Synthetic cannabinoids are a recent addition to a plethora of common drugs of abuse that can wreak havoc on the unsuspecting user. These are often called fake marijuana and marketed as a substitute for regular old-fashioned marijuana, and multiple chemical versions of synthetic cannabinoids can be added to plant material and sold, often over the Internet. Small doses can mimic well-known pleasurable marijuana effects, but large doses can fully and potently stimulate cannabinoid receptors to the point of severe toxicity and even fatalities.
Some identified synthetic cannabinoids are DEA schedule 1 substances, but many other similar compounds escape detection and classification. More problematic is the fact that the psychoactive cannabinoids will not be detected by a toxicology urine screen that readily identifies natural marijuana, specifically the THC component. A number of synthetic cannabinoids, such as spice or K2, have been regulated by the DEA, but their use is still problematic for the patient and the emergency physician. Unfortunately, the toxicity of synthetic cannabinoids can also mimic a variety of other drugs or medical conditions, and one must make important empirical treatment decisions based only on a clinical diagnosis. Patients are often unable to relate if they ingested or inhaled anything, let alone the specific component, even if they knew it. Only a few articles in the medical literature specifically address synthetic cannabinoids, largely because they cannot be readily identified at present.
Clinical Presentation of Intoxication Due to Synthetic Cannabinoids
Cohen J, Morrison S, et al.
Pediatricians from Children's National Medical Center in Washington, D.C., report on the clinical presentation of three patients with synthetic cannabinoid toxicity and comment on diagnosis and treatment issues. The authors note that symptoms of synthetic cannabinoid toxicity are similar to the euphoric and psychoactive effects of regular old-fashioned marijuana, including some sympathomimetic symptoms such as tachycardia, restlessness, diaphoresis, and agitation. Actually, these reported patients, all relatively young, exhibited rather mild toxicity. Don't expect mild, easily handled toxicity always to be the case.
Case 1: A 16-year-old girl was transferred from another hospital for evaluation of altered mental status. She was refusing to speak, but presented awake. She did not respond to verbal or painful stimuli. Her boyfriend reported that they had been smoking marijuana containing K2. Basic blood tests were normal, and a urine toxicology screen was positive for THC. The synthetic compound had been mixed with marijuana, and that portion was identified as THC by toxicology testing.
The patient was catatonic, lying supine with her eyes open. She had a mild tachycardia but otherwise normal vital signs. Vertical nystagmus was noted, but examinations of the heart, lungs, and abdomen were normal. The lower extremities were slightly rigid and flexed. Being unresponsive to verbal and painful stimuli, she offered no complaints. Treatment included a single dose of diphenhydramine (50 mg IV), which appeared to improve the extremity issues and gave her the ability to speak partially. She was initially treated with a small dose of lorazepam and gradually improved. She was observed overnight, her motor and verbal functions returned to normal, and she was discharged from the hospital.
This is somewhat of an atypical case of synthetic marijuana use because the patient was catatonic and unresponsive rather than agitated, restless, or violent. But this presentation is also atypical for the THC toxicity alone based on her drug screen. The patient had some serotonergic-like effects in the lower extremities, but the overall scenario could mimic acute psychosis, an intracerebral problem, a CNS infection, hypoglycemia, and scads of other drug intoxications. Her clinical status was stable, and she improved with minimal treatment. The diagnosis of synthetic cannabinoid use was based on the history supplied by the boyfriend.
Case 2: An 18-year-old boy was found in an agitated and diaphoretic state at a party. EMS was called, and he subsequently complained of headache, dizziness, and diaphoresis. He was uncooperative, restless, and aggressive in the ED. Vital signs demonstrated a tachycardia of 130 bpm, but otherwise he had normal vital signs and normal oxygenation. The rest of the physical exam was normal, including a limited neurological evaluation. A standard urine toxicology screen, a serum ethanol level, and standard blood tests were all negative. Because of continued aggression and agitation, he was treated with lorazepam 2 mg IV. He appeared to improve and reported smoking spice. The patient was given diphenhydramine for some unexplained reason, and was admitted to the hospital. He returned to baseline, and was then discharged.
This presents a more common scenario of mild to moderate synthetic cannabinoid toxicity. The patient was restless, agitated, and anxious, had normal neurological and physical examinations, and the urine toxicology test was negative for any drugs normally evaluated. He did respond rather well to a small dose of lorazepam, and was subsequently back to normal over several hours.
Case 3: A 16-year-old boy was brought to the ED with altered mental status. He seemed to have a frozen face, and his speech was slowed. A case worker reported that he was agitated and appeared to be hallucinating. The patient reported smoking spice five hours before, stating that he bought the product on the street. He was agitated and dysarthric, with pressured speech, on arrival. He appeared to be somewhat dystonic and confused, but was alert and able to answer some questions. His vital signs were normal, and his cardiac, pulmonary, and abdominal examinations were unremarkable. His upper and lower extremities were hypertonic and hyperreflexic. Initial treatment consisted of 4 mg of IV lorazepam. Laboratory tests and a toxicology urine drug screen were negative. He began to return to baseline, and was discharged home three or four hours later.
Synthetic cannabinoid toxicity accounted for about 4,500 calls to the American Association of Poison Control Centers in 2010. It is clearly much more common now. The initial identified ingredient was termed JWH-018, a synthetic cannabis-like chemical sprayed on a variety of botanicals. The JWH classification was named after Dr. John W. Hoffman, an organic chemist who synthesized multiple analogues and metabolites of THC in the 1990s. As little as 1 mg of JWH-018 can produce significant intoxication through agonist activities of the cannabinoid's brain receptors, CB1 and CB2. This compound produces full agonism in the brain receptor sites, resulting in a more intensive effect than THC, which is only a mild and partial receptor agonist. These authors note that synthetic cannabinoids interact with serotonin receptors, and produce a serotonin or dystonic-like syndrome. This appears to be common if looked for and somewhat ameliorated by IV diphenhydramine. Because of the variability and composition of synthetic cannabinoids, a variety of unusual symptoms may occur.
The authors note that no specific antidote is presently available for synthetic cannabinoid intoxication. Usually the symptoms are short-acting or self-limited. Serious toxicity, however, can last for eight to 12 hours, be associated with severe agitation and restlessness, and progress to seizures and coma. Benzodiazepines appear to be an acceptable and effective first intervention. Diphenhydramine is used in some cases to reverse dystonic-like activity and muscle rigidity. It is recommended that routine laboratory tests include electrolytes, EKG, urine drug screen, blood ethanol level, and serum acetaminophen and salicylate levels.
Patients appear to prefer synthetic cannabinoids because of their perceived safety, a pleasurable high, and the inability of standard drug testing to detect their presence. K2 and spice, the initial-but-now-banned cannabinoids, are easily replaced by other unregulated cannabinoids. Apparently, these products are still available over the Internet, and most users are well informed on how to obtain them. You'll be impressed if you Google “where to buy K2 drug.” Small doses will produce THC-like pleasurable effects and symptomatology, but the overall outcome is unpredictable and can cause severe or life-threatening toxicity. Severe reactions include agitation, delirium, aggressive behavior, nausea, vomiting, and confusion. The agitation can progress to seizures, hyperthermia, rhabdomyolysis, and the symptoms noted with a variety of other drugs, including methamphetamines, cocaine, and a number of other drugs of abuse.
Synthetic marijuana intoxication is a clinical diagnosis. No current methods can prove its use, and many users don't exactly know what they smoked or ingested. Laboratory tests are not helpful.
The cases in this report are relatively mild, but don't underestimate the deadly potential of these substances. A colleague in a busy Philadelphia hospital recently reported a significant number of patients with K2 use who were comatose, vomiting, and required intubation. I suspect these cases are only the tip of the clinical iceberg.
The emergency clinician is faced with the rather daunting task of ferreting out the cause of altered mental status in otherwise healthy individuals. These three reports are in patients as young as 16, and use in high school is not uncommon. The differential diagnosis is rather wide, and multiple entities must be considered, even if the history or toxicology test is suggestive only of THC use. The scenario of agitation, restlessness, tachycardia, altered mental status, and fluctuating neurological findings can be seen with hypoglycemia, alcohol intoxication and withdrawal, CNS infection or head trauma, some electrolyte disturbances or thyroid hyperactivity, and acute psychosis in the mentally ill, and they can also be secondary to a laundry list of unidentifiable street drugs. Most commonly, cocaine and methamphetamines cause a similar clinical state, although toxicity from these drugs is often more severe. Seizures, CVA, renal failure, and myocardial infarction have been reported from those cannabinoids.
When evaluating a patient with unknown altered mental status, one must first check the vital signs and then the glucose. One does not want to miss hypoglycemia, which can present with similar bizarre symptoms. Standard blood tests can be ordered, and patients with chest pain should receive an EKG searching for myocardial ischemia. Troponins can also be sent. A chest x-ray may uncover a spontaneous pneumothorax from inhalation trauma.
Initial treatment is empirical, but benzodiazepines alone appear to be relatively effective in calming the agitation and altered mental status of mild toxicity. The best specific treatment is unknown. But unless one is focused on synthetic cannabinoids for the totally out-of-control patient, a number of sedatives may be used, including haloperidol, the atypical antipsychotics, and perhaps ketamine. The goal is to protect the airway, control the agitation, limit rhabdomyolysis, and monitor for cerebral or cardiac ischemia. The vast majority of the patient's symptoms will resolve spontaneously with a small dose of lorazepam or diazepam, not often the case with amphetamine, PCP, or cocaine toxicity. The addition of other substances will make the diagnoses and treatment more obtuse. Spice and K2 are now regulated, but it is expected that other synthetic cannabinoids will be similarly packaged and marketed as the next legal “marijuana.”
Ten years ago, one might first consider LSD or phencyclidine in a patient who presented with acute agitated delirium secondary to synthetic cannabinoids. Similar to those intoxications, management is supportive and will be determined by the presence and severity of specific clinical manifestations. In addition to benzodiazepines, diphenhydramine seems to be safe and somewhat effective for rather common extrapyramidal findings and serotonergic-like activity. It is certainly a challenge to treat patients who do not respond to benzodiazepines or have coexisting intoxication from other substances. I would expect that these drugs will continue to be abused.
Increase in Adverse Health Effects from Synthetic Cannabinoid Use
The Centers for Disease Control and Prevention received notification in April of a 330 percent increase in poison center calls about adverse health effects from synthetic cannabinoid use. These included spice, K2, black mamba, and crazy clown monikers. (MMWR 2015;64:618.)
Some synthetic cannabinoids have been regulated, but manufacturers frequently change formulations to avoid detection and FDA regulation. The most common symptoms in more than 3,500 calls were agitation, tachycardia, lethargy, vomiting, and confusion. About 12 percent of the calls described major adverse effects, and 15 deaths were reported. Men between 30 and 39 years of age were most likely to exhibit a more severe outcome. The conclusion was that synthetic cannabinoids represent an emerging public health threat.
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