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Intensivists, Take Note: Synthetic Marijuana Product Associated with Stroke Cases

Talan, Jamie

doi: 10.1097/01.NT.0000440973.63886.f1
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Two cases of stroke were associated with synthetic marijuana. Experts discuss the emerging public health problem.

Synthetic marijuana has been linked to stroke in two siblings who developed symptoms within hours of getting high. This is the first scientific report that links stroke to these synthetic substances that are now on the rise. The report was published in the Nov. 8 online issue of Neurology.

One patient was a 26-year old Florida man who made it to the hospital within an hour of smoking and was given tissue plasminogen activator (tPA), which resolved his symptoms. Six months later, his 19-year-old sister smoked synthetic marijuana, also known as spice (or K2), from the same source and experienced severe hemiplegia, sensory loss, and aphasia. She wasn't taken to the hospital in time to receive tPA, and she is left with severe stroke-related disabilities — right hemiparesis and expressive aphasia.

Although they say these two cases comprise their first medical reports linking stroke to the synthetic drug, the clinicians at the University of South Florida have identified several other young stroke victims in the past year whose symptoms emerged on the heels of smoking synthetic marijuana. [Other street names for the synthetic marijuana are fake weed, Yucatan Fire, Skunk, Moon Rocks, Bliss, Black Mamba, Bombay Blue, Blaze, Genie, and Zohai.]





“This is the Wild West of pharmacology,” said study author W. Scott Burgin, MD, Cerebral Vascular Division chief and professor of neurology at University of South Florida. There have been dozens of reports showing an increase in cardiovascular symptoms — chest pain, heart attack, tachycardia, and palpitations — and seizures in people who smoke these synthetic forms of marijuana. In addition to cardiovascular and psychiatric symptoms, acute kidney damage has also been associated with synthetic marijuana.

There was never any doubt that these two young patients suffered a stroke.

Dr. Burgin and Melissa Freeman, MD, a stroke fellow, ordered tests to identify possible causes. In both cases, the brain scans suggested an embolic etiology, which is “consistent with reports of serious cardiac events with spice use,” Dr. Freeman said. They found a large clot in the M1 segment in the 26-year old, and thrombi in multiple insular branches in his sister.

The first patient arrived to the emergency room last year with complaints of slurred speech and weakness on the right side of his body. A medical history obtained from his parents came up negative. After he was a bit more coherent and able to speak, he admitted that he had smoked spice an hour before the symptoms started.

Six months later, Dr. Burgin had an eerily familiar feeling when he looked at the family of a young girl brought in severely aphasic with significant weakness on her right side. It was the young man's sister. This time, doctors knew to ask about recent use of spice. Her boyfriend reported that she had used it. The ER staff called state poison control experts and ordered tests to look for a range of compounds found in synthetic marijuana. She tested positive.

Dr. Burgin said that they went out of their way to ensure that the brother and sister did not have any known genetic risks for stroke. They also ordered clotting studies, heart tests, and vascular imaging. They suspect that spice produces stroke by means of a cardiac mechanism that is not yet identified. They can't rule out a neurotoxic mechanism without further study, Dr. Burgin said.

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Spice is created by an underworld of rogue chemists who tweak molecular recipes for cannabinoid receptors that were initially developed as testing tools in the lab. These molecules were never meant for human consumption. There are a handful of cannabinoid-like chemicals that have been marked as a Schedule 1 controlled substance but these chemists tweak the recipe so that they are no longer selling a regulated compound. These synthetic cannabinoids bind to CB1 and CB2 cannabinoid receptors in the brain.

“They are relatively new compounds and we really don't know much about how they work,” said Dr. Burgin. They also don't know what other chemicals are in these preparations that could be toxic or the variations in what people are smoking. The teenager tested positive for JWH-018, the most common chemical that is used in the lab for testing endogenous cannabinoid receptors.

John W. Huffman, PhD, of Clemson University is the organic chemist who created JWH-018. He spent his career synthesizing analogues and metabolites of delta-9-tetrahydrocannabinol, also known as THC. Dr. Huffman published information on the compound but had no idea that a decade later it would be a main source for a recreational high.

Apparently dealers sprinkle JWH-018 on plant products and sell them in packets as herbal blends, incense and air fresheners. Scientists have reported that it is about ten times more potent than the THC found in marijuana. THC analogues are now used for the treatment of nausea and pain, and are being tested for the treatment of glaucoma and appetite control.

THC, a partial agonist at the CB cannabinoid receptor, inhibits GABA receptor neurotransmission. By contrast, JWH-018 is a full agonist and has been reported to cause psychosis and severe anxiety and agitation. That it targets GABA receptors also explains why there have been reports of seizures.

In 2008, scientists first identified JWH-018 as an active ingredient in spice. The rogue chemists keep making small changes in the molecule and that makes detection far more difficult.

“These chemicals are dangerous and potentially life-threatening,” said Dr. Burgin. “Their quasi-legal status is petrifying,” he added. “This is an enormous public health problem.”

In fact, the products have been banned in 41 states.

Dr. Burgin added that neurologists and emergency medical doctors should be on the lookout for these new drugs. It needs to be part of the social and medical history taking when young patients come in with neurological and cardiovascular symptoms. It is important to get toxicologists on board early. There are tests available for these synthetic substances but they have to be ordered specifically. They are not part of routine drug tests.

“Think to ask about designer drugs,” added Dr. Freeman. “People may not volunteer this information.”

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“The findings are interesting and alarming,” said Ramy El Khoury, MD, assistant professor of neurology at Tulane University and stroke director at Lakeview Regional Medical Center. “These synthetic cannabinoids seem to be linked to more cardiac and vascular problems than marijuana itself.”

“We don't have enough cases to say that they are definitely linked, but it is time to be aware of these risks,” he added. “And we need to figure out the mechanism.” He said that the diagnosis of stroke in young people has increased significantly in the past decade, but it could be any number of reasons: more high blood pressure, high cholesterol, and obesity.

Leon Gussow, MD, a retired emergency medicine physician and medical toxicologist who has been consulting for the Illinois Poison Center, has been following the evolution of spice on the recreational drug scene. He said that drug screening should be part of any workup in stroke in a young person. But he also cautions that these screens would not necessarily pick up designer drugs that have been altered.



The National Institute on Drug Abuse (NIDA) has been aware of synthetic marijuana and has been studying its effects in the laboratory. The agency has also added a question about its use into its national survey — Monitoring the Future. Every year, they ask thousands of students about their drug use. In 2012, the survey captured the use of synthetic marijuana and found that 4.4 percent of 8th graders, 8.8 percent of 10th graders, and 11.3 percent of high school seniors reported use of synthetic marijuana.

“These drugs are not designed for human consumption and they are not regulated, so we really don't understand the effects they have on the body,” said Wilson Compton, MD, director of the Division of Epidemiology Services and prevention research at NIDA. “We have quite a bit of work to do. This finding demands more research to determine the strength of the association.”

As for the new paper identifying synthetic marijuana as a risk factor for stroke, he added: “We know that cannabinoid receptors are in the blood vascular endothelial cells. This could explain why there are reports on the cardiovascular effects, and now stroke. We hope that this inspires physicians to ask about the use of these substances.”

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Michael Baumann, PhD, runs the Designer Drug Research Unit at the National Institute on Drug Abuse intramural research program. Synthetic marijuana is now high on their research agenda. They are conducting animal studies to see how these drugs affect heart rate, blood pressure, and temperature. They are also studying the pharmacokinetics of these chemicals to understand how the substances are metabolized by the body once internalized.

Dr. Baumann said that there is growing evidence that bioactive metabolites can be formed, and these metabolites could be associated with the adverse effects that are being reported. The federal scientists and other groups have confirmed the increased potency of these designer drugs, which Dr. Baumann said could be causing different central nervous system effects than marijuana.

Also, the way the drugs are made — spraying the chemicals on to a plant mixture — means that some areas of the plant mixture will have high concentrations of the chemical while other areas have low concentrations. “That means that people smoking from the same product could be exposed to dramatically different amounts of the chemical. These drugs are quite potent in their cardiovascular effects.”

—Jamie Talan

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•. Freeman MJ, Rose DZ, Myers MA, et al. Ischemic stroke following use of the synthetic marijuana “spice.” Neurology 2013; E-pub 2013 Nov. 8.
    •. Thornton SL, Wood C, Friesen MW, et al. Synthetic cannabinoid use associated with acute kidney injury. Clin Toxicol 2013; 51(3):189–190.
      •. PubMed archive on synthetic marijuana:
        •. FBI advisory on synthetic marijuana:
          © 2013 American Academy of Neurology