Many factors might explain the variability in concordance between UDS and self-reported use between substances and study sites. First, there is evidence that individuals might not be aware of what they are, in fact, using. Among people self-reporting use of a substance, between 2.5% and 49.5% of participants had a negative UDS to that substance, with oxycodone, heroin, and benzodiazepines showing the lowest positive predictive values. In contrast, between 21.4% and 81.5% of individuals with a positive UDS did not disclose using that substance, mostly hydromorphone, heroin, oxycodone, and benzodiazepines. These results are in line with drug checking reports showing that, between April 2018 and August 2019, about 13% of opioids samples, 11% of methamphetamine samples, 5% of cocaine samples, and 36% of fentanyl samples contained at least one other unexpected psychoactive substance. ³⁴ A 2017 report from the U.S.-China Economic and Security Review Commission showed that fentanyl was often mixed with heroin. ³⁵ Another more recent report showed that between 20% and 50% of opioid samples from British Columbia were contaminated with benzodiazepines. ³⁶ Therefore, data from drug checking services indicate that individuals who use illicit substances may be more likely to be unknowingly exposed to opioids and benzodiazepines, in line with our results showing lower accuracy of self-reported use for these substances. This hypothesis is further supported by our results showing significant regional differences – participants from British Columbia, Alberta, and Ontario were more prone to inaccurately self-report their substance use compared to participants from Québec. For instance, between 2018 and 2019, 15% of opioids samples from British Columbia contained at least one other non-opioid psychoactive substance. ³⁴ In contrast, in Québec, that percentage was only 7%. ³⁴ This report also showed that 91% of opioids from British Columbia contained fentanyl, compared to only 14% in Québec. ³⁴ This volatility of the unregulated drug market probably had a substantial impact on the accuracy of self-reporting.

Second, the discrepancy between UDS and self-reported use may be explained by some limitations of the immunoassay technique used to analyse urine samples. Cross-reactivity of immunoassay UDS may arise when screened substances have similar metabolites. For example, opioids from the epoxymorphinans family (i.e. oxycodone, heroin and hydromorphone) are mostly metabolized into morphine and hydromorphone, which is usually what UDS are detecting in urine samples. ⁵ Therefore, UDS might have a very low ability to differentiate specific opioids from this family. ⁵ This hypothesis is supported by our findings showing an increased concordance between UDS and TLFB when considering hydrophilic opioids together. Drug–drug interactions might also impact UDS validity. Both methadone and buprenorphine are metabolized by cytochromes P450 3A4 and 2D6.^{37bibr38-07067437251367180bibr39-07067437251367180–40} These enzymes are also involved in the metabolism and excretion of oxycodone, hydromorphone, heroin, and fentanyl, as well as commonly prescribed medications such as antipsychotics, antidepressants, and antiretroviral medications.^37,38,41 Therefore, using opioids while being on opioid agonist treatment or other medications can lead to a prolongation of the effects of opioids and an increase in opioid blood concentrations.^38,42,43 These drug–drug interactions, combined with interindividual variability in drug metabolism, likely impacted the duration during which opioids were detected in the urine, potentially leading to a mismatch between self-reported use and UDS. These limitations can significantly impact the quality of the treatments provided, as false positives can lead to an inappropriate adjustment of opioid agonist treatment doses, contribute to an untrusting relationship between patients and clinicians, and impact treatment retention by limiting access to take-home doses.^2,3,44 However, opioids false negatives could also greatly impact safety by increasing the risk of overdose, especially for individuals prescribed methadone. ¹¹

Several factors could also have impacted the reliability of self-reported use. First, since the TLFB retrospectively measures substance use, it is susceptible to recall bias. ⁴⁵ This might be especially relevant for people with OUD, who may have cognitive impairments in executive functioning and memory processing.^46,47 Individuals with OUD often present with comorbid psychiatric disorders, ⁴⁸ which are also likely to impair cognitive functioning.^49,50 Participants presenting memory deficits could inaccurately self-report their substance use, with no deceptive intent. Social desirability can also impact the accuracy of self-reported measures, especially considering that people who use drugs are often stigmatized. ³ Some individuals might be inclined to underreport their substance use for fear of being denied treatment, loosing take-home doses of opioid agonist treatment or being judged or mistreated by the study and clinical staff.^2,3,44 To improve the accuracy of self-reported measurements, research staff and clinicians should address these fears prior to data collection, in order to reassure participants that self-reporting their substance use will not impact their access to quality health services.

In summary, oxycodone, heroin, hydromorphone, and benzodiazepines showed lower concordance between self-reported use and UDS results, likely due to the limitations of the immunoassay technique and the adulteration of the unregulated drug market. Individuals using cannabis, amphetamines, and fentanyl on a voluntary basis accurately self-reported their substance use. For these substances, self-report may be sufficient to measure drug use exposure in clinical care and research. However, an ‘objective’ measure might be necessary to measure the exposure to other opioids and benzodiazepines to properly adapt opioid agonist treatment modalities such as doses to limit the risk of overdose. The use of mass spectrometry or gas chromatography is highly encouraged to avoid some of the limitations of immunoassay UDS. To ensure acceptability of such strategies, reasons for conducting UDS and consequences of a positive result should be properly explained to patients to build a trusting relationship. Combining both UDS and self-reported use can help to differentiate between undesired drug exposure and substance use patterns. From a research perspective, the use of one method over the other should be driven by the outcome of interest. When researchers are interested in measuring changes in drug-seeking behaviours, self-report of substance use might be sufficient. However, laboratory-confirmed UDS may be better at measuring actual drug use exposure.