In 2006, deaths caused by poisoning accounted for 20.8% of all deaths caused by injury in the United States, surpassing the percentage of deaths caused by firearms (17.3%) and second only to deaths caused by motor vehicle collisions (24.4%).  Given that an element of intoxication is involved in many motor vehicle collisions, the vital role toxicologic analysis plays in modern death investigation becomes clear.
Deaths related to drug overdoses in celebrities have brought mass media attention to the drug abuse pandemic. Whereas historically drugs such as heroin and cocaine have been considered the "dangerous" drugs, in recent years, prescription drug abuse has far surpassed "illegal" drugs as agents of lethal drug toxicity. This trend is expected to continue.
Entire textbooks have been written on forensic toxicology and individual drugs and chemicals that can cause death. This article highlights aspects not necessarily found in general textbooks. Discussions of common classes of drugs and other poisonous substances can be found at Medscape Reference, as listed in the Further Reading section.
The image below depicts the scene of a death caused by drug overdose.
Toxicologic analysis is applied analytical chemistry; modern toxicologic analysis depends upon screening and confirmatory tests. Screening tests are typically performed with commercial kits that contain antibodies directed toward common drugs of abuse. If this screening test is negative, then the decedent is usually considered negative for an intoxicating substance. If the screening test is positive, then that positive result must be confirmed, typically with gas chromatography/mass spectrometry (GC/MS).
GC/MS analysis allows separation of compounds based on their retention time within a chromatography column and identification of each compound by the characteristic fragments into which a given chemical is broken following ionization of the compound. (A concise account of the technique of GC/MS is available here.) Over the years, technologic advances in electronics and detectors have allowed GC/MS to detect ever smaller concentrations of compounds, as has the addition of other analytical techniques, such as liquid chromatography.
In general, screening tests can be performed quickly, but they provide only a qualitative result (eg, a substance is or is not present). Confirmatory testing usually takes longer, but it provides an actual concentration of the substance in the body fluid analyzed.
As mentioned in the Introduction section, poisonings account for some 20% of all deaths caused by injury in the United States; these include both intoxication from abuse of illicit drugs and deaths resulting from a consequence of medication taken as medical therapy.  The 20-21% figure only accounts for deaths caused by intoxication and does not include cases in which an intoxicant was found that did not cause death. Several medical examiners' offices that routinely test for alcohol and drugs of abuse report finding some substance on toxicologic analysis in at least 50% of their cases. 
Overview of the Entity
The Introduction and Epidemiology sections have both mentioned that drugs are found in 50% of forensic autopsies (when tested) and that drugs or medications are responsible for causing or contributing to death in over 20% of deaths unrelated to natural causes in the United States. The prevalence of drug use is reiterated here to emphasize the vital role that toxicologic analysis plays in autopsy pathology.
Blood, urine, bile, ocular fluid, gastric contents, liver, and brain tissue can all be useful specimens. Peripheral blood (femoral or subclavian) specimens are optimal for postmortem toxicologic quantification; urine is the primary body fluid used for drug screening. Specimens need not necessarily be tested automatically, but the best practice is to at least collect and hold the specimens until completion of the autopsy report and death certificate. Sometimes, additional history does not become known until after the body is released, which is then too late to collect samples.
Indications for the Procedure
Based on the prevalence of substances within the population of decedents examined by forensic pathologists, simply dying in circumstances that would bring one's body to the medical examiner's office for investigation is sufficient indication to warrant toxicologic analysis.  Nevertheless, factors such as cost or a prolonged lag in receiving toxicologic results can make it impractical to perform a thorough analysis on every case. History then becomes the best guide to determining when and what tests to order.
Cases in which a history or evidence of alcohol or drug abuse exists certainly merit toxicologic analysis, as do cases for which no visible cause of death can be found at autopsy. Ordering toxicologic analysis in all homicides and accidents is also wise, as questions concerning the presence or absence of intoxicating substances are likely, not only from relatives of the decedent but in any legal proceeding that may later arise. Such questions may arise in suicides as well, and 3 separate studies within the United States have reported that 68-73% of suicides have some substance detected in the body on toxicologic analysis. 
The only manner of death not yet discussed is cases in which death appears to be due to some natural cause. Certainly some of these cases do not seem to need toxicologic analysis, but even here a pathologist cannot always anticipate questions that may later arise, particularly when an unexpected civil suit is brought to the pathologist's attention. One approach is to perform simple screening assays on apparently natural deaths to quickly rule out the presence of substances that may have contributed to death (eg, cocaine may trigger a myocardial infarct or cerebrovascular accident). Pathologists rarely regret ordering toxicologic analysis on a case; regret usually comes from cases in which no toxicologic testing was performed, the specimens have been discarded, and only then do questions come from family and their attorneys.
History and scene investigation, powerful as they are, are not infallible guides in ordering toxicologic analysis in a medical examiner population (see Scene Findings, below). (Scene investigation is discussed in detail in a separate article.) Gruszecki et al reported that history and scene findings detected only 63% of all cases in which intoxicating substances were found; hence, the authors' suggestion that dying in circumstances that bring a body to the medical examiner for investigation is sufficient in and of itself to warrant toxicologic analysis. 
These agents are a family (or class) of drugs used as antianxiety agents. Often abused in conjunction with opiates, benzodiazepines can potentiate the effects of opiates. Diazepam (Valium) and alprazolam (Xanax) are members of this family.
Cooker spoons are spoons used for melting a substance for injecting. The bottom of the bowl is heated, usually with a lighter, until the substance in the bowl melts; as a result, the bottom of the bowl is usually coated with soot.
This is a device used for smoking crack cocaine. Crack pipes are generally a short length of a hollow cylinder, such as a glass or metal tube. The ends are charred, and one end often contains a tuft of copper mesh (See the image below). The ends may be wrapped in electrical tape to insulate the fingers and lips from the hot pipe.
Date rape drugs
These drugs include any of several sedative hypnotics, such as gamma hydroxybutyrate (GHB) or flunitrazepam Rohypnol), that can induce hypotonia and amnesia when ingested. GHB is endogenous in mammals at nanomolar concentrations.
Any substance that depresses or suppresses the normal function of the central nervous system is a depressant (eg, alcohol, opiates, and benzodiazepines).
Drugs that have been altered chemically so that the substance falls outside of a list of substances that are legally proscribed are known as designer drugs. The chemical side groups of amphetamines, for example, can be altered slightly while retaining the stimulant properties characteristic of amphetamines. Similar chemical changes can be made to cannabinoids.
This is an initial test on a body fluid that is performed to look for the presence of classes of commonly abused drugs. Screens often rely upon antibodies directed against specific drug classes and some specific drugs. A drug screen is qualitative only and is subject to false positives.
Excited delirium refers to an agitated state that may or may not be associated with the use of stimulant drugs. This condition is typically manifested as rash, abnormal behavior, often associated with delusion or paranoia and extraordinary strength. Hyperthermia is common.
This is the practice of inhaling volatile compounds to experience a "high."
A needle track is a line of needle marks or scars left on the skin along the course of a vein. Such tracks are often on the arms but can also be found in sites generally hidden from public view, as seen in the images below.
Opioids are also known as narcotics, the family or class of drugs that are narcotic analgesics, exemplified by the prototype morphine. Natural and synthetic analogues of morphine exist, and all have the potential for abuse. Heroin, oxycodone, methadone, and fentanyl are members of this family.
Any drug used to induce relaxation or anesthesia is a sedative; these agents depress the central nervous system. Benzodiazepines, opiates, and alcohol all have sedative properties.
Any substance that stimulates or increase the normal function of the central nervous system is a stimulant (eg, cocaine and amphetamines). Caffeine is a mild stimulant.
(See also the Pill Identifier tool.)
The presence of drugs or drug paraphernalia at a scene alerts the death investigation team to the possibility of an overdose. Drug evidence may be marijuana, pills, crack cocaine (as in the image below), or powdery material, or the containers these drugs were packaged in, such as plastic baggies, medication containers, or bottles for liquids.
Paraphernalia includes articles used for selling (eg, pocket scale), injecting (eg, syringes, lighters, cooker spoon with soot on bottom of bowl; see the first image below), smoking (eg, roach clips, bong, lighter, crack pipe (as shown in the second image below), or snorting (eg, razor blade, card, mirror) drugs. Of course, family or friends may hide or dispose of this evidence before the arrival of the death investigator. Likewise, the decedent may have hidden his stash -- for example, by placing a rock of crack cocaine inside a partially empty pack of cigarettes.
Additional history may come from examination of writings of the decedent in a diary or calendar, from examination of websites visited on the decedent's computer, or from examination of e-mail messages, text messages, or information within a social networking site. When computer evidence is found, it should be recorded in some way such that if the site is later changed, the information will not be lost to the forensic pathologist.
Given the widespread nature of prescription drug abuse, all medications found on scene should be carefully documented.  Pills should be counted to establish appropriate usage patterns. Over-the-counter (OTC) medications present at the scene should also be recorded -- some of these medications, such as acetaminophen, can have potentially lethal consequences if taken inappropriately.
Trace evidence may be found at the scene or when examining the body in the morgue. Paraphernalia described in the Scene Findings section can be found within pockets of a decedent's clothing or in belongings. Paraphernalia or drugs are often hidden, and whoever looks through pockets must be careful to avoid a stab from a needle on a syringe or a cut from a broken crack pipe. Long forceps or surgical clamps are useful tools for looking through pockets rather than using a hand to reach into the pocket. Evidence can be hidden in any significant crease in the skin including under a breast, in the intergluteal cleft (such as in the image below), or simply within a fold of fat. Evidence may also be found in any body cavity (eg, within the vagina or rectum).
A crack pipe or a syringe likely contains residue from the drugs used. If deemed necessary, washings of paraphernalia can be tested for drugs via gas chromatography/mass spectrometry (GC/MS), but it is important to remember that the amount of drug in such washings may be much greater than the amount of drug extracted from a blood sample. This results in a potential technical hazard for the laboratory. If enough drug is present, it can overwhelm the binding sites on a chromatography column, and subsequent slow elution of drug from the column can then contaminate subsequent samples. The column must be washed until clean after confirming the presence of any drugs.
Gross Examination and Findings
Gross examination may reveal evidence of drug abuse on either external or internal examination. Drugs or drug paraphernalia may be found during examination of the clothing or tucked between clothing and the body, such as in underwear or within the cup of a bra. Examination of the body itself may reveal needle marks or scarred needle tracks, as in the first image below. These marks are often on the arms but may be found elsewhere. In rare cases, the needle mark is in a specific location, generally hidden from public view, where the decedent habitually injected drugs, as in the second image below.
Internal examination may reveal pills or chalky white material within the stomach, particularly in a suicidal overdose. Usually, however, the pills have dissolved completely and are no longer evident, even when toxicologic analysis reveals a lethal concentration of some drug taken by mouth. In other words, the absence of pills in the stomach does not rule out a suicidal drug overdose.
Various organ systems can be affected by drug abuse at the gross level. For example, massive hepatic necrosis is commonly seen following acetaminophen toxicity (see the images below), endocarditis may involve cardiac valves if intravenous drug abusers are not using sterile technique, and cerebrovascular accidents and myocardial infarcts may be seen in the setting of stimulant use. Other changes may be seen at the microscopic level in the brain, lungs, heart, kidney, liver, and skin.
Forensic pathologists are familiar with the practice of smuggling drugs within the bodies of people entering the United States, a process reported as early as 1975.  Those who smuggle drugs in this way are called body packers or mules, and these people are at risk for sudden death from a massive overdose if one or more packets should the drugs leak. 
A variant of this sort of death can occur when an individual swallows drugs, package and all, to try to avoid discovery of the drugs when confronted by the police. Death can occur from massive intoxication, but it can also occur if the decedent aspirates the evidence rather than swallowing it (see the image below). The findings in such a case can be subtle; if the drug was wrapped in a small portion of plastic wrap, only a diligent search of gastric contents will reveal the colorless piece of plastic.
Vomiting and aspirating gastric contents into the airways or lungs is not uncommon for persons dying of drug toxicity. Remember that although terminal aspiration may have occurred, the underlying cause of death is drug toxicity and, in most cases, this will be an accidental manner of death. Similarly, pulmonary edema and anoxic encephalopathy are commonly seen following drug intoxication. These findings are not the underlying cause of death and do not result in a natural manner of death.
If the pathologist wishes to document a needle track mark microscopically as well as grossly, then an incision is made immediately to one side of the vein with the track mark. Extravasated blood from the venipuncture may be visible in the soft tissue adjacent to the vein. A portion of the vein may then be dissected out of the body, fixed, and submitted for histologic examination. The best view comes from a section taken perpendicular to the long axis of the vein. Microscopic examination typically shows scarring around the vein, foreign body giant cells, and, upon polarization, birefringent material such as crystals or fibers (see the image below).
Special Autopsy Procedures
From a medical point of view, collecting and retaining specimens for potential toxicologic analysis is always appropriate in every autopsy that is undertaken to determine the cause of a person's death. Thorough specimen collection is possible in examinations mandated by law, but hospital autopsies are authorized by the permission of the decedent's next-of-kin. Therefore, the discussion below must be tempered, in hospital practice, by abiding by the restrictions stated in the autopsy permit.
Blood obtained from a peripheral vessel is the preferred blood specimen for toxicologic analysis, as the concentration of compounds in blood from the heart may be altered after death by redistribution of blood from the lungs or liver.  Some authors claim that blood from a femoral or iliac vein is least susceptible to contamination from the liver when the vein is first occluded by a tie or clamp,  but others report that ligation of the vein has no significant effect on the blood sample.  Even authors who advocate ligation of the peripheral vein before obtaining blood acknowledge that such procedures are sometimes impractical.  The worst mistake, of course, is to have no sample at all. At least some of the collected blood should be stored in a gray-top tube containing sodium fluoride.
When available, urine should be obtained from every autopsy, because it is ideally suited for rapid screening assays. Vitreous fluid can be screened for drugs and ethanol as can cerebrospinal fluid and bile. Depending on the case, vitreous fluid may be stored in a red-top tube (if analysis for electrolytes is being considered) or a gray-top tube (if drug screening may be performed) (forensic vitreous analysis is discussed in detail in a separate article.) Many medical examiner offices also routinely retain liver, brain, bile, and gastric contents for toxicologic analysis if needed. Splenic tissue and skeletal muscle may be used in decomposed bodies. Subdural hematomas should be sampled if present; they may contain drugs or alcohols that have since been metabolized in the peripheral blood.
If an individual was evaluated at a hospital before death, then they likely had blood drawn for tests. This perimortem blood is a precious, irreplaceable resource for toxicologic analysis and should be routinely obtained as part of the death investigation.  Blood obtained at the hospital would not be subject to postmortem redistribution the way that blood obtained at autopsy is. Hospital pathology laboratories hold blood only for several days, so requesting that the laboratory hold the sample as soon as investigation of the death begins is important. A sample of blood may be retained in the blood bank longer than elsewhere in the laboratory.
The brain can be an especially useful matrix for toxicologic analysis; this organ is little affected by postmortem redistribution of drugs.  Furthermore, the brain, which is fatty and sequestered both by its anatomic location and by the blood-brain barrier, can harbor a drug longer than other matrices.  Thus, the brain may be the only matrix positive for cocaine in a case in which a pathologist suspects a drug of abuse, such as cocaine in a young person who has died from a hypertensive bleed in the basal ganglia. Hair analysis can be used in the same sort of way.  The brain can also be used for molecular analysis in cases of excited delirium. 
Some substances, such as ethanol, are stable after death and require no special handling. Cocaine, on the other hand, is notoriously unstable, undergoing both enzyme-mediated and spontaneous hydrolysis even after death. The enzyme-mediated hydrolysis of cocaine is inhibited by fluoride and by cold.  Given the frequent presence of cocaine in forensic practice, forensic pathologists use fluoride as an anticoagulant and refrigerate toxicologic samples. (Sodium fluoride is in gray-top tubes; it also inhibits in vitro glycolysis in blood samples.) Refrigeration retards other unwanted chemical reactions as well. Although ethanol is stable after death, one does not want samples to putrefy, allowing bacteria to produce additional ethanol.
Some individuals enjoy the intoxication brought on by inhaling volatile fumes, such as gasoline, toluene, or halogenated hydrocarbons, a process commonly called huffing. When confronted with such a case, the pathologist must make certain to obtain and save specimens in a way that minimizes loss of these volatile compounds to evaporation before analysis. Samples of the usual matrices (blood, urine, vitreous humor, bile, liver, and brain, if available) should be saved, and, if desired, samples of lung tissue or gas aspirated from the trachea can also be saved and analyzed.
The solid and liquid samples should be placed in airtight, nonreactive containers, and the containers should be as full as possible to reduce the head space available within the specimen container, thus minimizing loss of the volatile compound when the container is opened for analysis.  Glass specimen tubes are nonreactive and readily available, but toluene can be absorbed by rubber; so, if possible, insert a sheet of aluminum foil between the specimen and the stopper before stopping the tube, especially for samples of solid tissue that require removal of the stopper.  (This is easier than it might seem; first, fit the foil tightly around the base of the stopper, and then insert the stopper into the tube.)
Volatile compounds are less volatile at lower temperatures; thus, the specimens should be refrigerated promptly and kept cool until analysis.  For any case in which unusual steps are necessary, personal communication with the toxicology laboratory that will perform the analysis will help assure that the specimens are collected, stored, transferred, and analyzed correctly. 
Actual drugs found at postmortem examination, whether in property or during internal examination, require special handling. With illicit drugs, the handling may be to transfer the evidence to a police officer or to a police drug laboratory, with an appropriate form documenting transfer of this evidence. Some drugs, such as opioids, have potential for abuse even though they may be licit. If such drugs are held at the coroner's or medical examiner's office, they should be held as securely as any other evidence, such that tampering would be evident. When the time comes to dispose of such drugs, disposal is best done in some way that is above reproach -- for example, in the presence of witnesses in the office -- and the disposal should be documented in the office records.
If the examination and analysis of drugs or other evidence may have eventual importance in a legal proceeding, then the transfer of items from the custody of one person to another must be documented in a way that is acceptable in court. This documentation is called the chain of evidence or chain of custody. A chain of evidence is used in court to show who had control of the item or specimen in question at all times. This is necessary, because United States law states that anyone on trial has the constitutional right to question his or her accusers about the circumstances of the trial.
If no chain of custody is documented, or if a link in the chain is missing, then it may not be possible to satisfy a jury that the specimen was handled properly, and thus the item may be excluded as evidence in a trial. The chain of custody paper trail describes the item and lists the names (with signatures), dates, times, and places when the item changed hands. A fuller discussion is available in the book Pathology and Law. 
Histology and Microscopic Examination and Findings
In addition to the findings seen in association with needle track marks, as discussed in the Special Dissections section, microscopic examination can show features of intravenous drug abuse in internal organs. The lungs are particularly apt to contain birefringent crystalline material, as drugs and insoluble material injected intravenously must pass first through the pulmonary circuit, where the pulmonary capillaries act as a filter for debris (see the first image below). In some cases, crystals may be seen in the liver in addition to the lungs. When present, crystals in the liver are in the connective tissue of the triads (see the second image below). Not everyone who abuses drugs intravenously, however, has birefringent material in either of these organs.
Alcoholics sometimes consume ethylene glycol, which produces an anion gap. Ethylene glycol is converted to oxalic acid in the body, and with time, this acid is deposited as birefringent oxalate crystals in the renal tubules (see the image below). A forensic pathologist should routinely screen for these crystals when examining histologic sections of a kidney, especially if no vitreous chemistry has been performed. The yield is low, but when present, these oxalate crystals may be the only sign alerting the pathologist to tell the toxicology laboratory to test specifically for ethylene glycol. Ethylene glycol is not very volatile, hence its usefulness as antifreeze, but as a consequence of its low volatility, ethylene glycol is not found in routine toxicologic screens for volatile compounds, such as ethanol or acetone. Ethylene glycol must be specifically sought.
Other histologic findings seen in drug abusers includes aggregates of hemosiderin around cerebral vessels and fibrointimal hyperplasia of coronary arterioles in chronic stimulant users, bacterial endocarditis in intravenous drug abusers, hepatic necrosis and steatosis following toxicity with acetaminophen and other substances (see the images below), and deep tissue abscess formation at injection sites.
Photography and Documentation
Needle marks, track marks, and illicit substances found during examination all deserve photographs. Weighing illicit drugs is also wise, as this weight both quantifies the amount of drug and records how much drug was present should questions later arise about the amount of drug remaining. In cases of ingested drug overdoses, the gastric contents should be measured and collected to facilitate calculation of the amount of drugs swallowed.
Ancillary and Adjunctive Studies
Toxicologic tests for substances commonly found are easily performed, as such tests are routine. Sometimes, however, an unusual substance requires unusual measures. Sending samples of a substance rarely abused in a given region to a reference laboratory twice a year may be more economical than for a local toxicology laboratory to buy a machine dedicated solely to a test that is seldom needed.
More rarely still, the pathologist and toxicologist may need to create a new means to test for a substance that is suspected in a given case. For example, the book Final Exit offers techniques for committing suicide, one of which is to place one's head into an airtight bag filled with helium from a hose connected to a helium canister.  Recognition of the cause of death in such a case is simple enough, if the bag, hose, and canister remain in place, but toxicologic analysis for helium requires alteration of the normal procedure for gas chromatography, because helium is typically used as the carrier gas. Auwaerter et al have reported a procedure for detecting helium in such a case by using nitrogen as the carrier gas. 
Other cases have been reported regarding the development of a new analytical procedure to assess a given case.  When faced with a unique compound, communication between the pathologist and the toxicologist is critically important so that both parties know what is possible and can plan how to proceed to best evaluate a given case.
See also Adjuncts to the Forensic Autopsy.
Interpretation of concentrations of drugs, whether licit or illicit, is properly made from blood or solid organ concentrations determined and confirmed by gas chromatography/mass spectrometry (GC/MS) within the context of the circumstances that surrounded death.  By itself, a positive screening test of urine, or any other matrix for that matter, is insufficient to conclusively prove use of a drug by the decedent, although it may strongly suggest recent use and can provide valuable information when taken in concert with the circumstances of death.
Further, screening tests (such as immunoassays) do not provide concentrations for any class of compounds they detect -- they are purely qualitative. Sometimes, however, no specimen is available for confirmation of screening results, and quantification of drug concentrations in the blood at the time that an injury or overdose happened is not possible. An example of such a scenario occurs when an individual with a positive drug screen upon admission lingers in a coma for over 1 week in a hospital or extended care facility before dying. In these cases, although a drug screen performed on urine detected some intoxicating substance, no blood remains from the time of admission for quantification and, of course, the substance was metabolized and excreted by the body long before death.
In such a case, the results of a screening test must be accepted for what they are -- a screen and no more. Coupled with additional evidence, however, such as a crack pipe in a pocket and witness reports that the decedent had been smoking crack cocaine before suddenly collapsing, then a screening test that detected cocaine metabolites in the urine is probably accurate, and it would be appropriate to opine that evidence exists that cocaine was in the decedent's system at the time of admission.
Note that some screening tests are subject to false-positive results, sometimes by cross-reactivity of the antibodies with prescribed medications.  Quite commonly, decomposed bodies test positive on amphetamine screens, because the production of phenylethylamine is part of the putrefaction process. Good medical practice always calls for correlation of the history with the physical findings. If a screening test result cannot be validated by some other means, then it must be considered possible that the screening test result is a false positive.
The determination that death was caused by intoxication with a single substance or with a mixture of substances is the business of forensic pathology, sometimes a fiendishly tricky business. Finding a range of concentrations of a given substance that have been reported as the cause of death in the medical literature is usually possible. Biologic systems know nothing of cutoffs, however, and studies abound that show that a drug concentration that caused death in one case was an incidental finding in another.
For example, Darke et al reported no significant difference in morphine concentrations in individuals dying of a drug overdose when compared with individuals killed by homicidal violence, such as shooting or stabbing.  Such a finding should come as no surprise when one remembers the pharmacologic concept of the LD50, the dose of a given drug that will kill 50% of the rats exposed to that dose. If a given dose kills 50% of the rats, then a smaller dose presumably would kill 10% of the rats or a larger dose 90% of the rats. The variability in biologic systems means that the same concentration of drug may kill one individual but leave another unscathed, even if one ignores the effect of drug tolerance.
How, then, does a pathologist make a determination of the role a drug plays in causing death based on reproducible criteria and not intuition? Irey suggested a useful scheme in the book Pathology of Drug Induced and Toxic Diseases.  In brief, Irey provided several categories of significance that any substance found in a decedent may have, including the following  :
Causative: The substance is unequivocally responsible for illness or death.
Probable cause of death: Death is a known complication of that substance and the clinical picture is in keeping with previous experience and reports, provided other causes of death have been reasonably eliminated.
Possible cause of death: The clinicopathologic picture could be caused by the drug in question, but it could just as easily be caused by some other process found in the decedent; assigning the drug in question as the cause of death would be unique and warrant publication in the medical literature.
Coincidental: The substance happens to be present but has no bearing on illness or death.
Negative: The substance is not detected.
Application of Irey's criteria is reproducible, as properly applied science should be. The decision of whether death was caused by a given drug or combination of drugs in a given case remains difficult sometimes, but Irey's criteria provide a useful conceptual framework for making accurate, defendable diagnoses.
Misconceptions concerning drugs are held by those who abuse drugs and health practitioners. Due to the popularity of forensic-themed television series, many laypeople assume that thorough toxicologic analysis takes as long as a commercial break. Even under the best of circumstances, conducting toxicologic analyses correctly may take days to weeks, and it may take much longer than that in some busy jurisdictions. People also tend to think that laboratories are interchangeable, which is a credit to the uniformity of good practice followed by accredited laboratories. Not all laboratories are accredited, however, as pointed out in the National Academy of Sciences 2009 report on forensic science in the United States.  Variation in quality of work is but one reason that laboratory results are subject to challenge in court, a point discussed in more detail below in Issues Arising in Court.
Drug users also fall victim to fallacies pertaining to their drug of choice. They often think of the drugs that they choose to use as safe, ignoring the overlap that exists between the therapeutic and lethal ranges for controlled substances and illicit drugs. Further, drug users who have been incarcerated for a time often resume drug use again upon release from prison but fail to take into account the loss of tolerance that occurred during their internment. Therefore, they are at risk of dying when they use the same amount of drug that they had been using before their imprisonment. Moreover, no agency oversees drug purity for street drugs, and the purity of the substance being abused may have changed while an individual was in jail.
Misinterpretation of public health advisories has also resulted in fatalities. In the interest of promoting public health, officials have occasionally issued warnings to the public to avoid certain neighborhoods because a drug being sold there was unusually powerful and likely to cause death. Paradoxically, these warnings have led to increased traffic and deaths in the area, because some drug users took the information as an advertisement rather than as a warning.
Practitioners may also be duped by drug users by failing to acknowledge that addicts are distributed across every socioeconomic cohort. As described earlier in the section Indications for the Procedure, some drug users take great care not to be detected. Assuming that a specific person could not possibly abuse drugs is naïve.
Blindly sticking to a published "lethal" range for a drug, as described above in the section Diagnostic Criteria, is also naïve. Certainly a published lethal range is useful and must be considered, but to dismiss some drug as causing death because its concentration is 0.01 mg/L below the reported lethal range is to ignore the truth, if the circumstances indicate that the death is caused by a drug overdose. Suffice it to say that if a person died due to the effects of a drug on that person, the level is lethal regardless of where the blood concentration falls on a table.
Finally, overdose as a concept may be misunderstood by both drug users and health practitioners. Some deaths certainly occur because a lethal concentration of drug is in the body, but, in other cases, drugs can lead to death by alternate mechanisms irrespective of the concentration of the drug in the body. Cocaine, for example, can cause death at any concentration.  Mechanisms by which a drug can cause death at low concentration are being elucidated, as described below in Future Developments.
Issues Arising in Court
Forensic pathologists most often testify in murder trials, and those trials often include discussion of the degree to which the decedent's behavior was altered by intoxicating compounds found in the body. For alcohol, data exist that provide some degree of confidence in answering a question about the decedent's behavior in general terms based on a given blood ethanol concentration.
For other drugs, such as cocaine, no such data exist. Furthermore, for cocaine and other drugs, the behavior of the individual depends not only on the concentration of the drug in the blood but also on whether the concentration is increasing or decreasing.  The honest forensic expert limits speculation concerning the behavior of an individual based on drugs found in the system to generalities, for example, saying that cocaine does alter behavior, that it has stimulant properties, but that predicting from the blood concentration alone what a given person's behavior would have been is not possible.
Part of preparing for court is anticipating questions that may arise. This process begins at the autopsy and includes preservation of evidence. For example, saving fentanyl patches in bottle labeled with the appropriate case number is prudent practice in cases of unexpected death.  In the event that a legal suit later alleges that the patch was defective, the patch is available for examination and testing. Remember that the purpose of court is to resolve disputes, so whenever a pathologist is able to produce evidence that settles a dispute, then the pathologist has served the court well.
The wise pathologist acts to resolve disputes about a finding or diagnosis before the disputes reach court. As an example, the following scenario recurs periodically: Toxicologic analysis detects an illicit substance in an individual who, the decedent's family adamantly maintains, never used drugs. Once the pathologist realizes that the family doubts the results of the initial toxicology test, sending a sample for toxicologic analysis to a second toxicology laboratory other than the initial facility may head off litigation.
The pathologist tells the family it is only proper to double check in cases of such vehement disagreement, because mistakes do sometimes occur, but makes no promise of what the second laboratory will find. If the toxicology results from the second facility disagree with those of the first -- that is, if the offending substance is not found in a repeat test -- then evaluation of what went wrong in the first laboratory test is appropriate, as is an apology to the family for any distress caused. If, however, the second laboratory confirms the presence of the offending substance, then the pathologist has already taken the step that any court will first order if the family sues.
The family may or may not accept the truth of their loved one's intoxication, but others without the blinders of vested interest will be convinced, and the pathologist's part in the dispute is essentially done. The family may not be done, however, and may demand DNA testing to prove the blood is from their loved one. The pathologist may perform such testing, but telling the family that the pathologist is satisfied is also possible, and any further testing will be done at the family's expense. If the family chooses a laboratory for DNA analysis, then the pathologist transmits the blood sample for DNA testing directly to the laboratory with appropriate chain of custody. The sample must not be given to the family unless so ordered by a court.
On June 25, 2009, the US Supreme Court ruled that pathology laboratories are not exempt from US laws that require that evidence against a person accused in court is subject to challenge in the form of cross-examination. This means that a laboratory report alone may no longer be sufficient as evidence in a trial; the analyst who performed the test may also be subpoenaed and may have to testify in court.
The Supreme Court ruling runs counter to the experience of pathology laboratories, which are accustomed to dispensing many reports a day that are almost always accepted as true and accurate without question. Someone calling and questioning the results of a laboratory test is not unheard of; medical practitioners call to double check and challenge unexpected results daily.
What makes the Supreme Court's ruling different is that routine laboratory results that are seldom questioned in clinical practice will require the presence of a pathologist or technician in court to explain and justify the results concerning any given laboratory test relevant to a criminal trial. Pathology laboratories are not staffed to provide such service to courts, and how this matter will impact upon laboratories when all is settled remains to be seen. Despite the inconvenience of the Supreme Court's ruling to pathology laboratories, this does afford pathologists an opportunity to get out of the laboratory, place themselves in the public eye, and demonstrate the importance and worth of pathology testing and pathologists to the community.
Enterprising individuals with sophisticated knowledge of chemistry have synthesized chemical analogs of common drugs of abuse, such as amphetamines, opiates, and marijuana. These chemical analogs are pharmacologically active, but because of their novel structure they technically escape legal restrictions on their sale and use.  These substances are marketed and sold under many names, such as bath salts, K2, or spice.  They can be bought at stores or over the Internet. Often, the substances bear a label stating that they are not intended for human consumption, another ploy to avoid legal repercussions for selling the material. Other new drugs available for purchase are the opiate agonists Salvia and Kratom, both derived from plants.  The sale and use of Salvia and Kratom are also largely unrestricted by law.
The compounds and laws continue to change in a never-ending game of cat-and-mouse faster than publications can keep up with the latest fad. Internet postings are the best source of information on this rapidly changing process. Perhaps most important is to remember that these substances are likely to be missed by a standard toxicological screen directed against the usual drugs of abuse. Therefore, if reason exists to have a high index of suspicion for drug use or intoxication, but no substance is detected on standard screens, one of these chemical analogs may be present. Testing for the chemical could be expensive, however.
Research in basic sciences will improve the understanding and practice of forensic pathology in the years ahead regarding deaths caused by intoxication. For example, cocaine and methadone can cause death at concentrations often perceived as too low to be "overdoses." Research indicates that cocaine  and methadone  both alter proper repolarization of the heart, helping to explain how death can occur at low concentrations of these drugs. Others are working in pharmacogenomics, which has the potential to help forensic pathologists understand the mechanism of death for certain individuals who may metabolize a drug more slowly than others, thus overdosing more easily.  These fields are interrelated, as the absence of a gene or gene copy necessary for proper repolarization of the heart can cause death just as surely as the absence of a gene or gene copy for proper metabolism of a drug.