Many people have difficulty falling asleep, but for those suffering from anxiety, PTSD, depression, or chronic pain, insomnia is a major problem that contributes to worsening of symptoms. Your body’s circadian rhythm, exposure to blue light from electronic devices, night shift work schedule, excessive coffee consumption, obesity, and sleep apnea all impact the duration and qualify of sleep. If you have severe insomnia, you should start with lifestyle modifications to improve your sleep, such as adhering to a steady routine, eliminating caffeine from your diet, and reducing TV, phone, and computer use before sleep. However, if these measures are insufficient you may still need medications to improve your quality of sleep.

All medications have side effects and variable efficacy – specific variations in your genes determine how your body processes medications and impact their efficacy and safety.  You may feel groggy and sleepy during the day if your body cannot clear sleep medication effectively, greatly increasing the risk of car and work accidents. If your body clears a hypnotic drug too fast, it would not be as effective, impacting your quality of life. Pharmacogenetics is an evidence-based tool that can help you and your doctor to select appropriate sleep medication and eliminate “trial and error” from the prescribing process.

If you suffer from anxiety, depression, or PTSD, an incorrect antidepressant dose or drug may disrupt your sleep even further. Tricyclic antidepressants (such as nortriptyline) and monoamine oxidase inhibitors (phenelzine) can cause severe nightmares. Bupropion is also thought to cause insomnia. A pharmacogenetic test such as Pillcheck can help find how your body metabolizes these drugs. You can read more about role of pharmacogenetics for selecting optimal antidepressant.  Other antidepressants, such as trazodone, are used for treating anxiety and sleeplessness.

Below we describe how various genes affect response to sleep medications.

Benzodiazepines (diazepam), triazolam (Valium), alprazolam (Xanax), lorazepam (Ativan), and temazepam (Restoril), are used for treating anxiety and insomnia. These medications helping people to stay a sleep longer. Contrastingly, oxazepam is short acting benzodiazepine used to help people fall asleep faster. Each drug may be metabolized by different enzyme, so sleep medication that works well for your spouse may not be a good fit for your metabolism.

Diazepam is metabolized by the CYP2C19 enzyme – 25% of people are Rapid metabolizers for this enzyme and may have reduced response to this medication. However, for 8-12% of people who slow or poor CYP2C19 metabolizers, diazepam would cause excessive sleepiness.

Oxazepam is metabolized by the UGT2B15 enzyme – up to 30% of people may need a lower dose or not use this medication at all due to reduced drug clearance.

Lorazepam, triazolam, alprazolam, and temazepam are metabolized by the CYP3A4 – 11% of people in North America have reduced activity of this enzyme and will experience excessive side effects to these medications.

Benzodiazepines can also cause dependence – i.e., you need to take the drug to be able to fall asleep. As with any addition, careful tapering of benzodiazepines is needed. Always consult with your physician or pharmacist if you decide to stop or re-start a benzodiazepine.

Doxepin is a tricyclic antidepressant that is also approved for treating insomnia. Doxepin works similarly to antihistamines to help with sleep maintenance, and also reduces hives. As other tricyclic drugs, doxepin is metabolized by both CYP2D6 and CYP2C19. Less than 40% of people have normal activity in both enzymes and will respond to this medication as desired. However, the majority may experience with highly variable response to doxepin – pharmacogenetic testing can help to find whether this drug is a good option for you.

Zopiclone (Imovane) and its stereoisomeric form eszopiclone (Lunesta), are hypnotic medications which help people fall asleep quickly. These potent medications significantly increase risk of impairment during the morning and day, therefore, starting with low dose is required.  Zopiclone and eszopiclone are primarily metabolized by CYP3A4 and would not be a good fit for over 11% of people who have inherently reduced activity of this enzyme. Because CYP3A4 metabolizes almost half of all medications, the use of zopiclone or eszopiclone with other medications processed by this enzyme will affect the risk of impairment. Consult with your pharmacist if you are starting any new medication while taking zopiclone.

Suvorexant (Belsomra) works differently from other sleep medications – it acts on the orexin receptors, blocking the orexin hormone that promotes wakefulness. Suvorexant is also metabolized by CYP3A4. Therefore, if you were feeling quite sleepy with alprazolam, lorazepam, triazolam, temazepam, or zopiclone, this medication may also leave you feeling groggy in the morning.

Ramelteon (Rozerem) is a new type of sleep agent that selectively binds to the melatonin receptors and regulates the sleep-wake cycle. Ramelteon can be used long-term because it has lowest risk of dependence or abuse. Similar to melatonin, ramelteon is also metabolized by the CYP1A2 enzyme. CYP1A2 is one of the most inducible cytochromes, and its function is significantly affected by your diet, lifestyle, and genetics. Most people will experience reduced effectiveness of ramelteon if they are smoking or regularly consuming barbequed meat. Any food or even smoke increases CYP1A2 expression and activity, therefore enhancing elimination of ramelteon. 5-10% of people may have mutations in CYP1A2 which reduce or abolish CYP1A2 activity.

Zolpidem (Ambien , Edluar, Intermezzo) aids in the process of falling asleep, and the extended release version helps staying asleep longer. Zolpidem is recommended only as a second line of treatment because it has very high risk of impairment. The FDA warns that you should not drive or operate machinery the day after taking zolpidem, particularly the slow release form because it stays longer in your body. This medication is also available as an oral spray called Zolpimist. Zolpidem is metabolized by three cytochromes: CYP3A4, CYP1A2, and CYP2C9. Because of the more complex drug metabolism (3 cytochromes are involved), your response to zolpidem might be affected by multiple genetic variations you possess, as well as your diet and smoking habits.

In a summary, we provided an overview how genetic variations in different liver enzymes may affect your response to sleep medications and antidepressants. Pillcheck service includes both pharmacogenetic test, and a medication review by an expert clinical pharmacist who can recommend which sleep medication may work better for you.

Selected references:

Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19genotypes and dosing of tricyclic antidepressants.

Hicks JK, Swen JJ, Thorn CF, Sangkuhl K, Kharasch ED, Ellingrod VL, Skaar TC, Müller DJ, Gaedigk A, Stingl JC; Clinical Pharmacogenetics Implementation Consortium.

Clin Pharmacol Ther. 2013 May;93(5):402-8.

OPRM1 Gene Interaction with Sleep in Chronic Pain Patients Treated with Opioids. Margarit C, Ballester P, Inda MD, Roca R, Gomez L, Planelles B, Ajo R, Morales D, Peiro AM. Pain Physician. 2019 Jan;22(1):97-107.

Effects of Genetic Polymorphisms of CYP2B6 on the Pharmacokinetics of Bupropion and Hydroxybupropion in Healthy Chinese Subjects.

Ma H, Zhang W, Yang X, Zhang Y, Wei S, Zhang H, Ma Y, Dang H.

Med Sci Monit. 2018 Apr 11;24:2158-2163.

Diazepam Therapy and CYP2C19 Genotype. Dean L. In: Pratt V, McLeod H, Rubinstein W, Dean L, Kattman B, Malheiro A, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012-.
2016 Aug 25.