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It's Not Your Father's Marijuana Anymore

Roberts, James R. MD

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doi: 10.1097/01.EEM.0000522214.99323.05
    synthetic marijuana
    synthetic marijuana:
    K2 and Spice are relatively old synthetic cannabinoids that are still widely available. Cannabinoid users have moved on, however, and the number of synthetic cannabinoids currently available is mind-boggling. Undetected by standard toxicology analysis, these cannabinoids cause a variety of toxic effects, and the clinician is faced with many perplexing patients. Treatment is supportive and the use of sedation, usually benzodiazepines, is commonplace. Treatment is empiric, and the challenge is to make sure one is not dealing with medical problems, such as hypoglycemia and CNS infection.

    It used to be so easy to deal with marijuana abusers, perhaps better termed users, in the emergency department. These individuals were omnipresent and the use of the drug so common that it was often considered normal flora on a drug screen. Even many medical personnel used it quite liberally.

    Good old-fashioned marijuana caused some disorientation, pleasant hallucinations, stimulation of the appetite, and an overall pleasurable effect, but individuals with serious problems from marijuana rarely come to the emergency department.

    How things have changed. Dozens of synthetic cannabinoids have become available on the street over the past 10 years, and they are used with reckless abandon by the general population, are easily available over the internet, and have chemical compositions so complex that they are not found by a standard drug screen even though they were chemically considered cannabinoids.

    Readily available and commonly abused cannabinoids are now undergoing a period of gargantuan proliferation and complex chemical diversification, spawning increasing challenges for the emergency physician in diagnosis and treatment. Synthetic cannabinoids are the fastest growing class of new psychoactive drugs with an amazing 177 new substances identified in 2014 by the United Nations Office on Drugs and Crime. Many cannabinoids were developed by chemical and pharmaceutical companies as ligands for studying the endocannabinoid system, but the synthetic cannabinoids show no structural relationship with the plant cannabinoid, delta 9 tetrahydrocannabinol (THC).

    The first brands of synthetic cannabinoids were available on the street in 2008, and were known as Spice and K2. A plethora of new synthetic cannabinoids have been developed by clandestine laboratories and drug dealers since then. Garden-variety marijuana rarely produces serious medical consequences, but the synthetic cannabinoids are not mere hallucinogens but very powerful toxins that have been associated with serious adverse effects. Currently available cannabinoids can produce psychosis, delirium, cardiotoxicity, seizures, acute kidney injury, hypothermia, and even death. Synthetic cannabinoids produce a variety of autonomic nervous system perturbations, with alterations in dopamine activity and even severe withdrawal syndrome. It's problematic that these powerful chemicals are even called cannabinoids, or synthetic marijuana, because they share little in common with the well-known pleasurable effects of THC.

    One example of a synthetic cannabinoid to reach the street and wreak havoc is AMB-FUBINACA, which was developed by Pfizer in 2009 but recently found on the street during an outbreak reported in New York City.

    “Zombie” Outbreak Caused by the Synthetic Cannabinoid AMB-FUBINACA in New York

    Adam AJ, Banister SD, et al.

    New Engl J Med


    This is an interesting report that describes an intense investigation of an outbreak of synthetic cannabinoid use in New York City in 2016. The authors identified 33 people exposed to an unknown drug that produced a curious clinical response. Individuals who smoked this street-bought cannabinoid had CNS depression, producing a blank stare that was termed the zombie effect. Patients were lethargic, but had no significant alterations in vital signs or physical examination. Standard laboratory testing, including a urine screen for drugs of abuse that included THC, revealed no abnormalities. The patients remained staring and obtunded for eight to 10 hours, and slowly returned to normal. The article described an intense investigation for the cause of this outbreak with the final outcome being discovery of a previously unknown cannabinoid termed AMB-FUBINACA.

    The substance was found to have potency 85 times that of a delta-9-THC and 50 times that of the previously well-known K2/Spice synthetic cannabinoids. The drug is available on the internet, and fortunately was a synthetic cannabinoid with rather benign effects. This report chronicles the amazing ability of drug abusers to obtain little known drugs of abuse and how rapidly they reach the street.

    Comment: Dozens of synthetic cannabinoids are now available, many with severe toxicity and others with milder effects, and the emergency physician has no way to identify the product used. Standard drug testing for THC will be negative, and the toxicity of the substances varies widely. It would not be uncommon to see a number of patients with similar bizarre symptoms and never ascertain which of the many drugs was the culprit. There is no antidote, and the treatment is general and supportive, predominantly employing sedatives and embarking on an evaluation for other possible medical problems. The users will have no idea what they put in their bodies, and they will be clouded and altered to an extent that they will be able to offer no help.

    The drug-abusing population has moved way beyond Spice and K2, but these synthetic cannabinoids are still widely available. K2 has been associated with acute myocardial infarction in patients with normal coronary arteries. The use of Spice and K2 results in hypertension, agitation, hallucination, psychosis, seizures, and panic attacks, but these are benign when compared with those caused by a never-ending supply of synthetic cannabinoids.

    Treating synthetic cannabinoid toxicity is relatively straightforward. The patient should be quickly sedated, usually with benzodiazepines in large doses significant enough to be effective. Standard laboratory testing, including glucose determination and CPK looking for rhabdomyolysis, should be routine. These patients will rarely require muscular paralysis or assisted ventilation. These patients will generally return to normal in eight to 24 hours, and admission for observation is often required. It certainly would seem reasonable to use aggressive sedation rather than physical restraints. It would be unlikely that these individuals would have hypoglycemia or CNS infection, but these conditions should always be kept in mind. One cannot identify synthetic cannabinoids in the ED, so a lot of time and effort will be spent evaluating and treating these patients.

    Adverse Effects of Synthetic Cannabinoids

    Severe Toxicity Following Synthetic Cannabinoid Ingestion

    Lapoint J, James LP, et al.

    Clin Toxicol (Phila)


    This is one of the few articles discussing the clinical aspects of synthetic cannabinoid use. It was written 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 ordered them knew what they were. These authors noted that the clinical effects of synthetic cannabinoids are due to 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.

    The authors reported a 48-year-old man who ingested an unknown powder that he had purchased on the internet. He quickly became agitated and had a generalized seizure. The seizure activity recurred numerous times, but it 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. Shortly after hospitalization, the patient developed refractory supraventricular tachycardia (SVT) that required cardioversion. The powder the patient ingested was analyzed, and it was found to contain JWH-018, a common potent synthetic cannabinoid. The patient became asymptomatic after three days of hospitalization and was discharged.

    Comment: These authors reported one of the first cases of repetitive seizures and SVT following the confirmed use of the widely available synthetic cannabinoid JWH-018. Seizures following THC use are rare. The authors pointed 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 glutamanergic and GABAergic synapses, and play a role in modulating neurotransmitting signaling mechanisms.

    Synthetic cannabinoids are now classified as Class 1 controlled substances by the DEA. It is currently illegal to possess, sell, or use a few specific synthetic cannabinoids. There are, however, many similar chemicals that have escaped regulation. The initial low-dose effects are similar to natural marijuana, but more serious and even life-threatening symptoms are associated with synthetic cannabinoids, likely due to 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 impossible to say what is in the current street drug. It is simply impossible for clinicians to keep up with the available cannabinoids.

    Numerous other substances, such as synthetic opioids, caffeine, and a potent B-2 agonist, clenbuterol, may be mixed with the cannabinoids. The basic chemicals are combined with herbs, regular marijuana, and other plant products, often merely sprayed on. No delta-9-THC is contained in true synthetic marijuana.

    Synthetic cannabinoids 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.

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