This article will examine the potential contributions to health and well being of each of the ingredients that make up Synthergine:

Arginine Hydrochloride
Lysine Hydrochloride
Methionine Hydrochloride
Sodium Glucuronate
Di-isopropylamine Dichloroacetate
Three ingredients are amino acids. It is appropriate to ask why one would need to administer specific amino acids when they are present in protein therefore this article will spend time addressing the failure of protein to engage some of the pharmacological properties of amino acids. In fact increasing the dietary protein intake to a high level will lead to a reduction in the availability of some amino acids.

The article will spend time discussing the ability of a combination of Arginine and Lysine to reduce whole body stress and cortisol levels. The ability of this combination to reduce stress induced cortisol may be far more significant then any of their specifically defined detoxification properties.

The fourth ingredient Sodium Glucuronate aids the elimination of various compounds by making them more easily eliminated through urination. Among those eliminated compounds are hormones.

While many people are of the belief that they are careful with the types of medications and chemicals they ingest few understand that they may be engaged in an activity that reduces the liver’s ability to metabolize hormones. That activity is specifically related to the “in plasma” profile of exogenously administered growth hormone. The non-pulsatile elevation of growth hormone or even the less pulsatile pattern that comes as we age has the effect of creating a feminized secretory pattern which will dramatically alter the ability of the liver to metabolize drugs and hormones.

Although this may seem a bit out of place I believe it is very much worth our while to examine before looking at the specific actions of Sodium Glucuronate.

The final ingredient in the list is Di-isopropylamine Dichloroacetate. This article is compelled to examine the toxicity and safety of this compound because early studies failed in their methodology and wrongfully arrived at a conclusion that this compound is potentially mutagenic. Like a great many things in the age of Google the wrongful conclusion is probably more oft repeated then the conclusions that neither pure Diisopropylamine nor pure Dichloroacetate is mutagenic. In untainted forms they were deemed safe.

This allows us to proceed to examine the actions of Di-isopropylamine Dichloroacetate in reducing specific liver damage.

We will conclude the article by returning to an amino acid, methionine. We will examine its role in limiting liver injury brought about by an increase of a liver enzyme and its protective role in preventing fibrosis and liver cell death.

All of these topics will underscore the need for balance.

Amino Acids – inducing pharmacological responses
Amino acids have specific pharmacological properties that are often lost or diluted when they are ingested together with other amino acids. To obtain the pharmacological levels necessary to achieve a benefit high levels of protein would need to be ingested. Unfortunately high levels of protein are inadequate to the task not because they fail in the attempted provision of the quantity needed but rather because high protein intake fails in the delivery.

Whole foods or whole-protein powder or tablets of free amino acids may present the desired quantity of amino acids to the liver but there it is processed by the liver over a period of time. This means that more of the amino acids will be catabolized to urea rather then reach systemic circulation. Bypassing the initial pass through the liver in favor of sublingual intake and absorption through the gastric and intestinal mucosa will increase the concentration of amino acid that makes it into the systemic circulation as will all administrations that bypass the liver.

However the problem does not end once the amino acids make their way into circulation. Amino acids compete for transport into cells with the limited availability of the amino acid transport system that shuttle amino acids across the cellular membrane into cells. While there are several types of transporters for different classes of amino acids they can become saturated when presented with a large quantity of amino acids.

None of this is specifically limiting to normal physiological functioning but can be if the pharmacological property of an amino acid or two is desired at a specific point in time.

Changes in protein intake lead to metabolic responses that induce amino acid balance. Increasing dietary protein level above a threshold leads to a reduction of amino acid availability. The body increases amino acid catabolism following high-protein feeding as a method of preventing the accumulation of some amino acids, primarily the aromatic amino acids. Aromatic amino acids are phenylalanine, histidine, tryptophan, and tyrosine.

These are amino acids that are indispensable to the brain. It takes the steps necessary to maintain physiological concentrations which means controlling the level of amino acids through the liver.

The “down regulation” is not instantaneous. During the first days on a high protein diet amino acid catabolism is not fully engaged and intake of large amounts of protein results in an imbalanced amino acid pattern that signals the brain to among other things depress appetite.

Briefly the aromatic amino acids phenylalanine and tyrosine are involved in the synthesis of two important neurotransmitters; dopamine and norepinephrine. However large amounts of phenylalanine in particular may affect blood pressure and bring on headaches.

Histidine is involved in neurotransmission activity in the central nervous systems as well as increasing the production of red and white blood cells. However large amounts can cause zinc deficiency.

Tryptophan is the precursor to Serotonin, a neurotransmitter in the brain.

From this brief description you can see that the brain has an interest in maintaining fairly stable levels of these amino acids.

Some of the regulatory mechanism involved also has an effect on the other amino acids. It has been demonstrated that during periods of prolonged high protein intake, liver concentrations of some amino acids are very much depressed even though via feeding their supply was plentiful. Catabolism and limitations in transport appear to be responsible. More specifically the amino acids threonine, serine and glycine which share the same metabolic pathway are depressed on high protein diets.

Glutamine may become limited however because of its endogenous synthesis bounces back quickly when a high protein diet is stopped. It appears that the decrease in lysine and histidine concentrations in muscle brought about by high protein diets are also quickly reversed.

But the liver metabolic pathway shared by threonine, serine and glycine is slow to respond. As a result levels of these amino acids may still be depressed more then seven days after a high protein diet is suspended.

I think it is worth noting the functions of threonine. Threonine aids in the synthesis of glycine and serine which in turn are beneficial in the production of collagen, elastin, and muscle tissue.Threonine directly helps build strong bones and tooth enamel and plays a role in wound healing by boosting the immune system.

It has been found to be beneficial in treating Lou Gherig’s Disease (ALS). Some research shows that symptoms of degraded nerve & muscle from Multiple Sclerosis (MS) may be alleviated with threonine treatment. As an immunostimulant it promotes the growth of the thymus gland.

In addition taurine an amino acid that appears to have a protective effect in cardiovascular disease has been found to be reduced by as much as 50% in plasma when high protein diets are given.

It would be important for everyone to takes steps not to continually depress these amino acids.

So high protein intakes are not the answer to achieving the amino acid concentrations necessary to bring out their pharmacological properties. The remedy is intake of specific amino acids during times when dietary protein is not elevated, via methods some of which will bypass the liver.

Arginine + Lysine reduces stress and cortisol levels: A Pharmacological Response
L-lysine has been found to reduce anxiety and normalize stress-induced hormonal responses in healthy individuals with high anxiety 1. When it is used together with L-Arginine it has been found to block stress-induced abnormalities and manifestations of disease in laboratory and farm animals2-4.

The explanatory mechanism has been postulated to relate to Lysine’s ability to act as both a partial serotonin receptor antagonist 5,6 and simultaneously as a partial benzodiazepine agonist7,8.

This research was recently carried over into healthy humans in a study that tested the combined ability of L-lysine and L-arginine to reduce anxiety, stress and stress hormones in response to laboratory induced trauma9.

Human Study

In this study carried out by Smriga (2007), they had fifty healthy people who had perceived stress in their lives orally ingest 1.32 grams of L-lysine HCL and 1.32 grams of L-arginine twice a day (a total of 2.64 of each per day) for seven consecutive days. On the seventh day participants where subjected to stress testing to evaluate mental stress. Cortisol and chromogranin-A were measured in saliva. These measurements had been done prior to treatment as well.

Cortisol is a hormonal marker of the hypothalamo-pituitary-adrenal axis. Chromogranin-A is a protein found in adrenergic neurons. This protein directly reflects stress response and “sympathetic tone”. The Sympathetic Nervous System is a part of the nervous system that is always active to some degree and becomes more active during times of stress. This state is called the “sympathetic tone”.

High base cortisol and increased base “sympathetic tone” lead to psychological disease induction and blunt normal responsiveness of both the hypothalamo-pituitary-adrenal and sympathetic nervous system to stress exposure. Anxiety is a reflection of this state and long term health problems can occur with prolonged exposure to this state.

After these tests were given to establish base levels the participants were exposed to a stress-filled environment for 20 minutes to increase mental stress. They used loud speakers and increasing frequency of beats per minute to induce mental stress and then retested the participants.

They then placed them in a relaxing environment for 20 more minutes and tested them a final time.

They found that the exposure to the stress environment increased anxiety in the placebo subjects by about 10% but this increase was significantly blunted by Lysine/Arginine treatment.

The authors had postulated based on their previous studies that a reduction in base cortisol and chromogranin-A by Lysine/Aginine would lower anxiety and improve the response of the hypothalmo-pituitary-adrenal axis and Sympathetic Nervous system to acute mental stress.

They found that in both men and women Lysine/Argine succeeded in blocking mental stress. While Lysine/Arginine was a significant anti-anxiety agent in both sexes declines in the two biomarkers do not account for the entire calming effect.

In men base values of cortisol and chromogranin-A declined significantly but this did not occur in women. Several factors such as lower salivary values in women, co-influence of menstrual cycle and the probable need to measure a more detailed time response in women likely account for the discrepancy.

In the Lysine/Arginine group of males chromogranin-A reacted to the stress event and returned to base levels within 20 minutes while the placebo males continued to experience high levels both during and after the mental stress events.

Pharmacological effects of Arginine/Lysine

The participants in the study continued their normal dietary lifestyle which included about 5 to 6 grams of each amino acid from whole food protein sources. Yet as evidenced by the placebo group this did not induce the stess lowering effect. The addition of 50% more of each of those amino acids did trigger the positive effects.

In addition to a lowering of cortisol and curbing sympathetic tone, the authors believed that Arg/Lys might also have triggered pharmacological-like effects in the gut and brain through the benzodiazepine, serotonin or amino acid-specific receptors.

To further underscore all of this another study recently found that mental fatigue triggered by a single mental test significantly decreased plasma lysine levels which persisted for at least 24 hours10.

The safety profiles of these two amino acids are well established and present no evidence of toxicity 11.

A note on suppression of cortisol

Over production of cortisol and prolonged elevations as seen under stressful conditions can lead to health problems. One of the effects of increased cortisol is an inhibition of protein synthesis which means that protein degradation will continue uncountered resulting in net protein breakdown. Elevated levels of cortisol also inhibit the transport and uptake of amino acids into tissue 12.

The accumulated rise in cortisol if unchecked begins to significantly affect muscle tissue after approximately 4 hours 13. Internal and external stress events can raise these levels and suppress the uptake of crucial amino acids for long periods of time which will result in some loss of muscle tissue if steps are not taken to counter the rise in central nervous system activity and pituitary & adrenal cortisol activity.

The co-administration of L-lysine HCl & L-Arginine is able to shutdown that potentiality.

References:
1 – Jezova D, Makatsori A, Smriga M, Morinaga Y and Duncko R , Subchronic treatment with amino acid mixture of L-lysine and L-arginine modifies neuroendocrine activation during psychosocial stress in subjects with high trait anxiety, Nutr Neurosci 8, 155-160 (2005)
2 – Smriga M and Torii K , Prolonged treatment with L-lysine and L-arginine reduces stress-induced anxiety in an elevated plus maze, Nutr Neurosci 6, 125-128 (2003)
3 – Smriga M and Torii K, Metabolic interactions between restraint stress and L-lysine: the effect on urea cycle components, AAmino Acids 24, 435-437 (2003)
4 – Srinongkote S, Smriga M, Nakagawa K and Toride Y, A diet fortified with L-lysine and L-arginine reduces plasma cortisol and blocks anxiogenic response to transportation in pigs, Nutr Neurosci 6, 283-289 (2003)
5 – Hasler WL, Lysine as a serotonin receptor antagonist: using the diet to modulate gut function, Gastroenterology 127, 1004-1006 (2005)
6 – Smriga M and Torii K, L-lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats, Proc Natl Acad Sci USA 100, 15370-15375 (2003)
7 – Chang YF, Wing Y, Cauley RK and Gao XM, Chronic L-lysine develops anti-pentylenetetrazol tolerance and reduces synaptic GABAergic sensitivity,Eur J Pharmacol 233, 209-217 (1993)
8 – Chang YF and Gao XM , L-lysine is a barbiturate-like anticonvulsant and modulator of the benzodiazepine receptor, Neuroch Res 20, 931-937 (1995)
9 – Smriga M, et al., Oral treatment with L-lysine and L-arginine reduces anxiety and basal cortisol levels in healthy humans Biomedical Research Vol. 28 (2007) , No. 2 April pp.85-90
10 – Mizuno K, Tanaka M, Nozaki S, Yamaguti K, Mizuma H, Sasabe T, Sugino T, Shirai T, Kataoka Y, Kajimoto Y, Kuratsune H, Kajimoto O and Watanabe Y, Mental fatigue induced decrease in levels of several plasma amino acids, Journal of Neural Transmission, Volume 114, Number 5 / May, 2007
11 – Tsubuku S, Mochizuki M, Mawatari K, Smriga M and Kimura T, Thirteen-week oral toxicity study of L-lysine hydrochloride in rats, Int J Toxicol 23, 113-118 (2005)
12 – Kettelhut, IC, Endocrine regulation of protein breakdown in skeletal muscle, Diabetes/Metabolism Rev 4: 751-772 (1988)
13 – McNurlan, MA and Garlick, PJ, Influence of nutrient intake on protein turnover, Diabetes/Metabolism Rev 5: 165-189 (1989)

Exogenously administered Growth Hormone leads to feminized secretory pattern and altered steroid metabolism
Men and women release growth hormone (GH) in patterns unique to their sex. Adult men secrete growth hormone in a pulsatile pattern with well pronounced peaks of plasma growth hormone occurring approximately every 3.5 hours followed by periods without measurable growth hormone (GH off-time) lasting about two hours.