Effects of Post-mortem Redistribution on Commonly Encountered Psychoactive Medicinal Drugs

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Effects of Post-mortem Redistribution on

Commonly Encountered Psychoactive

Medicinal Drugs

Angelo Figueroa

12228265

Msc Forensic Science

January 20

th

, 2021

Supervisor: Dr. Geli Gallego Herruzo

Examiner: Dr. Roelof Jan Oostra

Word count: 6014

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Key Words: Post-mortem, Toxicological, Psychoactive,

Redistribution, Blood, Drug

Abstract:

Psychoactive medicinal drugs are commonplace within the modern world, and as a result their use is becoming equally commonplace. As a result of their increased usage, the rate of misuse is also increasing, bringing about a subsequent increase of incidents including fatalities related to their use. These incidents require the use of forensic toxicological analysis to examine and determine the causes of these incidents. However, the phenomenon known as post-mortem redistribution can complicate these investigations due to their effects on the drug concentration levels within the blood of the victim after death has occurred. This report aims to explore the general effects of this phenomenon on common psychoactive medicinal drugs, as well as the elaborate and highlight factors that may influence how post-mortem redistribution affects the substances in question, alongside possible exceptions to the overall trends of each category. In particular, this report will cover the post-mortem redistribution of benzodiazepines, analgesic opioids, antipsychotics, antidepressants and anticonvulsants.

Introduction:

In the modern day, the use of medication has become commonplace, with many types of medication being widely available and generally accessible. Among these are psychoactive medicinal drugs (PMDs), which can be defined as medications that alter the perception, mood, consciousness, or behaviour of the individual consuming the drug. Given the affects that these medications have on the user, many countries have regulations in place to help control their usage, limiting their access to only those who truly require them. Even with these regulations in place, there are still incidents of misuse or abuse of these PMDs, occasionally leading to the death of the user directly through overdoses or indirectly through accidents brought on by the user’s impaired abilities. When any deaths suspected to be associated with the use of PMDs occur, toxicological tests must be carried out in order to confirm the presence of any substances within the individual’s body as well as to determine if and how the drug caused the death of the user. While the toxicological tests themselves may be relatively straightforward, there is one phenomenon that must be accounted for, as it may severely alter the results of the test and, consequently, lead to an incorrect conclusion in the investigation.

The phenomenon in question is known as post-mortem redistribution (PMR), which is the redistribution or changes in the concentrations of substances within the body after death has occurred. These changes, while varied between difference drug classes, are found to be highly reproducible in the general trends of their drug classes [1][3]. While the effects of PMR are not limited to blood samples, as it also affects substance concentrations in organs and other bodily fluids, it is of particular importance to understand its effects on post-mortem blood as it is the most commonly used sample for toxicological analysis. While the magnitude of the changes

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caused by PMR are not universal for every drug or substance, the effects brought on by it generally increase over time after death has occurred, which can possibly lead to severely skewed results if the samples are taken days after the individual has expired. It is also important to note that the changes caused by PMR are not uniform throughout the body, with the changes being more extreme in central areas such as the torso compared to more peripheral areas, such as the limbs [1][2][3].

As a result, one would expect to find much higher concentrations of a substance within blood drawn from the heart of an individual compared to blood drawn from the femoral blood vessels. These higher concentrations in central blood sources can be explained by the general mechanism of PMR, where the substance in question diffuses throughout the various tissues from areas of higher concentration to those of lower concentration as the cellular membranes begin to degrade after death. As the central part of the body, namely the torso, holds the highest density of tissues within the body, a significant amount of the substance would diffuse into the blood within those regions compared to blood found in more peripheral sources, as they would not have as much possible sources of diffusion given the comparative lack of surrounding tissue. It is because of this that blood taken from the femoral artery is considered the “golden standard” for most post-mortem blood samples, as it is generally considered to have the lowest levels of changes in drug concentrations levels overall, regardless of how extensive PMR may occur. Another important factor that generally affects the PMR of a substance are its physical and chemical properties, such as its solubility in certain mediums or its relative stability in the environment. For example, PMDs with high lipid solubility, such as many antidepressants, are generally heavily affected by PMR, while other substances may simply be less stable in the conditions the body is in and may break down if the body is in a warm environment or may degrade during the putrefaction process [2].

The metabolites of the drugs can also play an important role during an analysis, with both their concentration and chemical properties providing useful information. Drugs that share a common class may also share similar metabolites, and in such cases, while the drug itself may either be absent or found in low concentrations due to PMR or degradation, the metabolite itself may be used to indicate a high intake. However, the nature of each metabolite and drug must be taken on an individual basis as there may be some exceptions. For example, the opposite is found to be true in the case of morphine glucuronide, a metabolite of morphine, which reverts to morphine under post-mortem conditions. In such a scenario, exceedingly high levels of morphine may be found in an individual, insinuating a high dosage of morphine prior to death, which may not be the case [2]. The metabolites may even prove useful in rare incidents of genetic differences in some individuals, leading to the hyper-metabolization of a drug, leading to overdoses at levels much lower than those that would be expected. It is because of this that it is highly suggested at toxicologists compare the levels of metabolites and the substance itself to attempt to catch such rare occurrences [3].

With all of this information taken into consideration, it comes as no surprise that the interpretation of a toxicological analysis is not a simple task. Reaching an accurate and acceptable conclusion for such analyses can prove to be an exceedingly difficult medico-legal task given the sheer volume of information that must be taken into account with PMR alone. Unfortunately, the difficulty of such analyses and the resulting conclusions made are further complicated by other factors that may enhance or alter the effects of PMR, leading to results that may be ambiguous or extremely misleading. One such example would be the blood/plasma ratio

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of the individual, which could have a substantial effect on the drug concentration readings based on the ratio of plasma found within the blood [3]. Furthermore, while the physical and chemical properties have been mentioned previously for single substances, there can sometimes also be interactions between multiple drugs, both medical and non-medical, which would affect the concentrations of these substances or even the effects they would have on the user. For example, alcohol has been found to enhance the effects of opioids, which could lead to the user

experiencing impairment or toxicity on a much higher level than their intake would suggest [2][4]. In such a case, it would be prudent of the analyst to note the presence of alcohol alongside any opioids and take such information into consideration when forming a conclusion.

Other information about the user could also be useful when interpreting toxicological data, such as possible drug abuse or even mental conditions or illnesses. To give an example on how such information could be useful, imagine a scenario where the body of an elderly man was found alone at home with no signs of foul play, and toxicological tests show high levels of opioids in the blood. Assuming the cause of death is an overdose caused by the opioids, the question becomes a matter of determining if the death was intentional or unintentional. Without any other information, it may be hard to reach a conclusive decision, but considering the history of the elderly man could prove useful. If he had a history of drug abuse, his death may have been unintentionally brought about by a desire to achieve a “high”, thus intaking an excessive amount of the substance due to the built-up tolerance to said substance through years of abuse. On the other hand, if the user had a history of mental health issues, such as depression, it may be more likely that the death was an intentional suicide. There is even another possibility of unintentional death if the user suffered from memory loss, leading to an accidental overdose due to a lapse in dosage memory. While such personal information should not be used to build a theory, it could provide useful evidence under ambiguous circumstances and should not be actively ignored by an analyst [4].

While the secondary sources of information could be expanded upon, the subject that holds the greatest overall importance in such toxicological analyses is the post-mortem redistribution of drugs within the body given the variable effects it may have on the analyses. As stated

previously, there is no universal trend for PMR, but instead general trends that can be seen within various drug classes, such as opioids and antidepressants. With this in mind, it would be of great benefit to future toxicologists to provide a compilation of commonly abused substances for future reference. However, given the rising prevalence of available psychoactive medicinal drugs as well as the already extensive research done with most illicit drugs, this report shall focus on a select group of the most commonly abused psychoactive medicinal drug classes. This list consists of benzodiazepines, analgesic opioids, antipsychotics, antidepressants, and

anticonvulsants, where the general trends regarding the PMR will be discussed alongside any exceptions or additional information, such as important metabolites or the factors that may directly affect the rates of distribution.

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Overview:

Benzodiazepines:

Benzodiazepines (BZDs) are one of the most common psychoactive medicinal drugs found across the globe due to their wide variety of uses in varying treatments. While there are varied chemical structures within the BZD class, the overall structure includes a benzine and diazepine ring. While the effects of BZDs vary as stated previously, the general affects tend to be those of a depressant via their enhancement of the gamma-aminobutyric acid neuroreceptor. These effects are enhanced by simultaneous ethanol ingestion, possibly leading to incidents where an

individual may show signs of excessive intoxication even when toxicological tests may only show relatively small concentrations [5].

Overall, benzodiazepines seem to show little to no tendency towards PMR, with most changes being of insignificant value, even though some of the compounds have been found to be lipophilic [6]. Research has found that BZDs seem to concentrate uniformly throughout the blood and organs, negating the diffusion of substances from a higher concentration to a lower concentration, which the main source of PMR. While this may be the case, some BZDs show relative instability under certain post-mortem conditions, such as chloridiazepoxide or

nordiazepam which degrade over time at room temperature, while BZDs in the subcategory of nitrobenzodiazepines degrade rapidly in the presence of obligate anaerobe bacteria [5][7]. In cases involving such substances, it is imperative to understand the conditions the body has been kept in alongside the storage or collection methods used to prevent unnecessary exposure to harmful conditions that could alter analyses.

While the general trends of BZDs have been discussed, due to both their prevalence alongside some abnormal traits, diazepam and phenazepam will be briefly explored in further detail. In particular, the metabolites of both benzodiazepines will be explored rather than the substances themselves, as it is the metabolites that show peculiar properties. While most of the metabolites for diazepam show no particularly odd trends, one study by Holm et al found that one of the metabolites, desmethyldiazepam showed a significant increase in blood under post-mortem conditions. When comparing the levels of desmethyldiazepam in the blood to levels found in the brain, the levels were found to be approximately ten times greater in the blood than in the brain, while diazepam levels were consistent throughout both matrices [8]. While the reason for this is currently unknown, it is an important note to make which could prevent misinterpretations when such a large level is found in blood samples.

Phenazepam has two metabolites that are worth noting for toxicological analyses, namely 3-hydroxyphenazepam and 2-amino-5-bromo-2'-chlorobenzophenone (ABPH). The first

metabolite was found to almost always be in noticeably lower concentrations that phenazepam within the blood, as it was found to not accumulate within blood samples, making it a poor choice for analysis in blood samples [7]. ABPH on the other hand, was found to be the complete opposite and seems to have a significantly long lifespan within blood even when compared to phenazepam. In one case, a thirty-two-year-old female was found dead with clear signs of phenazepam use, including remnants of ingested pills of phenazepam, yet, while no phenazepam was detected in the blood, significant levels of ABPH were still found [9].

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Analgesic Opioids:

Analgesic opioids are another commonly abused PMD which are normally used for pain relief under legal medical use. Similarly to benzodiazepines, most opioids seem to show very little effects in regards to PMR, and also seem to have generally long lifespans within blood, making it an excellent, if not ideal source for toxicological analysis [10]. While they may not generally be affected much by PMR, there are three opioids that are of particular importance to investigate for toxicological analysis, namely morphine, methadone and fentanyl. Morphine acts similarly to most opioids and seems to undergo little to no PMR, although under certain circumstances, its concentrations in blood can shift severely under post-mortem conditions, leading to possible misinterpretation or faux evidence of PMR. Namely, when morphine use is combined with heroin, there is a tendency for morphine blood concentrations levels to spike post-mortem. This occurs because of one of the metabolites of heroin, 6-monoacetylmoprhine, is not stable under post-mortem conditions and rapidly converts into morphine shortly after death has occurred. This severe shift in morphine concentration can seem like a case of PMR, but such severe shifts in blood morphine levels have only been observed when heroin was also present [11]. In the case of simultaneous heroin and morphine use, the analyst should be cautious of any post-mortem

morphine blood concentrations as they may have shifted severely due to the metabolite conversion.

Fentanyl on the other hand, has proven to be a very difficult opioid with regards to its tendencies for post-mortem redistribution, as it seemed to vary between showing little to no PMR or

exceedingly high levels of PMR. Initially, most research seemed to show that, due to its high lipophilic nature, fentanyl was prone to severe changes in post-mortem blood levels due to PMR, even though the results were highly varied [12][13]. While it was initially suspected that this high variation was related to the fatty tissue reserves in individuals, these discrepancies were found to be caused by another factor entirely. This factor was found to be the level of distribution of fentanyl throughout the body prior to death, which was affected by both the method of use as well as the overall time period of use. In essence, when there were cases of acute abuse with no long term use, fentanyl was found to not have time to properly distribute itself throughout the body prior to death, and as a result of the unequal distribution, was prone to severe levels of PMR. On the other hand, long term use or chronic abuse of the drug allowed for proper

distribution throughout the body, which led to minimal diffusion after death and consequently, little to no PMR [14][15]. It is because of this high variability that any examination of fentanyl in post-mortem analyses should place a high degree of importance on acquired additional

information on the user in order to draw accurate conclusions on if PMR has affected the observed levels of fentanyl.

The third opioid to be discussed is methadone which, similar to fentanyl, shows inconsistent and varied levels of PMR across individuals. Unlike the other opioids however, methadone seems to undergo PMR even in peripheral sources such as the femoral artery, which can cause extensive issues during a toxicological analysis. The post-mortem methadone levels have been found to vary generally between two to four times those of the antemortem values within the blood [16]. While the exact cause has yet to be determined, much like the initial hypotheses for the

tendencies of fentanyl, it is believed that adipose tissues provide a large concentration gradient for methadone prior to death, which leads to diffusion into the blood post-mortem. This theory seems to be supported by the increased levels of PMR of methadone in females compared to

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males, with significantly higher levels of methadone being found in central and peripheral blood samples. As stated previously, it is hypothesized that the adipose storage sites, such as the female breasts, may be the cause of this gender bias in methadone PMR levels [17]. While this

hypothesis no doubt requires further research, it is imperative to understand possible causes of the differences in order to account for them.

Antipsychotics:

Antipsychotics are medicinal drugs that are generally used to treat severe mental conditions involving some form of psychosis, such as schizophrenia. While the previous PMDs discussed thus far have generally shown insignificant levels of PMR overall, antipsychotics tend to show moderate levels of PMR, which is mainly attributed to the lipophilic nature of most

antipsychotics [18]. As always, there are some exceptions to this trend, as well as two

antipsychotics with particular traits that may affect the concentrations alongside their expected redistribution. The currently known exceptions are aripiprazole, chlorprothixene, quetiapine, haloperidol and risperidone, all of which show little to no PMR [18][19]. While they all show almost no significant changes under post-mortem conditions, risperidone has been reported to occasionally show decreasing blood concentrations levels over time, although even these levels are generally considered insignificant.

The other two notable antipsychotics, chlorpromazine and olanzapine, while both still possessing notable levels of PMR, are also prone to highly variable changes in their post-mortem blood concentration levels over time. In the case of chlorpromazine, this can occur when the body is subjected to temperatures close to or above twenty-five degrees Celsius, as the drug becomes unstable and prone to degradation around these temperatures [20]. It is also vulnerable to certain bacteria, and as a result may be quickly degrades under putrefaction conditions or in areas near the gastric system if bacteria are able to escape or seep into surrounding tissues or blood vessels [18][21]. Olanzapine levels also vary wildly under post-mortem conditions due to the overall instability of the substance, particularly to oxidation. While there have been some studies that attempted to recover the oxidized olanzapine in post-mortem blood through reduction, the results were found to be conflicting, and over all relatively pointless given the rate of PMR of the substance [21]. In essence, the increases in blood concentration levels brought about by the moderate levels of redistribution of both chlorpromazine and olanzapine may compete with the simultaneous decreases in the substance levels due to these factors. It is due to this “competition” of sorts that leads to the highly variable changes in blood concentration of both substances in post-mortem conditions.

Antidepressants:

Antidepressants are a wide variety of medications that are used to treat individuals suffering from some form of depression or even occasional anxiety issues. While most other drugs

generally work through one general method, antidepressants can induce the same effect through a variety of pathways and are normally categorized based on the method in which they operate. As such, this are one of the PMD categories that can be split into a large variety of subcategories or classes. Due to this, rather than covering a general overall trend for the antidepressant

category, this report shall instead cover the trends of three of the most common subclasses of antidepressants, namely, the tricyclic antidepressants, the selective serotonin reuptake inhibitors

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(SRRIs) and the monoamine oxidase inhibitors (MOAs). While it may be possible that some exceptions to these trends may exist, as has been the case in previous drug categories, based on the observed literature, there have been no exceptions to these trends discovered thus far, although possible reasons for this will be discussed later on in this report.

Of the three categories covered in this section, the tricyclic antidepressants show the highest propensity for PMR, which is normally attributed to their highly lipophilic nature. [22][23]. The levels of PMR were sometimes found to be so severe that, in a study by Øiestad et al, the

differences in blood concentration levels between peripheral blood and central blood were found to be by a factor of ten, with a few cases even having higher levels [24]. SSRI’s, which are one of the more commonly used subcategories of antidepressants, seem to be moderately affected by PMR, although nowhere near the levels of tricyclic antidepressants. However, it must be noted that most of the data regarding this class has come from only two members of the subcategory, namely citalopram and fluvoxamine. While the effects of fluvoxamine have been explored in post-mortem conditions in humans and generally shows moderate levels of PMR, the

redistribution of citalopram has not been extensively examined in humans, although even in animal studies, it showed moderate levels of PMR [25][26].

Finally, the subcategory that shows the lowest tendencies for redistribution are the MOAs, that generally seem to show little to no redistribution at all. In particular, moclobemide was found to show almost no changes whatsoever in post-mortem environments, with almost no significant differences occurring between peripheral and central blood samples [22].

Anticonvulsants:

The final category of PMD to be discussed in this report is anticonvulsants. As their name implies, these medications are generally used to prevent or treat individuals who suffer from seizures, with one common treatment being towards those who suffer from epilepsy. Of the anticonvulsants observed within literature, there seem to be no exceptions to the general overall trend, although two drugs in particular are explored in greater detail, the first of which is

oxcarbazepine. While this substance shows very little changes in blood concentrations after death, the half life of the parent substance in blood is relatively short, and as a result may be difficult to detect in samples taken during an autopsy. Its metabolite however,

hydroxycarbazepine, has a significantly longer half-life in blood, and a as a result is normally the substance that should be screened for during a toxicological analysis [27]. However, in either case, both the parent drug oxcarbazepine and the metabolite hydroxycarbazepine show no significant differences between central and peripheral blood samples [28].

Another commonly used anticonvulsant, gabapentin, shows very little tendencies of

redistribution after death. However, in the case of gabapentin, it is believed that the acidic nature of the compound is what may play a role in its minimal PMR rates [29][30]. Overall, even when studies were carried out on other, less common anticonvulsants, there were no particular drugs within the category that showed any deviation from the general trend of little to no post-mortem redistribution [31]. As a result, anticonvulsants may be one of the few drug categories that are comparatively “simple” to analyse from a toxicological standpoint, given the lack of exceptions and overall adherence to a single trend.

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Discussion:

While PMR has become a widely known and accepted phenomenon in the medical and forensic fields, with a general consensus on the overall causes of the redistribution, the process is still not fully understood. While most scientists agree that certain properties generally make a substance prone to experiencing PMR, such as a highly lipophilic nature, these are closer to assumptions rather than absolute laws. While it is true that these assumptions are generally correct, as can be seen with most drugs, there are others such as the lipophilic benzodiazepines which show that simply having such a nature does not guarantee that a substance will undergo significant levels of PMR. This lack of understanding is further complicated by oddities in some of the studied substances that imitate or mitigate the affects of PMR, such as exposure to bacteria that may degrade certain compounds, possibly leading to lower concentrations than initially present in antemortem conditions or counteracting increased levels brought about by PMR. In a case involving degradation, the concentration levels may manage to balance out if PMR is occurring and the rate of degradation if high enough to match it, which would theoretically then show similar or negligible differences between blood concentration levels from different sources, even if PMR would normally occur. It would also be wise to understand the physical and chemical properties of analysed substances, as well at their metabolites. As stated previously, some substances are prone to degradation under particular circumstances, which could lead to complications in locating the drug during an analysis. In such cases, the analyst could instead choose to search for the metabolite of the parent drug, which is especially useful if the parent drug is either unstable or has a particularly short half-life. However, the properties of metabolites themselves should also be considered to avoid misinterpretations, such as those found when the metabolite of heroin, 3-monoacetylmorphine, converts into morphine under post-mortem conditions, leading to higher post-mortem levels of morphine compared to antemortem levels. While this may be known to occur with morphine and 3-monoacetylmorphine, there remains the possibility that similar occurrences may happen with other, yet to be studied substances. The literature has also made it apparent that, while the current “golden standard” of toxicological analysis comes from femoral blood samples, there may be other matrices in the body that could provide more accurate information as they are less prone to experiencing PMR or the other factors that could affect the drug concentration levels within the blood. One particularly important example of such a factor would be the stability or half-life of some of the substances or their metabolites within blood. These very same substances may quickly dissipate within blood, but may be completely fine or at least persist longer in other mediums within the body, with one particular medium of interest being the vitreous humour. While the goal of this report was to explore the effects of PMR of drugs within the blood of the human body, I believe it is still worth mentioning that there are other possible avenues for testing drug levels within the body under post-mortem conditions.

One particular substance shows exactly how our lack of a proper understanding of PMR can lead to severe misinterpretations of misunderstandings of results seen in research. The substance in question is Fentanyl, which caused no shortage of personal grief during the research process. While compiling and studying literature on fentanyl, most of the studies suggested that fentanyl was highly susceptible to PMR, with some results showing very significant differences between central and peripheral blood samples. This was attributed to the lipophilic properties of fentanyl, and the results even seemed to suggest that adipose tissue may have actually been a major source of the redistribution into blood after death had occurred. However, other sources proved that

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fentanyl only exhibited redistribution in cases where the drug had been taken shortly before death had occurred, preventing the substance from properly distributing itself throughout the body prior to expiration. In such cases, the fentanyl would then diffuse into the blood over time, showing the notable differences experienced in previous literature. However, in cases where the fentanyl was used over time prior to the death of the user, there were practically no significant differences between central or peripheral levels after death. If this was found to have occurred in fentanyl, it can call into question the results of many other studies on various other drugs which may also be affected by similar circumstances. One possible example can be seen in another opioid which shows very similar traits to fentanyl, methadone. Current literature also suspects that methadone concentrates in adipose tissue, just like previous literature had initially believed the be the case for fentanyl. While this does not automatically confirm that methadone acts similarly to fentanyl, the possibility alone can show how the discovery of the circumstances that effect the PMR of fentanyl may possibly be used to investigate other substances in the future.

With regards to the research and available literature, there are a few issues that had been

encountered that must be addressed. The first issue is in regards to determining a general trend of the drug categories and finding exceptions to these rules. As this is a review on literature, there are limitations as to how accurate these general trends can be given the selection of drugs that have been studied. While a focus was made for the more common and abundant substances, the sheer amount of possible drugs within a category make it difficult to definitively deduce what ratios of the drugs within a category follow the trends. While most of the substances within each drug class are a derivatives of a single compound or share a basic general structure, the subtle differences may sometimes lead to noticeable changes in the properties which may affect their tendency to undergo PMR. This issue was compounded by the apparent bias that occurred in the studies of certain drug classes towards a very select few substances while neglecting most other members of the class. This was very apparent for literature on antidepressants and

antipsychotics, of which most relevant literature focused on the exact same compounds within their respective categories. With little to no variation in the possible substance information, it is exceedingly difficult to draw an accurate conclusion on the drug category on a whole with a very high level of confidence.

Another issue was a lack of recent research in on some of the substances that could possibly refine, confirm or refute the current, possibly dated research available. While this is not to say that research inherently becomes irrelevant as time progresses, when comparing the

understandings of modern medicine and toxicology to the previous understandings expressed in older literature, it becomes apparent that some of the research may not have considered certain possibilities that could be tested now. This, alongside technological advances in analytical methods, makes it difficult to hold the findings of earlier research to the same standards as more recent studies. While the majority of the literature used in this review was within the past ten years, there were some PMDs for which the majority of research had been done near the turn of the century, which was particularly prevalent in antidepressant literature.

While there may have been a clear bias in which compounds were studied within certain drug categories, it was also apparent that there was a clear literature bias regarding the availability of research on particular drug classes on a whole. For example, while there was an abundance and large variety of post-mortem studies involving benzodiazepines and opioids, there was a notable lack of specific studies aimed at the other three categories. This additional bottleneck had a

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notable effect on the available information regarding the final three categories, making it particularly difficult to find any additional information that could be helpful.

As a final point of discussion, one of the major difficulties that is inherent in the field of toxicology is the lack of “pure” cases when compared to mixed cases. To elaborate, in the majority of data from the literature, there were cases where the target PMDs were found to have been combined with other substances, both legal and illicit. Given the complex nature of PMR and the possible interactions between the combined substances, it becomes very difficult to accurately deduce any effects of PMR on the targeted substances. Although this is not to say that there were never any cases where only the target drug was present, these number of such cases was comparatively low and provided a very small pool to draw data from, which further

complicated datasets was notable variation in concentration levels within such cases. While these may have been an inconvenience regarding the direct influence of PMR on the substances, it provided a clear insight as to what could be expected from relatively common combinations one would find working in the field of toxicology. Such information could prove valuable for future studies to determine exactly how some of these combinations may affect the redistribution of these substances.

Recommendations:

After extensively searching for and analysing research on the post-mortem redistribution of psychoactive medicinal drugs within blood, there are three recommendations that I would like to make for future research into this topic. The first two revolve around two issues discussed within the previous section, namely, the lack of variation within some research as well as the lack of recent studies for certain PMD categories. While there has clearly been extensive research into benzodiazepines and opioids, extending the same level of research into other categories would be highly beneficial as they are also relatively common drugs used within modern society,

especially regarding antidepressants given the mounting levels of depression being reported yearly across the globe. These recommendations, while aimed at both antipsychotics and anticonvulsants, are especially true for antidepressants as they lack both a variety in the substances studied as well as more modern research. Expanding research within these fields would be immensely helpful to the toxicological community and may help further our understanding of how PMR affects these drugs.

Finally, with the conflicting research involving fentanyl and how previous studies involving the effects of PMR on the substance had been misunderstood, it is imperative that such factors be taken into consideration for future research into the redistribution of PMDs. The fact that the manner of consumption, as well as the time between the consumption of a drug and death could affect PMR so severely is an extremely important factor to consider, as there could be an untold number of other substances that may be affected in a similar manner. This alone warrants new research into the PMR of drugs that have already been studied, such as methadone, as this may not have been taken into consideration or may even explain some of the variations seen in past studies that may have been attributed to some other factor.

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Conclusion:

While discussing the general trends of PMR in the five categories of common PMDs, we can see that three of these classes do not show significant levels of redistribution after death, those being benzodiazepines, opioids and anticonvulsants. While this may have been the case for the general trends, these categories did have a few exceptions to the general trends which were discussed in detail within their respective sections. Regarding the antidepressants, three subcategories were explored: Tricyclic, SSRIs and MOAs, of which only one subcategory was shown to be highly vulnerable to PMR. These were the tricyclic antidepressants, which were found to be highly lipophilic, explaining their high propensity for redistribution. Otherwise, the other subcategories within the antidepressant class also showed little to no effects of PMR. While the other

categories showed negligible overall trends, the antipsychotics were the only category to show a general trend of moderate PMR effects, with the few exceptions showing little to no

redistribution. While there are no doubt many other PMDs that could be encountered in the field of forensic toxicology, these five categories are some of the most commonly encountered drugs and thus, were of great importance to cover in this report.

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