Pharmacology 101: The Spice Must Flow! What to Know About Synthetic Cannabinoids

Pharmacology 101 is an online column designed to keep EMS providers informed on formularies, dosages, effects, applications, and current research related to medications administered in the prehospital setting. If you have a medication-related question you’d like the author to address, contact editor@emsworld.com.

Imagine responding to a call in the dead of night and picking up a patient with an acute psychosis. The patient is agitated and violent, presenting a danger to himself and to others (maybe you even have to administer some ketamine!), and the very last coherent thing you hear him say is, “That spice is the stuff, man! Who-o-o!”

Welp. What in the world is going on here, and what exactly is “spice”?

Synthetic Cannabinoids

Going by colorful names such as spice, K2, herbal incense, crazy monkey, cloud nine, mojo, and many others, synthetic cannabinoids (SCBs) represent an increasing public health concern thanks to their ease of abuse and variable toxic effects.¹ Initially appearing on the scene in the mid-aughts, SCBs were available in head shops, convenience stores, and gas stations, and on the Internet. Often labeled as research compounds or not for human consumption, these compounds were legal to purchase.^2–4

Synthetic cannabinoids were developed decades ago in laboratory settings as researchers attempted to understand the chemical structures behind THC, the active ingredient in marijuana.⁵ However, at some point more sinister-minded scientists realized their potential as street drugs, and SCBs eventually began turning up as substances of abuse. One key difference between THC and SCBs: SCBs bind to the cannabinoid receptors with a higher affinity than THC and thus come with a higher potential for potency and toxicity.¹

In appearance SCBs may look just like any other dried plant material, and many people believe they are natural. However, SCBs are fully synthetic. After being dissolved in acetone or ethanol, they’re sprayed onto plant material and left to dry, after which the plant material can be smoked or ingested just like marijuana. Additionally, due to lack of control of the amount of SCBs sprayed onto the dried plants, there may be widely variable concentrations of the substance.¹ Does this all come together to make a recipe for disaster? You bet! And it gets even better.

Legal Status

As noted by prominent University of Connecticut pharmacist C. Michael White, PharmD, FCP, FCCP, “The Federal Analogue Act was supposed to make illegal the sale, purchase, or possession of chemicals that were ‘substantially similar’ in their chemical makeup to Schedule I and II drugs, but it is exceedingly hard for prosecutors to convince non-science-minded jurors that the chemical is ‘substantially similar’ and that the non-science-minded sellers or purchasers knew that it was.” Forensic detection of these SCBs is a difficult process owing to the ease with which the molecular structures can be manipulated—consider that more than 150 new SCBs were created just in 2013 alone! Thus, many SCBs skirt the fringes of legality.³ Additionally, identification of these SCBs is difficult due to the lack of specific laboratory testing capabilities, making them popular among those desiring a chemical euphoria while avoiding detection from drug screening. For this reason, SCBs may be an attractive option to military personnel.⁶  

Safety

Many people believe spice and other SCBs are safe alternatives to marijuana. However, it cannot be assumed that the health risks are similar to cannabis—SCBs are more potent at cannabinoid receptors. Psychological effects include feelings of relaxation, perceptual alterations, giddiness, and increased appetite, and SCB can induce psychosis that may mimic schizophrenic episodes. While toxicity is rarely life-threatening, it may include tachycardia, hypertension, visual and auditory hallucinations, agitation and anxiety, tachypnea, nausea, and vomiting. The most dire consequences can include stroke, seizures, and serotonin syndrome.^4,5

Coronary effects have been reported, possibly due to an increased cardiac workload, and include case reports of ST elevation after smoking K2 and “black mamba” SCBs.⁵ A number of deaths have been reported in the literature, with pathological findings including acute kidney injury, liver failure, and pulmonary edema.⁷ These are not safe drugs!

A strange and extremely concerning adverse outcome associated with SCBs was a rash of severe bleeding experienced by SCB users in 2018. With the first cases reported in Illinois, more than nine states reported patients presenting with these complications. Over 150 patients presented to Illinois hospitals with bleeding.⁸ Eventually it was determined the patients had been using SCBs that were laced with a superwarfarin found in rat poison. The cause of this has never been determined, but it has been speculated to be a malicious contamination, possibly as an act of bioterrorism.⁸ 

Summary

SCBs have increased as substances of abuse in the United States. First responders should have an awareness of the unpredictable toxic potential of SCBs, as well as their abuse potential due to their ease of access and lack of drug screening. Adverse effects include central nervous system, cardiovascular, and GI effects, acute renal failure, and even death. In patients presenting with acute psychoses who are suspected to have substance abuse, first responders should be aware that SCBs may be a potential cause.

References

1. Mills B, Yepes A, Nugent K. Synthetic cannabinoids. Am J Med Sci, 2015; 350(1): 59–62.

2. Martinotti G, Santacroce R, Papanti D, et al. Synthetic Cannabinoids: Psychopharmacology, Clinical Aspects, Psychotic Onset. CNS Neurol Disord—Drug Targets, 2017; 16(5).

3. White CM. The Pharmacologic and Clinical Effects of Illicit Synthetic Cannabinoids. J Clin Pharmacol, 2017; 57(3): 297–304.

4. Le Boisselier R, Alexandre J, Lelong-Boulouard V, Debruyne D. Focus on cannabinoids and synthetic cannabinoids. Clin Pharmacol Ther, 2017; 101(2): 220–9.

5. Davidson C, Opacka-Juffry J, Arevalo-Martin A, et al. Spicing Up Pharmacology: A Review of Synthetic Cannabinoids From Structure to Adverse Events, Vol. 80, 1st ed. Elsevier Inc., 2017.

6. Berry-Cabán CS, Kleinschmidt PE, Rao DS, Jenkins J. Synthetic cannabinoid and cathinone use among US soldiers. US Army Med Dep J, 2012: 19–24.

7. Pintori N, Loi B, Mereu M. Synthetic cannabinoids: The hidden side of Spice drugs. Behav Pharmacol, 2017; 28(6): 409–19.

8. Kelkar AH, Smith NA, Martial A, et al. An outbreak of synthetic cannabinoid-associated coagulopathy in Illinois. N Engl J Med, 2018; 379(13): 1,216–23.

Daniel Hu, PharmD, BCCCP, has Doctor of Pharmacy degree and is a critical care and emergency medicine pharmacist. He is a frequent speaker at conferences and has many publications in peer-reviewed journals.