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5 Metabolism of Abused Drugs/Target of Immunoassay Antibodies

5 Metabolism of Abused Drugs/Target of Immunoassay Antibodies

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C H A P T E R 1 6:

D r ug s o f A b us e T e s t i n g

6-Acetylmorphine, which can be confirmed by gas chromatography/mass

spectrometric analysis (GC/MS), is considered as the marker compound for

heroin abuse. The majority of morphine is excreted in urine as morphine3-glucuronide. This metabolite is formed by conjugation in the liver by the

action of the liver enzyme uridine diphosphate glucuronosyltransferase.

Codeine is metabolized to morphine in liver, mostly by CYP2D6. Although

morphine is a stronger narcotic analgesic than codeine, morphine is poorly

absorbed from the stomach while codeine is easily absorbed after oral

administration. However, the conversion of codeine to morphine is essential

for pain relief. Almost 10% of the Caucasian population has a genetic polymorphism of CYP2D6 that makes the enzyme less active; these patients may

not get adequate pain relief during codeine therapy [4]. Hydromorphone is

also excreted in the urine, mostly in conjugated form, but a small part of free

hydromorphone can also be recovered in urine. Oxycodone is metabolized

to oxymorphone, which is then conjugated in liver. However, the antibody

used in opiate immunoassays only targets morphine. Therefore, the presence

of oxycodone in urine cannot usually be detected by opiate immunoassays

due to low cross-reactivity with the antibody.

Δ9-Tetrahydrocannabinol (marijuana, THC) is the most active component

(out of over 60 related compounds identified) of marijuana. THC is found

in various parts of the cannabis plant (Cannabis sativa), including flowers,

stems, and leaves. THC is rapidly oxidized by cytochrome P-450 enzymes to

the active metabolite, 11-hydroxy Δ9-tetrahydrocannabinol (11-OH-THC),

and the inactive metabolite, 11-nor-9-carboxy Δ9-tetrahydrocannabinol

(THC-COOH). In immunoassays for THC, the antibody recognizes the inactive metabolite THC-COOH.

Phencyclidine (PCP) undergoes extensive metabolism by liver cytochrome

P-450 enzymes (especially CYP3A4) into several hydroxy metabolites,

including cis-1-(1-phenyl-4-hydroxycyclohexyl) piperidine, trans-1-(1-phenyl4-hydroxycyclohexyl) piperidine, 1-(1-phenylcyclohexyl)-4-hydroxypiperidine, and 5-(1-phenylcyclohexylamino) pentanoic acid. The elimination

half-life of PCP varies significantly in humans (7 to 57 h; average 17 h).

Despite extensive metabolism of PCP, a significant amount of the parent drug

is also present in urine.

Barbiturates can be ultra-short-acting, short-acting, or long-acting (phenobarbital). Barbiturates are extensively metabolized. However, many barbiturate immunoassays use antibodies that recognize secobarbital. Although

there are more than 50 benzodiazepines, only about 15 are used in the U.S.

Benzodiazepines are also extensively metabolized. The antibody in many

benzodiazepine immunoassays targets oxazepam because it is a common

metabolite of diazepam and temazepam. Antibody targets of various

16.6 Immunoassays vs. GC/MS Cut-Off Concentrations

Table 16.3 Target Analytes in Immunoassays Used for Drugs of Abuse


Drugs of Abuse

Antibody Target








Methamphetamine or amphetamine


Phencyclidine (PCP)



Benzoylecgonine (metabolite)



6-Acetylmorphine (metabolite and marker of abuse)

11-Nor-9-carboxy Δ9-tetrahydrocannabinol (THCCOOH, metabolite)


Commonly oxazepam or nordiazepam

Commonly secobarbital

immunoassays used for drugs of abuse testing are summarized in

Table 16.3.



Immunoassays for various drugs have different cut-off concentrations as

mandated by SAMHSA guidelines. If the concentration of the drug is below

the cut-off concentration, the immunoassay test result is considered negative.

In workplace drug testing, a positive immunoassay test result must be confirmed by using a different analytical technique, preferably GC/MS, but the

confirmation concentration could be lower than the immunoassay screening

cut-off concentration. Immunoassay and GC/MS cut-off concentrations of

various drugs are listed in Table 16.4. Important points regarding the GC/MS

confirmation step for amphetamines as recommended by SAMHSA include:

If methamphetamine is confirmed by GC/MS, its metabolite

(amphetamine) must also be confirmed by GC/MS to at least a 100 ng/mL


This protocol ensures that no pseudoephedrine or ephedrine present in

the urine is converted into methamphetamine during the GC/MS

procedure as an artifact.

If the injector temperature in the GC is high, ephedrine/pseudoephedrine

may be thermally converted into methamphetamine.



C H A P T E R 1 6:

D r ug s o f A b us e T e s t i n g

Table 16.4 Immunoassay and GC/MS Confirmation Cut-Off

Concentrations for Various SAMHSA and Non-SAMHSA Drugs

Drug/Drug Class



GC-MS (ng/mL)





Cocaine metabolites























Usually 200 for

individual drugs

Usually 200 for

individual drugs








Non-SAMHSA Drugs










100 or 300



Immunoassays are subject to false positive test results. Amphetamine

immunoassays suffer from more interferences than any other immunoassays

used for screening of abused drugs in urine. Many over-the-counter cold and

cough medications containing ephedrine or pseudoephedrine can produce

false positive test results with amphetamine/methamphetamine immunoassays. Many sympathomimetic amines found in over-the-counter medications can also cause false positive test results. In addition, other drugs such

as bupropion (mostly metabolites), trazodone, labetalol, and doxepin can

also cause false positive test results (Table 16.5). Amphetamine and methamphetamine have optical isomers designated as d (1) for dextrorotatory and l

(2) for levorotatory. The d isomer (which is the abused isomer) is the

intended target of immunoassays. Ingestion of medications containing the l

isomer can cause false positive results. For example, Vickss inhaler contains

the active ingredient l-methamphetamine[5], and extensive use of this product can cause false positive results for immunoassay screening.

16.7 False Positive Immunoassay Test Results with Various Abused Drugs

Table 16.5 Most Commonly Encountered Drugs in False Positive Test Results Using

Immunoassays for Various Abused Drugs


Interfering DrugsT


Ephedrine, pseudoephedrine, phentermine, tyramine, methylphenidate, perazine, doxepin,


Oxaprozin, sertraline

Diphenhydramine, rifampin, dextromethorphan, verapamil, fluoroquinolones

Dextromethorphan, diphenhydramine, ibuprofen, imipramine, ketamine, meperidine,

thioridazine, tramadol

Non-steroidal antiinflammatory drugs, pantoprazole, efavirenz








These drugs are the most commonly encountered clinically, but this list does not provide names of all drugs that are known to

interfere with various immunoassays (as based on published literature). Please see any toxicology reference book for in-depth

information on this topic.


An emergency medical team responded at the residence of a

77-year-old man who had difficulty breathing. The patient

was transported to the emergency department and was

admitted. Approximately 12 h after admission he was unresponsive and died. His medical history included heart failure,

atrial flutter, and bronchial asthma. His urine screen was positive for amphetamine, and GC/MS confirmation was positive

for acetaminophen, nicotine, cotinine, caffeine, diltiazem,

doxylamine, and methamphetamine. When chiral analysis

was performed, the methamphetamine was identified as the

l-isomer, not the d-isomer. Further investigation revealed that

the decedent frequently used a Vicks inhaler for his bronchial

asthma, which led to the positive amphetamine screen as

well as the GC/MS confirmation [6].

Certain fluoroquinolone antibiotics can cause false positive test results with

opiate immunoassay screening. PCP is rarely abused today, but the dextromethorphan present in many over-the-counter cough mixtures can cause

false positive test results with PCP immunoassays. However, GC/MS confirmation is negative, indicating the absence of PCP in the urine specimen.

Studies indicate that non-steroidal antiinflammatory drugs can produce false

positive results in immunoassay screening [7]. Some of the drugs that can

cause false positive test results with immunoassays used for detecting various

drugs of abuse in urine are summarized in Table 16.5.


A 3-year-old girl was hospitalized due to behavioral disturbances of unknown origin. She was treated with niflumic

acid (including suppositories) five days prior to hospitalization. The urine toxicology screen was positive for cannabinoid

(marijuana), but her parents strongly denied any exposure to

marijuana. Another specimen from the same patient was analyzed using chromatographic techniques and no cannabinoid

was detected. The authors suspected that niflumic acid interfered with the immunoassay for cannabinoid and caused the

false positive test result [8].



C H A P T E R 1 6:

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Important points regarding false positive immunoassay test results include:

Amphetamine/methamphetamine immunoassay screening tests are most

commonly subject to interferences from over-the-counter cold

medications containing ephedrine/pseudoephedrine.

Although Vickss inhaler contains l-methamphetamine, which has less

cross-reactivity with amphetamine/methamphetamine immunoassays

that target d-methamphetamine, excessive use of Vickss inhaler can cause

false positive test results with both immunoassays and GC/MS

confirmations. Chiral derivatization is essential to resolve this issue

(it distinguishes the d-from the l-isomer).

Positive opiate test results may be observed due to therapy with

fluoroquinolone antibiotics, but GC/MS confirmation should be negative.

A common cause of positive PCP immunoassay screening results is the

presence of dextromethorphan in the specimen. GC/MS confirmation

should be negative.


Although false positive test results with immunoassays are more common,

false negative test results (where the drug was present in the specimen but

was not detected) can also be encountered during immunoassay screening

steps. Obviously, if the concentration of a particular drug is below the cut-off

concentration of the immunoassay, the test result should be negative. Major

reasons for false negative test results during immunoassay screenings include:

Drug concentration may be below the cut-off concentration. This is a

problem when detecting various benzodiazepines.

Cross-reactivity of a drug is poor with the antibody of the assay. The best

example of this is poor cross-reactivity of oxycodone with various opiate


The drug may not have been metabolized and appears in the urine. A

common example is a negative urine test for benzoylecgonine (cocaine

metabolite) in a patient with acute cocaine overdose.

Various benzodiazepines are common prescription drugs in the U.S. They are

widely abused. Physicians sometimes order urine drug tests in their patients

to ensure compliance. However, when using a 200 ng/mL cut-off concentration for benzodiazepine immunoassays, certain drugs may not be detected

after taking the recommended dosage due to low concentrations of the drug

in urine (in particular alprazolam, clonazepam, and lorazepam).

Clonazepam is metabolized to 7-aminoclonazepam. West et al. reported

that, when urine specimens collected from subjects taking clonazepam were

tested using the DRI benzodiazepine immunoassay at a 200 ng/mL cut-off,

16.8 False Negative Test Results

only 38 specimens out of 180 tested positive by the immunoassay (21% positive). However, using liquid chromatography combined with tandem mass

spectrometry (LC/MS/MS), 126 specimens out of 180 specimens tested positive (70% positive) when the detection limit of the LC/MS/MS assay was set

at 200 ng/mL, the same cut-off used by the DRI benzodiazepine assay. This

indicated poor detection capability of the benzodiazepine immunoassay for

clonazepam and its metabolite in urine. The authors concluded that the

200 ng/mL cut-off may not be adequate for monitoring patient compliance

with clonazepam therapy [9].

Opiate immunoassays usually utilize a morphine-specific antibody, and certain opioids cannot be detected by opiate immunoassays due to low crossreactivities. These opioids include:

Oxycodone and oxymorphone (keto-opioids).



Fentanyl and its analogs.


A 40-year-old man suffering from severe chronic migraine

attack was treated with oxycodone (20 mg dosage twice a

day). Although his pain was under control, he routinely called

the clinic stating that he had finished his medication faster

and needed a refill. Suspecting that the patient was selling

oxycodone on the street, a urine toxicology test was ordered

(it was negative for opiates) and the patient was dismissed

from the pain clinic. On his behalf, a family member

contacted a toxicologist who informed that oxycodone can

cause a false negative test result in a urine opiate drug screen

due to poor cross-reactivity of oxycodone with the antibody

used in certain opiate assays. An aliquot of the original urine

specimen was re-tested using GC/MS and the presence of

oxycodone at 1,124 ng/mL was confirmed. This value confirmed that the patient was compliant with his oxycodone

usage [10].

Cocaine overdose can be fatal. Sometimes the victim dies from cocaine overdose, but a urine toxicology screen for the cocaine metabolite benzoylecgonine can be negative because death can occur quickly from cocaine

overdose and sufficient time has not passed for the metabolite to be excreted

in the urine in enough concentration to trigger a positive response.


A 44-year-old Caucasian man was found dead in his apartment and police transported the body to the coroner’s office.

The urine toxicology screen using immunoassays (EMIT

assays) was negative for benzoylecgonine (cocaine metabolite) using a 300 ng/mL cut-off concentration. However, GC/

MS analysis of a post-mortem heart blood specimen showed

a very high cocaine concentration of 18,330 ng/mL, and it

was concluded that the cause of death was cocaine overdose [11].



C H A P T E R 1 6:

D r ug s o f A b us e T e s t i n g



Although urine specimens can be directly used for immunoassay analysis for

various abused drugs, a GC/MS confirmation test requires extraction of drugs

from the urine specimen using organic solvents or solid-phase extraction

(using BondElute or another solid-phase extraction column). In general, hexane, acetone, chloroform, methanol, ethyl acetate, 1-chlorobutane, or

dichloromethane are typically used for extraction. Some drugs, such as

amphetamine and methamphetamine, can be extracted directly from the

urine specimen using an organic solvent. However, a drug such as morphine

is present in urine as a glucuronide conjugate, which is water-soluble.

Therefore, prior to extraction, it is important to break this conjugate with

acid or alkali hydrolysis. It is also possible to cleave the conjugate by using

beta-glucuronidase enzyme. Although acid or alkali hydrolysis can be conducted by heating specimens for 30 min, usually several hours or more are

needed for enzymatic hydrolysis; enzymatic hydrolysis is a gentler method.

Derivatization is a chemical reaction where a polar group in a molecule (e.g.

a carboxyl or hydroxyl group) is chemically converted to a non-polar group

in order to make the molecule volatile so that it can be analyzed by GC/MS.

In general, molecules containing a carboxylic acid (ÀCOOH, e.g. THCCOOH and benzoylecgonine), hydroxyl (ÀOH, e.g. morphine), or primary

or secondary amine (such as amphetamine and methamphetamine) require

derivatization. Usually amphetamine and methamphetamine are analyzed as

trifluoroacetyl or pentafluoropropyl derivatives, although many other derivatization methods have been described in the literature. Benzoylecgonine is

usually analyzed as a trimethylsilyl or acetyl derivative. Codeine and morphine can also be analyzed as a trimethylsilyl derivative, while phencyclidine

can be analyzed without derivatization.



As expected, if a person is taking codeine for pain control, the opiate test

should be positive. Similarly, a positive benzodiazepine test result should be

expected if a person is taking a prescription medication of the benzodiazepine

class. Amphetamine and methamphetamine, as well as their analogs, are used

in treating attention deficit disorders, and, as expected, use of such drugs could

lead to a positive amphetamine/methamphetamine drug test result. Although

not employed frequently, cocaine is still used as a local anesthetic in ENT surgery, and a patient may test positive for cocaine metabolites 1À2 days after

the procedure. Poppy seeds contain both codeine and morphine. Therefore,

16.10 Analytical True Positive Due to Use of Prescription Drugs and Other Factors

eating foods containing poppy seeds can cause false positive opiate test results.

In order to circumvent this problem, the cut-off concentration of opiate was

be increased to 2,000 ng/mL from the original cut-off level of 300 ng/mL in

federal drug testing programs. However, some private employers still use the

300 ng/mL cut-off concentration for opiate testing in their workplace drug

testing protocols. Eating poppy seed-containing foods prior to drug testing

(1À2 days) can cause a positive opiate test result if the 300 ng/mL cut-off concentration is used. Hemp oil is prepared from hemp seed, which may contain

trace amounts of cannabinoid (marijuana). However, ingesting hemp oil

should not cause a positive marijuana test result at the 50 ng/mL cut-off level.

Analytical true positive test results due to the use of prescription medications

or other factors are summarized in Table 16.6.


A 54-year-old Caucasian male was involved in a physical

altercation and suffered a broken nose. Three days later a surgical procedure was performed to repair his nose and he was

released from the hospital later that day with a prescription of

Percocet (oxycodone, 5 mg; and acetaminophen, 325 mg) for

pain relief. He took one tablet at 4 PM and went to bed, but

at 8 PM when his wife tried to wake him, he was unconscious. She called the emergency medical team, and, despite

performing CPR, he was pronounced dead at the scene at

8:40 PM. Toxicological analysis revealed the presence of

cocaine (48 ng/mL) and benzoylecgonine (482 ng/mL) in his

urine specimen, but no cocaine or its metabolite was

detected in the subclavian blood specimen. In addition, oxycodone (73 ng/mL) was present in his blood as expected.

Upon detection of cocaine and its major metabolite in his

urine specimen, it was initially suspected that the subject

had abused illicit cocaine, but his family denied any drug

abuse by the deceased. It was later revealed that cocaine

was used during his nasal surgery as a local anesthetic,

which explained the presence of both cocaine and its metabolite (benzoylecgonine) in his urine specimen: it was from

medical use of cocaine [12].

Table 16.6 Analytical Positive Drug Test Results (GC/MS Confirmation) Due to Use of

Prescription Medication and Other Factors

Positive Drug Test

Prescription Medication


Adderall (contains amphetamine), lisdexamfetamine, desoxyn (contains methamphetamine),

clobenzorex, ethyl amphetamine, mefenorex, benzphetamine, famprofazone.

Cocaine use (as topical anesthetic) during ENT procedure. Drinking Inca tea or Coca de

Mate tea (South American teas) prepared from coca leaves.

Short-and long-acting barbiturates.

Short-and long-acting benzodiazepines.

Codeine, morphine, oxymorphone, hydrocodone, hydromorphone, oxycodone. Eating

poppy-seed-containing food.


Marinol (synthetic marijuana); drinking hemp oil should not cause a positive test at 50 ng/mL












C H A P T E R 1 6:

D r ug s o f A b us e T e s t i n g

Important points regarding analytical true positives include:

Prescription use of various drugs can cause analytical true positive test


Positive opiate test results can occur in a person who eats poppy seedcontaining food prior to drug testing, especially if the private employer

still uses a 300 ng/mL cut-off concentration for opiates.

Drinking coca tea (Health Inca tea, Inca tea, or Mate de Coca) can cause

a positive cocaine test result because these teas originate from South

America and are prepared from coca leaves.

Use of cocaine as a local anesthetic during ENT surgery can cause positive

cocaine test results 1À2 days after surgery.

Ingestion of hemp oil or passive inhalation of marijuana should not

cause positive marijuana test results.



People try to beat workplace drug tests. Usually people drink detoxifying

agents purchased off the Internet. Contrary to the claim that these agents can

purge drugs out of circulation, these products contain only diuretics such as

caffeine or hydrochlorothiazide, and if a person taking such products also

drinks plenty of water (as suggested in the package insert), it produces

diluted urine. Because specimen integrity checks (pH, creatinine, specific

gravity, and temperature) are routinely used in all urine specimens collected

for workplace drug testing, low creatinine (below 20 mg/dL) indicates that

urine is diluted and no further analysis is conducted. Specimen adulteration

is considered as a “refuse to test” and the person is denied employment.

Various household chemicals such as table salt (sodium chloride), vinegar,

liquid soap, liquid laundry bleach, sodium bicarbonate (baking soda), and

lemon juice are added to urine after collection in order to beat drug tests.

Although some of these products can invalidate the immunoassay screening

step, all of them can be detected indirectly by specimen integrity testing, and

thus the specimen will be rejected for further testing due to adulteration.

Although Visines Eye Drops significantly interfere with enzyme multiplied

immunoassay technique (EMIT) assays and other immunoassays, the presence of Visine Eye Drops in an adulterated specimen cannot be detected by

routine specimen integrity testing.

More recently, several products have become available through the Internet

for use as in vitro adulterants. These products usually contain strong oxidizing agents such as potassium nitrite, pyridinium chlorochromate, glutaraldehyde, and Stealth (hydrogen peroxide and peroxidase). These adulterants

16.12 Miscellaneous Issues in Drugs of Abuse Testing

cannot be detected by routine specimen integrity testing, and such products

can mask tests of marijuana metabolites not only in the immunoassay

screening step, but also in the GC/MS confirmation step because THCCOOH is slowly oxidized by these products. However, spot tests and special

urine dipstick analysis (AdultaCheck 6 or 10, Intect 7, etc.) are available for

detecting these adulterants [13].

Sometimes pain management patients sell their prescribed narcotic analgesics

on the street for more money. In addition, they may go to various doctors

(doctor shopping) to obtain extra prescriptions for narcotics. Drug testing in

urine is often conducted to ensure they are compliant with therapy. These

people want their urine drug test to be positive for the prescription drug and

often grind up the tablet to produce a fine powder that easily dissolves in

the urine. However, during analysis, high quantities of the parent drug are

recovered in the urine as expected, but no metabolite is detected, indicating

that these patients are attempting to cheat on their drug test. Important

points regarding urine adulteration:

If household chemicals are used as urinary adulterants, specimen

integrity testing (pH, creatinine, specific gravity, and temperature) should

be able to identify such adulterants.

The presence of Visines Eye Drops in adulterated urine cannot be

determined by specimen integrity testing.

The presence of adulterants purchased off the Internet, such as potassium

nitrite, glutaraldehyde, pyridinium chlorochromate, and Stealth, cannot

be detected by specimen integrity testing. However, spot tests and special

urine dipsticks (AdultaCheck 6 or 10, Intect 7) can be used for detection.

The presence of an adulterant in a urine specimen subject to workplace

drug testing is considered as a “refusal to test” and the person may be

denied the job (no further testing is usually conducted).



Lysergic acid diethylamide (LSD) was widely abused in the 1960s and 1970s,

and in some U.S. cities this drug is reappearing at rave parties. There is a

commercially available immunoassay for LSD testing. The rave party drug

3,4-methylenedioxymethamphetamine (MDMA) can be detected by some

amphetamine immunoassays and also by using special immunoassays that

detect both MDMA and amphetamine. However, other rave party drugs like

ketamine and gamma-hydroxybutyric acid cannot be detected by routine toxicology testing, although reference toxicology laboratories offer testing for

such drugs. Many designer drugs cannot be detected by routine toxicological



C H A P T E R 1 6:

D r ug s o f A b us e T e s t i n g

analysis, including the new designer drugs spice, K2 (synthetic marijuana),

and bath salts (synthetic amphetamine analogs).

As mentioned earlier, over 90% of drug testing is conducted using urine specimens. Hair testing provides a larger window of detection (up to six

months), while saliva (oral fluid) testing can identify impairment due to

recent abuse of a drug. In European countries, oral fluid testing is gaining

popularity for identifying impaired drivers. In addition, sweat testing can be

used for continuous monitoring of a drug in a person undergoing drug



Urine drug testing represents approximately 90% of all drug testing. Although

initial immunoassay screening results using urine specimens may not be

confirmed by gas chromatography/mass spectrometry (GC/MS) in medical drug

testing, GC/MS confirmation (or confirmation by another method) is mandatory in

legal drug testing. In addition, in legal drug testing the medical review officer

(MRO) must review and certify the positive drug test result, thus confirming that

there is no alternative explanation for a positive drug test. Moreover, a chain of

custody must be maintained.

Currently, the Substance Abuse and Mental Health Services Administration

(SAMHSA) have guidelines for federal workplace drug testing. SAMHSA

guidelines require testing for five abused drugs, including amphetamines

(amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine;

MDMA, ecstasy), cocaine (tested as benzoylecgonine), opiates, marijuana (tested

as marijuana metabolites), and phencyclidine (PCP).

In urine, most drugs can be detected for only 2À3 days after abuse, except for

PCP (14 days) and marijuana (up to 30 days, from chronic abuse).

Amphetamine/methamphetamine immunoassay screening tests are subject to

interferences, most commonly from over-the-counter cold medications containing


Although Vicks Inhaler contains l-methamphetamine, which has less

cross-reactivity with amphetamine/methamphetamine immunoassays

(d-methamphetamine is abused and measured by amphetamine/

methamphetamine immunoassays), excessive use of Vicks Inhaler can cause false

positive test results with both immunoassay and GC/MS confirmations. Chiral

derivatization is essential to resolve this issue.

Cocaine abuse is detected by the presence of benzoylecgonine (inactive

metabolite of cocaine) in urine.

Abuse of cocaine and ethanol (alcohol) is dangerous because cocaethylene is

formed due to the interaction between ethanol and benzoylecgonine;

cocaethylene is an active metabolite with a long half-life. Deaths have been

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