The purpose of the current article is to provide a comprehensive overview of synthetic cannabinoids (SCs), including pharmacokinetics, physiological and psychological adverse effects, epidemiology of use, legal and regulatory issues, and nursing implications. The goal of the article is to inform health care providers about the increased use of SC and heighten their awareness about common presentations seen in clinical settings.

Background SCs were originally developed as experimental agents designed to help investigators gain a better understanding of the human cannabinoid system. Early studies with SCs also examined the potential therapeutic effects of these compounds, as a number exhibited potential analgesic and anti-inflammatory actions. Although SC compounds are a structurally diverse class of agents, they may be divided into three main groups: (a) classic cannabinoids, (b) non-classic cannabinoids, and (c) aminoalkylindoles. Classic cannabinoids are structurally similar to Δ9-tetrahydrocannabinol (Δ9-THC) and include analogs such as nabilone, cannabinol, and HU-210. Non-classic cannabinoids include the cyclohexylphenols (CP-47) and other bicyclic and tricyclic compounds related to Δ9-THC, such as HU-308. Amino-alkylindoles are structurally the most prevalent SC compounds. They differ significantly from classic cannabinoids in terms of their structure, lipophilicity, and activity at cannabinoid receptors. Examples of aminoalkylindoles include JWH-018, JWH-073, and JWH-200. The JWH prefix comes from the name of the chemist, John W. Hoffman, who developed these compounds. Two distinct subsets of endogenous cannabinoid receptors have been identified in humans and designated CB 1 and CB 2 (Glass, Dragunow, & Faull, 1997). Both receptors are G-protein–linked receptors. The physiological role of these receptors is still being elucidated. CB 1 receptors are located primarily in the central nervous system (CNS), whereas CB 2 receptors are found mainly in peripheral tissues and may be involved in immune regulation. CB 1 receptors are concentrated in the hippocampus, mesolimbic system, and basal ganglia of the brain, thus may affect psychomotor activity. Research suggests that CB 1 receptors may play a specific role in appetite, as THC administration has been shown to increase food intake and weight gain in cancer and AIDS patients (Pacher, Batkai, & Kunos, 2006). The cannabinoid system may also be involved in the modulation of pain because CB 1 receptors have been identified in the regions of the brain and dorsal horn of the spinal cord, which are associated with pain transmission and perception. Animal studies indicate that cannabinoid ligands may be effective in the treatment of both chronic and neuropathic pain (Guindon & Beaulieu, 2006; Guindon, De Léan, & Beaulieu, 2006). However, prolonged activation of CB 1 receptors has been shown to result in tolerance to THC due to receptor desensitization and receptor down-regulation (Atwood, Lee, Straiker, Widlanski, & Mackie, 2011).

Pharmacology of Synthetic Cannabinoids CB 1 receptors are responsible for mediating the psychotropic effects of cannabis (Felder et al., 1995). As a result, the activity of SC compounds at CB 1 receptors directly affect their potency. To date, hundreds of different SC compounds have been developed. Unlike Δ9-THC, which is a partial agonist at CB 1 receptors, a number of these SC compounds, such as the aminoalkylindoles (e.g., JWH-018), are actually full agonists at the CB 1 receptors. Studies also indicate that many SC compounds have higher binding affinities (in the low nanomolar range) for the CB 1 receptor than Δ9-THC (Huffman & Padgett, 2005). Both of these attributes make SC compounds significantly more potent than traditional cannabis. Halogenation of SC compounds further intensifies their potency by increasing their lipophilicity and binding affinity for CB 1 receptors. Compounds such as AM-2201 and UR-144 are halogenated derivatives of previously marketed SC products. A number of SC products have also shown significant affinity for CB 2 receptors, which are found on immune cells (e.g., macrophages, B cells, T-lymphocytes) and the spleen and tonsils. As such, SC compounds may have an effect on immune response and function. SC products may also include substances such as O-desmethyltramadol and mitragynine, which are opioid receptor agonists (Dresen et al., 2010). Because the sale of cannabis and cannabis-containing products largely remains illegal, a number of SC products, such as Spice and K2, are legally sold as herbal blends and incense potpourris. Although labeled “not for human consumption,” these products are designed to be smoked, inhaled, or prepared as an herbal infusion for drinking. Once smoked, the SC compounds are rapidly absorbed from the lungs, and their lipophilicity allows them to readily cross the blood–brain barrier. The onset of CNS effects usually occurs within minutes of smoking. For JWH-018, maximal blood concentrations are observed 5 minutes after smoking. Blood levels of JWH-018 significantly decrease several hours after smoking, but the parent compound remains detectable 48 hours after administration (Teske et al., 2010). Absorption of SC compounds is significantly slower when ingested orally. The parent drugs for most SC compounds appear to be extensively metabolized by hepatic CYP 450 enzymes. Studies on human liver microsomes demonstrated that CYP2C9 and CYP1A2 were the primary liver enzymes involved in the oxidation of the SC compounds JWH-018 and AM2201. This finding is of particular interest because CYP2C9 is a liver enzyme that shows significant genetic polymorphism. Individuals who are genetically “slow” CYP2C9 metabolizers may experience a prolonged duration of action and excess blood levels following SC product use. SC metabolites are believed to be mainly excreted in the urine as glucuronide conjugates. The metabolites of SC compounds maintain varying degrees of activity at CB 1 receptors. For example, some of the 20 metabolites formed from the aminoalkylindole JWH-018 have affinities similar to the parent drug and a number remain full agonists at CB 1 receptors. Given the variety of compounds and herbal components found in SC products, there is a high probability that they may cause significant interactions with other drugs or medications an individual may be taking. Studies suggest that traditional cannabinoids, such as cannabis, may exert an inhibitory effect on the activity of CYP3A and CYP2C, enzymes that are involved in the metabolism of numerous prescription drugs (Kosel et al., 2002). CYP1A2, an enzyme involved in the metabolism of SC compounds, may in turn be inhibited by a number of widely used drugs, such as cimetidine (Tagamet®), ciprofloxacin (Cipro®), fluvoxamine (Luvox®), and atazanavir (Reyataz®), whose concomitant use could increase SC toxicity. Although the effects of SC compounds on CYP450 enzyme activity are currently not well-defined, the potential for significant drug interactions through CYP enzyme effects should be a source of concern for health care providers. Previous case reports in patients using traditional cannabis have documented potentially significant interactions with medications such as antidepressant agents, protease inhibitor agents, barbiturate agents, and lithium (Lindsey, Stewart, & Childress, 2012). Co-ingestion of opioid agents or alcohol can potentiate the CNS effects of SC products. Synergistic actions between cannabinoids and opioid agents have also been reported (Cichewicz, 2004). Activation of cannabinoid and opioid receptors share a number of pharmacological effects, such as sedation, hypotension, hypothermia, and reduced sensitivity to pain. In animal studies, chronic ethanol consumption has been shown to significantly alter gene expression of CB 1 - receptors in various regions of the brain (Ortiz, Oliva, Pérez-Rial, Palomo, & Manzanares, 2004). It has been suggested that a functional link may exist between the cannabinoid and opioid receptor systems with regard to regulating alcohol intake (Colombo, Serra, Vacca, Carai, & Gessa, 2005).

Legal and Regulatory Status of Spice Designer drugs, such as Spice, are marketed specifically to young users. They are sold using colorful and attractive packaging labels and are given a variety of fun and enticing product names, such as Spice, K2, Mr. Nice Guy, Black Mamba, Super Skunk, Bad to the Bone, Fire and Ice, G-Force, and Red Magic. As a result, synthetic marijuana products are popular with adolescents. Use is more prominent among young adult men than women (National Institute on Drug Abuse, 2012). Other likely users include members of the U.S. Armed Forces (Bebarta, Ramirez, & Varney, 2012). Synthetic marijuana products are not tested for human safety because they are labeled “not for human consumption.” Products such as Spice may contain a number of different chemical constituents whose actions are poorly characterized and whose potential toxicities are unknown. Individuals who smoke Spice and K2 essentially have no idea what chemicals are in the product. Although the dangerous effects of these products were first reported in the United States in 2009, use across the nation has increased dramatically. According to the American Association of Poison Control Centers (2014), 4,033 calls related to synthetic marijuana were received between January 1, 2014, and January 31, 2015, compared to only 13 calls received in all of 2009. In August 2014, New Hampshire’s Governor Maggie Hassan declared a state of emergency as a result of overdoses from SC product use (“Governor Hassan Declares,” 2014). SC products are sold at gas stations, liquor and convenience stores, smoke shops, and head shops. SC products may also be purchased at home through the Internet. The Internet, especially via online forums, has played a key role in raising awareness about SC products and the different sources for purchasing these items. The power of social networking regarding marketing SC products cannot be overlooked or underestimated. Use of social media is an innovative and efficient technique exploited by sellers to promote the different types of SC products available to potential users. Sellers attempt to promote new SC users by offering competitive prices, attractive gimmicks, and testimonials via the Internet (Tai & Fantegrossi, 2014). Currently, international government regulations are inconsistent regarding the status of Spice. According to Fattore and Fratta (2011), beginning in 2008, 14 European nations (i.e., Austria, Denmark, Estonia, France, Germany, Ireland, Italy, Latvia, Lithuania, Luxembourg, Poland, Romania, Sweden, and the United Kingdom) classified Spice as a controlled substance. However, in parts of Europe and other countries, Spice is legal and uncontrolled, which contributes to significant international marketing. At approximately the same time, several states (i.e., Alabama, Arkansas, Georgia, Kansas, Kentucky, and Missouri) started to take legislative action against the distribution and use of Spice (Fattore & Fratta, 2011). Kansas was the first state to ban the use of SC compounds in 2010 prior to any federal mandates. Almost all states have taken action to control one or more SC compounds as they are identified. Most states face challenges with SC regulations because of the amounts of different substances that may be present in the herbal mixtures that create the “high.” New SC compounds may be produced by changing the original elements, hence, effectively bypassing the ban. This ban, effective for at least 2 years, makes this class of drugs Schedule I. Congress also took steps to ban many of these substances at the federal level, and the Drug Enforcement Agency (DEA) has supported such efforts (Office of National Drug Control Policy, n.d.). In March 2011, the DEA also took action and placed five of the most common substances found in Spice (i.e., JWH-018, JWH-073, JWH-200, CP-47 497, and CP-47 497 C8 homologue) into Schedule I of the Controlled Substance Act (Stogner & Miller, 2014). In 2012, the Synthetic Drug Abuse Prevention Act, which is a part of the U.S. Food and Drug Administration Safety and Innovation Act of 2012, banned SC compounds most commonly found in Spice and classified them as Schedule I drugs. SC is a drug of concern, as a result of the surge in ED visits and calls to poison control centers related to these substances. The U.S. military added Spice to its list of random drug testing substances in 2013.

Case Report Mark, a 25-year-old Black man, presented to the psychiatric ED at a large teaching hospital in the southern United States. He was accompanied by his mother who stated, “My son has been smoking Spice and it is causing him to act crazy.” According to the patient’s mother, Mark has no known psychiatric history. The mother reported that in the past several days, Mark started to demonstrate “strange behaviors,” such as talking to himself, and stating that others want to steal his brilliant ideas. The patient’s mother also reported that Mark believes he was given special gifts, and everyone wants to get inside of his brain to obtain the same powers. During the interview, Mark denied any visual, auditory, or tactile hallucinations. He denied any substance or alcohol use. He stated he used cocaine years ago, but has since stopped. Mark reported he has no medical or psychiatric history. On assessment, Mark’s thoughts were disorganized, with flights of ideas and loose associations. He demonstrated bizarre behavior, such as talking and laughing to himself, grandiose ideation, stating, “I have special powers.” He also verbalized persecutory delusions: “Everyone is after my brilliance.” Later in the interview, Mark admitted to smoking Spice approximately 12 to 15 hours before coming to the psychiatric ED. All laboratory tests (e.g., complete blood cell count, basic chemistries, thyroid panel, urine drug screen, blood alcohol level) were unremarkable. Mark was evaluated by the psychiatric nurse practitioner and given a diagnosis of psychosis not otherwise specified. The psychiatric team decided to admit Mark for further observation to determine if any substances, medications, or medical conditions may have influenced his presentation. Following a 24-hour evaluation in the psychiatric ED, Mark no longer demonstrated any evidence of psychosis; he was psychiatrically cleared and discharged home to his family. This case report illustrates how SC products are used often by adolescents and young adults because of their cannabis-like effects as well as being readily available from gas stations, liquor stores, convenience stores, head shops, and the Internet. Because there is a lack of reliable toxicological methods to detect these products, SC products are attractive to users. As mentioned previously, some laboratories throughout the United States have begun to provide urine SC testing commercially; however, not all facilities have access to these laboratories. In addition, as stated previously, the variety of SC active components are continuously changing, which makes routine drug testing for these compounds challenging. Health care providers practicing in EDs must be on alert for the unique clinical signs and symptoms associated with SC use. Patients “high” on SC products may demonstrate physical effects, such as tachycardia, hypertension, gastrointestinal effects (e.g., nausea, vomiting), and neuromuscular symptoms (e.g., tremors, tingling, lightheadedness, seizures) (Zimmermann et al., 2009). In addition, pallor, tinnitus, and excessive sweating have been reported (Zimmermann et al., 2009). According to Every-Palmer (2011), the use of SC products has also been associated with acute psychosis or an exacerbation of an otherwise stable psychotic mental health disorder. The present case study described an unexplained sudden acute psychosis in a patient with no known history of mental illness. Therefore, it is imperative that health care providers become suspicious of SC use if a patient presents with clinical signs and symptoms of cannabis use, negative urine toxicity drug screens, is in a position/job or situation where his or her urine is routinely monitored, is a young adult, and presents with sudden onset psychosis (Castellanos & Thornton, 2012). Health care providers should be knowledgeable about the effects of SC product use and entertain a degree of suspicion of its use if a patient presents with the aforementioned clinical signs and symptoms.

Implications for Nursing Practice Nurses and other health care providers should be aware of the physiological and psychological effects of SC products. Health care providers must maintain a high degree of awareness for Spice, K2, and similar product use when unexplained psychiatric symptoms are present. In addition to observation and supportive care for individuals who present with adverse side effects, screening, brief intervention, and referral to treatment and social service involvement should be explored before discharge. Furthermore, nurses and health care providers must play a key role in educating the public about the dangers of these products. Young adults need to be educated that although these products may be purchased on the Internet or in convenience stores, they often contain unidentified and potentially toxic substances that may result in life-threatening health complications. Individuals should not underestimate the effects of SC products or assume they are less harmful than traditional marijuana. These products exert effects on the brain that are similar to THC; however, because SC compounds are often more potent and poorly characterized, the effects may be different. Similarly, parents and caregivers of high school students should be taught to look for drug paraphernalia (e.g., pipes, joint paper), coffee grinders that are used to make the product finer and easier to smoke, dried herbal residue, or colorful packets in their children’s rooms or trash cans. These products often have a strong smell resembling cloves. Parents and caregivers must also be educated about the physical and psychological signs that young adult SC users may manifest, such as confusion, agitation, anxiety, paranoid thoughts, uncontrolled/spastic body movements, and seizures. Synthetic drug abuse presents a serious public health challenge. As frontline health care providers, nurses should spearhead efforts to educate patients about the dangers associated with the use of these products and advocate for a complete ban on the sale of all SC products.

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