Z-Drugs: How Do They Work?

What are Z-Drugs? How do they vary from other hypnotics? What side effects do they have? In this article, we'll tell you.
Z-Drugs: How Do They Work?

Last update: 01 November, 2022

Z-drugs differ from other hypnotic agents in the duration of their action and their side effects. There are three Z-drugs: zolpidem, eszopiclone, and zaleplon. They’re among many drugs used to treat insomnia. However, Z-drugs cause little or no alteration of sleep architecture.

Insomnia has numerous causes. In fact, it may be involved in the onset, exacerbation, or relapse of many psychiatric disorders. It can also be a sign that there’s simply something wrong. After all, sleep is a basic need of the human being and studies recommend that adults should ideally sleep between seven and nine hours a night.

Sleep architecture

Sleep is a physiological process regulated by hormones connecting and disconnecting from each other within a large electrical and chemical circuit. When we talk about sleep architecture, we’re referring to the phases that the brain goes through from wakefulness to sleep.

  • Phase I or numbness. Light sleep occurs, the muscles begin to relax, and the eyes show slow movements.
  • Phase II  or light sleep. The heart and respiratory rate decreases, and the temperature and eyes hardly move.
  • Phase III  or transition. The phase in which the brain prepares for deep sleep. The muscles are relaxed and the waves characteristic of deep sleep appear, known as delta waves.
  • Phase IV or deep sleep. Both breathing and heart rate slow down. Delta waves predominate. This is known as the restorative phase of sleep.
  • Phase V or REM phase. It’s so-called because it’s the phase in which dreaming occurs. When you dream, your eyes move as if you were seeing in reality what you’re dreaming of.

Sleep is a cyclical process. The brain takes approximately 90 minutes to move from phase I to phase V. These phases are repeated throughout the usual eight hours of sleep. Therefore, as a rule, you go through each of these phases about five times a night.

Woman fast asleep

An approach to the neurobiology of sleep

Whether you’re awake or asleep depends on the stimuli you receive and your degree of activation. In your brain, there are molecules called neurotransmitters that are responsible for regulating the mechanisms that make you stay awake. They’re the molecules that control how much and how activated you are.

Neurotransmitters and receptors

A neurotransmitter is a kind of key. Two key neurotransmitters regulate sleep and wake switches: histamine and GABA.

  • Histamine. This is one of the neurotransmitters that regulate wakefulness. When there’s a lot of histamine in your system, you’re awake. When there’s little, you feel sleepy. That’s why the antihistamines you might take for the flu make you sleepy. They reduce (anti) the amount of histamine in the areas of your brain that are responsible for sleep.
  • GABA. This neurotransmitter acts in the opposite way to histamine. It makes you fall asleep. GABA is an inhibitory neurotransmitter because it ‘turns off’ the brain regions that are responsible for you being awake.

Sleep and wake mechanisms

Your brain and its functions are an electrical system full of circuits. In neurobiology, the circuit that controls sleep and wakefulness is known as the ascending reticular activating system . This system contains on and off switches:

  • The off switch. This is the brain region that’s responsible for making you fall asleep. In effect, it’s the promoter of sleep. It’s located in the ventrolateral preoptic nuclei (VPO) in the hypothalamus. When this region is activated, it produces the neurotransmitter, GABA.
  • The power switch. This region has the opposite function. When it’s activated, it produces the neurotransmitter histamine and you wake up. It’s located within the tuberomammillary nuclei (NTM) of the hypothalamus.

These mechanisms act in a special way. They’re known as flip-flop mechanisms. They can’t both be on or off at the same time. When one is on, the other must be off, and vice versa.

In your brain, you have multiple keys for multiple locks. The lock that’s of interest here, due to its relationship with the Z-drugs, is called GABA-A. The GABA-A receptor or lock works extremely well for the GABA neurotransmitter or key. Thus, when GABA and GABA-A come together, like a key in its lock, they produce sleep.

In addition, your brain also responds to the amount of light in your environment. When you’re in a bright place or it’s daytime, the light causes a region of your brain to turn off. The area is known as the suprachiasmatic nucleus, located in the hypothalamus. When the light decreases, this area of the brain is no longer turned off. The suprachiasmatic nucleus is activated. It secretes a hormone that also induces drowsiness, known as melatonin.

Pharmacological treatment of insomnia

Insomnia is understood as a state of activation during the night. In fact, it’s the product of an overactivated brain. From a neurobiological perspective, we can explain it as the activation of the power switch at night.

Drugs that reduce brain activation are those that, when you need to sleep, but can’t, force the off switch to be ‘pressed’.  Since, as we mentioned earlier, this mechanism is a flip-flop mechanism, the power switch is turned off. Among the various hypnotic drugs, are benzodiazepines, antihistamines, and Z-drugs.


Benzodiazepine or benzodiazepine hypnotics act like keys to the GABA-A lock. They produce sleep. As a matter of fact, these drugs both induce sleep (hypnotics) and reduce anxiety (anxiolytics). Examples of benzodiazepines are lormetazepam, lorazepam, clonazepam, diazepam, and alprazolam.

These drugs often produce side effects, such as:

  • Addiction with continued use. Therefore, a specialist should always be consulted before taking them.
  • Hangover-like symptoms on waking.
  • An increase in insomnia when they’re stopped. It’s known as rebound insomnia.
  • Interference in long-term memory.


As we’ve already mentioned, histamine is the neurotransmitter that flips the power switch. If you take a drug that reduces the amount of histamine in your body, the power switch will no longer be active. Since the mechanism is a flip-flop, the other switch, the off switch, will automatically turn on. This is what antihistamines do. Examples of antihistamine drugs are doxylamine or diphenhydramine.

What side effects do they have? Among others, are:

  • Drowsiness.
  • Dizziness and headaches.
  • Fatigue.
  • Dry mouth and constipation.
  • Blurry vision.
  • Dizziness.
Woman with dizziness


Z-drugs were synthesized during the early 1980s. Their hypnotic and sedative effect is similar to that produced by benzodiazepines. The Z-drugs, zaleplon, zolpidem, and eszopiclone, also act like keys that bind to the GABA-A receptor or lock. However, they act in a slightly different way than benzodiazepines.

In fact, these drugs bind to GABA-A in such a way that they don’t produce as much tolerance (less effect after taking the drug for a long time), or dependence (rebound insomnia after abruptly stopping treatment). Moreover, they have no known side effects on consciousness, memory, and learning.

The three kinds of Z-drugs

  • Eszopiclone. A drug with sedative, hypnotic, myorelaxant or muscle relaxant, and anticonvulsant effects. Nevertheless, its use has only been approved for the treatment of insomnia. The most common adverse side-effect is a persistent bitter taste in the mouth (dysgeusia), dry mouth (xerostomia), difficulty waking up, drowsiness, and headache. These effects last between four and five hours.
  • Zolpidem. When administered in low doses this drug doesn’t produce dependence or tolerance. Its sedative action is greater than its anxiolytic action. In other words, it makes you sleep more than relax. It’s indicated as a short-term treatment of insomnia. One of its most particular side effects is hallucinations. They might last between one and a half to two and a half hours.
  • Zaleplon. Several actions are attributed to this drug. It has sedative, hypnotic, muscle relaxant and anticonvulsant properties. It doesn’t produce tolerance, amnesia, or motor disturbances the following day. Of the three Z-drugs, it’s the one with the shortest effect. It only lasts for one hour.

Due to their short duration, Z-drugs are indicated for early insomnia, the kind that occurs when you have trouble getting to sleep. They’re not as effective as the drugs prescribed for maintenance insomnia which involves waking up many times throughout the night. Nor for mixed insomnia, which is a combination of sleep problems like early insomnia, maintenance insomnia, and early morning awakening.

Finally, it should be remembered that all of these drugs directly affect activity in the brain. For this reason, we recommend that, before you start using any of them, you talk to your doctor and follow their advice.

All cited sources were thoroughly reviewed by our team to ensure their quality, reliability, currency, and validity. The bibliography of this article was considered reliable and of academic or scientific accuracy.

  • Stephen, M. S. (2014). Psicofarmacología esencial de Stahl: bases neurocientíficas y aplicaciones prácticas (4.ª ed.). Aula Médica. Aula Médica.
  • Miró, E., Iáñez, M. A., & del Carmen Cano-Lozano, M. (2002). Patrones de sueño y salud. International Journal of Clinical and Health Psychology2(2), 301-326.
  • de Castro, F. L., Rodríguez, O. F., Ortega, M. M., & Agüero, L. F. (2012). Abordaje terapéutico del insomnio. SEMERGEN-Medicina de familia38(4), 233-240.

This text is provided for informational purposes only and does not replace consultation with a professional. If in doubt, consult your specialist.