Continuing Education Activity

Cannabinoids are a collective group of compounds that act on cannabinoid receptors. They include plant-derived phytocannabinoids, synthetic cannabinoids, and endogenously-derived endocannabinoids. The primary source of cannabinoid toxicity is from plant-derived cannabinoids and synthetic cannabinoids. These agents act as cannabinoid receptor agonists. More than 60 naturally occurring cannabinoids are found in the Sativa and Indica species of Cannabis, with delta-9 tetrahydrocannabinol (THC) being the main psychoactive compound. Other naturally occurring cannabinoids include cannabidiol and cannabinol. Marijuana is the most common colloquial name for crushed, dried leaves and flowers of the Cannabis plant. This activity describes cannabinoid toxicity and highlights the role of the interprofessional team in its management.

Objectives:

• Describe the pathophysiology of cannabinoid toxicity.
• Review the presentation of cannabinoid toxicity.
• Summarize the treatment options for cannabinoid toxicity.
• Explain modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by cannabinoid toxicity.

Introduction

Cannabinoids are a collective group of compounds that act on cannabinoid receptors. They include plant-derived phytocannabinoids, synthetic cannabinoids, and endogenously-derived endocannabinoids. The primary source of cannabinoid toxicity is from plant-derived cannabinoids and synthetic cannabinoids. These agents act as cannabinoid receptor agonists. More than 60 naturally occurring cannabinoids are found in the Sativa and Indica species of Cannabis, with delta-9 tetrahydrocannabinol (THC) being the main psychoactive compound. Other naturally occurring cannabinoids include cannabidiol and cannabinol. Marijuana is the most common colloquial name for crushed, dried leaves and flowers of the Cannabis plant.[1][2][3]

In recent years, there have been many reports of marijuana toxicity, primarily in the pediatric population, as medical and recreational marijuana has been legalized. The terms phytocannabinoids, marijuana and cannabis are used interchangeably. [4][5]Synthetic cannabinoids were created for therapeutic and research purposes; however, despite legal efforts to limit their availability, synthetic cannabinoids have become an increasingly common drug of abuse, sold under various street names such as K2, Spice, and Black Mamba. Synthetic cannabinoids are associated with much more morbidity and mortality than the phytocannabinoids. Prescription preparations for medical usage include dronabinol, or pure THC, nabilone, a synthetic cannabinoid, and cannabidiol (CBD). Pharmaceutical use of cannabinoids is an ongoing field of research.

Etiology

Cannabinoid intoxication occurs most frequently through inhalation, whether being used recreationally or medicinally. Cannabinoid toxicity usually occurs due to overuse and abuse or inadvertant ingestions of cannabis. Accidepntal overuse can occur with marijuana edibles due to excessive ingestion during the extended, unanticipated time it can take for peak action. [6]Inadvertant ingestions most often occur in the pediatric population due to exploratory behavior and ingesting what may otherwise look like a normal food product. Greater availability due to legalization and commercial availability has led to novel preparations of cannabis, including baked goods, various candies, hash, and oils. Despite the wider availability of cannabis, most significat cannabinoid toxicity is likely due to the abuse of synthetic cannabinoids, which are known to have more adverse effects.

Epidemiology

Internationally, cannabis is the most commonly abused illicit substance with a high incidence of usage in adolescents. Over 140 million people use cannabis worldwide. Trends in the United States to decriminalize marijuana have led to increased exposures reported to poison centers and presenting to emergency departments. Exposure characteristics are generally related to excessive use in adults and inadvertent ingestions in small children. This has been well documented throughout the recent legalization of recreational marijuana in Colorado, and now other states. Synthetic cannabinoids are the most abused synthetic drug and second most abused drug among adolescents. [7]Reports of abuse and toxicity are steadily growing, as the number of synthetic cannabinoids produced increases. Increasing varieties of synthetic cannabinoids have been synthesized over the last ten years to avoid classification as illegal agents by making chemical modifications to compounds. Geographic clusters of high use, toxicity and death have been reported. Despite known toxicity and increased availability of marijuana, many people continue to abuse synthetic cannabinoids for various reasons including lower cost as compared to marijuana and lack of detection on routine drug screening.

Pathophysiology

The endocannabinoid system is very complex, and research is still ongoing and necessary for a continued understanding of its function. Cannabinoids, whether endogenous or exogenous, act on specific cannabinoid binding receptors (CB), cannabinoid binding receptor 1 (CB1) and cannabinoid binding receptor 2 (CB2). CB1 is primarily centrally located but is also present in the periphery, while the opposite is true for CB2, which is primarily peripherally located but also found centrally. CB1 receptors are mainly involved in the central effects of cannabinoids, which include consequences on learning, memory cognition, emotion, movement, sensory perception, and nausea, as well as the psychoactive properties associated with cannabinoids.[8][9][10]

CB2 receptors are located peripherally and are thought to affect inflammation and immune system regulation. Cannabinoid receptors are G-protein linked receptors that inhibit adenylyl cyclase and thereby cyclic AMP, which affects calcium channels and potassium channels, leading to overall decreased intracellular calcium and extracellular potassium concentrations. This subsequently leads to decreased neurotransmission. However, depending on the specific location of the CB and specific G-protein involved, stimulation of CB1 may result in the inhibition or stimulation of various neurotransmitters, including acetylcholine, L-glutamate, γ-aminobutyric acid, dopamine, norepinephrine, and 5-hydroxytryptamine. This neurotransmitter modulation may contribute to the central and peripheral effects observed in cannabinoid toxicity.  The physiological effects of synthetic cannabinoids may vary based on the specific molecule in play, as many synthetic cannabinoids are continually being produced and often contaminated with other products. Chemically, synthetic cannabinoids and traditional cannabinoids like THC are vastly different. As opposed to THC, which is a partial agonist at the CB1 receptor, synthetic cannabinoids are full agonists. They exhibit a markedly higher affinity for CB receptors. As such, the effects of synthetic cannabinoids can be much more potent than THC thus increasing the effects seen physiologically and toxicologically.

Toxicokinetics

The toxic effects of cannabinoids are secondary to overstimulation of the endocannabinoid system by exogenous cannabinoids. This immoderate stimulation of the endocannabinoid system leads to the aforementioned erratic neurotransmitter modulation that can lead to toxicity. The absorption kinetics of cannabinoids and THC depends on the exposure route, with inhalation reaching peak serum concentrations in less than thirty minutes, and ingestion peaking in concentration at around 2 to 4 hours (or longer) after consumption. Duration of toxicity secondary to inhalation and ingestion lasts approximately 2 to 6 hours and 8 to 12 hours, respectively. THC's volume of distribution is approximately 3 liters per kilogram, and after exposure eventually collects in fat due to its high lipid solubility. Chronic exposures lead to increased accumulation in fat.

THC crosses the placenta and can accumulate in significantly elevated concentrations in breast milk. The hepatic cytochrome p450 system primarily metabolizes THC to many metabolites, mostly inactive. THC’s main active metabolite is 11-hydroxy-delta-9-tetrahydrocannabinol which is further broken down to numerous inactive metabolites, including 11-nor-delta-9-tetrahydrocannabinol-carboxylic acid (THC-COOH), which is detectable in urine, as excretion is through both feces and urine over the course of hours to days, with more prolonged elimination depending on the chronicity of use. The toxicokinetics of synthetic cannabinoids are less predictable as the specifically abused compound may vary, and adulteration is not uncommon.

History and Physical

Acutely, the physiologic effects of cannabis use include decreased systemic vascular resistance, elevated heart rate, decreased intraocular pressure, nystagmus, conjunctival injection, lethargy, decreased concentration and generalized psychomotor impairment. Whereas tachycardia may occur in acute use, slowing of the heart rate has been reported with more chronic use. Cannabis toxicity in children can be more concerning and can lead to decreased muscle coordination, lethargy, seizures and even obtundation. Synthetic cannabinoid toxicity is associated with similar symptoms. However, sympathomimetic toxicity, acute psychosis, and agitation, as well as seizures and sedation can occur. In severe cases, hyperthermia, rhabdomyolysis, and renal failure have occurred. Synthetic cannabinoids are commonly adulterated, leading to these worsened effects. Liberalization of marijuana laws have led to an increased incidence of cannabinoid hyperemesis syndrome which presents with cyclical vomiting, usually reported to be relieved with warm showers and cessation of cannabis abuse. Other chronic effects of prolonged cannabinoid use include lung disease, increased risk of cardiovascular disease, reduced fertility, and deficits in cognition and memory.

Evaluation

Diagnosis of cannabinoid toxicity is clinical, like most toxicities and exposures, and is established through history and physical examination. [11][12][13]In accidental exposures, particularly in young children, objective testing may be useful. Testing in the hospital setting for cannabinoid exposure is limited to diagnosis through urine drug screen via immunoassays that detect THC. Urine drug screens are not necessary for adults as they do not change management. However, in small children, particularly with accidental ingestions, a urine drug screen may aid in the diagnosis and help to avoid more costly and invasive testing, such as neuroimaging and lumbar puncture. Urine drug screens test for the presence of the inactive metabolite THC-COOH, which is detectable for as little as 6 hours and as long as 7 days in one-time users, but easily up to 30 days in a regular user. The threshold for a urinary screening of THC-COOH is 50 ng/mL. Reported false positives for THC-COOH include nonsteroidal anti-inflammatory agents, proton pump inhibitors, and riboflavin. However, it is very difficult to trigger a false positive with a detection concentration of 50 ng/mL. Passive smoke inhalation has been demonstrated to not reliably produce concentrations high enough to be detected in most urine drug screens. Serum concentrations may be quantified as a send out laboratory value, but this is not useful in the acute clinical setting. Serum concentrations of THC metabolites are useful for confirmatory testing and in legal situations and can be obtained through gas or liquid chromatography and mass spectrometry at a reference laboratory. Litigiously, urine drug screen and saliva samples can be used to determine relatively recent use. Synthetic cannabinoids, due to their many and varying chemical structures, are not detected by standard hospital urine drug screens and testing would have to be through a comprehensive drug screen at a reference laboratory.

Treatment / Management

Treatment of cannabinoid toxicity is largely supportive and focuses on symptomatic and supportive care. [14][15][16]Most adult patients with cannabis toxicity improve on their own with observation and little intervention, and admission is not required. However, pediatric patients may require longer observation and support, as well as the involvement of social services to assure safety in the home. Toxicity associated with synthetic cannabinoids can be more severe, requiring more aggressive treatment. Agitation or acute psychosis should be treated with benzodiazepines or, if necessary, antipsychotic agents, such as haloperidol or olanzapine. Tachycardia should be treated with benzodiazepines and hydration unless a specific dysrhythmia is present. Patients should be screened for underlying cardiovascular risk factors. Acute coronary syndrome can occur, possibly when preexisting conditions like coronary artery disease are present. An electrocardiogram can rule out ischemia and dysrhythmia. Seizures, which are well reported with cannabis use in the pediatric population and all ages with synthetic cannabinoid use, should be treated with benzodiazepines. Status epilepticus would be more likely to occur with synthetic cannabinoids and should be treated with adequate sedation and airway management. Cannabinoid hyperemesis syndrome is treated with cessation of cannabis use, and haloperidol has been shown to be helpful as the antiemetic of choice. Dermal application of capsaicin may also provide some benefit in cannabinoid hyperemesis syndrome. In cases of acute cannabinoid ingestion, gastrointestinal (GI) decontamination is not recommended as toxicity is rarely life-threatening. Patients should be observed for 6 hours for resolution of symptoms and be admitted for monitoring when there is central nervous system (CNS) depression, altered mental status, multiple seizures, or persistently abnormal vital signs. Longer periods of toxicity can be expected to occur with ingested edible products and with synthetic cannabinoids. Patients returning to baseline do not require any further testing or follow-up and should be counseled.

Differential Diagnosis

• Agent 15 poisoning

• Barbiturate toxicity

• Benzodiazepine toxicity

• CBRNE-incapacitating agents, LSD

• Panic disorder

• Sedative-hypnotic toxicity

• Toxicity, mushrooms

• Tricyclic antidepressant toxicity

• Withdrawal syndromes

Enhancing Healthcare Team Outcomes

With more states liberalizing the use of cannabis, many cases of toxicity are now being reported, esp in children and teenagers. These patients typicallly present to the emergency department with varying mental status changes. The toxicity is best managed by the emergency department physician, posion control, an internist, nurses, neurologist and or psychiatrist. Most cases of cannabis toxxicity are managed with supportive care with close monitoring. Pharmacological therapy is used to manage symptoms that arise.

Patients should be observed for 6 hours for resolution of symptoms and be admitted for monitoring when there is central nervous system (CNS) depression, altered mental status, multiple seizures, or persistently abnormal vital signs. Longer periods of toxicity can be expected to occur with ingested edible products and with synthetic cannabinoids. Patients returning to baseline do not require any further testing or follow-up and should be counseled. The outlook for most patients is good but repeat incidents of toxicity are starting to become common all over the US. [17][18](Level V)

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References

1.

Koltai H, Poulin P, Namdar D. Promoting cannabis products to pharmaceutical drugs. Eur J Pharm Sci. 2019 Apr 30;132:118-120. [PubMed: 30851400]

2.

Alipour A, Patel PB, Shabbir Z, Gabrielson S. Review of the many faces of synthetic cannabinoid toxicities. Ment Health Clin. 2019 Mar;9(2):93-99. [PMC free article: PMC6398358] [PubMed: 30842917]

3.

Armstrong F, McCurdy MT, Heavner MS. Synthetic Cannabinoid-Associated Multiple Organ Failure: Case Series and Literature Review. Pharmacotherapy. 2019 Apr;39(4):508-513. [PubMed: 30811628]

4.

Sánchez Artiles AE, Awan A, Karl M, Santini A. Cardiovascular effects of cannabis (marijuana): A timely update. Phytother Res. 2019 May;33(5):1592-1594. [PubMed: 30761633]

5.

Chomchai S, Phuditshinnapatra J, Mekavuthikul P, Chomchai C. Effects of unconventional recreational drug use in pregnancy. Semin Fetal Neonatal Med. 2019 Apr;24(2):142-148. [PubMed: 30744980]

6.

Blohm E, Sell P, Neavyn M. Cannabinoid toxicity in pediatrics. Curr Opin Pediatr. 2019 Apr;31(2):256-261. [PubMed: 30694824]

7.

Cordeiro SK, Daro RC, Seung H, Klein-Schwartz W, Kim HK. Evolution of clinical characteristics and outcomes of synthetic cannabinoid receptor agonist exposure in the United States: analysis of National Poison Data System data from 2010 to 2015. Addiction. 2018 Oct;113(10):1850-1861. [PubMed: 29806885]

8.

Verbanck P. [Short-term and long-term effects of cannabis use]. Rev Med Brux. 2018;39(4):246-249. [PubMed: 30320984]

9.

McCutcheon D, Raghavan M, Soderstrom J, Oosthuizen F, Douglas B, MacDonald E, Fatovich D. An early warning system for emerging drugs of concern in the emergency department: Protocol for the Western Australian Illicit Substance Evaluation (WISE) study. Emerg Med Australas. 2019 Jun;31(3):411-416. [PubMed: 30318770]

10.

Heinbockel T, Csoka AB. Epigenetic Effects of Drugs of Abuse. Int J Environ Res Public Health. 2018 Sep 25;15(10) [PMC free article: PMC6210395] [PubMed: 30257440]

11.

Williams MV, Gupta N, Nusbaum J. Points & Pearls: Cannabinoids: emerging evidence in use and abuse. Emerg Med Pract. 2018 Aug 01;20(Suppl 8):1-2. [PubMed: 30070813]

12.

Brown GR, McLaughlin K, Vaughn K. Identifying and treating patients with synthetic psychoactive drug intoxication. JAAPA. 2018 Aug;31(8):1-5. [PubMed: 30048361]

13.

Lucas CJ, Galettis P, Schneider J. The pharmacokinetics and the pharmacodynamics of cannabinoids. Br J Clin Pharmacol. 2018 Nov;84(11):2477-2482. [PMC free article: PMC6177698] [PubMed: 30001569]

14.

Dryburgh LM, Bolan NS, Grof CPL, Galettis P, Schneider J, Lucas CJ, Martin JH. Cannabis contaminants: sources, distribution, human toxicity and pharmacologic effects. Br J Clin Pharmacol. 2018 Nov;84(11):2468-2476. [PMC free article: PMC6177718] [PubMed: 29953631]

15.

Meyer MR. Toxicokinetics of NPS: Update 2017. Handb Exp Pharmacol. 2018;252:441-459. [PubMed: 29476337]

16.

Pintori N, Loi B, Mereu M. Synthetic cannabinoids: the hidden side of Spice drugs. Behav Pharmacol. 2017 Sep;28(6):409-419. [PubMed: 28692429]

17.

Monte AA, Calello DP, Gerona RR, Hamad E, Campleman SL, Brent J, Wax P, Carlson RG., ACMT Toxicology Investigators Consortium (ToxIC). Characteristics and Treatment of Patients with Clinical Illness Due to Synthetic Cannabinoid Inhalation Reported by Medical Toxicologists: A ToxIC Database Study. J Med Toxicol. 2017 Jun;13(2):146-152. [PMC free article: PMC5440319] [PubMed: 28397128]

18.

Heizer JW, Borgelt LM, Bashqoy F, Wang GS, Reiter PD. Marijuana Misadventures in Children: Exploration of a Dose-Response Relationship and Summary of Clinical Effects and Outcomes. Pediatr Emerg Care. 2018 Jul;34(7):457-462. [PubMed: 27050740]

Disclosure: Brian Kelly declares no relevant financial relationships with ineligible companies.

Disclosure: Thomas Nappe declares no relevant financial relationships with ineligible companies.