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Three Rx pill bottles: Zolpidem interactions
Drug Info

Zolpidem interactions to avoid

Medications that induce drowsiness may increase sedative effects to dangerous levels if taken with zolpidem
Chad Shaffer, MD, medical writer and reviewer for SingleCare
By | Dec. 12, 2023

Key takeaways

  • Any medication that can induce drowsiness, from pain pills to anxiety meds, could turn dangerous when coupled with zolpidem, based on additive sedating effects.

  • Zolpidem is metabolized via our body’s CYP3A4 enzyme, and numerous drugs either stimulate the enzyme, which lessens zolpidem’s effectiveness, or inhibit the enzyme, which could magnify the hypnotic’s action too much.

  • Insomnia and depression often coexist, so it is crucial to understand that selective serotonin reuptake inhibitors (SSRIs) can interact with zolpidem to increase the chance of adverse effects.

  • Alcohol and cannabis products are hazardous for zolpidem users based on the heightened risk of oversedation.

  • If you experience a reaction from zolpidem’s interaction with another drug or substance, get medical help immediately, but better yet, if you recognize that your med list or lifestyle poses a concern with zolpidem, seek out the advice of your healthcare provider right away.

Drug interactions | Food interactions | Other interactions | Avoiding interactions | When to see a doctor

Zolpidem tartrate, better known by its brand names Ambien and Ambien CR, is a famed hypnotic for the treatment of insomnia. It became infamous for reports of sleepwalking and even sleep-driving behaviors by users. Recognition of these next-day events has led to greater caution with the drug’s use and dosing, and just as important, concerns involving side effects have called attention to drug interactions that can escalate adverse reactions. Learning more about zolpidem’s interactions with other medications, alcohol, and disease states could help to keep you out of harm’s way.

Zolpidem drug interactions

Most of the interactions involving zolpidem fall into one of two categories, doubling up on drowsiness-inducing substances or affecting the drug’s metabolism. Otherwise, there are a couple of other notable interactions.

Opioids

Opioid agonist pain relievers commonly cause drowsiness. Combining them with other agents that induce sedation can be a recipe for disaster, with life-threatening reductions in breathing, increased falls, and deaths. The Food and Drug Administration (FDA) even sent a special communication to call attention to this risk. For that reason, it is typically best to avoid combining opiates with zolpidem. Examples of opiates include:

Benzodiazepines

A fast-acting class of anxiety medications, benzodiazepines are known to take the edge off of anxiety and panic symptoms. There is a fine line between reducing those symptoms and feeling overly sleepy, and sometimes that line is crossed even with careful dosing. As you may imagine, taking both a benzodiazepine and zolpidem could certainly overdo it, leading to a dangerous degree of drowsiness. Thus, this combination is generally avoided. Benzodiazepine examples include:

Anticonvulsants

Central nervous system (CNS) depressants is an umbrella category, covering a broad range of medications that cause sedation. Opiates and benzodiazepines fall under this umbrella of CNS depressants, but so do many other drug classes, including antihistamines and anticonvulsants. Seizures medications can cause sleepiness that can become too extreme when coupled with zolpidem. Hence, most times, zolpidem is not prescribed together with anticonvulsants, such as the following. 

Antipsychotics

Another class of CNS depressants, antipsychotics, can be used for more than psychosis; they treat mood disorders like depression and bipolar disorder too. Broader use makes it even more imperative to recognize that they cause drowsiness. This means that they could be hazardous for zolpidem users. Examples of antipsychotics include:

CYP3A4 inhibitors

By inhibiting the enzyme that breaks down zolpidem, CYP3A4 inhibitors heighten the risk of over-sedation with the insomnia medication. The degree of inhibition varies among these meds, some strongly block the enzymes, and others more weakly. A healthcare professional, either your doctor or pharmacist, can guide you on whether a dose adjustment will do or whether complete avoidance of the drug with zolpidem is necessary. Some strong CYP3A4 inhibitors are the following:

CYP3A4 inducers

Stimulating more enzyme degradation of zolpidem means less active drug and less effectiveness. This is what CYP3A4 inducers do. While you may be at less risk of being too drowsy, you may not get the desired benefit from zolpidem for insomnia. The following are examples of strong CYP3A4 inducers:

Melatonin

It is worth mentioning melatonin because although it is not considered a strong CNS depressant, it is a commonly used sleep aid that is available over-the-counter (OTC). Melatonin can interact with zolpidem to create excessive drowsiness. For that reason, combining insomnia remedies can be dangerous and is usually avoided.

Ciprofloxacin

Ciprofloxacin is a popular antibiotic, often used for urinary or intestinal infections. When taken with zolpidem, it can increase the chance of lethargy, and therefore, this combination may best be avoided.

SSRI antidepressants

SSRIs are the first-line treatment for depression. Accordingly, usage rates are relatively high, and with insomnia being common during depression, a scenario is easily imagined in which zolpidem use is considered while taking an SSRI. The trouble is that zolpidem can make SSRI side effects more profound. In addition, the SSRI sertraline can increase the blood levels of zolpidem, making it more likely to produce adverse effects. The medical advice of your healthcare provider is needed to determine whether to use zolpidem with an SSRI. Besides sertraline, other SSRIs include:

Zolpidem food interactions

Taking zolpidem with food can change the absorption and action of the drug. To get a consistent response to the med, you can take zolpidem on an empty stomach.

Zolpidem and grapefruit

Grapefruit juice is actually a CYP3A4 enzyme inhibitor. As you now know, this action leads to more zolpidem and more potential for impairment. The citrus fruit is considered a moderately strong inhibitor of the enzyme, so to be safe, you may be advised to steer clear of grapefruit juice if taking zolpidem.

Other zolpidem interactions

The list goes on when it comes to zolpidem interactions. Whether it’s raising the risk of over-sedation or negating its effectiveness, a number of other pitfalls exist.

Zolpidem and alcohol

Alcohol is, in fact, a CNS depressant. Based on the frank danger, alcohol and zolpidem should not be taken together. Even modest amounts of alcohol could be hazardous in the setting of zolpidem.

If you have a history of alcohol or drug abuse, you could be at higher risk of abusing zolpidem. The Drug Enforcement Administration (DEA) categorizes zolpidem as a controlled substance, meaning that it has significant potential for abuse.

Zolpidem and caffeine

On the flip side, caffeine stimulates our nervous system. It is in direct opposition to a sedative-hypnotic drug like zolpidem. Naturally, caffeine could dampen zolpidem’s effectiveness and propagate your insomnia problem.

Zolpidem and cannabinoids 

Marijuana and cannabinoid-containing products can induce drowsiness. Taking a cannabinoid with zolpidem represents a dangerous mixture. This is a great example of why it is vital that you report all drug and alcohol use to your prescribing healthcare professionals in order to help them recommend the safest therapeutics. 

Zolpidem and St. John’s Wort

St. John’s Wort is an herbal remedy for depression that is not typically advised by healthcare providers, partly because of potential drug interactions. One of those interactions involves zolpidem. St. John’s Wort can lower the blood concentration of zolpidem, rendering it less effective.

Zolpidem and liver disease

Confusion and mental status changes can result from taking zolpidem in the setting of liver disease. Impaired liver function means that zolpidem is not cleared from the body as readily, and higher drug levels can mean more adverse effects of zolpidem. The extended-release Ambien CR could be more problematic by lasting longer.

Zolpidem and respiratory disease

Anyone with sleep apnea or chronic obstructive pulmonary disease (COPD) has more risk from reduced breathing when taking CNS depressants. Myasthenia gravis is a disease that causes muscle weakness, which can also make one sensitive to anything that diminishes the drive to breathe. Zolpidem would be a concern in any of these situations.

Zolpidem and breastfeeding

When a breastfeeding mother takes zolpidem, the drug can be detected in her breast milk. Sedation in the infant is possible as a result. Get medical advice before taking zolpidem if breastfeeding.

How to minimize zolpidem interactions

It cannot be overemphasized how important it is to tell your healthcare team of providers and pharmacists everything that you take. Keep a list and share it, being sure to include prescription drugs, over-the-counter meds, supplements, and psychoactive substances like cannabis and alcohol. Taking an active role in monitoring interactions and communicating concerns can minimize your risk.

When to talk to a healthcare provider about zolpidem interactions

The best time to talk to your doctor about zolpidem interactions is before you even pick up the first prescription. If you are discussing zolpidem as an option for insomnia, be proactive and ask whether it might interact with your other pills, lifestyle, or medical conditions. Honest and direct questions like this should be appreciated by your medical providers as they demonstrate your commitment to being involved in healthcare decision making.