A Formulation for Sleep Support and Rejuvenation 
By Will Block

To sleep, perchance to . . . rejuvenate? Yes. More or less. Science has found that as we sleep we remain surprisingly biomolecularly active, restoring immune mechanisms and storing and "indexing" important information that we've acquired during the previous day. Moreover, we cycle through a variety of states of our subconscious, flowing freely in and out of dream states. All the while, the body is restoring some vital chemicals back into balance (the brain neurotransmitters noradrenaline and dopamine, for example) and using other ones (the inhibitory neuromodulator arginine-vasotocin, for example). In the process . . .

  • Short-term memory is transferred to more permanent storage
  • Emotional experiences become resolved
  • Extraneous memory is selectively forgotten
  • Memory is refreshed

Without these sleep events our new day would  not be new, but instead would trudge on, piling fatigue on top of fatigue. It would likely be a rehash of the old "history not remembered is repeated" adage. The building blocks of memory would crumble. Our new day would not be premised on the knowledge of what we had experienced and learned the previous day, and it would perhaps break links with certain knowledge of all our prior days. Memory is influenced in sleep, beyond our dreams, as we are rejuvenated.

Painting by Lord Leighton Fredrick, 1895

Insomnia is Age-Related
Sleep disorders are prevalent in the general population and may be associated with significant medical, psychological, and social disturbances. Insomnia may range from mild and temporary to severe and chronic, which can reflect physiological and  psychological disturbances. If you fail to get the sleep you need, you may end up decreasing memory, impairing immune functions, disabling mood, and squeezing the fun out of life. When associated with aging, sleeping problems are viewed as normal by most doctors and patients. But age-related sleep disturbances are not "normal" if something can be done about them, and the research is encouraging.

Research has been conducted to determine whether there is an age-related decline in the ability to enter and remain in sleep. The center of attention has been a hormone produced in the pineal gland, the production of which declines directly with age.1 In humans, production of this hormone, melatonin, begins at about the age of three months and reaches its highest nocturnal blood levels between the ages of one and three years. After this, and until adulthood, nocturnal peak levels drop progressively by 80%. Later, in old age, levels drop again by another 10%.

Although the biological significance of these changes in melatonin levels is not known, the immediate sedative action of this hormone has been well-documented. Recent studies have shown that melatonin causes a sleep-promoting action by:

  • Accelerating sleep initiation
  • Improving sleep maintenance
  • Marginally altering the "architecture" of sleep: how much we dream, for example.
The study of melatonin indicates that restoration with physiological amounts can help restore healthy sleep parameters and stem the decline associated with age.

Melatonin is Often Misused
What do aging people complain about the most? Three responses filter to the top: pain, energy loss, and inability to sleep. While these are interrelated, alleviating the last certainly helps the other two. "If only I could get a good night's sleep." How many times have you heard yourself, or others, say something like that? Information on melatonin is known but is not widely disseminated. So people may not try melatonin, and if they do try it, they may resort to pharmacological rather than physiological levels of supplementation. But because people tend to exceed the recommended amounts, melatonin may not give them the quality of sleep they desire. Also, being conditioned to expect an immediate "knock-out" effect, they may not recognize the initial subtlety of action. It is no wonder that some, after having poorly sampled alternatives, return to hypnotics or sleeping pills.

While several generations of these drugs have come and gone, their use is still a very mixed bag of benefits and liabilities. Some are habit-forming and so may even be addictive. Others cause loss of mental acuity, memory loss, or other side effects.

Sleeping Pills Alter Sleep Stages
Barbiturates were the first-generation hypnotics prescribed for sleep. They extend the intermediate stage of sleep at the expense of another stage, paradoxical sleep, also known as REM (rapid eye movement) sleep. In the second generation are the benzodiazepines, divided into the shorter-term-acting ones (for example, triazolam, also known as Halcion®) and those that act longer-term (for example, diazepam, also known as Valium®). The problem with these is that, while they get you into sleep more rapidly, they generally also increase the intermediate stage of sleep at the expense of paradoxical sleep. They are much like barbiturates in that respect. Generation number three includes hypnotics such as zolpidem (Ambien®) and zopiclone (Imovane®), which do not affect REM sleep but still alter other stages.2

The Risks of Sleep Disturbance
There is abundant evidence that the failure to obtain adequate sleep, both qualitative and quantitative, can  lead to serious consequences. Indeed, it has long been noticed that many diseases are associated with sleep disorders. The question has arisen whether this causality is a two-way street. The evidence now indicates that continued sleep disturbance may place otherwise healthy individuals in the general population at risk for certain psychiatric disorders, even if they have never been diagnosed as candidates for these kinds of disorders.3

Scientific literature suggests that any subjective insomnia lasting for at least two weeks may increase the likelihood of depression. Not as clearly decided in the literature, but nevertheless significantly linked, is a conclusion relating hypersomnia (excessive sleeping) and insomnia with the development of depression, anxiety disorders, or even substance abuse. Other data connect increasing (subjective) sleep disturbance with depression relapse.

Alcohol Doesn't Work
Many people turn to alcohol to solve their sleeping problems - often starting with a nightcap and then progressing - but the evidence shows clearly that alcohol doesn't work and makes matters worse. Alcohol interferes with certain stages of sleep. Moreover, it is strongly related to the development of psychiatric disorders and can interfere with the use of sleeping pills, complicating negative outcomes even more.

Even moderate alcohol consumption can affect the healthy function of neurotransmitters that have roles with regard to psychiatric and sleep functions. Alcohol use may cause imbalances of central nervous system neurotransmitter systems, which can undermine the therapeutic response to psychotropic medications.4 The rebound phenomenon, which is like drug  withdrawal, can be caused by neurotransmitter dysfunctioning; it can affect sleep and precipitate anxiety and mood symptoms.

The Natural Sleep Cycle
What is normal sleep? What are its parameters? Scientists have found that there are several well-defined stages of sleep. Once we doze off, we experience 90-minute cycles of non-REM and REM (rapid eye movement) sleep. Non-REM (which includes the deep or delta sleep that provides for daily physical and mental rest and renewal) dominates the first part of a night's sleep, while REM or dreaming sleep commands the second half. The amount of delta sleep tends to decrease with age, with children experiencing the most delta sleep and older people experiencing little or none. REM sleep is now thought to have had its origin in reptile species.5 Using EEG (electroencephalogram) equipment, which measures brain waves, researchers have shown that most dreaming occurs during REM sleep, when our eyes flutter inside their lids. It's almost as if we scan the dreams we're experiencing. While the role of dreams is still not understood, when the REM sleep in which dreams occur is disrupted or foreshortened with certain sleeping pills, sleep is not as satisfying or rejuvenating.

Growth Hormone Release Rejuvenates Sleep
Possibly the most important aspect of rejuvenation during sleep occurs when a critical substance known as growth hormone (GH) is released in delta sleep, just preceding the entry to REM sleep. GH, in turn, is believed to help regulate sleep during the REM stage.6 The value of adequate levels of GH is so great that loss of REM sleep, during which GH apparently exercises control, can be a dire threat to overall health. Certain drugs, including most sleeping pills, alcohol, and even sugar, can disrupt normal GH activity and REM sleep.

GH is typically secreted as a series of pulses. In normal young adults, a major release occurs about one hour after the onset of sleep (see Figure 1), in what is known as slow-wave sleep, which occurs when delta sleep is greatest during the first period of sleep. In men, this release represents about 70% of the daily GH output. In women, the GH release is more variable, but studies have shown that early sleep is the primary determinant of human GH release for both men and women.

Figure 1: The natural sleep cycle
of a healthy adult

REM is rapid eye movement; NREM is non-rapid eye movement; delta sleep is slow-wave sleep. Evidence has compiled showing that when the early phase of sleep is lengthened through nutrient precursor stimulation, there is a concomitant increase in GH release, with all accompanying benefits, including prolonged REM sleep. The decline of both early-phase, slow-wave sleep and GH release are age-related. This has raised the possibility that too little GH (at the most propitious time) may speed aging and its associated conditions, including sleep disturbance. Too much GH at the wrong time may also prove detrimental.

Other studies have shown that the diminishment of REM sleep is connected to decline of memory functions7 including declarative memory, recognition, recall, spatial memory, and other cognitive activities.

Getting to Sleep
There are a number of questions that we should all ask ourselves about sleep. However, before the questions of whether we've gotten enough, whether we're refreshed enough, and whether we're up to par as the day goes on, the important question is: Did we fall asleep quickly, or did we wrestle with the day's events, unable to let go and surrender to sleep?

Melatonin Helps
Melatonin has been found to be quite helpful for falling asleep.8 Low doses of melatonin have been found effective in decreasing sleep latency (shortening the time needed to fall asleep), increasing sleep efficiency, and raising sleep quality scores in the elderly, who are known to be melatonin-deficient insomniacs. Operating in the cardiovascular system, melatonin seems to regulate the tone of cerebral arteries. In so doing, it appears to participate in the regulation of body temperature, resulting in heat loss, which may be the principal mechanism in the initiation of sleepiness caused by melatonin (there are other causes as well).

A placebo-controlled, double-blind, crossover study conducted at Littlemore Hospital, Oxford, UK, found that a single 1-mg dose of melatonin, administered orally in the evening to 15 healthy, middle-aged volunteers, increased actual sleep time, sleep efficiency, non-REM sleep, and REM-sleep latency.9 Compared to placebo, the 1-mg dose significantly increased all of the measured parameters, but a smaller amount (0.3 mg, which was also given as part of the study) did not do as well. These findings were consistent with the hypothesis that low-dose (0.3-1 mg) melatonin has hypnotic effects in humans.

Melatonin for Tinnitus
An often-overlooked sleep problem is tinnitus (ringing or buzzing in the ears). In a randomized, prospective, double-blind, placebo-controlled, crossover trial, 30 patients with subjective tinnitus were given 3 mg of melatonin or a placebo for 30 days, after which the two groups were switched over, the melatonin group now taking placebo, and the placebo group now taking melatonin.10 There was a one-week washout period (no melatonin or placebo given) in between.

Melatonin was about equal with placebo for tinnitus improvement (about 20% improvement each), but among those who complained that their tinnitus made it difficult to sleep, the melatonin users had a far easier time getting to sleep - about 47% improvement, compared with 20% for placebo. In those whose tinnitus affected both ears rather than one ear, there was also a statistically significant difference in improvement.

Other Benefits of Melatonin
Melatonin has also been found to improve immune function, to help prevent stress-induced immunodepression, and to be beneficial for a long list of degenerative diseases.8 In the digestive tract, melatonin reduces the incidence and severity of gastric ulcers and prevents severe symptoms of colitis, such as mucosal lesions and diarrhea. Additionally, it improves gastrointestinal function.

5-HTP for Sleep
Once sleep is entered, there's the problem of not going deep enough, sleeping long enough, and getting the rejuvenation effect needed to wake refreshed. The amino acid 5-hydroxytryptophan, or 5-HTP as it is more commonly called, may be able to enhance melatonin's effects while it addresses some of the other problems of sleep. Scientists have found that anxiety and depression are closely associated (and often magnified) by sleeplessness. To the extent that you can improve your sleep, you can minimize some of the physiological and psychological effects of anxiety and depression. Tryptophan (precursor to 5-HTP) has long been used as a sleep aid, and evidence suggests that 5-HTP may be effective as well.11,12

An explanation of how 5-HTP works to induce sleep was recently published by researchers at the University of Freiburg in Germany, one of the few centers in the world still avidly studying tryptophan.13 Along with tryptophan, 5-HTP is a serotonin precursor, although 5-HTP is more direct because it is one metabolic step closer to serotonin (see Figure 2). Increased serotonin has been shown to help reestablish a physiological sleep pattern in patients with chronic sleep problems. It has even has been shown to ease withdrawal symptoms for those dependent on hypnotics. Recently published studies have shown that acute tryptophan depletion can lead to impairment of sleep continuity. This should be true for 5-HTP as well, as a great many anecdotal reports attest.

Figure 2. Metabolic pathway from tryptophan to melatonin

Awake Refreshed with Valerian
Recently the extract of the valerian root (Valeriana officinalis) was tested against a so-called second-generation hypnotic, a benzodiazepine drug (bromazepam, marketed in Europe as Brazepam®).14 In a randomized, double-blind, controlled clinical trial, patients suffering from sleep disorders who took valerian compared quite favorably with those who took the bromazepam. Sleep quality, fitness, and quality of life were determined by a battery of tests at the beginning and end of therapy, which lasted for two weeks, and then again one week later. Sleep health improved through the study with both therapies, but then fell off when neither was taken any longer. Only with the bromazepam drug were there any withdrawal symptoms, not with the valerian. There were only slight gastrointestinal side effects, one for valerian and one for the bromazepam.

The effects of valerian extract in another double-blind study were shown to improve sleep in 89% of the subjects, with perfect sleep reported in 44%.15 There were no side effects. It has been thought that valerian might decrease vigilance, but a study conducted in Switzerland found just the opposite.16 Tested against flunitrazepam (a benzodiazepine) and a placebo, valerian was examined for any impact it might have on hangover effects in subjects who drive and operate machinery, where any loss of vigilance is unacceptable. Cognitive psychomotor performance was evaluated, as well as subjective questionnaires on well-being. There were no hangover effects in the morning from the valerian. On the contrary, there were even measurable vigilance and cognitive gains. Not so with the flunitrazepam.

The study reported improved subjective self-assessment in the valerian users; more alert, more active, and feeling better. With the drug, however, an impairment of vigilance the morning after ingestion, frequently reported in other studies, was confirmed, so this should be considered a potential hazard.

In a double-blind, placebo-controlled, randomized study of 128 patients, a valerian formulation was able to help the subjects fall asleep more rapidly.17 They also reported a significant improvement in sleep quality. The latter results were most notable among those subjects who considered themselves poor or irregular sleepers, smokers, and people who thought they normally had long sleep latencies. They reported feeling sleepier upon waking in the morning. This may have been the result of other plant extracts that were also contained in the formulation, along with valerian (400 mg). Other studies of nonproprietary valerian have not reported this morning-after sleepiness, except when given in much larger doses.

The results were similar in another small study of eight volunteers with mild insomnia who were given valerian extracts of 450 and 900 mg or placebo in a double-blind, repeated-measures, randomized study.18 Sleep latency decreased significantly (meaning that sleep occurred rapidly) with the 450-mg dose of valerian compared with placebo, but the higher valerian dose provided no added benefits.

Valerian extract appears to operate through several mechanisms that depend on its individual constituents. Valerenic acid has been shown to inhibit the enzyme-induced breakdown of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the brain, resulting in sedation.19 The valepotriates contribute to the extract's overall activity through a sedative effect on the central nervous system, although the mode of action is not clearly known. More recent studies suggest that aqueous extracts of the valerian root contain appreciable amounts of GABA, which could directly cause sedation, but it is not clear if the GABA is bioavailable. Researchers have also found a component that binds to benzodiazepine receptors.

Choline for REM Sleep and Staying Asleep
The primary systems that determine the way our minds process messages - excitatory, inhibitory, and amplificatory - are governed significantly by three neurotransmitter systems: the noradrenergic (using principally noradrenaline and dopamine), the serotonergic (using principally serotonin), and the cholinergic (using principally acetylcholine) systems. When we are asleep, these systems are all still active. They are thought to function as controllers of sleep and wakefulness,20 with arousal functions largely in the realm of the noradrenergic system, and the inhibitory functions in the realm of the serotonergic system. Each dominates different parts of the sleep cycle.

The cholinergic system is believed to induce and maintain paradoxical (REM) sleep, a type of sleep related to increased memory performance. In this regard, acetylcholine may also serve to induce vigilance and act as a sleep sentry, screening extraneous sounds and other disruptive activity. In this way the cholinergic system operates a stimulus-barrier mechanism that prevents interruptions of sleep that are not genuine triggers for arousal. During sleep, the cholinergic system mediates the transition of states from deep to light sleep, to permit arousal as the occasion warrants.21 Acetylcholine is the guardian of sound sleep, protecting us from awaking with every draft, creak, or murmur - or our spouse. Because choline is the primary precursor of acetylcholine, supplemental amounts can help prevent the nonessential disruption of sleep.

Improve Your Quality of Life
Sleep is important for health and the quality of life at all ages. When it is disrupted, we are none the better. Poor sleep is associated with many medical conditions that can reduce the quality of one's life. The elderly are particularly susceptible to insomnia, and diseases of the mind as well as the body seem to feed upon bad habits and poorly chosen lifestyles.22  Moreover, as health degenerates with age, sleep quality often declines. Degenerative diseases such as heart disease, stroke, cancer, and respiratory disorders often disturb sleep, as does pain. Psychiatric disorders, including dementia and depression, may exacerbate sleep disturbances - or vice versa.

Since the medical profession has taught us that sleeping problems are normal with aging, masked nutrient deficiencies may go undetected. But quality of sleep in age-related decline can often be relieved with one or more nutrients that are difficult or impossible to obtain sufficiently from food sources. This is especially true as our bodies become less efficient. So instead of settling for Stone Age nutrition in food that has remained practically the same since the dawn of agriculture, step up to the computer age of high-powered nutrition in the form of dietary supplements.

In actuality, age-related sleep deterioration begins far earlier in life than old age itself, so it is important that we address the problems as they arise, lest we find ourselves on the slippery slope, unable to recover our sleep hygiene. Dietary supplementation with herbs such as valerian, amino acids such as 5-HTP, hormones such as melatonin, and nutrients such as choline help halt sleep decline and help restore healthy sleep function. Otherwise, much of the joy of life is given over to weariness, anxiety, depression, and pain. Wouldn't you rather be energetic, confident, and exhilarated about what each day may bring?


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