"Sleep Aids" or Z-drugs

Inner Compass Initiative has developed these informational pages because many descriptions of the safety and effectiveness of psychiatric drugs that are provided by popular online medical, psychiatric and mental health websites are often brief, vague, and more promotional than factual. (For an examination of some of the reasons why this is the case, please read ICI’s “How Psychiatric Drugs are Researched and Marketed”.) We believe that, when trying to make serious, potentially life-changing decisions about whether to take or discontinue psychiatric drugs, people deserve a fairer opportunity to properly understand and evaluate the potential risks and benefits, and thereby be empowered to make informed choices. Our articles will take you more time to read because they provide more detailed information than most of the overviews you’ll read elsewhere – but isn’t your health worth the investment?

If you notice an error, broken link or needed update, please contact us. Click here to learn more about Inner Compass Initiative.

Inner Compass Initiative’s mini-booklets about the six main classes of psychiatric drugs do not review all of the scientific research about these drugs. That would be an extremely ambitious effort that could easily fill an entire book for each drug class, after which even the most neutral team of researchers could still be accused of “cherry picking” evidence from tens of thousands of available studies. We have taken a different approach. We’ve focused mainly on reporting and clarifying what is arguably the single most important body of evidence: The evidence that drug companies themselves provided to government health regulators in order to try to establish evidence that their drugs are safe and effective.

If a pharmaceutical company wishes to market a prescription drug for a specific use in the United States, the company is legally required to provide scientific evidence in support of its application to the Food and Drug Administration (FDA). If the drug is approved by the FDA, this evidence is then summarized in the official “drug label”. The information pamphlets for consumers that come with prescription drugs are often unregulated, general information about the drug or just a brief collection of highlights from the drug label. In its complete form, the official drug label can be ten to fifty pages or longer in length, and includes the “Full Prescribing Information” and “Medication Guide” that are intended to inform physicians, psychiatrists, pharmacists and others about the most important scientific evidence relating to the safety and effectiveness of that drug. Since the drug labels are generally based on evidence provided to the FDA by the drug companies themselves, and are developed in collaboration between the drug companies and FDA, they tend to be strongly biased in favor of the drugs. Yet even with this bias, we at Inner Compass Initiative believe that most readers, like us, will find much of the information in them to be enlightening, surprising, concerning and even at times shocking – and nothing if not helpful for making more informed decisions weighing the potential risks and benefits of psychiatric drugs. So in creating our mini-booklets, we distilled the contents of a representative sampling of drug labels from each major class of psychiatric drugs -- supplemented at times with information from related scientific studies and the FDA's own medical reviews. (Also included are some general Q&As about key ideas in psychiatric science such as safety, effectiveness, and drug dependence, which apply to essentially all psychiatric drugs and are duplicated across the mini-booklets.)

Still, we urge anyone who is considering or already taking any psychiatric drug to read the official drug label in full. These are freely available online at a variety of commercial websites, but the most reliably up-to-date sources are those run by the federal government such as DailyMed. (Instructions and links for obtaining and understanding drug labels and related information such as FDA medical reviews can be found in “The Inner Compass Initiative's Guide to the FDA-approved Drug Labels”.) We also strongly recommend doing additional self-directed research, such as examining the FDA’s internal medical reviews, using online tools for searching scientific journal articles, perusing Inner Compass Initiative’s resources, conferring with people who’ve taken the drug, and consulting with well-informed, supportive prescribers or pharmacists. Choice is only truly meaningful – and truly possible – when it is informed.

“Z-drugs” is an informal name for a group of psychotropic drugs that have strong sedative-hypnotic effects and are usually prescribed to help people with sleeping.  The generic names for these drugs include eszopiclone, zolpidem and zaleplon (e.g. U.S. brand names Lunesta, Ambien and Sonata).  They are also sometimes called central nervous system depressants (CNS depressants) or  “non-benzodiazepines”. They have many similar effects to benzodiazepine drugs.

Z-drugs are also sometimes prescribed to treat restless leg syndrome, but this use has not been approved by the U.S. Food and Drug Administration (FDA). In fact, Z-drugs are often prescribed by psychiatrists and physicians to help with aspects of sleep for which the drugs are not actually approved by the FDA, either (see below for more information).

Some psychiatrists and physicians also prescribe benzodiazepine and antipsychotic drugs “off-label” to help people with sleeping. (When a physician prescribes a drug for a use that has not been approved by the FDA and is not listed on the official drug label, the physician is prescribing “off-label”.) Read ICI’s “Anti-anxiety Benzodiazepines” or “Antipsychotics” for more information on those classes of drugs. This page focuses on Z-drugs.

Notably, the answer to the above question is, in some important ways, similar for all of the major classes of psychiatric drugs: We don't truly know. It can be misleading to talk about how Z-drugs work, because the word “work” implies that the drugs have a well-understood effect on a discrete pathway in the brain that’s involved in sleep, or cure an abnormal biological condition, disease or disorder. For many it can be surprising to hear because we’re so often led to believe otherwise, but there is still today no known, biologically detectable mental disorder or discrete “sleep pathway” that Z-drugs specifically treat or cure. (For more information, read ICI’s “How Mental Disorders are Diagnosed” and “How Psychiatric Drugs are Researched and Marketed”.)

Z-drugs are psychoactive chemicals that act on the brain in a variety of ways. It is common for popular medical websites, news media, non-profit organizations, and even medical professionals to make claims that Z-drugs “target only a certain type of GABA receptor” and “certain centers in the brain” to create drowsiness.

Z-drugs certainly do affect GABA receptors, but this is only part of what they do, and the research is in fact unclear about exactly how these drugs affect wakefulness. Indeed, the FDA and pharmaceutical manufacturers have developed medically definitive descriptions of the mechanisms of action for every Z-drug that is approved for use in the United States. These can normally be found in the “Clinical Pharmacology” section of the official drug label. (Instructions and links for obtaining and understanding drug labels can be found in “The Inner Compass Initiative's Guide to the FDA-approved Drug Labels”.) According to these explanations, the biological mechanisms by which any Z-drugs might help some people sleep are “hypothesized” or “unknown”. 

It is known that, in part, Z-drugs interact with gamma-aminobutyric acid receptors (GABA receptors) in human neurons. GABA is a neurotransmitter or chemical messenger that plays key roles in the basic internal communication systems of the human brain and body. GABA’s main role seems to be inhibitory: It often influences neurons that it contacts to slow down or stop firing. Since Z-drugs interact with some of the same receptors that GABA does, it is hypothesized that Z-drugs amplify some of GABA’s inhibitory effects to create sedation. However, it is important to note that GABA’s main activity is precisely to alter the activities of every other neurotransmitter in the human brain and body, including dopamine, serotonin, adrenaline etc. These latter neurotransmitters are in turn involved in everything from moods and cognitive function to motor control and the operation of vital organs. Consequently, once a Z-drug has begun to amplify some of the activities of GABA, understanding all of the resulting effects and side effects in the body and brain, and exactly how sedation is produced along the way, is beyond our current level of scientific understanding.

We often hear that certain psychiatric drugs are effective. But it’s rarely explained what exactly “effective” means. Does effective mean that the drug makes everyone feel completely better? Or if some people feel better when taking the drug, in what ways do they typically feel better, by how much, and for how long a time? And do some people feel worse in certain ways because of the drug?

Unless you ask probing questions, or carefully and critically analyze scientific studies yourself, it’s difficult to know exactly what certain people mean when they state that a particular psychiatric drug is effective. Often, different people can even look at the same scientific evidence and reach opposite conclusions about whether a psychiatric drug demonstrated true effectiveness or not. (For more information, please read ICI’s “How Outcomes are Measured in Psychiatric Research” and “How Psychiatric Drugs are Researched and Marketed”.) Yet when deciding if a drug is right for you or for someone you care about, it is very important to have a strong understanding of in what ways the drug is apparently effective and to what degree it is apparently effective, so that you can reasonably weigh the potential benefits of the drug against its potential adverse effects.

As we described in our introductory section, one helpful way to resolve these challenges and learn about a psychiatric drug’s effectiveness is to examine the actual medical evidence that resulted in the FDA approving the drug to legally be described by the pharmaceutical manufacturer as “effective” for the drug’s intended use. This evidence comes from the clinical trials that a pharmaceutical company presented to the FDA in order to try to establish their drug’s effectiveness. Though these trials were sponsored and selected by the drug companies and so tended to be biased in favor of the drugs, they are still extremely instructive. So in this article, we provide some representative examples of how drug companies tried to prove to the FDA that their drugs were effective – and we examine what “effective” actually meant in that context.

Ambien and Sonata have been approved by the FDA as effective only for short-term use in slightly increasing how quickly people fall asleep. Lunesta has been approved as effective for use in both slightly increasing how quickly people fall asleep and slightly reducing the frequency and duration of awakenings during the night. According to the evidence provided to the FDA, none of these drugs have been shown to improve the depth of sleep, lengthen the number of hours spent in bed sleeping, or increase the restfulness of sleep.

In many of the trials, people taking Z-drugs went to sleep on average only about 9-15 minutes sooner than people taking placebo pills. A formally structured meta-analysis of all of the clinical trials for Z-drugs submitted to the FDA was published in the British Medical Journal in 2012. In that, the researchers concluded that, overall, Z-drugs seemed to make people fall asleep on average about 22 minutes sooner than people taking placebo pills.

When trying to appropriately weigh the potential benefits of Z-drugs against their potential harms, it’s important to clearly understand how drug “effectiveness” is being defined, and how limited these effectiveness rates are. And significantly, the FDA medical reviews revealed how these results were likely even weaker than they appeared:

• The more substantial effects generally involved much larger doses of the drugs – doses that were often much higher than the recommended doses in the drug labels.
• The trials were usually only about 2-5 weeks in length, and generally, tolerance to the drugs built rapidly so that their effectiveness began to decline almost immediately.
• People taking the drugs experienced much higher rates of side effects such as impaired muscle control, sleep-walking, memory loss, and impaired functionality the next day. However, these adverse effects were not relevant to the measuring of the effectiveness of the drugs at specifically reducing the amount of time needed to get to sleep.
• The trial participants were not representative of many of the people who typically take Z-drugs. Most often, people were excluded from the trials if they were taking any other psychotropic drugs, even though it is common for physicians and psychiatrists to prescribe Z-drugs to people who have been diagnosed with mental disorders and are already taking other psychiatric drugs such as stimulants, antidepressants and antipsychotics.

Only Lunesta was approved by the FDA as effective for longer-term use, and this was on the basis of just one study that lasted 6 months. This trial did not include objective tests of the drug’s effectiveness; rather, the participants simply reported that they subjectively believed that they were still going to sleep about 15 minutes more quickly and not awakening as frequently.

Related reading:

U.S. Food and Drug Administration. Sonata (zaleplon) Drug Approval Package: Medical Review. (1999).

U.S. Food and Drug Administration. Lunesta (eszopiclone) Drug Approval Package: Medical Review. (2004).

U.S. Food and Drug Administration. Ambien (zolpidem) Drug Approval Package: Medical Review. (1992).

Huedo-Medina, Tania B, Irving Kirsch, Jo Middlemass, Markos Klonizakis, and A Niroshan Siriwardena. “Effectiveness of Non-Benzodiazepine Hypnotics in Treatment of Adult Insomnia: Meta-Analysis of Data Submitted to the Food and Drug Administration.” The BMJ 345 (December 17, 2012). doi:10.1136/bmj.e8343.

According to their drug labels, none of the Z-drugs have been proven to be safe or effective for children, and they should not be given to children.

The limited effectiveness of Z-drugs may seem surprising to some people who have used them. However, it’s not only possible but indeed likely that in real-world conditions we would feel that these drugs are more effective than they are. This is because a user of the drug may experience both a drug effect and a placebo effect added together. In other words, while the drug may help us get to sleep 10 minutes earlier than we otherwise would have, the additional placebo effect (often arising from the belief that a drug will help us) may help us get to sleep an additional 20 minutes earlier. For example, a 2015 study published in the journal Sleep examined this issue across 32 randomized controlled trials and concluded that two-thirds of the effects of sleep drugs are actually placebo responses, and one-third is the effect of the drug. But if we are unaware or disbelieving of this placebo effect, then we will attribute all of the improvement in our sleep to the drug.

Further, Z-drugs are known to begin to cause memory losses shortly after taking them. While it is not uncommon for us to awaken in the night and later forget our thoughts or even that we were awake, Z-drugs are known to increase memory loss substantially and so could potentially distort our memories of how long and how often we were awake during the night.

Related reading:

Winkler, Alexander, and Winfried Rief. “Effect of Placebo Conditions on Polysomnographic Parameters in Primary Insomnia: A Meta-Analysis.” Sleep 38, no. 6 (June 1, 2015): 925–31. doi:10.5665/sleep.4742.

Z-drugs are known to cause dependence. Therefore, after a period of regular use of the drugs, it becomes increasingly likely that a person will experience unusually poor sleeps – among many other possible adverse physical and mental effects – for a period of time after suddenly stopping taking them.

All of the Z-drugs come with FDA warnings that people who take Z-drugs regularly for even short periods will experience more than normal degrees of trouble sleeping when they stop taking the drugs. This is sometimes referred to as “rebound insomnia”. The frequency, intensity and duration of rebound insomnia or other withdrawal effects varies depending on many factors, such as the dose a person was taking, and how regularly and for how long the person was taking the drug. However, it is known that dependence and other mild-to-severe withdrawal effects such as rebound insomnia can occur even after just a week or two of nightly use at recommended dose levels. See below for more information about dependence and withdrawal effects. (For more information about dependence, see The Inner Compass Initiative’s overview essay, “Psychiatric Drug Tolerance, Dependence and Withdrawal”.)

It’s often claimed that psychiatric drugs are safe. But what does “safe” actually mean? Different people can mean different things when they say that a drug is generally safe.

The FDA requires pharmaceutical companies to conduct some basic studies into the safety of their drugs. The findings from these studies are then included in the official FDA-approved drug labels under the assumption that patients and prescribers will then together review and weigh a drug’s potential risks and benefits. All prescribing physicians, psychiatrists and pharmacists are ethically and legally required to ensure that patients are informed about the potential harms of any drug that is being prescribed to them. In practice, though, this rarely occurs with respect to any drugs let alone psychiatric drugs, and patients often receive information which is incomplete or inaccurate. 

Prescribers themselves are not always fully informed. The lists of potential adverse effects for most psychiatric drugs are lengthy, and many prescribers are too busy to either learn about them all or, if they do learn them, convey them all to patients. Some prescribers don’t want to dissuade or frighten people from taking psychiatric drugs that they are recommending. Even the more responsible prescribers often just direct patients to read unregulated information or brief highlights of the drug labels that may accompany packages of prescription drugs. Relatively few of us ever read even these inserts, though, and instead we simply trust general reassurances from prescribers. This attitude is usually founded on a basic, deep trust of the medical profession, drug regulators, and scientific research. To learn more about why this trust should be balanced with healthy skepticism, please read ICI’s “How Psychiatric Drugs are Researched and Marketed”.

As we discussed in our introduction, even though the risk and safety information included in the drug labels tends to be biased in favor of the drugs, these labels can still be very informative. That said, it’s easy to feel like it’s not worth the effort to read about all of the adverse effects identified in these lengthy drug labels, because many of them can seem relatively trivial, while many of the more serious side effects are identified as being rare. However, there are other important factors to take into consideration:

• The real adverse effect rates are unknown and often higher. Most of the adverse effects that are listed in the FDA-approved drug labels are the ones that appeared in relatively short clinical trials involving small numbers of people – so the actual adverse effects in typical users are unknown, and reasonably likely to be (and are often later found to be) much larger in number and varied in type. Indeed, sometimes the drug labels include reports of many more adverse effects in a section called “Post-marketing Experience” – these are lists of adverse effects that started being identified and voluntarily reported to the FDA after many more people in the general population began regularly using the drugs. Because these reports are voluntary, though, the absence of such reports cannot be taken as evidence of a drug’s safety.
• "Infrequent" doesn’t always mean unlikely. It’s true that any particular, individual user is relatively unlikely to experience any one particular, infrequent adverse effect. However, taken all together, in most cases it’s very likely that most users will experience at least some of the listed adverse effects.
• "Rare" can add up to a lot of people. In the drug labels, some potentially very serious adverse effects may be described as “rare”. This refers to the fact that small numbers of people will experience a particular adverse effect relative to the overall number of people taking the drug. However, it’s important to remember that, with millions of Americans taking certain psychiatric drugs, “rare” can easily mean that thousands or ten of thousands of Americans will be experiencing that very serious adverse effect.
• Minor adverse effects may be warning signs. Apparently minor adverse effects can sometimes be early warning signs for more serious, rarer adverse effects; therefore, knowing the minor adverse effects could help prevent more serious harms or even, sometimes, save your life. 
• Adverse effects reveal a lot about how a drug works. Understanding the full range of possible adverse effects helps you better understand the ways in which a drug is acting on your body and brain.
• Your choice is better informed. Understanding the adverse effects helps you make a more informed choice about whether, for you, the relative effectiveness of a drug truly outweighs the potential harms.

Deciding to take a psychiatric drug or encouraging a friend or loved one to take a psychiatric drug, especially when it could potentially be for a long time, is a significant choice that could change the course of your or someone else’s life. The only way to make a truly, meaningfully informed choice is to try to ensure that you get the best information and advice that you can to help you think through the decision. If you or someone close to you is taking or considering taking any psychiatric drug, we encourage you to make the time to read the entire drug label. In this article, we have reviewed only a small sampling of the adverse effects identified in these labels, so below we also include links to several places where the U.S. FDA-approved drug labels can be viewed freely in full. However, in light of the limitations of this information, it’s even better to supplement it by examining the FDA’s “drug approval packages” (which include internal medical reviews of a drug), doing wider research, and consulting with well-informed, supportive practitioners.

At the same time, for anyone taking any psychiatric drug, the complexity of all of this information is an important reminder of the vital importance of always trying to listen closely to the wisdom in what your own body is telling you.

Related reading:

Instructions and links for obtaining and understanding drug labels can be found in “The Inner Compass Initiative's Guide to the FDA-approved Drug Labels”.

U.S. Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products.

U.S. Food and Drug Administration. Drugs@FDA Instructions: Health Information. (A quick guide to searching the FDA’s drug information system.)

U.S. National Library of Medicine. DailyMed

Their drug labels state that some of the more frequent adverse effects of Z-drugs include headache, agitation, excessive thirst, loss of strength, loss of muscle coordination, nausea, gastrointestinal problems and joint pain. Less common but often more serious adverse effects include heightened risk of respiratory infections, impotence, heart attacks, mania, and rectal hemorrhage. Some of these are discussed in more detail below.

It was initially widely believed that the Z-drugs would prove to have fewer adverse effects than benzodiazepine drugs. This was because the Z-drugs appeared to have a more “selective” mode of acting on GABA receptors compared to benzodiazepines (see above, “How do Z-drugs work?”). However, this belief has not been borne out, and the adverse effect profiles of benzodiazepines and Z-drugs have proven to be in many ways similar.

For example, a 2012 review of zolpidem led by Tufts University pharmacologist David J. Greenblatt found that, “When directly compared to typical benzodiazepine agonists in controlled pharmacodynamic or kinetic-dynamic trials, the majority of studies demonstrate that zolpidem is identical or closely similar to the comparator benzodiazepine in terms of sedative, performance-impairing and amnestic effects.”

Related reading:

Greenblatt, David J., and Thomas Roth. “Zolpidem for Insomnia.” Expert Opinion on Pharmacotherapy 13, no. 6 (April 1, 2012): 879–93. doi:10.1517/14656566.2012.667074.

All Z-drugs come with warnings on their drug labels that they can commonly cause memory loss even at recommended dosage levels. This occurs especially in the initial hours after ingestion of the drugs, but also after waking, and into the following day.

The drug labels also warn about the possibility of getting out of bed while not fully awake and doing activities that you do not realize that you are doing, and that you will not remember doing when you wake up. The sleep-activities that have been most often reported by users include driving a car, making and eating food, talking on the phone, having sex, and sleep walking. It is not clear if or how Z-drugs might cause such events and the drug labels do not provide percentages for the likelihood of them occurring, but one study found that over 5% of those taking zolpidem had experienced sleepwalking or amnesia about a night-time activity, or both.

Since Z-drugs also impair muscle coordination and balance, these kinds of behaviors obviously create greater risks of harmful accidents as well.

Related reading:

Tsai, Jui-Hsiu, Pinchen Yang, Cheng-Chung Chen, Weilum Chung, Tze-Chun Tang, Shing-Yaw Wang, and Jong-Kang Liu. “Zolpidem-Induced Amnesia and Somnambulism: Rare Occurrences?” European Neuropsychopharmacology 19, no. 1 (January 1, 2009): 74–76. doi:10.1016/j.euroneuro.2008.08.007.

All Z-drugs come with FDA warnings that the drugs significantly impair coordination and balance and can create dizziness and grogginess. These effects are strongest within the first few hours after taking the drugs, and therefore can be especially dangerous for people when getting out of bed to use the bathroom, during sleepwalking, or if responding to an emergency. This has been found to be an especially serious problem for the elderly. In one study, zolpidem use was associated with a near doubling of hip fractures in the elderly.

Related reading:

Kang, Dong-Yoon, Soyoung Park, Chul-Woo Rhee, Ye-Jee Kim, Nam-Kyong Choi, Joongyub Lee, and Byung-Joo Park. “Zolpidem Use and Risk of Fracture in Elderly Insomnia Patients.” Journal of Preventive Medicine and Public Health = Yebang Uihakhoe Chi 45, no. 4 (July 2012): 219–26. doi:10.3961/jpmph.2012.45.4.219.

Mets, Monique A. J., Edmund R. Volkerts, Berend Olivier, and Joris C. Verster. “Effect of Hypnotic Drugs on Body Balance and Standing Steadiness.” Sleep Medicine Reviews 14, no. 4 (August 2010): 259–67. doi:10.1016/j.smrv.2009.10.008.

All Z-drugs come with FDA warnings that you should not take them unless you have at least 7-8 hours before you need to be active again. In addition, all of these drugs come with warnings that you should not engage in hazardous occupations or activities such as driving or using heavy machinery even a full day after taking a Z-drug, because motor coordination, reaction times, memory function, and alertness may well still be impaired for hours after waking, even if you obtained a full night’s sleep. The risks increase substantially when higher-than-recommended doses are being used. And much like with alcohol impairment, these deficiencies in functional ability are often not detectable to the person who is impaired by the drug. 

Related reading:

Mets, Monique A.J., Juna M. de Vries, Lieke M. de Senerpont Domis, Edmund R. Volkerts, Berend Olivier, and Joris C. Verster. “Next-Day Effects of Ramelteon (8 Mg), Zopiclone (7.5 Mg), and Placebo on Highway Driving Performance, Memory Functioning, Psychomotor Performance, and Mood in Healthy Adult Subjects.” SLEEP, October 1, 2011. doi:10.5665/sleep.1272.

Verster, Joris C., Edmund R. Volkerts, Antonia H. C. M. L. Schreuder, Erik J. E. Eijken, Janet H. G. van Heuckelum, Dieuwke S. Veldhuijzen, Marinus N. Verbaten, et al. “Residual Effects of Middle-of-the-Night Administration of Zaleplon and Zolpidem on Driving Ability, Memory Functions, and Psychomotor Performance.” Journal of Clinical Psychopharmacology 22, no. 6 (December 2002): 576–83.

All of the Z-drugs come with explicit warnings in their drug labels that the drugs can lead to “abnormal thinking and behavior changes.” These include anxiety and panic, unusually outgoing or aggressive behaviors, bizarre behaviors, confusion, agitation, visual and auditory hallucinations, “depersonalization” (a feeling of unreality), emerging or worsening of depression, and suicidal thoughts or actions.

According to the drug labels, these kinds of experiences are not necessarily tremendously uncommon. In some short-term adult trials, for example, 1-3% of people reported having hallucinations, while in one pediatric clinical trial 7% of the children reported experiencing hallucinations. In short-term adult trials, Z-drugs at times quadrupled the likelihood of people experiencing depression.

If these kinds of experiences are not properly recognized as adverse drug effects, a person experiencing them may get diagnosed with a mental disorder and prescribed additional drugs to treat that perceived mental disorder.

All Z-drugs come with FDA warnings about the possibility of severe allergic reactions, including swelling of the tongue and throat, that can be fatal.

There is also evidence that Z-drugs may somehow cause a higher risk of respiratory infections, urinary tract infections, and other kinds of infections. Generally, Z-drugs seem to increase the risk of contracting a range of infections by between 25 and 64 percent. Depending on the type of infection, or if a person is immune-compromised or elderly, this could present serious risks. In addition, higher rates of infection have been linked to elevated risks for contracting more serious health problems like cancer.

One 2012 study published in the British Medical Journal found that receiving prescriptions for Z-drugs was linked to nearly three times higher chances of dying over a 2.5 year observation period, even in cases where patients received less than 18 pills per year. In cases where patients were prescribed greater than 132 Z-drug pills per year, their chances of dying were increased by 500%. This same study found that people taking over 132 Z-drug pills per year were 35% more likely to develop some form of major cancer. While these kinds of studies do not prove cause and effect, they can be important cautionary signals.

Related reading:

Joya, Florendo L., Daniel F. Kripke, Richard T. Loving, Arthur Dawson, and Lawrence E. Kline. “Meta-Analyses of Hypnotics and Infections: Eszopiclone, Ramelteon, Zaleplon, and Zolpidem.” Journal of Clinical Sleep Medicine: JCSM: Official Publication of the American Academy of Sleep Medicine 5, no. 4 (August 15, 2009): 377–83.

Huang, Chih-Yuan, Frank Hunag-Chih Chou, Yung-Sung Huang, Chang-Jen Yang, Yu-Chieh Su, Shiun-Yang Juang, Pin-Fan Chen, Pesus Chou, Ching-An Lee, and Ching-Chih Lee. “The Association between Zolpidem and Infection in Patients with Sleep Disturbance.” Journal of Psychiatric Research 54 (July 2014): 116–20. doi:10.1016/j.jpsychires.2014.03.017.

Kripke, Daniel F., Robert D. Langer, and Lawrence E. Kline. “Hypnotics’ Association with Mortality or Cancer: A Matched Cohort Study.” BMJ Open 2, no. 1 (2012): e000850. doi:10.1136/bmjopen-2012-000850.

According to the drug labels for all of the Z-drugs, no adequate studies of the effects of these drugs on pregnant women and fetuses have been done. Nevertheless, Z-drugs interfere with the functioning of body and brain neurotransmitters, which are fundamental to fetal development, so it seems likely that the risks of taking these drugs during pregnancy would be significant.

The Ambien and Sonata labels specifically recommend against pregnant women taking the drugs. They also warn that the drugs have been found in human breast milk at concentrations that could have impacts on infants, and recommend against lactating mothers using these drugs.

When you complain about adverse effects after starting a psychiatric drug, it is common for physicians and psychiatrists to advise you to continue to take the drug anyway because some adverse effects will likely stop. Even popular medical websites like WebMD do this, advising that some of the adverse effects “may go away after you take the medicine for a while” because “your body can adjust” to the presence of the drugs.

This is certainly possible. What is not often explained, though, is that this body “adjustment” indicates growing drug tolerance. Your body is compensating for the presence of a foreign chemical and is developing ways to diminish some of the chemical’s impacts. So while you may begin experiencing fewer adverse effects or less intense adverse effects as your body compensates and adapts to the presence of the drug, it’s possible that you’ll begin experiencing decreased beneficial effects as well. And other adverse effects will often be continuing, if unnoticed.

Further, this increasing tolerance also indicates that your body is starting to develop physical dependence on the drug, which could bring the risk of uncomfortable, painful or even dangerous withdrawal symptoms if you try to stop the drug suddenly. Prescribers should warn patients more often about the risks of developing dependency on and tolerance to psychiatric drugs, but they often do not.

All Z-drugs are both addictive and dependence-forming. Addiction most often develops when people take Z-drugs at levels above the recommended doses. According to their drug labels, the drugs can produce euphoric sensations and cravings for more, and can lead to tolerance and a need to take higher doses to get the same effects. However, even at the lowest recommended doses, Z-drugs can still cause dependence to form. This means that, over time, the body and brain adjust and adapt to the presence of the drug, and people can experience a wide variety of uncomfortable, painful or even dangerous withdrawal symptoms when they abruptly stop taking the drug. The drug labels for all Z-drugs warn about the risks of developing dependency.

It is not fully understood how Z-drugs affect the body and brain, and so it is also not understood exactly how sudden discontinuation of these drugs can produce the wide variety of difficult or dangerous withdrawal symptoms that they often do, even after just brief periods of regular use. However, it is known that Z-drugs at least in part enhance some of the activities of the neurotransmitter GABA. (Neurotransmitters are the key chemical messengers in the brain and body’s internal communications and functional systems.) GABA’s main role seems to be to “inhibit” or decrease the activities of other neurotransmitters in the body and brain. Human and animal studies and research into the similarly-acting benzodiazepine drugs suggest that, over time, the body compensates for or adapts to the ongoing presence of a Z-drug – the body seems to do this by reducing its sensitivity to GABA. Consequently, if a person suddenly stops taking the drug after a period of regular use, the person could experience a sudden “hyperexcitability” or increase in biochemical and electrical activities throughout your central nervous system until your sensitivity to GABA is naturally restored.

According to their drug labels, common withdrawal symptoms from discontinuation of Z-drugs even after just a few weeks of use at normal doses can include dysphoria, insomnia, abdominal and muscle cramps, vomiting, sweating, uncontrolled crying, anxiety and panic attacks, tremors, and convulsions. Withdrawal effects are usually worse after longer periods of use with higher doses.  

Although physical dependency is recognized and discussed in the drug labels for Z-drugs, there are virtually no formal scientific studies into the safest methods or time frames for tapering. Since there are similarities between Z-drugs and benzodiazepines, some of the research into benzodiazepine dependency and withdrawal can be helpful.

Stopping any psychiatric drug can be risky or even dangerous. In particular, many official drug labels, formal scientific studies, and a growing evidence base of anecdotal reports from physicians and patients alike suggest that coming off psychiatric drugs abruptly or too rapidly for the central nervous system to manage tends to be especially risky and in some circumstances can even produce severe seizures or other life-threatening withdrawal reactions. Therefore, aside from situations where a medical emergency may deem rapid withdrawal to be necessary, tapering off a psychiatric drug is a major decision that is very personal and should involve forethought and careful planning. All of the possible benefits, risks and consequences of tapering should be carefully weighed in light of each individual’s life circumstances, physical health, resources, supports, and other factors.

ICI has been gathering the anecdotal reports and accumulated insights from laypeople who have experienced psychiatric drug withdrawal. If you or someone close to you is considering tapering, you may find it helpful to read discussions about common methods of tapering, what “slow” and “responsible” tapering looks like, how to prepare for tapering, and how to develop a plan of action for withdrawal that ideally involves the collaborative support of a well-informed prescriber, pharmacist, family and friends. At The Inner Compass Exchange people considering coming off psychiatric drugs can also connect with others who have experienced psychiatric drug withdrawal, are in withdrawal, or are considering withdrawal.