The Dangers of Sleeping Pills by Jeffrey Dach MD

Mary is a 52 year old house wife from Wyoming who takes an Ambien sleeping pill every night for the last three years. Because of worrisome menopausal symptoms of vaginal dryness, hot flashes and night sweats, Mary was starting on hormone replacement with bioidentical estrogen and progesterone. A problem was apparent early on. Mary required three times the dosage of estrogen cream compared to all the other patients. Perhaps the Ambien sleeping pills are interfering with or blocking the progesterone and estrogen receptors in the brain?

Header Image: A lion and a lioness sleeping in the Serengeti. 31 July 2002 by Vincenzo Gianferrari Pini. Courtesy of Wikimedia Commons.

Sleeping Pills Mechanism of Action

The most commonly prescribed sleeping pills in the U.S. are the “Z drugs” (zolpidem, zopiclone, and zalephon). How do they work? The the Z drugs have a mechanism very similar to the benzodiazepine class of drugs, they inhibit the Type A- GABA neurons in the brain. The GABA neurons are inhibitory while the Glutamate neurons are excitatory. (9)

Above Left Image: Unable to sleep, person with with eye bags. February 2022, Digital art work by Itzamna3211, Creative Commons CC0 1.0 . Courtesy of Wikimedia Commons.

Z-Drugs Inhibit Estrogen and Progesterone Receptors in the GABA Neurons

The problem is these GABA neurons have estrogen and progesterone receptors attached to them, so when we inhibit these neurons with a sleeping pill “Z-drug”, this also inhibits the estrogen and progesterone receptors, thus requiring higher doses of hormones to be effective for relief of menopausal symptoms.

Z- Drugs Increase Mortality and Cancer

Two large studies show the Z drug sleeping pills are associated with increased mortality and a host of other medical problems. In addition, sleeping pills become ineffective through tolerance for chronic users, and actually reduce functionality the following day.

Progesterone Induces Sleep Via Same GABA receptors

How does progesterone help with sleep? What is the mechanism of action? This was aptly described in 2021 by Dr. B. J. Nolan who states progesterone metabolites inhibit the GABA neurons, in a mechanism very similar to the Z-drug sleeping pills. Dr. B. J. Nolan who writes:

Preclinical data has shown progesterone metabolites improve sleep parameters through positive allosteric modulation of the γ-aminobutyric acid type A receptor [GABA Type A Receptor]….(5)

CBT and Bright Light Therapy

Cognitive Behavior therapy and Bright Light Therapy are considered first line treatment for sleep. For post menopausal women, hormone replacement with estrogen and progesterone is usually effective and should be first line therapy.

Conclusion: Sleeping pills interfere with estrogen and progesterone receptors in GABA neurons in the brain, requiring much larger hormone doses to have efficacy. Z-drug sleeping pills are associated with increased mortality. It is best for the post-menopausal woman to taper off sleeping pills and use progesterone for sleep, a much safer choice not associated with the increased mortality of sleeping pills.

Articles with Related Interest

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Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
my blog: www.jeffreydachmd.com 
Natural Thyroid Toolkit by Jeffrey Dach MD
Cracking Cancer Toolkit by Jeffrey Dach MD
Heart Book by Jeffrey Dach MD

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References

HRT Menopause Sleep

!!!!!!!!!!!!!!!!!!!!! BEST !!!!!!!!!!!!!!!!!!
1) Almey, Anne, Teresa A. Milner, and Wayne G. Brake. “Estrogen receptor α and G-protein coupled estrogen receptor 1 are localized to GABAergic neurons in the dorsal striatum.” Neuroscience letters 622 (2016): 118-123.

This experiment demonstrated that ERα and GPER1 are localized to GABA neurons in the STR [striatum]. ERs were observed in GABAergic terminals and dendrites, where they are positioned to modulate transmission at GABA synapses. These ERs on GABAergic profiles are a possible mechanism for the rapid E2-induced decreases in GABA in the STR, and suggest that estrogens may indirectly affect dopamine transmission in this region by decreasing GABA availability…

Estrogen receptors have been shown to be membrane associated in the dorsal striatum…. Here we confirm that and show that they are localized to GABA neurons.

ERα and GABA most frequently colocalize in dendrites and terminals
There are moderate levels of colocalization between ERα and GABA in the STR. Colocalization of ERα- and GABA- IRs was most commonly observed in dendritic shafts (Fig. 2 A, B), with 35.3% of ERα immunoreactive dendrites containing GABA-IR (see Table 1). Colocalization of GABA- and ERα- IRs was also frequently (27.1%) observed in axon terminals (Fig 2B).

Thus, to determine whether ERα or GPER1 are localized to GABAergic neurons, we double labeled the striatum with antibodies for ERα or GPER1 and GABA and examined them using electron microscopy. Ultrastructural analysis revealed that ERα and GPER1 are localized exclusively to extranuclear sites in the striatum, and ~35% of the dendrites and axon terminals labeled for these receptors contain GABA immunoreactivity. Binding at membrane-associated ERα and GPER1 could account for rapid estrogen-induced decreases in GABA transmission in the striatum, which, in turn, could affect dopamine transmission in this region.

2) Thind, Khushdev K., and Paul C. Goldsmith. “Expression of estrogen and progesterone receptors in glutamate and GABA neurons of the pubertal female monkey hypothalamus.” Neuroendocrinology 65.5 (1997): 314-324.

In summary, certain subpopulations of Glu and GABA neurons in principal hypothalamic regions of the female monkey express ER and PR at midpuberty. Taken together with previous findings, these results suggest that Glu and GABA neurons which become sensitive to steroid hormones may help regulate GnRH neurohormone release and promote the onset of puberty.

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3) Kapur, Jaideep, and Suchitra Joshi. “Progesterone modulates neuronal excitability bidirectionally.” Neuroscience letters 744 (2021): 135619.

Progesterone acts on neurons directly by activating its receptor and through metabolic conversion to neurosteroids. There is emerging evidence that progesterone exerts excitatory effects by activating its cognate receptors (progesterone receptors, PRs) through enhanced expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). Progesterone metabolite 5α,3α-tetrahydro-progesterone (allopregnanolone, THP) mediates its anxiolytic and sedative actions through the potentiation of synaptic and extrasynaptic γ-aminobutyric acid type-A receptors (GABAARs).

Progesterone synthesized in the ovaries and adrenocortical glands can easily cross the blood-brain barrier and can also be synthesized locally in the brain from cholesterol.

The most commonly studied molecule is its metabolite allopregnanolone (THP). These effects are rapid and potentiate the inhibitory neurotransmission mediated through the GABAARs [GABA Type A Receptors] .

Estrogen stimulates PR expression;

4) Guennoun, Rachida. “Progesterone in the brain: hormone, neurosteroid and neuroprotectant.” International journal of molecular sciences 21.15 (2020): 5271.

Progesterone has a broad spectrum of actions in the brain. Among these, the neuroprotective effects are well documented. Progesterone neural effects are mediated by multiple signaling pathways involving binding to specific receptors (intracellular progesterone receptors (PR); membrane-associated progesterone receptor membrane component 1 (PGRMC1); and membrane progesterone receptors (mPRs)) and local bioconversion to 3α,5α-tetrahydroprogesterone (3α,5α-THPROG), which modulates GABAA receptors.

5) Nolan, B. J., B. Liang, and A. S. Cheung. “Efficacy of Micronized Progesterone for Sleep: A Systematic Review and Meta-analysis of Randomized Controlled Trial Data.” The Journal of Clinical Endocrinology and Metabolism 106.4 (2021): 942-951.

Conclusions: Micronized progesterone improves various sleep outcomes in randomized controlled trials, predominantly in studies enrolling postmenopausal women.

Preclinical data has shown progesterone metabolites improve sleep parameters through positive allosteric modulation of the γ-aminobutyric acid type A receptor….Our search strategy retrieved 9 randomized controlled trials comprising 388 participants.

mice study
6) Lancel, Marike, et al. “Progesterone induces changes in sleep comparable to those of agonistic GABA-A receptor modulators.” American Journal of Physiology-Endocrinology and Metabolism 271.4 (1996): E763-E772.

The effects of progesterone on sleep closely resemble those of agonistic modulators of GABAA receptors such as benzodiazepines and correlate well with the increases in the levels of its GABAA agonistic metabolites. These observations suggest that the hypnotic effects of progesterone are mediated by the facilitating action of its neuroactive metabolites on GABAA receptor functioning.

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7) Jeon, Gyun-Ho. “Insomnia in Postmenopausal Women: How to Approach and Treat It?.” Journal of Clinical Medicine 13.2 (2024): 428.

menopausal hormone therapy (MHT) should be considered as the treatment of choice among pharmacological treatments, following cognitive behavioral therapy, which is suggested as the first-line treatment in the general population insomnia treatment guidelines. Additionally, melatonin and 5HT-based drugs, which have fewer side effects, along with MHT should be preferentially recommended in menopausal women…menopausal women with insomnia also need an individualized approach and
treatment (MHT, prolonged-release melatonin, 5HT-based drugs, etc.) under the premise that CBT should be used as the first-line treatment, following the treatment guidelines of
insomnia for the general population.

Previous studies have reported beneficial effects of female sexual hormones on sleep…Estrogen blocks wake-promoting neurotransmitters, such as acetylcholine, histamine, norepinephrine, serotonin, and dopamine [19], and is known to have a thermoregulatory effect of regulating the lowest body temperature during the night, which provides good conditions
for falling asleep [20]. Overall, estrogen seems to increase the rapid eye movement sleep and total sleep time and decrease sleep latency and awakenings after sleep [21].
Estrogen may also exert an antidepressant effect by regulating 5HT [22]. Progesterone stimulates benzodiazepine receptors, causing the release of gamma-aminobutyric acid (GABA),
a sedating neurotransmitter, and thus induces sleep favoring non-rapid eye movement sleep [23,24]. Progesterone is also known to exert an anxiolytic and respiratory stimulant effect [24,25], which may also help promote good sleep.

Menopausal Hormone Therapy
Based on the identified roles of reproductive hormones in sleep and the theory that vasomotor symptoms (VMS), such as HFs, in menopause cause insomnia, as discussed above, MHT can be an important treatment for insomnia in menopausal women with
hot flashes. Indeed, a meta-analysis including 15,468 women from 42 trials published in 2017 showed that MHT improved sleep quality in menopausal women with VMS, along with improvement in concomitant VMS. There was no significant difference when women without VMS were analyzed separately or combined in this study [53]. However, several previous studies exploring the effects of estrogen and progesterone on sleep efficiency have
shown mixed results. While some studies suggested that hormone therapy, such as low dose estrogen with micronized progesterone or drospirenone, 17β-estradiol-progesterone, and low-dose oral estradiol and venlafaxine, reduced insomnia symptoms compared with a placebo [54–58], some contrary results were also reported, which failed to identify any superiority of MHT over the placebo [59,60]. Even studies favoring the effectiveness of MHT mainly showed improvements in subjective sleep quality and tended to show inconsistent results in objective PSG variables [61–63]. This lack of consistency is due to the heterogeneity of the trials regarding differences in study populations, age, definitions of
menopausal stages, types of menopause, preparations of hormones, and unstandardized sleep scales; therefore, there is a limitation of overall certainty in the evidence of the MHT
effects on sleep disturbances [11,53]. Nevertheless, based on the fact that MHT is effective for HFs in peri- and post-menopausal women and helps improve quality of life, there is an emerging view that MHT can be considered as the first-line treatment when insomnia is suspected to be part of VMS, and it is better to first evaluate the response of MHT and then
consider other treatments for insomnia in menopausal women with VMS [64]. In the same context, it was reported that the degree of improvement in VMS was an important predictor
of insomnia improvement [65]. Considering the bidirectional relationship between insomnia and depression, it is difficult to determine whether insomnia in postmenopausal women is related to the high prevalence of clinical depression or depressed mood during that period or due to menopause itself. The only way to differentiate may be a trial of MHT and consideration of other therapy if insomnia or depression persists after three months of
successful MHT [64]. Before using MHT to relieve insomnia in menopausal women, it is important to monitor the side effects of MHT, such as thromboembolic events and breast cancer, and whether the benefits outweigh the risks should be evaluated. Additionally, there are recent studies showing that transdermal treatment was the safest type of hormone therapy in the assessment of risk of venous thromboembolism [66], and micronized progesterone was more effective for improving sleep, as well as reducing HFs [67], which suggests to consider transdermal estradiol and micronized progesterone for the patients at risk of thromboembolism.

8) Cheng, Yu-Shian, et al. “Pharmacologic and hormonal treatments for menopausal sleep disturbances: a network meta-analysis of 43 randomized controlled trials and 32,271 menopausal women.” Sleep Medicine Reviews 57 (2021): 101469.

Therefore, the results of the present NMA suggest that oral combined hormone replacement therapy may be useful for sleep disturbances in women suffering from vasomotor symptoms due to menopause…

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9) Segal, Alan Z. “Sleeping Pills Increase Risk of Death.” Internal Medicine Alert 36.12 (2014).

Hypnotic and anxiolytic drugs have been associated with an increased risk of dementia, daytime fatigue, ataxia, falls, and traffic accidents. Medical ailments such as cancer, pneumonia, and other infections have been associated with use of these medications.

The Z-drugs (zolpidem, zopiclone, and zalephon) are the most commonly prescribed medications for insomnia in the United States.

10) Weich S, et al. Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards: Retrospective cohort study. BMJ 2014;348:g1996.
In this large cohort of patients attending UK primary care, anxiolytic and hypnotic drugs were associated with significantly increased risk of mortality over a seven year period, after adjusting for a range of potential confounders. As with all observational findings, however, these results are prone to bias arising from unmeasured and residual confounding.

11) Kripke, Daniel F. “Hypnotic drug risks of mortality, infection, depression, and cancer: but lack of benefit.” F1000Research 5 (2016).

Evolving concern with hypnotic risks provides many new studies for this review, including four additional large epidemiologic analyses relating hypnotic prescriptions to excess mortality and two complementary meta-analyses demonstrating associations of hypnotic prescriptions to specific cancers. Meanwhile, the data base has grown demonstrating superior results with cognitive-behavioral therapy of insomnia and with bright light treatment.

The most important risks of hypnotics include excess mortality (especially overdose deaths, quiet deaths at night, and suicides), infections, cancer, depression, automobile crashes, falls, other accidents, and hypnotic-withdrawal insomnia. Short-term use of one-two prescriptions is associated with even greater risk per dose than long-term use. Hypnotics have usually been prescribed without approved indication, most often with specific contraindications, but even when indicated, there is little or no benefit. The recommended doses objectively increase sleep little if at all, daytime performance is often made worse (not better) and the lack of general health benefits is commonly misrepresented in advertising. Treatments such as the cognitive behavioral treatment of insomnia and bright light treatment of circadian rhythm disorders offer safer and more effective alternative approaches to insomnia.

12) Sun, Y., M. K. Tsai, and C. P. Wen. “Association of sleep duration and sleeping pill use with mortality and life expectancy: A cohort study of 484,916 adults.” Sleep Health (2023): S2352-7218.

Objectives: To compare mortality risk and life expectancy among individuals with different sleep durations and sleeping pill use.

Methods: A cohort of 484,916 community-dwelling adults in Taiwan was recruited into a health screening program from 1994 to 2011. Subjects were categorized by daily sleep duration into 4 groups: extremely short (<4 hours), short (4-6 hours), medium (6-8 hours), and long (>8 hours). Cox proportional hazards models were used to investigate the associations of mortality risk with sleep duration and sleeping pill use. Models were adjusted for sociodemographic characteristics, lifestyle, and comorbidities. Life expectancy tables were calculated among sleeping pill users and nonusers with different sleep durations.

Results: With 6- 8 hours of daily sleep, sleeping pill nonusers had the lowest mortality risk. Sleeping pill users, even with this optimal amount of sleep, had a 55% (p < .001, 95% CI, 1.38-1.73) higher mortality risk than nonusers. The life expectancy of 30-year-old male sleeping pill users with extremely short or long sleep durations was 12-13 years shorter than sleeping pill nonusers who had 6-8 hours of sleep. On average, life expectancy in individuals using sleeping pills (vs. nonusers) was shorter by 5.3 (95% CI, 4.10-6.32) years in men and 5.7 (95% CI, 5.28-7.98) years in women.

Conclusions: This study suggests that the use of sleeping pills is associated with an increased risk of mortality and shortened life expectancy, especially in extreme sleepers. Regular users should be aware of potential harms from sleeping pills.
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13) Kripke, Daniel F., et al. “Mortality hazard associated with prescription hypnotics.” Biological psychiatry 43.9 (1998): 687-693.

14) Kripke, Daniel F. “FDA ASKED TO SEVERELY RESTRICT USE OF MOST COMMONLY-PRESCRIBED SLEEPING PILLS.”

16) Kripke, Daniel F. “Chronic hypnotic use: deadly risks, doubtful benefit.” Sleep medicine reviews 4.1 (2000): 5-20.

In the United States, roughly 2/3 of all hypnotic prescriptions go to chronic users, who have taken hypnotics for an average of 5 years or more. Two large prospective epidemiological studies have shown that reported hypnotic use, especially use 30 times per month, is associated with an excess hazard of death. Indeed, use of hypnotics 30 times per month is associated with a similar mortality hazard to smoking 1–2 packs of cigarettes per day. Moreover, the hypnotic user’s wish to improve daytime function is usually unfulfilled. The preponderance of evidence is that hypnotics impair performance, cognition and memory, increase the risk of automobile accidents and falls and promote unfavourable changes in personality. Due to tolerance, the sleep-promoting effects of hypnotics appear to be lost with chronic use. With long-term use, there is little controlled evidence that hypnotics produce benefits of any sort. More study of long-term hypnotic effects by public agencies is needed, but available evidence weighs strongly against long-term prescribing.

17) Kripke, Daniel F., Robert D. Langer, and Lawrence E. Kline. “Hypnotics’ association with mortality or cancer: a matched cohort study.” BMJ open 2.1 (2012): e000850.

As predicted, patients prescribed any hypnotic had substantially elevated hazards of dying compared to those prescribed no hypnotics. For groups prescribed 0.4–18, 18–132 and >132 doses/year, HRs (95% CIs) were 3.60 (2.92 to 4.44), 4.43 (3.67 to 5.36) and 5.32 (4.50 to 6.30), respectively, demonstrating a dose–response association. HRs were elevated in separate analyses for several common hypnotics, including zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates and sedative antihistamines. Hypnotic use in the upper third was associated with a significant elevation of incident cancer; HR=1.35 (95% CI 1.18 to 1.55). Results were robust within groups suffering each comorbidity, indicating that the death and cancer hazards associated with hypnotic drugs were not attributable to pre-existing disease.

18) Kripke, Daniel F. “Surprising view of insomnia and sleeping pills.” Sleep 36.8 (2013): 1127-1128.

19) Kripke, Daniel F. “Hypnotic drug risks of mortality, infection, depression, and cancer: but lack of benefit.” F1000Research 5 (2016).
This update adds new findings about the accelerating overdose epidemic that is suddenly reducing U.S. life expectancy. The overdose role of hypnotics and other benzodiazepine agonists in combination with opioids is further reviewed. Evidence is expanded that most hypnotic prescriptions are not indicated—indeed, the great majority have been contraindicated or result in misuse. The “weak” evidence relating minimal benefit with indicated hypnotics does not support over 90% of actual U.S. ingestion, wherein the hypnotic was not indicated or rather was contraindicated. For >90% of cases, there seems to have been no scientific evidence of benefit. On the other hand, the evidence of severe risks appears to apply to all hypnotic utilization whether or not given for an approved indication. Evolving concern with hypnotic risks provides many new studies for this review, including four additional large epidemiologic analyses relating hypnotic prescriptions to excess mortality and two complementary meta-analyses demonstrating associations of hypnotic prescriptions to specific cancers. Meanwhile, the data base has grown demonstrating superior results with cognitive-behavioral therapy of insomnia and with bright light treatment.

This is a review of hypnotic drug risks and benefits. Almost every month, new information appears about the risks of hypnotics (sleeping pills). The most important risks of hypnotics include excess mortality (especially overdose deaths, quiet deaths at night, and suicides), infections, cancer, depression, automobile crashes, falls, other accidents, and hypnotic-withdrawal insomnia. Short-term use of one-two prescriptions is associated with even greater risk per dose than long-term use. Hypnotics have usually been prescribed without approved indication, most often with specific contraindications, but even when indicated, there is little or no benefit. The recommended doses objectively increase sleep little if at all, daytime performance is often made worse (not better) and the lack of general health benefits is commonly misrepresented in advertising. Treatments such as the cognitive behavioral treatment of insomnia and bright light treatment of circadian rhythm disorders offer safer and more effective alternative approaches to insomnia.
Keywords: hypnotics and sedatives, mortality, cancer, infection, depression, insomnia, sleep
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20) The Dark Side of Sleeping Pills, Mortality and Cancer Risks, Which Drugs to Avoid & Better Alternatives By Daniel F. Kripke, M.D.

in my view, the risks of death, cancer, depression, and infection with sleeping pills, besides the behavioral impairments and accidents, are much more important than any small benefits. Besides, use of sleeping pills seems to cause insomnia, at least after withdrawal.

Even with tiny increases in sleep that they provide for a few days, hypnotics do not improve an insomnia patient’s daytime function. More often, the pills make daytime function measurably worse. Patients often seek improved function, but they usually do not receive it. Further, although we hear colleagues mention that perhaps a patient will be healthier if the patient sleeps better, our research found that patients taking sleeping pills were more likely to develop new medical disorders than matched control patients who avoided sleeping pills. I have located no reliable evidence that any sleeping pill improves general health, but there is much evidence of serious harm to physical and mental health.

The specific sleeping pills we studied were zolpidem (e.g., Ambien), temazepam (e.g., Restoril), eszopiclone (e.g., Lunesta), zaleplon (e.g., Sonata), other benzodiazepines such as triazolam (e.g., Halcion) and flurazepam (e.g., Dalmane), barbiturates, and sedative antihistamines such as diphenhydramine (e.g., Benadryl). Most of the patients in this study were taking zolpidem or temazepam.

As a young medical student in my first year of training, one of the first things I learned in our student laboratory was that the humane way to “put an animal to sleep” was to administer a fatal dose of a barbiturate such as pentobarbital. A bit later, I learned that pentobarbital was being prescribed almost automatically as a sleeping pill for patients in the hospital. Pentobarbital and related drugs are currently used to execute the death penalty on prisoners. Any medical student knows that these drugs can kill.

Doctors have a wonderfully complete understanding of how sleeping pills such as pentobarbital kill animals. These drugs bind with protein molecules called GABA receptors on the surface of nerve cells. The same protein receptor molecules bind at the same time with a neurotransmitter chemical called GABA, which gives them their name. Barbiturates and other sleeping pills accentuate the action of GABA, which is to cause the receptor molecule to allow chloride ions to enter the nerve cells. Since the chloride ions are negatively charged, they make the inside the nerve cell more negatively polarized, which in turn, makes the nerve cells less likely to fire (to generate nerve activity). When the nerve cells which stimulate the muscles of breathing are overly inhibited from firing by sleeping pills, the animal stops breathing. When breathing stops, the animal dies within a few minutes from lack of oxygen. This same mechanism explains how sleeping pills kill people who take an overdose. Mixture with other drugs, particularly opioids, alcohol and other sedatives, greatly magnifies the risks, as do various medical conditions, possibly stopping breathing with a dose not intended to be lethal.

Use of sleeping pills is very strongly associated with suicide from all causes.

Suicide, accidental overdose and cancer are probably not the most common ways in which sleeping pills kill,

All approved sleeping pills can cause “hangover,” that is, they not only reduce the action potentials of our brain cells during sleep, but they can also reduce brain cell activity during the day.[13] This can make us sleepy, less alert, confused, and weak during the day.

As explained above, sleeping pills suppress the action potentials of a wide variety of brain cells. The psychological effects are to make us sleepy, reduce alertness and vigilance, slow reaction times and judgment, and impair aspects of intelligence and memory. Literally hundreds of studies have been done concerning the psychological effects of sleeping pills, both within a few hours after ingestion and then during the day following taking a sleeping pill at bedtime.[20] To summarize an extremely complex group of studies, almost all sleeping pills produce immediate impairments of memory and performance. Further, there is extensive evidence that sleeping pills impair performance and memory on the following day.

Sleeping pills generally make function WORSE the next day.

To view sleeping pill advertising, you might imagine sleeping pills help you to work better, think better, or function better the next day. This is deceptive. With very few exceptions, controlled studies supported by the manufacturers showed that sleeping pills made test performance WORSE on the following day, or else had no definite effect on performance. Look through the FDA files for Ambien, Lunesta, Sonata, Rozerem, Belsomra, or Silenor at the FDA website.[21] See if you can find any evidence that these drugs improved next-day performance for people with insomnia. You will not find any. For the older sleeping pills, there are less definite data available in FDA files, but many studies of older hypnotics showed that sleeping pills impaired performance the next day.

Because the build-up of these drugs in blood happens slowly, patients may not realize that their intelligence, reflexes, and judgment are slowly fading, and relatives may not know the cause.

That is a lesson in the misperception of sleeping pill users. These patients were self-deceived about the value of the medication, almost deluded, thinking the medicines made them better which actually made them worse. Users of addicting sleeping pills are like heroin addicts: they may claim they need the drug, but to medical people and their own families, it looks like the addicting drugs are very harmful.

The studies showed that sleeping pills produced no long-term benefits, only harms. Also, the studies showed that the volunteers thought they were benefitting from the drugs (even placebo), even when they were being harmed.

Patients who continued to take zolpidem as-needed after two years slept worse than patients who tapered off zolpidem. [29] I would interpret these studies as indicating that continuing use of zolpidem made insomnia worse.

The manufacturers now admit that both zolpidem (Ambien) and eszopiclone (Lunesta) cause withdrawal insomnia on the night after you stop the pill. Anxiety may also occur as a withdrawal symptom. People become addicted to these drugs because they experience such anxiety and poor sleep, whenever they try to stop. If they stayed off the drug for a few days, they might sleep just as well without the medication. Even worse, newer studies indicate that with sleeping pills, drug-withdrawal damage may be surprisingly lasting. Indeed, we are not certain if the damage ever completely heals.

Disastrous side effects.

having taken Ambien, people can act like somnambulists or sleep walkers or robots gone haywire. In the more amusing examples, they may sleep-walk to the refrigerator and stuff themselves with strange foods that they would not normally eat in such quantity. Of course, this is not amusing if it leads to obesity, which can be a life-threatening condition, or if they eat something unhealthy. The behavior of the so-called Ambien Zombies is not always amusing. In a few reported cases, people intoxicated with Ambien have climbed into their cars and engaged in sleep driving. Some had serious accidents.[30] Hallucinations have been reported with zolpidem, zaleplon, and eszopiclone.[31] At other times, people receiving sleeping pills have become confused or disoriented. Another odd symptom is complete amnesia for events, even during the day. For example, a successful businessman told me that while taking Ambien at night, he might have absolutely no recollection of a conference which his own notes showed that he had attended the following day. From viewing various reports, I now realize that these terrible side effects may develop in about one percent of users of sleeping pills.

Multiple studies have found that sleeping pill use is associated with very high suicide rates, but as yet, the evidence that sleeping pills cause increased suicide is based on the strong evidence that the pills cause depression, as well as very high rates of suicide observed among those known to have taken sleeping pills.

Everyone has heard the stories of nurses awakening patients to give them sleeping pills. When I was a medical student, I learned that nurses want to keep their patients quiet for the night. Physicians routinely write sleeping pill orders in the hospital without specific medical goals, because they hate for nurses to call at night and wake the doctor up to get a sleeping pill order. As a medical student, I was instructed that if I wanted to sleep at night, I had better routinely prescribe a sleeping pill for every patient. The sleeping pill was to help the doctors and nurses sleep, not for the patients. Moreover, there is no evidence that sleeping pills really help hospital personnel at night, since sleeping pills seem to produce problems like falls and delirium that do not make the work of the night staff easier.

2.E. The problem of addiction.

All U.S.-approved prescription hypnotics are addicting (with the exception of ramelteon and the new drug Silenor). By addicting, we mean that these sleeping pills have two properties. First, when we take addicting drug such as narcotics or barbiturates, we develop tolerance so that a given dosage has less and less effect or “stops working.” People who develop tolerance are prone to increase their dosage more and more. Second, addicting drugs cause physical withdrawal symptoms when addicts try to stop. The withdrawal symptoms of hypnotics such as barbiturates and benzodiazepines are very well known.[34] Symptoms include insomnia, shakiness and tremor, nervousness and anxiety, panic, hyperactivity and increased reflexes, rapid heart rate: even epileptic seizures and death in the most severe cases.

Remarkably, even recent studies show that most people given sleeping pill prescriptions do not have complaints or diagnoses of insomnia in their medical records. This suggests that gift-giving or doctor-marketing explains much hypnotic prescribing.

2.G. Disinhibition of punished behaviors and the dark side of tranquilization.

Scientists say that benzodiazepines disinhibit punished behavior, which means that the animals become more likely to hurt themselves or to behave in a way in which they will be hurt. Another way of saying this is that benzodiazepines disinhibit aversive behaviors. There is a human analogy.

In humans, an action of benzodiazepines is to reduce fears of being harmed, which we may call being tranquilized. People very much like this feeling of reduced fear, and there is no doubt that many people like how they feel when taking benzodiazepines.

When we consider that benzodiazepines increase people’s tendency to act in a self-harmful way, it is logical that taking harmful sleeping pills may be one of the harmful behaviors which benzodiazepines tend to increase.

2.H. Infection.

Working with colleagues at Scripps Clinic, we found that people who take sleeping pills such as eszopiclone, zaleplon, and zolpidem have about a 44% higher risk of developing infections such as sinusitis, pharyngitis, upper respiratory tract infections, influenza, herpes, and so forth.[38]

A new study from Great Britain showed that use of benzodiazepines (including popular older sleeping pills) was associated with a 50% increase in hospitalizations for pneumonia and about a 30% increase in subsequent mortality. For more scientific data about infections, see this review: [39

According to those recordings, volunteers who slept 5.0 to 6.5 hours had the lowest mortality.[41] If you feel you sleep five to seven hours a night and feel rested, there is no evidence that you should try to sleep any more as far as life expectancy is concerned, and that is largely true of other health measures.

Adopting good sleep habits and attitudes is extremely effective in solving long-term sleep problems. It is more effective than sleeping pills.[42]

For help with insomnia by changing habits and attitudes, try a program of Cognitive-Behavioral Therapy for insomnia, abbreviated CBT-I.
CBTforInsomnia.com[43] and SHUTi[44],\

CBT-I helps more than sleeping pills and CBT-I is much safer.

There have now been dozens of randomized trial comparisons of CBT-I versus sleeping pills, showing that in the long run, CBT-I is more helpful and safer than sleeping pills.

In summary, there is expert consensus that the medical evidence does not support chronic use of sleeping pills.

Getting Off Sleeping Pills

Even with slow tapering, withdrawal from sleeping pills can cause at least a few nights of insomnia, anxiety (both day and night), tremulousness, and other symptoms. People will have much less difficulty withdrawing from sleeping pills if they first begin CBT-I treatment as described in Chapter 3 above, or obtain CBT-I from a therapist or web site.

Even people with no intrinsic depression or anxiety are likely to become anxious when withdrawing from a sleeping pill. It helps to understand that this anxiety and fear of insomnia is usually a drug withdrawal reaction which will go away in time, often within a day or two, so starting a replacement drug may not be advisable. People withdrawing from sleeping pills may become filled with the idea that they can never do without their pill, when a few days later, they do perfectly well without it.

The most reasonable substitute drugs might be trazodone, Silenor (doxepin 3 or 6 mg.) and melatonin, but I say this without recommending substitution. Trazodone and melatonin are not FDA-approved as hypnotics as of September, 2018.

8.A. Why haven’t you heard from the FDA?

When we reported that people who took sleeping pills died 4.6 times faster and suffered more cancer,[66]

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Sun, Nov, and Aims Scopes. “Inside Insomnia: Pharmacist Management of Sleep Disorders.”

There are 5 benzodiazepines that are FDA approved for insomnia: estazolam (Prosom), flurazepam (Dalmane), quazpam (Doral), temazepam (Restoril), and triazolam (Halicon). Pharmacists can counsel patients on the use of these prescribed medications, but for many patients, insomnia can be mitigated through lifestyle modifications and appropriate sleep hygiene. “According to the CDC, some examples of good sleep hygiene include going to sleep and waking up at a consistent time every day, removing electronic devices from the bedroom, keeping the a comfortable temperature, exercising during the day—but not too late because that can keep you awake later—and avoiding large meals, caffeine, and alcohol too close to bedtime,” Khorassani explained.

Other agents such as diphenhydramine HCI (Benadryl) and doxylamine (Unisom) are also options, but they come with more adverse effects than melatonin, such as dry mouth and next-day drowsiness. Because of this, these agents are best used for short-term insomnia only.2

“I’ve had a few patients who have complained of insomnia because they were taking [the antidepressant bupropion (Wellbutrin)], which can cause insomnia,” Khorassani said. “Several of them were taking it twice daily and were taking the second dose at bedtime. If this medication is taken twice daily, the second dose is ideally given before 4 PM because of its stimulating properties.

Campbell will occasionally recommend melatonin but said she is more concerned about a patient’s sleep hygiene. Before melatonin, she will remind patients to ensure that their bedroom is optimized for sleep and that they aren’t eating too close to bedtime or drinking too much alcohol.

“If they are at the age where they are not producing as much melatonin as they need, I will put them on a very low-dose melatonin,” she said. “I incorporate a lot of nutrition science and a lot of stress science into how I approach and coach patients.”

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914492/
Bruni, Oliviero, et al. “Herbal remedies and their possible effect on the GABAergic system and sleep.” Nutrients 13.2 (2021): 530.

https://scholar.google.com/scholar?output=instlink&q=info:JbOjymzUU3AJ:scholar.google.com/&hl=en&as_sdt=40005&sciodt=0,10&scillfp=11812132856043006320&oi=lle
Guadagna, S., et al. “Plant extracts for sleep disturbances: A systematic review.” Evidence‐Based Complementary and Alternative Medicine 2020.1 (2020): 3792390.

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Phototherapy: Is bright light an effective alternative for the treatment of insomnia disorders?

Phototherapy: Is bright light an effective alternative for the treatment of insomnia disorders?
14 noviembre, 2020 3:13 pm , Ciencia Cognitiva
Marc Dalmau Rodríguez
Facultad de Psicología, Universitat Oberta de Catalunya, España

In conclusion, the treatment of insomnia should follow, first and foremost, a non-pharmacological approach. Although cognitive therapy is the most effective treatment to date, its limitations in terms of involvement and abandonment must be considered. Phototherapy, on the other hand, has proven to be effective in treating insomnia, although its efficacy must be investigated in greater depth,

Click to access The_role_of_bright_light_therapy_in_mana20160326-14838-ppkd12.pdf

Lovato, Nicole, and Leon Lack. “The role of bright light therapy in managing insomnia.” Sleep Medicine Clinics 8.3 (2013): 351-359.

Chambe, Juliette, et al. “Light therapy in insomnia disorder: A systematic review and meta‐analysis.” Journal of sleep research 32.6 (2023): e13895.

Lei, Huabin, et al. “Efficacy and safety evaluation of bright light therapy in patients with post-stroke insomnia: A protocol for systematic review and meta-analysis.” Medicine 100.50 (2021): e27937.

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Published on June 28th, 2024 by Jeffrey Dach MD