Gerald Scott Winder, MD; Bradley Stilger, MD; Colleen Ehrnstrom, PhD; and Avinash Hosanagar, MD
Dr. Winder is a psychosomatic medicine fellow, and Dr. Stilger is a psychiatry resident, and Dr. Hosanagar is on the faculty and a psychiatrist all at the University of Michigan Department of Psychiatry in Ann Arbor, Michigan. Dr. Hosanagar is a psychiatrist and Dr. Ehrnstrom was a clinical psychologist at the VA Ann Arbor Health Care System and at the University of Michigan Department of Psychiatry and now is a clinical psychologist at the Eastern Colorado Health Care System in Aurora, Colorado.
Mr. W is a 58-year-old veteran with a history of alcohol dependence and PTSD who reported use of the synthetic cannabinoid “Spice” during intake assessment for treatment of alcohol dependence. He reported using Spice about 4 times over a 2-month period. He purchased a small jar of the substance from a party store for $15 per gram and understood its contents to be synthetic marijuana, which he appreciated for its low cost and assumed legality. He denied having any understanding of the package’s contents beyond “synthetic marijuana.”
The patient ingested the drug by smoking and inhaling from a pipe. For the first 3 times that he used the substance, Mr. W reported feeling a pleasant sensation that started quickly and lasted about 30 minutes. The fourth time that he used synthetic cannabis he felt nauseated and vomited several times, had auditory hallucinations, and increased anxiety; he also reported a hangover effect after this use. He identified that the effects may have been different the fourth time “because the brands were changing.”
Mr. W also reported that his neighbor—a daily user of synthetic cannabinoids for several months—became paranoid, suspicious, and developed incomprehensible speech. His neighbor’s symptoms and his own unpleasant experiences prompted a discontinuation of use.
Synthetic cannabinoids are a diverse group of agents numbering in excess of 100 artificial compounds that act as agonists at cannabinoid receptors, mimicking the effects of tetrahydrocannabinol (THC), an active ingredient in marijuana.28,54 The availability of these drugs online and in specialty shops has been documented since the mid-2000s.27,28,32 Their packaging often describes the contents as incense or herbal blends, using various names. Spice is a common name, but these products are also known by a myriad of other designations (Table 1).28 A single packet usually contains several grams of the drug and costs about $30.55
To the user, who may already be familiar with marijuana, the contents intentionally appear similar to the dried buds of cannabis.30,56 In reality, the drug has just been sprayed onto inert plant material.57 The drug is smoked, and the psychoactive dose can be as little as 1 mg.30 Users describe potent drug effects (Table 2). There is a rapid onset of action, and duration of effects last 1 to 2 hours.58
The compounds’ mechanism of action and appeal are derived from their high affinity for the cannabinoid receptors. The CB1 receptor is located primarily in the central nervous system and is responsible for the psychoactive component of the drugs’ actions.27,30,58,59 Two particular synthetic cannabinoids, cannibicyclohexanol and JWH-018, are potent cannabinoid CB1 agonists with affinity exceeding their natural counterparts.27,30, 32,56,58,59
Chemically, these drugs are varied. The largest structural family of these compounds is the JWH group, which includes JWH-018.60 Also common are CP 47,497 and other CP compounds.58 HU compounds, such as HU-210, have also been identified and have been shown to be 100 to 800 times more potent at the CB1 and CB2 receptors than is THC.60,61 A final group includes the benzoylindoles, such as AM-964 and RCS-4, which also bind strongly to CB1 and CB2.60,62
Constitutional symptoms of synthetic cannabinoid intoxication include disorientation, anxiety, tremulousness, palpitations, tachycardia, agitation, injected conjunctivae, hyperreflexia, nausea, vomiting, lateral gaze nystagmus, and myoclonic jerks, which have been mistaken for seizure activity.27,30,55 Pupils are often normal sized.55 Withdrawal phenomena are similar to those of cannabis withdrawal: irritability, anxiety, tremor, palpitations, diaphoresis, insomnia, headache, diarrhea, nausea, and vomiting.59
Given the established link between cannabis use and psychosis, synthetic cannabinoids may stand as a precipitant of psychotic symptoms, which may include visual hallucinations, auditory hallucinations, disorganized speech, paranoia, grandiose delusions, disorganization, or bizarre behavior.58,63-66 These symptoms may represent a relapse of a primary thought disorder or, for some unfortunate individuals, a de novo psychotic illness.58,65,66 Symptoms can linger for months after drug use.65
A key risk in the use of synthetic cannabinoid moieties may involve the absence of cannabidiol. Cannabidiol naturally occurs in many strains of cannabis and is thought to have antipsychotic, neuroprotective properties.67 The absence of this molecule in synthetic cannabinoids may at least partially explain their severe psychoactive effects. Treatment for synthetic cannabinoid intoxication and related psychosis is largely supportive and may include the use of antipsychotic medication.66
Detection of synthetic cannabinoids in urine is difficult, yet many compounds can be detected via GC-MS or LC-MS. Molecules of significance include JWH-018, JWH-073, JWH-015, JWH-250, CP-47 497, HU-210, cannabicyclohexanol, and oleamide; however, these compounds are rarely excreted in urine in their pure form. The many hydroxylated or dealkylated metabolites of these compounds, mostly unnamed, are more consistently detected in urine.68,69 One author has noted that the pentanoic acid metabolite of JWH-018 seems to appear most reliably in urine specimens.68
