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Synthetic Cannabinoids

By Alicia Minns, MD

Introduction

Synthetic cannabinoid (SC) compounds were originally developed to study the pharmacology of cannabinoid receptors. However in recent years, they have emerged as drugs of abuse. Synthetic cannabinoids first emerged in Europe in 2005, and then appeared in the United States in 2009, where they were marketed initially as “K2” and “Spice” and inhaled via a pipe or rolled into a cigarette. The poorly labeled contents have been found to include a mixture of psychoactively inert herbs and aromatic extracts sprayed with SC compounds and are packaged with labels stating “not for human consumption” or “incense”. Despite federal and state regulations prohibiting the sale and distribution, illicit use continues. Many SCs are more potent than delta-9-tetrahydrocannabinol (THC) and are more likely to be associated with sympathomimetic effects (tachycardia, hypertension) and hallucinations. There is also an increase occurrence of seizures as well as reports of unanticipated acute kidney injury. HU-210 had previously been the only synthetic cannabinoid that had been classified as Schedule 1 under the Controlled Substances Act. As of March, 2011, the US Drug Enforcement Administration (DEA) has designated five SC chemicals (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) as Schedule 1 substances, however there are many more SC compounds available for purchase. There are numerous street and commercial names for SC products including K2, Spice, Barely Legal, Black Mamba, Galaxy, Mojo, and Yucatan Fire. They are available through the Internet, in gas stations, and in specialized stores such as head shops.

Case presentation

A 16-year male was brought to the Emergency Department after reportedly having a seizure. He was smoking “K2” with friends when he became agitated and started to have jerking movements of his upper extremities, which had stopped when paramedics arrived on scene. His initial vital signs were a temperature of 99.1°F, blood pressure of 152/84 mmHg, heart rate of 120 beats per minute, respiratory rate of 20 and oxygen saturation of 99% on room air. He was intermittently agitated and laughed inappropriately at times. His exam was otherwise unremarkable. His ECG demonstrated a sinus tachycardia, but was otherwise normal. Complete blood count and serum electrolytes were within normal limits. He was given 1mg intravenous lorazepam. His urine drug screen for THC metabolites and other drugs of abuse was negative. He was subsequently discharged home without any adverse effects after 8 hours of observation.

Questions

  1. What is the classic toxidrome associated with synthetic cannabinoid exposure?
  2. What is the mechanism of action of synthetic cannabinoids?
  3. How is synthetic cannabinoid toxicity treated?

Epidemiology

Synthetic cannabinoids are increasingly being abused especially in those seeking a “legal high”. Between January 1, 2010 and October 1, 2010, there were 1,898 exposures to SCs reported to the National Poison Data System. The median age of reported exposure was 20 years, and most were men. The majority of exposures reported to poison centers are acute exposures however reports regarding chronic exposures are reported. Marijuana is the most widely used illicit substance in the United States however there are many more calls to poison centers regarding synthetic cannabinoid exposures. One explanation for this may be that physicians have more experience managing marijuana exposures and are less likely to need the assistance of poison centers. However another explanation for this discrepancy is that SCs cause more severe clinical effects.

Pathophysiology

Synthetic cannabinoids are receptor agonists that bind to the same endogenous cannabinoid receptors as THC, Cannabinoid 1 and Cannabinoid 2 (CB1/CB2). JWH-018 is one of the earliest and best characterized compound. JWH compounds are named after John W. Huffman, a chemist from Clemson University who synthesized many SC compounds to research CB1/CB2 receptors. CB1 receptors are found throughout the body but are densely concentrated in the brain, spinal cord and peripheral nervous system affecting pain. This receptor is responsible for most of the psychoactive effects of cannabinoids such as elevating a person’s mood. Other effects mediated by this receptor include inducing analgesia, memory impairment and altering one’s sense of time. CB2 receptors are found primarily in tissues of the immune system and have a role in pain as well. Activating these receptors modulate the immune system and are anti-inflammatory. CB2 receptors have been the focus of research due to the possibility that they could decrease pain caused by inflammation without the psychoactive effects of CB1 receptors. The chemical structures of SCs are very different than THC. They are also far more potent than traditional marijuana. For example, JWH-018 has four times the affinity for the CB1 receptor and ten times the affinity for the CB2 receptor. Also, THC is a partial agonist at the CB1 receptor and many of the SCs are full agonists. In addition to the JWH compounds, there are multiple other groups of SCs including CP compounds, HU compounds (developed at Hebrew University) and the benzoylindoles. All are far more potent agonists at the CB receptors compared to THC.

Clinical presentation

The clinical presentation of patients presenting with SC toxicity is variable. For many users, the desired effects of spice consumption resemble cannabis intoxication including relaxation, dishinhibition and euphoria. Nausea and vomiting are among the most common physical complaints. Most patients present with some degree of altered mental status such as central nervous system depression, hallucinations, anxiety, and agitation. Seizures are uncommon, and when they do occur, are typically single episodes, although status epilepticus has been reported. Psychosis characterized by paranoid delusions, and a disorganized, confused state, can occur. Most patients have sinus tachycardia, which typically normalizes over a 4-hour period of observation. Compared to marijuana exposures, there is more tachycardia, agitation, hallucinations and hypertension seen with SCs. With many patients, due to the increased activity, there is a potential for rhabdomyolysis and subsequent acute kidney injury. There are also reports of patients presenting with chest pain and ischemic changes on ECG, although this is rare. The variability in presentation is likely multi-factorial including the SC compound used, individual susceptibility to drug effects and the dose. Chronic use of these drugs can lead to addiction syndrome and withdrawal symptoms similar to what is seen with cannabis use.

Diagnosis

Diagnosis is usually based on a history of exposure. There is not a specific toxidrome associated with SC products and given the variability in clinical presentation, diagnoses based on the physical exam can be challenging. Screening for other substances potentially ingested should be considered particularly in pediatric patients. SCs are not detected in routine medical drug of abuse screens although independent labs offer testing. Patients tend to have negative drug screens for THC metabolites. Clinical testing for these compounds is under development however these tests will most likely only detect the most common synthetic cannabinoids. Very little is known about the metabolism of synthetic cannabinoids, therefore exposure to SCs cannot be proven without data on the metabolites. Thus far, analysis of body fluids relies on the detection of the parent drug.

Treatment

Treatment is primarily supportive. Initial management of these patients should include cardiac monitoring, testing serum electrolytes, and ensuring a secure airway. Recommended supportive care includes intravenous fluids and electrolytes to manage volume and electrolyte disturbances. Benzodiazepines, such as lorazepam 1-2mg IV (children: 0.04mg/kg) should be administered as needed for hallucinations, agitation and seizures. Antiemetics such as ondansetron 4-8mg IV (children: 0.15mg/kg) can be administered as needed for nausea and vomiting. In the majority of patients, clinical effects resolve within 8 hours. A minority of patients may need admission for ongoing symptoms. ED observation is recommended until the patient demonstrates clinical improvement and can be safely discharged.

Discussion of case questions

  1. There is no specific toxidrome associated with synthetic cannabinoid exposure. Clinical effects are variable. The most common clinical effects are tachycardia, hypertension, agitation/irritability, drowsiness/lethargy, confusion, nausea and vomiting, hallucinations and chest pain.
  2. Synthetic cannabinoids are agonists at the CB1 and CB2 receptors and are typically more potent than marijuana.
  3. Treatment of SC toxicity is mainly supportive. Benzodiazepines should be considered to treat the hallucinations, agitation and especially if seizures occur. Antiemetics should be given as needed for nausea and vomiting. Patients should be observed until clinical improvement is demonstrated.