The Pharmacokinetics and Pharmacodynamics of Cannabis

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat coming to you from Children’s Healthcare of Atlanta/Emory University School of Medicine

and I'm Rahul Damania from Cleveland Clinic Children’s Hospital. We are two Pediatric ICU physicians passionate about all things MED-ED in the PICU. PICU Doc on Call focuses on interesting PICU cases & management in the acute care pediatric setting so let’s get into our episode:

Welcome to our Episode a three-year-old girl with altered mental status and acute respiratory failure

Here's the case presented by Rahul—

A three-year-old presents to the PICU with altered mental status and difficulty breathing.

Per the mother, the patient was in the usual state of health on the day prior to admission when the mother left her in the care of her maternal grandmother. When mom arrived home later in the afternoon, mom was unable to wake her and reported that she seemed "stiff". She did not have any abnormal movements or shaking episodes. Mom called 911 and the patient was brought to our ED. No known head trauma, though the patient is in the care of MGM throughout the day. No emesis. No recent sick symptoms. No witnessed ingestion, however, the patient's mother reports that MGM is on multiple medications (Xarelto, zolpidem, Buspar, gabapentin, and acetaminophen) and uses THC-containing products specifically THC gummies. In the ED: The patient had waxing and waning mentation with decreased respiratory effort. GCS was recorded at 7. Arterial blood gas was performed showing an initial pH of 7.26/61/31/0. The patient was intubated for airway protection in the setting of likely ingestion. The patient has no allergies, immunizations are UTD.

BP 112/52 (67) | Pulse 106 | Temp 36.2 °C (Tympanic) | Resp (!) 14 | Ht 68.5 cm | Wt 14.2 kg | SpO2 100% | BMI 30.26 kg/m²

Physical exam was unremarkable-pupils were 4-5mm and sluggish. There was no rash, no e/o of trauma

Initial CMP was normal with AG of 12, CBC was unremarkable, and Respiratory viral panel was negative. Serum toxicology was negative for acetaminophen, salicylates, and alcohol.

Basic Urine drug screen was positive for THC

To summarize key elements from this case, this patient has:

• Altered mental status: - waxing and waning with GCS less than 8 suggestive of decreased ventilatory effort pre-intubation
• impending acute respiratory failure
• Dilated but reactive pupils
• All of which brings up a concern for possible ingestion such as THC (but cannot rule out other ingestion)
• This episode will be organized…
• Pharmacology of Cannabis
• Clinical presentation of Cannabis toxicity
• Workup & management of Cannabis toxicity

The Cannabis sativa plant contains over 500 chemical components called cannabinoids, which exert their psychoactive effect on specific receptors in the central nervous system and immune system. The 2 best-described cannabinoids are THC and cannabidiol (CBD)—and are the most commonly used for medical purposes. Patients with intractable epilepsy or chronic cancer pain may be using these drugs. THC is the active ingredient of the cannabis plant that is responsible for most symptoms of central nervous system intoxication. The term cannabis and the common name, marijuana, are often used interchangeably).

Rahul, can you shed some light on the pharmacokinetics/pharmacodynamics of cannabis?

Cannabis exists in various forms: marijuana (dried, crushed flower heads, and leaves), hashish (resin), and hash oil (concentrated resin extract), which can be smoked, inhaled, or ingested. 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 non-psychoactive component of cannabis. The potency of cannabis is usually based on the THC content of the preparation. The THC is lipid soluble and highly protein bound and has a volume of distribution of 2.5 to 3.5 L/kg. The THC binds to brain cannabinoid receptors, producing dose- and time-dependent stimulant, hallucinogenic, or sedative effects. Cannabis can be consumed through inhalation (smoking or vaporization) and oral ingestion, as well as via transcutaneous, rectal, and vaginal routes. On inhalation of cannabis, due to rapid delivery to the brain, the THC serum concentrations peak within 15 to 30 minutes and have a duration of up to 4 hours. Approximately 2 to 3 mg of inhaled THC is sufficient to produce drug effects in a naive user.

In contrast to oral consumption, due to poor bioavailability, cannabis has a delayed onset of psychoactive effects that ranges from 30 minutes to 3 hours, lasting up to 12 hours. Because of enterohepatic circulation and slow release from lipid storage compartments, the elimination half-life of THC after oral intake ranges from 25 to 36 hours. In naive users, psychotropic effects occur with 5 to 20 mg of ingested THC.

Pradip, what's the mechanism of action of THC?**

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. The action of cannabinoids at these locations is thought to contribute to cannabis' ability to produce the cognitive and motor impairment of cannabinoid toxidrome

THC 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 conjunctiva), cardiovascular (tachycardia), and gastrointestinal (nausea, vomiting, increased appetite, or thirst) systems.

Rahul, what are the manifestations of Cannabis toxicity in children?

Unintentional Cannabis poisoning in children may be a consequence of legalizing cannabis for adult use. Edible gummies, chocolates, and baked goods with THCannabinol are now available in most parts of the US & Canada. A recent NEJM study (Myran et al NEJM Aug 2022) reported that the legalization of cannabis products was associated with an increased incidence in hospitalizations for children with cannabis poisoning in certain provinces of Canada. 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. 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

More recently, Canna-vaping or the use of the vaporized form of THC is common amongst teenagers. 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.

The manifestations of cannabis intoxication among infants are primarily related to changes in the sensorium, from encephalopathy to frank coma. 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

The term “edibles” is commonly used to refer to food products containing cannabis. Edibles are available in numerous forms including baked goods, candies, gummies, lozenges, butter, oils, and beverages. Typically, edibles are sought out for recreational use due to their greater concentration of THC. Also newer synthetic versions of THC are constantly being developed and may remain undetected on drug testing.

• If you had to work up this patient with cannabis toxicity, what would be your diagnostic approach?
• Acute cannabis intoxication is a clinical diagnosis especially with a clear h/o of an adult using THC gummies with unintentional ingestion by the toddler is highly suggestive of acute cannabis intoxication. 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.
• Labs include: Blood gas, basic metabolic panel (to check serum glucose and electrolytes), serum toxicology panel, urine drug screen, etc. may be sent.
• EKG, and chest radiograph is warranted based on clinical manifestation such as chest pain.
• cEEG may be required if a comatose patient is intubated.
• We need to be aware of co-investments such as cocaine, opioids, acetaminophen, etc, and expand the workup accordingly.
• If our history, physical, and diagnostic investigation led us to acute cannabis toxicity as our diagnosis what would be your general management of framework?
• PICU care of the infant or older child with acute cannabis intoxication is largely supportive with a focus on airway, breathing, and hemodynamics. Naloxone will not reverse coma, apnea, or hypoventilation associated with cannabis and intubation may be needed.
• Provide IV fluids to correct hypovolemia, and correct any electrolyte abnormalities, especially hypoglycemia.
• 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. 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.
• Patient may complain of cannabis hyperemesis syndrome, which consists of abdominal pain, vomiting, or nausea relieved by hot showers. Although cannabis hyperemesis syndrome is seen with chronic ingestion, it may be seen with acute on chronic use. Acute treatment consists of symptomatic care, including intravenous fluid hydration, antiemetics (eg, ondansetron), benzodiazepines, and cessation of cannabis use.
• Pradip, what are some clinical pearls regarding Cannabis for pediatric critical care medicine folks?
• Pearl # 1: Acute cannabis intoxication can result in altered mental status & acute respiratory failure in infants and children.
• Pearl # 2: 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.
• Pearl # 3: Studies have reported that daily cannabis : Studies have reported exposure was associated with a significantly higher propofol dose to achieve adequate sedation compared to those without cannabis exposure. However, there was not an increased incidence of adverse events in these patients. Similarly, studies report an increased need for fentanyl and midazolam in patients with daily cannabis exposure. It is hypothesized that propofol may impart a portion of its sedative effect via the endocannabinoid system. In patients with daily cannabis exposure, down-regulation of the cannabinoid (CB)-1 receptor in chronic cannabis users versus partial agonism/antagonism at the CB-1 receptor by other phytocannabinoids in marijuana products that may compete with propofol, increasing the required dose.

This concludes our episode on acute cannabis ingestion We hope you found value in our short, case-based podcast. We welcome you to share your feedback, subscribe & place a review on our podcast! Please visit our website picudoconcall.org which showcases our episodes as well as our Doc on Call management cards. PICU Doc on Call is co-hosted by myself Dr. Pradip Kamat and Dr. Rahul Damania. Stay tuned for our next episode! Thank you!

References

• Fuhrman & Zimmerman - Textbook of Pediatric Critical Care Chapter 132- Sedation and Analgesia Heard C. et al. page1599-1600
• Reference 1: Barrus DG, Capogrossi KL, Cates SC, et al. Tasty THC: promises and challenges of cannabis edibles. Methods Rep RTI Press. 2016;2016. doi:10.3768/rtipress.2016.op.0035.1611.
• Reference 2: Wong K, Baum C. Acute Cannabis toxicity. Pediatric Emergency Care. November 2019, Volume 35 (11), p 799–804.
• Reference 3: Boadu O, Gombolay GY, Caviness VS, et al. Intoxication from accidental marijuana ingestion in pediatric patients: what may lie ahead. Pediatr Emerg Care. 2018
• Blohm E, Sell P, Neavyn M. Cannabinoid toxicity in pediatrics. Curr Opin Pediatr. 2019;31:256–261.
• Imasogie N, Rose RV, Wilson A. High quantities: Evaluating the association between cannabis use and propofol anesthesia during endoscopy. PLoS One. 2021 Mar 4;16(3):e0248062.