Synthetic Cannabinoid Intoxication

A Case Series and Review

Carson R. Harris, MD; Ashley Brown, PHARMD


J Emerg Med. 2013;44(2):360-366. 

In This Article


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.[14] 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 (Table 3). 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]

Figure 1.

Delta-9-THC and synthetic cannabinoid structures (2).

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.