Synthetic Cannabis and Respiratory Depression

Introduction

N atural cannabis is the most common drug of abuse; in recent years, however, synthetic cannabis use has been increasing in appeal among adolescents, and its use is now at a 30 year peak among high school seniors (Hu et al. 2011; United Nations Office on Drugs and Crime 2011). Based on the Monitoring for Future survey in 2011, 11.2% of 12th graders admitted using synthetic cannabis within the previous 12 months (Johnston et al. 2011; Vandrey et al. 2012). Also known by numerous attractive street names such as “Spice,” “K2,” “Aroma,” and “Topaz,” this alternative to natural cannabis can be purchased in convenience stores and gas stations or over the Internet (Jack 2009; Marzouk 2009). It is commonly packaged in colorful and attractive packages, resembling incense or tea packets, to entice consumers who would not otherwise smoke cannabis (Fattore and Fratta 2011). Synthetic cannabis is an appealing drug not only because it is easily accessible and cleverly packaged, but also because it is perceived as safe and undetectable with the standard urine drug screen (Lindigkeit et al. 2009). However, a range of adverse clinical outcomes has been reported following synthetic cannabis use.

The constituents of synthetic cannabis are difficult to monitor, given the drug's easy accessibility. Currently, 40 U.S. states have banned the distribution and use of some known synthetic cannabinoids, and have included these drugs in the Schedule I category (Leonhart 2011). However, ambiguity remains regarding regulating newly synthesized compounds (Chang et al. 2012).

Synthetic cannabis products are marketed as incense with powder from herbal plant extracts laced with multiple cannabinoid ligands to produce potent psychoactive effects. The users perceive synthetic cannabis' effects to be stronger than those of natural cannabis, with the effects being energizing, euphoric, and disinhibiting (Auwärter et al. 2009). The most common adverse outcomes among users included visits to the emergency department with acute onset nausea, anxiety, agitation/panic attacks, paranoid ideation, and hallucinations (Simmons et al. 2011a).

Synthetic cannabis use is associated with debilitating adverse effects other than those mentioned. Similar to natural cannabis intoxication, synthetic cannabis abuse can present as an acute exacerbation of psychosis (Müller et al. 2010). Long-term use may increase the risk for new onset psychosis (McGrath et al. 2010; Hurst et al. 2011). Psychotic relapse after smoking Spice was reported in 15 psychotic patients in New Zealand (Every-Palmer 2011). Another common presentation is anxiety (Schneir et al. 2011). An adolescent committed suicide as a result of intolerable anxiety after smoking synthetic cannabis (Gay 2010). Another case reported on a 19-year-old man with new onset convulsions after smoking “Happy Tiger Incense” (Schneir and Baumbacher 2012). Simmons et al. have also reported cases of seizures following exposure to these compounds (Simmons et al. 2011a,b). Synthetic cannabis ingestion may cause hypokalemia, hyperglycemia, acidosis, and autonomic effects, such as fever and mydriasis. Zimmermann and colleagues reported a 20-year-old patient who, in addition to meeting criteria for substance dependence, on day 4 of abstinence from Spice inhalation demonstrated profuse sweating, nausea, tremor, drug craving, hypertension, and tachycardia (Zimmermann et al. 2009). Serious adverse cardiac outcomes in teenaged subjects have included death from a coronary ischemic event, arrhythmias, and cardiotoxicity following synthetic cannabis use (Fisher 2010; Lapoint et al. 2011; Young et al. 2011).

The depressive respiratory effect in humans caused by synthetic cannabis inhalation has not been thoroughly investigated in the medical literature. We are the first to report, to our knowledge, two cases of self-reported synthetic cannabis use, leading to respiratory depression and necessary intubation.

Case Reports

Discussion

Understanding the link between synthetic cannabis inhalation and respiratory depression is vital to perfecting critical care treatment of patients who demonstrate signs and symptoms of synthetic cannabis intoxication. In order to better understand this, it is necessary to characterize the distribution and role of the cannabinoid receptors. CB₁ receptors are located in the brain, particularly in the hippocampus, basal ganglia, cortex, amygdala, and cerebellum; CB₂ receptors, which are peripheral, interact with the immune system (Onaivi et al. 2006). Theoretically, CB₁ and CB₂ receptors may also modulate noncannabinoid receptors such as muscarinic, nicotinic, opioid, and serotonergic receptors (Pertwee et al. 2010). Their stimulation by structurally distinct synthetic cannabinoids may lead to a breadth of unpredictable psychological and physiological effects.

Following the discovery of CB₁ and CB₂ receptors, there was extensive research within the pharmaceutical industry to develop molecules that act as ligands on these receptors (Ameri 1999; Rieder et al. 2010; Seely et al. 2011). These cannabinoid ligands can be broadly classified into five types based on their chemical structure: 1) classical, which has a Δ tetrahydrocannabinol (THC) structure, for example, HU 210 developed by Hebrew University; 2) nonclassical or cyclohexylphenols (CP compounds) developed by Pfizer in the 1970's; 3) naphthoylindoles, for example,. JWH 018, initially developed by J.W. Hoffman, and AM compounds developed by Alexandros Makriyannis; 4) eicosanoids, fatty acid ester-like compounds; and 5) unclassified, such as WIN 55,212-2 (Uchiyama et al. 1994; Eissenstat et al. 1995; Atwood et al. 2010; Hudson and Ramsey 2011; Zuba et al. 2011; Carroll et al. 2012).

These cannabinoids vary in potency, affinity, selectivity and molecular activity ranging from full agonist, partial agonist, and inverse agonist as compared with plant-derived ΔTHC, which is a partial agonist. For example, JWH-018 has fourfold affinity to the CB₁ receptor and approximately a 10-fold affinity to the CB₂ receptor, compared with THC. This, in addition to the fact that JWH-018 metabolites retain their metabolic activity at CB₁ receptors, helps explain the greater prevalence of adverse effects observed with JWH-018 than with natural cannabis (Huffman and Padgett 2005; Brents et al. 2011).

Synthetic cannabis' effect on respiratory function via CB₁ receptors has not been extensively detailed in humans, and likely involves multiple mechanisms. According to research proposed by Schmid, cannabis' effect on respiration in humans was indeterminate; however, rats demonstrated a marked respiratory depression, characterized by a decrease in respiratory rate, hypoxia, hypercapnea, and arterial blood acidosis. Synthetic cannabis' effect on peripheral receptors, such as chemo- and baroreceptors, increased airway resistance in bronchi, and CB₁ receptor stimulation is a possible method of synthetic cannabis-induced respiratory depression (Schmid et al. 2003).

Synthetic cannabis' stimulation of CB₁ receptors results in a series of downstream signaling changes involving a number of molecular pathways. G protein-coupled pathways are affected by CB₁ stimulation. Specifically, the CB₁ receptor is linked to G_i/o activity, and, upon stimulation, inhibits adenylyl cyclase and decreases cellular cAMP levels. As CB₁ receptors are found on both glutamatergic and GABAergic terminals, their stimulation can suppress both excitatory and inhibitory neuronal activity (Carroll et al. 2012).

The mitogen-activated protein kinase (MAPK) pathway is also linked to CB₁ receptor activity. Specifically, synthetic cannabinoid agonist activity at CB₁ receptors activates the MAPK pathway, resulting in phosphorylation of nuclear transcription factors. This in turn impacts cell transcription, translation, motility, shape, proliferation, and differentiation. In addition, prolonged phosphorylation may result in CB₁ receptor desensitization and internalization (Carroll et al. 2012). These changes demonstrate the various molecular changes that can occur in the central nervous system (CNS) after CB₁ receptor stimulation by products such as synthetic cannabis, and could indirectly impact respiration. The drug concentration to produce these effects has a wide range; as observed in an in vivo study of mice, analgesic effects can be seen at a median effective dose (ED₅₀) of 0.09 mg/kg, and hypothermia was noticed at doses of 1.47 mg/kg. According to a rat repeat dose study, drug concentrations of 10 mg/kg decreased breathing rates with subsequent death (Vardakou et al. 2010; Carroll et al. 2012).

A common misperception regarding synthetic cannabis use is the lack of laboratory testing to confirm its use. A study by ElSohly determined the structure of JWH-018 metabolites that might be excreted in the urine, and that therefore can be used to detect the drug's use through urine analysis. In fact, several monohydroxylated metabolites, a carboxy metabolite, a dihydroxy metabolite, and a trihydroxy metabolite were detected in the urine provided by a human subject after smoking synthetic cannabis (ElSohly et al. 2011). Additionally, a study from 2011 suggests that synthetic cannabinoids could be detected in oral fluid, as quickly as 20 minutes after smoking; JWH-018 was detectable up to 12 hours after a single use. These data suggest that through the use of mass spectrometry, urine and saliva could be used to confirm recent synthetic cannabis use (Coulter et al. 2011; Hutter et al. 2012).

The toxic effects of herbal mixtures that act as a vehicle for synthetic cannabis use are of prominent medical concern (Dresen et al. 2010). As this is a relatively new drug of abuse, heathcare professionals should be aware of its atypical presentations, including negative urine drug screens, and of the greater toxic potential of synthetic cannabis compared with natural cannabis. Future basic science research needs to be directed toward understanding the molecular interactions with different receptor types and subsequently the mechanism for adverse effects. Interventional approaches must include not only early education of children and adolescents about the harmful potential of such drugs, but also advocacy from mental health agencies for stricter legislation.