Theme : Dreams

Some Basic Features of the New Sleep-Aid Tea (SAT) for the Treatment of Insomnia

Liu Shiyi (S.Y. Liu)
Shanghai Institute of Physiology, Academia Sinica
Shanghai Huake Institute of Sleep and Anti-dementia (SHISA)
Shanghai, China
Abstract
The "immediate-onset"-acting hypnotics (1-2 h after oral administration) (e.g., benzodiazepines) serve as the leading approach and great progress has been made in this century. They are exogenous from artificial synthesis and mainly fit for short-term insomnia. The "gradual-onset"-acting hypnotics (3-5 d after oral administration) are mild and gradually effective, but are very safe and without noticeable side or adverse effects. They are endogenous or endogenous-mimetic from natural isolation. It may serve as a more natural approach for the treatment of chronic or long-term insomnia, which is mainly gradually developed. This approach is especially useful in treating elderly people, whose numbers are rapidly increasing worldwide, especially in the next century. Sleep-Aid Tea (SAT) is a naturally processed Tea consisting of endogenous or endogenous-mimetic sleep-inducing substances isolated from specific natural and edible fruits and plants well known for the treatment of insomnia, e.g., Compendium of Materia Medica (Li, 1596) associated with modern knowledge and isolation technology (Liu, 1990, 1993). SAT is especially fit for the treatment of insomnia in aged people because it is mild, "gradual-onset"-acting (3-5 d after oral administration), natural, safe and without side effects.

Current Claim: The "gradual-onset"-acting medication is more fit for the treatment of chronic or long-term insomnia which is mainly and largely gradually developed.

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Insomnia is a worldwide problem in modern society. Approximately 20-30% of the adult population complains of difficulty in falling or maintaining sleep (Liu, 1995; Okuma, 1993). It is also known that the number of elderly people is increasing rapidly throughout the world. According to the recent World Heath Organization (WHO) estimation (1997), the population of individuals over 60 years of age is expected to be over 600 million (9.8%) worldwide by the year 2000. Based on the recent Census of China (July, 1997) the population of individuals over 70 years of age was over 12 million. Thus, the search for new types of hypnotics or pills for the treatment of chronic or long-term insomnia, especially for the elderly population, will serve as an important question that merits attention.

It is known that insomnia, at large, is caused by "stress" or an intranquil mind, which is largely and mainly gradually, but not acutely, developed. In the meantime, it is noteworthy that only the "immediate-onset"-acting hypnotics (1-2 h after oral administration) serve as almost the absolute approach for the treatment of insomnia in this century. The sleeping pills, like different analogs of barbiturates (Borbely, 1988) or benzodiazepines (Langer and Arbilla, 1988; Perrault et al., 1990), zopiclone (Fleming, 1990), zolpidem (Roth et al., 1995), etc., are all "immediate-onset"-acting hypnotics. They are mainly exogenous based on artificial synthesis and available mainly for short-term insomnia (<2-4 weeks), but side- or adverse effects still could not be avoided (Fleming et al., 1990; Roth et al., 1995). Thus, it seems intriguing whether the "gradual-onset"-acting hypnotics (3-5 d after oral administration) with no noticeable side- or adverse effects will serve as a more natural approach for the treatment of insomnia, especially long-term, which is largely and mainly gradually developed. The "gradual-onset"-acting hypnotics (Liu, 1990, 1995; Liu et al., 1993) are mainly endogenous or endogenous-mimetic based on natural isolation from animal, fruit or plant origin.

The idea that "endogenous substances can be isolated only from animal origin" should be updated, because it is now known that many endogenous substances in the brain can also be isolated from plant or fruit origin (Liu, 1996; Liu et al., 1994). For instance, dopamine, melatonin or 3'3'-cyclic adenylic-acid (CAMP) can be isolated from Dioscorea opposite Thumb, Barley or Arocado, respectively (Liu, 1995; Liu et al., 1994), so it is not only the pineal body of the animal's brain which contains melatonin (Armstrong, 1989). We also demonstrated that the Sleep-Promoting Substances (SPS) (SPS-A: uridine, SPS-B: oxidized glutathione [GSSG]) isolated from the rat's brain (Kamoda et al., 1990) can also be isolated from Ganoderma capense (Zhang et al., 1986) or Panax ginseng C.A.Meyer, respectively (Liu, 1996; Liu et al., 1993). The Sleep-Aid Tea (SAT) (Liu, 1993, 1997; Liu et al., 1996) is a naturally processed TEA consisting of isolated endogenous molecules, not truly from animal, but from fruit and plant origin.

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Sleep-Aid Tea (SAT) is a naturally processed Tea consisting of endogenous substances isolated from natural specific fruits and plants well known for the treatment of insomnia (e.g., Compendium of Materia Medica, 1596) (Li, 1596), associated with modern knowledge and isolation technology (Liu, 1990; Liu et al., 1993). The sleep-inducing efficacy of SAT and its pharmacological and toxicological studies were first done in some species of animals (rats, mice, rabbits) (Liu, 1993, 1997; Liu et al., 1996). Chronic toxicological studies have shown that no toxicity was seen, even in mice (KM) fed only with SAT instead of ordinary feeds for 14 consecutive days (N=20), followed by an observational period of two months (Liu et al., 1996). The present study presents only some of its basic features as examples: (1) SAT (6 g, daily for 3 or 7 d, p.o.) enhanced the total sleep time (TST) in 10 adult New Zealand rabbits of either sex weighing 2.5-3.5 kg; (2) SAT (20 g, daily for 5 d, p.o.) mainly enhanced dSWS (SWS-III-IV) at the first half of the night (2300-0300) in 10 adult human volunteers of either sex (5 males, 5 females, age 25-30 yrs); and (3) SAT (40 g, daily for 8-10 d, p.o.) enhanced TST in 40 additional hospitalized or outpatient chronic insomniacs (19 males, 21 females, age 25-79 yrs). SAT in its granulated form was orally administrated twice daily (20 g in the morning, 20 g in the evening).

Whole night rabbit recordings (1800-0800) were done in an electrically shielded sound attenuated chamber, whereas whole night human recordings (2300-0700) were carried out in an electrically shielded soundproof sleep laboratory. A 24 h light-dark cycle (L:D=12:12) and constant ambient temperature (20°C) were maintained throughout all experiments. A ND-82 type recorder was used for polysomnographic monitoring of EEG, EOG and EMG in both rabbits and human volunteers, respectively. EEG signals of the magnetic tape were fed into a 7T08 Signal Processor to perform the FFT and power spectrum analysis. The techniques of recording have been described previously (Ji et al., 1983). For rabbit studies, stainless steel electrodes were implanted stereotaxically under pentobarbital anesthesia. At least 8-10 days were allowed for recovery from surgery before recording. EEG signals were recorded by unipolar or bipolar leads from frontal-motor and occipital regions. Whole night recordings of each rabbit included one night for adaptation followed by one night for control with placebo and two nights after SAT (on 3rd or 7th d). For human volunteers, according to the international 10-20 system, EEG (C3, C4 with common reference), EOG and chin EMG were recorded. The human polysomnogram was mainly analyzed visually according to the criterion of Rechtschaffen and Kales (1968). Student's t-test was used for statistical analysis. Each volunteer spent three nights in the sleep laboratory: one night for adaptation, followed by one night for control with placebo, and one night after SAT (on 6th d).

The ten adult human volunteers were healthy young males and females recruited from the general University population who complained of no, or only occasional slight, insomnia. All volunteers or patients answered a brief questionnaire before selection. Volunteers were not recruited if they had previous endogenous sleep disorders, such as sleep apnea syndrome (SAS), narcolepsy, etc., based on the International Classification of Sleep Disorders (ICSD, 1990). Thus, the patients in the present study had mainly exogenous (environmental) or circadian rhythm sleep disorders.

The sleep-promoting effects of SAT in insomniacs was first reported elsewhere (Liu, 1993; Liu et al., 1996). The additional 40 chronic insomniacs were hospitalized or outpatient insomniacs from a University Hospital in Shanghai. All had a duration of insomnia longer than 10 years and different kinds of sleeping pills (e.g., benzodiazepines) had repeatedly been used and they complained of dependence and turnover, etc., and other adverse effects. No EEG, EOG and EMG recordings were done in these patients, but a self-assessment of subjective quality of sleep was made accompanied with some Mini-Logger2000 recordings.

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The whole night recordings of adult rabbits of either sex (N=8) revealed that SAT (6 g, daily for 3-7 d, p.o.) could significantly enhance the total sleep time (TST) (1800-0800) in contrast to the control (placebo). It mainly enhanced slow wave sleep (SWS) because basically no changes of the paradoxical sleep (REM) were seen. Table 1 illustrates that after oral administration of the SAT for 3-7 d, the TST was enhanced from 191.7±56.5 min (control) to 230.6±68.2 min (after 3 d) (+20.3%) or 257.9±12.7 min (after 7 d) (+34.6.%) (N=8), respectively, p<0.05 (Table 1). Also, no dependence and turnover were observed after cessation of 14 d consecutive oral administration of the SAT (6 g, daily for 14 d, p.o.) in adult rabbits (N=9).

The whole night recordings of human volunteers of either sex (N=10) also revealed that the SAT (20 g, daily for 5 d, p.o.) mainly enhanced SWS with no noticeable enhancement of the REM sleep. Further analysis showed that the percentage of deep slow wave sleep (dSWS) (Stage 3-4) in TST (dSWS/TST) was mainly enhanced during the first half of the night (2300-0300) in contrast to the second half of the night (0300-0700). Table 2 indicates that the whole night dSWS/TST after consecutive oral administration of the SAT (20 g, daily for 5 d) was increased from 17.1±3.3 (control) to 22.0±4.8 (after 5 d) (+29.1%, p<0.05) (N=10). The enhancement of dSWS/TST took place mainly during the first half of the night (2300-0300) from 23.2±4.9 (control) to 31.0±9.9 (after 5 d) (+33.6%, p<0.05) (N=10), when compared to the second half of the night (0300-0700) from 10.9±4.8 (control) to 13.1±3.7 (after 5 d) (+19.2%, p>0.05) (N=10).

SAT (20 g, daily for 5 d, p.o.) was also evaluated in 50 early-stage insomniacs (30 males, 20 females, age 24-71 yrs). Thirty-seven of them (74.0%) reported improvement of sleep (e.g., early sleep-onset, more sound sleep) and the total sleep time (TST) at night, on average, was increased from 6.5±1.6 h to 7.6±1.4 h (N=50), p<0.05. SAT (40 g, twice daily for 8-10 d, p.o.) was further evaluated in 40 chronic insomniacs (insomniac history: 10-20 years with no sleep apnea syndrome) (19 Males, 21 females, age 25-79 yrs), twenty of whom were hospitalized chronic insomniac patients. The majority of these chronic insomniacs suffered rebound or withdrawal symptoms after repeated administration of benzodiazepine or benzodiazepine-like pills. Enhancement of ~1.5 h of TST at night on average was reported. No allergic reaction and abnormality concerning routine blood, stomach, liver and kidney functions were seen following consecutive oral administration of SAT, even for 10-20 days.

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As mentioned before, the efficacy of the "immediate-onset"-acting hypnotics (1-2 h after oral administration) (e.g., benzodiazepines, BZD) is well known (Borbely, 1988; Perrault et al., 1990). It is also known that some new or "third generation" agents, like zopiclone (Imovan) or zolpidem (Stilnox) induce less dependence (<4 weeks) and side- or adverse effects (Fleming et al., 1990; Roth et al., 1995). They are all exogenous based on artificial synthesis and their pharmacological profile is still similar to BZD (zopiclone) or related to BZD receptor (zolpidem, 1) (Roth et al., 1995). They are not safe and mainly fit for short-term insomnia (Roth et al., 1995). On the other hand, the "gradual-onset"-acting hypnotics (3-5 d after oral administration) (e.g., SAT) are endogenous or endogenous-mimetic based on natural isolation of edible fruit and plant origin. They are very safe with no noticeable side- or adverse effects and also fit for chronic or long-term insomnia. From an epidemiological and philosophical point of view, insomnia is basically not as acute as "toothache" or "fever," but is largely and mainly gradually developed, so that the "gradual-onset"-acting hypnotics may serve as a more natural approach for the treatment of insomnia, especially for elderly people.

Based on the present study, it is interesting that SAT mainly enhanced slow wave sleep (SWS) in both rabbits and human subjects. It seems intriguing that SAT mainly enhanced deep slow wave sleep (dSWS) (Stage 3-4) in the first half of the night (2300-0300) in human subjects. It is known that even for healthy adults (18-30 years) who sleep for 7-8 h daily, dSWS occupies only around 15% of the total sleep time (TST), on average, per night (Anch, 1988; Liu, 1996). But due to various reasons (e.g., stress, age, excessive work, jet lag, shiftwork), many adults enjoy much less dSWS mainly in the first half of the night (Mendelson, 1987), and this will cause early-stage or chronic insomnia. The dSWS mainly distributed in the first half of the night is important for maintaining good health and longevity (Liu, 1996; Horne, 1988), as well as for enhancing endogenous immunomodulatory function (Krueger, 1997) and the release of growth hormone (Brandenberger, 1992) in the brain. Since 1985 we have been interested in the search for endogenous sleep-inducing substances from natural isolation either from animal (Liu, 1990; Liu et al., 1994) or fruit and plant origin (Liu, 1993; Liu et al., 1993). It seems to hold true that the brain contains not only a single sleep-inducing substance, so a recipe for success is important. This might also be the reason that, though melatonin seems "magic" for the treatment of "jet lag" syndrome or for the treatment of melatonin-deficient insomniacs (Liu, 1999), it does not seem not "magic" for the treatment of long-term or chronic insomnia.

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This work was supported by grants 9389007 and 39379223 from the National Natural Science Foundation of China (NNSFC). The technical assistance of Y. Zhang, W.Y. Zhang and X.J. Dai is gratefully acknowledged. The clinical assistance of Dr. L. Xu is also gratefully acknowledged.

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