Unholy Smokes
Synthetic cannabinoid use and related emergency department (ED) visits are skyrocketing in the United States. Here are answers to questions that every emergency physician should know about this recent epidemic.
1. What are synthetic cannabinoids, and how are they different from marijuana?
Back in the 1980s, John W. Huffman, a chemistry professor Clemson University, worked on compounds that targeted endocannabinoid receptors to develop new therapies for multiple sclerosis and HIV/AIDS, and reduce adverse effects of chemotherapy. Over a 20-year period, Huffman and his team synthesized more than 450 synthetic cannabinoid compounds, many bearing his initials “JWH.” In the early 2000s, synthetic cannabinoids based on JWH compounds were marketed as marijuana alternatives in Germany.
These compounds are mechanistically similar to tetrahydrocannabinol (THC), the active ingredient in marijuana, and bind to the cannabinoid receptors (CB1 and CB2), but display different pharmacologic properties. THC is a partial agonist, while many synthetic cannabinoids are full agonists, with an affinity more than 100 times greater than THC [3]. Attempts to use them clinically have been unsuccessful, due to difficulty separating the desired properties from unwanted psychoactive effects. Illicit drug manufacturers seized on the mind-altering potential of these chemicals and began distributing synthetic cannabinoid compounds in the early 2000s. To date, most have not been clinically tested, but many JWH compounds possess psychoactive properties and are implicated in today’s epidemic. When asked about the recreational use of synthetics, Dr. Huffman said, “I figured once it got started in Germany it was going to spread. I’m concerned that it could hurt people. I think this was something that was more or less inevitable. It bothers me that people are so stupid as to use this stuff [1].”
By contrast, synthetic tetrahydrocannabinol (THC) is available as dronabinol (Marinol) and nabilone (Cesamet) and is used primarily to treat nausea and vomiting in patients undergoing chemotherapy and for AIDS-related cachexia. However, these compounds are Food and Drug Administration approved, have known safety and efficacy, and predictable potency and purity profiles. These formulations are unrelated to synthetic cannabinoids and the products that contain them.
Today, companies buy these synthetic cannabinoids in bulk, often from laboratories in China. They are then sprayed on inert dried plant material. The look of the final product leads to the misguided belief that these products are “synthetic marijuana.” Synthetic cannabinoids are sold under a variety of product names, including K2, Spice, Spice Gold, Spice Diamond, Yucatan Fire, Solar Flare, K2 Summit, Genie PEP, Spice Fire “n” Ice, Bliss, Black Mamba, Bombay Blue, Zombie World, Bad-to-the-Bone, Blaze, Dark Night, Earthquake, Berry Blend, The Moon, G-Force, K2 Blonde, K2 Standard, Blueberry Haze, Dank Demon, Passion Smoke, Hawaiian Hybrid, Magma, Ninja, Ono Budz, Panama Red Ball, Puff Sativah, Herbal Smoke, Skunk Ultra, Chronic Voodoo, Spice Aroma, and others. This list includes some more of the common products and brand names are ever-changing.
2. How fast is synthetic cannabinoid use increasing?
ED visits for synthetic cannabinoid visits more than doubled in the U.S. from 11,406 in 2010 to 28,531 visits in 2011 [2]. Although marijuana continues to be the most frequently used substance by teens and adolescents, synthetic cannabinoids are second, with 10% of high school students reporting use in 2014 in one survey [3]. In another survey published in 2015, drugs appeared more optimistic, suggesting the drugs use is in decline over the last three years in high school seniors [4]. However, according to recent reports in TIME, the New York Times, The Washington Post, and NPR, use of synthetic cannabinoids have become an epidemic. For example, the New York Times reported earlier this year 2,300 ED visits over a two-month period in New York City alone [5].
3. Where do people obtain synthetic cannabinoids and how do they use them?
Synthetic cannabinoid-containing products are sold in gas stations, smoke shops, and other venues around the country. They are also widely available online, with little regulatory oversight, and some varieties are as inexpensive as $5 a gram, with free shipping. They are generally sold under the guise of herbal incense or other household products, and are labeled “not for human consumption.” This disclaimer has a dual purpose. It protects the marketer of compounds with abuse potential (which is a legal practice, as with gasoline) and it has come to be a signal that a product contains a psychoactive compound. Regardless, based on the packaging, the intended use of these products is quite obvious. Synthetic cannabinoids are typically smoked in a manner similar to marijuana, and the pure chemical obtained prior to spraying on plant material can also be used in electronic cigarettes such as vaporizers. Other users prefer to make “edibles” by adding synthetic cannabinoid or synthetic cannabinoid-containing products to cookies and cakes. In one study, the most commonly reported route of administration of use was a water pipe (‘bong’, 54%), while approximately one-quarter smoked synthetic cannabinoids in a ‘joint’ (27%) or ‘pipe’ (23%). Only a few respondents ate the products (4%) or inhaled them using a vaporizer, a device that vaporizes active ingredients from plant material for inhalation without combustion (2%) [6].
4. How do patients with synthetic cannabinoid intoxication present in the emergency department?
Two clinical syndromes are commonly seen in ED patients after using synthetic cannabinoids. Patients may appear highly agitated and have symptoms similar to phencyclidine (PCP) or methamphetamine use including hallucination, aggressive behavior, or paranoia. Alternatively, patients may appear sluggish and have symptoms similar to an opioid overdose including lethargy, confusion, respiratory depression, hypotension, bradycardia, vomiting, seizure, elevated heart rate, or depressed level of consciousness.
In a case series of 22 patients presenting to the ED, hyperglycemia was seen in 59%, hypokalemia in 41%, acidosis in 32%, tachycardia in 59%, nausea/vomiting in 36%, confusion/disorientation in 32%, aggression in 32%, somnolence/unresponsiveness in 32%, and seizures in 14%. Complications included pneumonia, rhabdomyolysis, and myocardial infarction. Twenty-seven percent of patients were admitted to the intensive care unit and 23% required assisted ventilation [7]. In review of calls to US poison control centers from January to April 2015, among 2,961 calls for which a medical outcome was reported, 335 (11.3%) callers had a major adverse effect (signs or symptoms that are life-threatening or result in substantial residual disability or disfigurement) and 1,407 (47.5%) had a moderate effect [8].
Because of their structural distinction from THC, synthetic cannabinoids are not detected on any standard immunoassay-based urine drug screen. For this reason, they often appeal to people whose jobs require drug testing, such as government employees, athletes, parolees, students, and members of the armed forces. However, they are easy to identify with more advanced analytical testing done at a reference lab. The clinical need for this testing is limited, and given the long turn-around times such testing is usually only done for epidemiologic or forensic purposes.
Treatment is generally supportive. There is no specific antidote or antagonist for the cannabinoid receptor. Benzodiazepines have been used successfully to treat sympathomimetic effects, such as agitation and aggressiveness, as well as prolonged or recurrent seizures. For patients who present primarily with hallucinations or other psychiatric effects, haloperidol or atypical antipsychotics, though unstudied, seem reasonable. Antipsychotics are not optimal as the sole therapy for patients with stimulant toxidromes. However, although some patients can be severely ill on presentation, the effects of synthetic cannabinoids are usually short-lived and most patients do well if they can be supported through the first several hours. Therefore it is best to try to temporize with short-acting drugs if safe and practical.
The full scope of health effects with synthetic cannabinoids is still incompletely understood; however, stroke, myocardial infarction, rhabdomyolysis, renal failure, pulmonary disease as well as severe neurologic and psychiatric morbidities have been described.7 Although uncommon, deaths from exposure to synthetic cannabinoids have occurred. A major safety concern is that the content of any particular brand of synthetic cannabinoid can vary between or even within packages, meaning that the “dose” and clinical effects are not predictable. Even if some synthetic cannabinoids themselves are safe in small doses, this unpredictability carries significant risks for overdose or drug interaction.
5. Why is it legal to sell synthetic cannabinoids?
Despite legislative attempts to stem the tide of synthetic products flooding the market, synthetic cannabinoids remain widely available. These drugs pose a unique challenge to legislators given the open nature in which the drugs are being sold and the speed with which novel compounds are being developed. Initially, laws targeted individual versions of these drugs with individual bans. However, as hundreds of designer compounds, falling into several major families, were reformulated in an effort to stay ahead of drug enforcement agencies, these efforts became futile. Newer laws are more general in nature, targeting entire classes of substances and using broad language to describe the prohibited drugs.
In the United States, prior to 2010, synthetic cannabinoids were not controlled by any state or at the federal level. As of today, all 50 states have banned synthetic cannabinoids as well as synthetic cathinones (e.g., bath salts), with most doing so by legislative action. Congress has also taken steps to ban these substances at the federal level with broad support from the current administration. In 2011, the Drug Enforcement Agency (DEA) exercised its emergency scheduling authority to control five of the most common types of the drugs (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol). The following year, President Obama signed into law The Synthetic Drug Abuse Prevention Act as part of the Food and Drug Administration Safety and Innovation Act of 2012. This law permanently placed 26 types of synthetic cannabinoids and cathinones into Schedule I of the Controlled Substances Act (CSA) as well as expands the power of the DEA to administratively schedule substances under its emergency scheduling authority. More recently, a few states also have passed laws restricting marketing, display, labeling, and advertising of these substances by utilizing consumer protection laws or classifying these activities as deceptive trade practices.
Efforts to curtail use have been in place since 2008, when products containing JWH-018 were listed as a controlled substance by the Austrian Ministry of Health. In addition, an increasing number of countries are passing laws to make synthetic cannabinoids illegal, including France, Germany, United Kingdom, and Russia. Synthetic cannabinoids remain unregulated in Slovakia, Spain, as well as many South American countries, and Mexico. The situation in Canada remains unclear as no specific forms of the drugs have been prohibited, but they are listed as schedule II drugs.
6. What can be done?
Legislative action and law enforcement efforts are ongoing worldwide and in the U.S. at both the state and federal levels. In some areas, such as Washington, DC, local health departments are obtaining blood and urine tests for suspected synthetic cannabinoid exposures for epidemiologic purposes. As this epidemic grows, the number of poison control calls, ED presentations, and hospital admissions will likely continue to increase. Emergency physicians should be familiar with common presentations and side effects of synthetic cannabinoid exposure. Early recognition and aggressive supportive care, especially during the first several hours can dramatically improve outcomes and save lives. In addition, an ED visit presents an opportunity to educate your patients about the harmful effects of synthetic cannabinoids, and why they should never ever take them again.
REFERENCES
- C&EN Talks With John W. Huffman. Chemical & Engineering News. Available at: http://cen.acs.org/articles/88/i26/John-W-Huffman.html?type=paidArticleContent, Accessed Oct. 19, 2015
- Update: Drug-Related Emergency Department Visits Involving Synthetic Cannabinoids – SR-1378.pdf [Internet]. [cited 2015 Oct19]. Available from: http://www.samhsa.gov/data/sites/default/files/SR-1378/SR-1378.pdf
- Wiley JL, Marusich JA, Lefever TW, Antonazzo KR, Wallgren MT, Cortes RA, et al. AB-CHMINACA, AB-PINACA, and FUBIMINA: Affinity and Potency of Novel Synthetic Cannabinoids in Producing Δ9-Tetrahydrocannabinol-Like Effects in Mice. J Pharmacol Exp Ther. 2015 Sep;354(3):328–39.
- Monitoring the Future. Available at: http://www.drugabuse.gov/related-topics/trends-statistics/monitoring-future/monitoring-future-survey-overview-findings-2014, Accessed Oct. 19, 2015
- New York Times. April 25, 2015 Available at: http://www.nytimes.com/2015/04/25/health/surge-in-hospital-visits-linked-to-a-drug-called-spice-alarms-health-officials.html?_r=0, Accessed Oct.19, 2015
- Barratt MJ, Cakic V, Lenton S. Patterns of synthetic cannabinoid use in Australia. Drug Alcohol Rev. 2013 Mar;32(2):141–6.
- Notes from the field: Severe illness associated with synthetic cannabinoid use – Brunswick, Georgia, 2013. MMWR – Morb Mortal Wkly Rep. 2013 Nov;62(46).
- Increase in Reported Adverse Health Effects Related to Synthetic Cannabinoid Use — United States, January–May 2015. Available at: http://s3.documentcloud.org/documents/2096641/mm6422-ebook.pdf
