[2][11][6] Side effects of suvorexant include somnolence, daytime sleepiness and sedation, headache, dizziness, abnormal dreams, dry mouth, and impaired next-day driving ability.

[6][34][9][36] Lower approved doses of suvorexant in the United States in the range of 5 to 10 mg were not extensively evaluated in clinical trials.

[37] Orexin receptor antagonists are not used as first-line treatments for insomnia due to their costs and concerns about possible misuse liability.

[2] Suvorexant has shown teratogenic effects in animals such as decreased body weight at doses much higher than the equivalents of those approved for therapeutic use in humans.

[2][39] Teratogenic effects with therapeutic doses of suvorexant in humans have not been established due to lack of research and available data.

[9][2] Besides the clinical trial data, a case report of rapidly worsened depression and onset of suicidal ideation with suvorexant has been published.

[2] Besides the side effect of daytime somnolence, suvorexant may dose-dependently reduce alertness and motor coordination and impair driving ability.

[2] In another study in elderly people who were awakened in the night, impaired balance was present at 1.5 hours after taking 30 mg suvorexant whereas memory was unaffected.

[2] A 2017 systematic review and meta-analysis of suvorexant for the treatment of insomnia found that the medication significantly increased the rate of somnolence by 3.5-fold, daytime sleepiness/sedation by 3.1-fold, fatigue by 2.1-fold, abnormal dreams by 2.1-fold, and dry mouth by 2.0-fold.

[8] Tolerance, dependence, withdrawal, and rebound effects do not appear to occur with suvorexant in the treatment of insomnia at studied doses.

[42][12][13] The orexin neuropeptides augment the signaling of the mesolimbic dopamine reward pathway and are thought to potentiate hedonic tone.

[43][44][22][45] In line with these findings, suvorexant and other orexin receptor antagonists have not shown misuse liability in animal studies in rats and non-human primates.

[19][46][47][48] Paradoxically however, orexin receptor antagonists, including suvorexant, lemborexant, and daridorexant, have consistently shown drug-liking responses in human studies of recreational sedative users.

[2][6][19] Besides its subjective side effects, suvorexant has been found to cause dose-dependent increases in serum cholesterol levels in clinical trials.

[2][25] Although the increases in cholesterol levels with approved doses of suvorexant (10–20 mg) are small, they could be important over a long duration of treatment.

[52][53][6] In humans, orexin receptor antagonists including suvorexant have not been found to affect body weight in rigorous clinical trials that lasted up to 12 to 14 months.

[2][5][54] Examples of important CYP3A4 modulators which are expected to interact with suvorexant include the strong CYP3A4 inhibitors boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, and telithromycin (concomitant use not recommended); the moderate CYP3A4 inhibitors amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fosamprenavir, grapefruit juice, imatinib, and verapamil (lower doses of suvorexant recommended); and the strong CYP3A4 inducers apalutamide, carbamazepine, efavirenz, enzalutamide, phenytoin, rifampin, and St. John's wort (expected to decrease suvorexant effectiveness).

[2][57] The orexin neuropeptides are produced exclusively by a relatively small population of 20,000 to 80,000 neurons located in the lateral hypothalamus in the brain.

[66][65] There is an 80 to 100% loss of orexin-producing neurons in the lateral hypothalamus and very low or undetectable levels of orexin-A in cerebrospinal fluid in people with narcolepsy.

[57] An animal study of chronic high-dose suvorexant administration that showed development of narcolepsy-like changes suggests that this may be possible however.

[71] Endogenous orexinergic tone is expected to play an important moderating influence in terms of the effects of orexin receptor modulators.

[2] Suvorexant exposure with a single dose is not greater in people with moderate hepatic insufficiency compared to healthy individuals.

[6][9] Orexin receptor antagonists with shorter half-lives and faster onsets of action are theoretically more optimal for therapeutic use as sleep aids.

[11] Suvorexant is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, and JANTooltip Japanese Accepted Name.

[1] Public Citizen, a progressive consumer rights advocacy group, issued a letter in June 2013 urging the FDA not to approve suvorexant.

[25] In its reasoning, it cited marginal benefits and excessive potential for harm, including next-day effects like driving impairment and possible accidents.

[91][30] A phase IV clinical trial of suvorexant as an adjunct to antidepressant therapy in people with major depressive disorder and residual insomnia was underway as of 2019.

[30][93] Although orexin receptor antagonists including suvorexant could be useful for treatment of depression and anxiety, there is also indication that they could have harmful effects in these conditions (e.g., animal studies and suicidal ideation in clinical trials).

[40][46][59] More clinical research is needed to determine the place of orexin receptor antagonists in the treatment of people with depression and anxiety.

[92][100] Suvorexant has been studied in people with type 2 diabetes and insomnia and has been reported to improve sleep and metabolic parameters in these individuals.