The active ingredient in marijuana or cannabinoid (CB), is known as THC. The most commonly referenced and typically, the most plentiful substance is the psychoactive cannabinoid, Δ9-THC. Δ8-THC is a structural isomer of Δ9-THC (Figure 3) (Tagen and Klumpers, 2022). Δ9-THC is nearly completely metabolized by hepatic hydroxylation and oxidation through cytochrome P450 (CYP 450) isozymes to an active and more potent primary metabolite, 11-hydroxy-Δ9-THC (11-OH-Δ9-THC). Similarly, Δ8-THC is metabolized to a more potent 11-hydroxy-Δ8-THC (11-OH-Δ8-THC) via the same metabolic pathway (Figure 3) (Tagen and Klumpers, 2022).

THC works on two major receptors: CB1 and CB2 receptors. CB1 receptors are neuronal receptors present in the central nervous system, and CB2 receptors are expressed in immune cells. CB1 and CB2 have been demonstrated in myocardium and vascular endothelium. An earlier study indicated that Δ9-THC and Δ8-THC have similar binding affinities to CB1 and CB2 receptors (Babalonis et al., 2021). However, a more recent study suggested that Δ8-THC binds to CB1 with less affinity than Δ9-THC but has a similar binding affinity to CB2 (Tagen and Klumpers, 2022). Existing reports suggest that Δ9-THC and Δ8-THC oral products produce similar effects, and Δ8-THC is thought to be generally less potent than Δ9-THC (Hollister and Gillespie, 1973). However, the potency difference between the 11-OH metabolites may not be equivalent to the potency difference between the parent Δ9-THC and Δ8-THC. Given that large quantities of Δ8-THC are chemically synthesized, little is known about the comparative clinical aspect of the now available Δ8-THC to that of Δ9-THC (Tagen and Klumpers, 2022).

Although CB1 and CB2 receptors have been demonstrated in myocardium and vascular endothelium (Mukhopadhyay et al., 2007), because of the abundance of those receptors in the brain, cardiac manifestations of THC are considered to be through its activity on the autonomic nervous system. Cardiovascular effects of THC are biphasic: at low or moderate doses, there is a surge in sympathetic activity causing tachycardia and hypertension, and at higher doses, there is prominent parasympathetic stimulation resulting in bradycardia and hypotension (Fisher et al., 2005). A variety of cardiovascular effects of THC has been described in adults, from dysrhythmias including atrial tachyarrhythmias (atrial tachycardia, flutter, and fibrillation), ventricular tachyarrhythmias (ventricular tachycardia and fibrillation), symptomatic bradyarrhythmia, complete atrioventricular block, vasovagal syncope, sudden cardiac death due to atherosclerosis in the coronary arteries, and coronary vasospasm in normal coronaries causing ischemia and sudden cardiac death (Richards et al., 2020; Mathew et al., 2003; Kasuda et al., 2021). Brancheau et al. reported a 28-year-old male who had THC-induced asystole (Brancheau et al., 2016).

The etiology of asystole, in this case, could possibly be attributed to profound direct vagal stimulation and/or THC-induced CNS depression and somnolence causing apnea that then led to a strong autonomic system modulation producing extreme bradycardia and asystole (Koehler et al., 2011). Extreme vagal stimulation prolongs the atrial refractory period, causing bradycardia.

American Association of Poison Control Centers (AAPCC) recommends healthcare facility referral for all symptomatic children (drowsiness, mental status change, persistent vomiting), children who are expected to sleep within 3 h of exposure, and asymptomatic and symptomatic children who are exposed to amounts greater than their weight-based threshold for age (6 months-5 years: >0.2 mg/kg; 6–12 years: >0.3 mg/kg; 13–79 years: >0.4 mg/kg) (Supplementary Material S1). Our patient ingested 75 mg of THC, or, 3 mg/kg, which is 10 times the weight-based threshold for his age. Half-life of THC in plasma is about 30 h (Ashton, 2001). Inhaled cannabis has a rapid onset of action with peak effect in 15–30 min and lasts up to 2–3 h. Ingested cannabis has a delayed onset of action ranging from 30–90 min, peak effect in 2–3 h, and lasts up to 12 h (Grotenhermen, 2003).

Typically described toxic effects of THC in children are CNS-related (Shaker et al., 2023; Akpunonu et al., 2021). It has been shown that lethargy and somnolence along with the increased duration of clinical effect and length of hospital stay were most commonly observed in the THC-naïve group than the non-THC-naïve group (Richards et al., 2020). Toxicity in children usually occurs after ingestion of a highly concentrated product. The current edible THC products in the form of gummies, and suckers are obviously attractive to children as they resemble candy, and this could lead to ingestion in large quantities resulting in intoxication. Continued free availability of such products call for some serious policy change consideration in order to protect the vulnerable population such as our patient.

The current recommendation is monitoring for 3–6 h (AAPCC: 3–4 h, UpToDate: 4–6 h) for asymptomatic children (Supplementary Material S1). Our patient was clinically stable with no concern for respiratory depression and had asystole and apnea after 7 h of ingestion. This is genuinely concerning as the life-threatening event occurred outside of the recommended observation time. In 2016, Heizer et al. did a retrospective chart review of children who had unintentional exposure to THC where they found the degree of symptoms corresponded to the amount of THC ingested and that correlated with the level of management they needed. As described in this paper, observation vs. hospital admission vs. ICU monitoring should be determined based on a weight-based threshold for age rather than how well they appear clinically at initial presentation (Heizer et al., 2018). We suggest it would be prudent to transfer children who ingest large amounts of THC to higher centers with ICU facilities.

“I was concerned when my son ingested the THC gummies, but I had no idea that while spending time at the Emergency Department, his heart would stop beating! I was not aware that something terrible could happen from having too much THC. My son received great care at the hospital, and I am so glad that he was discharged back to his usual self. I think the community should be aware that something like this could happen to a child. Thank you for allowing me to voice my thoughts!”

Although the THC substance consumed was a gummy with less chance of contamination with other illicit drugs, a comprehensive serum drug screen was not obtained.