You are working a shift in the emergency department, and you hear the ambulance sirens. EMS is bringing you two patients, friends from a nearby shelter. Per report, the two men were “smoking drugs” together outside of the shelter. Bystanders noted that the 29-year-old man became increasingly agitated, shouting, banging on the door, and threatening his other shelter mates, while the other, a 50-year-old man, laid down on the sidewalk. EMS also reports picking up these patients in an area known for high “K2” use.
Synthetic Cannabinoids: Background
Synthetic cannabinoids (SC), sometimes called synthetic cannabinoid receptor agonists (SCRA), were originally developed to allow investigation of the human endocannabinoid receptor system. As more was learned about this endogenous system, interest grew in their use as therapeutic drugs for various medical ailments, such as the alleviation of the gastrointestinal side effects of chemotherapeutic agents. These compounds interact with the cannabinoid (CB) receptors as does delta-9-tetrahydrocannabinol (THC), the psychoactive component in Cannabis, but they are structurally different and generally more potent [1-3].
Currently, SCs can be classified into several different types: [1, 4]
- THC analogues (also referred to as classic synthetic cannabinoids)
Synthetic chemists, primarily in China, can create hundreds of different SCs, and this helps account for the unpredictable clinical effects seen in the ED. The HBO video below elaborates about the production of SCs in China.
Growing popularity of SC’s
SCs entered the “black market” in 2004 as a novel class of designer drugs marketed with names such as “Spice” and “K2.” Since then, they have grown in popularity throughout Europe and North America. Initially SCs were sold legally (“hidden in plain sight”) as an alternative to Cannabis and they became readily available in gas stations, head shops, and over the Internet. Because of the chemicals’ high potencies and small volumes needed, they are often sprayed onto a bulky substance (e.g., crushed dried plant matter) that resembles Cannabis to allow for easy delivery. It is impossible to predict the dose of SCs associated with any product mainly because of the method in which they are produced (i.e. the bulky plant matter can have any amount of SCs or none at all). The average cost in 2010 was approximately $20-30 per 3 grams of herbal material . In 2012, the Monitoring the Future survey on adolescent drug use reported that about 12% of 12th-graders use SCs .
Despite legal efforts since 2011 to ban these substances, SC use has skyrocketed in urban areas, predominantly among the homeless population. Its falling price, as low as five dollars per “bag” containing from four to ten grams, its association with a “stronger high” when compared to Cannabis, and its easy accessibility all add to its popularity [3, 7]. With recent seizures in small shops in New York City yielding over two million packages, the supply of SCs appears to be so vast that this may account for its dropping price. In addition, SCs’ inconspicuous nature (i.e they are not detected by standard drug testing for THC) made them popular in schools and among athletes.
This New York Times article depicts the more current use of SCs in east Harlem .
Can SC’s be easily detected in the urine today?
The answer is still NO. The most common urine drug screen still used today is the EMIT, or enzyme mediated immunoassay technique, specifically designed to detect a chemical structure present above a specified cutoff of detection. Currently, some assays screen for “cannabinoid” but typically only detect THC-COOH (a metabolite of THC) at concentrations greater only than 50 ng/mL. At best, newer urine drug tests detect the original SCs such as JWH-018, which are no longer in widespread use. Newer SCs are structurally very different from THC and JWH-018 [Figure 1]. Therefore, the newer SCs continue to evade routine testing.
Figure 1. Cannabis and synthetic cannabinoids. 
How are SC’s marketed, and what is the problem with calling it “synthetic marijuana” or “K2?”
SCs are being marketed as “synthetic marijuana” for 2 reasons already mentioned:
- They are often crushed dried plant matter onto which synthetic compounds are sprayed or soaked.
- This synthetic product binds to the same receptor as THC.
However, referring to these products as synthetic marijuana is misleading because Cannabis is a plant and not a chemical. Furthermore, the clinical effects do not resemble those of marijuana use. THC is mainly responsible for the psychoactive effect of Cannabis. It is a partial agonist at the CB1 and CB2 receptors, whereas SCs are full agonists at these receptors [1, 3]. Furthermore, Cannabis contains over 60 other cannabinoid compounds, one of which is cannabidiol (CBD). CBD has non-psychoactive effects that occur through antagonism at CB1 receptors [8, 9, 12]. In fact, CBD is being evaluated as an anti-epileptic agent due to its neuroinhibitory effects. Some theorize that adjusting the THC:CBD ratio may help abate the psychoactive effects of Cannabis. SCs lack CBD and other compounds found in Cannabis, possibly contributing to their greater potency and association with more severe toxicity.
SCs collectively are commonly referred to as “K2,” which was one of the original “brand names” for these drugs. However, this too is misleading, because SC products are now being marketed with names such as “Clown,” “Scooby Snax,” “Green Giant,” “iBlown,” “Ninja,” and “Loopy,” among many others. They are packaged in small bags and labeled “not for human consumption” to evade legal scrutiny. However, this “caveat” placed on the packaging has largely served as a covert marker for the actual intent of the product [1, 3]. A package can contain one SC, more than one SC, none at all, and there may even be variability in the SC content within a given brand product. Newer SCs that have been discovered in products include AB-Chiminaca, AB-Fubinaca, AB-Pinaca, MAB-Chiminaca, and LXR-11.
How are SC’s classified and what are the clinical effects?
Since April 2015, the number of ED visits and calls to Poison Control Centers for SC-related toxicity has skyrocketed. In a single 2-month period, there were over 2,000 SC-related ED visits in New York City alone . Patients tend to present in 1 of 2 ways :
- Somnolent, sometimes with other signs/symptoms similar to sedative-hypnotic intoxication including bradycardia or hypotension
- Agitated, resembling sympathomimetic use with tachycardia, hypertension, and sometimes seizure activity
Of note, some patients quickly fluctuate from one state to the other. Several deaths with confirmed SC exposure have been reported [11, 13].
How are patients who present with SC intoxication treated?
As with any ED patient, management should begin with managing the airway, breathing, and circulation. In patients with agitation or seizure activity, benzodiazepines should be first-line agents. The use of antipsychotic agents, such as haloperidol, is NOT recommended due to their association with QT prolongation. Furthermore, evidence based support for the safety of ketamine in toxin-induced agitation is still lacking. Ketamine administration in patients with SC-induced agitation may worsen hypertension and tachycardia, and the long-term psychiatric effects are unknown. Additionally, agitated patients should be evaluated for hyperthermia, and cooling measures employed quickly if necessary. They should also be assessed for rhabdomyolysis.
If CNS depression occurs, observation is warranted until the patient returns to baseline mental status. Respiratory depression has not been a consequential problem, but should be assessed and monitored as needed. Hypotension is treated with intravenous crystalloids, and if persistent, vasopressors may be necessary. Bradycardia treatment is rarely required, but should follow standard measures.
The 29-year-old man with agitation required sedation with midazolam. His initial vital signs were notable for: BP, 145/92 mmHg; HR, 120/min; RR 22/min; T 38C. Once he was adequately sedated, his vital signs normalized and he returned to baseline within approximately 4 hours. The 50-year-old man presented with initial hypotension (88/56 mmHg) with a heat rate of 90 beats per minute. His temperature and respiratory rates were within normal limits. He was given a total of 3 liters of normal saline and was observed for 6 hours prior to discharge with normal mentation and vital signs. They both endorsed daily SC use.
- Su MK, Seely KA, Moran JH, Hoffman RS. Metabolism of classical cannabinoids and the synthetic cannabinoid JWH-018. Clin Pharmacol Ther. 2015; 97(6):562-4. PMID: 25788107
- Shanks KG, Winston D, Heidingsfelder J, Behonick G. Case reports of synthetic cannabinoid XLR-11 associated fatalities. Forensic Sci Int. 2015; 252:e6-9. PMID: 25979131
- Seely KA, Lapoint J, Moran JH, Fattore L. Spice drugs are more than harmless herbal blends: a review of the pharmacology and toxicology of synthetic cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry. 2012; 39(2):234-43. PMID: 22561602
- The Chemistry of Cannabis & Synthetic Cannabinoids. Compound Interest. Published May 2015. Accessed April 18, 2016.
- Reed T. K2: Easily Accessible Substance That Mimics Marijuana – and Is Legal – Sold in Ann Arbor. The Ann Arbor News. Published February 2010. Accessed April 18, 2016.
- Monitoring the Future National Survey Results on Drug Use 1975-2012. 2012 Overview, Key Findings on Adolescent Drug Use [PDF]. Accessed April 19, 2016.
- Casey N. New York K2, a Potent Drug, Casts a Shadow Over an East Harlem Block. Times. Published Sept 2, 2015. Accessed April 19, 2016.
- Friedman D, Devinsky O. Cannabinoids in the Treatment of Epilepsy. N Engl J Med. 2015; 373(11):1048-58. PMID: 26352816
- Ameri A. The effects of cannabinoids on the brain. Prog Neurobiol. 1999; 58(4):315-48. PMID: 10368032
- Stewart N. New York City Council Initiates Steps to Ban the Manufacture of K2. New York Times. Published September 2015. Accessed April 18, 2016.
- Schwarz A. Potent ‘Spice’ Drug Fuels Rise in Visits to Emergency Room. New York Times. Published April 2015. Accessed April 18, 2016.
- Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO. Cannabidiol–recent advances. Chem Biodivers. 2007; 4(8):1678-92. PMID: 17712814
- Trecki J, Gerona RR, Schwartz MD. Synthetic Cannabinoid-Related Illnesses and Deaths. N Engl J Med. 2015; 373(2):103-7. PMID: 26154784
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