Chemistry, toxicology & urinalysis

Toxicology and therapeutic drugs

Drugs of abuse

Last author update: 1 March 2021
Last staff update: 1 March 2021

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PubMed Search: Drugs of abuse[title] pathology review[ptyp]

Vishnu Amaram Samara, Ph.D.
Kathleen A. Kelly, Ph.D.
Page views in 2022: 448
Page views in 2023 to date: 181
Cite this page: Amaram Samara V, Kelly KA. Drugs of abuse. website. Accessed May 31st, 2023.
Definition / general
  • Drug abuse is a global major public health problem
  • Includes prescription and nonprescription drugs that are either overdosed or illicitly abused for pleasure
  • Testing is performed for patient compliance in pain management and for addiction management
Essential features
  • Drugs of abuse are commonly analyzed in urine because of the longer window period for detection; less commonly analyzed in serum or plasma
  • Drugs are excreted in urine, either in their native form or as their metabolites
  • Absence of drugs in the urine indicates inappropriate specimen collection, diversion (i.e. not taking the prescribed dose), diluted urine or adulterated urine
  • Dilution of urine samples can be confirmed by measuring the urine creatinine levels (normal 24 hour urine creatinine: 500 - 2000 mg/day; random urine creatinine: 20 - 300 mg/dL)
  • Identification of drugs of abuse in pregnant women / neonates during antenatal testing can have serious consequences
  • For neonates, meconium can be used to detect drug abuse by the pregnant mother for up to 4 - 5 months before delivery; results are reported as ng/g (Clin Chem 2018;64:1671)
  • Cutoff levels for urine testing of drugs of abuse are established in ng/ml for both the screen and confirmation
  • Meconium
  • Kinetic interaction of microparticles in solution (KIMS)
  • Liquid chromatography tandem mass spectrometry (LC-MS / MS)
  • Gas chromatography mass spectrometry (GC-MS)
ICD coding
  • ICD-10: F01-F99 - mental, behavioral and neurodevelopmental disorders
Detection methodologies
  1. Immunoassay screening for drugs of abuse is performed mostly by the kinetic interaction of microparticles in solution (KIMS) method
    • Other immunoassay methods, such as enzyme multiplied immunoassay technique (EMIT) and cloned enzyme donor immunoassay (CEDIA), are also performed for drugs of abuse testing
    • Results are provided as positive or negative based on the cutoff concentration detection limits
    • Immunoassays recognize or detect only 1 or certain drugs in a class and cannot differentiate between the main drug and their metabolites
  2. Confirmation of drugs of abuse is carried out by quantitative measurement by liquid chromatography tandem mass spectrometry (LC-MS / MS) or gas chromatography mass spectrometry (GC-MS) methods
  3. Point of care testing (POCT) methods / assays are available for some drugs of abuse testing
Common drugs of abuse
  • Amphetamines:
    • Belong to phenylethylamine class of drugs and stimulate central nervous system (CNS)
    • Pharmacologically used for the treatment of narcolepsy, obesity and ADHD
    • High doses and frequent heavy use can create an amphetamine induced psychosis
    • Forms of amphetamines used in abuse include crystal methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), also referred to as ecstasy
    • Amphetamines are metabolized by liver and eliminated in urine with an average detection window of 3 days
    • Quantitative LC-MS / MS based detection cutoff concentrations for amphetamine is 50 ng/ml and for all others, such as methamphetamine and MDMA (ecstasy), is 200 ng/ml
  • Barbiturates:
    • Class of sedative drugs
    • CNS depressants used in treatment of insomnia and seizures
    • Short acting sedative barbiturates, such as pentobarbital, secobarbital and amobarbital, are more subjected to abuse compared to long acting phenobarbital that is rarely abused
    • Withdrawal symptoms include agitation, anxiety, insomnia, nausea and vomiting
    • Detection window for barbiturates ranges from 24 hours to 4 days (for long acting phenobarbital)
    • Quantitative analysis by GC-MS can detect individual barbitals with positive cutoff of 50 ng/ml
  • Benzodiazepines:
    • Include a wide range of compounds that consist of a benzene ring, phenyl ring and a diazepine ring, with a common molecular structure
    • LC-MS / MS quantitative detection positive cutoff for most benzodiazepines is 20 ng/ml
    • LC-MS / MS can also identify individual derivatives, including lorazepam, oxazepam and flurazepam
  • Cocaine:
    • Cocaine or coke is a strong, addictive CNS stimulant, chemically an alkaloid made from the leaves of the coca plant
    • Cocaine salt form is most commonly abused through snorting (intranasal delivery) or by intravenous injection
    • Base form, also known as crack, is consumed as smoke after heating
    • Cocaine is metabolized to benzoylecgonine, norcocaine or ecgonine methyl ester and excreted in urine, mostly as benzoylecgonine that can be detectable for 1 - 3 days
    • Both oral fluid and urine samples can be tested for detection of cocaine or its metabolite benzoylecgonine; however, because of the short half life of cocaine, benzoylecgonine is the most common analyte measured for cocaine (J Appl Lab Med 2020;5:935)
    • Side effects of cocaine abuse cause heart attack, stroke, headache and seizures
    • Quantitative GC-MS detection in urine can identify cocaine and its metabolite benzoylecgonine with a positive cutoff of 50 ng/ml
  • Cannabinoids:
    • Cannabinoids are the products of the plant Cannabis sativa or indica and the most highly consumed drugs of abuse
    • Commonly known or available as marijuana, pot and weed; consumed as smoke
    • Consumption of cannabinoids results in euphoria, relaxation and mood changes, including psychosis and panic attacks
    • Marijuana withdrawal symptoms include anxiety, insomnia and anorexia
    • Major psychoactive component of cannabinoids is delta-9-tetrahydrocannabinol (THC), which gets deposited in the adipose tissue after consumption
    • THC is mainly metabolized to 11-hydroxy-delta-9-THC by the liver CYP450 enzymes
    • THC has a longer detection window ranging from 3 to 90 days, depending on the usage
    • Quantitative LC-MS / MS detects THC metabolite, 11-Nor-9-carboxy-THC, with cutoff concentration of 15 ng/ml
  • Opioids:
    • Opioids are a group of compounds that bind to the opioid receptors
    • Natural alkaloids opioids, also called opiates, are morphine and codeine and are derived from the opium plant
    • Other opioids include semisynthetic heroin, hydrocodone, oxycodone and synthetic opioids such as fentanyl, methadone and tramadol
    • Opioids are used as analgesics and are highly addictive, causing nausea, sedation, physical dependence and breathlessness
    • Opioid withdrawal symptoms include vomiting, diarrhea, muscle and joint pain, restlessness
    • Morphine is metabolized majorly to morphine-3-glucuronide and minorly to hydromorphone when used longterm
    • Immunoassay screening for opiates can detect morphine and codeine but not the semisynthetic and synthetic opioids
    • Quantitative LC-MS / MS detects hydrocodone, oxycodone and their metabolites, including morphine and codeine, with cutoff concentration of 20 ng/ml
  • Fentanyl:
    • Synthetic opioid that is 50 - 100 times more potent than morphine
    • Prescription drug for management of severe pain or postsurgery
    • Illicitly synthesized and sold as China Girl, China White and Dance Fever
    • Severe respiratory distress is a common display of fentanyl overdose
    • Half life of fentanyl in blood is 3 - 10 hours and in urine is 2 - 3 days
    • In a suspected case of fentanyl abuse or overdose, the urine opioid screening results will be negative and a targeted analysis of fentanyl testing is necessary (MMWR Morb Mortal Wkly Rep 2019;68:687)
    • Metabolized by CYP450 enzyme in a CYP3A4 mediated N-dealkylation to norfentanyl (major) and less than 1% to hydroxyfentanyl and hydroxynorfentanyl
    • Quantitative LC-MS / MS detects hydrocodone, oxycodone and their metabolites, including morphine and codeine, with cutoff concentration of 20 ng/ml
  • Phencyclidine (PCP):
    • Phencyclidine or phenylcyclohexyl piperidine (PCP) is a synthetic drug that was originally developed as an anesthetic and now is a Schedule II controlled substance
    • Mind altering drug; belongs to the class of hallucinogens and its recreational use has been increasing in recent years (J Med Toxicol 2015;11:321)
    • PCP is most commonly taken by smoking; street name is angel dust
    • Serious effects of PCP abuse include agitation, anxiety, coma and death (with high doses of more than 20 mg)
    • Quantitative LC-MS / MS detection cutoff for PCP is 10 ng/ml
Diagrams / tables

Contributed by Vishnu Amaram Samara, Ph.D.

Chemical structures of a few common drugs of abuse

Images hosted on other servers:

Benzodiazepine metabolic pathways

Amphetamine metabolic pathway

Cannabinoid metabolic pathway

Opioid metabolic pathways

General cutoff limit concentrations of common drug classes by immunoassay screening and LC-MS / MS quantitative confirmation
Drug class / metabolites
Immunoassay screening
typical cutoff limits
Quantitative cutoff
limits using LC-MS / MS
Board review style question #1
In highly suspected cases of drug abuse where the urine results are negative, the dilution of urine samples can be confirmed by measuring which of the following?

  1. Serum creatinine
  2. Serum electrolytes
  3. Urine creatinine
  4. Urine electrolytes
  5. Urine volume
Board review style answer #1
C. Urine creatinine. A random urine average creatinine concentration is 20 - 300 mg/dL and if the creatinine concentration is less than 20 mg/dL, the urine is diluted leading to negative drug results.

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