Severe Toxicity Following Synthetic Cannabinoid Ingestion

Abstract

Objective

To report a case of seizures and supraventricular tachycardia (SVT) following confirmed synthetic cannabinoid ingestion.

Background

Despite widespread use of legal synthetic cannabinoids, reports of serious toxicity following confirmed use of synthetic cannabinoids are rare. We report severe toxicity including seizures following intentional ingestion of the synthetic cannabinoid JWH-018 and detail confirmation by laboratory analysis.

Case Report

A healthy 48 year old man had a generalized seizure within thirty minutes of ingesting an ethanol mixture containing a white powder he purchased from the Internet in an attempt to get high. Seizures recurred and abated with lorazepam. Initial vital signs were: pulse, 106/min; BP, 140/88 mmHg; respirations, 22/min; temperature, 37.7 °C. A noncontrast computed tomography of the brain and EEG were negative, and serum chemistry values were normal. The blood ethanol concentration was 3.8 mg/dL and the CPK 2,649 U/L. Urine drug screening by EMIT was negative for common drugs of abuse, including tetrahydrocannabinol. On hospital day 1, he developed medically refractory SVT. The patient had no further complications and was discharged in his normal state of health 10 days after admission. The original powder was confirmed by gas chromatography mass spectrometry to be JWH-018, and a primary JWH-018 metabolite was detected in the patient’s urine (200 nM) using liquid chromatography tandem mass spectrometry.

Discussion

Synthetic cannabinoids are legal in many parts of the world and easily obtained over the Internet. Data on human toxicity are limited and real-time confirmatory testing is unavailable to clinicians. The potential for toxicity exists for users mistakenly associating the dose and side effect profiles of synthetic cannabinoids to those of marijuana.

Conclusion

Ingestion of JWH-018 can produce seizures and tachyarrhythmias. Clinicians, lawmakers, and the general public need to be aware of the potential for toxicity associated with synthetic cannabinoid use.

Introduction

Synthetic cannabinoids marketed under brand names like “K2” and “SPICE” herbal preparations have been previously reported in Western Europe and Asia and are gaining popularity in the United States. These products are widely available through local “head shops” and Internet resources and are typically labeled as “incense” and “not for human consumption,” or “for aromatherapy only”. Despite package labeling, these herbal mixtures are frequently laced with a variety of synthetic cannabinoids, which when smoked can deliver a “legal” high and avoid detection in common drug screens. ^1–4

In 2008, The United States (US) Customs and Border Protection service analyzed “SPICE” products and found them to contain pharmacologically active compounds, some of which were originally manufactured as investigative drugs but not further developed because of their undesirable psychoactive properties. ⁵ At the time of identification, these products were not subject to regulatory authority in the US due to their unique chemical classification and the packaging designating them as “not for human consumption.” With increased prevalence of human use came the recognition of significant public health threats, and several states and municipalities adopted ordinances to control the sale and distribution of synthetic cannabinoids. In response to increasing reports through the National Forensic Laboratory Information System and the American Association of Poison Control Centers, the US Department of Justice initiated the process of formally scheduling several synthetic cannabinoids in November 2010⁶ resulting in temporary Schedule I status for JWH-018, JWH-073, JWH-200, CP 47,497 and a C8 homologue of CP 47,497 effective from March 2011.

The clinical effects of the synthetic cannabinoids laced in herbal products are mediated through agonism at the CB1 receptor, the same receptor through which Δ⁹-THC exerts its psychoactive effects. ^7,8 However, the lack of quality control for these products raises concern regarding the potential for toxicity following human consumption. In addition, emerging data suggest that there may be stark differences in relative potency between synthetic cannabinoids and Δ⁹-THC. Unlike the low efficacy partial agonist effects of Δ⁹-THC, JWH-018, one of the more popular synthetic cannabinoids found in “K2” products, has been characterized as a full agonist with significantly increased potency relative to Δ⁹-THC.^7,9–15 This increased potency is likely to be associated with an increased likelihood of adverse effects.

Case reports of human exposure and toxicity are limited. The few cases published in the medical literature report similar adverse clinical effects to those of marijuana including anxiety, tachycardia and hallucinations. ^16–19 Like marijuana, withdrawal from synthetic cannabinoid use is also reported after abrupt cessation in tolerant individuals. ²⁰ Additionally, two deaths have been reported in the US with “K2” product use. The first case involved an adolescent who committed suicide after experiencing extreme anxiety following use, and the second case involved an adolescent who died following a coronary ischemic event. ^21,22 In previously reported cases, “K2” or “SPICE” was smoked in the same manner as traditional cannabinoids and to our knowledge no account of a large ingestion of pure JWH-018 has been reported.

We report serious toxicity in a 48 year-old man who ingested the synthetic cannabinoid JWH-018 obtained from a bulk supply. We confirm exposure to JWH-018 through forensic evaluations of the product and through the use of a quantitative assay for a primary metabolite of JWH-018 excreted urine.

Case Report

A previously healthy 48 year-old man was witnessed to ingest a mixture of ethanol and an unknown a powder he purchased over the Internet. Within thirty minutes after ingestion the patient exhibited agitation and had a generalized seizure witnessed by his wife. EMS providers observed additional seizure activity while on route to the Emergency Department (ED). On arrival, he was awake with the following vital signs: pulse, 106/min; BP, 140/88 mmHg; respirations, 22/min; temperature, 37.7 °C. Initial electrocardiogram showed sinus tachycardia with regular intervals. Seizure activity recurred in the ED and abated following the administration of intravenous lorazepam. The patient was subsequently intubated for airway protection. Initial laboratory values were: sodium 134 mEq/L, potassium 4.6 mEq/L, chloride 98 mEq/L, bicarbonate 24 mEq/L, blood urea nitrogen 23 mg/dL, creatinine 1.0 mg/dL, glucose 145 mg/dL, ethanol 3.8 mg/dL, and creatinine phosphokinase 2649 U/L. Acetaminophen and salicylates were not detected. A non-contrast computed tomography (CT) scan of the brain and EEG were unremarkable. Urine toxicology screening by the hospital clinical laboratory was negative for drugs of abuse, including THC. The patient’s family corroborated that he had no recent use of marijuana. On hospital day 1 the patient developed refractory supraventricular tachycardia that required electrical cardioversion. No elevations in cardiac enzymes were detected and the patient had no further dysrhythmias. On the third day of hospitalization his wife produced a small bag of the powder he had ingested as well as a receipt for its purchase via the Internet. The rest of his clinical course was unremarkable and the patient was subsequently discharged home in his baseline state of good health.

The product suspected of being self-administered was characterized as an off-white powder containing JWH-018. The product was analyzed by gas chromatography mass spectrometry (GC-MS) to assess cannabinoid content and to determine if other drugs were present. GC-MS procedures were validated forensic procedures commonly used by the Arkansas State Crime Laboratory. GC-MS characteristics of the powder were consistent with a JWH-018 analytical standard (Cayman Chemical) (Fig. 1). No other drugs were detected using analytical procedures capable of detecting trace levels of many Aminoalkylindoles (AAIs) and other synthetic cannabinoids and cathinones commonly present in a variety of “K2” products.

Fig. 1.

(A) Mass spectra generated from the white powder (A), the glucuronic acid conjugate excreted in urine (B), and the JWH-018 carboxy metaboloite excreted in urine (C). The white powder was analyzed using GC-MS while the urinary metabolites were analyzed using LC-MS/MS. Mass spectra were compared with purchased standards of JWH-018 and its carboxy metabolite (Cayman Chemical). An analytical standard of the glucuronic acid conjugate was not available.

As a way to confirm product use, the patient’s urine sample was analyzed by negative ion mode, liquid chromatography tandem mass spectrometry methods established to detect major JWH-018 metabolites, ^34–36 as approved by the Institutional Review Board at the University of Arkansas for Medical Sciences. The method used a purchased standard (Cayman Chemical, Ann Arbor, Michigan) to confirm the presence of a major omega carboxyl metabolite previously shown to be excreted after JWH-018 use. ^23,34–36 The urinary concentration of this metabolite was approximately 200 nM (Figs. 1, 2). In addition, analysis of resulting mass spectra and reactions with β-glucuronidase showed that approximately 50% of the carboxyl metabolite was excreted as the glucuronic acid conjugate (Figs. 2, 3). This is consistent with previous reports showing that JWH-018 metabolites are primarily excreted as conjugates. ^23,34–36

Fig. 2.

Extracted ion chromatographs from LC-MS/MS experiments performed with the urine specimen before (black dash tracing) and after (red tracing) β-glucuronidase incubation (see colour version of this figure online).

Discussion

JWH-018 is a relatively potent agonist of G-protein coupled cannabinoid receptors and is commonly used to lace “K2” and “SPICE” products.²⁴ It has nonselective agonist effects at both centrally and peripherally located CB1 and CB2 receptors. ⁷ Studies in animals have shown that CB1 receptors are located presynaptically on both glutamanergic and GABAergic synapses, suggesting a role for these receptors in modulation of neurotransmitter signaling mechanisms. ²⁵

Although traditional and nontraditional cannabinoids lower the seizure threshold in animal models, seizures following THC use in humans are rarely reported. ^26,27 However, the selective CB1 antagonist, rimonabant induced seizures in animal models. ²⁸ It is possible that the patient experienced seizures through a dose-response mechanism. One postulation is that high doses of JWH-018 and the resulting CB1 agonism result in a presynaptic release of excitatory neurotransmitters or a decrease in inhibitory neurotransmitters.

Tachycardia and tachyarrhythmias have been reported following use of traditional ^29–31 as well as synthetic cannabinoids.^16–19 The patient’s medically refractory supraventricular tachycardia may have resulted from increased circulating catecholamines or oxidative demands on the myocardium, both of which have been previously reported with CB1 receptor agonists. ³²

Public health risks of synthetic cannabinoids are of great concern due to the known variability in potency in “K2” and “SPICE” products.^1–4,7 As marijuana is the most frequently abused illicit drug in the US, ³³ the continued availability of a legal marijuana substitute to both users and retailers may result in consequential exposures to a novel drug that is likely more dangerous than the illicit one it supplants. Further development of analytical methods for the analysis of these emerging drugs of abuse will help delineate the clinical pharmacology and toxicology of these compounds in man. This case study indicates that JWH-018 is orally bioavailable in humans, and with the quick onset of seizure, appears to be rapidly distributed.

Conclusion

We describe a patient with repetitive seizures and supraventricular tachycardia following confirmed ingestion of the synthetic cannabinoid JWH-018. Clinicians should consider synthetic cannabinoid exposure in the differential diagnosis of patients who present with agitated delirium and seizures following recreational drug abuse.