K2: From Fad to Enemy #1

Synthetic cannabinoids like K2 and Spice are more dangerous than ever, and they’re here to stay.

Synthetic cannabinoids often referred to as K2, Spice, or ‘legal highs’ first appeared in the United States in 2008 and in Europe as early as 2004 [1]. While sold under a variety of names, they are all cannabinoids and act on the same receptors as marijuana. While they act on the same receptors and for the most part are sold legally, their effects are much more toxic than marijuana and as dangerous as many other illegal or scheduled drugs. Due to the intense media attention and the severe morbidity associated with these drugs, Emergency Physicians Monthly published a column last October about the 6 things EVERY emergency physician should know about these ‘legal highs [2].’ Before we get to WHAT ELSE every emergency physician needs to know, I’ll briefly review some key points from last year’s publication.

While synthetic cannabinoids may look like marijuana, their pharmacologic properties are not similar, which leads to a very different clinical picture than what is typically associated with marijuana. In fact, their physical appearance is only similar to marijuana because manufacturers spray these chemicals on herbaceous materials to make them look alike, which unfortunately leads the user to believe that they may not be any more dangerous than typical marijuana. This has severe consequences because these drugs can cause sympathomimetic effects and severe agitation that is not normally seen with marijuana. They are associated with myocardial infarctions, intracranial hemorrhages, and seizures. Also even with the signing of The Synthetic Drug Abuse Prevention Act and other state-level legislation, most of these cannabinoids are still legal, and unfortunately, easily assessable at gas stations and head shops. In addition to being difficult to outlaw, synthetics are easily and cheaply produced in large capacity in countries such as China. From there, they are shipped to the US where they flood the market with cheap drugs that can easily be replaced with new versions once older forms become illegal.

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Unfortunately, this epidemic has only continued to get worse. US poison centers reported a 330% increase in reported cases in the first 4 months of 2015 [3]. In March of 2015, 269 cases were reported to poison centers. This number jumped to 1,512 case in April of that year [4]! New York had to issue a health alert after more than 160 citizens were hospitalized over a 9 day period in April 2015 [5]. Over an 11 hour period one Tuesday in July 2016, 33 people collapsed in Brooklyn after abusing synthetic cannabinoids [6]. This trend was also reported by the DEA, who recently reported 22 clusters including 2 deaths and another 25 episodes including 18 more deaths in 5 states between 2011–2015 [7]. What makes this so remarkable is that, in general, as emergency physicians become more familiar with certain drugs of abuse, they tend to call the poison center less to ask for management assistance. How many of us call a poison center, for instance, for each heroin overdose? So the fact that the number of K2 cases did not level off but has astronomically increased is even more concerning than it already seems.

In July, the American College of Medical Toxicology and the Toxicology Investigator’s Consortium (ToxIC) published 5 years worth of data regarding patient exposures to synthetic cannabinoids [8]. ToxIC is a voluntary registry composed of patients personally evaluated by a medical toxicologist for any reason. During that time period, medical toxicologists treated 456 patients with synthetic cannabinoid intoxication. While that may not seem like a lot, consider 2 points: 1) ToxIC members represent a limited number of sites (50 as of this publication) and 2) this likely only consisted of patients sick enough that someone requested a bedside consultation by a toxicologist. Toxicologists are less likely to be consulted on the “typical” patient that presents with intoxication from one of these agents, sobers up over a few hours, and is then discharged. Among the 456 exposures, 125 (27.4%) occurred in children aged 13–18. This is disturbing not only due to how dangerous these drugs are, but also, we know that use of drugs at an early age predisposes people to further drug addiction and substance abuse later in life. In addition in 2015, the annual percentage of reported cases increased in all US regions. In 2014, less than 1.5% of all ToxIC cases reported in the Northeast and <1% of all cases reported in the Midwest were due to synthetic cannabinoids. In 2015, this jumped to approximately 3.5% in the Northeast and 1.5% in the Midwest even though the total number of cases in the registry also increased. While some of the increase could be from better recognition, it likely is better explained by increasing toxicity and morbidity.

As alarming as these numbers are, they likely represent an underreporting for a variety of reasons. Currently, there is not a clinically useful test to confirm the diagnosis. Even if the correct diagnosis is made, the correct ICD-10 code is inconsistently applied, which could make cases difficult to find when retrospectively reviewing data. While poison center data is likely coded better, this data is well known to be underreported as calling the poison center is voluntary in most states.

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More concerning than just the numbers alone is the constant change and severity in patient’s symptomatology. Most emergency physicians associate these drugs with agitation and sympathomimetic toxicity. In many cases, these patients require some sedation but can be discharged from the emergency department. Of course some can get very sick, including a patient who developed a hemorrhagic stroke after smoking Spice [9]. However, recent data seems to indicate this pattern is changing for the worse. In addition to agitated delirium, many patients are now presenting with significant central nervous system (CNS) or respiratory depression, in some cases so severe that patients are intubated for airway protection. Lately, we have seen a large number of patients presenting to our institution with CNS depression and bradycardia. While many recovered with general supportive care, it took a while to recognize this new pattern leading to large and unnecessary evaluations to determine the cause of their symptoms. Even after determining the cause, many patients still re-quired intensive monitoring and even ICU admissions in a few cases. Even more interesting is that recently published data demonstrates that a number of patients have rapidly fluctuating mental statuses ranging from severe agitation to unresponsiveness. This makes it very challenging to treat them because patients can present so differently. In addition it is difficult for the physician to anticipate the effect of treatment on these patients. Eleven patients recently presented over 1.5 months after exposure to a novel synthetic, MAB-CHMINACA.5 Of the 11 patients, 9 required intubation! Some patients fluctuated between obtundation and severe agitation, while some remained obtunded until they became sober and woke up. Only 2 of the 11 could be discharged the same day; many were admitted to the ICU and some occupied hospital beds for almost a week. An 18 year old was diagnosed with serotonin syndrome following ingestion of “Damnation,” which contains the synthetic MDMB-CHMICA [10]. The patient’s measured blood concentration of the synthetic was relatively low compared to the rest of the subjects in the case series, suggesting a very potent drug. Adamowicz reports 2 patients that were found unresponsive after smoking synthetic cannabinoids; 1 patient developed respiratory depression [11]. The same author reports the death of a 25 year old whom suddenly had an asystolic cardiac arrest within minutes of smoking the legal high “Mocarz [12].” Jinwala reported 2 patients requiring intubation due to respiratory failure [13]. One patient had waxing and waning of his mental status before developing respiratory failure; the second patient presented obtunded and apneic.

Treatment is supportive. Agitated patients need emergent sedation and cooling if they are hyperthermic. Sedated or unconscious patients need close monitoring of their airway and may need to be intubated. Best treatment practices are based on opinion and personal experiences. Most toxicologists would treat agitation with aggressive titration of benzodiazepines. While benzodiazepines can be administered intramuscularly for patients without IV access, high dose ketamine (4–5 mg/kg IM) has been successfully used in the pre-hospital setting in severely agitated patients. While that literature does not specifically include patients with synthetic cannabinoid intoxication, it is reasonable to conclude that ketamine should be effective in managing these patients. While neuroleptics are commonly administered in the emergency department, most toxicologists would likely recommend benzodiazepines. If neuroleptics are to be used, haloperidol has a negligible amount of anticholinergic activity. Neuroleptics with more anticholinergic activity can be dangerous as they can prevent hyperthermic patients from sweating and cooling themselves. However, haloperidol can lower the seizure threshold, something these patients are already at an elevated risk of having.

In addition to new presentations of acute intoxication, withdrawal from these agents is also now being reported. While the validity of a withdrawal syndrome is not established, one cohort study reported on 47 patients presenting with synthetic cannabinoid withdrawal [14]. Of course, the majority of symptoms were subjective and not life threatening in nature. Zimmerman reported a 20 year old who developed diaphoresis, nausea, tremor, hypertension, tachycardia, and cravings four days after abstaining from Spice [15]. Depending on the amount and frequency of drug use, withdrawal symptoms can develop even sooner after patients stop smoking synthetic cannabinoids. Some have reported withdrawal symptoms as their main reason for continued use, which is not too different than some patients with opioid use disorders [14]. One patient reported smoking every 45 minutes throughout the night to avoid withdrawal [16]. Common adverse events reported included cravings, headache, anxiety, and insomnia; seizures, chest pain, palpitations were also reported [1].

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Synthetic cannabinoids continue to be a source of major morbidity and mortality. This is particularly unfortunate as many underestimate the severity of their effects as they are legal and made to look like common marijuana. There may even be a withdrawal syndrome associated with them. Given the constant changes to their chemical structures, we can continue to expect that patients will present with new and constantly changing signs and symptoms, which makes diagnosis and treatment challenging.

REFERENCES

1. Cooper ZD. Adverse Effects of Synthetic Cannabinoids: Management of Acute Toxicity and Withdrawal. Curr Psychiatry Rep 2016;18(5): 52
2. Tatusov M, Mazer-Amirshahi M, Nelson L, Pines J. 6 Things Every EP Needs to Know about K2/Spice & the Synthetic Cannabinoid Epidemic. Emergency Physicians Monthly. https://epmonthly.wpengine.com/article/6-things-every-ep-needs-to-know-about-k2spice-the-synthetic-cannabinoid-epidemic/. Accessed August 6, 2016.
3. Law R, Schier J, Martin C, Chang A, Wolkin A. Increase in reported adverse health effects related to synthetic cannabinoid use—United States, January–May 2015. MMWR Morb Mortal Wkly Rep 2015;64:618–9
4. Synthetic Marijuana Data. American Association of Poison Control Centers Web site. Available at: https://aapcc.s3.amazonaws.com/ files/library/Syn_Marijuana_Web_Data_through_7.6.15.pdf. Accessed on August 5, 2016
5. Katz KD, Leonetti AL, Bailey B, Surmaitis RM, Eustice ER, Sacinko S, Wheatley SM. Case Series of Synthetic Cannabinoid Intoxication from One Toxicology Center. West J Emerg Med 2016;17(3):290-4.
6. Scutti S. Suspected overdose of synthetic pot, K2, sends 33 people to Brooklyn hospitals. http://www.cnn.com/2016/07/13/health/k2-overdose-brooklyn-synthetic-marijuana/. Accessed on August 5, 2016.
7. US Drug Enforcement Administration Office of Diversion Control. Schedules of controlled substances: temporary placement of three synthetic cannabinoids into Schedule I. 21 C.F.R. Part 1308 (2015). http://www.deadiversion.usdoj.gov/fed_regs/rules/2015/fr0130.htm
8. Riederer AM, Campleman SL, Carlson RG, Boyer EW, Manini AF, Wax PM, Brent JA. Acute Poisonings from Synthetic Cannabinoids-50 U.S. Toxicology Investigators Consortium Registry Sites, 2010-2015. MMWR Morb Mortal Wkly Rep 2016;65: 692-695.
9. Rose DZ, Guerrero WR, Mokin MV, Gooch CL, Bozeman AC, Pearson JM, Burgin WS. Hemorrhagic stroke following use of the synthetic marijuana “spice.” Neurology 2015;85(13):1177-9.
10. Seywright A, Torrance HJ, Wylie FM, McKeown DA, Lowe DJ, Stevenson R. Analysis and clinical findings of cases positive for the novel synthetic cannabinoid receptor agonist MDMB-CHMICA. Clin Toxicol 2016;54(8):632-7.
11. Adamowicz P, Gieron J. Acute intoxication of four individuals following use of the synthetic cannabinoid MAB-CHMINACA. Clin Toxicol 2016;54(8):650-4.
12. Adamowicz P. Fatal intoxication with synthetic cannabinoid MDMB-CHMICA. Forensic Sci Int 2016;261:e5-10.
13. Jinwala FN, Gupta M. Synthetic cannabis and respiratory depression. J Child Adolesc Psychopharmacol 2012;22(6):459-62.
14. Marfarlane V, Christie G. Synthetic cannabinoid withdrawal: a new damand on detoxification services. Drug Alcohol Rev 2015;34:147-153.
15. Zimmerman US, Winkelmann PR< Pilhatsch M, Nees JA, Spanagel R, Schulz K. Withdrawal phenomena and dependence syndrome after the consumption of Spice Gold. Dtsch Arztebl Int 2009;106:464-7.
16. Rodgman CJ, Verrico CD, Worthy RB, Lewis EE. Inpatient detoxification from a synthetic cannabinoid and control of postdetoxication cravings with naltrexone. Prim Care Companion CNS 2014;16:4.