoms in depression.

Spadone C.

Source
Hôpital Saint-Louis (AP-HP) Paris, France.

Abstract
Selective serotonin reuptake inhibitors, the antidepressants most widely prescribed today, exert specific action against various anxiety disorders and have an excellent acceptability profile. In addition, anxiety problems are commonly seen in depression, in the form of either characterised anxiety disorders or associated anxious symptoms. Such symptoms of anxiety result in increased risk of suicide and appear to be associated with development of more severe and chronic depressive disorders. Because of the adverse [depressive] effects associated with anxiolytics, in particular benzodiazepines, their indications have been restricted. Consequently, first-line drug therapy for anxiety symptoms associated with depression involves selection of an antidepressant having anxiolytic properties. Specific serotonin reuptake inhibitors are commonly favoured at present since they have a less pronounced sedative effect than the tricyclic antidepressants (e.g. amitriptyline, maprotiline). Escitalopram, the active enantiomer of citalopram, has demonstrated efficacy and rapidity of action upon depressive symptoms seen in major depressive episodes. 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 component of depressive disorders. Anxiety was quantitatively evaluated using item 6 (inner tension) of the MADRS, and for two of the three studies, using the anxiety sub-score of the HAM-D as well as the HAM-A total score. 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 associated with depression, together with particularly interesting rapidity of action. Use of an antidepressant with proven activity against anxiety accompanying depression avoids the need for co-prescription of tranquillizers, which themselves are not devoid of adverse effects.

PMID: 12386549
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Encephale. 2008 Sep;34(4):400-8. Epub 2008 Aug 15.

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

Pelissolo A.

Source
Service de psychiatrie adulte et CNRS centre Emotion, groupe hospitalier de la Pitié-Salpêtrière, AP-HP, 47, boulevard de l'Hôpital, 75013 Paris, France.

Abstract

INTRODUCTION:

Anxiety disorders are highly prevalent and disabling disorders, for which selective serotonin reuptake inhibitor (SSRI) antidepressants are an effective treatment. 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.

AIM OF THE REVIEW:

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 basis of numerous recent short-term and long-term controlled studies in these disorders. In a 10-week randomised, double-blind trial in patients with panic disorder, escitalopram (flexible doses 5-10 mg/d) was significantly more effective than placebo in reducing the panic attack frequency, with a faster onset of action than citalopram. Fifty percent of escitalopram recipients and 38% of placebo recipients experienced no panic attacks, with a similar incidence of the most common adverse events for both groups. LITERATURE FINDINGS IN PD: In an open-label study in elderly (>65 years) patients with panic disorder, improvement in panic attack frequency and secondary efficacy variables occurred more rapidly in escitalopram than citalopram recipients. LITERATURE FINDINGS IN GAD: In four double-blind, comparative, eight- to 12-week studies in patients with GAD, escitalopram was more effective than placebo and at least as effective as paroxetine in reducing the mean Hamilton Rating Scale for Anxiety total score. Escitalopram 10-20 mg/d demonstrated continued efficacy in a 24-week extension study of short double-blind trials and in a placebo-controlled, double-blind, 24/76-week relapse-prevention study. In this trial, escitalopram recipients showed a significantly longer time to relapse and reduced risk of relapse than placebo recipients, and the risk of relapse was 4.04 times higher in the placebo group than in the escitalopram group. Escitalopram was well tolerated and only 7% patients withdrew, due to adverse events in the escitalopram group, versus 8% in the placebo group. LITERATURE FINDINGS IN SOCIAL PHOBIA: In two randomised, double-blind, 12- and 24-week studies in patients with social anxiety disorder (social phobia), escitalopram 10-20 mg/d was generally more effective than placebo and at least as effective as paroxetine in reducing the mean Liebowitz Social Anxiety Scale total scores. In a 24-week double-blind, placebo-controlled relapse-prevention study, escitalopram recipients had a longer time to relapse and reduced risk of relapse compared with placebo recipients, and significantly fewer escitalopram than placebo recipients relapsed (22% versus 50%). In these studies, the treatment effects of escitalopram were independent of gender, symptom severity and chronicity, and comorbid depressive symptoms, and the drug was tolerated well. LITERATURE FINDINGS IN OCD: Finally, in patients with OCD, escitalopram 20mg/d for 12 weeks was more effective than placebo, and at least as effective as paroxetine 40 mg/day, with respect to a mean reduction from baseline in the Yale-Brown Obsessive Scale total score. In a 24-week, randomised, placebo-controlled relapse-prevention study, the proportion of patients who relapsed in the escitalopram group (23%) was 2.74 times lower than in the placebo group (52%). In both groups, the majority of adverse events reported were mild to moderate.

CONCLUSION:

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. Beyond short-term demonstrations of efficacy in these disorders, several controlled relapse-prevention studies showed the necessity and utility of maintaining the treatment six months or more after the remission has been obtained.

PMID: 18922243
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J Nerv Ment Dis.2010 Jun;198(6):458-61.

Escitalopram for persistent symptoms of generalized anxiety disorder after CBT: a pilot study.

Schneier FR, Belzer KD, Kishon R, Amsel L, Simpson HB.

Source
Anxiety Disorders Clinic, New York State Psychiatric Institute, New York, NY 10032, USA. frs1@columbia.edu

Abstract
Cognitive behavioral therapy (CBT) and pharmacotherapy are each efficacious for generalized anxiety disorder (GAD). It is not known, however, whether GAD partial and nonresponders to one treatment modality benefit from the other. This study explored acceptability and efficacy of escitalopram for persons with persistent GAD symptoms after a course of CBT. Twenty-four patients with GAD were treated with CBT and 15 completed at least 12 sessions. Eight completers continued to have clinically significant symptoms and were offered 12 weeks of treatment with escitalopram, and 7 started escitalopram treatment. During CBT, patients evidenced significant improvement in GAD, depression, and quality of life. During escitalopram treatment, patients evidenced trends toward further improvement in GAD, depression, and quality of life. Escitalopram phase completers had initially reported low-to-moderate preferences for medication treatment. Escitalopram may benefit GAD patients with clinically significant symptoms after CBT and merits further study under controlled conditions in a larger sample.

PMID: 20531128
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Hum Psychopharmacol. 2009 Jun;24(4):269-75.

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.

Source
Clinical Neuroscience Division, School of Medicine, University of Southampton, Southampton, UK. dsb1@soton.ac.uk

Abstract

OBJECTIVE:

To extend the knowledge of course of improvement in patients with major depressive disorder (MDD), social anxiety disorder (SAD) or generalised anxiety disorder (GAD) participating in randomised placebo-controlled trials (RCTs) and to infer the optimal duration of initial escitalopram treatment in clinical practice, after which intervention might be reasonable in case of non-response.

METHODS:

Post hoc analysis of pooled clinical trial database for escitalopram in MDD (14 studies), GAD (4 studies) and SAD (2 studies). 'Onset' of action was defined as a 20% or more decrease from baseline score in disorder-specific psychopathological rating scales: 'response' as a 50% or more decrease from baseline score.

RESULTS:

In MDD, the probability of responding at week 8 if no onset was apparent at week 2 was 43%; in patients with an onset of effect the probability was nearly 80%. Similar patterns were observed in GAD and SAD. The chance of responding beyond week 4 in MDD, GAD and SAD was 20% or less if no effect had occurred by week 2.

CONCLUSIONS:

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.

PMID: 19334042


PROPRANOLOL

PROPRANOLOL is NOT a GABA RECEPTOR AGONIST. Its primary mechanism of action is that of NON-SELECTIVE BETA BLOCKER, in that it blocks the action of EPINEPHRINE (a.k.a. ADRENALINE) and NOREPINEPHRINE (a.k.a. NORADRENALINE) on the BETA-ADRENERGIC RECEPTORS, thereby inhibiting their physiological effects.

PROPRANOLOL also appears to UPREGULATE (as opposed to DOWNREGULATE) the GABAergic SYSTEM.

I have added PROPRANOLOL to the "POSSIBLY" list for "WHAT IS SAFE AND EFFECTIVE TO TAKE" for two reasons.

Firstly, when it comes to treating ANXIETY and PANIC related disorders (e.g. PANIC ATTACKS) there are conflicting studies regarding its efficacy in treating said conditions, in that whilst some studies report PROPRANOLOL to be effective others report it to be ineffective. Specifically it is apparant that PROPRANOLOL may be effective in treating certain types or causalities of ANXIETY but not others. This fact is further supported by anecdotal patient user reports.

Secondly, because PROPRANOLOL is somewhat a double-edged sword, in that it has the potential to induce both postive and negative effects (i.e. side effects); and it is its relatively high incidence and potential severity of side effects. Some individuals are able to take PROPRANOLOL without suffering intolerable side effects, but others are not.

See the following:

POSITIVE STUDIES:

Biochem Pharmacol. 1992 Aug 4;44(3):465-70.

Increased activity of the GABAergic system in selected brain areas after chronic propranolol treatment in spontaneously hypertensive rats.

Remiszewska M, Jastrzebski Z, Czyzewska-Szafran H, Wutkiewicz M, Czarnecki A.

Source
Department of Pharmacology, Institute of Drug Research and Control, Warsaw, Poland.

Abstract
The influence of chronically administered propranolol on the functional state of the gamma-aminobutyric acid-ergic (GABAergic) system in spontaneously hypertensive rats was studied and compared with the effect of dihydralazine. GABA content, synthesis and turnover rate in selected brain areas were assessed. Hypotensive activity of propranolol and dihydralazine after injection of GABA antagonist pictrotoxin was examined in acute experiment. Prolonged administration of propranolol increased GABA content, synthesis and turnover rate in the hypothalamus and the pons-medulla. After chronic injections of dihydralazine there was no change in GABA indices. Antihypertensive activity of dihydralazine in picrotoxin-treated animals remained unchanged. On the contrary, picrotoxin suppressed the propranolol-induced decrease in blood pressure. 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.

PMID: 1510697
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Hosp Community Psychiatry 1982 Apr;33(4):282-6.

Newer uses for older psychotropic medications.

Liebowitz MR.

Abstract
New uses are still being discovered for a number of psychotropic agents that have been available for some time. Among the more important recent discoveries are the efficacy of the tricyclic antidepressants for panic disorder and agoraphobia with panic attacks; the use of the monoamine oxidase inhibitors for the above disorders and for atypical depression and hysteroid dysphoria; the use of propranolol for anxiety disorders and for uncontrollable violent outbursts; the antianxiety and antipanic effects of clonidine; and the usefulness of lithium in treating schizophrenia and schizoaffective disorder and for emotionally unstable character disorders. In addition to strengthening the therapeutic armamentarium, the author says, the discovery of new drug response patterns helps generate or strengthen hypotheses about the pathophysiology of various psychiatric disorders.

PMID: 6122638
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J Pediatr. 1984 Oct;105(4):661-5.

Panic attack syndrome.

Van Winter JT, Stickler GB.

Abstract
Panic attack syndrome in four generations of a family and in six additional pediatric patients is reported. The syndrome appears to have an autosomal dominant mode of inheritance. Diagnosis of panic attack syndrome in children has not been reported previously, but the existence of this disorder has been noted for at least 100 years under various synonyms. There is substantial evidence that the syndrome has an endogenous origin and is therefore a biochemical illness. The triggering effect of sodium lactate infusion and the alleviation of symptoms by use of monoamine oxidase inhibitors or beta-blocking agents support this view. Imipramine hydrochloride, propranolol hydrochloride, phenelzine sulfate, and alprazolam are often useful in the treatment of panic attacks, and except for propranolol, any of them may be effective against depression also.

PMID: 648154
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Lancet. 1981 Mar 7;1(8219):520-2.

Benzodiazepine withdrawal symptoms and propranolol.

Tyrer P, Rutherford D, Huggett T.

Abstract
40 patients seen in general practice and psychiatric outpatient clinics who had taken lorazepam or diazepam alone in regular dosage for a mean period of 3.6 years had their benzodiazepine replaced by propranolol (60--120 mg/day) or placebo for two weeks under double-blind conditions. Depending on the criteria for the definition of an abstinence syndrome, 27--45% of the patients had withdrawal symptoms during the study. Propranolol did not affect the drop-out rate or the incidence of withdrawal symptoms but significantly reduced their severity in patients completing the study. The percentage fall in serum levels of desmethyldiazepam in patients who experienced withdrawal symptoms after stopping diazepam was significantly greater in patients with no withdrawal symptoms.

PMID: 6111632
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Compr Psychiatry. 1985 Jan-Feb;26(1):80-9.

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

Munjack DJ, Rebal R, Shaner R, Staples F, Braun R, Leonard M.

Abstract
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. An independent blind assessor was used as well as several standard rating scales. There was no placebo group. Twenty-three patients completed a trial of both drugs. Approximately half of the patients lost their panic attacks completely, both on imipramine and propranolol. Other patients were partially, but not completely improved. The implications and limitations of this finding and others are discussed.

PMID: 3881216
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BOTH POSITIVE & NEGATIVE STUDIES:

Am J Psychiatry 1976 Dec;133(12):1389-94.

The treatment of pathological panic states with propranolol.

Heiser JF, Defrancisco D.

Abstract
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. The authors suggest that further study of these findings may clarify other clinical problems.

PMID: 984238
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NEGATIVE STUDIES:

Arch Gen Psychiatry. 1984 Mar;41(3):287-92.

Diazepam and propranolol in panic disorder and agoraphobia.

Noyles R Jr,Anderson DJ, Clancy J, Crowe RR, Slymen DJ, Ghomeim MM, Hinrichs JV.

Abstract
The response to diazepam and propranolol hydrochloride was compared in 21 patients who (with one exception) met DSM-III criteria for panic disorder and agoraphobia. Each drug was administered for two weeks in double-blind fashion according to a crossover design. The response to diazepam was significantly superior on all measures. By observer rating, 18 patients showed at least moderate improvement with diazepam compared with seven receiving propranolol. Panic attacks and phobic symptoms responded to diazepam, but not to propranolol. The results suggest that benzodiazepines constitute effective short-term treatment for these newly defined disorders.
PMID: 6367691
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J Clin Psychopharmicol. 1989 Feb;9(1):22-7.

Alprazolam, propranolol, and placebo in the treatment of panic disorder and agoraphobia with panic attacks.

Munjack DJ, Crocker B, Cabe D, Brown R, Usigli R, Zulueta A, McManus M, McDowell D, Palmer R, Leonard M.

Source
University of Southern California Medical School.

Abstract
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. There was no concomitant behavioral treatment. Patient and therapist rating scales included Sheehan's Panic and Anxiety Attack Scales, the Marks-Sheehan Phobia Scale, the Hamilton Anxiety Scale, the Hamilton Depression Scale, and the Side Effects Checklist. The results generally support the efficacy of alprazolam, but not propranolol, in the treatment of panic disorder and agoraphobia with panic attacks. The significance of the results are discussed, as well as a number of the unique aspects of our procedures and patient population.

PMID: 2651490


INOSITOL (MYO-INOSITOL)

Firstly, it is important to note that there are in fact many different forms of INOSITOL and that MYO-INOSITOL specifically is the form that possesses possible ANXIOLYTIC and ANTIDEPRESSANT physiological therapeutic effects.

MYO-INOSITOL’s primary mechanism of action specifically with regards to its ANXIOLYTIC effects appears to be that of UPREGULATION of the SEROTONIN RECEPTORS; possibly through functioning as a PRECURSOR to the PHOSPHATIDYLINOSITOL CYCLE, which is the second messenger system for several neurotransmitters including several subtypes of SEROTONIN RECEPTORS.

MYO-INOSITOL does not appear to affect actual MONOAMINE levels, which would include SEROTONIN and GABA.

The scientific evidence supporting MYO-INOSITOL’s ANXIOLYTIC efficacy is somewhat inconclusive, in that there exists some conflicting evidence supporting its ANXIOLYTIC effects; this is further compounded by mixed anecdotal user feedback reports, in that some individuals report that they find it to be an effective ANXIOLYTIC, whereas others report no ANXIOLYTIC effect whatsoever. There are even

Furthermore, there is substantiated evidence that MYO-INOSITOL’s ANXIOLYTIC efficacy is somewhat dependent on firstly what is the SCALE of the ANXIETY, in that MYO-INOSITOL appears to be significantly less effective in treating ACUTE ANXIETY than it is in treating CHRONIC ANXIETY; and secondly on what is the TYPE of the ANXIETY DISORDER, in that for example it appears that MYO-INOSITOL may be somewhat effective in treating OBSESSIVE-COMPULSIVE DISORDER (OCD) and PANIC DISORDER, but less effective in treating STRESS RELATED ANXIETY, such as POST TRAUMATIC STRESS DISORDER (PTSD).

SAFETY & SIDE EFFECTS:

MYO-INOSITOL is SAFE and NON-TOXIC; no changes have been found in studies of hematology, kidney, or liver function.

However, it should be noted that SIDE EFFECTS include: INCREASED ANXIETY, INSOMNIA, and GASTROINTESTINAL UPSET, including (but not limited to) DIARRHEA, NAUSEA, FLATULENCE, and STOMACH UPSET.

Some of these SIDE EFFECTS can occur upon commencement of usage, but then subsequently dissipate within two weeks consistent usage. For example, INOSITOL may for some (but not all) people initially induce ANXIOGENIC effects; however, in such instances the ANXIOGENIC effects typically vanish entirely within two weeks usage, and are subsequently replaced with ANXIOLYTIC effects. It is therefore recommended if trying out INOSITOL for treating ANXIETY to take it consistently for a period of at least 3-4 weeks in order to properly evaluate its therapeutic effects.

CONTRAINDICATIONS:

MYO-INOSITOL has been demonstrated to EXACERABATE pre-existing symptoms of ATTENTION DEFICIT DISORDER WITH HYPERACTIVITY (ADDH), and hence should not be used by ADDH sufferers.

MYO-INOSITOL should be avoided by pregnant women, since high dose MYO-INOSITOL may induce uterine contractions.

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

See the following:

Behav Brain Res. 2001 Jan 8;118(1):77-83.

The antidepressant activity of inositol [Myo-Inositol] in the forced swim test involves 5-HT(2) receptors.

Einat H, Clenet F, Shaldubina A, Belmaker RH, Bourin M.

Source
Beer Sheva Mental Health Center, Faculty of Health Sciences, Ben Gurion University of the Negev, P.O. Box 4600, Beer Sheva, Israel.

Abstract
The effect of Inositol [Myo-Inositol] as an antidepressant was previously demonstrated in both animal models of depression-like behavior and in clinical trials. 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 study attempted to draw a psychopharmacological profile of Inositol [Myo-Inositol]'s behavioral effects by exploring the interactions between the drug and specific receptor agonists and antagonists in the forced swim test. Rats received Inositol [Myo-Inositol] treatment (or control) in combination with the serotonergic metabolism inhibitor PCPA or with the noradrenergic neurotoxin DSP-4. Results indicated that PCPA but not DSP-4 abolished the ability of Inositol [Myo-Inositol] to cause a reduction in immobility time in the forced swim test. In mice, the specific 5-HT(2A)/5-HT(2C) antagonist ritanserin, but not the 5-HT(1A)/5-HT(1B)/beta adrenergic antagonist pindolol, abolished Inositol [Myo-Inositol]'s effect in the forced swim test. The 5-HT(2A)/5-HT(2C) agonist DOI and the 5-HT(1A) agonist 8-OH-DPAT did not have any significant effects on Inositol [Myo-Inositol]'s activity. The present data indicates that the antidepressant effect of Inositol [Myo-Inositol] may involve 5-HT(2) receptors. It is thus possible that the effects of reuptake antidepressant drugs and the effects of Inositol [Myo-Inositol] may have a common final pathway.

PMID: 11163636
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Brain Res. 1993 Dec 24;631(2):349-51.

Myo-inositol reduces serotonin (5-HT2) receptor induced homologous and heterologous desensitization.

Rahman S, Neuman RS.

Source
Faculty of Medicine, Memorial University, St. John's, Nfld, Canada.

Abstract
The effect of myo-inositol was examined on 5-HT2 receptor mediated facilitation of NMDA depolarization of rat neocortical neurons in vitro. Myo-inositol (1-10 mM) potentiated the 5-HT facilitation, the potentiation increasing linearly with log 5-HT concentration. Myo-inositol also eliminated 5-HT induced heterologous desensitization of muscarinic and alpha 1-adrenergic receptor mediated facilitation. Our findings suggest that 5-HT induced homologous and heterologous desensitization results in part from depleting phosphoinositide substrate.

PMID: 8131066
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Metab Brain Dis. 2004 Jun;19(1-2):51-70.

Effects of myo-inositol versus fluoxetine and imipramine pretreatments on serotonin 5HT2A and muscarinic acetylcholine receptors in human neuroblastoma cells.

Brink CB, Viljoen SL, de Kock SE, Stein DJ, Harvey BH.

Source
Division of Pharmacology, Potchefstroom Campus of the North-West University, Potchefstroom, South Africa.

Abstract
myo-Inositol (mI) is a key metabolic precursor to the phospoinositide (PI) metabolic pathway as a key component of central G-protein coupled receptor signaling systems, including several subtypes of adrenergic, cholinergic, serotonergic and metabotropic glutamatergic receptors. 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. The current study aimed to investigate the possible modulatory role of mI [Myo-Inositol] versus fluoxetine or imipramine pretreatments on serotonin-2A receptor (5HT2A-R) and muscarinic acetylcholine receptor (mAChR) function and binding in in vitro systems. After pretreating human neuroblastoma cells with different concentrations of mI [Myo-Inositol], fluoxetine, or imipramine, receptor function was measured by second messenger [3H]-IPx accumulation and [35S]-GTPgammaS binding to G alpha(q) protein. Total [3H]-mI [Myo-Inositol] uptake into cells was measured, as well as specific receptor binding to determine receptor binding after the pretreatments. Results suggest that mI [Myo-Inositol] reduces 5HT2A-R function at the receptor-G protein level. While fluoxetine also reduced 5HT2A-R function, but to a lesser degree, imipramine increased 5HT2A-R function, which may explain why mI [Myo-Inositol] seems to be effective exclusively in selective serotonin reuptake inhibitor-sensitive disorders. In addition mI [Myo-Inositol], and at high concentrations fluoxetine and imipramine, also reduces mAChR function. Furthermore the results suggest that the attenuating effect of mI [Myo-Inositol] on mAChRs is partially dependent on the PI metabolic pathway. The data provide novel information on understanding the mechanism of action of mI [Myo-Inositol] in depression and related anxiety disorders and added to the evidence suggesting a role for the cholinergic system in the pathophysiology of depression.

PMID: 15214506

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Eur Neuropsychopharmacol. 1997 May;7(2):147-55.

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

Levine J.

Source
Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel.

Abstract
Inositol [Myo-Inositol] is a simple polyol precursor in a second messenger system important in the brain. Cerebrospinal fluid Inositol [Myo-Inositol] has been reported as decreased in depression. A double-blind controlled trial of 12 g daily of Inositol [Myo-Inositol] in 28 depressed patients for four weeks was performed. Significant overall benefit for Inositol [Myo-Inositol] compared to placebo was found at week 4 on the Hamilton Depression Scale. No changes were noted in hematology, kidney or liver function. Since many antidepressants are effective in panic disorder, 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. Frequency and severity of panic attacks and severity of agoraphobia declined significantly with Inositol [Myo-Inositol] compared to placebo. Side-effects were minimal. Since serotonin re-uptake inhibitors benefit obsessive compulsive disorder (OCD) and Inositol [Myo-Inositol] is reported to reverse desensitization of serotonin receptors, 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. A controlled double-blind crossover trial of 12 g daily of Inositol [Myo-Inositol] for a month in twelve anergic schizophrenic patients, did not show any beneficial effects. A double-blind controlled crossover trial of 6 g of Inositol [Myo-Inositol] daily vs. glucose for one month each was carried out in eleven Alzheimer patients, with on clearly significant therapeutic effects. Antidepressant drugs have been reported to improve attention deficit disorder (ADDH) with hyperactivity symptomatology. We studied oral Inositol [Myo-Inositol] in children with ADDH [Attention Deficit Disorder with Hyperactivity] in a double-blind, crossover, placebo-controlled manner. Eleven children, mean age 8.9 +/- 3.6 years were enrolled in an eight week trial of Inositol [Myo-Inositol] or placebo at a dose of 200 mg/kg body weight. Results show a trend for aggravation of the syndrome with myo-inositol as compared to placebo. Recent studies suggest that serotonin re-uptake inhibitors are helpful in at least some symptoms of autism. However a controlled double-blind crossover trial of Inositol [Myo-Inositol] 200 mg/kg per day showed no benefit in nine children with autism. Cholinergic agonists have been reported to ameliorate electroconvulsive therapy (ECT)-induced memory impairment. Inositol [Myo-Inositol] metabolism is involved in the second messenger system for several muscarinic cholinergic receptors. Inositol [Myo-Inositol] 6 g daily was given in a crossover-double-blind manner for five days before the fifth or sixth ECT to a series of twelve patients, without effect. 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.

PMID: 9169302
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Am J Psychiatry. 1996 Sep;153(9):1219-21.

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

Fux M, Levine J, Aviv A, Belmaker RH.

Source
Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel.

Abstract

OBJECTIVE:
Earlier studies reported that inositol [Myo-Inositol], a simple polyol second messenger precursor, was effective in controlled trials for patients with depression and panic. In this study its effectiveness in obsessive-compulsive disorder was investigated.

METHOD:
Thirteen patients with obsessive-compulsive disorder completed a double-blind, controlled crossover trial of 18 g/day of inositol [Myo-Inositol] or placebo for 6 weeks each.

RESULTS:
The subjects had significantly lower scores on the Yale-Brown Obsessive Compulsive Scale when taking inositol [Myo-Inositol] than when taking placebo.

CONCLUSIONS:
The authors conclude that inositol [Myo-Inositol] is effective in depression, panic, and obsessive-compulsive disorder, a spectrum of disorders responsive to selective serotonin reuptake inhibitors.

PMID: 8780431
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Am J Psychiatry. 1995 Jul;152(7):1084-6.

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

Benjamin J, Levine J, Fux M, Aviv A, Levy D, Belmaker RH.
Source

Soroka Medical Center, Kupat Holim Sick Fund of the Histadrut, Beersheba, Israel.
Abstract

OBJECTIVE:

Because they found in an earlier study that Inositol [Myo-Inositol], an important intracellular second-messenger precursor, was effective against depression in open and double-blind trials, the authors studied its effectiveness against panic disorder.
METHOD:

Twenty-one patients with panic disorder with or without agoraphobia completed a double-blind, placebo-controlled, 4-week, random-assignment crossover treatment trial of 12 g/day of Inositol [Myo-Inositol].
RESULTS:

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.
CONCLUSIONS:

The authors conclude that Inositol [Myo-Inositol]'s efficacy, the absence of significant side effects, and the fact that Inositol [Myo-Inositol] is a natural component of the human diet make it a potentially attractive therapeutic for panic disorder.
PMID: 7793450
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J Clin Psychopharmacol. 2001 Jun;21(3):335-9.

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

Palatnik A, Frolov K, Fux M, Benjamin J.

Source
Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheba, Israel.

Abstract
Only 70% of patients respond to current treatments for panic disorder, and many discontinue drugs because of side effects. myo-Inositol, a natural isomer of glucose and a precursor for the second-messenger phosphatidyl-inositol system, has previously been found superior to placebo in the treatment of depression, panic disorder, and obsessive-compulsive disorder (OCD), but a direct comparison with an established drug has never been performed. A double-blind, controlled, random-order crossover study was undertaken to compare the effect of inositol [Myo-Inositol] with that of fluvoxamine in panic disorder. Twenty patients completed 1 month of inositol [Myo-Inositol] up to 18 g/day and 1 month of fluvoxamine up to 150 mg/day. Improvements on Hamilton Rating Scale for Anxiety scores, agoraphobia scores, and Clinical Global Impressions Scale scores were similar for both treatments. In the first month, inositol [Myo-Inositol] reduced the number of panic attacks per week (mean and SD) by 4.0 (2) compared with a reduction of 2.4 (2) with fluvoxamine (p = 0.049). Nausea and tiredness were more common with fluvoxamine (p = 0.02 and p = 0.01, respectively). Because inositol [Myo-Inositol] is a natural compound with few known side effects, it is attractive to patients who are ambivalent about taking psychiatric medication. Continuing reports of inositol's [Myo-Inositol’s] efficacy in the treatment of depression, panic disorder, and OCD should stimulate replication studies.

PMID: 11386498
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Anxiety. 1996;2(1):51-2.

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

Kaplan Z, Amir M, Swartz M, Levine J.

Source
Beer-Sheva Mental Health Center, Ben-Gurion University of the Negev, Israel.

Extract from Full Text

INTRODUCTION
Inositol [Myo-Inositol] is a second messenger system precursor that can affect the function of several neurotransmitters including serotonin (Rahman and Newman, 1993). Inositol [Myo-Inositol] has been shown in controlled double-blind studies to ameliorate symptoms of depression (Levine et al., 1995) and panic disorder (Benjamin et al., 1995). 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.

RESULTS
Table 1 shows the means and standard deviations for the overall score and the two subscales of the IES for Inositol [Myo-Inositol] and placebo. 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 (3.76 *6.42 for Inositol [Myo-Inositol] and -.38 f 8.46 for placebo), for the avoidance subscale (.15 c 3.81 for Inositol [Myo-Inositol] and -.77 –c 5.95 for placebo) or for the intrusion subscale (3.62 * 3.75 for Inositol [Myo-Inositol] and .38 c 5.72 for placebo).

Among the eight patients at the Abarbanel clinic we did not find any significant differences between the improvement score for Inositol [Myo-Inositol] and placebo on the Hamilton Depression Scale (mean and S.D. = 2.5 f 1.9 for Inositol [Myo-Inositol] and 3.1 -c 3.1 for placebo, p > 0.05) or for the Hamilton Anxiety Scale (mean and S.D. = 5.3 * 3.5 for Inositol [Myo-Inositol] and 4.4 f 5.0 for placebo, p 1 0.05).

For the five patients at the Beer-Sheva clinic we found a significant difference on the depression subscale of the SCL-90 (mean and S.D. = 3.4 6.03 for Inositol [Myo-Inositol] and -5.6 2 2.70 for placebo, p = 0.04, one-tailed), but no difference on the anxiety subscale (mean and S.D. =.80 2 2.28 for Inositol [Myo-Inositol] and .40 8.62 for placebo, p > 0.05). All the analyses were done by paired t-tests.

DISCUSSION
This preliminary double-blind crossover study showed no effect of Inositol [Myo-Inositol] on PTSD core symptoms of intrusion and avoidance. However, depression was lowered in the Beer-Sheva subsample of five patients as a resultof the Inositol [Myo-Inositol] treatment. 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 (Katz et al., 1995)…

PMID: 9160600
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World J Biol Psychiatry. 2002 Jul;3(3):147-9.

Myo-inositol has no beneficial effect on premenstrual dysphoric disorder.

Nemets B, Talesnick B, Belmaker RH, Levine J.

Source
Department of Psychiatry, Faculty of Health Sciences, Ben Gurion University of the Negev, Israel.

Abstract
Inositol [Myo-Inositol], a simple isomer of glucose, which serves as a precursor in the phosphatidyl-inositol (PI) second messenger cycle, was shown to be effective in double-blind, placebo-controlled studies of depression, panic and obsessive compulsive disorders as well as in bulimia. The following study was designed to investigate whether inositol [Myo-Inositol] has beneficial effects in another disorder shown to be responsive to SSRIs: premenstrual dysphoric disorder (PMDD). Eleven female patients with PMDD diagnosed according to DSM-IV participated in a cross-over, double-blind, placebo-controlled trial. The active drug was myo-inositol, 12 g daily, whereas placebo was d-glucose administered at the same dose. Each drug was given during the luteal phase only (14 days prior to menses). For each patient treatment alternated between these two drugs for six menstrual cycles. No beneficial effect was demonstrated for inositol [Myo-Inositol] over placebo.

PMID: 12478879

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.

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Hum Psychopharmacol. 2011 Oct;26(7):526-30. doi: 10.1002/hup.1241.

Myo-inositol in the treatment of premenstrual dysphoric disorder.

Gianfranco C, Vittorio U, Silvia B, Francesco D.

Source
AGUNCO Obstetrics and Gynecology Centre, via G. Cassiani, Rome, Italy. gianfranco.carlomagno@gmail.com

Abstract

OBJECTIVE:
Premenstrual dysphoric disorder (PMDD) is a mood disorder disrupting social and/or occupational life of affected women. Premenstrual dysphoric disorder etiology is unknown, although a pivotal role is played by the serotoninergic system. Indeed, one of the most effective treatments is selective serotonin reuptake inhibitors. 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. In the present study, we aimed to investigate the effect of myo-inositol in the treatment of PMDD.

METHODS:
We used a two-phase clinical trial approach (phase I: placebo washout; phase II: comparisons between treatment and placebo) and treated PMMD patients with two different myo-inositol formulations: powder or soft gel capsules. We decided to test these two formulations because according to the manufacturer, 0.6 g of myo-inositol in soft gel capsule has a pharmacokinetic equivalent to 2 g of myo-inositol in powder.

RESULTS:
Our results showed a significant improvement of three different scales: a reduction in the Daily Symptoms Records scale and an improvement of the Hamilton Depression Rating and Clinical Global Impression-Severity of Illness scales. Results were similar for both formulations.

CONCLUSIONS:
In the present study, by using a new pharmaceutical formulation, we were able to clearly prove the efficacy of myo-inositol in PMDD [premenstrual dysphoric disorder].

PMID: 22031267

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J Neural Transm. 2000;107(2):241-53.

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

Kofman O, Einat H, Cohen H, Tenne H, Shoshana C.

Source
Department of Behavioral Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Abstract
Inositol [Myo-Inositol], a precursor for membrane phosphoinositides involved in signal transduction, has been found to be clinically effective in a number of psychiatric disorders and to reverse behavioural effects of lithium. To gain insight into the mechanism of action of inositol [Myo-Inositol], it is critical to establish its efficacy in animal models. Following the initial report by Cohen et al. (1997b) that inositol [Myo-Inositol] was anxiolytic in the elevated plus maze model of anxiety, the effect of chronic intraperitoneal and chronic dietary inositol [Myo-Inositol] administration in rats was tested in four experiments. There was a significant increase in closed arm and total arm entries following chronic injection of inositol [Myo-Inositol], but no effect of inositol [Myo-Inositol] when it was given chronically in rat chow. Because the first 2 experiments suggested that the mode of drug administration affected the control levels of anxiety (open arm entries and time in open arms) in control groups, the effect of chronic dietary inositol [Myo-Inositol] was tested in rats that were exposed to a mild and a more severe form of stress. Chronic saline injections elevated anxiety in the plus maze, which was only marginally affected by chronic dietary inositol [Myo-Inositol]. Following 3 weeks administration of 5% dietary inositol [Myo-Inositol] rats were pre-exposed to a cat. There was a clear increase in number of entries into open arms, suggesting an anxiolytic effect of inositol [Myo-Inositol].

PMID: 10847563
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J Affect Disord. 2001 Jan;62(1-2):113-21.

The effects of inositol [Myo-Inositol] treatment in animal models of psychiatric disorders.

Einat H, Belmaker RH.

Source
Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel.

Abstract
Clinical trials indicate that inositol [Myo-Inositol] may be effective in the treatment of patients with depression, panic disorder and obsessive compulsive disorder (OCD), but not in the treatment of patients with schizophrenia, Alzheimer's disease, ADHD or autism. This spectrum of clinical action parallels that of serotonin selective reuptake inhibitors (SSRIs), but inositol [Myo-Inositol] is a precursor in the phosphatidylinositol cycle, a second messenger system distal to the receptor for 5HT-2. To study its mechanism of therapeutic action there is a need to test inositol's [Myo-Inositol’s] activity in animal models of psychopathology. In rats, chronic inositol [Myo-Inositol] was demonstrated to increase activity levels, reduce immobility time in the forced swim test and in the reserpine-induced hypoactivity models of depression, and reduce anxiety-like behaviors in the elevated plus-maze. The reduction in anxiety-like behaviors appears to be related to baseline levels of activity. Inositol [Myo-Inositol] treatment was not observed to have any effect on amphetamine-induced hyperactivity, apomorphine-induced stereotypy, or on the performance of memory tasks by monkeys. Clinical controlled trials of inositol [Myo-Inositol] 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.

PMID: 11172878
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Am J Psychiatry. 1995 May;152(5):792-4.

Double-blind, controlled trial of inositol [Myo-Inositol] treatment of depression.

Levine J, Barak Y, Gonzalves M, Szor H, Elizur A, Kofman O, Belmaker RH.

Source
Yehuda Abarbanel Mental Health Center, Bat Yam, Israel.

Abstract

OBJECTIVE:
CSF levels of inositol [Myo-Inositol] have been reported to be lower than normal in depressed subjects. The authors administered inositol [Myo-Inositol] to depressed patients in a double-blind, controlled trial.

METHOD:
Under double-blind conditions, 12 g/day of inositol [Myo-Inositol] (N = 13) or placebo (N = 15) was administered to depressed patients for 4 weeks.

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

CONCLUSIONS:
This may be the first use of the precursor strategy for a second messenger rather than a neurotransmitter in treating depression. Although inositol [Myo-Inositol] had a significant antidepressant effect in this study, replication is crucial.

PMID: 7726322
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Cochrane Database Syst Rev. 2004;(2):CD004049.

Inositol [Myo-Inositol] for depressive disorders.

Taylor MJ, Wilder H, Bhagwagar Z, Geddes J.

Source
Department of Psychiatry, University of Oxford, Neurosciences Building, Warneford Hospital, Oxford, Oxfordshire, UK, OX3 7JK.

Abstract

BACKGROUND:
There are a number of effective interventions for the treatment of depression. It is possible that the efficacy of these treatments will be improved further by the use of adjunctive therapies such as inositol [Myo-Inositol].

OBJECTIVES:
1. To determine the effectiveness of inositol [Myo-Inositol] in the treatment of depression.2. To determine the adverse effects and acceptability of treatment with inositol [Myo-Inositol].

SEARCH STRATEGY:
The Cochrane Controlled Trials Register (CCTR), The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) incorporating results of group searches of EMBASE, MEDLINE, LILACS, CINAHL, PSYNDEX and PsycLIT were searched. Reference lists of relevant papers and major textbooks of affective disorder were checked. Experts in the field and pharmaceutical companies were contacted regarding unpublished material.

SELECTION CRITERIA:
All randomised controlled trials that compare treatment with inositol [Myo-Inositol], whether as monotherapy or adjunctive therapy, to an alternative treatment, whether another antidepressant medication or placebo, for patients with a diagnosis of depressive disorder (diagnosed according to explicit criteria).

DATA COLLECTION AND ANALYSIS:
Data were independently extracted from the original reports by two reviewers. Statistical analysis was conducted using Review Manager version 4.2.1.

MAIN RESULTS:
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, nor any evidence of poor acceptability.

REVIEWERS' CONCLUSIONS:
It is currently unclear whether or not inositol [Myo-Inositol] is of benefit in the treatment of depression. Ongoing studies should reduce this uncertainty.

PMID: 15106232
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Behav Brain Res. 2001 Jan 8;118(1):77-83.

The antidepressant activity of inositol [Myo-Inositol] in the forced swim test involves 5-HT(2) receptors.

Einat H, Clenet F, Shaldubina A, Belmaker RH, Bourin M.

Source
Beer Sheva Mental Health Center, Faculty of Health Sciences, Ben Gurion University of the Negev, P.O. Box 4600, Beer Sheva, Israel.

Abstract
The effect of inositol [Myo-Inositol] as an antidepressant was previously demonstrated in both animal models of depression-like behavior and in clinical trials. 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 study attempted to draw a psychopharmacological profile of inositol's behavioral effects by exploring the interactions between the drug and specific receptor agonists and antagonists in the forced swim test. Rats received inositol treatment (or control) in combination with the serotonergic metabolism inhibitor PCPA or with the noradrenergic neurotoxin DSP-4. Results indicated that PCPA but not DSP-4 abolished the ability of inositol to cause a reduction in immobility time in the forced swim test. In mice, the specific 5-HT(2A)/5-HT(2C) antagonist ritanserin, but not the 5-HT(1A)/5-HT(1B)/beta adrenergic antagonist pindolol, abolished inositol's effect in the forced swim test. The 5-HT(2A)/5-HT(2C) agonist DOI and the 5-HT(1A) agonist 8-OH-DPAT did not have any significant effects on inositol's [Myo-Inositol’s] activity. The present data indicates that the antidepressant effect of inositol [Myo-Inositol] may involve 5-HT(2) receptors. It is thus possible that the effects of reuptake antidepressant drugs and the effects of inositol [Myo-Inositol] may have a common final pathway.

PMID: 11163636
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Int Clin Psychopharmacol. 1999 Nov;14(6):353-6.

Inositol [Myo-Inositol] augmentation of serotonin reuptake inhibitors in treatment-refractory obsessive-compulsive disorder: an open trial.

Seedat S, Stein DJ.
Source

Department of Psychiatry, University of Stellenbosch, Tygerberg, South Africa.
Erratum in

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

Abstract

Inositol [Myo-Inositol], an isomer of glucose and precursor in the phosphatidylinositol cycle, may be effective in a number of psychiatric disorders, including obsessive-compulsive disorder (OCD). There is little data, however, on inositol [Myo-Inositol] as an augmenting agent of serotonin reuptake inhibitors (SRIs) in treatment-refractory patients. 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. Symptoms were rated at 2-weekly intervals using the Yale-Brown Obsessive-Compulsive Scale, the Montgomery-Asberg Depression Rating Scale, and the Clinical Global Impressions (CGI) Scale. The majority of patients (n = 7) did not respond to treatment with inositol [Myo-Inositol] augmentation on the CGI improvement item. However, a small number of patients (n = 3) did report a clinically significant response on the CGI improvement item. OCD patients who fail to respond to a number of trials of SRIs may be a particularly treatment-refractory group of subjects. Unfortunately, inositol [Myo-Inositol] augmentation of a SRI did not lead to significant improvement in the majority of such cases. Nevertheless, further research on the mechanism of inositol [Myo-Inositol] efficacy in some patients with anxiety and mood disorders is warranted.

PMID: 10565802

[liltokamak]

ok op it's pretty sad how you seem to get off of acting all wise and scientific, yet most of your thread is absolutely incorrect.

!you are spread borderline dangerous misinformation and keep people from actually getting the help they undoubtedly need.

where the fuck do I even start jesus Christ...

1. NOT ALL GABAERGICS WORK THE SAME WAY, NOR DO ALL OF THEM DOWNREGULATE GABA.

Ever heard of receptor subunits? if not, then you really shoul do your research properly before spreading lies to ppl in need.

etizolam for example has comparatively low a1 to a2 a3 affinity, therefore more anxiolytic and less dependence forming and sedating.
z drugs, unsurprisingly, are a1 selective.
imidazeninil is like the holy grail. it's perfect. now we'll need to source this shit and bye Depressionen and anxiety, for eternity.

practically, pagoclone is the best option ATM, ez to get, affordable, good selectivity and pronounced anxiolysis with zero impairment. still binds to a1 slightly, best used for tapering or emergencies.

same goes for the according you highly dangerous aligning as well as skullcap. they should be highly selective, just like Many plant based non-sedating anxiolytics like some Valeric compounds idk.

2. ASH IS BARELY GABAERGIC FOR ABOUT 30 MIN. THAT'S IT

In accordance with the papers I've read, ash IS a gaba for sure, but not very strong if used reasonably and the half life is like under an h. of course i took a heroic dose for sciencd sake and it was veeeery nice, but gone in what felt like 20 min. next day i had HYPERTHYROIDISM so never do this. what's up with the anxiety effect them?
probably accumulating changes like cortisol, testo, lower inflammation and what not.

OPIOIDS? WHAT THE HELL DO THEY CARE ABOUT GABA W/D?

NEFIRACETAM: not really gabaergic im the classical sense, definitely recommend bc it fights anxiety in a unique, more healthy way.

KAVA HAS NEVER BEEN SHOWN TO IMPACT GABA NEGATIVELY. AFAIK

SSRI SUCK MUCH ASS DURING WD PLS EITHER TITRATE THE DOSE LONG BEFORE OR AFTER.
GOOD ALTERNATIVE mianserin>mirta>quetiapin imo
if ssri combine with one of the first 2 and go with fluoexetine no matter what. It induces production of endo benzoz and antidepressants.

PREGABILN AND GABAPENTIN have little to now cross tolerance, will fucking destroy wd and, just as with meantime, will reduce symptoms, prevent nerve damage and will help with kindling. please always always taper as slow as possible with at least one of the former compounds (important to take them before wd sets in). paws, protracted, wd duration, brain damage as well long lasting emotional and intellectual abilities will be very mush reduced.
ok op it's pretty sad how you seem to get off of acting all wise and scientific, yet most of your thread is absolutely incorrect.

!you are spread borderline dangerous misinformation and keep people from actually getting the help they undoubtedly need.

where the fuck do I even start jesus Christ...

1. NOT ALL GABAERGICS WORK THE SAME WAY, NOR DO ALL OF THEM DOWNREGULATE GABA.

Ever heard of receptor subunits? if not, then you really shoul do your research properly before spreading lies to ppl in need.

etizolam for example has comparatively low a1 to a2 a3 affinity, therefore more anxiolytic and less dependence forming and sedating.
z drugs, unsurprisingly, are a1 selective.
imidazeninil is like the holy grail. it's perfect. now we'll need to source this shit and bye Depressionen and anxiety, for eternity.

practically, pagoclone is the best option ATM, ez to get, affordable, good selectivity and pronounced anxiolysis with zero impairment. still binds to a1 slightly, best used for tapering or emergencies.

same goes for the according you highly dangerous aligning as well as skullcap. they should be highly selective, just like Many plant based non-sedating anxiolytics like some Valeric compounds idk.

2. ASH IS BARELY GABAERGIC FOR ABOUT 30 MIN. THAT'S IT

In accordance with the papers I've read, ash IS a gaba for sure, but not very strong if used reasonably and the half life is like under an h. of course i took a heroic dose for sciencd sake and it was veeeery nice, but gone in what felt like 20 min. next day i had HYPERTHYROIDISM so never do this. what's up with the anxiety effect them?
probably accumulating changes like cortisol, testo, lower inflammation and what not.

OPIOIDS? WHAT THE HELL DO THEY CARE ABOUT GABA W/D?

NEFIRACETAM: not really gabaergic im the classical sense, definitely recommend bc it fights anxiety in a unique, more healthy way.

KAVA HAS NEVER BEEN SHOWN TO IMPACT GABA NEGATIVELY. AFAIK

SSRI SUCK MUCH ASS DURING WD PLS EITHER TITRATE THE DOSE LONG BEFORE OR AFTER.
GOOD ALTERNATIVE mianserin>mirta>quetiapin imo
if ssri combine with one of the first 2 and go with fluoexetine no matter what. It induces production of endo benzoz and antidepressants.

PREGABILN AND GABAPENTIN have little to now cross tolerance, will fucking destroy wd and, just as with meantime, will reduce symptoms, prevent nerve damage and will help with kindling. please always always taper as slow as possible with at least one of the former compounds (important to take them before wd sets in). paws, protracted, wd duration, brain damage as well long lasting emotional and intellectual abilities will be very mush reduced.

[liltokamak]

Am I incorrect in thinking transdermal magnesium supplementation (epsom salt baths) is controversial? I mean to say is it proven to penetrate the skin?

doesn't rlly matter anyway,imma doubt it's the threonate salt so even if passes the skin it won't pass the brain. get powdered mag l threonate it's cheap and ridiculously effective for psychiatric needs. fuck that expensive ass shit you get in drug stores they barely don't scam you