Exclusive Interview with Durk Pearson & Sandy Shaw® on Their New Serene Systems®

The Durk & Sandy Way to a
Quiet Mind™ for Sleep or Daytime Calmness

urk Pearson & Sandy Shaw have been taking tryptophan supplements for about 30 years, having discussed their use for calming, sleep, and control of carbohydrate cravings in their 1982 million-copy bestseller, Life Extension, A Practical Scientific Approach, and in their 1986 bestseller, The Life Extension Weight Loss Program.

In 1989 they discontinued offering their tryptophan formula for providing essential nutrients needed for sound sleep and natural calmness because of the FDA’s ban on the sale of tryptophan in dietary supplements. (The FDA ban exempted FDA-favored suppliers, such as drug companies offering products for babies that included the essential nutrient tryptophan.)

The eosinophilia-myalgia syndrome that occurred in some users of tryptophan dietary supplements was tracked down to manufacturing defects (contamination of tryptophan with neurotoxins) at a single company, which had to settle billions in lawsuits. Durk & Sandy had examined samples from this supplier and expressly prohibited the use of this product in any of their formulations. Their licensing contracts require that only approved (by them in writing) manufacturers be used, so neither Durk & Sandy nor others who used their products were injured.

Only now has it become possible (e.g., the FDA will no longer seize your product and throw you in jail) to once again offer tryptophan for inclusion in dietary supplements and foods.

Durk & Sandy are very happy to once again offer tryptophan-containing formulations—with major systemic improvements—for nutritionally supporting natural sleep (nighttime formula) or calmness (daytime formula), as well as to help control carbohydrate cravings. Moreover, they are also offering daytime and nighttime formulas containing 5-hydroxytryptophan, a natural metabolite of tryptophan. The interview that follows was conducted by Will Block for Life Enhancement.

Serene Systems

Will: Why do you call this family of your four new formulations Serene Systems? Before the ban, you used to have just one formula.

Sandy: As with all of our formulations, we extensively study the biochemical pathways involved in the use of dietary ingredients by the brain and body for specific purposes. By including nutrients that work together to perform a function, rather than a single substance or a collection of substances not known to work together, you can get increased effectiveness.

Durk: Let’s review how the essential nutrient tryptophan is converted to the neurotransmitter serotonin. Neurotransmitters are not drugs. They are natural substances made by neurons from nutrients in your diet. Neurotransmitters transmit signals from one nerve to another across the synapses, the gaps between nerves.


Nitric oxide decreased the uptake of
serotonin by SERT, the serotonin
transporter, thus acting as a
natural serotonin reuptake inhibitor
(a result similar to that of Prozac).


First, the tryptophan must be transported across your blood-brain barrier. Tyrosine and phenylalanine compete with tryptophan for entry into your brain. A small amount of glucose releases some insulin that increases the ratio of tryptophan to its competitors in the blood by selectively increasing uptake of tyrosine and phenylalanine into other tissues. This allows more of the tryptophan in your diet to enter your brain.

5-Hydroxytryptophan

Next, tryptophan is hydroxylated by the enzyme tryptophan hydroxylase to form 5-hydroxytryptophan. Some people have a mutation in their tryptophan hydroxylase gene that reduces its activity. For these people, tryptophan supplements are not as effective as in those who have the fully active form of tryptophan hydroxylase.

Will: Are there any clues as to whether one has a low-activity form of tryptophan hydroxylase? What would be the most likely consequences?

Sandy: If a tryptophan-and-cofactors supplement doesn’t seem to have any effect on you, you may have low-activity tryptophan hydroxylase. Studies have shown that people with impulse, anger, and rage management problems are likely to have a low-activity tryptophan hydroxylase, which prevents them from making normal amounts of serotonin from tryptophan.

Will: Is that why you have day and night Serene Systems formulations that contain 5-hydroxytryptophan rather than tryptophan?

Durk: Precisely! If you take 5-hydroxytryptophan, you entirely bypass the serotonin production bottleneck caused by a low-activity isoform of tryptophan hydroxylase. You are directly ingesting the compound that the enzyme should be making.

Will: Then why have a formula containing tryptophan? Why shouldn’t everyone simply take the 5-hydroxytryptophan versions?

Durk: With 5-hydroxytryptophan, serotonin production is under the control of a single enzyme conversion step, rather than the two steps required to make serotonin from tryptophan. This means that a 5-hydroxytryptophan supplement is more likely than a tryptophan supplement to produce too much serotonin in some tissues. For example, 5-hydroxytryptophan tends to give me a stuffy nose. It is a minor annoyance but doesn’t happen to me when I take a tryptophan supplement instead. 5-Hydroxytryptophan has a nearly 30-year-long record of safe human use, both as a supplement and in scientific studies on human subjects.

Serene Systems: Which Version Is for You—Tryptophan or 5-Hydroxytryptophan?

Will: How does someone know whether they should take the Serene Systems tryptophan day or night formulations or the Serene Systems 5-hydroxytryptophan day or night formulations?

Are You Angry?

Sandy: If you tend to have a problem with impulse regulation and/or anger or rage management, then that suggests that you may have a low-activity isoform of tryptophan hydroxylase, which is associated with state anger, trait anger, and angry temperament.0 We would expect such individuals to respond more strongly to the 5-hydroxytryptophan versions.

Durk: I’d suggest trying to find which you prefer by how you feel after taking each formulation. If there is enough demand, Will could produce a trial package containing a few servings of each to make it easier to discover which version is right for you.

Will: OK. So we’ve gotten to 5-hydroxytryptophan and have learned how to bypass a bottleneck in serotonin production that some people have. What comes next?

Sandy: 5-Hydroxytryptophan is converted to serotonin by an enzyme called aromatic amino acid decarboxylase. This enzyme is dependent on both vitamin B6 and copper as essential nutrient cofactors. Our Serene Systems formulations contain these essential nutrients for that purpose, just as our original formulation did 20 years ago.

Will: You were way ahead of your time! Even today, most tryptophan and 5-hydroxytryptophan supplements don’t have these essential cofactors.

Durk: Our Serene Systems formulations have far more comprehensive and advanced cofactors than our 20-year-old formulation.

Why We Include the Amino Acid L-Arginine in Our Serene Systems Formulations

Will: The most obvious change is that you include a proportional dose of the InnerPower™ ingredients in all four of your new Serene Systems formulations. Does this have something to do with the neurotransmitter effects of the nitric oxide produced from the InnerPower?

Durk: Yes, indeed. Since tryptophan sales in dietary supplements were banned by the FDA, it has been discovered that serotonin, the neurotransmitter the brain uses tryptophan to make, modifies the activities of neuronal nitric oxide synthase (the neuronal version of the enzyme that makes nitric oxide from the amino acid L-arginine) and vice versa.1,2,3 The study of this relationship has revealed a number of important consequences.

One very recent paper1 describes the physical interaction between the serotonin transporter (which carries serotonin into and out of neuronal synapses) and neuronal nitric oxide synthase. The studies were done using cultured HEK293 cells, mouse embryonic mesencephalic neurons. Synaptosomal fractions isolated from homogenized brains were also studied. The authors first found that neuronal nitric oxide synthase (nNOS) was one of several proteins that interacted with the C-terminus of the serotonin transporter SERT.

Their most intriguing finding was that nitric oxide released by neuronal nitric oxide synthase decreased the uptake of serotonin by SERT, the serotonin transporter, thus acting as a natural serotonin reuptake inhibitor [a result similar to that of fluoxetine (Prozac®) and other selective serotonin reuptake inhibitor drugs].

Sandy: Conversely, serotonin uptake into brain synaptosomes was increased in both nNOS-deficient mice and wild-type mice injected with a drug that disrupted interaction between SERT and nNOS. As the authors interpret their data:

According to the present findings, increased nNOS levels would lead to intracellular sequestration of SERT, thereby preventing excessive 5-HT [serotonin] uptake and enhancing 5-HT neurotransmission. . . . A loss of the inhibitory influence of nNOS on the activity of SERT in serotonergic terminals may conceivably be involved in the pathogenesis of psychiatric disorders, including depressive states and enhanced aggressiveness and impulsivity, as reported for instance in nNOS [knockout] mice. [References deleted]

Brain serotonin dysfunction has been reported to account for aggression in male nNOS knockout mice.3a

Will: So the nitric oxide produced from arginine in your brain with the help of cofactors such as choline and vitamin B5, folate, etc., has a natural Prozac-like activity? (See “Putting More Power into Your Life” in the April 2006 issue.)

Durk: That’s right. It was quite a surprise! It helps to explain why so many InnerPower and InnerPower Plus users report that its regular use seems to give them a feeling of well-being.

The relation between nitric oxide and serotonin works the other way, too: serotonin uptake stimulates nNOS activity with the increased production of nitric oxide.1

Garthwaite, commenting on paper #2, notes: “By diminishing the amount of SERT in the cell membrane, binding of nNOS should adjust extracellular 5-HT [serotonin] upward. In effect nNOS would be acting like an endogenous antidepressant. . . . Perhaps tonic NO from SERT-associated nNOS, by engaging the cGMP [cyclic GMP]-dependent pathway that enhances intrinsic SERT activity, allows for a continual homeostatic fine-tuning of 5-HT uptake according to the ambient extracellular 5-HT concentration: the higher it is, the more rapidly it will be removed.” [References deleted]

Better Sleep and Impulse Regulation—Possibly Even Better Learning Acquisition and Memory Consolidation

Will: So your new formulations should help one to get a good night’s sleep naturally without sedative drugs?

Sandy: Yes, these findings suggest that prevention of excessive 5-HT (serotonin) uptake and the increase of 5-HT neurotransmission resulting from increased nitric oxide release should improve sleep as well as impulse and anger regulation, among other functions of 5-HT.

Will: Serotonin is a neurotransmitter involved in both sleep and impulse and anger regulation—what else does it do?

Durk: Enhanced serotonergic neurotransmission in the brain’s hippocampus following tryptophan administration has been shown to improve learning acquisition and memory consolidation in rats.4,5

A randomized, double-blind, crossover study in 12 healthy (with no previous history of depressive disorder) human female volunteers6 reported that a tryptophan-free amino acid mixture that significantly lowered plasma total and free tryptophan concentrations produced deficits “similar to those observed previously in cases of clinical depression.” The deficits were not due to a global sedative effect, as planning ability was unimpaired. “Both TRP [tryptophan] depletion and depression thus seem to slow responses to positive stimuli rather than speed responses to S [sad] stimuli.”

Hunger, Food Intake, and Stress

Sandy: Serotonin also helps to control excessive food intake by increasing satiety, especially in response to carbohydrates. In a rat study, 5-hydroxytryptophan suppressed food intake. The suppression of food intake was especially large in stressed rats.6a

Why We Include Glycine in Serine Systems: Glycine Inhibits Motor Activity During Sleep

Will: Your nighttime formulations include melatonin, which helps initiate sleep. What does the glycine do?

Sandy: Researchers studied the effects of antagonists of the inhibitory neurotransmitters GABA (gamma-aminobutyric acid) and of glycine, seeking to determine which of these was principally responsible for the inhibitory drive that prevents active motion of muscles during spontaneous, quiet (nonREM) sleep in cats.7 Strychnine, an antagonist of glycine, was statistically significantly effective in blocking inhibitory postsynaptic potentials (IPSPs). Antagonists of GABA, picrotoxin and bicuculline, did not decrease the frequency of the IPSPs that bombard lumbar motoneurons during active sleep. (However, the GABA antagonists did modify some aspects of the kinetics of IPSPs, and thus GABA may play some role.) Part of the choreography of sleep is the suppression of muscle activity during nonREM sleep. Hence we have included glycine as a component of Serene Systems. Glycine might be particularly helpful to sleepwalkers or those who are awakened by thrashing about, though this is just a plausible conjecture on our part. We don’t know of any clinical trials.

Will: It’s obvious why you don’t include melatonin in your daytime formulas: it would cause daytime drowsiness and tend to desynchronize your day/night wake/sleep cycles. You include glycine in both day and night versions. Why glycine during the day? Will the glycine promote daytime sleepiness?

Durk: Glycine is not a sedative. Even very large doses won’t make you sleepy. It does help control undesirable motor activity at night. It is plausible that it might help to do the same thing during the day. People who are nervous and edgy frequently exhibit motor agitation. We hope that the glycine may help to control this, though there have been no clinical studies on its use for this purpose that we know of.

Sleeping to Scavenge Hydroxyl Radicals

Will: There are several free radical scavengers, including gamma-tocopherol and melatonin, in your formulations. Would you like to comment on that?

Sandy: Melatonin is well known to be a very powerful scavenger of hydroxyl radicals, highly reactive radicals that can react with and damage nearly every biomolecule, including nuclear DNA, mitochondrial DNA, proteins, and membrane lipids. Tryptophan and vitamin C are also reported to scavenge hydroxyl radicals. In a recent study,8 researchers investigated the ability of 5-hydroxytryptophan (produced in your body from tryptophan as well as an ingredient in two of our four new formulas) to scavenge hydroxyl radicals and found the compound to be the most efficient radical scavenger in their experiments in comparison with melatonin or vitamin C.

Aging Effects on Serotonin Systems—Better Sleep Might Have Antiaging Effects

Will: You two have been studying aging mechanisms and intervening in them since 1968. Might these four new formulas have anything to do with aging and its effects?

Durk: Sleep and wake states are all part of circadian rhythms controlled by a plethora of biochemical pathways. Serotonin, for example, synchronizes the circadian clock located in the brain’s SCN (suprachiasmatic nucleus) and thus affects the entire daily activity-rest cycle. A recent study reported age-related changes in the activity-rest circadian rhythm in ringdoves and the effect of administering tryptophan to old and young ringdoves.9

The authors of this paper propose that insufficient tryptophan availability may cause some of the deficiencies in 5-HT (serotonin) and melatonin seen in old animals and humans. For example, it has been observed in elderly humans and in aged rats that there is an upregulation of the kynurenine pathway, which activates the degradation of tryptophan, thus reducing tryptophan levels available for converting to serotonin. In the ringdove study, the old ringdoves had a reduced difference in activity between the light and dark periods as compared to the young ringdoves. (Ringdoves are diurnal animals like people and are active during the day and sleep at night.)

In young ringdoves, the oral administration of L-tryptophan (100 and 240 mg/kg) 2 hours before the onset of the dark period decreased the nocturnal activity as compared to vehicle (no tryptophan). However, only the high L-tryptophan dose was able to significantly decrease the nocturnal activity of the old ringdoves as compared to vehicle. The treatment with both L-tryptophan and melatonin at the high dose (240 mg/kg and 5 mg/kg, respectively), but not the low dose, increased the amplitude of the activity-rest cycle of the old ringdoves. The treatments resulted in a significant increase in the sleep efficiency of old ringdoves—up to the point of resulting in similar levels as those in the young ringdoves—due to an increase in the number of hours of sleep as well as a reduction of the number of wake bouts.

Sleep like a baby? Well, no, but you can make your circadian rhythms look a lot more like a younger person.

References

0. Rujescu et al. Association of anger-related traits with SNPs in the TPH gene. Molec Psychiatry 7:1023-9 (2002).
1. Chanrion et al. Physical interaction between the serotonin transporter and neuronal nitric oxide synthase underlies reciprocal modulation of their activity. Proc Natl Acad Sci USA 104(19):8119-24 (2007).
2. Garthwaite. Neuronal nitric oxide synthase and the serotonin transporter get harmonious. Proc Natl Acad Sci USA 104(19):7739-40 (2007).
3. Breard et al. The endogenous neurotransmitter, serotonin, modifies neuronal nitric oxide synthase activities. Free Rad Res 41(4):413-23 (2007).
3a. Chiavegatto et al. Brain serotonin dysfunction accounts for aggression in male mice lacking neuronal nitric oxide synthase. Proc Natl Acad Sci USA 98(3):1277-81 (2001).
4. Halder et al. Enhanced serotonergic neurotransmission in the hippocampus following tryptophan administration improves learning acquisition and memory consolidation in rats. Pharmacol Rep 59(1):53-7 (2007).
5. Haider et al. Long-term tryptophan administration enhances cognitive performance and increases 5HT metabolism in the hippocampus of female rats. Amino Acids 31(4):421-5 (2006).
6. Murphy et al. The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers. Psychopharmacol 163:42-53 (2002).
6a. Amer et al. 5-Hydroxy-L-tryptophan suppresses food intake in food- deprived and stressed rats. Pharmacol Biochem Behav 77:137-43 (2004).
7. Chase et al. Evidence that glycine mediates the postsynaptic potentials that inhibit lumbar motoneurons during the atonia of active sleep. J Neurosci 9(3):743-51 (1989).
8. Keithahn and Lerchi. 5-Hydroxytryptophan is a more potent in vitro hydroxyl radical scavenger than melatonin or vitamin C. J Pineal Res 38:62-6 (2005).
9. Garau et al. Age related changes in the activity-rest circadian rhythms and c-fos expression of ring doves with aging: effects of tryptophan intake. Exp Gerontol 41:430-8 (2006).

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