What are Synthetic Cannabinoids?

What are Synthetic Cannabinoids?

Under the Radar: Synthetic Cannabinoids and Vaping-Related Lung Injuries

Synthetic cannabinoids are a class of hundreds of research compounds designed to interact with the endocannabinoid system. JWH-018 was the first sCB to emerge as an abused substance in the mid-2000s along with other “designer drugs” like synthetic cathinones (sometimes called bath salts)1

Synthetic cannabinoids can be directly sprayed on cannabis or other herbs, and then are sold as products with names such as bonsai, K2, spice, herbal incense, Armageddon, and Agent Orange, among others. Products contain anywhere from one to a handful of active compounds. Some sCB products are sold as powders or concentrated oil extracts suspended in propylene glycol.

It’s nearly impossible to detect hundreds of potential sCBs in a single test, and dozens of new sCBs are designed every year. The variety of compounds also makes dosing risky for consumers, since each sCB has a different potency. If someone can’t gauge a ‘normal’ dose, they are much more likely to overdose.

There is no consistent set of symptoms during a sCB overdose, so nurses and doctors who encounter such patients in the emergency room rarely have guidance or experience to direct their actions. Between 2016-2018, a large fraction of reports pertained to two of these chemicals, called AMB-FUBINACA and 5F-ADB, either because they are particularly common or particularly lethal.

Synthetic cannabinoids and the lungs

Synthetic cannabinoids have been reported to cause a variety of health problems and are potentially deadly. Diffuse alveolar hemorrhage and acute respiratory failure, heart attack, stroke, seizures, and kidney damage are all possible consequences of sCB use.

The 2016 episode reported as the “New York City zombie outbreak” has been attributed primarily to the synthetic cannabinoid AMB-FUBINACA 45 So has a spate of roughly 50 deaths in New Zealand in 2017 and 2018 6. Because relatively few people use sCBs, the total number of deaths is small. But sCBs are highly dangerous drugs.

A handful of case reports have associated sCBs with lung toxicity. It is not the biggest risk of sCBs, considering their other potential harms, but there is a fairly consistent set of symptoms that aligns with the CDC’s diagnostic for a “confirmed cases” in the recent vaping outbreak.

While analyzing ICU visits of patients overdosing on sCBs, doctors at MedStar in Washington, DC, noted that “Pulmonary edema and tachycardia were the most common findings” of sCB use and organ failure was “primarily driven by altered neurologic status and respiratory failure.”7They went on to implicate “synthetic cannabinoids as a potential cause of acute lung injury and acute respiratory distress syndrome.”

The various cases of sCB-induced respiratory depression have generally presented as follows:

  • Individual was using synthetic cannabinoids for 1-3 months.
  • Lung condition worsened either suddenly (within an hour of use) or over the course of a few days.
  • Patient was hospitalized in significant distress with low blood-oxygen.
  • Patient, if still alive, was intubated for up to a week.
  • Patient was diagnosed with pulmonary edema and a CT scan showed ground-glass infiltrates in the lungs.
  • Patient responded to short-term corticosteroid treatment.
  • Pulmonary edema resolved and lung inflammation typically subsided.

Synthetic cannabinoids can cause respiratory failure

There are numerous case reports of respiratory failure after intentional sCB use. These reports often align with the CDC’s current classification of a confirmed case of vaping-related illness.

The first case appears to have been reported in 2011 and was followed by several others:

  1. Loschner et al (2011): A 19-year-old entered the ER after smoking a sCB called “the Greenhouse Effect.” He had been using sCBs for the prior two months. Radiography showed ground-glass opacities and alveolar infiltrates. The doctors ruled out infection as a cause and confirmed the patient had diffuse alveolar hemorrhage. He required mechanical ventilation for 60 hours and received methylprednisolone.8
  2. Alhadi et al (2013): A 21-year-old male who had recently used sCBs was hospitalized with “a chronic inflammatory infiltrate in both the airways and alveolar spaces.” The authors highlight that synthetic cannabinoids may have produced “distinct and rapidly resolving pulmonary lesions,” which responded to corticosteroid treatment.9
  3. Berkowitz et al (2015): The authors described “pneumonia in response to smoking synthetic [cannabinoids]” in four young men. All four patients had negative biological screens, ruling out infection. Three of four patients received steroids. All had ground-glass opacities in CT scans.10
  4. Öcal et al (2016): A case of acute eosinophilic pneumonia was diagnosed in a 21-year-old man. CT scan showed “irregular areas of ground glass opacities … evidently in the central part of the lower lobes.” Infectious diseases were ruled out as possible causes. The man admitted to using sCBs the previous month and had increased his use during the preceding week. The CT abnormalities had mostly resolved after three days of treatment with prednisolone.11
  5. Chinnadurai (2016): A 29-year-old man was brought to the ER after smoking K2. He had the same radiographic symptoms described by Berkowitz but they resolved spontaneously within 24 hours. He was brought to the ER because of agitation, sedated with lorazepam and haloperidol, and was kept because of a fever, not because of any residual lung symptoms.12
  6. Yamanoglu et al (2018): A 19-year-old smoked twice his normal dose of sCBs. He was comatose an hour later when the ER received him. Radiography suggested pulmonary edema and showed the typical “patchy ground glass density unexplained by a separate condition.”13
  7. Imtiaz et al (2019): Reporting on a similar case of respiratory failure within an hour of smoking K2, the authors stated, “We believe that the diagnosis of synthetic cannabinoid-induced respiratory failure can be established by the acute onset of hemoptysis and respiratory failure that is delayed 24-48 hours after inhalation of the drug, provided that alternative conditions … have been excluded.”14

All these reports match the CDC’s classification for a probable or confirmed case in the current outbreak. In most instances, respiratory depression was linked to diffuse alveolar hemorrhage, but the exact mechanism varies between different cases (perhaps because of different sCBs).

Fake weed, real dangers

There are many other published reports of respiratory depression related to sCBs that don’t precisely fit the CDC’s classification.

For example, Ivanov presented the death of an 18-year-old boy who had been using sCBs for some months 15. The night before his death, he smoked three “fake weed” joints containing AMB-FUBINACA and 5F-ADB. Postmortem analysis indicated acute respiratory distress syndrome, pulmonary edema, and lung inflammation. However, pulmonary infiltrates are not mentioned in this report, making it unclear if this matches the CDC’s criteria for vaping-related pulmonary injury.

A report from 2016 mentions that AB-CHMINACA is sometimes added to “propylene glycol… for use in electronic cigarettes” 16 In this paper, Gieron and Adamowicz describe the death of an individual within hours of using AB-CHMINACA. They report that “the cause of death was acute cardiorespiratory failure of indeterminable cause,” however no details of the individual’s lung condition are given. This particular sCB, which appears to have emerged in 2014, has been implicated in several other cases.

At a 2015 meeting of Society of Forensic Toxicologists, Shanks et al described three cases of respiratory failure related to AB-CHMINACA.17 In one individual, “autopsy included severe pulmonary edema and congestion,” along with other signs of organ damage. In another case, a woman involved in a car crash was found to have AB-CHMINACA in her bloodstream and “bilateral pulmonary edema and congestion along with general visceral congestion.”

In 2019, Adamowicz reported on pulmonary edema and “left-side pleural adhesions” after sCB use.18 But histological analysis didn’t show ground-glass infiltrates or inflammatory changes. Two years earlier, Maeda and colleagues reported on a death in Japan with “[s]evere alveolar effusions with evidence of air bubbles and hemorrhage,” however they suggest that sCBs caused seizures which precipitated respiratory depression.19 And a 2012 report identified a teen who was in respiratory distress and required ventilation after a seizure from sCB use.20

When intentionally using sCBs, people tend to smoke rather than vape. But inadvertently vaping oil contaminated with sCBs is likely to result in the same toxicity as intentionally smoking sCB-laced herbs, so all these cases are potentially relevant to the current vaping scourge.

Challenges detecting synthetic cannabinoids

Given the consistency of published reports on respiratory failure associated with intentional sCB use, their association with quasi-legal cannabis products, and documented examples of sCB-contaminated cannabis oils, synthetic cannabinoids should be considered a prime suspect in the outbreak of vaping-related lung injuries.

But there are a number of challenges that make it hard to detect sCBs. For starters, there are hundreds of compounds in this class of drugs, and it is unlikely that those reporting cases to the CDC have ruled out every possible chemical. Additionally, many synthetic cannabinoids are orders of magnitude more potent than THC. A chemical 100 times more powerful than THC has to be detected at very low concentrations, and most labs do not specialize in sCB detection.

Another issue: case reports have demonstrated that sCBs can be cleared from the blood within hours of administration,21 so a negative blood test does not mean there was no sCB use. It would be better to test the product, if it is available.

Efforts have been made to classify sCBs.24A handful of common chemical scaffolds make up the bulk of sCBs that authorities encounter. In cases where officials have access to the product that injured consumers had used, detection should be possible. The CDC and other official bodies should work with toxicology labs to iron out a consistent testing methodology.

Why are synthetic cannabinoids added to vape oil?

If synthetic cannabinoids are indeed contributing to the outbreak of vaping-associated respiratory failure, the obvious question is why? Why would products be adulterated with sCBs? Why are they particularly common in illicit products? Is bad public policy partially to blame?

Synthetic cannabinoids are cheap to produce and not easily detected in standard drug tests. In theory, producers can heavily dilute the base oil to extend their profits, then bump the “potency” back up by adding synthetic cannabinoids. This would additionally create an association with thinning agents – a combination that is consistent with the range of products linked to vaping-related illnesses.

Nicotine products have been implicated as well as black market and legally sold THC vapes. Since legal markets do not require testing for sCBs, they could make their way into both licit and illicit products, although the bad actors adulterating products are more likely to be in the black market, evading taxes and quality controls. Currently around 80 percent of reported vaping-related lung injury cases involve THC products (mostly illegal) and about 60 percent involve nicotine. Most people are using both.

While synthetic cannabinoids have not been officially confirmed as a contributor to the vaping outbreak, they are plausible culprits. From what we know thus far, it seems certain that multiple causes are involved in the outbreak, and synthetic cannabinoids may be playing a significant yet underappreciated role.

Consuming sCBs is dangerous for many reasons. They can trigger seizures, for example, as well as heart attack and acute kidney injury. But if synthetic cannabinoids are contributing to respiratory ailments, then why haven’t we also seen a spike in these other health problems?

In fact, vaping Juul, the dominant e-cigarette, has been associated with seizures. 22 After announcing an investigation in April 2019, the FDA compiled 127 reports of seizures and neurological problems associated with vaping nicotine e-cigs in the past 10 years.23 This information was released in August of 2019, in the middle of the outbreak of vaping-related respiratory failure. It appears that these neurological symptoms are a side effect of high doses of nicotine, not a synthetic cannabinoid issue. Seizures sometimes occur when people accidentally swallow vaping liquid, according to the FDA.24

Continue to “Cannabinoid Pharmacology”


Adrian Devitt-Lee, Project CBD’s chief science writer, is pursuing a PhD in Mathematics at the University College of London.


Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. These chemicals are often all lumped together as New Psychoactive Substances (NPS). This can obfuscate the differences between novel research chemicals. Synthetic cathinones like mephedrone and MDPV gained notoriety around 2008-2011 as major NPS. Synthetic cannabinoids are now considered to make up the majority of NPS use. Fentanyl analogues and other new opioids are a growing problem as well 23
  2. “Spice-Like Products.” Erowid Spice Product Vault (Spice, K2, Black Magic, Smoke, JWH-018, JWH-073, Etc), www.erowid.org/chemicals/spice_product/spice_product.shtml.
  3. “Experimental & Research Chemicals.” Erowid Psychoactive Vaults : Research Chemicals (Synthetic Drugs, Novel Psychoactive Substances, New Psychoactive Substances, NPS, Replacement Psychoactives), www.erowid.org/psychoactives/research_chems/research_chems.shtml.
  4. Rosenberg, Eli, and Nate Schweber. “33 Suspected of Overdosing on Synthetic Marijuana in Brooklyn.” The New York Times, The New York Times, 13 July 2016, www.nytimes.com/2016/07/13/nyregion/k2-synthetic-marijuana-overdose-in-b….
  5. Adams, Axel J., et al. “‘Zombie’ Outbreak Caused by the Synthetic Cannabinoid AMB-FUBINACA in New York.” New England Journal of Medicine, vol. 376, no. 3, 2017, pp. 235–242., doi:10.1056/nejmoa1610300.
  6. Penman, Carla. “New Kind of Deadly Synthetic Drug Surfaces in Auckland.” NZ Herald, NZ Herald, 29 May 2018, www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=12060187.
  7. Pulmonary edema is when fluid accumulates in the lungs and hinders breathing.
  8. Tatusov, Michael, et al. “Clinical Effects of Reported Synthetic Cannabinoid Exposure in Patients Admitted to the Intensive Care Unit.” The American Journal of Emergency Medicine, vol. 37, no. 6, 2019, pp. 1060–1064., doi:10.1016/j.ajem.2018.08.048.
  9. Loschner, Anthony, et al. “Diffuse Alveolar Hemorrhage: Add ‘Greenhouse Effect’ to the Growing List.” Chest, vol. 140, no. 4, Oct. 2011, doi:10.1378/chest.1119854.
  10. Alhadi, S., Tiwari, A., Vohra, R. et al. J. Med. Toxicol. (2013) 9: 199. https://doi.org/10.1007/s13181-013-0288-9
  11. Berkowitz, Eugene A., et al. “Pulmonary Effects of Synthetic Marijuana: Chest Radiography and CT Findings.” American Journal of Roentgenology, vol. 204, no. 4, 2015, pp. 750–757., doi:10.2214/ajr.14.13138.
  12. Ocal, Nesrin, et al. “Acute Eosinophilic Pneumonia with Respiratory Failure Induced by Synthetic Cannabinoid Inhalation.” Balkan Medical Journal, vol. 33, no. 6, 2016, pp. 688–690., doi:10.5152/balkanmedj.2016.151145.
  13. Chinnadurai, Thiru, et al. “A Curious Case of Inhalation Fever Caused by Synthetic Cannabinoid.” American Journal of Case Reports, vol. 17, 2016, pp. 379–383., doi:10.12659/ajcr.898500.
  14. Yamanoglu, Adnan, et al. “A New Side Effect of Synthetic Cannabinoid Use by the Bucket (Waterpipe) Method: Acute Respiratory Distress Syndrome (ARDS).” Turkish Journal of Emergency Medicine, vol. 18, no. 1, 2018, pp. 42–44., doi:10.1016/j.tjem.2017.06.001.
  15. Coughing up blood.
  16. Imtiaz, Muhammad, et al. “A Case of Acute Life-Threatening Pulmonary Hemorrhage from Synthetic Cannabinoid Abuse.” Case Reports in Pulmonology, vol. 2019, 2019, pp. 1–3., doi:10.1155/2019/8137648.
  17. Ivanov, Ivo D., et al. “A Case of 5F-ADB / FUB-AMB Abuse: Drug-Induced or Drug-Related Death?” Forensic Science International, vol. 297, 2019, pp. 372–377., doi:10.1016/j.forsciint.2019.02.005.
  18. Gieroń, Joanna & Adamowicz, Piotr. (2017). Fatal poisoning with the synthetic cannabinoid AB-CHMINACA and ethyl alcohol – A case study and literature review. Z Zagadnien Nauk Sadowych. 106. 482-495.
  19. Shanks, Kevin G. “Three Fatalities Associated with the Synthetic Cannabinoid AB-CHMINACASOFT 2015, 2015. http://soft-tox.org/files/meeting_abstracts/SOFT_2015_meeting_abstracts.pdf
  20. Piotr Adamowicz, Ewa Meissner & Marta Maślanka (2019) Fatal intoxication with new synthetic cannabinoids AMB-FUBINACA and EMB-FUBINACA, Clinical Toxicology, 57:11, 1103-1108, DOI: 10.1080/15563650.2019.1580371
  21. Hideyuki Maeda, Ruri Kikura-Hanajiri, Maiko Kawamura, Erika Nagashima & Ken-Ichi Yoshida (2018) AB-CHMINACA-induced sudden death from non-cardiogenic pulmonary edema, Clinical Toxicology, 56:2, 143-145, DOI: 10.1080/15563650.2017.1340648
  22. Jinwala, Felecia N., and Mayank Gupta. “Synthetic Cannabis and Respiratory Depression.” Journal of Child and Adolescent Psychopharmacology, vol. 22, no. 6, 2012, pp. 459–462., doi:10.1089/cap.2011.0122.
  23. Piotr Adamowicz, Ewa Meissner & Marta Maślanka (2019) Fatal intoxication with new synthetic cannabinoids AMB-FUBINACA and EMB-FUBINACA, Clinical Toxicology, 57:11, 1103-1108, DOI: 10.1080/15563650.2019.1580371
  24. Potts, AJ., et al. “Synthetic cannabinoid receptor agonists: classification and nomenclature” Clinical Toxicology, 2019. doi:10.1080/15563650.2019.1661425
  25. Edney, Anna, and William Turton. “Juul Devices Cited in Seizure Reports That Started FDA Probe.” Bloomberg.com, Bloomberg, 29 Aug. 2019, www.bloomberg.com/news/articles/2019-08-29/juul-devices-cited-in-seizure….
  26. Commissioner, Office of the. “FDA Seeks Reports Related to Seizures Following e-Cigarette Use.” U.S. Food and Drug Administration, FDA, 7 Aug. 2019, www.fda.gov/news-events/fda-brief/fda-brief-fda-encourages-continued-sub….
  27. “Some E-cigarette Users Are Having Seizures, Most Reports Involving Youth and Young Adults.” U.S. Food and Drug Administration, FDA, 10 Apr. 2019, https://www.fda.gov/tobacco-products/ctp-newsroom/some-e-cigarette-users…