The following article is printed in its entirety from the Journal of Emergency Medicine, February, 2013. Those of us who attend high volume emergency rooms have seen a recent spike in drug-related overdoses connected to the ingestion of "spices" laced with synthetic cannabinoids. The article that follows will provide a basic understanding of this new toxic exposure in our communities.
Background: Synthetic cannabinoid receptor agonists are becoming increasingly popular with adolescents as an abused substance. Chronic use of these drugs can lead to addiction syndrome and withdrawal symptoms similar to cannabis abuse. Due to their potential health risk, several countries have banned these substances.
Objectives: To report the clinical presentation and legislation status of synthetic cannabinoids in "Spice" products and alert the health care community about the identification and risk assessment problems of these compounds.
Case Reports: We retrospectively reviewed cases presenting to our Emergency Department (ED) during a 3-month period with chief complaints of Spice drug use before arrival. Six cases presented to our ED after using Spice drugs. Two patients were admitted after reporting seizures. All but one presented with tachycardia. Two patients had hallucinations. The average length of ED observation was 2.8 h. No patient with seizures had recurrent episodes.
Conclusion: Spice drugs can cause potentially serious health care conditions that necessitate ED evaluation. Most cases can be discharged from the ED after a period of observation. Legal issues surrounding these drugs are yet to be finalized in the United States.
Introduction
Synthetic cannabinoid receptor agonists are becoming increasingly popular with adolescents as an abused substance (). Teens and young adults are presenting to Emergency Departments (EDs) with effects of smoking "Spice drugs." These Spice drugs, used to attain an "herbal high," are an herbal mixture marketed as legal marijuana, or a legal alternative to marijuana (). They are purported to have a similar psychoactive effect as cannabis. In December 2008, a European drug monitoring system found that these herbal mixtures contained synthetic indole derivatives that affect the Cannabinoids 1/Cannabinoids 2 receptors (CB1/CB2).[1] These drugs are widely marketed in Europe, the United States, and Japan, and easily accessible from the Internet. The packaging typically describes the content as herbal incense and "not for human consumption." Many of these drugs are much more potent than delta-9-tetrahydrocannabinol (THC), therefore, the psychoactive dose may be < 1 mg.[1,2].
Common Street Names of Synthetic Cannibinoids:
Albino Rhino Buds Aroma
Barely legal
Black Mamba Bliss
Bombay Blue Caneff 5 star Chillin XXX D-Raw
Dark Matter
Dream
Everlast
Ex-ses (Platinum) Experience: Chill Experience: Ignite Experience: Red Ball Fake marijuana Fake Weed
Fusion Galaxy
Genie
Gorilla
Herb Dream Herbal incense
Ice Bud Extra Cold K2
K3
K3 Legal
Kronic
Krypto Buds Magic
Mojo
Moon Rocks
Pep Spice
Red Magic
Sence
Skunk
Smoke
Solar Flare
Space
Space Truckin'
Spice
Spice Arctic Synergy Spice Tropical Synergy Spice Diamond
Spice Gold Spice Gold Spirit Spice Silver Spicey XXX SpiceWorld420 Spice99 (Ultra) Spike99
Smoke
Splice Platinum Star Fire
Syn
Yucatan Fire Zohai
Zohai SX
Chronic use can result in an addiction syndrome and withdrawal symptoms similar to cannabis abuse.[3] Several European countries and, more recently, the United States (US), have placed restrictions or banned the use and sale of Spice drugs due to the dangerous effects and abuse potential of the drugs.[4–7] The US Drug Enforcement Administration (DEA) has temporarily designated five of these chemicals (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) as Schedule I substances. This action makes selling and possession of these substances illegal for at least 1 year, giving the DEA and the US Department of Health and Human Services (DHHS) time to study whether these agents will be permanently controlled in the United States.[7]
The potency and psychoactive effects of these agents make them potentially addictive and hazardous compounds. We report a series of cases presenting to our ED after the use of Spice drugs and provider request of a Toxicology consult. We will provide a review of the clinical, pharmacological, and legal aspects of synthetic cannabinoids.
Case Reports
Case 1
A 19-year-old woman was brought to the ED after reportedly having a seizure. She was smoking "Bayou Blaster®" with three friends when she began having jerking motions of the extremities. When paramedics arrived, the patient was awake but agitated and required physical restraints. She arrived with altered mental status, somnolent, and would not speak to ED personnel, but would repeat periodically, "Is this real?" On physical examination, the vital signs included a blood pressure of 153/84 mm Hg, pulse 116 beats/min, and respirations 18 breaths/min. She was hyper-reflexic, otherwise, the remainder of the examination was unremarkable. The urine drug screen for THC metabolites and other drugs of abuse were negative. After 3 h of observation in the ED, she remained somnolent and was admitted to the hospital. The hospitalization was uneventful, except the patient expressed depression and suicidal ideations and was transferred to the Mental Health ward. She was discharged on the 4th hospital day.
Case 2
The parents of a 17-year-old boy attempted to bring him to the ED due to dangerous behavior described as "running in and out of traffic." The teen had apparently smoked "legal marijuana" known as "Humboldt Gold" (by Happy Shaman Herbs®) and became agitated and was hallucinating. The parents described myoclonic jerking en route to the ED, and the patient attempted to get out of the moving car by breaking the window with his head. The parents stopped the car and called 9-1-1 for Emergency Medical Services. Paramedics were able to subdue the patient and transport him to the ED. In the ED he described being in multiple dreams, occurring one after the other and he "couldn't get out." The vital signs were remarkable for sinus tachycardia (pulse rate 134 beats/min), and blood pressure 144/68 mm Hg. The examination revealed flushed skin, dilatated pupils, and the appearance of responding to internal stimuli (inappropriate laughter and silence when asked questions). Neurologic examination revealed hyperreflexia without clonus, and there was occasional jerking of the limbs, but no obvious seizure activity. The urine toxicology screen for drugs of abuse, including THC metabolites, was negative. After approximately 2 h of observation in the ED, the patient gradually became less agitated, his heart rate decreased to 93 beats/min, and he was discharged in the company of his father.
Case 3
Paramedics transported a 17-year-old boy from a party after he complained of inability to move his limbs. He admitted to smoking "Space" and several minutes later the symptoms occurred. He stated that this was his first experience with the substance. His symptoms began after taking three "hits" of the Space cigarette. On examination, he appeared anxious and repeatedly asked "what's wrong with me, why can't I move my arms?" The general examination was remarkable for anxious appearance and mild hyperreflexia, and initial pulse rate was 130 beats/min. Pupils were mid-positioned; and he would hold his arm in the abducted position placed by the examiner, then would slowly lower it. He gradually began moving all extremities and was able to ambulate with minimal assistance after 2 h of ED observation. At approximately 3 h of observation, his heart rate was 94 beats/min, he walked without assistance, and he was discharged with his parents. A urine drug screen was not obtained.
Case 4
A 19-year-old man was brought to the ED by paramedics for possible seizure. The patient's mother heard him scream, and then ran to his room to find him "hallucinating," swinging his fists and having the appearance of being frightened. Subsequently the mother described seizure-like activity, followed by "foaming at the mouth," cyanosis, and unresponsiveness. Approximately 20 min earlier he had returned home after smoking "K2" with a friend. His mother stated that he had been smoking this substance for 2 months. Paramedics initially found the patient lying prone, but he soon became combative, requiring four-point restraints. Pre-hospital pulse was recorded as 220 beats/min. On arrival in the ED, he appeared somnolent and had a pulse rate of 180 beats/min. The patient had a history of heavy cannabis abuse and had recently lost his job due to a positive urine drug screen for THC metabolites. He was admitted to the hospital and had an uneventful course. His urine drug screen was positive for THC (184.7 ng/mL). He was discharged on the second hospital day.
Case 5
A 24-year-old man presented to the ED with chest pain, nausea, vomiting, and syncope after smoking 3 gm of K2. The patient stated that approximately 20 min after he smoked the herbal, he became extremely nauseous and vomited. He then had a syncopal episode of unknown duration. Upon awakening he had continued nausea and noted pleuritic chest pain, which prompted him to come to the ED. On arrival he appeared anxious and his pulse was 95 beats/min. The physical examination was unremarkable. The electrocardiogram and chest radiograph were within normal limits. He was discharged from the ED and instructed to follow-up with his primary care physician.
Case 6
A 22-year-old man was transported to the ED by paramedics after smoking "K2 herbal" for the first time and complained of being in a "dream state" and that he "cannot get out." In the ED he was mildly agitated and was thought to be hallucinating. The physical examination was within normal limits except for an initial pulse of 104 beats/min and respiratory rate of 33 breaths/min. The patient was cooperative and was observed in the ED for 4 h, during which his hallucinations and dream state resolved.
Discussion
Pharmacokinetics/Pharmacology of Synthetic Cannabinoids
To date, two endogenous cannabinoid receptors, CB1 and CB2, are well characterized. CB1 and CB2 are G i/o protein- coupled receptors (GPCRs) that inhibit adenylyl cyclase activity and thereby inhibit the conversion of Adenosine Triphosphate (ATP) to cyclic Adenosine Monophosphate (AMP). They also inhibit N- and P/Q-type calcium channels. In addition, GPCRs activate A-type and inwardly rectifying potassium channels and mitogen-activated protein kinase. Under certain conditions, CB1 receptors can also act through Gs proteins to activate adenylate cyclase. There is also evidence that CB1 can mobilize arachidonic acid and close 5-HT3 receptor ion channels when activated. It has been found that
cannabinoids can close sodium channels, but it is unclear if this is receptor mediated.[8]
Although CB1 receptors can be found at non-neuronal cells and tissues, such as reproductive organs, pituitary gland, and immune cells, they are predominantly found on central and peripheral nerve terminals, where they mediate inhibition of transmitters.[9] CB1 receptors are densely concentrated in the brain in the cortical and subcortical regions, the spinal cord in the dorsal root ganglion, and peripheral nervous system areas affecting pain from peripheral organs and tissues.[10] The CB1 receptor effects can be responsible for elevating a person's mood and inversely inducing emotions such as anxiety and panic. This receptor is responsible for most of the psychoactive components of cannabinoids.[11] Examples of this include the ability to induce analgesia, decrease motor function, impair memory and sense of time, and affect auditory and visual cognition.[8,12]
Activating CB2 receptors impacts anti-inflammatory and immune modulatory effects, peripherally and centrally.[13] The receptor can be found primarily in the tissues of the immune system, spleen, lymph nodes, and tonsils, but may also have a role in pain.
The receptor controls cytokine release and immune cell migration. There is some evidence to suggest that CB2 receptors may exist in the brain stem, cortex, and cerebellum, and play a role in the control of emesis.[15] CB2 receptor agonists have been the focus of research due to the possibility that they could decrease inflammation pain without the psychoactive effects that the CB1 receptors elicit. While researching CB2 analogs, Huffman et al. developed JWH-018, a CB1/CB2 agonist with a fourfold affinity for the CB1 receptor and a tenfold affinity for the CB2 receptor in comparison to delta 9-tetrahydrocannabinol, the main psychoactive agent in Cannabis sativa (marijuana).[16,17] HU-210 is reported to have 100 times the potency of delta-9-THC.[17]
Little is known about the detailed pharmacokinetics and toxicology of the synthetic cannabinoids, and few formal human studies have been published. Understanding the pharmacokinetics of synthetic cannabinoids found in Spice drugs is required to understand the clinical toxicology, forensic toxicology, and to interpret drug screens. Evidence suggests that synthetic cannabinoids are more potent compared to cannabis and could have longer half-lives, potentially leading to prolonged toxicological effects.[8,17] In addition, there is considerable inter- and intra-batch variability in terms of both substances and quantity of substances, making the clinical effects unpredictable.[1,2] The duration of effects in humans compared to delta-9-THC seems to be shorter for JWH-018 (1–2 h), and longer for CP-47,497 and its C8 homologue (5–6 h).[1,2] In a self-experiment done by Auwärter (2009) in hope of proving pharmacologic activity, 0.3 g of a "Spice Diamond" in a cigarette was smoked and the effects were recorded. Approximately 10 min post-inhalation, the first noticeable effects occurred; reddened conjunctiva, significant increase in pulse rate, xerostomia, and alteration of mood and perception.[17] In a human study by Möller et al., subjects reported they had the impression they were moderately impaired, and the effects continued for approximately 6 h and slowly tapered. The subjects also reported that during the entire following day, some minor after-effects were still noticeable.[18]
Clinical Presentation of Spice Drugs of Abuse
The clinical presentation of patients presenting to our ED was variable (). The majority of cases typically present with altered mental status, nearly all have had sinus tachycardia, and most return to a normal or near-normal state after 2–4 h of observation. The alteration in mentation includes seizures, central nervous system depression, hallucinations or expression of vivid dreams, and anxiety. Seizure activity has been described by lay witnesses as shaking of the extremities, followed by confusion and agitation. News reports across the United States have raised the concern that Spice drugs may be associated with deaths of adolescents and young adults using the herbal blend. Many of these are not confirmed, but the dangerous behavior associated with hallucinations and dreams potentially places the patient in a position for harm or even death. The four cases that were discharged from the ED demonstrated adequate cognitive awareness; however, because they were not followed clinically, it is not known if there was an extended or recurrent effect from their use. According to our local Poison Control Center, 76 exposures were documented during 2010.[19]
Delta-9-THC has demonstrated an inhibitory effect on γ-aminobutyric acid (GABA) neurotransmission in the brain via several pathways.[20,21] Thus, these agents with full agonist activity (e.g., JWH-018) may cause intense anxiety, agitation, and summarily may cause seizures and convulsions by inhibiting GABA neurotransmission more effectively than THC. These clinical effects of potent cannabinoid receptor agonists may lead to serious outcomes with excessive use.
Until a larger series is published about laboratory findings, predictions of test abnormalities cannot be made. With many patients having increased activity, there is potential for rhabdomyolysis, elevated creatine kinase, and risk of subsequent renal failure. Variability in clinical presentation is unknown, but may be due to the Spice compound used, the individual susceptibility to the drug effects, the dose, or it may be multi-factorial.
Laboratory Testing
In most cases within our series, laboratory results are not obtained, presumably due to substantiated history, but patients tend to have negative urine drug screens for THC metabolites. Although in one case with known use of a Spice drug, the patient had a positive urine screen for THC metabolites but had recently used marijuana. As often is the case with new designer drugs, the ability to detect these compounds through drug testing lags behind the popularity of their emergence.[22] Because little is known about the metabolism of synthetic cannabinoids, it makes it difficult to regulate these popular abusive drugs. Thus far, analysis of body fluids largely relies on the detection of the parent drug, and once the parent drug is metabolized, the consumption of the drug cannot be proven without data on the metabolites.[12]
A few studies have been published in Germany on the metabolism of the synthetic cannabinoid JWH-018, one of the common active agents found in Spice and other herbal blends. Recently, an in vitro study was performed via incubation of the drug with human liver microsomes and yielded mainly the parent drug, hydroxylated metabolites, and N-dealkylated metabolites.[12] Möller et al. used those findings and conducted an in vivo study with urine samples of healthy men that claimed to have smoked Spice products. They screened the urine for potential phase-one and -two metabolites. Many of the same metabolites seen in previous in vitro studies were detected, as well as their respective monoglucuronides. The monohydroxylated metabolite was the most abundant and was actually chosen as a target for sports drug testing purposes in Cologne, Germany. The method of analysis was honed and was then applied to approximately 7500 urine doping control samples and yielded two urine samples positive for JWH-018. The finding demonstrated its capability for a sensitive and selective identification of JWH-018 and its metabolites.[18] Recently, NMS labs in Willow Grove, PA released an update claiming to be able to use liquid chromatography/tandem mass spectrometry to screen, confirm, and quantitate JWH-018, JWH-073, and JWH-250, and to screen and confirm JWH-019 in serum samples. At this writing, they can screen and confirm JWH-018 and JWH-073 in urine samples using the hydroxy-metabolites. The company claims to have highly specific and legally defensible testing.
Although the identification of some of the synthetic cannabinoids has been reported, the detection of a whole range of all related chemicals remains elusive. To our knowledge, there are no routine urine screening tests in the United States capable of detecting the synthetic cannabinoids. Laboratories have reported mass spectrometry testing on synthetic cannabinoid products, but no official mass or UV spectra library exists.[18] Furthermore, almost daily, new products claiming to be "herbal incense" with a new mix of chemicals and herbals appear; some of them do not contain any pharmacologically active compounds, which may misguide researchers. The mass spectrometry analyses that have been done on Spice products have shown complex matrices and non-psychoactive materials, such as vitamin E, that mask the active components.[18]
Legal Issues
Before November 24, 2010, the DEA had not yet placed synthetic cannabinoids into Federal Schedule I, but as of September 2010 labeled five synthetic cannabinoids commonly found to be contained in Spice products as "substances of concern." These substances included CP 47,497 and homologues, HU-210, HU-211, JWH-018, and JHW-073.[23] As a
result, the legal status of synthetic cannabinoids became an evolving patchwork of local and state laws. On November 24, 2010, the US DEA temporarily designated five chemicals (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) as Schedule I substances. This action makes selling and possession of these substances illegal for at least 1 year, giving the DEA and the DHHS time to study whether these agents will be permanently controlled in the United States.
HU-210 previously was the only synthetic cannabinoid that had been placed in Federal Schedule I, and has been reported to be found in some Spice products. It was classified as Schedule I under the Controlled Substances Act (CSA). The CSA controls THC substances that have chemical structure and pharmacological activity similar to THC substances that occur in Cannabis sativa. Many of the other synthetic cannabinoids reported to be contained in Spice do not have the classic cannabinoid structure and cannot be regulated under the CSA (Figure 1). Worth noting, however, is that the enantiomer of HU-210, HU-211 is classified as a THC substance and has the classic cannabinoid structure, but does not have the same delta 9-THC-like pharmacologic activity and therefore is not regulated under CSA.[23]
US military branches seem to be in agreement that possession, use, intoxication, or distribution of mind-altering chemicals, with the exception of alcohol and tobacco, are punishable under the Uniform Code of Military Justice. The US Air Force, Marines, Army, and Navy have all banned "Spice".[3]
Before November 24, 2010, state lawmakers were acting quickly to curb the growing availability and use of these substances by passing laws to designate certain synthetic cannabinoids as Schedule I controlled substances and outlaw their possession or distribution.[24] By October 2010, compilations of the most common synthetic cannabinoids had been banned in 10 states and were pending legislation in another four states. Because there are at least seven documented categories of synthetic cannabinoids, state laws identify specific types or specific chemical substances commonly found in them. Many cities across the country did not wait for state legislation but were aggressive and banned the products before state or federal action.[24]
Compared to THC, synthetic cannabinoid receptor agonists have a significantly higher potency that leads to an exaggerated psychoactive state. The use and abuse of herbal mixtures containing these chemicals has rapidly gained popularity among teenagers and, primarily, those in their early twenties. The attraction is the lack of legal consequences and the potent high that is achieved when these agents are smoked. The recent action of the US Food and Drug Administration to place an emergency classification of Schedule I agents is a bold and necessary step to help prevent ED visits, serious injury, and abuse. As illustrated in our case series, adolescents are presenting to the ED with varied symptoms, but consistently have unwanted or frightening hallucinations, and at times these can be life-threatening.
European experience with Spice drugs has been extensive compared with the United States, but momentum is gaining and teens and young adults are at risk of becoming addicted and potentially having a fatal outcome associated with use. Several European countries have instituted a ban or outlawed these agents due to serious presentations, potential for widespread abuse, and addiction.
Conclusion
In conclusion, complete pharmacological knowledge of synthetic cannabinoids is lacking, and further research is needed to gain a thorough understanding of the physical and psychological impact. Our cases presented over a 3-month period and illustrate increased use in our area. The clinical presentations are serious, and most cases required ambulance transfer to the ED, all adding to the drain of health care dollars. We recommend ED observation until the patient demonstrates clinical improvement and can be safely discharged in the presence of a responsible adult. Chemical dependency counseling or social service involvement should be considered before discharge.
It is hoped that legal action will curtail the use until further information can be obtained to elucidate the risks associated with use and abuse of these chemicals. Without such action or stringent prohibition of synthetic cannabinoids, we can expect the problem to increase, and expect to see an increase in morbidity and mortality in a young and vulnerable population associated with these chemicals.
References
- European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Forensic identification, pharmacology and toxicology of synthetic cannabinoids. In: Thematic papers. Understanding the 'Spice' phenomenon. Lisbon: European Monitoring Centre for Drugs and Drug Addiction; 2009. Available at: http://www.emcdda.europa.eu/publications/thematic-papers/spice. Accessed October 18, 2010.
- European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Synthetic cannabinoid receptor agonists: a brief chemical overview. In: Thematic papers. Understanding the 'Spice' phenomenon. Lisbon: European Monitoring Centre for Drugs and Drug Addiction; 2009. Available at: http://www.emcdda.europa.eu/publications/thematic-papers/spice. Accessed October 18, 2010.
3. Vardakou I, Pistos C, Spiliopoulou C. Spice drugs as a new trend: mode of action, identification and legislation.
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- Hoffman AF, Lupica CR. Mechanisms of cannabinoid inhibition of GABAA synaptic transmission in the hippocampus. J Neurosci 2000;20:2470–9.
- United States Department of Justice, Drug Enforcement Administration, Office of Diversion Control. Spice Cannabinoid. Drug Enforcement Agency, 2009. Available at: http://www.deadiversion.usdoj.gov/drugs_concern/spice/. Accessed October 18, 2010.
- NationalConference of StateLegislatures. Synthetic drug threats.Denver, CO:NationalConference of State Legislatures; 2010.Available at: http://www.ncsl.org/?TabId=21398. Accessed November 24, 2011.
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J Emerg Med. 2013;44(2):360-366. © 2013 Elsevier Science, Inc.
