Polydrug use has become the new defining characteristic of the world’s ongoing opioids crisis. This trend towards abusing more than one substance at a time not only increases the chances of overdose and death, but the fast-growing number of drug combinations available also makes it harder for researchers, clinicians and forensic scientists to identify precisely which drugs are being consumed. In this article, we explain the meaning, scale and dangers of combined drug use, examine the main challenges in polydrug testing, and discuss how quality reference materials and analytical research standards can support better polysubstance testing and research.

What is polydrug use?

“Polydrug use”, “polysubstance use”, and “combined drug use” are all terms that describe an individual using more than one drug, or more than one type of drug. These drug combinations – which may include legal substances such as alcohol and prescription medicines – can be taken either together or soon after one another, as well as intentionally or unintentionally. As defined by the United States Centres for Disease Control and Prevention (US CDC), intentional polysubstance use “occurs when a person takes a drug to increase or decrease the effects of a different drug, or wants to experience the effects of the combination.” Unintentional polysubstance use, on the other hand, “occurs when a person takes drugs that have been mixed or cut with other substances... without their knowledge.”

How big a problem is polydrug use?

Polysubstance use has been described as the “defining feature” of the current - and fourth - wave of the global opioid crisis, and the “new normal” for those involved in drugs. As an article in Psychology Today points out, “most people with an SUD (Substance Use Disorder) are polysubstance abusers (and) polydrug use is... a significant factor in opioid-related overdose deaths.” In particular, the fourth wave is characterised by people consuming combinations of psychostimulants and illicit opioids (often including methamphetamine, heroin and fentanyl).

In the US in 2023, analysis of more than four million urine samples from patients testing positive for fentanyl revealed that there were additional drugs in almost 93% of them. Another US study published earlier this year tracked drug intake among people who use opioids and other substances in Oakland, California – and discovered that “On any given day, 71 % of participants reported using multiple substances within in the same hour...with opioids commonly combined with stimulants, alcohol, or additional opioids.” According to the Substance Abuse and Mental Health Services Administration (SAMHSA), 63% of opioid-related deaths in America involve other substances, such as cocaine, methamphetamine, or benzodiazepines, while overdose deaths involving the combined use of opioids and stimulants increased 50-fold in the United States between 2010 and 2022. Finally, in 2022 alone, half of the estimated three million years of life lost to opioids in the US involved polysubstance use.

While not identical to America, the polydrug use picture in Europe is similarly bleak. The European Drug Report 2025, published by the European Union Drugs Agency (EUDA), states that “the majority of fatal overdoses involve the use of more than one substance, with opioids usually involved in combination with other drugs.” According to the BBC’s Scottish social affairs correspondent, Chris Clements, “Poly-drug use is rife” in Scotland, where a record 1,339 people died of a drug overdose in 2020 – 93% of them with more than one drug present in their bodies. In neighbouring England, Wales and Northern Ireland, meanwhile, polysubstance use was a factor in 82% of deaths involving the use of a psychedelic drug between 1997 and 2022.

Why is polydrug use so dangerous?

As the US CDC explains, “mixing drugs is never safe because the effects from combining drugs may be stronger and more unpredictable than one drug alone.” EUDA adds that “interactions between different substances, consumed close together in time, can increase drug toxicity”, as well as impairing people’s judgement and potentially escalating the risky use of other substances. Around 15% of opioid overdose deaths involve alcohol, which further suppresses the central nervous system, while combining benzodiazepines and opioids significantly increases the risk of respiratory depression. According to Clements, fatal drug overdoses in Scotland are often the result of mixing prescription methadone and heroin with benzodiazepines “pressed by gangsters and flooding communities at 50p a pop”, all of which “come together to slow a person's breathing until it stops.”

Even aside from the thousands of fatalities it causes - and the wider negative impacts on society, such as increased criminality and strain on healthcare budgets - polydrug use also causes myriad smaller tragedies for individual drug consumers. As Lorvick et al. state, “Polysubstance use has long been established as a predictor of poor substance use treatment outcomes and infectious disease risk” – including hepatoxicity and hepatitis C - while the “tremendous comorbidity” across drug substances could explain the wide range of mental health disorders experienced by polydrug users. In addition, polydrug use among adolescents is associated with poor school performance, truancy, trouble with police, engaging in physical violence, having unprotected sex and psychosis.

Why is combined drug use increasing?

The phenomenal growth in polydrug use can perhaps be explained by a combination of international drug market factors and individual users’ needs or preferences. As EUDA’s just-released European Drug Report points out, “The... drug market is evolving rapidly as both suppliers and consumers are finding ways to adapt to geopolitical instability, globalisation and technological advances... Increasingly, we are observing that almost everything with psychoactive properties can appear on the drug market, often mislabelled or in mixtures, leaving consumers potentially unaware of what they are using.”

Another key factor is “the increasing integration of the markets for new psychoactive substances and illicit drugs”, which means that many new polydrug combinations – such as stimulants mixed with synthetic cathinones and ketamine, or new synthetic opioids mixed with or mis-sold as heroin or benzodiazepines - have become available.

Researchers have also posited a number of reasons why consumers of illegal substances might turn to polydrug use, despite its potentially lethal consequences. “Drug users appear to have discovered that BZDs (benzodiazepines) are able to enhance the positive subjective effects of opioids,” states one early research paper on the subject. “As such, individuals may be combining opioids and BZDs in order to achieve a greater level of euphoria.” A Canadian government report reviewing literature on patterns and motivations in polysubstance use also suggests several reasons why people choose to take more than one drug, including: alleviating opioid and stimulant withdrawal symptoms, prolonging or enhancing a “high”, balancing the effects of drugs, self-medicating for pain, or counteracting a drug’s effects on sexual performance or appetite. Reviewing the available evidence, Psychology Today concludes simply that “Drug users, in essence, have conducted a real-life study of maximizing brain reward, and it appears from their behavior that they prefer polydrug use, risks, and all.”

Legislation and testing regulations for combating polysubstance use

Governments and international regulatory authorities continue to make strenuous efforts to combat the global epidemic of drug and polysubstance abuse - from national anti-drug legislation such as the US Drug Enforcement Administration’s Drug Schedules I-V to international treaties including the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances. As well as counter-measures against drug trafficking and street dealers, law enforcement authorities also deploy drug testing to gather evidence in drug-related criminal cases - from rapid roadside saliva testing where Driving Under the Influence of Drugs (DUID) is suspected, to complex forensic analysis carried out in accredited laboratories. Employees in many workplaces are also subject to mandatory drug testing in the interests of safety – including hundreds of thousands of US government employees and those working for major employees including Amazon. In turn, accredited laboratories providing forensic, clinical, and workplace testing on drug analytes must comply with industry standards and guidelines to ensure the reliability of their results – notably ISO 17025 (regarding competence, impartiality and consistent operation of testing and calibration labs) and ISO 15189 (on competence and quality management for medical laboratories). They are furthermore required by these guidelines to use reference materials provided by competent providers, and should also participate regularly in accredited proficiency testing (PT) schemes as part of their quality control processes.

Challenges in polysubstance testing

Polysubstance testing presents several challenges due to the complexity of drug interactions, the diversity of substances involved, and limitations in testing methods. Key issues include:

• Unpredictable drug interactions: users combining substances like opioids and benzodiazepines can create dangerous effects that are difficult to detect and predict in clinical settings.

• Diverse substances: users often mix prescription drugs, illicit substances, and alcohol – complicating testing, as each substance may require different detection methods.

• Emerging synthetic drugs: new synthetic substances may not be detectable with traditional testing methods, making constant updates to testing protocols necessary.

• Testing sensitivity and specificity: immunoassays may miss low levels of substances, while more accurate methods like Gas Chromatography-Mass Spectrometry (GC-MS) are costly and time-consuming.

• Detection windows: different drugs have different detection times, making it difficult to interpret results, especially in mixed-use cases.

• Quantification and interpretation: drugs may mask or enhance each other's effects, making accurate quantification challenging.

• Legal and ethical considerations: test results can have significant legal or medical consequences, requiring careful interpretation within legal frameworks.

• Lack of standardised protocols: variations in testing methods across labs can also make it more challenging to compare results.