by Dr. Andrew Holt, Pharm.D., BCMAS, Clinical Pharmacist, Aegis Sciences Corporation
Designer drugs, also known as novel (or new) psychoactive substances (NPSs) or synthetic compounds, are substances usually created to mimic the effects of traditional drugs while evading controlled substance regulations and detection via drug testing. However you refer to these compounds, the reality is that they can contribute to an individual’s risk of adverse events, including overdose. Though designer drugs have recently gained public attention, they have been in circulation for many years, with the most recognizable classes being synthetic cannabinoids, sometimes referred to as “K2” or “Spice,” and cathinones, which are also known as “bath salts.” While these specific classes remain in the illicit drug supply, in recent years new classes of drugs have emerged, presenting different risk profiles and, if left unrecognized, new dangers for the public.
Designer opioids are perhaps the most well-known of these new classes, with numerous reports of illicitly manufactured fentanyl (IMF) and fentanyl analogs, sometimes referred to as “fentalogs,” detected by various agencies. In addition to fentanyl-based opioids, clandestine labs have begun introducing other opioid classes into the illicit drug supply, with benzimidazoles being the latest. The potency and purity of these substances are somewhat unknown, which in turn creates an unknown risk to the end user. They are distributed as adulterants in heroin or, increasingly, as counterfeit versions of common prescription drugs and are often identified in overdose death cases.
Designer benzodiazepines (DBZDs) have emerged over the last decade and are more frequently detected as testing increases for these less-studied substances. As with other designer drugs, DBZDs are created to evade testing and controlled-drug laws. Sometimes they are found in combination with counterfeit opioids, which is colloquially known as “benzo-dope.” The primary issue with these compounds, as with prescription medications, is that the combination of opioids and DBZDs places the user at increased risk of adverse events. DBZDs are often sold as counterfeit versions of prescription benzodiazepines, although there are some websites claiming to sell named substances within this class.
Synthetic cannabinoids and cathinones have evolved over the years, with new molecular structures and, in some cases, new classes developed in order to evade drug scheduling actions. For example, a large class ban in 2021 prompted a notable change in the structure of cannabinoids detected over the past year. In addition to cathinone molecular structure shifts, novel, non-cathinone stimulants have also emerged, with analogs of amphetamines and methylphenidate also detected recently as part of drug testing.
In addition to these classes, other designer drugs have been identified in the illicit drug supply, with varying impacts on public health. While some may have only minor effects, many have significant implications for community health, such as xylazine. Xylazine is approved for use in veterinary medicine as a tranquilizer for certain animal species and is often illicitly manufactured and cut into heroin and fentanyl supplies, a combination referred to as “tranq-dope.” This combination carries devastating and potentially deadly consequences: While xylazine has the ability to suppress central nervous system (CNS) activity, it is not an opioid. Therefore, it is not believed to respond to naloxone reversal, leaving users who may suffer overdoses potentially defenseless. In addition to xylazine, drugs such as phenibut and tianeptine have been detected, along with designer hallucinogens and dissociatives, with the most detected substances being analogs of ketamine and PCP.
Routine Testing Options
The approach to testing for designer drugs is similar to other traditionally monitored drugs, with the primary utilized options being immunoassay and mass spectrometry. Immunoassay testing offers the primary advantage of rapid results; however, results can be non-specific and miss key factors. Mass spectrometry testing is much more specific, but results are not available as rapidly as through immunoassay, and testing is typically more costly. Because providers use both options in routine medical practice, a further discussion of testing capabilities and limitations for both methods can further understanding of each methodology’s capability to detect designer drugs.
Immunoassay
Immunoassay testing is based on the principle of competitive binding of an antibody to a target analyte and can be performed via cups, strips, and analyzers at the point of care. If a drug is similar in structure to the target analyte, it may bind to the antibody and trigger a presumptive-positive result. However, some drugs with no clear structural similarity to the target analyte may still bind to the antibody. These cross-reacting compounds result in false positives; on the other hand, lack of cross-reactivity across a class may result in false negatives. The extent of cross-reactivity among designer drugs may vary depending on the immunoassay used, which means it is crucial to know everything that reacts with the antibody to understand if designer drugs are detectable. One other limitation is that immunoassays do not inform how many drugs within a class are present. These factors present a number of limitations for providers, especially when it comes to interpreting results. Despite these limitations, the primary advantage of immunoassay is that it yields a rapid result, and it is often used on-site when an immediate result is desired, despite the sacrifice in accuracy.
Mass Spectrometry
Gas chromatography-mass spectrometry (GC/MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS), and time of flight-mass spectrometry (TOF-MS) are a few of the ways that scientists can identify drugs and their related metabolites via mass spectrometry. Although definitive methods are not limited to these, LC-MS/MS is the most utilized method in high-throughput laboratories for designer drug testing; however, not all mass spectrometry methods are equivalent. This is especially true when testing for designer drugs, as the substances in circulation change frequently in response to changes in supply or regulations. These changes necessitate regular method updates to include the most prevalent drugs in the illicit drug supply – a constant game of cat and mouse that providers and testers continue to struggle with.
When evaluating a test offering, one approach is to learn what drugs are in the area through various channels, including law enforcement, medical examiners, or forensic laboratories. These can then be compared to a laboratory’s test offering to determine the breadth of coverage.
Result Interpretation
Regardless of testing method, when interpreting a drug test result, one of the first points of consideration should be what drugs are included in testing, which varies based on technology and the laboratory utilized. With immunoassay-based testing, this includes not only the drugs of interest, but also the potential causes of false positives. Many clinicians are conditioned to conclude that false positives are caused by unrelated drugs or substances and may assume that a cross-reactive designer drug was a false positive when the results do not confirm via traditional mass spectrometry. However, when evaluating the definitive test, providers must be aware of the drugs included in the test menu, as negative mass spectrometry results could occur because a designer drug was not included. This could lead clinicians to incorrectly believe that a false positive immunoassay occurred.
Additionally, many samples contain more than one designer drug, and some contain traditionally monitored drugs with designer drugs from the same class of substances. This can result in therapeutic duplication and increased risk of adverse events. Some patients may solely utilize designer drugs to circumvent traditional testing. These scenarios, and others, may place patients at greater risk of harm. This is why comprehensive, definitive testing is essential for care: Provider knowledge of designer drug use can change measures designed to mitigate adverse events for a patient.
If utilizing definitive testing to confirm immunoassay results, there should be a particular focus on substances that cross-react with immunoassay tests but are not included as part of routine mass spectrometry testing, as these scenarios may be misinterpreted as false positives and allow for potentially harmful substance use to go undetected. When evaluating definitive testing menus for designer drugs, one should ensure that test menus are representative of the majority of observed drugs in circulation. As the designer drug landscape continues to evolve, it is important for all involved in ordering, performing, or interpreting tests to be aware of these substances in the illicit drug supply and the capabilities in identifying these drugs based on the test that is performed. A strong understanding of testing advantages and limitations is imperative when interpreting drug test results – for individual care and for community health at large.
About the Author: Dr. Andrew Holt is a clinical pharmacist at Aegis Sciences Corporation, a national healthcare testing lab that is based out of Nashville, Tenn.