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InFocus: Synthetic Cannabinoids They're Not Marijuana

Roberts, James R. MD

doi: 10.1097/01.EEM.0000469324.92259.70
InFocus

Dr. Robertsis a professor of emergency medicine and toxicology at the Drexel University College of Medicine in Philadelphia. Read the Procedural Pause, a blog by Dr. Roberts and his daughter, Martha Roberts, ACNP, CEN, athttp://bit.ly/ProceduralPause, and read his past columns athttp://bit.ly/RobertsInFocus.

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Most clinicians are well aware of the clinical aspects of regular old-fashioned, run-of-the-mill marijuana use. Patients high on marijuana rarely come to the ED, but frequently patients test positive for THC, the active portion of marijuana. Its presence in a urine toxicology screen is almost considered normal flora in many EDs. Simply stated, marijuana by itself is not particularly toxic, probably much less toxic than ethanol and clearly less toxic than many other street drugs. It's even entirely legal in some states. The average marijuana user hangs out with friends, laughs, chows down at the local restaurant, and enjoys listening to music in a mellowed-out state.

Such a benign milieu is hardly the case with the use of the increasingly popular synthetic cannabinoids. Sold under a variety of monikers, most commonly spice and K2, synthetic cannabinoids, while analogues of tetrahydrocannabinol, otherwise known as THC, are hardly natural substances. First used in Europe, its use has skyrocketed in the United States over the past 10 years, and it has been associated with increasingly severe side effects and even death.

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Severe Toxicity Following Synthetic Cannabinoid Ingestion

Lapoint J, James LP, et al.

Clin Toxicol

2011;49(8):760

This is one of the few articles discussing the clinical aspects of synthetic cannabinoid use. It was written in 2011 when the commonly used K2 and spice were still available in various head shops and on the Internet. They were labeled “not for human consumption” or “aroma therapy only,” but those who bought them knew what they were. These authors note that the clinical effects of synthetic cannabinoids are from full agonism and increased potency for the CB1 and CB2 receptors, the same receptors to which delta-9-THC exerts its psychoactive effect. THC has only partial CB1-CB2 agonism, while the synthetics fully stimulate the body's receptors.

A few reports in the literature describe a withdrawal scenario in those who are frequent users and have abrupt cessation. Two deaths, a suicide and a coronary ischemic event had been reported when this article was written. This article is a single case report and a discussion of exposure to the synthetic cannabinoid JWH-018 found in K2 and spice.

The authors reported a 48-year-old man who ingested an unknown powder that he had purchased on the Internet to get high. He quickly became agitated and had a generalized seizure. The seizure activity recurred numerous times, but was eventually abated with IV lorazepam. The patient was intubated because of concerns for airway protection. Initial basic blood tests, except for a mildly elevated CPK, were negative, as were an EEG and a noncontrast head CT. The urine toxicology screening by the hospital's laboratory was negative for drugs of abuse, including THC. The patient developed refractory SVT shortly after hospitalization that required cardioversion. When the powder that the patient ingested was analyzed, it was found to contain JWH-018, a common potent synthetic cannabinoid. The patient became asymptomatic after three days of hospitalization and was discharged.

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These authors reported one of the first cases of repetitive seizures and supraventricular tachycardia following the confirmed use of the widely available synthetic cannabinoid, JWH-018. Seizures following THC use are rare. The authors point out that synthetic cannabinoids stimulate the central and peripheral CB1 and CB2 receptors, the same sites of THC activation. CB1 receptors are located presynaptically on glutaminergic and GABAergic synapses, and play a role in modulating neurotransmitting signaling mechanisms.

Comment: Naturally grown marijuana is a complex substance that is composed of 50 to 60 cannabinoids. The most psychoactive component is delta-9-THC. This is the component tested for in urine immunoassay toxicology screens. Analogues of natural cannabinoids are the synthetic cannabinoids, substances that are chemically created. Available in Europe for about 10 years, with the first reported case in the United States in 2008, some synthetic cannabinoids are now classified as Class 1 controlled substances by the Drug Enforcement Administration (DEA). It is currently illegal to possess, sell, or use a few specific synthetic cannabinoids. Many similar chemicals have escaped regulation, however.

Commonly marketed as incense, aromatherapy, or herbal remedies, the compounds are sold under a variety of names, the most common being K2 and spice. The initial low-dose effects are similar to natural marijuana, but more serious and even life-threatening symptoms are associated with synthetic cannabinoids, likely from increased and full stimulation of cannabis receptors throughout the body. The chemical analogues of THC used in synthetic cannabinoids are constantly changing to avoid control and regulatory oversight, and it is difficult to say what is in the current street drug.

Synthetic cannabinoids are made from inexpensive compounds that can be obtained legally online. Those in spice and K2 are termed JWH-018 and JWH-073, and are now classified as schedule 1 substances. A 2012 analysis found that street cannabinoids were relatively pure mixtures of these compounds. Unlike many other drugs, impurities or residue from the manufacturing process were not the culprits. Numerous other substances, such as synthetic opioids, caffeine, and a potent B-2 agonist, clenbuterol, may be mixed with the cannabinoids, however.

The basic chemicals are combined with herbs, marijuana, and other plant products, often merely sprayed on. No delta-9-THC is contained in true synthetic marijuana, so the urine drug screen for marijuana will be negative. No assay is currently available for emergency clinicians to identify synthetic marijuana. Advanced symptoms simulate a number of other conditions and drug toxicities. Synthetic cannabinoid users are usually young men in their 20s and 30s, but it is also commonly used in high school.

More than 50 known synthetic cannabinoids can be manufactured by illegal drug producers, and are candidates for synthetic marijuana. The degree of toxicity depends on the amount used and the specific compound added, but specific additives are constantly changing to avoid governmental regulations.

The psychological effects of synthetic cannabinoids are similar to THC and in small doses cause pleasurable mood-changing effects as well as tachycardia, red eyes, increased appetite, ataxia, and slurred speech. Synthetic cannabinoids, however, have a much greater potential for serious toxicity, including hallucinations, delirium, psychosis, and fever. The emergency clinician is most likely to see the more virulent cases.

A wide spectrum of clinical effects can be experienced from taking synthetic cannabinoids. They are mostly used by inhalation of smoke, and the effects last several hours to days depending on the specific compound and the potency. The most common clinical effects are agitation, vomiting, and confusion, typically lasting four to eight hours, but serious toxicity includes severe agitation, seizures, hyperthermia, and rhabdomyolysis, symptoms seen with methamphetamines, cocaine, and a variety of other drugs of abuse. Other symptoms include headache and varying degrees of dystonia, hyperreflexia, and hypertonic limbs. Some patients may present with catatonia, coma, or difficult-to-describe altered mental status. The vast majority are tachycardic.

The letters JWH in the chemical ingredients are the initials of the inventor Dr. John W. Hoffman, an organic chemist who developed multiple synthetic THC analogs to study cannabinoid receptors in the mid-1990s. A single mg of JWH-018 can produce significant intoxication. The DEA issued a final order in March 2011 banning five specific synthetic cannabinoids, JWH-018, JWH-073, JWH-200, CP-47, 497 and CP-47, 497-C8. Schedule 1 drugs are substances that are unsafe, highly abused, and have no medical usage. To be defined as class 1 drugs by the DEA, only these specific substances must be present, so many other synthetic cannabinoids are still unregulated.

The affinity of JWH chemicals to cannabinoid brain and peripheral receptors is much greater than that of THC. Contrary to the partial action of THC at the marijuana receptors, synthetic cannabinoids have full agonist activity and potency, with a longer duration of action and an increased likelihood of adverse effects. There are likely other neuroreceptors, such as serotonin and NDMA, involved in toxicity. Multiple side effects may occur. Diphenhydramine has had some success in reversing some of the dystonic-like reactions from synthetic cannabinoids. Overall, the use of other substances and the variability of the synthetic cannabinoids in the products make it difficult to identify and relate a specific agent to specific symptoms.

Synthetic cannabinoid intoxication, therefore, is a clinical diagnosis. There is no way to prove use, patients usually don't know exactly what they smoked, and laboratory tests are unremarkable. It makes little sense to send off a urine test to a commercial laboratory for a very expensive, delayed analysis, but that can be done in unusual cases. I don't know whether the medical examiner checks the presence of synthetic cannabinoids in routine toxicology studies, but I doubt it. The reference laboratory can use liquid chromatography and mass spectrometry to identify synthetic cannabinoids. It may be difficult for a reference laboratory to accurately analyze a substance, however, with constantly changing chemical structures and compounds.

Most users obviously are aficionados of synthetic cannabinoids because of their similar effect to marijuana, often thinking they are safer. Some use it because its negative drug screen may be required for work or other purposes. Interestingly, the U.S. Air Force is now screening urine for synthetic cannabinoids. The Air Force can detect five synthetic cannabinoid compounds, but there are hundreds of potentially available substances that are fair game to be considered synthetic marijuana.

Next month: The empiric treatment of synthetic cannabinoid toxicity.

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