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Acute Cannabis Toxicity

Wong, Kei U. MD*; Baum, Carl R. MD, FAAP, FACMT

doi: 10.1097/PEC.0000000000001970
CME Review Article
Free
CME

The change in legal status of cannabis (the botanical species Cannabis sativa, commonly known as marijuana) in the United States has had significant impact on pediatric drug exposures. In states with decriminalization of recreational and medicinal use of cannabis, emergency department visits and poison control center calls for unintentional pediatric cannabis intoxication are on the rise in the last few decades. Exploratory or unintentional ingestions of cannabis-containing products (as opposed to those derived from synthetic cannabinoids, which may mimic the structure and/or function of cannabis, but are not the focus of this article) can lead to significant pediatric toxicity, including encephalopathy, coma, and respiratory depression. With the increasing magnitude of the public health implications of widespread cannabis use, clinicians who care for pediatric patients routinely must be adept in the recognition, evaluation, management, and counseling of unintentional cannabis exposure.

*Fellow (Wong), Department of Pediatrics

Professor (Baum), Departments of Pediatrics and Emergency Medicine, Section of Pediatric Emergency Medicine, Yale School of Medicine, New Haven, CT.

The authors, faculty, and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interest in, any commercial organizations relevant to this educational activity.

Reprints: Kei U. Wong, MD, Section of Pediatric Emergency Medicine, Department of Pediatrics, School of Medicine, Yale University, 100 York St (Suite 1F), New Haven, CT (e-mail: Kei.Wong@yale.edu).

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TARGET AUDIENCE

This continuing medical education activity is intended for physicians, nurse practitioners, physician assistants, and emergency medical services personnel who care for pediatric patients in the prehospital, emergency, or primary care settings.

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LEARNING OBJECTIVES

After completion of this article, the reader should be better able to:

  1. Understand the background, mechanism of action, and toxicity of cannabis use.
  2. Evaluate and manage patients with suspected acute intoxication of cannabis.
  3. Discuss the medicolegal status of cannabis.

Cannabis, derived from the Cannabis sativa plant, is the most commonly used illicit drug (the terms cannabis and the common name, marijuana, are often used interchangeably).1 According to the National Survey on Drug Use and Health in 2016, an estimated 24 million Americans aged 12 years or older (approximately 6.5% among 12- to 17-year-olds) were current users of cannabis.2 Although cannabis remains a schedule I substance (ie, no currently accepted medical use and a high potential for abuse) under the Controlled Substances Act of the United States, as of November 2018, 10 states have been decriminalized recreational use, and an additional 22 states have decriminalized medicinal use of cannabis-containing products.3

The changes in cannabis legalization in the United States has had significant impact on pediatric exposures.1,3,4 Emergency department (ED) visits for cannabis have increased for both adults and adolescents, with rates doubled in those age 12 to 17 years between 2004 and 2011.5 From 2002 to 2015, the prevalence of cannabis use by parents with children in their home has also increased from 4.9 to 6.8%.3,6,7 Wang et al8–11 reported that exploratory ingestions in children younger than 10 years nearly doubled from 1.2 to 2.3 per 100,000 population with decriminalization, whereas cannabis-related ED visits among adolescents have increased from 1.8 to 4.9 per 1000 visits in Colorado.3

The increase in unintentional pediatric exposures is likely multifactorial: it is most certainly related to the increased availability, diverse modes of delivery, and improved palatability of cannabis.1 Over the last few decades, the potency of cannabis-containing products has increased substantially.4,12 In the 1980s, the percentage of the active ingredient, Δ-9-tetrahydrocannabinol (THC), in recreational marijuana was 4%, but it had increased to 12% by 2012.13–16 Because access to cannabis rises, providers who care for pediatric patients routinely face new challenges of counseling patients and their caregivers about the risk of cannabis exposure, as the perceptions of this drug have changed.3,6,7,12,16

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MECHANISM OF ACTION

The C. sativa plant exists in various forms, such as marijuana (dried, crushed flower heads, and leaves), hashish (resin), and hash oil (concentrated resin extract), which can be smoked, inhaled, or ingested.17,18 Cannabis contains over 500 chemical components called cannabinoids, which exert their psychoactive effect on specific receptors in the central nervous system and immune system.19–21 The 2 best-described cannabinoids are THC and cannabidiol (CBD).22 Most of the other compounds are not yet understood, and their mental and physical effects are unknown.15,19,22 The THC is the active ingredient of the cannabis plant that is responsible for most symptoms of central nervous system intoxication, in contrast to CBD, the main nonpsychoactive component of marijuana.1,19,20,22,23 The potency of cannabis is usually based on the THC content of the preparation.14,15,19,22,23

The THC is lipid soluble and highly protein bound and has a volume of distribution of 2.5 to 3.5 L/kg.19,20,23 It is the main psychoactive ingredient that binds to brain cannabinoid receptors, producing dose- and time-dependent stimulant, hallucinogenic, or sedative effects.21,22 It can produce wide-ranging symptoms and signs involving the neurological (euphoria, disorientation, impaired memory, ataxia, stupor or coma), ophthalmological (dilated and sluggish pupils with injected conjunctivae), cardiovascular (tachycardia), and gastrointestinal (nausea, vomiting, increased appetite, or thirst) systems.4,19

There are 2 known cannabinoid receptors: CB-1 and CB-2. The CB-1 is a G-protein coupled receptor that provides inhibitory modulation of neurotransmitters, including norepinephrine, dopamine, serotonin, γ-aminobutyric acid, and acetylcholine. The CB-1 receptors are found in high densities in the cerebellum, basal ganglia, cerebral cortex, and hippocampus.1,3,20,23–26 The action of cannabinoids at these locations is thought to contribute to cannabis' ability to produce the cognitive and motor impairment of cannabinoid toxidrome.19,23,24

Over the past several decades, there has been an emergence of new, synthetic chemical analogs of THC, sometimes referred to as synthetic cannabinoids receptor agonists. These synthetic cannabinoids may have been available in Europe as early as 2004 and were first reported in the United States in December 2008.20,27–29 Initially developed for research purposes to study the CB-1 receptor and its biological activity, these synthetic cannabinoids are structurally unrelated and have a different pharmacodynamic profile (higher CB-1 receptor binding affinity and agonist activity) than their plant-derived predecessors.30 Synthetic cannabinoids may also produce clinical findings not encountered with consumption of cannabis.3,7 Currently, federal regulation of synthetic cannabinoids lags behind their rapid clandestine development, as drug manufacturers have changed certain aspects of the structure that complicate detection by reference toxicology laboratories.27,28 Synthetic cannabinoids are easy to obtain and often remain undetected on drug testing, which may encourage adolescent abuse.20,31

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Pharmacokinetics by Route of Use (Inhalation vs Ingestion)

The psychotropic effects of THC vary by route and quantity of exposure (Table 1). Cannabis can be consumed through inhalation (smoking or vaporization) and oral ingestion, as well as via transcutaneous, rectal, and vaginal routes.13,20,22

TABLE 1

TABLE 1

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Inhalation

Compared with other forms of consumption, smoking cannabis has the highest addictive potential owing to rapid and efficient drug delivery to the brain.11,13 Because THC is highly lipophilic, the serum concentrations peak within 15 to 30 minutes and have a duration of up to 4 hours. The THC undergoes rapid hepatic metabolization, which renders blood analysis impractical.17,19,23 The psychotropic effects of smoked cannabis mirror plasma THC concentrations. Pulmonary THC bioavailability varies from 10% to 35% of an inhaled dose and is determined by the depth of inhalation along with the duration of breath holding.17,19,22,23,32 Approximately 2 to 3 mg of inhaled THC is sufficient to produce drug effects in a naive user. The psychotropic effects of THC continue long after the serum concentrations become undetectable.17,19,20,23,32

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Ingestion

When compared with inhalation, orally consumed cannabis has lower bioavailability (5%–20%) because of chemical degradation in gastric acid and substantial first-pass metabolism in the liver.17,19,21,33 Cannabis ingestion has a delayed onset of psychoactive effects that ranges from 30 minutes to 3 hours, lasting up to 12 hours. The peak THC concentration typically occurs within 1 to 2 hours but may be as long as 8 hours after oral consumption.13,20,22,33 In naive users, psychotropic effects occur with 5 to 20 mg of ingested THC.22,32

The THC metabolism occurs via hepatic cytochrome oxidases (CYP2C9 and 3A4) to the primary active metabolite, 11-hydroxy THC, and the inactivated metabolite THC-carboxylase (THC-COOH).17,18,22 Because of enterohepatic circulation and slow release from lipid storage compartments, the elimination half-life of THC ranges from 25 to 36 hours.17 After metabolism, THC is excreted primarily as hydroxylated and carboxylated metabolites via feces (65%) and urine (20%).17,18

Cannabis is the most commonly used recreational drug among breastfeeding women, with as many as 11% reporting recent use during pregnancy.34–37 However, there is a paucity of data on the effects of breastfeeding exposures from maternal cannabis, with available research demonstrating variable concentrations of THC in human milk (peaking at 4 hours and detectable in breast milk for up to 6 days after last maternal use).17,37,38 Although cannabis use during pregnancy may be associated with fetal growth restriction, stillbirth, and preterm birth, data are far from uniform regarding adverse perinatal outcomes.36,39 Despite the limited data on the prenatal cannabis exposures to fetal neurobehavioral and neurodevelopment through breast milk, the American Academy of Pediatrics and American Congress of Obstetricians and Gynecologists have advised that cannabis use should be discouraged while breastfeeding.37,40

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POPULARITY AND PUBLIC HEALTH IMPACT

Modes of cannabis delivery have evolved alongside its growing popularity. Although the most common route of THC consumption is inhalation, alternative forms of marijuana use have recently expanded in scope. In regions with increased cannabis availability, ingested and vaporized forms pose a risk of unintentional exposure in children, and diversion of drug from registered users may also encourage adolescent abuse.8–11,41–46 The practice of “cannavaping” can easily conceal use of a THC-containing e-liquid in a stealth vaporizer (ie, JUUL device, which resembles a universal serial bus flash memory drive) or e-cigarette device.47,48 Morean et al47 found that rates of vaporizing cannabis were high (approximately 27%) among high school students who reported use of e-cigarettes. The THC can also be extracted by lipophilic volatile organic solvents (eg, butane or propane) into a highly concentrated waxy resin (commonly referred to as “dab,” “shatter,” or “butane hash oil”) with a THC content often exceeding 70% by weight.49

In young children, the most common place of unintentional cannabis exposure is in the patient's home, with more than one half of them consuming an edible form of cannabis.9,13,50 Edible products are particularly attractive to, and easily consumed by, younger children, as they are often in the form of baked goods (such as cookies, brownies), chocolate bars, gummies, and hard candies.44,51 The potency of cannabis in a single product can be variable and potentially high. A single food item can contain 400 mg or more of THC (10–20 times the typical oral dose of THC). In some instances, a single chocolate bar or brownie can contain 10 to 50 adult doses of THC, a toxic dose for a young child.51 In the last several years, the increasing THC concentration in cannabis-containing products has been recognized as a contributing factor to the risk and severity of cannabis intoxication incidents among pediatric patients.33,50,52,53

Although packaging is often intended to mimic non-THC food items, there is currently no federal regulation of packaging of edible forms of cannabis. Despite a few bills passed in state legislatures (eg, California AB-266) that aim to set regulatory standards for child-resistant packaging, there is little enforcement.54 As such, there are numerous case reports of cannabinoid toxicity in young children after exploratory ingestion of an edible cannabis product.1,3,21,25,53–57 Among children under 10 years presenting to a children's hospital with THC exposure, 50% are related to an edible cannabis product, with cases attributed to poor child supervision or lack of adequate storage or child-resistant packaging.7,9,44 In 1 case series, Vo et al44 described activation of a mass-casualty response with 21 patients (12 children and 9 adults) presenting to the ED after unintentional ingestion of THC-infused gummy candies at a birthday party.

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CANNABIS TOXICITY: CLINICAL MANIFESTATIONS

Pediatric cannabis intoxication has variable presentations, ranging from mental status changes to encephalopathy and coma. Lavi et al25 reviewed the clinical signs observed in older children and adolescents, including psychosis, ataxia, tremor, nystagmus, behavior changes, and excessive motor activity. Because there is no clear demarcation between doses that achieve desired psychoactive properties versus those that produce noxious effects, recreational cannabis use can often lead to adverse consequences.29 In adolescents and adults, an inhaled dose of 2 to 3 mg or an ingested dose of 5 to 20 mg THC can impair attention, concentration, short-term memory, and executive functioning.17–19,23,29 Toxicity in younger children is most often reported after ingestion of a highly concentrated food product. For example, an oral dose between 5 and 300 mg in a child has caused symptoms of intoxication.11,29,46,58–60

Whereas older children and adults with marijuana intoxication typically present with diverse symptoms, ranging from cardiovascular (tachycardia, hypertension), ophthalmological (conjunctival injection, nystagmus), respiratory (tachypnea, bradypnea), and gastrointestinal (dry mouth, increased appetite) to neurological (sleepiness, somnolence, ataxia, slurred speech) abnormalities,1,19 the manifestations of cannabis intoxication among infants are primarily related to changes in the sensorium, from encephalopathy to frank coma.25,58 Furthermore, the severity of neurological manifestations among infants is likely related to the cannabis dose consumed relative to body weight. Given the nonspecific neurological symptomatology of cannabis intoxication in infants and the wide differential for unexplained, acute-onset encephalopathy, diagnosis of acute intoxication may be delayed.25

To date, a relatively small number of case reports and case series of pediatric cannabis intoxication have been documented, but the full scope of symptoms in young children is not fully known.53 In children less than 6 years old, Boadu et al1 reported that the overwhelming majority of symptoms were neurological in nature, ranging from mild tremor and ataxia, to extreme lethargy, stupor, coma, and, rarely, seizures, with treatment being mainly supportive. Similarly, in a retrospective study conducted by Claudet et al,52 the most frequent symptoms reported among 29 children under 3 years of age with confirmed cannabis ingestion were sinus tachycardia, drowsiness, hypoventilation, and agitation. Other less specific symptoms such as nausea and vomiting have been reported, along with bradycardia, bradypnea, hypotension, and respiratory depression necessitating mechanical ventilation.7,21,33,53,60 The nonspecific neurological manifestations of cannabis toxicity can mimic postictal states, encephalitis, or sepsis and may lead to unnecessary diagnostic evaluations and interventions.21,25

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EVALUATION AND ACUTE MANAGEMENT OF CANNABIS EXPOSURE

The differential diagnosis for acute cannabis exposure in pediatrics is broad, because toxicity most commonly presents as altered behavior, lethargy, or coma. Regardless of age, acute cannabis intoxication is a clinical diagnosis, and the management consists mainly of supportive care.29

Challenges in the assessment of pediatric cannabis ingestion include the quantification of active components consumed, as well as the lack of information related to pharmacology, toxicity, and lethality of THC, especially in younger children.60 Route of drug administration and drug formulation determine the rate of drug absorption. Oral absorption, in contrast to inhalation, is slower and often delayed; THC clearance and elimination may be prolonged owing to the wide distribution of THC in fatty tissues.21,22 Compared with oral ingestion, the bioavailability of THC while smoking has been reported between 2% and 56%, owing in part to variability in smoking dynamics (ie, depth of inhalation, frequency of puffs, breath-hold time).18,22 With oral ingestion of THC, the bioavailability ranges from 10% to 20%, with degradation of the drug in the stomach and first-pass metabolism affecting absorption.18,22,23,25 Cannabis intoxication should be suspected when an afebrile child with no prior medical history presents with neurological impairment, such as drowsiness, lethargy, or coma with no focal neurological signs.52

Standard treatment of acute cannabis ingestion is largely supportive, with a focus on airway, breathing, and circulation, followed by treatment of cannabis-related symptomatology. Children with apnea or at risk for aspiration should undergo rapid sequence intubation and assisted mechanical ventilation. In children presenting with lethargy, measuring electrolytes, blood gas analysis, and rapid blood glucose (particularly concerns for hypoglycemia) should be considered. In any unknown ingestion, it is prudent to obtain an electrocardiogram, serum toxicology panel (including acetaminophen, salicylate, and ethanol levels), and urine drug screen, as coingestions are common. It is also important to consider seizure associated with coingestions (eg, cocaine), treated initially with benzodiazepines. Although naloxone will not reverse coma owing to cannabis toxicity, it can be administered to patients presenting with features of opioid intoxication. In addition, intravenous fluid administration should be considered to correct hypovolemia.1,3,13,21,25,57,59

Compared with young children, most adolescents and adults presenting with acute cannabis toxicity have mild intoxication, with dysphoria that can be managed supportively in a dimly lit room, decreased stimulation, and, for patients with marked anxiety or agitation, benzodiazepines.17,19,61 Chest pain in adolescents and adults may arise from a pneumothorax (prolonged breath holding during cannabis use), exacerbation of underlying pulmonary disease (eg, asthma), or, rarely, myocardial ischemia or infarction.17,19,29,62,63

Patient may complain of cannabis hyperemesis syndrome, which consists of abdominal pain, vomiting, or nausea relieved by hot showers.64 Although cannabis hyperemesis syndrome is typically seen with chronic cannabis use, it may occur with acute or acute-on-chronic use. Acute treatment consists of symptomatic care, including intravenous fluid hydration, antiemetics (eg, ondansetron), benzodiazepines, and cessation of cannabis use.64,65

Consultation with a regional poison control center (800-222-1222) and a medical toxicologist is encouraged for all symptomatic pediatric cannabis intoxications.29 No antidote exists for cannabis toxicity, and activated charcoal is usually not effective.20,21 In severe cases of cannabis toxicity, flumazenil, a selective benzodiazepine antagonist, may have some therapeutic effect.7,25,66 In the absence of fevers, deteriorating mental state, or persistent or progressive encephalopathy, CSF studies are usually not indicated. Most pediatric patients can be observed and will return to baseline within 8 to 12 hours.7,20 Pediatric cannabis intoxication should be reported to child protection services to identify neglect and at-risk families.7,21

Prompt urine screening can prevent costly and invasive evaluations.67 If the urine assay is positive for cannabinoids, further invasive evaluations (such as brain imaging, lumbar puncture) or treatments (eg, mechanical ventilation, antibiotics, or antivirals) may not be necessary.1,58 The primary inactive metabolite of THC, THC-COOH, is found in high concentration in urine for 3 to 5 days after a single drug exposure.3,23 The lower limits of detection range in standard urine drug screens range from 20 to 100 ng/mL, depending upon the specific assay.68 Chronic cannabis users or those with higher body fat content can have detectable urinary THC-COOH levels up to 1 month after last use.3,22,23

Although most urine drug tests detect the presence of THC-COOH, clinicians should not use this test to determine acute intoxication.18 Cannabis testing does not provide any specific information on the timeline of exposure or the severity of intoxication.69 Furthermore, it is important to consider other substances that may not be detected by standard methodologies, such as synthetic cannabinoids, which are notoriously difficult to detect and quantify.1 Although initial urine toxicology tests typically performed with the highly sensitive enzyme multiplied immunoassay technique, there may be false-positive results, as other drug metabolites may influence the test.70 The confirmatory testing of urine, blood, or serum, using gas chromatography–mass spectrometry, will test positive only for THC, making it highly specific for cannabis ingestion.70,71 Levene et al21 reported the case of a 13-month-old female presenting with self-limited altered mental status and lethargy after consuming hemp seed milk (a cannabinoid-containing product with a high CBD-to-THC ratio), with a subsequent diagnosis of THC exposure on confirmatory gas chromatography–mass spectrometry.71 Chinello et al72 also described a case of a 2-year-old child who developed neurological symptoms after ingesting 2 teaspoons of hemp seed oil per day for 3 weeks. In general, however, the results of confirmatory testing are usually delayed and do not return quickly enough to affect clinical care.29

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CONCLUSIONS

Pediatric cannabis exposures are more frequent owing to rising use of this natural product in the United States.11,25,62 Increased bioavailability and higher potency of cannabis can lead to high serum THC levels in younger children. In a comparison of state trends of unintentional pediatric cannabis exposures, the call volume reported by poison control centers has increased by 30% in states that have passed cannabis legislation before 2005, compared with states without permissive laws, where call volume has remained unchanged.11,21,46

With the growing popularity of edible cannabis products, which may be alluring to the exploratory toddler, health care personnel working in EDs, urgent care centers, and general clinics must recognize pediatric cannabis toxicity.11,21,33 Most often, a history of cannabis exposure is obtained only after a urine toxicology screen is reported as positive for cannabinoids. Because prompt urine screening can prevent further invasive diagnostic investigations and unnecessary treatments, providers must be vigilant and consider potential cannabis toxicity in any young child presenting with unusual clinical manifestations or common presentations with unclear etiology.25

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Keywords:

cannabis; Δ-9 tetrahydrocannabinol; marijuana; tetrahydrocannabinol; toxicity; toxicology

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