Charna Albert
March 2021—Synthetic cannabinoids. Toxic household substances. Over-the-counter medicine. These and other drug and non-drug substances are favored by adolescents and young adults and tough to detect, and the pandemic has exacerbated their use.
“Many drugs that are of interest for this age group are household substances, things they can get their hands on easily, and often those tests are not available as immunoassays,” said Sarah E. Wheeler, PhD, medical director of the automated laboratory, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, and assistant professor of pathology, University of Pittsburgh, in a session on adolescent and young adult substance abuse testing at AACC’s virtual annual meeting last year.
Cough medicine, Sudafed, and Benadryl, Dr. Wheeler says, all are “overrepresented compared to what we were seeing before” the pandemic. Also more popular now are novel psychoactive substances that can be ordered by mail, says Sara A. Love, PhD, director of clinical and forensic toxicology laboratories, Hennepin Healthcare/HCMC in Minneapolis, who co-presented with Dr. Wheeler and Ann Arens, MD, Hennepin Healthcare/HCMC emergency medicine physician and medical toxicologist.
“There have been more synthetic cannabinoids,” Dr. Love says, “which has been locally relevant here in terms of what we’re seeing in the emergency department,” and overrepresented recently among adolescents. “Otherwise, opiates are still a favorite because not everybody’s medicine cabinet is being precisely monitored.”
Overall, fewer fentanyl analogs are circulating in Minneapolis, she says. “We’re seeing a limited number. It’s not the craziness with all the variety we were seeing a couple years ago. And that’s a pandemic effect I would say, locally,” driven by changes in supply.
The same is true in Pittsburgh, Dr. Wheeler says. “We’ve been seeing more prescription opioid abuse at our hospitals than synthetic derivatives,” likely for access reasons. “I suspect it varies.”
As always, Dr. Love says, she sees cases in which an adolescent presents in the emergency room after overdosing at a party. In one such recent case, a poisoned patient’s sibling told clinicians they had taken flualprazolam and fentanyl, she says. “The savviness of that answer surprised me. Usually, ‘they’re taking M30s [counterfeit oxycodone]’ is the kind of clinical story I hear.”
If there is suspicion of a cough medicine overdose, or poisoning by a similar household substance, “we have to send it out,” Dr. Wheeler says. “There’s nothing we can do in terms of immediate screening, which has been a definite difficulty and limitation.”
Though immunoassays can detect classic drugs of abuse, young adults are more likely to have false-positive or false-negative results, she says, because the screening assays haven’t been well-characterized in the pediatric population. “We see, thankfully, lower overall rates of the drugs of abuse for which we have immunoassays in this population compared to the adult population. So we don’t have as many people to test to see how they interact.” The interferences can be different in the pediatric population because of elimination kinetics and differences in how young adults metabolize drugs.
Further, she says, “most of the drug screens were developed with the federal guidance for workplace testing in mind,” and cutoff concentrations are based on those guidelines and not as pertinent to children and young adults. “We’re concerned about, did this kid who was not prescribed amphetamines have amphetamines in there? They may come up negative on our immunoassay despite having ingested” the compound of interest.
The one-size-fits-all assay isn’t going to be as successful in this population, Dr. Love says. With mass spectrometry, “sensitivities and scope are different. That same flexibility is not as easily managed on the immunoassay side.”
“In a perfect world, in my head,” she continues, “everyone’s screen would include mass spectrometry because you have specificity. And it’s relevant for my clinical colleagues to know what the drug is.”
While immunoassay extended panels can detect fentanyl, Dr. Wheeler says, “that does not mean we can detect all the fentanyl analogs, which can be even more potent. If they have an analog on board, we may give them naloxone, but the dose isn’t high enough, so we can’t tell the difference between, ‘Do we need to give them more naloxone,’ or ‘is this not an opioid overdose?’ And that’s a limitation of having only immunoassay screening available.”
Nonetheless, Dr. Love says, the broad availability of immunoassays makes emergency toxicology testing possible. “And that’s relevant in this patient population.”
“It’s one of those natural tensions,” she adds, “between sensitivity and specificity, given available resources and the needed quality.”
[dropcap]“I[/dropcap]mmunoassays, as applied to drug screens, often depend on extended panels, run on the laboratory’s automated instrumentation or as point-of-care dipstick tests, Dr. Wheeler said in the session. For the latter, “the interpretation is often the inverse of what we’re used to seeing.” With lateral flow assays, like a pregnancy test, “if you see a line, you are pregnant. Many of these drug assays work in the opposite manner. If you have the line, you’re negative; if you don’t, then you do have the potential drug of interest on board.” So training is important.
Extended panels can detect fentanyl, hydrocodone, methadone, oxycodone, buprenorphine, and tramadol, but “it’s important that you have in your procedure all of the potential cross-reactions,” she said. NSAIDs, for example, can cause a false-positive cannabinoids screen, and diphenhydramine can cause a false-positive for some opioids and a false-positive for phencyclidine. “So it’s important that you communicate with your clinicians” about potential cross-reactivities, and “follow up with mass spec if they see something in the drug screen that doesn’t match the clinical picture.”
“Usually we find out about cross-reactivities because a confirmation assay has come back unexpectedly negative or positive for something we didn’t see,” Dr. Wheeler says, “so then we investigate the patient chart to see what might be cross-reacting.” If something that looks like it might be a cross-reactant is found, she says, “we do a spiking study and then add it to our procedure list of things that might cross-react.” In her lab, she says, they haven’t yet identified any previously undefined cross-reactants significant enough to be added as a comment, “but that’s always top of mind.”
When setting up testing for adolescents and young adults, she said, a chief question is, when is quantitation necessary? The first consideration is whether urine or serum is being analyzed. “Urine levels usually aren’t particularly helpful in managing patients.”
When a compound is identified in a urine drug screen, said Dr. Arens of Hennepin’s ED, that “doesn’t mean that’s what’s causing the symptomatology you see. And just because it’s not there doesn’t mean it’s not causing it.” So urine drug screens can’t be counted on to provide the answers.
They do tend to be useful in very old or young patients, she said, “who may have been exposed to something they weren’t expecting.” If an 11-year-old presents with agitation and hypertension and there’s no underlying medical cause, “a positive cocaine, for example, on a urine drug screen, can be helpful.” And a positive urine drug screen can save the patient from invasive testing.
Therapeutic drug monitoring relies on quantitation, Dr. Arens said, citing antiseizure medication as an example. “Are they having seizures because they don’t have enough Keppra—it’s subtherapeutic—or do we need to change to a different medication?” In some cases, she said, quantitation is needed to separate therapeutic use from overdose. “It’s important that I know, for example, Dilantin concentration, because that number can help me identify if there is toxicity.”
In some clinical scenarios, quantitation is used to determine treatment. In the case of salicylate overdose, Dr. Arens said, concentration determines whether the patient can be treated with sodium bicarbonate or if the overdose is severe enough to warrant dialysis. Acetaminophen overdoses, too, are frequent, and knowing “the number of the concentration tied to the clinical presentation” is critical.
“Sometimes quantitation means the difference between somebody needing an antidote or not, or somebody needing additional testing or not,” she said.
Says Dr. Wheeler, “Our main laboratories usually do have quantitative immunoassays” for salicylate and acetaminophen, “with the caveat that with all these immunoassays there are cross-reactivities and between-platform differences.” At the University of Pittsburgh Medical Center, she says, the emergency medicine physicians rotate between hospitals that have different platforms. “And the therapeutic windows for salicylate and acetaminophen are slightly different between hospitals, so it’s important that we communicate that to our physicians. Obviously if levels are very high it doesn’t matter what assay they’re using. But if you do need to pay attention to the therapeutic window,” it’s important for physicians to be aware of the reference intervals.
“With immunoassay,” she added, “our numbers are not going to be as accurate as they can be with mass spectrometry.”
[dropcap]I[/dropcap]n their AACC session, Dr. Love presented the case of a 17-year-old male who was found wandering in downtown Minneapolis, sweaty, incoherent, and partially clothed, and taken to Hennepin County Medical Center. The patient reported taking MDMA (Molly/Ecstasy) and an amphetamine at a concert. This “did not jibe with his urine drug screen, which came back positive for cannabinoids and cocaine,” Dr. Love said. “Clinically, he had evidence of rhabdomyolysis, elevated liver function tests, and apparent acute kidney injury. Additionally, he was hyperthermic: That matched the club drug use as described, despite the initial urine drug screen findings.”
Dr. Wheeler added: “In the general chemistry lab we don’t screen for MDMA, so we would not have a negative screen for this [MDMA]. We would simply be able to find his cocaine and cannabinoid use.”
“If you look at the chemical structures of MDMA and its associates,” Dr. Arens said, “it gives you an idea of what its effects are.” Methamphetamine, a related drug, causes hyperactivity, agitation, and hypertension; mescaline, another relative, has hallucinogenic effects. “If you put those together, that describes the effects we see with MDMA.”
Eighteen- to 25-year-olds had the highest lifetime usage of MDMA and the highest usage in the prior year and month, according to the 2018 National Survey on Drug Use and Health, and lifetime use among adolescents was “not insignificant,” Dr. Arens said.
Critical to this case, she said, “was not so much that there was MDMA potentially present, but that there were other things. There are a lot of posers in MDMA,” she said, referring to data collected by the organization DanceSafe, which provides partygoers with drug testing kits (Saleemi S, et al. J Psychopharmacol. 2017;31[8]:1056–1060). Colorimetric reagent assays identified MDMA in only 60 percent of the 529 samples collected. Adulterants included, among others, cathinones, methamphetamine, cocaine, dextromethorphan, and 2C compounds. “There can be adulterants in there that the user is not anticipating,” she said.
In another case presented in their session, this one on synthetic cannabinoid receptor agonist use (and taken from the literature: Adamowicz P, et al. Clin Toxicol. 2016;54[8]:650–654), four individuals, ages 15 to 18, smoked powder from a package labeled “AM-2201,” which the four referred to as a “legal high.”
“These are incredibly popular now,” Dr. Arens said, of synthetic cannabinoid receptor agonists. “They’re one of the biggest things we’re trying to track down and being researched in the field of novel psychoactive substances.”
The four individuals started smoking from a pipe at 5 PM, after which they began to vomit profusely. All displayed different symptoms when they were brought to the hospital: seizures, aggression, agitation, slurred speech, blood pressure spikes, respiratory failure, and loss of consciousness, among others.
The patients were screened for classic drugs of abuse and prescription drugs using ELISA and LC-MS/MS, with pan-negative results. A novel psychoactive substances screen performed on blood samples by LC/MS/MS identified MAB-CHMINACA, a potent agonist of the endogenous cannabinoid CB1 receptor, which is responsible for the psychoactive effects of THC. AM-2201, however, was not present. The authors speculate that the substance the patients took may have been sold as AM-2201 because it is the more widely known of the two. Both compounds are full CB1 receptor agonists, but MAB-CHMINACA is three to four times as potent, with a binding affinity (k1) of 0.289 nM, while that of AM-2201 is 1.0 nM. In contrast, the binding affinity of THC, a partial CB1 agonist, is 40.7, plus or minus 2 nM—about 140 times weaker than MAB-CHMINACA.
SCRAs, sometimes called spice or K2, were developed originally as ligands for studying the endocannabinoid system; they have no structural commonality with THC. Herbal mixtures sold in the United States and Europe were found in 2008 to contain the SCRAs JWH-018 and CP 47,497-C8, and since then they have continued to be sold illicitly for recreational use (Adams AJ, et al. N Engl J Med. 2017;376[3]:235–242). Since publication of the case in Clinical Toxicology in 2016, Dr. Arens said, “we’ve seen an explosion of different kinds of SCRAs.”
“They are often referred to as synthetic marijuana, which they are absolutely not,” she said. Severe clinical effects include pulmonary edema of the lungs, ischemic stroke, rhabdomyolysis, CNS depression, and others. “They bind more tightly [than THC] to the receptors, so you get these different effects,” she said.
A survey of SCRA exposures reported in 2018 found the highest usage in those 19 and younger (Cordeiro SK, et al. Addiction. 2018;113[10]:1850–1861). “The reason we think a lot of people use these,” Dr. Arens said, “is because they’re easy to get”—they are inexpensive and can be purchased online from dark web retailers—and they are “almost completely undetectable.” New structures can be developed faster than the DEA can identify them, which has led the agency to pursue a novel approach, she said. “Rather than trying to track down each individual structure and schedule them retroactively, the DEA now recognizes the receptor activity as what constitutes the scheduling.”
Hennepin’s emergency medicine physicians in 2017 treated 36 people who had overdosed on 5F-ADB-PINACA, a potent SCRA, over 24 hours. “As clinicians and toxicologists,” Dr. Arens said, “we are trying as best as we can to keep up with the effects of these different compounds.”
[dropcap]D[/dropcap]r. Love presented a case in which an 18-year-old man was found on the ground at a gas station, partially clothed and amid extreme amounts of emesis. The patient had a medical history of depression, cannabis use disorder, a recent suicide attempt, and vaping. Because he was completely altered and noncommunicative, emergency medical personnel administered Narcan, without success.
Initial laboratory testing found a positive acetaminophen (26.5 mcg/mL), slightly elevated lactate (3.1 mmol/L), and a minor number of ketones in the patient’s urine. Otherwise, “there weren’t a lot of clinical findings that narrowed this down. There wasn’t a clear report of seizure-like activity,” or anything similar, she said.
When the clinical team called the lab to inquire about further testing, Dr. Love said, she was forced to tell them that “the obvious things this could be are the things we don’t test for.”
“It’s not usual that I get to go back to my clinical partners and say, ‘Did they have anything in their pockets that might guide us forward?’” she continued. But the answer was no.
A sample was sent to a reference laboratory for a comprehensive novel psychoactive substances screen, which was returned after the patient had recovered and was discharged. “It came back completely negative,” she said. “And we called to confirm that there wasn’t anything they saw for out-of-scope findings.”
The clinical team determined this was likely a case of synthetic cannabinoid receptor agonist use, she said, and the large amount of emesis and inordinate amount of fluids the patient was given may explain the pan-negative screen.
“I wanted to include this case,” Dr. Love said, “because sometimes, even with our best efforts, we can’t get to a discrete answer. And I think that’s an important takeaway for anybody in the laboratory to keep in mind. Sometimes the answer is, ‘I don’t know.’”
Charna Albert is CAP TODAY associate contributing editor.