Testing for drugs of abuse (DOAs)

INTRODUCTION — For the purpose of this topic, "drug of abuse" (DOA) is defined as a drug, chemical, or plant product that is known to be misused for recreational purposes. Although DOA testing is often performed in the clinical setting, many studies evaluating such screening have failed to demonstrate clinical benefit, and most clinical toxicologists suggest obtaining such testing only when there is a clear indication [1-4].

The apparent simplicity of the results provided with a DOA screen, typically reported as negative or positive for the presence of a given drug, can mislead clinicians into believing that DOA testing is straightforward and the results easy to interpret. In fact, DOA testing is extremely complex and proper interpretation requires specialized knowledge. Several studies of DOA testing show that many clinicians who regularly order DOA tests do not understand proper testing techniques, which drugs are detected, or how to properly interpret positive and negative results [5-7]. Proper interpretation of the results of a DOA screen depends upon the clinical context. Clinicians must consider the type of testing being performed, level of suspicion for drug use or exposure (ie, pretest probability), purpose of obtaining the test, and likelihood of false-positive and false-negative results.

This topic will review important concepts and issues involved in DOA testing in clinical settings, particularly the emergency or acute care setting. It is not intended to guide workplace or most forensic DOA testing, and does not address issues related to nonclinical DOA testing. Management of the poisoned patient, therapeutic drug monitoring, and the use of serum drug concentrations to diagnose or aid in the management of toxicity from specific medications are reviewed separately.

●(See "General approach to drug poisoning in adults".)

●(See "Initial management of the critically ill adult with an unknown overdose".)

●(See "Approach to the child with occult toxic exposure".)

WHAT IS INCLUDED IN A BASIC DOA SCREEN? — The content of DOA tests varies and clinicians should learn what is included in the tests available to them.

The basic DOA screen used consistently across the United States tests for five drugs or drug classes:

●Amphetamine (see "Acute amphetamine and synthetic cathinone ("bath salt") intoxication" and "Methamphetamine: Acute intoxication")

●Cocaine (see "Cocaine: Acute intoxication")

●Marijuana (THC)

●Opioids (see "Acute opioid intoxication in adults")

●Phencyclidine (PCP) (see "Phencyclidine (PCP) intoxication in adults")

The tests included in other basic DOA screens can vary by medical facility, region, and among and within specific countries. Many basic DOA screens used outside the United States omit PCP but include tests for benzodiazepines and a wider range of opioids (possibly including oxycodone and methadone). This is the case in Australia, New Zealand, and much of the European Union and Asia. Additional drugs may be detected depending on what a given facility’s clinical laboratory chooses to include in a DOA test panel. Other drugs that may be tested for include barbiturates, methamphetamine, and other synthetic opioids (eg, fentanyl, meperidine). However, many widely used drugs are not detected by the routine DOA screening tests used in many locales [8]. A partial list of such drugs would include: GHB; numerous newly developed amphetamines such as MDMA, MDPV ("bath salts"), ephedrone, and mephedrone; synthetic opioids such as meperidine, tramadol, methadone, fentanyl, and loperamide; ketamine; plant-derived substances such as hallucinogenic mushrooms, ayahuasca, and peyote; and synthesized substances such as LSD, many synthetic cannabinoids, tryptamines, and nitrous oxide.

The importance and frequency of drug testing varies from country to country. In the United States, current testing procedures developed from federally mandated workplace drug testing begun in 1986 and the wider-reaching (United States) Drug-Free Workplace Act of 1988. In that era, the five drugs listed above were considered most important and thus were included in the routine drug screening panel [9]. As epidemiologic trends in substance use have changed significantly since 1988, the range of substances detected by DOA testing has evolved. Most importantly, many new variants of amphetamines, synthetic marijuana/cannabinoids, opioids, and PCP that are not detectable with routine DOA testing have come into widespread use [10]. PCP is now relatively obscure and used with much lower frequency than numerous other street drugs, and amphetamine is used with relative infrequency compared with methamphetamine and amphetamine derivatives, such as MDMA (Ecstasy), MDPV (bath salts), and numerous other drugs in this class.

There is no uniformity as to what is included in extended DOA assays, or what the cutoff values for detection should be for drugs not covered by workplace testing laws. In order to know what is detected on a particular assay, it is necessary to consult the manufacturer’s literature for a given assay. In the United States, only amphetamine, cocaine, marijuana, opioids, and PCP should be expected on a DOA test, unless otherwise noted by the clinical laboratory performing the test or by the manufacturer.

INDICATIONS: WHEN IS A DOA SCREEN USEFUL (OR NOT)?

Utility of DOA screening — Despite widespread use, DOA screening is of extremely limited value in the acute clinical management of most patients [1-4]. As a result, there are no absolute indications for DOA testing in such circumstances. Specific settings in which DOA testing may have some value include drug treatment programs, pain management programs [11-16], and psychiatric treatment [17,18], although the results of studies in psychiatric patients are conflicting [19-23] and non-psychiatrists managing these patients in the emergency setting may disagree about the need and usefulness of DOA screening [24].

Despite the many limitations of DOA screens, there are a few scenarios where detection of a particular drug might alter medical management. Other possible scenarios include the following:

●Seizure/status epilepticus – Might avoid administration of phenytoin if DOA screen is positive for cocaine

●Cardiovascular event (eg, ACS, aortic dissection) – Might avoid administration of a beta adrenergic antagonist (beta blocker) if DOA screen is positive for cocaine

●Psychiatric event (eg, acute psychosis) – Might consider stimulant-induced psychosis for new-onset psychotics if DOA screen is positive for cocaine or amphetamine

●Patient awaiting organ transplant might be ineligible if a DOA screen is positive

●Pediatric patient with a positive DOA screen might undergo further evaluation for abuse (eg, skeletal survey), or their siblings might be screened

The settings of drug rehabilitation, pain management, and some areas of psychiatry involve patients with a risk or propensity for substance use [25,26], and successful treatment may require the treating clinician to be aware of recent or ongoing drug use by the patient. Beyond these settings, it is unclear that routine DOA testing in any group of patients is useful. Drug testing in the setting of drug rehabilitation and pain management is discussed separately. (See "Prescription drug misuse: Epidemiology, prevention, identification, and management", section on 'Identification and management' and "Continuing care for addiction: Components and efficacy" and "Use of opioids in the management of chronic non-cancer pain".)

In some circumstances, DOA testing may be indicated for legal or forensic reasons. (See 'Forensic purposes' below.)

There is a clear association between drug use and trauma, and numerous studies confirm the increased incidence of positive DOA tests among trauma patients [27-37]. Nevertheless, although the American College of Surgeons considers the capability for DOA testing essential for level I and level II trauma centers, and clinicians caring for trauma patients routinely perform DOA testing of trauma patients [38], it is unclear if detection of drug exposure affects clinical management [39]. Some authors suggest that selective DOA testing of trauma patients based upon criteria likely to identify patients at risk may be a more sensible approach than routine, empiric testing [40].

DOA may cause or contribute to numerous clinical signs and symptoms. Commonly encountered clinical problems associated with DOA include neurologic findings, such as acute alteration of mental status and seizure, and cardiovascular events, such as acute coronary syndrome (ACS), myocardial infarction (MI), aortic dissection, and stroke. The rationale for using DOA testing in such circumstances is to obtain positive or negative corroboration that a DOA may be contributing to the clinical problem. Although this approach seems sensible, DOA testing is usually unhelpful in such situations. The primary reason that DOA screening is of limited value is that it cannot determine if a patient has consumed a clinically meaningful quantity of drug; DOA screening can only confirm that the patient has recently used such a drug, usually within the past several days. As a result, DOA testing may be positive for a drug exposure that has no relevance to the clinical circumstance at hand, and this can be misleading or even dangerous [41]. (See 'What does a positive DOA test result mean?' below.)

Forensic purposes — There are circumstances in which DOA testing is indicated for forensic purposes. Examples include the following [42]:

●Drug-facilitated sexual assault involving administration of chemical agents to impair the victim’s ability to resist or recall the event (this typically involves a "date rape" drug)

●Malevolent poisoning

●Child abuse or neglect, particularly when a child is too young to use drugs volitionally and appears to have a toxidrome or symptoms consistent with exposure to a DOA

In such cases, information obtained from a DOA screen might provide important evidence of a crime or corroborate child abuse or endangerment. (See 'Specific drug assays: Methods and capabilities' below.)

In most countries, if an initial screening test (commonly an immunoassay) is positive in circumstances such as those described above the result is not used for any legal or forensic purpose until it is confirmed by a second test (often gas chromatography/mass spectrometry (GCMS), but occasionally others such as thin layer chromatography or liquid chromatography). Confirmatory testing is routine in North America, Europe, Australia, and New Zealand, but practices vary significantly in other countries. Some countries limit forensic DOA testing to law enforcement authorities only and do not use the results of tests performed by clinical facilities. Other countries may use DOA results from clinical facilities as definitive forensic evidence without performing confirmatory testing. We recommend that clinicians become familiar with forensic and law-enforcement practices in their locales.

Drug-facilitated sexual assault — Clinicians must exercise caution when performing DOA screening in cases of alleged sexual assault or "date rape" because DOA screens often fail to detect the agents used to facilitate sexual assault [43]. Such agents may include gamma hydroxybutyrate (GHB), flunitrazepam (Rohypnol) or other benzodiazepines, ketamine, or other sedative drugs. Some commercial laboratories offer a specific "date rape" DOA screen that includes drugs commonly used in sexual assaults. Standard DOA screens may not only fail to corroborate exposure to drugs actually used in an assault, but may be positive for common DOA and thereby impugn the reputation of the victim. Even specialized screens may not detect the presence of a "date rape" drug if it has a short half-life (eg, GHB) or is not included in the assay. (See "Evaluation and management of adult and adolescent sexual assault victims in the emergency department".)

Chain of custody for evidence — Any lab result may be used as evidence in a criminal case. For any sample that is likely to serve as such evidence, it is advisable to collect and transport it using a traceable chain of custody, including careful documentation. Laboratory results for samples for which a chain of custody was not maintained may still be used as evidence, but problems establishing validity may arise.

A proper chain of custody typically involves direct collection and secure storage, all carefully documented, until the evidence is given to the police. Secure storage involves maintaining the evidence in a secure location with limited access and where anyone who gains access is documented. This may include a hospital safe or secure storage in a laboratory facility. Transfer to police custody may occur immediately after the sample is obtained, or at any subsequent time. Evidence collection kits for sexual assault typically include forms to facilitate documentation, including who collected the evidence, who had custody of the evidence and when, and the time of transfer to law enforcement. When transferring the evidence to law enforcement authorities, it is generally recommended to note the officer’s name, badge number, and precinct or district.

Clinicians should assume that the results of forensic testing conducted by law enforcement agencies will not be made available to them. If information from laboratory testing is needed for clinical management, the clinician should perform whatever testing is needed through their hospital laboratory, even if such testing repeats any forensic testing.

CONTRAINDICATIONS, ETHICAL CONSIDERATIONS, AND RELATED PROBLEMS WITH DOA TESTING — The primary contraindication to obtaining DOA screening is a patient who does not consent to such screening, and the absence of any legal basis for testing against the patient’s will. If performed for clinical purposes, DOA testing generally does not require explicit consent, and the general consent signed at the time of registration in an emergency department or clinic, or the implied consent that occurs when presenting for medical care, are adequate in most circumstances. Obtaining DOA tests that may be used to harm the patient in any manner can jeopardize patient-clinician trust, and it is widely accepted that a clinician’s primary responsibility is to their patient’s well-being rather than the interests of law enforcement [44].

Ethical or medico-legal dilemmas may arise when DOA test results are sought for a patient who presumably would not want such results to be made available, and for whom there is no clinical indication for testing. Examples include police requesting DOA or other toxicology tests for a prisoner when there is no medical indication, or ethanol testing being performed where involuntary testing is not supported by local laws. Other ethically problematic circumstances arise when a family member, usually the parent of a minor but occasionally a spouse or another family member, requests DOA testing of a patient to be performed without the patient’s knowledge or against their will. In most of these circumstances, DOA testing is not justified.

For unemancipated pediatric patients, the issues surrounding DOA testing are complex. Parents or legal guardians, who hold decision-making authority for medical treatment of minors, may seek DOA testing if they so choose. Although DOA testing conducted without the child’s knowledge or even against their will is legal, the American Academy of Pediatrics suggests that parental requests for DOA testing of their children not be conducted surreptitiously or against the child’s will in the absence of medical need [45]. Often, these scenarios involve adolescents and occur in the setting of psychiatric or substance use disorder treatment. Cases in which a child requires psychiatric care are similar to adults, and in such cases DOA screening is considered medically necessary and is routinely performed regardless of the patient’s knowledge or consent.

In the United States, DOA testing of pregnant women has caused controversy. The United States Supreme Court has ruled that DOA testing of pregnant patients without their knowledge in cases that might result in criminal charges constitutes an unreasonable and unconstitutional search if performed without the woman’s consent [46]. This ruling resulted from a lawsuit filed by 30 South Carolina women, two of whom served prison sentences. The women, who underwent DOA testing without their knowledge, were subsequently arrested after testing positive for cocaine and were prosecuted for child endangerment and distribution of drugs to a minor. In 2020, the New York City Health and Hospitals Corporation discontinued the practice of randomly performing such DOA screening of mothers of newborn children [47]. This came after charges that such testing was biased against minority women. These examples cannot and should not be presumed to be applicable to other clinical settings, patient groups, or jurisdictions, but may provide insight into the problems that can arise when obtaining DOA testing without a patient’s consent.

Additional concerns relating to DOA testing include: clinician liability; adverse effects on an insurance claim or workers' compensation payment or future insurability for the patient who tests positive; ramifications in child custody cases in regions that permit DOA screening results to be considered as evidence; and, racial, socioeconomic, or other bias in obtaining DOA tests. Patients with a positive DOA test are often at risk for substance use disorders and the sequelae of substance misuse. Questions of responsibility, and potentially liability, arise when the physician who obtained such a DOA test fails to provide subsequent counseling or referral to substance use disorder specialists. In some states, health insurers may refuse to pay for medical care necessitated by injuries resulting from alcohol or substance use, and patients may become unable to obtain health insurance [48]. Depending upon local law, patients who test positive for DOA may lose eligibility for unemployment compensation if dismissal from employment was due to substance use. In the United States, some research suggests that racial bias plays a role in determining which patients undergo DOA testing, with Black and Hispanic American patients disproportionately tested [49,50].

In order to insulate clinicians from liability, and ensure equitable and optimal treatment of all patients, it is important to ensure that DOA testing is performed in a rational, understandable, and consistent manner without regard to race, ethnicity, sex, socioeconomic status, or other factors, and in a way that cannot be construed as biased or punitive. Additionally, patients with positive DOA tests should receive appropriate screening for alcohol and substance use, and appropriate referral to counseling or substance use disorder treatment should be provided as needed.

PERFORMANCE OF DOA TESTS

Biologic samples — Urine is by far the most commonly used biologic substance used in DOA testing (table 1). Blood or serum is used regularly for testing in some institutions, and in some circumstances and institutions hair, feces, sweat, or saliva may be used to detect DOA [51]. In most circumstances, clinicians should limit DOA testing to urine specimens, unless they are in a specific setting that routinely tests lesser-used or alternative specimens.

Specific drug assays: Methods and capabilities — Assays of biologic samples for DOA fall largely into three categories: immunoassays, chromatography, and mass spectrometry. Immunoassays are typically the initial screening test used to detect the presence of a DOA or metabolite, and gas chromatography/mass spectrometry (GCMS) is typically used as a confirmatory test.

Immunoassay — Immunoassays are by far the most widely used method of initial testing for DOA in the clinical setting. Typically providing a result within minutes after sample application, immunoassays are able to detect low concentrations of a substance with a high degree of specificity. They are technically easy to perform and relatively inexpensive.

Immunoassays use antibodies that recognize a drug or metabolite [52]. There are two general types of immunoassay techniques: noncompetitive and competitive. Noncompetitive assays recognize an analyte that is sandwiched between two antibodies, each of which recognizes a different site (or epitope) of the molecule. In a competitive immunoassay, non-labeled analyte in the patient’s serum or urine competes for a limited number of binding sites with a labeled version of the analyte that is provided with the immunoassay; displacement of the labeled analyte is the signal that suggests the presence of the drug.

The immunoassays most widely used for routine DOA testing are microparticle capture assays. These use a substance, often latex, that can collect in high concentration in a particular location, forming a colored band that can be visually read. The simplest such design uses an antidrug antibody with colored micro-particles and a capture zone consisting of the immobilized drug. Similar technology is used in other widely available point-of-care (POC) testing kits, such as those for urine pregnancy or streptococcal antigen. These are all typically conducted in a cassette containing the strip or matrix to which the biologic sample (and sometimes reagent) is added. After a period of minutes, the presence or absence of a colored band is interpreted as a positive or negative result.

Chromatography — Chromatography offers a highly sensitive and specific technique for detecting drugs or metabolites. However, it requires highly trained laboratory staff, instruments, and commonly takes many hours to provide results, and thus it is usually not a methodology used for initial DOA testing. A notable exception is when an extended, comprehensive toxicology screening, which may detect hundreds of medications and drugs, is performed as an initial investigation.

Chromatography refers to several related techniques whose common approach involves physical separation of substances [52]. The multiple methods (such as liquid chromatography, thin layer chromatography, and gas chromatography) all include a combination of a mobile phase and a stationary phase. The stationary phase usually consists of fine particles, and the mobile phase is usually liquid or gas. The time required to traverse the length of the chromatography column or the distance traveled in a media during a set time (in thin layer chromatography) is consistent and highly reproducible.

Gas-chromatography/mass spectrometry — Gas chromatography/mass spectrometry (GC/MS) is considered the most accurate method to identify DOA. GC/MS is technically complex, requires elaborate instruments and laboratory staff with training and expertise, and requires hours to complete.

The mass spectrometer is highly sensitive, capable of detecting even minute quantities of a given substance, and able to create highly specific mass spectra for the compounds that it clears [52]. Prior to entering a mass spectrometer, substances must be ionized, usually by bombardment with electrons. The mass spectrometer then uses electromagnetic filtering to direct ions of a specific mass-to-charge ratio to a detector. By scanning the range of masses that pass the detector, a mass spectrum is generated. The mass spectrum of any compound is highly distinctive, somewhat like a fingerprint. As a result, mass spectrometry is usually considered to have the highest specificity of all lab detection methods, and is usually part of the confirmatory test method.

An important limitation of GC/MS is its inability to distinguish between optical isomers. This is relevant for the detection of methamphetamine and levorphanol. Mass spectrometry cannot differentiate between l-methamphetamine, the active ingredient in widely available nasal inhalers, and d-methamphetamine, which is the neurologically active methamphetamine isomer; nor between the main metabolite (d-3-hydroxy-17-methymethorphinan) of dextromethorphan, which is commonly found in over-the-counter cough syrups, and the main metabolite (l-3-hydroxy-17-methorphinan) of levorphanol, a controlled prescription opioid.

Few hospitals or medical centers have clinical laboratories able to conduct GC/MS testing. This is generally not problematic, as GC/MS is a confirmatory technique that is primarily of forensic importance. It rarely provides results that are clinically necessary or useful beyond those obtained by standard immunoassays or chromatography. GC/MS testing is most commonly provided by highly equipped reference laboratories.

Point-of-care DOA testing — There are numerous point-of-care (POC) tests for detecting DOA. Their ease of use (no instruments are required), rapid results, and ease of interpretation are considered major benefits. Most of these assays use urine samples as the substrate. The US Food and Drug Administration (FDA) has approved a limited number of POC DOA tests that use saliva and a fentanyl test that uses urine [53,54].

Unfortunately, in actual clinical settings POC tests generally underperform manufacturers’ claims, particularly for marijuana/cannabinoid detection. Many publications report sensitivity and specificity of POC DOA tests as close to 100 percent [55-57], but most POC tests have lower sensitivity and specificity, and sometimes the discrepancies are so great that the assays should be considered unreliable [58-63]. In addition, when POC DOA testing is conducted by non-laboratory staff, as would be the case with emergency department POC testing or clinic testing, errors in technique and interpretation are more likely. The United States Department of Health and Human Services (HHS) has recognized that specific training is necessary for clinicians to properly collect and interpret POC DOA tests, and mandates training for workplace testing [64]. Since the implementation of these standards in the United States and comparable standards in much of Europe and Asia, clinical laboratories and reference laboratories have demonstrated extremely high accuracy and precision identifying positive and negative biologic samples for DOA. In the United States, no such training is required for non-workplace testing, though the shortcomings in test performance and interpretation persist.

INTERPRETING RESULTS

Important warnings — The apparent simplicity of the results provided with a DOA screen, typically reported as negative or positive for the presence of a given drug, can mislead clinicians into believing that DOA testing is straightforward and the results easy to interpret. In fact, DOA testing is extremely complex and proper interpretation requires specialized knowledge. Several studies of DOA testing show that many clinicians who regularly order DOA tests do not understand proper testing techniques, which drugs are detected, or how to properly interpret positive and negative results [5-7]. Proper interpretation of the results of a DOA screen depends upon the clinical context. Clinicians must consider the type of testing being performed, level of suspicion for drug use or exposure (ie, pretest probability), purpose of obtaining the test, and likelihood of false-positive and false-negative results.

Usually the initial screening test performed is an immunoassay. The results of confirmatory testing are almost never available in a sufficiently timely manner to play any role in the clinical management of acute medical problems. When confirmatory testing is needed (eg, for forensic purposes), the most common test is gas chromatography/mass spectrometry (GCMS), but may thin layer chromatography, liquid chromatography, or another method may be used. (See 'Specific drug assays: Methods and capabilities' above.)

What does a positive DOA test result mean? — A true positive initial screening test means that the DOA or metabolite of interest was present at or above the threshold concentration at the time the sample was obtained. The presence of a DOA or metabolite does not necessarily indicate active intoxication, as drugs may be detected at levels that cause no clinical effects. The period after use during which a test remains positive for a substance varies by drug, but typically begins within minutes of exposure and lasts for days.

Following ingestion of common DOA, the typical periods during which testing is positive are as follows:

●Amphetamines – One to three days

●Cocaine – One to three days

●Opioids – One to three days; methadone has a highly variable but long half-life, permitting detection for 3 to 10 days

●Marijuana – Days to months, depending on chronicity of use; chronic users have been reported to continue testing positive for months after discontinuation.

●Benzodiazepines ‒ Varies significantly by half-life, but generally one to seven days; diazepam metabolites may be detected for weeks after discontinuation.

●Phencyclidine (PCP) – One to seven days

●Ketamine ‒ Three to seven days

Importantly, a positive result does not mean an individual is currently under the influence of the DOA in question, nor does a positive result mean the DOA is present in a quantity that is physiologically relevant. An illustrative example would be an individual who smoked marijuana once. After such an exposure the patient might be intoxicated for several hours, but would likely have a positive urine DOA assay detecting THC for several days, long after the clinical effects of the marijuana had ceased.

Misinterpretation of a positive DOA test can be dangerous. As an example, consider a patient who presents to the emergency department with altered mental status and cannot provide a history, but whose DOA test is positive for cocaine metabolites. If such a patient has encephalitis, and coincidentally had used cocaine several days earlier, the misdiagnosis of cocaine intoxication could cause a potentially life-threatening delay in diagnosis and appropriate treatment.

Because rapidly available DOA testing cannot determine if a clinically meaningful quantity of drug or metabolite is present, it cannot be used to diagnose drug intoxication. This concept is widely misunderstood or unknown by many clinicians. Even some authors of major studies of DOA testing mistakenly presume that a positive DOA test implies the patient is actively intoxicated with the drug in question [65]. Clinicians should diagnose drug intoxication or toxicity based primarily on clinical findings rather than DOA test results.

False-positive results — Many DOA assays, particularly immunoassays, can yield false-positive results if specific cross-reacting medications or drugs are present in the sample. For the basic five DOA, cross-reacting substances include the following:

●False-positive amphetamine results: Pseudoephedrine, ephedrine, phenylephrine, and other commonly used medications (eg, propranolol, atenolol, bupropion, levodopa, carbidopa)

●False-positive opioid results: Poppy seed ingestion (eg, bagels, pastries)

●False-positive PCP results: Over-the-counter cold medications (eg, doxylamine, dextromethorphan), tramadol

●False-positive cannabinoid/marijuana results: Hemp-containing food products; rare medication exposures (eg, Marinol [dronabinol])

Misinterpretation of results may be harmful, such as when they are used to initiate the involvement of protective services agencies when a child has a false-positive DOA test [66,67].

When a DOA test is obtained for forensic or legal reasons, any positive result on the initial screening assay is verified using another confirmatory assay. A confirmatory test is used specifically because false-positive DOA results are known to occur with initial tests, and the confirmatory test substantially improves accuracy.

What does a negative DOA test result mean? — A true negative initial screening test means that at the time the sample was obtained, the DOA or metabolite of interest was not present at or above the threshold concentration. Individuals with a negative DOA testing may have used the DOA in the past, may be currently intoxicated (with a drug not detected by the DOA test), or in rare cases may have a physiologically meaningful quantity of the drug present. As an example, one case report describes a patient who died from complications of cocaine toxicity whose initial DOA test was negative for cocaine [68]. Subsequent, more detailed laboratory investigations detected high levels of a cocaine metabolite (benzoylecgonine). In this case, the metabolite was detected by the initial screening tests but at a concentration below the threshold for a positive result.

False-negative results — False-negative results for DOA testing can occur for many reasons, including improper specimen collection, transport, or testing procedures. In addition, patients may use a variety of methods to subvert DOA testing. (See 'How can DOA screens be subverted?' below.)

The most common cause of a false-negative DOA test is failure of the test to detect a drug in the given class whose chemical structure renders it unreactive with the assay. As an example, most opioid screening tests fail to detect meperidine. Instead, a specific test to detect meperidine or its metabolites would be needed for detection.

There are many examples of false-negative results:

●Amphetamine screens do not routinely detect MDMA (Ecstasy) or methamphetamine. A patient may be using or actively intoxicated with methamphetamine, but depending on the assay used, the amphetamine DOA test result may be negative.

●Ketamine is a widely misused DOA not included on most routine DOA screens. A patient may be using or intoxicated with ketamine, but the drug would not be detected by routine DOA screening in most instances.

●Many commonly misused drugs, such as gamma hydroxybutyrate (GHB), lysergic acid diethylamide (LSD), designer amphetamines (eg, ephedrine, mephedrone, MDPV), some synthetic cannabinoids, and tryptamines (eg, DMT, MEO, DeoMT), are not detected by many commonly used DOA screening assays.

DOA screening is semi-quantitative, meaning that positive results can be attributed to the presence of a DOA in a specific threshold quantity, below which the DOA may be present but does not trigger a positive result and is reported as negative. One method for reducing false-negatives and increasing false-positive results with DOA testing is to lower the thresholds used for detection. Current thresholds for detection in the United States were established for workplace testing, and there are no restrictions on laboratories for lowering thresholds when DOA testing is used for clinical purposes. Lowered detection thresholds will detect samples that are positive for a drug or metabolite but at a concentration below the accepted the Substance Abuse and Mental Health Services Administration (SAMHSA) cutoff value [69]. Testing of alternate samples, such as hair and meconium, is conducted in laboratories using methodology ordinarily used for urine samples, but with lower thresholds.

How can DOA screens be subverted?

Overview — The creativity of individuals seeking to subvert DOA testing is astounding, and there exists an entire industry dedicated to making and marketing products intended to assist patients in subverting urine drug screening. Methods for undermining DOA tests include:

●Ingestion or addition of large amounts of water to dilute the urine and decrease the drug concentration below the detection threshold.

●Ingestion of masking agents intended to hide the presence of the DOA.

●Addition of adulterants intended to prevent detection of the DOA.

●Substitution of a drug-free urine sample obtained from another individual or synthetic urine.

In order to prevent subversion of urine DOA tests, the Substance Abuse and Mental Health Services Association (SAMHSA) of the United States has specific requirements for urinary specific gravity, pH, and creatinine concentration for a specimen to be considered valid for testing. However, hospital laboratories that perform clinical testing do not uniformly adhere to the same standards, making it more likely in some cases that such testing can be successfully undermined by patients.

Although some circumstances, such as military DOA testing, require directly observed urine specimen collection, in most clinical circumstances direct observation of patient production of urine samples is unnecessary, and may be illegal. Even directly observed urine specimen collection can be subverted. Commercial devices, such as prosthetic phalluses used to dispense clean urine from a reservoir in a manner that mimics urination by a male, may be used to deceive an observer. Another deceptive practice involves placing a urinary catheter for retrograde insertion of "clean" (ie, drug-free) urine that subsequently can be urinated while under direct observation.

In most clinical settings it is impossible to prevent motivated patients from subverting DOA tests, and clinicians should presume that patients who intend to undermine such testing will likely have an opportunity to do so. We suggest that clinicians and facilities make reasonable attempts to obtain appropriate specimens, but should not take extraordinary measures.

Dilution by free water intake — Consumption of fluid, usually water, to dilute urine for the purpose of lowering the concentration of drugs is widely known, easy, and a commonly performed method used to subvert DOA testing [70]. According to an observational study, consumption of 2 quarts (1.9 L) of liquid just prior to providing a sample for drug testing resulted in negative tests for cocaine and marijuana/cannabinoid in patients whose urine tested positive prior to and hours after the consumption [71]. For workplace or forensic testing, negative results from a dilute urine sample with an unacceptably low specific gravity or urine osmolality are disregarded and not reported as negative. The urinalysis findings in such cases resemble those of patients with polydipsia and are discussed separately. (See "Causes of hypotonic hyponatremia in adults", section on 'Primary polydipsia due to psychosis'.)

Ingestion of only 800 mL of water, or approximately 26 ounces, may result in urine dilution below the specific gravity considered acceptable by SAMHSA for DOA testing [72]. Therefore, dilute urine should not be presumed to be the result of intentional subversion. Dilution may also be an issue for patients receiving IV fluids, who commonly receive over 800 mL, and for patients treated with diuretics.

Of note, significant morbidity and even mortality may result from ingestion of large quantities of water intended to dilute urine [73]. (See "Manifestations of hyponatremia and hypernatremia in adults", section on 'Clinical manifestations of acute hyponatremia'.)

Ingestion of masking agents — Many substances have been used as masking agents allegedly capable of “cleansing” urine that would otherwise test positive for DOA. Goldenseal (Hydrastis canadensis) tea is one commonly used masking agent. Niacin is another purported masking agent, and numerous cases of niacin toxicity have resulted from patients taking large doses for the purpose of subverting urine drug tests [74,75].

Adulterants added to urine samples — Numerous adulterants exist that are capable of interfering with DOA tests and causing negative results when added to urine samples, despite the presence of DOA. Some adulterants are sold commercially specifically for such uses while others are commonly available chemicals. The effect of adulterants varies depending upon the specific assay used for testing and the analyte (ie, DOA or metabolite) being detected [76,77]. Adulterants are generally most effective in interfering with the detection of marijuana/cannabinoid. However, many substances purported to be effective adulterants are easily detectible or ineffective.

Some adulterants exert their effect via oxidation or alterations in pH. Others alter or destroy the drug or metabolite being tested for, in which case even testing with gas chromatography/mass spectrometry (GC/MS) will fail to detect the substance [78]. This is a major problem because GC/MS is generally highly sensitive and considered the gold standard test for confirming the presence of a drug.

Chemicals used as adulterants include zinc sulfate [79,80], ammonia, bleach, chromate, glutaraldehyde, hydrogen peroxide, iodine [81], liquid soaps, nitrite, papain [82,83], peroxidase/peroxide [84], potassium hydroxide, pyridium chlorochromate [85], sodium chloride, and vinegar. All are capable of interfering with DOA tests. Natural products, including various radish and mustard seed extracts, are capable of interfering with some tests, and are largely undetectable by routine laboratory methods [86]. Commercially available kits or easily performed laboratory techniques for detecting many adulterants are available [87-89], but some adulterants appear to be effective and undetectable using routine laboratory methods [90].

Adulterating ("spiking") urine samples to obtain positive DOA test results — Some patients being treated in pain management or substance use disorder clinics may adulterate their urine samples to create false-positive results for particular drugs on DOA screens, and thereby feign compliance with their prescribed medication regimen. Reasons for noncompliance vary. Some patients want to divert their prescription opioids (eg, methadone, buprenorphine, other opioids) for illicit sale or distribution to other individuals. Others want to avoid less euphorigenic agents, such as the agonist/antagonists, buprenorphine, butorphanol, nalbuphine, or pentazocine, and use heroin or other euphorigenic opioids instead.

Aware that their treatment plan requires urine drug testing to detect both their prescribed medications and illicit drugs, some patients may attempt to spike their urine with their prescribed drug in order to have a positive test for the appropriate agent. Therefore, DOA testing for patients being treated for addiction, or chronic pain patients with a propensity for opioid misuse, usually involves testing for a metabolite of the parent drug in addition to, or instead of, simply testing for the parent drug. As an example, urine testing for methadone detects both methadone as well as EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine), a major methadone metabolite. Patients with urine that contains methadone, particularly extremely high levels, but no EEDP are easily detected by this method. A similar approach to screening is used for partial opioid agonists, such as buprenorphine, butorphanol, and nalbuphine, which are used in addiction management and chronic pain patients with a propensity for opioid misuse.

SPECIFIC DRUG ASSAYS — A table summarizing common urine drug assays is provided (table 1). The assays used to detect specific drugs are discussed below.

Amphetamines — DOA testing for amphetamine and methamphetamine is discussed in detail separately, but some relevant issues are noted here. (See "Acute amphetamine and synthetic cathinone ("bath salt") intoxication" and "Methamphetamine: Acute intoxication".)

Screening for amphetamines produces more false-positive results than any other DOA testing, as chemicals that share a basic chemical structure with amphetamine are present in many over-the-counter medications and herbal supplements. Nasal inhalers containing l-methamphetamine, an isomerically pure amphetamine that does not affect the central nervous system, are widely use and frequently cause false-positive DOA tests for amphetamine. In this case, even mass spectrometry cannot differentiate between samples containing l-methamphetamine and those containing mixed d,l-methamphetamine.

There are over 100 amphetamine derivatives that may be used as illicit drugs. Some of these are so widely used (eg, methamphetamine, MDMA) that commercial manufacturers of DOA screening tests have adapted their immunoassays to detect these specific agents. However, numerous structural variations and substitutions to the basic amphetamine structure are used to produce countless amphetamine derivatives and analogues with the clinical effects of standard amphetamines. Many of these are sold by online vendors as "legal high" substances or as substances not for consumption (eg, "bath salts" or plant food) in a thinly veiled manner that allows manufacturers to circumvent laws banning them.

Thus, it is crucial to remember that patients with an apparent sympathomimetic or adrenergic toxidrome may be severely intoxicated with amphetamines or amphetamine-like substances despite a DOA screening test that is negative for amphetamines. Conversely, amphetamine screening assays may be falsely positive due to exposure to an over-the-counter or herbal medication.

Benzodiazepines — DOA testing for benzodiazepines is discussed in detail separately, but some relevant issues are noted here. (See "Benzodiazepine poisoning".)

Though not one of the five drugs included in the standard DOA screen, benzodiazepine assays are often included in DOA testing due to the widespread use and misuse of these medications. Benzodiazepine tests generally have good specificity but variable sensitivity for particular benzodiazepines. Due to the limited sensitivity, the National Academy of Clinical Biochemists in the United States does not recommend that screening for benzodiazepines be available in the emergency department setting [91].

The earliest and most widely used benzodiazepine screening assays detect oxazepam, a common metabolite of many benzodiazepines. Benzodiazepines that do not undergo metabolism to oxazepam, such as alprazolam, clonazepam, lorazepam, midazolam, and triazolam, are not detected by any screening test that relies on the detection of oxazepam. In response to the large number or newer benzodiazepines with unique metabolites, many DOA test manufacturers have expanded the range of benzodiazepines detected by their assays. Each commercial DOA test for benzodiazepines is unique, and so it is necessary to use reference chemicals to know what specific drugs are detected by the assay. Benzodiazepines that are not detected by most commercial tests include flunitrazepam (Rohypnol) as well as the benzodiazepine-like "z" drugs used as sleep aids, such as eszopiclone, zaleplon, zolpidem, and zopiclone.

Cocaine — DOA testing for cocaine metabolites is discussed in detail separately, but some relevant issues are noted here. (See "Cocaine: Acute intoxication".)

The standard assay used to detect cocaine is likely the most accurate of the DOA screening tests. The specificity of these immunoassays, which detect the cocaine metabolite benzoylecgonine, is extremely high, and false-positive results are extremely uncommon.

Cocaine is a schedule II drug in the United States, but its medicinal use is typically limited to topical anesthesia for minor otolaryngologic procedures. Patients treated with cocaine for such a procedure may have a true positive test for several days afterwards. Drinking coca tea [92] or chewing coca leaves also produce metabolites that could cause a positive cocaine DOA test. Importing coca leaves or coca tea to the United States is illegal, but these substances are available in other countries. Appropriate urine analysis can distinguish between exposure to cocaine and coca leaves/tea based on the different metabolites that result from each type of exposure.

Marijuana/cannabinoids — Assays for marijuana/cannabinoid testing detect a metabolite of tetrahydrocannabinol (THC) rather than THC itself, which is only present for several hours after marijuana use. The metabolite (Delta-9-THC) remains in the serum and urine for a much longer period (days to weeks). Older assays for marijuana/cannabinoids that are no longer in use may have caused some false-positive results [93,94], but current DOA assays are highly specific. (See "Cannabis (marijuana): Acute intoxication", section on 'Drug testing for cannabinoids'.)

Distinguishing between exposure to hemp products and marijuana or hashish use can be difficult, as either may cause a positive test for Delta-9-THC. In one case, hospitalized neonates had positive urine drug screens for marijuana/cannabinoids from hemp-containing soap [95]. Positive tests have also been associated with ingestion of hemp products, particularly hemp oil [96].

Many clinicians question the relevance and utility of DOA testing for marijuana or its metabolites. The National Academy of Clinical Biochemists in the United States does not recommend that testing for marijuana/cannabinoids be available in emergency departments [91]. Doubts about the usefulness of such testing exist for several reasons, including the extended period following marijuana use during which DOA tests may be positive (from one week in a naïve user to as long as two months in chronic users [97,98]), and the lack of clinical circumstances for which corroboration of marijuana exposure would be helpful. The decriminalization or legalization of marijuana for medicinal or recreational use in much of the United States and other countries makes marijuana/cannabinoid screening increasingly less meaningful.

Synthetic cannabinoids have become popular recreational drugs in the United States and Europe. These drugs, typically sold openly under a variety of names (eg, Spice, K2) via the internet or drug paraphernalia shops, are more likely to cause serious side effects, including a 200-fold higher incidence of acute psychosis relative to natural marijuana. The increasing popularity of these drugs has prompted commercial forensic laboratories to develop screening assays for several of the most widely available synthetic cannabinoids. These screening tests do not cross-react with natural cannabinoid from marijuana, hashish, or hemp, but have variable cross reactivity with some other synthetic cannabinoid molecules. (See "Synthetic cannabinoids: Acute intoxication", section on 'Testing for synthetic cannabinoids'.)

Opioids — DOA testing for opioids metabolites is discussed in detail separately, but some relevant issues are noted here. (See "Acute opioid intoxication in adults".)

Opioid screening tests typically detect morphine, a common metabolite of not only heroin but all natural opioids (eg, codeine). Synthetic opioids, including fentanyl, meperidine, methadone, pentazocine, propoxyphene, and tramadol, are not detected by routine opioid screening. The semisynthetic opioids hydrocodone, hydromorphone, oxycodone, and oxymorphone, which are widely prescribed and misused, are also not detected by routine opioid screening. However, specific screening assays that detect these drugs are available and commonly used. Buprenorphine is a semisynthetic opioid agonist-antagonist used in substance use disorder programs whose detection requires a specific assay.

Positive opioid screening results from poppy seed consumption prompted the United States Substance Abuse and Mental Health Services Administration (SAMHSA) to raise the threshold for workplace urine testing to 2000 ng/mL of morphine from the previous cutoff of 300 ng/mL. As this recommendation is for occupational or workplace screening, many toxicology laboratories do not adhere to it and continue to use the lower 300 ng/mL threshold for a positive result. Positive test results potentially due to consumption of poppy seeds, which contain trace amounts of morphine, can be distinguished from heroin using an assay that detects 6-monoacetylemorphine (6MAM), a metabolite found only following heroin exposure. Neither standard testing nor testing with the 6MAM assay can differentiate between positive results from poppy seeds and positive results due to codeine.

In clinical management, it is important to recognize that patients may have significant opioid toxicity despite a negative DOA test for opioids. Conversely, a positive opioid screening test in a patient who lacks any signs and symptoms of opioid toxicity indicates possible opioid exposure rather than intoxication.

Phencyclidine — DOA testing for phencyclidine (PCP) is discussed in detail separately, but some relevant issues are noted here. (See "Phencyclidine (PCP) intoxication in adults" and "Phencyclidine (PCP) intoxication in children and adolescents".)

The accuracy of assays for PCP has suffered from the significant decline in PCP use (ie, low pre-test probability), and the false-positive results that may occur from diphenhydramine, doxylamine, dextromethorphan, lamotrigine, and tramadol [99,100]. Confirmatory methods easily identify false-positive immunoassays. PCP assays have variable sensitivity for detecting the dozens of PCP congeners (substances with slight variations in the basic PCP structure that cause similar intoxication and clinical findings).

Other drugs — In some circumstances it may be desirable to test for drugs other than those included in DOA screens. The United States Department of Defense (DOD) workplace drug testing program provides an example of such expanded testing. The United States DOD has dropped PCP from its routine screening procedures, but retains the capability to test for PCP if desired. Beyond tests for amphetamine, cocaine, marijuana/cannabinoid, and opioids, the United States DOD DOA screen includes [101]:

●Benzodiazepines

●Certain amphetamine derivatives: Methamphetamine, MDMA (Ecstasy), MDA

●Opioids: Hydrocodone, hydromorphone, fentanyl, oxycodone, oxymorphone

●Multiple synthetic cannabinoids

It is technologically possible to develop assays that detect nearly any drug or metabolite. Some DOA for which both qualitative and quantitative assays exist are listed below. Most such tests must be performed at a reference laboratory, and typically a minimum of several days is needed to obtain results.

●All over-the-counter and prescription amphetamine derivatives and analogues, including cathinones, phenylethylamines, and piperazines

●All benzodiazepines and benzodiazepine-like drugs, including gamma hydroxybutyrate (GHB) and "z" drugs (eg, zolpidem, zopiclone)

●All barbiturates and similar sedative hypnotic drugs, such as methaqualone

●All over-the-counter and prescription opioids, as well as the natural analogue kratom

●Various hallucinogens, including dextromethorphan, DMT and other tryptamines, ketamine, LSD, mescaline, psilocybin, and others.

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment of acute poisoning caused by recreational drug or alcohol use".)

SUMMARY AND RECOMMENDATIONS

●Terminology – "Drug of abuse" (DOA) is defined as a drug, chemical, or plant product that is known to be misused for recreational purposes. Although DOA testing is often performed, many studies evaluating such screening have failed to demonstrate clinical benefit, and most clinical toxicologists suggest obtaining such testing only when there is a clear indication. (See 'Introduction' above.)

●Basic DOA screens – The tests included in basic DOA screens vary by region. In the United States, the basic DOA screen tests for amphetamine, cocaine, marijuana, opioids, and phencyclidine. Many basic DOA screens used outside the United States omit phencyclidine (PCP) but include tests for benzodiazepines and a wider range of opioids (possibly including oxycodone and methadone). This is the case in Australia, New Zealand, and much of the European Union and Asia. (See 'What is included in a basic DOA screen?' above.)

●Indications and contraindications to DOA testing – DOA screening is of extremely limited value in the acute clinical management of most patients. As a result, there are no absolute indications for acute DOA testing. DOA testing may have value for patient monitoring in substance use disorder treatment programs, pain management programs, and some psychiatric programs. Scenarios when the results of a DOA screen might alter acute management include:

•Seizure/status epilepticus – Might avoid administration of phenytoin if DOA screen is positive for cocaine

•Cardiovascular event (eg, ACS) – Might avoid administration of a beta adrenergic antagonist (beta blocker) if DOA screen is positive for cocaine

•Psychiatric event (eg, acute psychosis) – Might consider stimulant-induced psychosis for new-onset psychotics DOA screen is positive for cocaine or amphetamine

•Patient awaiting transplant might be ineligible if a DOA screen is positive

•Pediatric patient with a positive DOA screen might undergo further evaluation for abuse (eg, skeletal survey), or their siblings might be screened

DOA testing may also serve forensic purposes. The primary contraindication to obtaining DOA screening is a patient who does not consent to such screening, and the absence of any legal basis for testing against the patient’s will. (See 'Indications: When is a DOA screen useful (or not)?' above and 'Contraindications, ethical considerations, and related problems with DOA testing' above.)

●Biologic samples and assay categories – Urine is by far the most common biologic substance used for DOA testing, although other biologic substances (eg, serum) may be used. Assays of biologic samples for DOA fall largely into three categories: immunoassays, chromatography, and mass spectrometry. Immunoassays are by far the most widely used method of initial testing. Each major method is described in the text. (See 'Performance of DOA tests' above.)

●Limitations of DOA immunoassays – The apparent simplicity of the results provided with a DOA screen, typically reported as negative or positive for the presence of a given drug, often misleads clinicians. Proper interpretation of the results of a DOA screen depends upon the clinical context. Clinicians must consider the type of testing being performed, level of suspicion for drug use or exposure (ie, pretest probability), purpose of obtaining the test, and likelihood of false-positive and false-negative results. A table summarizing the urine DOA assays and false positives is provided (table 1). (See 'Important warnings' above.)

●Interpreting positive DOA results – A true positive initial screening test means that the DOA or metabolite of interest was present at or above the threshold concentration at the time the sample was obtained. The presence of a DOA or metabolite does not necessarily indicate active intoxication, as drugs may be detected at levels that cause no clinical effects. The period after an ingestion during which a test remains positive for a substance varies by drug, but typically begins within minutes of consumption and lasts for days. Many DOA assays, particularly immunoassays, can yield false-positive results if specific cross-reacting medications or drugs are present in the sample. Common false-positive tests are described in the text. (See 'What does a positive DOA test result mean?' above and 'False-positive results' above.)

●Interpreting negative DOA results – A true negative initial screening test means that at the time the sample was obtained, the DOA or metabolite of interest was not present at or above the threshold concentration. Individuals with a negative DOA testing may have used the DOA in the past, may be currently intoxicated with a drug not detected by the DOA test, and in rare cases may have a physiologically meaningful quantity of the drug present. False-negative results for DOA testing can occur for many reasons, but the most common cause is failure of the test to detect a drug in the given class whose chemical structure renders it unreactive with the assay. (See 'What does a negative DOA test result mean?' above and 'False-negative results' above.)

●Subverting DOA screens – Methods used to subvert DOA screens and the assays used to detect specific drugs include ingestion or addition of large amounts of water to dilute the urine, ingestion of masking agents, addition of adulterants, and substituting urine samples and are discussed further in the text. (See 'How can DOA screens be subverted?' above and 'Specific drug assays' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Stephen J Traub, MD, former section editor of the toxicology program, for 20 years of dedicated service.