Dextromethorphan misuse and poisoning: Clinical features and diagnosis

INTRODUCTION — The epidemiology, pertinent pharmacology, and clinical features of dextromethorphan poisoning will be reviewed here. The treatment of dextromethorphan poisoning is discussed separately. (See "Dextromethorphan poisoning: Management".)

EPIDEMIOLOGY — Approximately one million United States youth and young adults (age 12 to 25 years) misuse over-the-counter (OTC) cough and cold medicines that contain dextromethorphan (DXM) each year [1]. Nonmedical use of DXM results in approximately 6000 emergency department (ED) visits annually in the United States [2]. Adolescents (age 12 to 20 years) account for almost 50 percent of ED visits. Co-ingestion of ethanol is frequently seen. Reports from other countries suggest that DXM misuse is prevalent outside of the United States as well [3,4].

Initially introduced in tablet form during the late 1950s as the OTC cough suppressant Romilar, DXM has a long history of misuse. Because of diversion to recreational use, Romilar was removed from the OTC market in 1973 [5,6]. Subsequently, pharmaceutical companies introduced liquid formulations that were designed to reduce misuse by creating an unpleasant taste if ingested in large amounts [6]. Before geltabs became more widely available, it took approximately one bottle of cough syrup to achieve a euphoric effect [7].

Recreational DXM misuse is known as "going pharming," "Dexing," "Robodosing," or "Robotripping" among adolescent and adult users [8-10]. Myriad slang terms exist for DXM based upon tablet appearance and their similarities with popular candies (table 1) [8,9].

In 2006, Coricidin, Nyquil, and Robitussin formulations accounted for almost 66 percent of reported instances of DXM misuse among United States persons between the ages of 12 to 25 years [1]. These cough medicines often combine DXM with acetaminophen, antihistamines, or decongestants [7,8,11-15]. In order to extract DXM from unwanted products in combination cold preparations, individuals sometimes perform a two-phase acid base extraction technique using common household products ("Agent Lemon" technique) [16]. This technique was applied quantitatively to 295 mL of a combination cough and flu medication and found to markedly reduce the amount of acetaminophen and pseudoephedrine in the final product while yielding significant quantities of DXM and doxylamine [17]. Others prefer a single phase acid base extraction technique that results in a substance known as "Crystal Dex" [16].

DXM may encourage initiation and progression of substance use in adolescents [18]. Some younger adolescents consider DXM to be a harmless and legal high [19]. Because it is easily available and produces an intense effect, DXM may entice young users to experience broader and illicit substance use experiences [19]. For example, among young adults who ever misused DXM, 82, 49, and 44 percent reported use of cannabis, inhalants, or hallucinogens (eg, lysergic acid diethylamide [LSD], phencyclidine [PCP], 3,4-methylenedioxymethamphetamine [ecstasy, MDMA]), respectively [1].

PHARMACOLOGY AND CELLULAR TOXICOLOGY — Dextromethorphan (DXM) is the D- isomer of the codeine synthetic analog, levorphanol. DXM also contains an alkylated amine adjacent to a cyclohexane ring, a chemical structure that is seen in other dissociative agents (eg, ketamine, phencyclidine [PCP]). (See "Ketamine poisoning" and "Phencyclidine (PCP) intoxication in children and adolescents".)

Indications — DXM is marketed as a nonsedating and non-habit-forming cough suppressant.

Formulation — There are over 140 products that contain DXM available worldwide, including:

●Combination cough syrups (concentration range 5 to 40 mg per 5 mL, often combined with antihistamine, acetaminophen, guaifenesin and/or pseudoephedrine)

●Sustained release cough syrup suspensions (eg, Delsym, 30 mg per 5 mL)

●Liquid filled capsules (15, 30 mg)

●Oral strips (7.5, 15 mg)

●Lozenges (5, 7.5, 10 mg)

Toxic dose — DXM toxicity occurs in a dose dependent fashion. Neurobehavioral effects typically begin 30 to 60 minutes post-ingestion and persist for up to six hours [20]. The different stages of effect are often referred to as "plateaus" by users [21,22], and are listed below along with the approximate range of doses associated with them:

●Mild stimulation (first "plateau"): 1.5 mg/kg (adult dose: 100 to 200 mg)

●Euphoria and hallucinations (second "plateau"): 2.5 to 7.5 mg/kg (adult dose: 200 to 400 mg)

●Dissociative "out of body" state (third "plateau"): 7.5 to 15 mg/kg (adult dose: 300 to 600 mg)

●Complete dissociation with unresponsiveness (fourth "plateau"): 15 mg/kg (adult dose: >600 mg)

DXM may produce a life-threatening serotonin syndrome when co-ingested with monoamine oxidase inhibitors or other serotonergic agents (eg, serotonin specific reuptake inhibitors, meperidine, cocaine) (table 2), even in a regular daily dose. (See "Serotonin syndrome (serotonin toxicity)".)

DXM cough and cold products frequently contain acetaminophen, antihistamines, or pseudoephedrine that has significant toxic potential as well. (See 'Co-ingestant findings' below and "Anticholinergic poisoning" and "Acetaminophen (paracetamol) poisoning: Management in adults and children".)

Mechanism of action — In regular daily dosing, DXM's antitussive effect derives from the binding of sigma opioid receptors in the medulla by the active metabolite, dextrorphan. Because of its stereochemistry, DXM and its metabolites do not bind the mu and delta opioid receptors, thus avoiding classic opioid toxicity [23]. Dextrorphan also has serotonergic activity at the 5-hydroxytryptophan 2 receptor which explains why a regular dose of DXM can cause serotonin syndrome, especially when co-ingested with other serotonin agonists (eg, monoamine oxidase inhibitors) [24-26]. (See "Serotonin syndrome (serotonin toxicity)".)

In overdose, the active metabolite, dextrorphan, inhibits N-methyl-d-aspartate (NMDA) receptors. This action results in neurobehavioral effects similar to ketamine and phencyclidine (PCP) including hallucinations, "out of body" sensation, and dissociation. DXM also inhibits adrenergic neurotransmitter reuptake in the peripheral and central nervous system resulting in tachycardia, hypertension, and diaphoresis [18,27-29].

KINETICS — The pharmacokinetics of dextromethorphan (DXM) are as follows [18,23,30-33]:

●DXM is well absorbed with peak serum concentration occurring 2.5 hours after oral ingestion of a regular dose [18]. Volume of distribution is estimated at 5 to 6.7 L/kg.

●DXM undergoes metabolism in the liver via cytochrome CYP2D6 to dextrorphan (primary active metabolite) and 3-methoxymorphinan [18,31,33].

●Peak plasma concentration of the active metabolite, dextrorphan, is achieved at 1.6 hours.

●Average half-life of the parent compound in therapeutic use is approximately three hours in individuals who are rapid metabolizers and 30 hours in slow metabolizers [34]. DXM and its metabolites, dextrorphan and 3-methoxymorphinan, are almost exclusively renally excreted [32].

The neurobehavioral effects of DXM are primarily mediated by the action of the metabolite, dextrorphan at the N-methyl-d-aspartate (NMDA) receptor. Individual response to DXM ingestion is strongly affected by the genetically determined activity of the CYP2D6 enzyme. Approximately 85 percent of the US population have high CYP2D6 activity and would be expected to rapidly develop high dextrorphan concentrations after overdose. Medications that inhibit cytochrome CYP2D6 (eg, monoamine oxidase inhibitors, fluoxetine, paroxetine, and haloperidol) increase DXM concentrations, decrease dextrorphan concentrations, and thus dampen the associated neurobehavioral effects [23]. (See 'Mechanism of action' above.)

CLINICAL FEATURES

History — Historical features of dextromethorphan (DXM) poisoning vary significantly by age.

Youth and adults — DXM misuse is most frequent in adolescents and young adults [1]. These patients often arrive in the emergency department (ED) with altered mental status and may not provide a history. Witnesses of the ingestion or emergency medical services (EMS) personnel, who may have recovered containers at the scene, should be interviewed in this setting. Key information includes the specific DXM containing substance, amount ingested, time of ingestion, and co-ingestion of ethanol, serotonergic agents (especially ecstasy [3,4-methylenedioxymethamphetamine]), or other recreational drugs.

Additional history should identify the likelihood of trauma (particularly head trauma) and rape. Often, EMS reports regarding the environment in which the patient was found and whether the patient was partially or fully undressed can assist in identifying physical or sexual assault.

Up to 14 percent of DXM overdoses in teenagers and young adults seen in the emergency department are part of a suicide attempt [2]. Thus, direct questioning regarding suicidal intent should occur in all intentional DXM ingestions. If suicidal ideation is present, further mental health evaluation is indicated after the patient recovers from the intoxication.

Children — Infants and young children intoxicated by DXM, may also present with an intercurrent viral illness and sudden change in behavior. Fever is variably present. The caretaker should be carefully questioned about the use of over-the-counter (OTC) medications including the exact name of the medication, the amount of medication being given, and the frequency of dosing. Although OTC cough and cold medications intended for use in children under two years of age have been removed from the United States market, caregivers may still have supplies at home or may give liquid formulations intended for older children.

Exploratory ingestions of OTC cough and cold medications occur frequently in young children. As a general rule, ingestion of an amount that is less than the estimated total daily dose for the child does not produce significant toxicity other than self-limited lethargy [35]. In this circumstance, caretakers should also be questioned regarding other medications in the house and asked to check the home for signs of other toxic exposures. The patient's or caretaker's pharmacy may provide valuable information regarding prescribed medications available for ingestion, the date of the most recent refill, and the total number of pills dispensed. (See "Over-the-counter cough and cold preparations: Approach to pediatric poisoning", section on 'Dextromethorphan'.)

Physical examination

Acute overdose — Following acute overdose DXM produces several characteristic physical findings that may be variably present depending on the dose ingested [7,8,21,28,29,36] (see 'Toxic dose' above):

●Neurobehavioral changes that include euphoria, hallucinations, inappropriate laughing, psychosis with dissociative features, agitation, and coma

●Tachycardia

●Dilated pupils

●Diaphoresis (in the absence of anticholinergic co-ingestion)

●"Zombie-like" ataxic gait

Tachycardia is such a consistent finding that its absence should call in to question the diagnosis of DXM intoxication unless the patient is also taking another agent (eg, beta-blocker, calcium channel blocker, digoxin) that would prevent tachycardia.

Agitation in association with severe DXM intoxication may also result in hyperthermia and metabolic acidosis with potential for rhabdomyolysis [7,8,21,28,29].

DXM may precipitate serotonin toxicity/syndrome (altered mental status, seizures, autonomic instability, and/or muscular hypertonicity (algorithm 1)) in overdose and when combined with monoamine oxidase inhibitors, serotonin specific reuptake inhibitors, linezolid, meperidine, tramadol, and other serotonergic agents [25,37]. (See "Serotonin syndrome (serotonin toxicity)".)

Nystagmus is sometimes seen, but this finding may also indicate serotonin toxicity/syndrome, ethanol intoxication, anticonvulsant overdose, ketamine toxicity, or PCP exposure.

Respiratory depression and apnea have occurred in infants and young children [38,39]. Dystonia responsive to diphenhydramine has also been described [29,36].

Co-ingestant findings — In addition to DXM, over-the-counter cough formulations frequently contain other pharmaceutical agents such as chlorpheniramine or other antihistamines, acetaminophen, or pseudoephedrine whose toxicity may complicate DXM poisoning [40] (table 3):

●Co-ingestion of antihistamines with high H1-receptor antagonist properties (eg, chlorpheniramine) can cause features of anticholinergic (antimuscarinic) poisoning such as tachycardia, hypertension, hyperthermia, flushing, warm and dry skin, sluggishly reactive pupils, delirium, and agitation (table 4). Rarely, seizures and rhabdomyolysis may occur [8]. (See "Anticholinergic poisoning".)

●Alpha-1 adrenergic agonist decongestants (eg, phenylephrine or pseudoephedrine), typically causes tachycardia or reflex bradycardia with hypertension. Headache, agitation, and hypertensive emergency may develop in patients with severe toxicity. (See "Phenylephrine and related decongestants: Pediatric poisoning", section on 'Clinical features and diagnosis'.)

●Acetaminophen is commonly present in cough and cold preparations. Although it rarely causes immediate symptoms, acetaminophen has high potential to cause severe delayed hepatotoxicity, hepatic failure, and death. It is imperative for the emergency provider to obtain an acetaminophen concentration in all patients with serious DXM exposure in order to detect this threat. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation" and "Acetaminophen (paracetamol) poisoning: Management in adults and children".)

Signs of chronic use — A rapidly progressive tolerance is frequently described by experienced DXM users [6,21,41,42]. Repeated DXM use has also been associated with toxic psychosis and cognitive deterioration [41,43-45]. In addition, habitual use and craving may occur in susceptible individuals [7,46]. Abrupt cessation of DXM in these patients may result in dysphoria and intense craving [41-44].

Because DXM is produced as the crystalline hydrobromide salt, bromism marked by fatigue, ataxia, headache, and memory loss is a rare consequence that has also been observed in heavy chronic users of DXM [47]. A negative anion gap or elevated chloride concentration on serum laboratory testing should raise the concern for bromism [48].

ANCILLARY STUDIES

Acetaminophen concentration — A serum acetaminophen concentration should be obtained in all patients with dextromethorphan (DXM) exposure, including asymptomatic patients, unless co-ingestion of acetaminophen can be reliably excluded. Serum acetaminophen should also be obtained in patients who ingested DXM with suicidal intent.

The serum acetaminophen concentration should be measured between 4 and 24 hours after a single acute overdose of an immediate-release preparation and plotted on the modified Rumack-Matthew nomogram (figure 1) to determine the need for antidotal therapy with N-acetylcysteine. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'General approach and laboratory evaluation' and "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Acetaminophen concentration'.)

Other studies — Further laboratory evaluation of DXM intoxication varies depending on the clinical findings. Other ancillary studies may be indicated in selected patients in whom ingestion of other toxic agents, trauma, or sexual assault are suspected. (See "Evaluation of stupor and coma in children" and "Approach to the child with occult toxic exposure" and "Trauma management: Approach to the unstable child" and "Evaluation and management of adult and adolescent sexual assault victims in the emergency department" and "Testing for drugs of abuse (DOAs)", section on 'Drug-facilitated sexual assault'.)

We suggest the following tests in patients with altered mental function and suspected DXM overdose:

●Bedside glucose determination, to exclude hypoglycemia as the cause of altered consciousness.

●Arterial or venous blood gas measurement and continuous pulse oximetry to evaluate the adequacy of ventilation in patients with serious and persistent central nervous system depression.

●Serum electrolyte determination to assess for electrolyte disturbance and to calculate the anion gap in the setting of likely co-ingestants or evidence for metabolic acidosis. A negative anion gap or elevated chloride concentration should prompt a consideration for possible bromism [48].

●Serum blood urea nitrogen and creatinine to identify patients with renal insufficiency who may have delayed elimination of DXM and its metabolites after overdose.

●Liver enzyme studies (aspartate transferase [AST], alanine transferase [ALT]) to determine presence of liver injury; if abnormal, prothrombin time (PT) and partial thromboplastin time (PTT) to establish baseline values.

●Serum creatine phosphokinase in patients with agitation, seizures, or likely serotonin syndrome to diagnose rhabdomyolysis. Urine tests that are supportive but not diagnostic for rhabdomyolysis include reddish brown discoloration, rapid urine dipstick that is positive for heme, and the presence of urine myoglobin. (See "Rhabdomyolysis: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

●Serum ethanol concentration, to identify patients at a higher risk for coma with respiratory depression due to co-ingestion of DXM and ethanol.

●A plasma salicylate concentration, especially in patients with altered mental status, tachypnea, tachycardia, vomiting, or evidence for an anion gap metabolic acidosis. (See "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation", section on 'Clinical manifestations'.)

●Rapid urine toxicology screen for drugs.

●Rapid urine pregnancy test in postmenarchal women.

●Electrocardiogram (EKG), to evaluate for drug-induced cardiac electrical dysfunction (especially sodium channel blockade [eg, prolonged QRS complex and/or significant R wave in lead aVR] or QTc prolongation) [49].

●Chest radiography, if the history or exam suggests the possibility of pulmonary aspiration.

Role of dextromethorphan testing — DXM poisoning is usually diagnosed based on history and clinical findings. Commonly available rapid urine drug screens rely on immunoassay techniques that do not detect DXM [18]. However, DXM will frequently cause a false positive for phencyclidine (PCP) on rapid tests that utilize liquid chromatography [50-52].

Quantitative and qualitative testing for DXM is available from dedicated toxicology reference laboratories with methodology such as gas chromatography or mass spectroscopy. However, the results usually cannot be obtained in time to be useful for patient management. Thus, specific measurement of DXM in the blood or other fluids is typically performed only for forensic or other nonclinical purposes.

DIAGNOSIS — Dextromethorphan (DXM) poisoning is a clinical diagnosis. The emergency provider should suspect DXM ingestion in youth, young adults, and adults who have abrupt change in behavior associated with hallucinations, gait disturbance, and clinical findings of sympathetic stimulation (dilated pupils, tachycardia, and diaphoresis). Infants and young children may have an acute onset of altered mental status ranging from coma to irritability.

The clinical diagnosis of DXM poisoning may also be supported by a false positive for phencyclidine (PCP) on rapid tests that utilize liquid chromatography as well as a negative anion gap or elevated chloride (in setting of bromism). Quantitative and qualitative testing for DXM is available but not usually performed for diagnostic purposes. (See 'Role of dextromethorphan testing' above.)

DIFFERENTIAL DIAGNOSIS — There are many causes of neurobehavioral changes with psychotic features that deserve consideration when evaluating the patient with suspected dextromethorphan (DXM) poisoning (table 5 and table 6). In the poisoned patient, it is especially important to consider hypoglycemia and potential traumatic brain injury. The approach to acute onset psychosis in children is discussed in detail separately. (See "Emergency department approach to acute-onset psychosis in children".)

Toxicologic causes of ataxia, nystagmus, and mental status changes include ethanol (a common co-ingestant with DXM), ketamine, phencyclidine (PCP), methoxetamine, lithium, phenytoin, or carbamazepine. The clinical findings after overdose of these agents may be very similar. The specific agent causing toxicity can be identified by history; serum concentrations of ethanol, lithium, phenytoin, and carbamazepine; and rapid urine testing for PCP. (See "Ethanol intoxication in children: Clinical features, evaluation, and management" and "Ethanol intoxication in adults" and "Phencyclidine (PCP) intoxication in children and adolescents" and "Phencyclidine (PCP) intoxication in adults" and "Intoxication from LSD and other common hallucinogens" and "Ketamine poisoning" and "Lithium poisoning" and "Carbamazepine poisoning" and "Phenytoin poisoning".)

Wernicke-Korsakoff syndrome, serotonin syndrome from agents other than DXM, and abstinence syndromes (eg, ethanol withdrawal) have findings that overlap significantly with DXM toxicity, but are more commonly seen in adults [6]. A history of alcohol use disorder or ingestion of another serotonergic agent is essential to recognize these conditions. (See "Wernicke encephalopathy", section on 'Clinical manifestations' and "Management of moderate and severe alcohol withdrawal syndromes", section on 'Delirium tremens' and "Serotonin syndrome (serotonin toxicity)", section on 'Clinical features'.)

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse" and "Society guideline links: Poisoning prevention".)

SUMMARY AND RECOMMENDATIONS

●Pharmacology - Dextromethorphan (d-3-methoxy-N-methylmorphinan, DXM) is an over-the-counter (OTC) cough suppressant that is commonly diverted for illicit recreational use among teenagers and young adults. While structurally related to the opioid receptor agonist codeine, DXM in overdose expresses a unique combination of euphoric, stimulant, and dissociative effects in older children and adolescents that is similar to ketamine and phencyclidine (PCP). (See 'Epidemiology' above and 'Pharmacology and cellular toxicology' above.)

●Toxic dose and onset – DXM toxicity occurs in a dose dependent fashion. Neurobehavioral effects typically begin 30 to 60 minutes after ingestion and persist for up to six hours. (See 'Toxic dose' above.)

●Manifestations in children – In infants and children, DXM poisoning may follow excessive dosing by a caregiver in attempts to treat an upper respiratory illness. Exploratory ingestions in young children and infants usually have minimal symptoms but have the potential to cause marked respiratory depression and apnea. (See 'Children' above and 'Physical examination' above.)

●Manifestations in adolescents and adults – Prominent clinical findings of DXM overdose in teenagers and adults consist of neurobehavioral changes (eg, euphoria, hallucinations, inappropriate laughing, psychosis with dissociative features, agitation, and coma), tachycardia, dilated pupils, diaphoresis, and "zombie-like" ataxic gait. (See 'Clinical features' above and 'Physical examination' above.)

●Risk of serotonin syndrome (serotonin toxicity) – DXM may also precipitate serotonin syndrome (altered mental status, seizures, autonomic instability, and muscular hypertonicity) alone in overdose and in regular daily dosing when inappropriately combined with monoamine oxidase inhibitors, serotonin specific reuptake inhibitors, linezolid, meperidine, tramadol, and other serotonergic agents (table 2). (See "Serotonin syndrome (serotonin toxicity)" and 'Physical examination' above.)

●Potential for co-ingestants – With DXM poisoning, additional toxicity derives from the ingestion of other ingredients in common OTC cough and cold medications such as acetaminophen, antihistamines, and decongestants (table 3). (See 'Formulation' above and 'Co-ingestant findings' above.)

●Diagnosis – The diagnosis of DXM poisoning depends upon recognition of the clinical presentation and exclusion of other causes for acute psychosis, especially hypoglycemia and hypoxia (table 5 and table 6). (See 'Diagnosis' above and 'Differential diagnosis' above.)

●Treatment – The treatment of DXM poisoning is discussed separately. (See "Dextromethorphan poisoning: Management".)