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The Best Analytical Techniques for Testing Drugs of Abuse

The Best Analytical Techniques for Testing Drugs of Abuse

Because drugs tend to be small-molecule structures, gas-chromatography-MS (GC-MS) serves as confirmation both for alcohol level and for most drugs.

Angelo DePalma, PhD

Angelo DePalma is a freelance writer living in Newton, New Jersey. You can reach him at

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GC-MS: The Swiss Army Knife of Forensics

Mass spectrometry (MS) has emerged as an everyday analysis tool suitable for screening and confirmatory analysis, and in some cases it blurs the distinction between the two.

Gas chromatography (GC) equipped with a headspace and flame ionization detector (FID) remain the workhorses for blood alcohol analysis. While the drunk driving rate has dropped in the US and Canada, labs have seen an increase in these tests because in some jurisdictions, drivers may opt out of curbside breath analysis in the hope that their blood alcohol content (BAC) will fall to legal limits between arrest and test.

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Drugs of abuse, are in many ways, moving targets. Ne’er-do-wells with degrees in synthetic organic chemistry operate several steps ahead of the law; freelance compounders substitute substances not normally considered to be human medicines into street drugs. Thus, targeted screening may miss dangerous, illegal compounds such as synthetic cannabinoids and their derivatives or, as has recently been reported, heroin laced with elephant tranquilizers.

HRMS Inching Toward US Markets

Because drugs tend to be small-molecule structures, gas-chromatography-MS (GC-MS) serves as confirmation both for alcohol level and for most drugs. “There is still an advantage in terms of comfort level compared with liquid chromatography–based methods,” says Lisa Thomas, senior director for vertical marketing for clinical and forensic toxicology at Thermo Fisher Scientific (Sunnyvale, CA). Thomas describes GC-MS as the “Swiss army knife” of forensics, because in addition to drug testing it serves investigations of arson, explosives, and seized drugs, as well as the characterization of common substances such as inks.

Thermo Fisher offers both MS and non-MS workflows for forensics laboratories within the fields of forensic toxicology, controlled substance analysis, trace evidence, explosive investigations, and human identification.

“High-resolution MS has taken forensic toxicology by storm in European markets, but adoption has been slower in the US due to capital cost, validation, and residual effects of the overpromise and finicky behavior of the first-generation quadrupole time-of-flight instruments,” says Thomas.

Today’s orbitrap-based high-resolution systems now rival triple-quad spectrometers in sensitivity. Thermo has released a GC-orbitrap system that is currently under evaluation at national forensics organizations for the analysis of seized drugs.

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Thomas therefore sees “a significant shift” to quantitative high-resolution mass spec based on technology improvements, greater affordability and ease of use, and most important, the reduced need to send samples to independent labs for death investigations in which abuse of designer drugs is suspected. Thermo Fisher’s Q Exactive™ Focus Hybrid Quadrupole-Orbitrap™ mass spectrometer provides those benefits, Thomas says, and incorporates high-resolution MS libraries of hundreds of novel psychoactive substances, with the ability to update regularly using a cloud-based resource. The system, mzCloud™, overcomes proprietary monthly updates of conventional updating mechanisms.

More private laboratories now offer isotope ratio MS (IRMS) as part of their forensics capabilities. IRMS pinpoints the geographic origin of counterfeit or illicit drugs, and traces sources of adulterants.

GC-MS has been the go-to method for seized drugs, usually after screening with FTIR. Novel DOBs have swamped border patrol, DEA, and other officials with identification workloads. Thomas says that by serving the two major detection workflows, GC Orbitrap HRMS “enables screening, identification, and quantification for customers more comfortable with non-HPLC workflows.”

Health Care Settings

Professor William Clarke of Johns Hopkins University (Baltimore, MD) notes that the testing of legal drugs in health care settings is growing rapidly. “Many such tests are conducted not for legal purposes but to manage a patient’s condition, for example, at childbirth and in pain management settings.” Here, physician liability, not legal prosecution, becomes the main driver.

For maternity testing, the presence of any opioid will raise red flags to health care providers. Within pain management, screening should consist of more definitive identification. Immunoassays used for prenatal and perinatal tests cannot distinguish between morphine and codeine, for example, but in opioid management, doctors want to know which agent is in the bloodstream. That is where LC-MS comes in.

MS is increasingly used in screening mode as well, but is not yet standard. Clarke makes the case that MS could be applied to many screens, followed by a confirmatory test with appropriate standards. In today’s practice, analysts may be prepared for about 40 drugs but only include standards for three or so.

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Commercially available standards covering a much broader range of drugs of abuse are possible, of course, and Clarke says they will be available at some point, adding that “commercially available standards would make life a lot easier for many labs.” For many workflows, standards prep eats up more time than sample prep.

At some point, curated databases of abused drugs will be available to analysts online, including high-resolution masses and perhaps fragmentation values and LC retention times as well. “Having those tools available will allow non-targeted screening,” says Clarke, “which could be important in public health settings.”

Drug-Agnostic Sampling, Analysis

In June 2016, Phytronix Technologies (Quebec City, Canada) introduced the Luxon Ion Source, based on a next-generation sample introduction and ionization technology, LDTD®, for high-throughput screening using MS.

Luxon uses a fiber-coupled laser diode that analyzes samples in less than one second. The redesigned device improves performance and robustness in applications with very low sample volumes.

Traditional screening methods require multiple immunoassays that lack drug specificity, depend on reagent availability, and generate a high false-positive rate due to interference and cross-reactivity.

LDTD is reagent-free and drug-class agnostic. “It enables laboratories to optimize revenue potential by offering presumptive test menus for over 100 compounds by a single extraction sample preparation method,” says Ted Palashis, president of Overbrook Scientific (Boston, MA), which markets and supports Luxon and LDTD in the United States. Palashis refers to LDTD as a “paradigm shift” for high-throughput laboratory workflows. “We believe LDTD will replace traditional immunoassay screening methods as it incorporates critical analysis attributes with quantitative analysis by mass spectrometry.”