Synthetic cannabinoids are a heterogenous group of novel, legally regulated psychoactive substances that can result in broad, multisystemic, dangerous effects. Despite growing literature regarding synthetic cannabinoid toxicity, little is known about the extent of these effects in young children. Caregivers of drug-endangered children may not provide an accurate history of exposure when children present with symptoms of intoxication, and lack of swift detection on routine urine drug screens may further obscure and delay the diagnosis. Clinical recognition carries forensic relevance that may support interventions to aid in protecting vulnerable children. We describe a case of near-fatal child maltreatment due to supervisory neglect resulting from ingestion of an increasingly common synthetic cannabinoid. Furthermore, we highlight clinical findings that should increase a physician’s index of suspicion for synthetic cannabinoid toxicity, even in the absence of a history of exposure.

Synthetic cannabinoids are a heterogenous group of novel psychoactive substances purposely designed to avoid detection and prosecution, circumventing US restrictions.1  Effects typically include alterations in mood, perception, and psychomotor activity.2  However, their heterogeneity generates unpredictable clinical presentations that challenge physicians’ ability to direct testing and anticipate symptom severity. Synthetic cannabinoid use has been associated with significant illness, described mostly in adult and adolescent males.3  Meanwhile, effects in children remain poorly described. Despite attempts to tighten restrictions, synthetic cannabinoid popularity has increased since their advent, likely fueled by undetectability on routine urine drug screens (UDS), relatively low cost, ready accessibility, and perceived legality, among other yet to be determined factors.4  In turn, public health concerns have expanded, compounding the risk of exposure by young, drug-endangered children.

A typically developing 3-year-old child (“S.P.”) was suddenly heard crying after having been playing in a room for ∼40 minutes without direct adult supervision. The caregivers responded to S.P.’s cries, finding S.P. inconsolable on the floor. Within 20 minutes, S.P. appeared dazed and unbalanced, prompting caregivers to seek medical attention. They arrived at an emergency department ∼10 minutes later by private vehicle.

Primary assessment did not identify external signs of trauma. A neurologic examination revealed a minimally responsive child, withdrawing to pain, but unable to follow commands or visually track; the assigned Glasgow Coma Score was 9. Horizontal nystagmus and generalized hypotonia was also noted. The caregivers denied any known medical conditions, recent illness, ill contacts, or toxic exposures. A head computed tomography scan performed shortly after arrival did not reveal intracranial injury. Because of decreasing level of consciousness, S.P. was transferred to a nearby tertiary pediatric hospital, arriving ∼90 minutes after symptom onset.

On arrival to the pediatric hospital, the following was noted: Glasgow Coma Score of 7, heart rate of 102 beats per minute, respiratory rate of 25 breaths per minute, blood pressure of 84/64 mm Hg, and oxygen saturation at room air of 96%. In addition to the previously described neurologic findings, examination revealed brisk symmetric reflexes and bilateral clonus, as well as an irregular breathing pattern, apnea, and eye-rolling. Apneic episodes raised concern for opioid toxicity, whereas eye-rolling and nystagmus raised concern for seizures. However, these findings did not resolve after naloxone or lorazepam was administered. Neurologic status continued to deteriorate over the following 60 minutes, necessitating endotracheal intubation for airway protection. Approximately 10 minutes after successful intubation, S.P. developed bradycardia requiring resuscitation measures. After 3 minutes of chest compressions and 2 doses of epinephrine, S.P.’s hemodynamic status stabilized, but required continuous vasopressor infusion. Nearly 3 hours after symptom onset, S.P. was transferred to the PICU.

Approximately 24 hours after symptom onset, S.P.’s hemodynamic status improved. Vasopressors were successfully discontinued at the time. However, S.P. remained on mechanical ventilation after extubation-readiness assessment revealed an irregular breathing pattern and lack of purposeful movements despite discontinued sedation. A brain MRI revealed a Chiari 1 malformation with cranio-cervical junction crowding, whereas ancillary test results, including lumbar puncture, EEG, and electrocardiogram, were normal.

Laboratory test results revealed hyperglycemia and elevated transaminase levels (Table 1). Although the UDS was negative for acetaminophen or other hepatotoxic drugs, the amphetamine screen result was positive. These results, coupled with S.P.’s acute neurologic symptoms and the lack of caregiver disclosure, heightened concerns for intoxication with illicit substances, prompting a report to law enforcement. Symptoms, however, were inconsistent with a typical amphetamine toxidrome, eliciting concerns for intoxication with unidentified substances. Medical providers discussed the incongruence between clinical symptoms and toxicology findings with law enforcement officers. At this time, a urine sample for additional testing was collected.

TABLE 1

S.P.’s Pertinent Laboratory Test Results

Admission Laboratory Test ResultsDischarge Laboratory Test Results
Sodium, mmol/L 139 142 
Potassium, mmol/L 3.7 4.7 
Chloride, mmol/L 112 112 
Carbon dioxide, mmol/L 17 24 
SUN, mg/dL 10 
Creatinine, mg/dL 0.29 0.23 
Glucose, mg/dL 221 97 
AST, U/L 1226 108 
ALT, U/L 849 235 
Admission Laboratory Test ResultsDischarge Laboratory Test Results
Sodium, mmol/L 139 142 
Potassium, mmol/L 3.7 4.7 
Chloride, mmol/L 112 112 
Carbon dioxide, mmol/L 17 24 
SUN, mg/dL 10 
Creatinine, mg/dL 0.29 0.23 
Glucose, mg/dL 221 97 
AST, U/L 1226 108 
ALT, U/L 849 235 

ALT, alanine aminotransferase; AST, aspartate aminotransferase; SUN, serum urea nitrogen.

Although the caregivers denied illicit substance exposure, scene investigation recovered dry leaves in a small plastic bag. A sample was sent to the state crime laboratory for identification, and patient biological samples were sent to a bioanalytical and forensic laboratory for expanded drug testing. Notably, there were no signs of methamphetamine or amphetamines in the home, and amphetamine confirmatory testing by mass spectrometry yielded negative results.

Approximately 72 hours after symptom onset, S.P.’s neurologic status markedly improved, with resolution of nystagmus, clonus, and brisk reflexes. S.P. demonstrated purposeful movements and response to commands, whereas return of spontaneous, regular respiratory pattern allowed for successful extubation. Aminotransferase levels remained elevated at this time, but had revealed a consistent decreasing trend with supportive care. Abdominal examination findings were benign, and aminotransferase levels were not repeated. Approximately 96 hours after symptom onset, cardiorespiratory and neurologic status returned to baseline. S.P. was discharged on the fifth day of hospitalization.

Substance forensic testing yielded positive results for the synthetic cannabinoid 5-fluoro-MDMB-PICA. Patient urine samples confirmed the presence of 5-fluoro-MDMB-PICA metabolites by liquid chromatography and tandem mass spectrometry, specifically 5-fluoro-PICA-3,3-dimethylbutanoic acid and 5-fluoro-PIC-ACID. Multidisciplinary pediatric subspecialty assessment, including pediatric intensive care, neurosurgery, and neurology, determined Chiari 1 malformation to be incidental and unrelated given the acuity of presentation, associated symptoms, laboratory test findings, and clinical evolution. Clinical findings were, otherwise, determined to be consistent with acute synthetic cannabinoid intoxication. S.P. was placed in kinship foster care by child protective services because of recurrent concerns for drug endangerment, supervisory neglect, and near-fatal child maltreatment.5  No further complications were reported after discharge.

The US Code classifies synthetic cannabinoids as Schedule 1 controlled substances. The Synthetic Drug Abuse Prevention Act of 2012 nationally banned the sale of synthetic cannabinoids,6  with individual state laws providing further regulation. Utah state law7  defines synthetic cannabinoids as cannabinoid compounds “chemically synthesized from starting materials other than a naturally occurring cannabinoid,” and subsequently defines tetrahydrocannabinol (THC) analogs as “structurally or pharmacologically substantially similar to, or is represented as being similar to, delta-9-THC.” Typically sprayed onto dried plant material to smoke or sold as a vaping liquid to inhale, synthetic cannabinoids are commonly known by the street names “K2” and “Spice,” among others.

It is important to note that “synthetic cannabinoid” is a misleading term. Although synthetic cannabinoid molecules are designed to uniquely bind to the same receptors as marijuana components, delta-9-THC and cannabidiol, these compounds are not clinically similar. Delta-9-THC and cannabidiol are partial agonists of cannabinoid receptor-1 and cannabinoid receptor-2, whereas most synthetic cannabinoids are full agonists, including 5-fluoro-MDMB-PICA.8  As a result, these chemicals carry the potential for more profound and prolonged toxicity, leading to higher rates of medical interventions and hospitalizations.9  Continuous development of new synthetic cannabinoid compounds perpetuates the sale of these unregulated dangerous substances. Signs and symptoms of synthetic cannabinoid intoxication may be numerous and unpredictable, involving multiple organ systems and not generally resembling marijuana-related effects (Table 2).10 

TABLE 2

Reported Signs and Symptoms Associated With Acute Synthetic Cannabinoid Intoxication

Signs and Symptoms
Cognitive 
 Agitation 
 Somnolence 
 Loss of consciousness 
 Hallucinations 
 Aggression 
 Panic attacks 
 Psychosis 
 Paranoia 
 Suicidality 
Neurologic 
 Ataxia 
 Clonus 
 Hyperreflexia 
 Seizures 
 Nystagmus 
 Mydriasis 
 Vertigo 
Cardiovascular 
 Bradycardia or tachycardia 
 Cardiac arrest 
 Myocardial infarction 
 Cerebral ischemic events 
 Hypertension or hypotension 
Respiratory 
 Dysregulated breathing 
 Respiratory failure 
 Dyspnea 
Metabolic 
 Acute kidney injury 
 Metabolic acidosis 
 Hyperglycemia 
 Fever 
Gastrointestinal 
 Nausea or emesis 
 Diarrhea 
 Hepatitis 
Signs and Symptoms
Cognitive 
 Agitation 
 Somnolence 
 Loss of consciousness 
 Hallucinations 
 Aggression 
 Panic attacks 
 Psychosis 
 Paranoia 
 Suicidality 
Neurologic 
 Ataxia 
 Clonus 
 Hyperreflexia 
 Seizures 
 Nystagmus 
 Mydriasis 
 Vertigo 
Cardiovascular 
 Bradycardia or tachycardia 
 Cardiac arrest 
 Myocardial infarction 
 Cerebral ischemic events 
 Hypertension or hypotension 
Respiratory 
 Dysregulated breathing 
 Respiratory failure 
 Dyspnea 
Metabolic 
 Acute kidney injury 
 Metabolic acidosis 
 Hyperglycemia 
 Fever 
Gastrointestinal 
 Nausea or emesis 
 Diarrhea 
 Hepatitis 

Despite increasing medical understanding of synthetic cannabinoid toxicity, little is known about these toxic effects in the pediatric population. Most pediatric medical literature addressing synthetic cannabinoid intoxication is limited to adolescents.11  We are aware of one published brief report describing acute neurologic and cardiorespiratory deterioration in an infant after reported unintentional synthetic cannabinoid ingestion.12  An unpredictable presentation, lack of UDS detection, and caregiver denial of recreational drug use can delay or impede the recognition of acute intoxication. Oral exploratory behaviors in young children increase the risk of unintentional poisoning, particularly in drug-endangered environments. Although medical providers recognize an associated risk for child abuse and neglect at the hands of drug-impaired caregivers, children are also at risk from direct effects of drugs in these environments.13 

During S.P.’s evaluation, a positive UDS result fueled concerns for acute amphetamine or methamphetamine intoxication. However, clinical findings did not correlate with a sympathomimetic toxidrome. To the best of our knowledge, a false-positive amphetamine screening result due to cross-reactivity with synthetic cannabinoids has not been specifically described in the medical literature. However, immunoassays targeting amphetamines are known to carry significant cross-reactivity issues, given poor antibody specificity. Additionally, given lack of regulation, synthetic cannabinoids may contain unrecognized substances that may produce unexpected UDS results.14  Reiterating these concerns with law enforcement officials allowed for a quick and thorough scene investigation, with collection of a substance later confirmed to be 5-fluoro-MDMB-PICA, an increasingly common synthetic cannabinoid.15  There have been increasing reports of hepatotoxicity associated with synthetic cannabinoid intoxication, some cases resulting in fulminant hepatic failure.16  Deaths associated with 5-fluoro-MDMB-PICA have also been reported.17  Clinically differentiating whether S.P.’s postintubation hemodynamic collapse was solely related to acute toxicity or a combination with vagal stimulation is nuanced. Prolonged vasopressor requirement and delayed onset of bradycardia after successful intubation may support synthetic cannabinoid intoxication. However, although most intubation-related bradycardias occur during intubation attempts and stabilize with reoxygenation and a pause in the laryngoscopy, progression to hemodynamic collapse requiring vasopressor support may also occur, particularly in children who are critically ill.18 

Current testing for synthetic cannabinoid detection is inherently hindered by time-consuming techniques, false-positive results, and a limited extent. Studies focused on refining synthetic cannabinoid detection have yielded promising findings. Receptor activation bioassays could improve detection for diverse, rapidly changing compounds,19  and comprehensive confirmatory UDS assays in drug-endangered children, rather than rapid enzyme-linked immunosorbent assay–based screening, have been shown to aid in occult drug detection.20  Although this case most likely suggests accidental ingestion by a drug-endangered, ambulatory child, the differential diagnosis should also elicit the possibility of intentional administration, a rarely reported form of child abuse.21  Although identifying the specific substance may not change supportive management, identification carries meaningful forensic relevance, with important implications for safety assessments and future harm prevention strategies. Efforts to improve detection should continue to be supported.

A high index of suspicion for acute synthetic cannabinoid intoxication should be maintained by physicians when a young child presents with altered mental status in the absence of traumatic or infectious findings, and with a negative or incongruent UDS result. Acute intoxication must also be considered when altered mental status remains unexplained and external signs of trauma concerning for child physical abuse are recognized. Given the paucity of literature regarding synthetic cannabinoid toxic effects in drug-endangered pediatric patients, case reports are valuable in improving clinical suspicion and communication with agency officials to identify and reduce risks in vulnerable pediatric populations.

FUNDING: No external funding.

Dr Ruiz-Maldonado obtained data for the case, conceptualized this report, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Dorey and Christensen obtained data for this case and critically reviewed and revised the manuscript; Dr Campbell obtained data for the case, conceptualized this report, and critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

     
  • THC

    tetrahydrocannabinol

  •  
  • UDS

    urine drug screen

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: Drs Ruiz-Maldonado, Christensen, and Campbell have provided medicolegal consultation and expert testimony on cases of suspected child abuse and neglect. Dr Campbell’s institution and Dr Christensen has received compensation for providing expert testimony; and Dr Dorey has indicated she has no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.