K2 Synthetic Marijuana: Heart Attacks, Suicides, and Surveillance
Sixteen-year-old boys having heart attacks.
Blog reports of deaths and suicides.
And a little known chemistry and public health resource mobilized to identify "legal highs."
The chemical and biological phenomenon that is "synthetic marijuana" continued to develop over the last week as we learn more about these products from the medical and public health communities.
Most notably, pediatric cardiologists reported in the journal Pediatrics on three cases of Texas teenagers who experienced myocardial infarctions - heart attacks - after using a synthetic marijuana product (DOI: 10.1542/peds.2010-3823).
(Many thanks to Dr. Ivan Oransky, Executive Editor at Reuters Health, for providing us with primary information after their own excellent report by Frederik Joelving).
Sold under names like K2 or Spice as "incense" or "potpourri" and labeled as "not intended for human consumption," these products are laced with one or more synthetic psychoactive compounds that were published in 1990s work studying structure-activity relationships on cannabinoid receptors. The vast majority of the synthetic work was done in the laboratory of Dr. John W. Huffman, now professor emeritus of the Department of Chemistry at Clemson University, with his compounds know by "JWH-" nomenclature.
The US Drug Enforcement Agency secured emergency prohibition of five of these compounds late last year, spurring "legal highs" manufacturers to reformulate second-generation Spice products containing related compounds not explicitly designated as illegal. Although the DEA does have the authority to prosecute sale and possession of these analogs, such action is rare. To learn more, we've put together a compilation of our synthetic marijuana posts for the reader's further reference.
Adolescent heart attacks
In this week's advance Pediatrics publication, the three cases - all in 16-year-old boys - were seen at the UT-Southwestern Medical Center in Dallas within three months of one another. The common presentation was a 3- to 7-day history of chest pain with myocardial infarction confirmed by electrocardiographic and biochemical endpoints (ST elevation in the inferolateral leads and substantial increases in cardiac troponin-I released into the bloodstream).
As you might predict, heart attacks are extremely rare in otherwise healthy 16-year-olds. But marijuana itself is known to cause cardiac effects, with rare cases of myocardial infarction. In the discussion of the Pediatrics report, Dr. Arshid Mir and colleagues describe literature extending back to 1979 (DOI: 10.3109/15563657909010604) on the increased risk of cardiac disturbances, including myocardial infarction, within the first hour of marijuana use. Increased heart rate is a well-recognized effect of marijuana that is mediated by increased sympathetic nervous system outflow to the heart. This 1976 paper in Circulation describes how the majority of this tachycardia can be prevented by premedication with the non-selective beta-blocker, propranolol.
But what about these synthetic compounds in today's products?
Unfortunately, most of our information comes from these human toxicology reports. However, the adverse actions of the JWH compounds could be predicted by their biochemical effects on cannabinoid receptors. Most of these compounds are more potent that THC from marijuana in binding CB1 receptors and they exert greater maximum effects at these receptors - in pharmacology terms, THC is called a "partial agonist" while JWH compounds are often "full agonists" at these receptors.
As alarming as the Pediatrics report may seem, a confirmation of causation between JWH compounds in K2 products and myocardial infarction remains incomplete.
First, all three teenagers reported using marijuana in the weeks prior to their recent use of K2 that more acutely preceded their hospitalization. While myocardial infarction from marijuana alone is rare, one cannot conclude that synthetic marijuana products were solely responsible.
Second, specific urinary drug screening for synthetic JWH cannabimimetics was only done for one of the patients and found to be negative for JWH-018 and JWH-073. However, both of these compounds were explicitly outlawed by the emergency DEA action so these negative results might be expected. The authors acknowledged this deficiency in the paper's discussion. One hopes that urine and/or blood samples were saved for further analysis.
Lastly, no chemical analysis was performed on the products the teenagers used and only described in the paper as, "K2, Spice (Dallas, Texas, manufacturer unknown)." Follow-up studies on the potential cardiac risks of these compounds would be aided greatly by knowing what compounds were in the products used by the boys. Given the geographical isolation of the report, one possibility is that this batch of product contains a particularly cardiotoxic product.
Potential solution: The CDC's Laboratory Response Network
The greatest challenge in assessing the relative public health risk of synthetic marijuana products is the chemical complexity of the spectrum of products being sold in the US. For example, the risk of illicit use of a prescription opioid drug like OxyContin is straightforward. We know exactly how much of what compound (oxycodone) is in each tablet and the drug has a long history of use. We know the nature of adverse reactions and an antidote is available for oxycodone overdoses.
But for so-called legal highs, we have a case of multiple manufacturers spiking their various products with inconsistent amounts of potentially dozens of compounds. (In fact, this situation is not dissimilar from assessing the risks of herbal and non-botanical dietary supplements.)
Our biochemistry colleague, Dr. Melissa Turman, alerted us to an article in Nature Medicine about an underappreciated public health surveillance system that might aid in tracking and identifying these compounds (DOI: 10.1038/nm1111-1339). Therein, Jeffery H. Moran, branch chief of the Public Health Laboratory at the Arkansas Department of Health, describes how his state corralled the resources of the federal Laboratory Response Network (LRN):
The LRN was established by the US Department of Health and Human Services and US Centers for Disease Control and Prevention in accordance with Presidential Decision Directive 39. The mission of the LRN is to develop and support a network of laboratories “that can respond quickly to needs for rapid testing, timely notification, and secure messaging of results associated with acts of biological or chemical terrorism and other high priority public health emergencies.” To achieve this objective, LRN laboratories are staffed, trained and equipped to perform complex clinical chemical analyses required to assess human exposure to dangerous chemicals.
One typically thinks of international bioterrorism and chemical warfare when considering the capacities of the LRN network. But when Arkansas legislators began debating whether or not to regulate synthetic cannabinoids, the state health officer took the innovative step of turning to the LRN-Chemical laboratories in Arkansas, because the circumstances of K2 meshed closely with the intended purpose of this network.
Thanks to Nature, this important article was open-access at the time of this posting.
No, I hadn't known about this system either. Dr. Moran goes on to describe how the resources of the LRN-Chemistry labs have provided authorities across the US with authentic chemical standards and analytical testing methodologies for, "keeping pace with 'street chemists' who are highly motivated to stay one step ahead of regulatory efforts and laboratory detection capabilities."
Perhaps the UT-Southwestern cardiologists might care to follow up with the LRN about their findings just published in Pediatrics.
The additional pharmacology work and clinical investigations allows public health officials to keep enforcement authorities posted on the public health risks of these compounds as they emerge. I'm still unclear as to where results from LRN work are published, even in preliminary form, but the network appears to offer resources that offset the budgetary cuts and overwhelming analytical load suffered by state crime laboratories.
Stories from families
Behind each statistic of adverse events due to sort-of-legal highs is, most often, a young person. This blog and its previous iterations at ScienceBlogs and as an independent site on WordPress have garnered hundreds of anecdotal reports from users and families of users of these products since we first wrote on the subject in February 2010. The more these comments I accumulate, the more I wish a formal mechanism existed to interface with public health officials. Of course, blog comments are most often anonymous but the IP address and voluntary identifying information (such as e-mail address - although real ones don't have to be given to comment) might be used to at least localize reports.
Here's a comment that came in last week that makes me wish I could do more:
From the US Centers for Disease Control and Prevention. Click on the map to go to the source page for more information.
My son killed himself on Sunday 6 Nov 2011. He was taking very large amounts of Spice and was addicted. The alteration of his mental state definitely contributed to his Suicide. People fail to see the spiritual side and how evil forces attach to drugs and use them as a medium to provoke such thoughts and behavior. My son was very successful and not someone you think would be prone to suicide. There is no doubt in my mind he would still be alive today if he had not been involved with the use and eventual addiction to Spice.
I've redacted the online identity of the writer because a little Google-fu allowed me to confirm this report.
Again, causation is difficult to establish without a proper study design based on these anecdotal reports. To play devil's advocate, impulsive young men with ready means to harm themselves might already be predisposed to suicide. But I've gotten too many of these sorts of comments to think that the compounds in K2, Spice, and similar products aren't causing some chronic psychological disturbances. These anecdotes, as are even the most carefully-documented case reports, are fertile for the generation of scientific hypotheses.
Here's another one that came in earlier this year:
My son smoked K2 or Spice – laced with variations of JWH-xxx -018, -073, -250, -081 and -372 from purchases of products being sold in NC prior to the ban and is NOW in a psych hospital dealing with the resulting anxiety attacks, rapid heartbeat, agression, anger, depression etc. He is being treated as a bipolar/schizophrenic person heavily sedated and on suicide watch, when previously he had only normal 20-year old behavioral indications.
What's clear to me is that this phenomenon is not going away. The DEA action against five synthetic cannabimimetics has simply driven chemists to make analogs not explicitly mentioned in the DEA emergency ruling. While these can technically be prosecuted under the "analogue [sic] act," few such cases have been reported.
Of course, we also need to put these cases - disturbing as they are - into the context of overall public health risks. Dr. Moran noted in his Nature Medicine piece that US Poison Control Centers received 4,421 reports on synthetic marijuana from January through August of this year. In contrast, the 2009 US Poison Control Centers annual report (PDF, the latest one available) shows at least 100-fold more reports of poisonings with opioid analgesics and sedative/hypnotic drugs (such as benzodiazepines).
But the public health question is whether the synthetic marijuana compounds have more long-lasting and potentially irreversible effects. One can hope that the work of the LRN is one step toward understanding these risks and providing a scientific basis for further enforcement legislation.
Online chat on synthetic marijuana
Tonight - Monday night, November 14th - at 6 pm EST, Kelcey Carlson of WRAL-TV in Raleigh, North Carolina, will air a report on synthetic marijuana products in the Research Triangle area. Immediately thereafter at 6:30 pm, she'll field a live chat on the topic. While we were not among those consulted for this report, we'll be present to participate in the discussion.
Update (15 November) - A transcript of the live chat is available here at the WRAL website.
Mir, A., Obafemi, A., Young, A., & Kane, C. (2011). Myocardial Infarction Associated With Use of the Synthetic Cannabinoid K2 Pediatrics DOI: 10.1542/peds.2010-3823
Moran, J. (2011). Smart resource allocation needed to study 'legal highs' Nature Medicine, 17 (11), 1339-1339 DOI: 10.1038/nm1111-1339