May 5, 2021

The Potential Benefits of Oral and IV Peptides

One practitioner's perspective on a recent study
A recent study offers some important clinical takeaways about the potential of amino acid and polypeptide therapies, as well as the use of phosphatidylserine to lower cortisol levels.

A recent publication by Tsuda et al found that a mixture of several amino acids were able to blunt the normal increase of cortisol after exercise.1 This study compared cortisol before and after exercise in 48 active, healthy men aged 20-39 years. The exercise trial was on a stationary bicycle for 80 minutes at 50% maximal oxygen consumption. The amino acid mixture was composed of arginine, serine, and valine. The authors imply that this effect is helpful, but is it?

In my estimation, no. Because serine directly blunts cortisol response, this effect does not demonstrate that the supplement is helpful, but rather simply that cortisol response can be blunted by serine, and perhaps arginine and valine. This is not necessarily a good thing in this setting. But the study gives an opportunity to discuss and introduce:

  1. The benefits of phosphatidylserine for altered circadian rhythm
  2. The growing and important area of IV and oral polypeptide therapies

This study showed that an amino acid mixture containing 1.8 g of arginine, 1.1 g of valine, and 0.1 g of serine supplement could reduce the usual increase in cortisol immediately after heavy exercise in conditioned individuals. The authors are trying to make the case it may be helpful for athletes.

This mix does not impress me as being beneficial for athletes (or in general), but the study does provide several very important clinical takeaway points. We will discuss the potential of amino acid and polypeptide therapies at the end of this article. But first let’s discuss the use of phosphatidylserine 100-300 mg to lower elevated cortisol levels, especially at bedtime.

Because of the stress of modern life, we are seeing a shifting of the diurnal cortisol rhythms with high bedtime levels. Normally, healthy people run morning cortisol of about 16-18 mg/dL. At bedtime, this needs to drop below 2 mg/dl for people to be able to fall asleep. Otherwise, people find that their mind is racing at bedtime and they are wide awake.

Simply giving phosphatidylserine (100-300 mg) 90 minutes before bedtime can bring down elevated cortisol. Usually, doing this for even 1 night is enough to tell if it will be helpful, settling down the racing mind so the person can fall asleep. I usually give it 3 or 4 nights to be more certain. I go with the lowest dose that works. Otherwise, although people may find they can fall asleep, cortisol gets too low during the night. Then blood sugar drops, and people find themselves wide awake between 2 and 4 a.m. In this case, more is not necessarily better.

Meanwhile, I add a 1- or 2-ounce protein snack (a hard-boiled egg is perfect, or some meat, cheese, or fish) right at bedtime to help maintain blood sugar during sleep.

What Does This Study Show?

Before I discuss how this study relates to the benefits of oral and IV peptides, let’s first look at what this study shows.

In very athletic people, a mix of serine, valine, and arginine can blunt the increase in cortisol production with intense exercise.1 The authors then propose that this effect is beneficial by making the following argument:

  1. Cortisol is released in response to glycogen depletion or reduced blood glucose levels to maintain the blood glucose level.
  2. Highly trained athletes have diminished responses of adrenocorticotropic hormone (ACTH) and cortisol to corticotropin-releasing hormone (CRH).
  3. Thus, the suppression of the level of cortisol means less stress or better physical conditioning. There are some nutritional strategies for the suppression of cortisol levels during exercise.
  4. Because athletes have lower cortisol responses to stress, artificially blocking a person’s cortisol response to stress will make them healthier and more athletic.

I find the jump in logic from the first 3 points to the fourth to be faulty, akin to saying “athletes have lower heart rate; therefore, giving high doses of digitalis to lower the heart rates will make people more athletic.”

Serine, as phosphatidylserine, has been shown to bring down elevated cortisol levels (even if the cortisol response is needed by the body). Blocking this cortisol response with serine does not, however, confer the benefits of increased conditioning. In fact, we have no idea whether the blunting of HPA axis response here with the mix is ultimately beneficial of harmful to a given individual. This study, in my opinion, does not answer this question.

Blocking this cortisol response with serine does not, however, confer the benefits of increased conditioning.

Arginine could theoretically be helpful in conditioning because it is the precursor for both growth hormone and nitric oxide production.2 Over time, one could theorize that both might be helpful. But the research shows otherwise.

Overall, increasing nitric oxide seems to be most helpful in people who have poor conditioning, but much less so in athletes.3

What about the benefits of arginine on stimulation of growth hormone? Growth hormone is indeed important for athletes and people in general, and arginine is the precursor. But real life has a funny way of not always going the way we would predict it to be. What the research actually shows is that using oral arginine alone increases resting growth hormone levels at least 100%, while exercise can increase growth hormone levels by 300-500%. But the combination of oral arginine plus exercise decreases the growth hormone response, to 200%, compared to 300-500% without the arginine.4

So basically, an athlete who adds arginine will decrease their growth hormone production and muscle mass. This makes using arginine in athletes less attractive. Arginine has the added downside of stimulating the growth of herpes viruses. In fact, the reason lysine works to block herpes outbreaks is because it lowers arginine levels.

Looking at all the above, one can start to understand why in the overall multivitamin I recommend, the arginine levels are kept fairly low.

For the valine, although branched-chain amino acids do have an anabolic effect, this is much more pronounced with leucine.

Amino Acids and Polypeptides

For the last half-century, the focus and research in nutritional supplementation has largely been focused on micronutrients, such as vitamins, minerals, and cofactors. Research on amino acids has largely been on driving reactions with high doses of a single amino acid (e.g., tryptophan to produce serotonin), general nutritional support, or for their enzymatic activity.

But natural medicine is starting to become aware of the power inherent in the new frontier of “polypeptide therapies.” Let’s start with some definitions.

What are peptides?

Peptides are short chains of 2–50 amino acids. Chains with fewer than 15 amino acids are called oligopeptides and include dipeptides, tripeptides, and tetrapeptides. A polypeptide is a longer chain of up to approximately 50 amino acids. Chains longer than 50 amino acids are proteins.

The growth of IV polypeptide use

IV polypeptide use is a major new area of treatment that is being explored. More than 60 FDA-approved peptide medicines are on the market, approximately 140 peptide drugs are currently in clinical trials, and another 500+ therapeutic peptides are in preclinical development.5 You may also have seen promotions for a number of workshops on the use if IV polypeptides in integrative medicine practice.

Oral absorption

Early in my practice (about 45 years ago), it was considered useless to take oral proteins for anything besides basic nutritional support. The presumption was that they would be digested down to their component amino acids.

The findings that enzymes were orally absorbed was a major step forward.6 For example, it allowed the beginnings of a scientific basis for the work by Nicholas Gonzalez, MD, using pancrease for pancreatic cancer.

Recently, that work has been expanding to other oral polypeptides. For example, an area that has gained a lot of attention is use of oral collagen. Once again, the presumption was that taken orally, the collagen would go through complete digestion down to its basic amino acids. But animal studies have shown that this is not the case.7

This concept has now evolved considerably and has been a game-changer in my chronic fatigue syndrome and fibromyalgia syndrome practice. Gaetano Morello, ND, and I found that an oral porcine serum polypeptide extract resulted in dramatic improvement in complex and disabling health cases. This led us to do a small open study using the extract. In the study, 60% of people improved, and they showed an average 69% in both energy and overall wellbeing, along with an average 14% increase in total IgG and IgG 1-4 protective antibodies in those who had low total antibody levels prestudy.8 We just completed a second study of 100 people that showed similar clinical effects, which we are getting ready to submit for publication.

In addressing and optimizing nutritional support, in addition to vitamins, minerals, and other micronutrients, remember amino acids. Polypeptide therapy is an exciting new frontier with great potential.

Conflict of Interest Disclosure

Dr. Teitelbaum has partial ownership of Recovery Nutraceuticals, which markets the extract used in the studies mentioned.

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  1. Tsuda Y, Murakami R, Yamaguchi M, Seki T. Acute supplementation with an amino acid mixture suppressed the exercise-induced cortisol response in recreationally active healthy volunteers: a randomized, double-blinded, placebo-controlled crossover study. J Int Soc Sports Nutr. 2020;17(1):39.
  2. Mori M, Gotoh T. Regulation of nitric oxide production by arginine metabolic enzymes. Biochem Biophys Res Commun. 2000;275(3):715-719.
  3. Bescós R, Sureda A, Tur JA, Pons A. The effect of nitric-oxide-related supplements on human performance. Sports Med. 2012;42(2):99-117.
  4. Kanaley JA. Growth hormone, arginine and exercise. Curr Opin Clin Nutr Metab Care. 2008;11(1):50-54.
  5. Fosgerau K, Hoffmann T. Peptide therapeutics: current status and future directions. Drug Discov Today. 2015;20(1):122-128.
  6. Rothman S, Liebow C, Isenman L. Conservation of digestive enzymes. Physiol Rev. 2002;82(1):1-18.
  7. Watanabe-Kamiyama M, Shimizu M, Kamiyama S, et al. Absorption and effectiveness of orally administered low molecular weight collagen hydrolysate in rats. J Agric Food Chem. 2010;58(2):835-841.
  8. Teitelbaum J, Morello G, Goudie S. Nutritional intervention in chronic fatigue syndrome and fibromyalgia (CFS/FMS): a unique porcine serum polypeptide nutritional supplement. Open Pain J. 2020;13:52.