Supplements and Benzodiazepine Recovery

[[Buddie]]

Supplements and Benzodiazepine Recovery

As the popularity of supplements continues to increase companies selling supplements developed and marketed for withdrawal have begun to emerge.  Due to the ever increasing popularity of supplements and this new marketing avenue, it is important to for those of us affected by benzodiazepines (benzos) to take a closer look at the situation, break it all down, and separate real science from pseudoscience.  In this review we will be discussing the following topics as outlined below:

1.0   Ashton’s comments on supplements and benzo withdrawal
2.0   Supplements that are Cross-tolerant to Benzos
2.1   GABAA Receptor (GABAAR) Positive Allosteric Modulators
2.1.1   Kava, Skullcap, Valerian
2.1.2   L-Theanine
2.2   GABAAR Negative Allosteric Modulators (NAMs)
2.2.1   Dehydroepiandrosterone (DHEA)
3.0   Manufacturers of Supplements Marketed for Withdrawal
3.1   Neurogenesis
3.1.1   NeuRelieve
3.2   Point of Return
3.2.1   Relax
3.2.1.1   Relax Active ingredient αs1-casein tryptic hydrolysate
3.3   Alliance for Addiction solutions
3.3.1   Amino Acid Therapy
3.3.1.1   L-Tryptophan and 5-HTP
3.3.1.1.1   ‘Serotonin deficiency’
3.3.1.1.2   L-Tryptophan and Eosinophilia-Myalgia Syndrome
3.3.1.1.2.1   Genetically Modified Organisms in Amino Acid Manufacturing
3.3.1.1.3   Serotonin syndrome
3.3.1.2   GABA
3.3.1.2.1   Phenibut and Picamilon
3.3.1.3   L-Glutamine
4.0   Supplement Safety
4.1   FDA MedWatch program

1.0 Ashton’s comments on Supplements as it pertains to Benzo Withdrawal
   
Ashton addressed supplement usage in benzo withdrawal in a 2001 supplement to the Ashton Manual where she stated the following:

“Nutritional supplements (added April 12, 2012)
There is no evidence that nutritional supplements such as vitamins, minerals, amino acids etc. are helpful in benzodiazepine withdrawal. Excessive doses of some can be toxic and others may even contain benzo-like substances that have the same adverse effects as benzodiazepines themselves. Nor is there any evidence that suggests benzodiazepine withdrawal causes vitamin, mineral or other deficiencies. No-one should take supplements without clear evidence of a specific deficiency. Those who advocate multiple supplements should first show evidence of any deficiency and then conduct proper controlled trials. In particular, taking GABA precursors does not increase GABA concentrations in the brain. Benzodiazepines do not decrease GABA concentrations; instead they alter GABA-receptor affinity. This slowly reverses without the need for supplements and there is no evidence that supplements speed the process. People taking or withdrawing from benzodiazepines should eat a normal healthy diet - which, after all, consists of "natural" substances and contains all the ingredients necessary for the body.

Some products which people have tried and found to be at best useless, at worst harmful include: mineral and vitamin supplements, valerian, St. John's Wort, kava-kava, melatonin, Rescue Remedy, BeCalm'd, choline, Noni juice, 5htp, SAMe and GABA. Most recently someone reported adverse effects from a product called Exhilarin (see Terri's Story-)” (1)

You can read Terri’s Story here - http://www.benzo.org.uk/terrif.htm

2.0 Supplements that are Cross-tolerant to Benzos

Cross tolerance means that one drug will alleviate the withdrawal effects of another. It also means that tolerance of one drug will result in tolerance of another similarly-acting drug. (5)

2.1 GABAA Receptor (GABAAR) Positive Allosteric Modulators

The benzo-like substances that Ashton referred to previously are known as GABAA receptor (GABAAR) positive allosteric modulators (PAMs).  These substances indirectly modulate the effects of the GABA neurotransmitter in a similar fashion to benzodiazepines by enhancing the action of the neurotransmitter GABA.  This results in an increase of negatively charged chloride influx because this type of modulation causes the ion channel opening more frequently.  PAMs are considered to be cross-tolerant to benzodiazepines.


2.1.1   Kava, Skullcap, and Valerian are classified as GABAAR PAMs, as shown in the two examples below:

“Positive allosteric modulators: Alcohols (2M2B, Ethanol, Ethchlorvynol, Methylpentynol, Barbiturates, Benzodiazepines, Carbamates, Chlormezanone, Clomethiazole, Etomidate, Kavalactones (Kava), Loreclezole, Metomidate, Neuroactive steroids, Nonbenzodiazepines [aka z drugs] (β-Carbolines, Cyclopyrrolones, Imidazopyridines, Pyrazolopyrimidines, etc.), Phenols, Piperidinediones, Propanidid, Pyrazolopyridines, Quinazolinones, ROD-188, Skullcap, Stiripentol, Valerenic acid (Valerian)” (2)

“GABA Receptor Ligands- Agonists/Positive allosteric modulators: ethanol, barbiturates, benzodiazepines, carisoprodol, chloral hydrate, etaqualone, etomidate, glutethimide, kava, methaqualone, muscimol, neuroactive steroids [e.g. progesterone], z-drugs [e.g. zaleplon (Sonata), zopiclone (Imovane), zolpidem (Ambien), eszopiclone (Lunesta), propofol, scullcap, valerian, theanine, volatile/inhaled anaesthetics.” (3)


2.1.2   L-Theanine

This supplement has gained popularity for neuroprotective effects and promoting relaxation.  It is listed as a PAM because scientists discovered after Theanine administration the GABAAR antagonist bicuculline prevented its neuroprotective effects.  This would indicate that the GABAAR is being modulated by Theanine:

“This neuroprotective effect of theanine was prevented by bicuculline (GABAA-receptor antagonist, 10 mg/kg) but not 3-mercaptopropionic acid (glutamate decarboxylase inhibitor). These results suggest that the neuroprotective effect of theanine is mediated, at least in part, by GABAA receptors.” (4)


2.2   GABAAR Negative Allosteric Modulators (NAMs)

NAMs have the opposite effect of PAMs.  NAMs decrease the action of the neurotransmitter GABA so the chloride channel opens less frequently.  This results in a decrease of negatively charged chloride entering the neuron.


2.2.1 Dehydroepiandrosterone (DHEA)

DHEA is a neuroactive steroid hormone that is available in supplement form. DHEA acts a negative allosteric modulator (NAM) of the GABAAR (20), which means it reduces the effect of GABA.  It is also acts as a PAM of the NMDA receptor (NMDAR), which means it enhances the modulation of NMDARs.  Obviously, this would be the exact opposite effect one would desire while recovering from benzos.

When considering supplement use it is important to bear in mind that many supplements labeled as ‘natural’ may contain pharmacologically active substances.


3.0 Manufacturers of Supplements Marketed for Withdrawal

There are many companies that manufacture products marketed for withdrawal.  In this section we will take a look at the active ingredients in some of these supplements in the context of benzo tolerance and withdrawal.
 
3.1 Neurogenesis, http://neurogenesis.com/  (Note: also the makers of BeCalm’d, previously mentioned by Ashton).

3.1.1 NeuRelieve

The following is an excerpt from the Neurogenesis NeuRelieve product information page:

“NeuRelieve is nutritional support for restoring and rebuilding healthy brain chemistry that has been Altered or depleted by the long-term use of antianxiety drugs

Amino Acid sources: D-phenylalanine, L-Glutamine, Taurine, Glycine, 5HTP

Neurotransmitters affected: GABA, Serotonin, Enkephalins” (6)

As Ashton pointed out, recovery involves a reversal of benzo induced changes to GABAAR gene expression which resulted in decreased GABA affinity.  When benzos bind to GABAARs they cause the ion channel to open more frequently.  This allows a greater amount of negatively charged chloride to enter the cell.  This throws off the cells equilibrium, so the neuron makes changes to combat this effect of the drug.  To correct the situation the neuron will swap out GABAARs with high affinity for GABA with ones that have less affinity through changes in gene expression.  In this way the neuron attempts to bring the level of chloride influx back down to the pre-benzo level.  These changes are the mechanisms underlying tolerance to the drug.

If benzos are discontinued after tolerance has set up the level of negatively charged chloride entering the cell will decrease.  This causes the neuron voltage gradient to now shift in a positive direction.  The change in voltage once again disrupts the neurons equilibrium.  This prompts the internal mechanisms of the cell to begin reversing the benzo-induced changes to gene expression in order to restore equilibrium once again. The neuron reverses these changes for the same reason they instituted them in the first place- to restore homeostasis.  These types of changes are known as neuroadaptations and are a form of neuroplasticity.  Therefore, recovery involves restoration of receptors, not GABA concentrations.  Ashton also pointed out that amino acid precursors, such as L-Glutamine, have not been shown to increase GABA concentrations in the brain.  We will discuss this amino acid more in depth a little later.

Another matter to consider is that these amino acid precursors would not address the Long-Term Potential (LTP) like occurrences which may occur during the transition from tolerance to withdrawal.  Studies have shown that while tolerance to benzos generally involves changes to GABAARs, symptoms of dependence (which emerge during withdrawal from the drug) may actually be the result of GABAAR mediated changes to Glutamate receptors:

“The results suggest an involvement of GABA-mediated processes in the development and maintenance of tolerance to diazepam, whereas excitatory amino acid-related processes (presumably via AMPA receptors) may be involved in the expression of signs of dependence after withdrawal.” (7)

“Activity-dependent changes in synaptic function are primarily the consequence of intracellular Ca2+-dependent biochemical cascades and involve changes in synaptic AMPAR number and/or function. A GABAR-mediated depolarizing potential, which is present in 2-day FZP-withdrawn CA1 neurons, has been shown to activate NMDARs and may contribute to increased postsynaptic Ca2+-mediated signal transduction. Thus, in the context of BZ withdrawal, the initial trigger for AMPAR upregulation, though as yet unidentified, may also involve Ca2+-mediated mechanisms similar to that which occur during other forms of activity-dependent neuronal plasticity.” (27)

A Neurogenesis company research draft for product development stated the following:

“The issue that is most important and the issue that causes all the problems of dependency is this: when the auxiliary receptors are occupied for longer than normal periods of time by drugs such as benzo’s the result is that the brain begins to reduce the supply of GABA.” [8]

As we discussed earlier, dependence results from benzo induced changes to gene expression, not reductions in ‘the supply of GABA.’

During my first year in benzo withdrawal I took NeuRelieve.  After hitting my one year anniversary and still having an impressive list of symptoms I decided to stop taking it.  I noticed my anxiety actually came down a few notches after stopping the supplement.  In my case it seemed to have actually made the anxiety I was experiencing worse.


3.2 Point of Return, http://www.pointofreturn.com/

The following is from their web page entitled “Learn how to taper off Benzodiazepines and Sleeping Pills Safely”:

“You begin the Point of Return nutraceuticals to help prepare your nervous system for the withdrawal process.” (9)

(Note: this website has two spellings for ‘nutraceuticals,’ the other is ‘nutriceuticals.’) 

There are no studies that I am aware of that have shown that a person needs to prepare their nervous system with any of the Point of Return ‘nutriceuticals’ prior to withdrawing from benzodiazepines.  Anyone wishing to come off benzodiazepines safely should always consult with their doctor.  If there are any existing health conditions that might impact the withdrawal process it would be advisable to have your physician involved.  There is no way to determine whether a consumer may be deficient in nutrients without proper testing.


3.2.1 Relax

The following is a statement is from the Point of Return ‘Relax’ supplement information page.

“Benzodiazepines enhance GABA-A…The brain then reduces its own production of GABA, and during a too rapid withdrawal process, insufficient GABA is present to alleviate the tension.” (10)

Once again, GABA production is not the issue.  This appears to be a common misconception.

3.2.1.1 Relax Active Ingredient αs1-casein tryptic hydrolysate

The main ingredient of the supplement Relax is listed as a milk protein decapeptide, αs1-casein tryptic hydrolysate (αs1-CnTH).  Point of return provided the following information regarding this decapeptide on the Relax product information web page:

“Scientists from University Henri Poincare-Nancy & Georgetown University Medical Center gathered a group of medical scientists to test the peptide found in milk. They discovered that a milk protein constituent mimicked the action of anxiety reducing drugs but did not trigger any side effects.” (10)

In the study cited above, αs1-CnTH was tested in vitro on benzodiazepine (BDZ) receptors and checked in vivo for its anticonvulsant and anxiolytic effects in Wistar rats.  In this study scientists found that αs1-CnTH shares the anticonvulsant and anxiolytic properties of benzodiazepines:

“In two behavioral tests, elevated plus maze test and CDB [conditioned defensive burying] paradigm, αs1-CnTH exhibited the characteristic profile of full BDZ agonists such as diazepam. Moreover, αs1-CnTH suppressed the inhibitory effect of PTZ [pentylenetetrazole] on the GABAergic system.” (11)

They also discovered that αs1-CnTH binds to the benzodiazepine site on the GABAAR via the α-casozepine peptide, and suggested that this peptide might be 10 times more active than benzodiazepines:

“A peptide (α-casozepine) of the αs1-CnTH binds on the BDZ site of the GABAA receptor… Despite a lower in vitro affinity than diazepam for the BDZ site of the GABAA receptor, α-casozepine might be ∼10-fold more active in vivo than the BDZ.” (11)

These findings would classify it as a GABAAR PAM which would also make it cross-tolerant to benzodiazepines. There have been no studies to determine whether there is either a potential for tolerance or dependence, which is a concern as this supplement binds to the same place on the GABAAR that benzos do.

As for the claim regarding side effects, putting this statement back into the context of the study, the scientists did not observe any side effects in the rats in their observations during these relatively short experiments.  The duration of αs1-CnTH administration during the experiments was well below the threshold established for benzo tolerance.  Without studies investigating potential αs1-CnTH tolerance there is no way to know whether long term use of this supplement might lead to tolerance or dependence.

αs1-CnTH may have another characteristic in common with benzos. A study involving human test subjects showed αs1-CnTH had a negative effect on cortisol concentrations (CC), which may be an indication of HPA Axis suppression which is known to happen with benzo usage (29):

“The subjects were (double blind) randomly allocated to ingest three times, 12 hours apart, two capsules containing either 200 mg of alphaS1-casein hydrolysate (TS) or bovine skimmed milk powder as a placebo (CS)… the results showed a significant decrease of the CC in the TS but not in the CS throughout the ST [Stroop Test] + CPT [Cold Pressor Test] combined stress tests.” (28)


3.3   Alliance for Addiction Solutions (AAS), http://transformingaddiction.com/[/b]


3.3.1   Amino Acid Therapy

The following is a statement from the AAS the web page entitled “Amino Acid Therapy and Key Recovery Supplements and Nutraceuticals for Addiction Treatment”:

“The most crucial nutrients for early recovery, however, are amino acids… There are 22 amino acids in food, but, for the treatment of addictive disorders, we are most interested in supplementing five to eight of them. Each of these amino acids influences the activity of a particular neurotransmitter that directly affects cravings for a specific drug.”   

Since changes to receptors are generally the universal underlying mechanism behind tolerance and dependence, this philosophy echoes the misconception regarding neurotransmitters previously discussed.

Next we will look at a few amino acids from their amino acid therapy page and discuss them in the context of benzo withdrawal.  A long the way we will also discuss general safety and adverse events associated with amino acid supplements.


3.3.1.1   L-Tryptophan and 5-HTP

In the next section we will discuss on of the supplements L-Tryptophan and 5-HTP as recommended by AAS for amino acid therapy.


3.3.1.1.1 ‘Serotonin Deficiency’

AAS stated the following on their amino acid therapy web page under ‘L-Tryptophan and 5-HTP’:

“L-Tryptophan and 5-HTP 5-Hydroxy TryptoPhan) is used to manufacture serotonin, the brain’s natural antidepressant. Serotonin deficiency symptoms: depression, self-deprecation, irritability, panic, anxiety, compulsive thoughts and behaviors, suicidal thoughts and behaviors, sleep disorders, seasonal affective disorder, cravings worse in the afternoon or evening, sensitivity to heat, minimal sense of humor. Symptoms of deficiency may include cravings for sweets and starches; uses nicotine, marijuana, and alcohol for relaxing and comfort when stressed; Use of Prescribed SSRI drugs like Lexapro, Zoloft, Paxil, Prozac or SNRI drugs like Effexor or Cymbalta.”(1)

Serotonin deficiency has also been referred to as a ‘chemical imbalance.’  This assumption has recently been brought into question, as pointed out by the Counsel for Evidence Based Psychiatry (cepuk.org):

“Psychiatric drugs have often been prescribed to patients on the basis that they cure a ‘chemical imbalance’. However, no chemical imbalances have been proven to exist in relation to any mental health disorder. There is also no method available to test for the presence or absence of these chemical imbalances.” (13)

Since there are no tests to measure serotonin levels in the brain it would be difficult to determine whether these symptoms were the result of serotonin levels or something else.  There are many organic conditions, such as conditions which may cause hormone irregularities for example, that could produce the same symptoms.  Changes to receptors is a universal mechanism underlying most tolerance and dependence which may also produce the same symptoms. There is a lack of scientific evidence not only to back up these claims, but also that low serotonin levels produce cravings for certain foods or drugs.


3.3.1.1.2 L-Tryptophan and Eosinophilia-Myalgia Syndrome

In 1981 there was an outbreak Eosinophilia-Myalgia Syndrome (EMS) that was traced back to L-Tryptophan supplements:

“Eosinophilia-myalgia syndrome, a newly recognized disorder that occurred in epidemic proportions during 1989, is associated with ingestion of manufactured tryptophan... As of July 10, 1990, a total of 1531 cases had been reported nationwide, including 27 deaths.” (14)

This actually happened to one of the members of benzobuddies who was prescribed benzos to treat symptoms of EMS.

While the outbreak was initially thought to be isolated to one manufacturer, an article published in 2013 in the International Journal of Tryptophan Research suggested there may be more:

“The ingestion of L-Tryptophan is associated with eosinophilic fasciitis and the eosinophilia myalgia syndrome. Although initially attributed to the contaminant 1,1-ethylidenebis tryptophan detected in the product manufactured by Showa Denko, other authors have reported the same adverse reaction from L-Tryptophan supplied by other manufacturers.” (15)


3.3.1.1.2.1 Genetically Modified Organisms and Amino Acid Manufacturing

Investigations into the origin of the outbreak discovered that the L-Tryptophan was manufactured using biotechnology-derived products which were used to increase yield:

“…the manufacturer was genetically engineering bacteria to produce the L-Tryptophan more economically. Genes had been inserted into bacteria s DNA in order to produce high concentrations of several enzymes used in its production.” (16)

These changes to the manufacturing process may have resulted in an impurity contamination:

“An epidemic of a new disease, termed eosinophilia-myalgia syndrome, occurred in the USA in 1989. This syndrome was linked to the consumption of L-Tryptophan manufactured by a single company utilizing a fermentation process. All the findings indicate that the illness was probably triggered by an impurity formed when the manufacturing conditions were modified. This outbreak highlights the need for close monitoring of the chemical purity of biotechnology-derived products, and for rigorous testing of such products following any significant changes to the manufacturing process.” (17)

Information may be difficult to obtain when determining whether biotechnology-derived products were used in amino acid supplements:

“Production methods with genetically modified microorganisms are known for a range of amino acids. However, little information is accessible as a rule on the subject of whether and to what degree these production methods are commercially employed. Market leaders in amino acids are Japanese firms. The following amino acids can be produced with the aid of gene technology: lysins, threonine, phenylalanine, methionine, tryptophan, arginine, leucine, glutamic acid and cysteine. The culture medium on which the microorganisms grow may contain raw materials from genetically modified plants (e.g. soybeans, rapeseed). It is possible that these plant proteins may have been derived from genetically modified plants such as soybeans. The applied enzymes may be manufactured with the aid of genetically modified organisms.”
“Amino acids that have been produced with the aid of genetically modified organisms in closed systems do not require labelling, provided that the amino acid in question has been purified and contains no microorganisms.[/b]” (18)


3.3.1.1.3 Serotonin Syndrome

There is another topic that should mentioned regarding both L-Tryptophan and 5-HTP.  As more and more people are being prescribed antidepressants, it is important to note that there is an increased risk of Serotonin Syndrome (aka 5HT Syndrome) when these types of drugs and supplements are combined:

“One caveat is that with the increasing use of 5HT drugs (agents that enhance 5HT function) in society, most notably 5HT reuptake inhibitors [e.g., fluoxetine (Prozac), citalopram (Celexa), fluovoxamine (Luvox), sertraline (Zoloft), and escitalopram (Lexapro)], the use of one or more of such agents, in combination with Trp, can occasionally elicit a serious condition termed the “5HT syndrome,” which requires intervention.” (19)

Drug-supplement interaction has become an important factor doctors have to consider when prescribing medications with the rise in supplement use.


3.3.1.2 GABA

AAS stated the following on their amino acid therapy page under the section ‘GABA’:

“GABA is used to augment the neurotransmitter GABA (gamma amino butyric acid), the anti-stress chemical. GABA deficiency symptoms: anxiety, tension—emotional and physical—and feeling overwhelmed by stress. Symptoms of deficiency may include cravings for: carbohydrates, nicotine, marijuana, or alcohol to relax when stressed. Use of Prescribed tranquilizers like Valium, Neurontin, Xanax, and Ativan.”

As stated previously, there is no test to measure GABA levels in the brain and a lack of scientific evidence supporting an association between GABA deficiency and ‘cravings.’

Scientifically and medicinally relevant evidence shows that GABA supplements do not cross the blood brain barrier (BBB) at therapeutic doses. (3)


3.3.1.2.1 Phenibut and Picamilon

Russian scientists developed two derivatives of GABA, phenibut and picamilon, which are capable of circumventing the BBB.  They added a phenyl ring to the GABA molecular structure to form Phenibut. For Picamilon, niacin was bound to GABA in order to ‘piggy back’ it through the BBB.

The blood brain barrier is there for a reason- to keep certain things out like bacteria, toxins, and apparently GABA supplements.  If it was ok for it to enter your brain nature would not have set up a barrier to prevent it.  In addition to that, the brain actually has a one way pump to get rid of excess GABA - the GABA can go out but not come in.  With all of these precautions in place I think it would be safe to say that forcing GABA into your brain is probably not a good idea.

Some members of benzobuddies had problems after ingesting Phenibut.  You can read about their experiences by typing ‘phenibut’ in the search box located in the upper right hand corner of this web page.


3.3.1.3 L-Glutamine

Glutamine is synthesized into the neurotransmitter Glutamate in the presynaptic terminal by the enzyme Glutaminase. Normally levels of free Glutamate in the brain are kept fairly low by a tightly regulated system. (21)  After the presynaptic neurons fires and releases Glutamate into the synapse, any excess is quickly removed by Glutamate transporters located on both the membranes of neurons and a type of glial cell known as astrocytes.  This protects neurons from excitotoxicity.  The Glutamate is then converted back into Glutamine by Glutamine Synthetase for recycling.  Next transporters transfer the Glutamine from the astrocytes back to the presynaptic neuron terminal where is it converted once again into the neurotransmitter Glutamate by the enzyme Glutaminase.  This is known as the Glutamate-Glutamine cycle. (22, 23, 24)

This recycled Glutamine may also be used to synthesize the neurotransmitter GABA as part of the Glutamate/GABA-Glutamine cycle:

“The glutamate/GABA-glutamine cycle is a metabolic pathway that describes the release of glutamate or GABA from neurons and then taken up into astrocytes (star shaped glial cells). In return, astrocytes release glutamine to be taken up into neurons for use as a precursor to the synthesis of glutamate or GABA.” (23)

L-Glutamine is a non-essential amino acid which means the body can manufacture its own and does not need to obtain it from dietary sources.  The amount of L-Glutamine circulating in the plasma which crosses the blood brain barrier (BBB) is tightly controlled to protect the brain from fluctuation of levels during the day.  Plasma levels can fluctuate due to changes in diet, metabolism, or protein turnover. It is crucial to maintain low levels in the interstitial space.  Without the protection of the BBB in place these fluctuations may otherwise disrupt synaptic brain communications. (21)  Therefore trying to increase levels through supplementation could potentially disrupt brain activity and increase excitatory activity in the brain.

The brains maintenance of levels of l-glutamate is fairly independent from the blood circulation:

“Glutamate concentration in brain interstitial fluid is only a fraction of that of plasma and is maintained fairly independently of small fluctuations in plasma concentration. Restricted brain passage is also observed for several excitatory glutamate analogs, including domoic acid and kynurenic acid. In summary, the BBB is one component of a regulatory system that helps maintain brain interstitial fluid glutamate concentration independently of the circulation.” (21)

Since withdrawal symptoms are the result of changes to receptor function rather than changes to the level of neurotransmitters, it would not be necessary to increase either GABA or Glutamate levels for recovery.

AAS stated the following on their amino acid therapy page under the section ‘L-Glutamate’:

“L-Glutamine is a perfect fuel for the whole brain, balancing blood sugar levels to maintain energy and clear thinking. Blood sugar deficiency symptoms: irritability, shakiness, weakness, dizziness, especially if too many hours have passed since the previous meal. Symptoms of deficiency may include cravings for whatever gives quick relief to low blood sugar, like sweets, starches, and alcohol. NOTE: Be cautious about taking L-glutamine if you have manic depression (bipolar disorder). While low doses of L-glutamine may relieve bipolar depression, in approximately 50% of bipolar cases normal doses of L-glutamine can trigger mania.”

This statement appears to be focused more on blood sugar levels.  Glutamine supplementation is being investigated for glycemia recovery in Diabetes.(30)  If you suspect that you are having trouble with blood sugar levels it would be best to have your levels evaluated by a physician.  It would be a good idea to first rule out a diagnosis of Diabetes or hypoglycemia before trying to manipulate your blood sugar levels on your own- as either too little or too much sugar in the blood can be dangerous.


4.0 Supplement Safety

The National Institutes of Health (NIH) have posted links on their ‘Supplement’ web page to the U.S. Food and Drug Administration (FDA) information about supplement warnings, safety alerts, and tips to spot fraud. (25)


4.1 MedWatch

The FDA has set up a program where consumers can report adverse events associated with medications and supplements known as ‘MedWatch.’ (26) The following information is from their list of guidelines of what can and cannot be reported:

“What to Report to FDA MedWatch:
Use the MedWatch form to report adverse events that you observe or suspect for human medical products, including serious drug side effects, product use errors, product quality problems, and therapeutic failures for:

-   Prescription or over-the-counter medicines, as well as medicines administered to hospital patients or at outpatient infusion centers…
-   …Special nutritional products (dietary supplements, infant formulas, and medical foods)” (26)

I hope this information helpful.  I believe that it is important to have all the facts in order to make educated decisions when it comes to putting something your body.

References
1)   A Supplement to Benzodiazepines: How They Work& How to Withdraw
Professor C Heather Ashton, DM, FRCP
The Ashton Manual Supplement (2002) April, 7 2011 (additions 2012 & 2013)
http://www.benzo.org.uk/ashsupp11.htm

2)   Theanine
GABAergics
From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Theanine#Effects_on_the_brain

3)   gamma-Aminobutyric acid
GABAergic Drugs
From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/GABA

4)   Involvement of GABAA Receptors in the Neuroprotective Effect of Theanine on Focal Cerebral Ischemia in Mice
Nobuaki Egashira, Kazuhide Hayakawa, Megumi Osajima, Kenichi Mishima, Katsunori Iwasaki,
Ryozo Oishi, Michihiro Fujiwara J Pharmacol Sci 105, 211 – 214 (2007)
https://www.jstage.jst.go.jp/article/jphs/105/2/105_2_211/_pdf

5)   Benzodiazepine Dependence
Cross tolerance
From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Benzodiazepine_dependence#Cross_tolerance

6)   NeuRelieve
Neurogenesis, Inc
http://neurogenesis.com/the-products-of-neurogenesis-inc/298-2/

7)   Glutamic acid decarboxylase and glutamate receptor changes during tolerance and dependence to Benzodiazepines
Emanuela Izzo, James Auta, Francesco Impagnatiello, Christine Pesold, Alessandro Guidotti, Erminio Costa
PNAS March 13, 2001 vol. 98 no. 6 3483–3488, doi: 10.1073/pnas.051628698
http://www.pnas.org/content/98/6/3483.full

8]   Symptom Reduction In Persons Withdrawing from Benzodiazepines
Study Report
Terry Neher, DDS, CCDC, NCAC Vice President, Research and Development
NeuroGenesis, Inc Houston, Texas
http://www.lifehealthsolutions.com/calm/bz_symptom_reduction.html

9)   Learn how to taper off Benzodiazepines and Sleeping Pills Safely
Point of Return, Inc.
http://www.pointofreturn.com/benzodiazepine_withdrawal.html

10)   Relax – natural stress reliever
Point of Return, Inc.
http://www.pointofreturn.com/relax.html

11)   Characterization of α-casozepine, a tryptic peptide from bovine αs1-casein with benzodiazepine-like activity
Laurent Miclo, Emmanuel Perrin, Alain Driou, Vassilios Papadopoulos, Noureddine Boujrad, Régis Vanderesse, Jean-François Boudier, Didier Desor, Guy Linden, Jean-Luc Gaillard
Published online before print June 8, 2001, doi: 10.1096/fj.00-0685fje August 2001 The FASEB Journal vol. 15 no. 10 1780-1782
http://www.fasebj.org/content/15/10/1780.full

12)   Amino Acid Therapy and Key Recovery Supplements and Nutraceuticals for Addiction Treatment
Alliance for Addiction Solutions Philosophy
Alliance for Addiction Solutions, Inc.
http://transformingaddiction.com/philosophy/philosophy-supplements-and-nutraceuticals/

13)   Myth of the chemical imbalance
Counsel for Evidence Based Psychiatry
http://cepuk.org/unrecognised-facts/myth-of-the-chemical-imbalance/

14)   Eosinophilia-Myalgia Syndrome
Leslie A. Swygert, MD; Edmond F. Maes, PhD; Leeann E. Sewell, MPH; Lynn Miller, DVM, MPH; Henry Falk, MD, MPH; Edwin M. Kilbourne, MD JAMA. 1990;264(13):1698-1703. doi:10.1001/jama.1990.03450130070029.
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15)   Immunohistochemical Studies of the Kynurenine Pathway in Morphea
Rowland Noakes, Nick Mellick, Int J Tryptophan Res. 2013 Dec 23;6:97-102. doi: 10.4137/IJTR.S13371. eCollection 2013.
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16)   A Deadly Epidemic and the Attempt to Hide its Link to Genetic Engineering
Jeffrey M. Smith Organic Consumers Association August 2005
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18)   Amino Acids
GMO Compass
http://www.gmo-compass.org/eng/database/ingredients/98.amino_acid.html
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John D. Fernstrom
J. Nutr. December 1, 2012 vol. 142 no. 12 2236S-2244S
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20)   Dehydroepiandrosterone
Mechanism of Action
Wikipedia the free encyclopedia
https://en.wikipedia.org/wiki/Dehydroepiandrosterone

21)   Transport of Glutamate and Other Amino Acids at the Blood-Brain Barrier
Smith Q.R. J Nutr. 2000 Apr;130(4S Suppl):1016S-22S.
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22)   Neuroscience/Cellular Neurobiology/Neurotransmitters
Glutamate
Wikipedia, the free encyclopedia
http://en.wikibooks.org/wiki/Neuroscience/Cellular_Neurobiology/Neurotransmitters#Glutamate

23)   Glutamate-glutamine Cycle
Glutamate
Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Glutamine-glutamate_cycle

24)   Glutamine Synthetase
Biological Function
Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Glutamine_synthetase

25)   Consumer Protection
National Institutes of Health
Office of Dietary Supplements
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26)   The FDA Safety Information and Adverse Event Reporting Program
MedWatch Online Voluntary Reporting Form
What to Report to MedWatch
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27)   Transient Plasticity of Hippocampal CA1 Neuron Glutamate Receptors Contributes to Benzodiazepine Withdrawal-Anxiety
Bradley J Van Sickle, Kun Xiang, Elizabeth I Tietz
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28)   Effects of a tryptic hydrolysate from bovine milk alphaS1-casein on hemodynamic responses in healthy human volunteers facing successive mental and physical stress situations.
Messaoudi M, Lefranc-Millot C, Desor D, Demagny B, Bourdon L.
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29)   The Stimulatory Effect of Canrenoate, a Mineralocorticoid Antagonist, on the Activity of the Hypothalamus-Pituitary-Adrenal Axis Is Abolished by Alprazolam, a Benzodiazepine, in Humans
S. Grottoli, R. Giordano, B. Maccagno, M. Pellegrino, E. Ghigo, E. Arvat
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DOI: http://dx.doi.org/10.1210/jc.2002-020331 Received: March 04, 2002 Accepted: June 28, 2002 Published Online: July 02, 2013
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30)   Oral Glutamine Is Superior Than Oral Glucose to Promote Glycemia Recovery in Mice Submitted to Insulin-Induced Hypoglycemia
Amanda Nunes Santiago, Vilma Aparecida Ferreira de Godoi-Gazola, Mariana FachinMilani, Vanessa Cristina de Campos, Vanessa Rodrigues Vilela, MariaMontserrat Diaz Pedrosa, and Roberto Barbosa Bazotte
Hindawi Publishing Corporation, International Journal of Endocrinology Volume 2013, Article ID 841514, 7 pages
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