US Pharm. 2010;35(4)(OTC Trends suppl):13-15.  

Serotonin syndrome, or serotonin toxicity, is considered a predictable consequence of excessive stimulation of serotonin receptors in the peripheral and the central nervous system (CNS). The incidence is believed to correspond to the increase in serotonergic agents prescribed.1 Symptoms are generally mild and may be difficult to recognize. A patient may present with mild tremor, myoclonus, anxiety, and restlessness that may continue for weeks or months. Conversely, symptoms may be life threatening, involving mental, autonomic, and neuromuscular characteristics.2,3 See TABLE 1 for examples of symptoms.4,5 Additionally, concomitant medications or comorbid conditions may mask the symptoms of serotonin syndrome. For example, a patient with postlaminectomy syndrome of the lumbar region with thoracic or lumbosacral neuritis or radiculitis may not be able to distinguish ataxia as a symptom of excessive serotonin activity. Many of these patients also receive chronic opioid therapy, which may further mask symptoms, such as diarrhea. The use of multiple CNS depressants may also dampen the mental status changes associated with serotonin syndrome. Ganetsky and Brush suggest that patients taking serotonergic medications chronically may have an excessive serotonergic state that goes undetected until the patient becomes more ill.4

In 1997, it was estimated that 85% of prescribers were unaware of serotonin syndrome.6 While this has likely improved significantly, the number of medications implicated in serotonin syndrome has grown over the past 15 years. Serotonergic agents may have varying mechanisms of action, including agents that increase serotonin synthesis, enhance release of serotonin, inhibit reuptake of serotonin, decrease serotonin metabolism, or exert direct receptor activity.5 TABLE 2 lists classes of agents that are considered serotonergic or have resulted in serotonin syndrome.2,4,5,7-11

This case study demonstrates that close monitoring of patients receiving serotonergic agents and careful evaluation of all medications used are necessary to avoid serious medication misadventures. The 40-year-old male patient with a history of postlaminectomy syndrome was being treated with a serotonin-norepinephrine reuptake inhibitor (venlafaxine) as well as a tricyclic antidepressant (amitriptyline) when an OTC dextromethorphan cough suppressant was added, resulting in serious consequences as a result of excessive serotonergic activity.

Case Report

A 40-year-old while male arrives at the emergency department in a coma and intubated. The patient's past medical history includes hypothyroidism, lung abscess, multiple back surgeries, chronic low back pain, depression, and alcoholism. Social history includes tobacco use of 1 pack per day for 14 years and abstinence from alcohol since 2001. The man denies any illicit drug use and has no known drug allergies. The patient lives with his wife, has no children, and is disabled. He previously installed heating, ventilation, and air conditioning units. Height and weight were not available.

Electronic medication transaction records show that the patient was receiving the following drug regimen at the time of hospitalization:

*  Venlafaxine XR 150 mg twice daily long-term

* Amitriptyline 100 mg/day (a dose increase within approximately 2-4 weeks prior to the hospital admission)

* Dextromethorphan cough syrup (duration and dose unknown; no drug concentrations obtained).

Other oral medications used chronically in the drug regimen were the following:

* Hydrocodone/acetaminophen 7.5 mg/750 mg (5-6 tablets/day, >4 g of acetaminophen/day)

* Quetiapine 150 mg/day

* Gabapentin 3,600 mg/day

* Clonazepam 4 mg/day

* Zolpidem CR 12.5 mg/day

* Levothyroxine 50 mcg/day.

Liver function tests were not performed during the time of admission. Polymorphism for CYP450 2D6 was not done in this case.

The patient was in a coma for 3 days and subsequently developed aspiration pneumonia.  A diagnosis of serotonin syndrome was made. During the course of hospitalization, amitriptyline and dextromethorphan were discontinued, and the patient was treated with supportive care. The patient received antibiotic therapy for aspiration pneumonia and was discharged with the above listed regimen, excluding amitriptyline and dextromethorphan.


Serotonin syndrome (or toxicity) or the spectrum of symptoms associated with excessive serotonergic activity is concentration dependent and is not idiosyncratic. These effects may be seen at therapeutic doses with proserotonergic agents, as a result of drug interactions, or as a result of an overdose with proserotonergic agents.3,12 See TABLE 2.2,4,5,7-11 Typically, the effects or toxicity develops within hours to days of increasing a serotonergic dose or adding a serotonergic agent to a drug regimen already containing a serotonergic medication.13 Patients may have symptoms that are mild and chronic, while others may progress quickly to death.2 Changes in mental status or behavior, neuromuscular changes, and autonomic changes may be seen. See TABLE 1.4,5 

Some medications or combinations that have been implicated in case reports to result in serotonin syndrome are dextromethorphan and paroxetine; dextromethorphan, phenelzine, and clomipramine; and dextromethorphan used recreationally in the absence of another serotonergic agent.2,14,15 Additionally, dextromethorphan toxicity was reported in a patient who received amitriptyline and dextromethorphan concomitantly.16 A diagnosis of serotonin syndrome was not made; however, genotyping showed that the patient was a poor metabolizer via CYP2D6. Reports indicate that 5% to 13.5% of the white population are poor CYP2D6 metabolizers.17 In the current case, the patient was receiving a higher total daily dose (300 mg) of venlafaxine than recommended. In vivo data suggest that venlafaxine is a weak inhibitor of CYP2D6 at a total daily dose of 150 mg.18 However, in vitro data also suggest that CYP2D6 inhibition may be related, in part, to dose, plasma concentration, and baseline isoenzyme activity.19,20 Amitriptyline in vitro appears to be a strong inhibitor of CYP2D6.21 The concomitant administration of dextromethorphan with agents that inhibit CYP2D6 has the propensity to inhibit the metabolism of dextromethorphan and result in toxicity. Forget et al recommend avoiding dextromethorphan use in patients taking a tricyclic antidepressant or other inhibitors of CYP2D6.16 Using the probability scale by Naranjo, there is a probable relationship between serotonin syndrome and the concomitant administration of venlafaxine, amitriptyline, and dextromethorphan.22

Recommendations for avoiding a recurrence of serotonin syndrome include avoiding additional serotonergic agents in the drug regimen and adjusting the current medication dosing based on renal or hepatic impairment if appropriate. It is paramount that the patient be counseled on the use of any additional prescription medication or OTC products. A drug interaction evaluation should be completed prior to initiation of any new agent to the regimen.


Polypharmacy is not uncommon in patients who are being treated for chronic pain. Drug therapy often includes a neuropathic co-analgesics and/or antidepressants such as venlafaxine concomitantly with low-dose amitriptyline for neuropathic pain. It is important for practitioners to remain vigilant regarding the use of agents that increase serotonergic activity by blocking receptor reuptake or mimicking serotonin activity. Because dextromethorphan is OTC, a patient may bypass a discussion with a health care professional concerning its use. Patients prescribed medications with the potential to precipitate serotonin syndrome must be well educated about their medications and coached to consult a pharmacist or physician prior to the addition of any new prescription or OTC medication, herbal product, or dietary supplement to the medication regimen. Symptoms associated with serotonin toxicity should also be conveyed to the patient if concomitant administration of serotonergic medications is required. Since dextromethorphan is readily available and is commonly recommended to treat a cough, it is prudent that the patient be advised of the risks associated with the use of dextromethorphan in combination with other serotonergic agents or with agents that inhibit CYP2D6. It is critical that practitioners be diligent in monitoring patient therapies and be mindful of the subtle symptoms of serotonin syndrome.


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