HHS Public Access: Neuropathology of Substance Use Disorders

HHS Public Access
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Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.
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Published in final edited form as:

Acta Neuropathol. 2014 January ; 127(1): 91–107. doi:10.1007/s00401-013-1221-7.
Neuropathology of substance use disorders

Jean Lud Cadet,
NIDA Intramural Research Program, Molecular Neuropsychiatry Research Branch, NIDA/NIH/
DHHS, 251 Bayview Boulevard, Baltimore, MD 21224, USA
Veronica Bisagno,
Instituto de Investigaciones Farmacológicas (ININFA-UBA-CONICET), Junín 956, piso 5, C1113
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Buenos Aires, Argentina
Christopher Mark Milroy

Eastern Ontario Forensic Pathology, Unit of the Ontario Forensic Pathology Service, Division of
Anatomical Pathology, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON K2A 2L4, Canada
Abstract
Addictions to licit and illicit drugs are chronic relapsing brain disorders that affect circuits that
regulate reward, motivation, memory, and decision-making. Drug-induced pathological changes in
these brain regions are associated with characteristic enduring behaviors that continue despite
adverse biopsychosocial consequences. Repeated exposure to these substances leads to egocentric
behaviors that focus on obtaining the drug by any means and on taking the drug under adverse
psychosocial and medical conditions. Addiction also includes craving for the substances and, in
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some cases, involvement in risky behaviors that can cause death. These patterns of behaviors are
associated with specific cognitive disturbances and neuroimaging evidence for brain dysfunctions
in a diverse population of drug addicts. Postmortem studies have also revealed significant
biochemical and/or structural abnormalities in some addicted individuals. The present review
provides a summary of the evidence that has accumulated over the past few years to implicate
brain dysfunctions in the varied manifestations of drug addiction. We thus review data on
cerebrovascular alterations, brain structural abnormalities, and postmortem studies of patients who
abuse cannabis, cocaine, amphetamines, heroin, and “bath salts”. We also discuss potential
molecular, biochemical, and cellular bases for the varied clinical presentations of these patients.
Elucidation of the biological bases of addiction will help to develop better therapeutic approaches
to these patient populations.
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Keywords
Cannabis; Cocaine; Methamphetamine; MDMA; Heroin; Cathinones; Bath salts; Dopamine;
Toxicity; Frontal cortex; Hippocampus; Nucleus accumbens; Striatum; Reward mechanisms
✉
jcadet@intra.nida.nih.gov.
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Introduction
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Addictions are brain disorders that affect neural pathways that subsume reward, motivation,
and memory. Because drugs such as amphetamines, cannabis, cocaine, and certain opiates
are illegal, it is difficult to know the exact prevalence of drug use. An estimated 149–271
million people have been reported to use an illicit drug worldwide in 2009. These numbers
represented 125–203 million cannabis users and 15–39 million users of opioids,
amphetamines, or cocaine [47]. The levels and patterns of drug addiction vary with the
pharmacological agents being used. For example, cocaine, marijuana, and methamphetamine
can create various degrees of psychological dependence that is related, in part, to drug-
induced euphoria and an obsessive desire to repeat the initial experience of “getting high”.
The repeated use of opiates induces physical dependence in addition to psychological
dependence. Nevertheless, addiction to any of these substances is associated with adverse
consequences that impact biological, psychological, and social spheres. Addiction also
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causes severe financial burdens on health-care systems throughout the world. The enduring
clinical manifestations of drug addiction are dependent on plastic changes that occur in
various brain regions involved in learning and reward processes (Fig. 1). The psychological
consequences are manifested by an inability to abstain from drug seeking and taking,
unbearable craving, and other characteristic behavioral impairments [198]. The social costs
of addiction also include interactions with the legal system because of behaviors focusing on
procuring illicit drugs, substantial loss of productivity at work, and multiple incarcerations
secondary to criminal behaviors. The National Institute on Drug Abuse has estimated the
cost of drug and alcohol abuse/addiction at around $600 billion annually [141]. The
psychosocial problems associated with addictions might be related to the various biological
effects of these drugs on the central nervous system (CNS). Indeed, these agents can impact
both brain structure and function [198]. Drug-induced CNS functions have been documented
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in clinical settings using cognitive tests and neuroimaging studies [39]. Moreover, a number
of investigators have reported significant biochemical and structural changes in brains of
humans addicted to illicit substances. The present review documents some of the evidence to
support the notion that the commonly used illicit substances do cause pathological changes
in the brain. We also propose some potential biological mechanisms for these abnormalities.
Marijuana use disorder

Cannabis remains the most widely produced and consumed illicit substance globally, ahead
of amphetamines, opioids, and cocaine [143]. In 2009, between 2.8 and 4.5 % of the world
population aged 15–64 years had used cannabis at least once. Cannabis use has increased
globally, particularly in Asia, since 2009 [143]. Cannabis sativa is a plant that grows wild in
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many temperate and tropical climates throughout the world. The cannabis plant contains 489
known compounds representing almost all classes of chemicals, including 70 cannabinoids,
of which delta-9-tetrahydrocannabinol (THC) is the most psychoactive [51]. Smoking is the
preferred route of delivery, but the drug can also be taken orally. The acute
psychopharmacological effects associated with cannabis use include euphoria, increased
self-confidence, relaxation, and a general sense of well-being [75]. Acute psychiatric and
behavioral abnormalities, such as anxiety, panic, and attentional abnormalities, have also
been reported [75]. Negative side effects including psychological and physical dependence

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have also been described in chronic cannabis users [75]. Risks of psychotic disorders or
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symptoms are higher in regular cannabis users [137].
The pharmacological effects of cannabis occur through stimulation of cannabinoid receptors

by Δ9-tetrahydrocannabinol (THC) [51]. These are the CB1 and CB2 receptors that are
abundant in brain’s reward circuitries implicated in addiction [112]. CB1 is found on
presynaptic terminals and modulates neurotransmission through inhibition of adenylyl
cyclase activation and cAMP production, decrease of Ca2+ influx, and increase of K+
conductance [120]. CB1 receptors are distributed heterogeneously throughout the human
brain and are widespread in the neocortex, with particularly high concentrations in frontal
regions and areas of associational function [66]. Thalamic nuclei known to be involved in
behavioral and cognitive function (anterior, mediodorsal, midline, and intralaminar) have
higher receptor density, as do other limbic regions, including the hippocampus, amygdalar
complex, and entorhinal cortex [66]. Within the basal ganglia receptor, distribution is highest
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in the globus pallidus and ventral pallidum [66]. Hindbrain localization is found primarily in
the cerebellar cortex, whereas the brainstem and spinal cord are almost deprived of any CB1
receptors [66]. CB1 receptors are also found in human peripheral tissue, but in much lower
concentrations. On the other hand, the second type of cannabinoid receptor, CB2 [139], is
present mainly in immune tissues and cells [61, 139], with more recent evidence showing
that it is also present in the CNS [207].
The accumulated evidence supports a role of the endocannabinoid system in various aspects
of drug addiction including influencing rewarding properties of drugs, drug-seeking
behavior, and craving/relapse [112]. Cannabis users suffer from deficits in broad cognitive
domains that include memory, attention, decision-making, and psychomotor speed [8].
Additionally, poorer cognitive performance in areas of risk taking, decision-making, and
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episodic memory may influence the degree to which cannabis users engage in risky
behaviors with negative health consequences [173].
Cerebrovascular effects
Marijuana use also impacts the cardiovascular system [179]. Marijuana use increases blood
pressure through sympathetic stimulation and reduced parasympathetic tone [63]. Marijuana
use is associated with cardiac ischemia in susceptible individuals, presumably by causing
catecholamine release that, in turn, increases resting heart rate, ischemia, and arrhythmias
[179]. Coronary vasospasm precipitated by marijuana smoking has also been proposed as a
mechanism for precipitation of acute myocardial infarction in individuals with either normal
or minimally diseased coronary arteries [28]. Myocardial infarction in adults [135] and
children [134] has also been reported with marijuana use. A recent study reported higher
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mortality rates associated with marijuana use among patients with high cardiovascular risks
[59]. Interestingly, smoking marijuana decreases vascular resistance, causes orthostatic
hypotension, and limits oxygen uptake by increasing levels of carboxyhemoglobin [179].
Some of the vascular effects of the drug might be related to the significant increases in
serum apoC-III levels found in heavy marijuana users [83] since there is a positive
relationship between apoC-III levels and risk of vascular disturbances.

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In addition, marijuana smoking may also be related to the precipitation of acute coronary
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syndrome (ACS) [181]. Although the mechanism by which marijuana use might precipitate
ACS is not yet clear, marijuana smoking may lead to the disruption of plaques due to
hemodynamic stresses and the formation of occlusive thrombi [135]. Further evidence for
increased vascular risk factors in marijuana users was provided in a paper that documented
high pulsatility index, a measure of cerebrovascular resistance, and increased systolic
velocity in marijuana users [78]. These vascular changes might be secondary to marijuana-
induced changes in receptor expression in the vasculature, since the drug causes increased
receptor expression after its chronic use [79]. In addition to high consumption of cannabis
[125, 211], potential triggering factors of stroke in these patients include concomitant
alcohol consumption [125, 204]. These observations support the notion that cerebrovascular
consequences of marijuana abuse may be underestimated [203].
Biochemical and structural abnormalities

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Several groups of scientists have investigated the possibility that the drug might cause
alterations in tissue volume, morphology, and composition in the brain [36, 118, 128, 182,
210]. These investigators have found marijuana-induced changes in the hippocampus [210]
and cerebellum [36]. These structural changes might be related, in part, to THC-induced
decreases in the number of neurons and synapses in animal models [98]. Marijuana abusers
also show lower gray matter density in the right parahippocampal gyrus and greater density
bilaterally near the precentral gyrus and the right thalamus as well as lower gray matter
volume in the right anterior hippocampus [17]. This patient population also suffers from
lower white matter density in the left parietal lobe and higher density around the
parahippocampal and fusiform gyri on the left side compared to non-users [118]. Within the
group of heavy cannabis users, reduced gray matter volume strongly correlated with
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individual differences in cannabis use and dependence. Specifically, current weekly cannabis
use was associated with reduced hippocampal volume, and the level of cannabis dependence
was associated with reduced amygdala volume [36]. Other investigators have reported that
cannabis users showed gender-dependent changes in the volume of the prefrontal cortex
[128].
The discovery of cannabinoid receptors in oligodendroglial cells [136] motivated a new line
of investigation on white matter status in marijuana users. For example, cannabinoid
receptors have been detected in white matter structures of the fetal and post-natal rat brain,
including the corpus callosum, anterior commissure, fornix, stria terminalis, and stria
medullaris [166]. In adults, the density of cannabinoid receptors is reduced in these
structures [66, 166]. These observations suggest the existence of a developmental period
during which white matter structures might be particularly sensitive to the enduring effects
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of exogenous cannabis exposure. Down-regulation of the endogenous cannabinoid system

due to long-term cannabis exposure during this developmental period [40] may result in
apoptosis of oligodendrocyte progenitors [136] and, thereby, alter white matter development
[6, 96, 183]. The age during which regular cannabis use begins might be a key factor
determining the severity of any white matter alteration in marijuana users [212]. In their
study, radial and axial diffusivity correlated positively with the age at which regular use
commenced [212]. Axonal connectivity was found to be impaired in the right fimbria of the

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hippocampus (fornix), splenium of the corpus callosum, and commissural fibers extending
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to the precuneus. These observations are consistent with the high levels of cannabinoid
receptors in the fornix and corpus callosum of the developing rat brain [136, 166]. All users
in the Zalesky et al. study [212] had started regular use of the drug during adolescence or
early adulthood, times of continuing white matter development [6].
In summary, the wealth of information gathered from neuroimaging studies has indicated
that marijuana abuse disorder is accompanied with both functional and structural changes in
various regions of the brain. There is still an almost complete lack of information generated
from postmortem studies. The one study that we located reported an increase in the density
of cannabinoid-1 receptors in the caudate and putamen of subjects who had recently ingested
cannabis [46], indicating that the drug can indeed impact the neurochemistry of the
cannabinoid system. To better understand the potential clinical impact of this drug, more
neuropathological studies that use modern neurobiological techniques are necessary to
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elucidate the long-term impact of this substance on the brain.
Cocaine use disorder

Cocaine is a highly addictive drug due to its short biologic half-life and strong reinforcing
properties that can lead to compulsive usage. The United Nations Office on Drugs and
Crime (UNODC) estimates the annual prevalence of cocaine use to be between 0.3 and 0.5
% of the world population aged 15–64, or about 14.2–20.5 million people in that age range
[142].
The acute effects of the drug include intense euphoria, increased energy, and alertness that
are linked to cocaine’s inhibition of dopamine (DA) transporter function and consequent
increased DA levels in the synaptic cleft [163] (Fig. 2). In contrast, cocaine overdose is
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associated with seizures, status epilepticus, headaches, and strokes [145]. The long-term
effects of the drug that include anxiety, depression, drug craving, and hypersomnolence
[199] might involve disturbances in various neurotransmitter systems including
neuropeptidergic stress systems [91]. Cocaine use is also accompanied by adverse
consequences on the cardiovascular, thermoregulatory, and respiratory systems in addition to
its neuropsychiatric sequelae [145]. These neuropsychiatric manifestations include
decrements in several cognitive domains including executive function, decision-making,
impulsivity, visuoperception, psychomotor speed, manual dexterity, verbal learning, and
memory [145]. These cognitive deficits are probably related to functional dysfunctions in the
prefrontal lobe [16, 68], since neurological patients who suffer damage in this brain region
manifest similar cognitive problem [12].
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Other neurological manifestations of cocaine abuse include movement disorders that are
probably due to disturbances in nigrostriatal dopaminergic transmission [31]. Tourette-like
symptoms, dystonic reactions, prolonged dyskinetic movements, and choreic movements
have all been reported with heavy use of the drug [15]. Some patients also suffer from
cocaine-induced excited delirium [194], a syndrome similar to neuroleptic-induced
neuroleptic malignant syndrome which is characterized by hyperthermia, extrapyramidal
signs, altered consciousness, and autonomic dysfunction [92, 194].

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Chronic cocaine abuse is known to be associated with destructive nasal, and midfacial bones
and soft tissue destruction [110]. These necrotic changes are secondary to the combined
effects of cocaine-induced vasoconstriction and damage to endothelial cells. The hard palate,
lateral nasal wall, and nasal septum are the most commonly affected sites [110]. Myocardial
infarction, life-threatening ventricular arrhythmias, and cerebral infarction are associated
with cocaine [145, 195]. Cocaine-induced seizures are usually single, tonic-clonic, and may
resolve without intervention [154, 199]. Neurological patients with known seizure disorders
are twice as likely to suffer from cocaine-induced seizures [54]. However, these events can
also be pre-terminal and the risk of patients dying increases with multiple seizures,
hyperthermia, acidosis, cardiac dysrhythmia, and cardiac arrest [199]. The abuse of large
doses of cocaine by young patients [99] can also cause hemorrhagic strokes when the drug is
taken either intravenously or smoked [156]. The cause of these strokes might be related to
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drug-induced hypertension [67]. Ischemic strokes have also been reported [90], with
vasospasm, cerebral vacuities, and arterial thrombosis having been suggested as causative
agents [16].
In addition, cocaine use might cause stroke by dislodging thromboemboli [171]. Importantly,
Nolte et al. [146] have reported that 59 % of cases of fatal intracranial hemorrhages followed
over a period of 1 year were associated with cocaine abuse [146]. This prospective study
found no specific pathologic lesions to support either inflammatory or vasculotoxic
etiologies. The authors suggested that cocaine-mediated pharmacodynamic changes such as
vasospasm and hypertension as possible mechanisms that would not have left any
pathological traces [146]. Other important mechanisms for cocaine-induced strokes include
impaired cerebral auto-regulation of blood flow with cerebral artery dilatation or reperfusion
injury [15]. Others have reported the presence of underlying aneurysms or arteriovascular
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malformations as causative factors for cocaine-associated intracerebral and subarachnoid

hemorrhages [24]. For example, there are reported cases of cocaine-associated aneurysm
rupture [105], with these occurring at an earlier age than expected in comparison to non-
drug-using patients [151]. Interestingly, Fessler et al. [56] reported that the average size of
the berry aneurysm observed in 12 cocaine users was 4.9 mm, compared to 11 mm in non-
drug-using patients. Also, this study suggested that chronic cocaine use appears to
predispose patients who harbor incidental neurovascular anomalies to present with ruptures
of aneurysm at an earlier point in the natural history of the disorder [56]. Nevertheless, much
remains to be done to better understand the pathobiological bases of the cardiovascular and
cerebrovascular effects of this drug.

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A number of abnormalities in gene and protein expression patterns have been found in
postmortem brains of cocaine addicts. Specifically, DAT levels and DA uptake are increased
in the ventral striatum of cocaine abusers [116]. Cocaine addicts who died because of
cocaine-induced delirium did not show similar increases in DAT expression, suggesting that
this patient population might represent an important subgroup of patients with differential
responses to the abuse of the drug [115]. Although cocaine exerts its biochemical effects in
the brain by increasing DA levels in dopaminergic synaptic areas, there is no evidence that

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the expression of either D1 or D2 receptor gene is affected in the nucleus accumbens,

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caudate, putamen, or substantia nigra of cocaine addicts [127]. There is, however, increased
D3 receptor mRNA expression in the nucleus accumbens in victims of cocaine overdoses
[176]. Serotonin transporter (SERT) densities are also increased in the nucleus accumbens
and striatum in victims of cocaine overdose [117]. Moreover, decreased levels of enkephalin
mRNA, mu opioid receptor binding, and dopamine uptake sites have been reported [88,
194]. In contrast, the levels of dynorphin mRNA and kappa opioid receptor binding are
increased [82, 185]. Other neuropeptides of interest include cocaine- and amphetamine-
regulated transcript (CART) that is increased in the nucleus accumbens of cocaine abusers
[1]. Of interest to the discussion of white matter abnormalities described above are the
observations that a number of myelin-related genes, including myelin basic protein (MBP),
proteolipid protein (PLP), and myelin-associated oligodendrocyte basic protein (MOBP) are
decreased in the brains of cocaine abusers [95]. These decreases occur in the ventral and
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dorsal regions of the caudate and putamen, suggesting that widespread changes to the
myelin structure could be associated with neuroadaptive changes in the brain of chronic
cocaine abusers.
Additionally, a study of brain biomarkers showed that fatal cases classified as excited
delirium exhibited elevated levels of heat shock protein 70 (HSP70). These changes in
HSP70 in conjunction with dopamine transporter levels were stated to be a reliable marker
of excited delirium [115]. A recent study also reported that HSPA1A and HSPA1B gene
expression, the HSP70-encoding genes, was increased in cocaine-related deaths in
comparison with drug-free controls [86]. Because elevated HSP70 expression was related to
a prolonged survival period, HSP70 might not be a reliable brain biomarker of excited
delirium [86].
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Cocaine addicts suffer from cognitive dysfunctions that are probably secondary to abnormal
functions in the prefrontal cortex (PFC) [74]. Structural abnormalities in the PFC have
indeed been found in cocaine addicts [55, 119, 180]. Specifically, Fein et al. [55] reported
that dependence on crack cocaine (with or without concomitant alcohol dependence) was
associated with reduced prefrontal cortical volume (dependence on both substances was not
associated with greater prefrontal volume reductions). Reduced prefrontal cortical volume
was associated with cognitive impairments in frontal cortex-mediated abilities (executive
function). These observations suggest that reduced cerebral volume might have functional
consequences. Matochick et al. [119] also found lower gray matter tissue density in the
frontal cortex of cocaine addicts. Reduced frontal gray volume was also observed in cocaine
addicts. There was also reduced gray volume in the temporal cortex and cerebellum of these
patients [180]. Cocaine abusers showed reduced total cortical volume and reduced thickness,
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including paralimbic cortices such as the insula and dorsal prefrontal cortex [111]. Recently,
another study documented lower gray matter volumes in the orbitofrontal cortex, right
Inferior frontal gyrus, right insula, left amygdala and parahippocampal gyrus, temporal
gyrus, and bilateral caudate in cocaine-dependent individuals [138]. Also, volume reduction
in the striatum and the right supramarginal gyrus has been found in this patient population
[7].

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Cocaine dependence is also associated with impaired integrity of the white matter in the
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frontal lobe and corpus callosum [100, 101]. Xu et al. [208] described reduced integrity of
the white matter, measured by diffusion tensor imaging, in the frontal, parietal, temporal,
and occipital lobes of cocaine abusers. Diffusion tensor imaging (DTI) is a quantitative MRI
technique that involves measuring the fractional anisotropy of the random motion of water
molecules in the brain. Since anisotropy is modulated by the presence of myelin, diffusion
indices have been used to measure changes in white matter integrity in many diseases that
involve myelin degeneration [58]. Although multiple indexes of tissue abnormalities have
been described using DTI, these changes will need to be linked to histological alterations to
validate the relationship of DTI to tissue changes on a microscopic level.
Recently, Bell et al. [13] provided more evidence for significant structural changes in the
white matter of abstinent cocaine addicts. These abnormalities were observed in the left
anterior callosal fibers, left genu of the corpus callosum, right superior longitudinal
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fasciculus, right callosal fibers, and the superior corona radiata bilaterally. The reason for
these abnormalities includes cocaine-induced repeated vasoconstriction and hypoperfusion
of the brain as suggested by Lim et al. [101]. This idea is supported by findings that chronic
cerebral hypoperfusion causes white matter abnormalities in an animal model [97]. Other
potential mechanisms include toxic effects of prolonged use of the drug through mechanisms
that include increased cellular calcium [98] and/or endoplasmic reticulum stress [27]. This
argument is consistent with the report of decreased dopamine cell numbers (−16 %) in the
anterior midbrain of human cocaine users [103]. The presence of reactive gliosis in this
brain region area suggests that the decreased number of dopamine cells found in cocaine
users might be a relatively recent event [103]. More studies are necessary to document the
potential neurodegenerative effects of this drug on the brain.
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Amphetamine analog use disorders

Use of amphetamines remains widespread globally and appears to be increasing [143].
Amphetamines are psychoactive substances with stimulant, euphoric, anorectic, and, in
some cases, empathogenic, entactogenic, and hallucinogenic properties [32]. These
compounds enter the brain very easily and cause significant changes in monoaminergic
neurotransmission [32]. Amphetamines act as competitive substrates at the membrane
transporters of noradrenaline (NAT), dopamine (DAT), and serotonin (5-HTT; SERT),
reducing the reuptake of endogenous neurotransmitters while inducing the reverse transport
of endogenous neurotransmitters [50]. Amphetamines also promote the release of DA, 5-HT,
and NE from storage vesicles and cause increases in their cytoplasmic concentrations,
rendering them readily available for reverse transport [93], (Fig. 3). This phenomenon
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occurs because the amphetamines can disrupt the pH gradient required for vesicular DA
sequestration, with a secondary release of DA into the cytoplasmic compartment [186, 187].
Of these amphetamines, methamphetamine is taken by oral, intravenous, nasal, or smoking
routes [93], whereas 3,4-methylenedioxymethamphetamine (MDMA) is usually ingested
orally [32].

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Methamphetamine use disorder

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Abuse of methamphetamine has become an international public health problem [143].

Annual prevalence estimates for amphetamine-like substances ranged between 0.3 and 1.3 %
in 2009, or about 14–57 million people aged 15–64 years [143]. Amphetamine abuse is
highly prevalent in Africa, the Americas, and Asia. The inexpensive production of
methamphetamine, its low cost, and long duration of action are factors that contribute to its
abuse profile [93]. Methamphetamine users experience a sense of euphoria, increased
productivity, hypersexuality, decreased anxiety, and increased energy after acute intake [81].
These effects can last for several hours, because the elimination half-life of
methamphetamine ranges from 10 to 12 h [171]. Long-term negative consequences of
methamphetamine abuse range from anxiety and insomnia to convulsions, paranoia, and
brain damage [93]. Consistent with abnormalities in brain structure and function, cognitive
impairments have also been observed in methamphetamine abusers [45]. A meta-analysis
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study by Scott et al. [175] identified significant deficits of a medium magnitude in several
different cognitive processes that are dependent on the functions of frontostriatal and limbic
circuits. These include episodic memory, executive functions, complex information
processing speed, and psychomotor functions [175]. Methamphetamine dependence is
associated with complaints of cognitive dysfunctions including memory problems and self-
reported deficits in everyday functioning [160].
Methamphetamine is a potent sympathomimetic that causes DA and NE release in the
vascular system, with resulting increases in pulse rate and blood pressure [93]. In a
retrospective study, Ho et al. [80] studied cases from patients who used methamphetamine,
documented by history or urine toxicology screening. They found an association of
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methamphetamine usage with ischemic strokes, intracerebral hemorrhages, and

subarachnoid hemorrhages. Other investigators have reported similar findings [76, 150, 155,
201]. There was a predominance of vascular pathology in the anterior circulation and these
included vascular stenoses, atherosclerosis, and aneurysms. Intracerebral hemorrhage is also
associated with the use of amphetamines and other related sympathomimetic drugs [76].
Methamphetamine-induced transient elevated blood pressure might be a causative factor for
the presentation of intracerebral hemorrhage [20], a mechanism similar to the known
consequences of idiopathic hypertension [102]. This idea is consistent with the report that
methamphetamine-induced strokes occur in regional distributions typical for hypertensive
hemorrhages (e.g., basal ganglia, thalamus, pons, and subcortical white matter). In several
reports, patients who used illicit drugs (including methamphetamine) were reported to have
irregular beading of vessels and small artery occlusive changes [126, 168]. More work is
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needed before firm conclusions can be drawn on this issue because other studies [209] have
failed to confirm these findings.
Biochemical and structural brain findings

As mentioned above, methamphetamine causes massive DA release in the synaptic cleft in
brain regions that receive dopaminergic projections from the midbrain [93, 186].
Postmortem studies have documented reduced levels of DA, TH, and DAT in the caudate of

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chronic methamphetamine users [202]. Consistent with these observations, neuroimaging

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studies also found significantly lower DAT binding in the brains of methamphetamine users
[124, 196]. Lower VMAT-2 binding was also reported in some methamphetamine addicts
[85]. DAT binding levels improved significantly in the caudate nucleus after a period or
protracted abstinence from methamphetamine use [85, 196]. Methamphetamine abusers also
show significant alterations in brain metabolism in several brain regions [174, 189]. These
abnormalities include hypometabolism in the frontal cortex [88] and the anterior cingulate
cortex (ACC) [104]. Higher parietal metabolic activity has been reported in
methamphetamine abusers [14, 197]. Methamphetamine addicts also show structural
abnormalities that include volume loss of cortical gray in the temporal and the insular
cortices that are age dependent [140]. Methamphetamine users also suffer from smaller
intracranial [174] and hippocampal volume [189]. Changes in white matter tissue integrity
and/or organization (prefrontal white matter, corona radiata, genu of the corpus callosum,
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and perforant path were also reported in these patients [190].
The idea that methamphetamine abuse might increase the risk of developing Parkinson’s
disease (PD) was stimulated by studies in animals that had documented methamphetamine-
induced neurotoxic effects in nigrostriatal dopaminergic terminal areas [93], (Fig. 3).
Interestingly, a recent epidemiological study found that the risk of developing PD was 75 %
higher among methamphetamine abusers than in a group of control subjects [29]. The risk of
PD was also higher in the methamphetamine group compared with a group of cocaine
abusers [31]. One of the consequences of methamphetamine toxicity is reactive astrocytosis
[19] and microglial activation in various brain regions [158, 177]. The presence of increased
microgliosis in the brains of methamphetamine addicts [177] and in PD patients [49]
together with the significant loss of dopaminergic markers in both groups [69] might provide
a partial explanation for the epidemiological data cited [29]. It is also possible that
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methamphetamine-induced astrocytosis might account for larger volume of the basal ganglia
reported in some methamphetamine addicts [33, 84].
MDMA use disorder

MDMA is a popular illicit drug in North America, Europe, and Oceania [143]. However,
MDMA use has been declining in some parts of the world [143]. MDMA is associated with
experience of euphoria, increased self-confidence, increased sensory perceptions,
tachycardia, and hyperthermia [64]. These effects wear off after 24–48 h, with patients
experiencing muscle aches, depression, fatigue, and decreased concentration [64]. Long-
term use of the drug is reported to be associated with serotonergic dysfunctions that impact
cognitive domains [70, 153]. Cognitive deficits include verbal fluency, verbal memory,
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working memory, executive function, and short and long-term prospective memory [153].
Heavy MDMA users scored higher than controls in a number of psychiatric symptoms that
include paranoid ideation, somatization, obsessionality, phobic anxiety, altered appetite, and
restless sleep [152].

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In human studies, acute MDMA administration can cause arrhythmias, hypertension,

increased myocardial oxygen consumption, cardiac ischemia, and heart failure [70, 114].
Intracranial hemorrhages have been reported as a result of pre-existing congenital
abnormalities [93]. Damage to vessel walls is also a possible cause of strokes concurrent
with MDMA use [87]. Additionally, several deaths in MDMA users have been reported
related to hyponatremia that can cause severe cerebral edema [131]. Patients usually present
with confusion, convulsions, delirium or both that can rapidly progress to coma and death
[74]. Some of these clinical observations are probably secondary to MDMA-induced
sustained high levels of circulating biogenic amines [192]. Interestingly, MDMA can also
stimulate catecholamine release from cardiovascular cells in vitro [57]. Alterations of
calcium homeostasis might also contribute to the acute and chronic cardiovascular changes
associated with MDMA use [192].
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MDMA is a substrate of the serotonin transporter (SERT) which enters the neurons and
releases serotonin (5-hydroxytryptophan) from storage vesicles [32, 76]. MDMA also
inhibits the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme for serotonin
synthesis, and inhibits serotonin degradation by monoamine oxidase B [30]. MDMA is also
a serotonin2A (5-HT2A) receptor agonist [9]. Some of the biochemical actions of MDMA
might be relevant to the clinical observations that MDMA users show reduced SERT ligand
binding across multiple brain regions in PET studies [121–123]. Another study also reported
that MDMA-preferring users showed significant decreases in SERT binding in the
neocortex, striatum, and amygdala [52]. SERT binding was negatively correlated with the
number of lifetime MDMA exposures [52]. The clinical data are consistent with postmortem
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evidence that MDMA users do exhibit decreased SERT protein levels in the striatum, and
occipital, frontal, and temporal cortices [89]. Active MDMA users also showed decreased 5-
HT2A receptor levels in their brains [161]. MDMA-treated rats have consistently been
shown to have abnormalities in their serotonergic system [107]. These include decreased
levels of 5-HT and of its major metabolite, 5-HIAA, decreased number of 5-HT transporters,
and decreased activity of the rate-limiting enzyme of 5-HT synthesis, TPH [34]. These
abnormalities are reported to last for months or even years after drug administration [107].
Consistent with these findings, lower 5-HIAA levels were measured in the cerebral spinal
fluid (CSF) of active recreational MDMA users [121].
MDMA abuse is also associated with long-lasting effects on glucose metabolism in the
human brain [22]. Reduced glucose metabolic uptake has been reported in the amygdala,
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hippocampus, and Brodmann area II [147]. There was reduced glucose uptake within the
striatum and cingulate cortex in MDMA users, effects that were more severe with a history
of very early abuse [147]. MDMA users also suffer from gray matter reduction in several
brain regions and these abnormalities might be relevant to reported cognitive impairments in
these patients [37]. Cowan et al. [38] compared MDMA users to non-MDMA users and
found that there was decreased gray matter in the Brodmann area, the cerebellum, and the
brainstem. Daumann et al. [43] also reported that experienced MDMA users showed several
regions of lower gray matter volume in the medial orbitofrontal cortex and the medial dorsal

anterior cingulate cortex in comparison to individuals with low levels of MDMA exposure.
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The thalamus was also affected in MDMA users [44]. The clinical findings are consistent
with the animal literature. DA-induced oxidative stress in 5-HT terminals, and 5-HT2A and
dopamine D1 receptor-mediated hyperthermia are potential causative factors for MDMA
neurotoxicity [44, 186]. There was no specific toxic or fatal concentration of MDMA,
though higher concentrations were observed in cases of MDMA toxicity, when compared
with polydrug use and trauma cases [130]. In determining the cause of death, the
postmortem concentration of MDMA cannot be taken to provide the cause of death without
consideration of the history and the other autopsy findings [129]. In a MDMA-related
autopsy, histological necrosis of the globus pallidus was reported, with intimal proliferation
in large blood vessels [184].
New drugs and new challenges: the emergence of “bath salts”—Drug culture
varies between different geographical locations and changes with time as different drugs
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emerge and with their availability on the drug scene. This may be related to availability or
synthesis of new drugs of abuse. One evolving phenomenon is the use of synthetic
cathinones, commonly referred to as “bath salts” [10, 133]. They are often snorted and this
may result in foreign material in the alveoli of the lungs and can be seen on microscopy at
autopsy. These β-ketoamphetamines are structurally related to methamphetamine and
MDMA. They are psychostimulants and the effects of these drugs in humans have been
increasingly reported in the last few years [42, 206]. They have been shown to have powerful
cocaine-like actions in experimental models [11]. Commonly encountered drugs include
mephedrone, methylone and 3,4-methylenedioxypyrovalerone (MDPV). Use of these drugs
in humans is associated, among other things, with dizziness, euphoria, anxiety, and
depression [42].These drugs can cause hot flushes and feelings of hyperthermia, known as
mephedrone sweats. Deaths have been associated with hyperthermia, but so far reported
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organ pathology in humans has been non-specific [130].
Animal models have shown central nervous system effects with locomotor effects [113],
affecting long-term cognitive function [48]. A study of mice given a binge-like regimen of
mephedrone caused hyperthermia and locomotor stimulation, but did not show decreased
levels of dopamine, tyrosine hydroxylase, or dopamine transporter [3]. There was no
microglial activation in the striatum and no increase was seen in glial fibrillary acidic protein
levels [3]. The same group found that, while mephedrone did not induce toxicity to
dopamine nerve endings in the striatum, it did potentiate the effects of other neurotoxic
drugs of abuse [4]. This could be very significant in view of the known polydrug use of users
of stimulant drugs and that tablets may contain both mephedrone and MDMA [65].
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Heroin use disorder

Use of opiates (heroin and opium) has been stable around the world (16.5 million people, or
0.4 % of the population aged 15–64 years), although a higher prevalence for opiate is found
in southwest and central Asia, eastern and southeastern Europe, and North America [143].
Heroin is the most commonly abused drug within opiates [25]. Heroin is a semi-synthetic
drug derived from opium. The drug is taken orally, via inhalation, and/or by intravenous
injections [23]. Opiates have their biochemical and physiological effects via stimulation of

three types of opiate receptors that are the μ, κ, and δ opioid receptors [191]. When
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administered via the oral route under medical supervision, opioids do not appear to produce
major adverse events; the risk of developing dependence was reported to be rather small
[25]. Dependence develops most rapidly after intravenous use [144]. Acute and chronic
effects of heroin include neurovascular disorders, leukoencephalopathy, and atrophy [23].
Heroin users show several cognitive deficits in neuropsychological tests. These deficits
include visual memory, working memory, processing speed, and executive function [71].
In up to 90 % of all cases, the brain of patients dying of heroin overdose shows cerebral
edema with increased brain weight at autopsy [148, 162]. Bilateral, symmetric ischemic
lesions/necrosis of the globus pallidus was found in 5–10 % of heroin addicts after
intravenous or intranasal abuse [162, 193]. These pathological findings are thought to be due
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to recurrent heroin-induced episodes of hypoxia [2, 162]. Single-photon emission computed

tomography (SPECT) studies in opiate-dependent subjects have also consistently reported
decreased regional cerebral blood flow (rCBF), especially in the frontal and temporal cortex
[41, 167].
Heroin use is associated with reports of ischemic strokes [73]. These strokes are probably
due to cardio-embolic phenomena in the setting of infective endocarditis [106]. Another
source for embolic phenomena in the heroin abuser is dislodgment of foreign bodies added
to heroin mixtures. These foreign bodies include starch, sugar, quinine, caffeine, and talcum
powder that may enter the circulation and become lodged in the lungs [106]. Granulomatous
reactions from these substances can lead to pulmonary hypertension [106]. Arteritis and
vasculitis have also been implicated as causes of heroin-related strokes [21]. Other potential
causes of stroke include hypotension and hypoxemia induced by opiate overdose that can
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result in global hypoxic-ischemic injury [2]. “Beading” on angiography has been reported,
but strong pathological evidence is lacking [21]. In addition to acute ischemia, white matter
changes from microvascular disease have been reported in chronic heroin abusers [25].
Diffuse, symmetric, and bilateral T2 hyperintensities have been observed in the subcortical
or periventricular white matter, in a manner consistent with the diagnosis of vascular
leukoencephalopathy [159].

Postmortem studies have reported that heroin addicts also show decrease of alpha
adrenergic-2 in the frontal cortex, hypothalamus, and caudate nucleus [60]. Astrocytes of the
frontal cortex of heroin addicts showed decreased density of I2-imidazoline receptors and
decreased immunoreactivity of the related imidazoline receptor protein [170]. Heroin addicts
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also showed alterations in the cortical density of G-protein subunits [53, 77]. Specifically,
there was a significant increase in the Gβ subunit immunoreactivity in the temporal cortex
[77] and increased density of Gα subunits in the frontal cortex of heroin addicts [53, 77].
These results appear to be consistent with the known coupling of opiate receptors to
guanosine triphosphate (GTP) binding (G) proteins [53]. Other findings of interest include
decreased NF-L protein levels in the frontal cortex of heroin addicts [62] that suggest that
opiate drugs might cause axonal damage after their chronic abuse.

Heroin addiction is also associated with profound alterations in brain structure and
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composition [25, 54]. Heroin addicts show alterations in gray and white matter morphometry
[149, 169] and functions [109] in the brain. Preclinical studies of opioid-induced effects on
neural systems support the idea that clinical changes in brain function and structure (e.g.,
altered dendritic spine density and neuronal apoptosis) are consequences of chronic heroin
exposure [165]. There are enlarged ventricular spaces [41] and loss of frontal volume loss in
heroin addicts [157]. Opiate-dependent subjects on methadone maintenance therapy showed
decreased gray matter density in the prefrontal, insular, temporal, and fusiform cortex [108].
Thalamic volume is also reduced in heroin-dependent patients [159].
A distinct entity, spongiform leukoencephalopathy, has been described after inhalation of

pre-heated heroin [94]. Other modes of heroin intake do not seem to be associated with the
disease. Although it has been suggested that the disorder was related to a contaminant
(poisoned heroin vapors, paralysis)-induced lipophilic toxin-mediated process that was
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enhanced by cerebral hypoxia, the exact etiology for these abnormalities has remained an
enigma [172, 205]. The neurological deficits associated with this entity are irreversible with
progression to death in some patients, and there is no effective therapy [200]. Scans of these
patients usually show symmetrical non-enhancing hypodense areas in the cerebral and
cerebellar white matter [178, 188, 200]. Selective involvement of the corticospinal tract, the
solitary tract, and the lemniscus medialis have also been reported in heroin abusers [188].
MRI scans revealed areas of decreased signal intensity (hypointense) on T1-weighted
images and increased signal intensity (hyperintense) on T2-weighted images [178, 188,
200]. The neuroradiological findings are usually not correlated with the extent of the
neurological deficits [205]. On neuropathological examination, spongiform degeneration of
the white matter is characterized by vacuoles surrounded by a network of thin myelinated
fibers, reduced number of oligodendrocytes, and reduction of axons [164, 178]. The absence
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of typical hypoxic lesions and the presence of spongiosis with massive astrogliosis
distinguish these cases from those with delayed leukoencephalopathy following severe
hypoxia [164]. Increased prevalence of white matter hyperintensity lesions was reported in
the frontal lobes of opiate-dependent patients compared with control subjects [108].
Recently, Bora et al. [18] also reported that long-term opiate abusers had significant
decreases in axial diffusivity in superior longitudinal fascicule and right frontal white matter,
suggesting that prolonged use is associated with axonal injury in these regions. Changes in
the expression of myelin-related genes and their products, drug-induced oxidative stress/
mitochondrial dysfunction, and/or apoptosis are potential mechanisms for the appearance of
white matter lesions in heroin addicts [18]. Additional neuropathological evidence indicates
that heroin addiction might cause deposition of hyperphosphorylated tau and
neuroinflammation in the brain [5, 26].
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Approach to autopsy in drug-related deaths

A pathologist conducting an autopsy on a potentially drug-related death or a
neuropathologist requested to examine a brain from a drug-related case needs to be aware of
the value and limitations of any examination. Also in assessing drug-related findings,
consideration of the effects of polydrug use needs to be determined. Polydrug use is now
common and the findings of organ damage may be related to more than one drug. One of the

questions that have to be dealt with is whether organ retention is justified or legally allowed
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[72]. Drug-related deaths are typically performed as medico-legal autopsies, which may
limit the ability to retain whole organs or tissue for future research [35] that is sorely needed
in this area.
The approach to the investigation of a drug-related death requires knowledge of the history,
scene, and toxicological findings. The neuropathologist needs to be cognizant of potential
pathological findings in such cases [132]. In many deaths where cannabis, stimulant, or
opiate drugs have been used, there will be no specific findings when routine
neuropathological techniques are used. However, pathology related to drug use will be
encountered in cases as detailed above, and anticipation of the needs for neuropathology and
specific tissue retention and examination may yield better outcomes. This issue is important
for both clinical and research purposes in view of a lack of enough strong supporting
evidence that certain drugs do cause incontrovertible neuropathological changes that form
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the substrates for the clinical presentations associated with drug addiction.
Conclusions
Substance dependence is characterized by abnormal goal-directed behaviors that are the
manifestations of pathological changes in the cortico-striatal-limbic circuitries that subsume
reward-related behaviors. However, acute and chronic effects of illegal drugs appear to reach
beyond the boundaries of these circuits. The data reviewed here indicate that the abuse of
illicit drug is accompanied by moderate to severe neuropsychological impairments that
appear to be secondary to functional and structural changes in various brain regions,
including both cortical and subcortical regions of the human brain. These abnormalities are
secondary, in part, to drug-induced vascular abnormalities, oxidative stress, and the
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induction of other biochemical cascades that have been identified as causative factors in
other classical neurologic disorders such as PD or strokes. Because drug dependence
develops over many months, it is highly likely that drug-related changes of behaviors are
mediated in part by these pathological phenomena in such a way that these alterations might
significantly impact the clinical course of addiction. Thus, impaired learning of verbal
instruction due to specific brain dysfunctions might negatively impact a patient’s ability to
follow instruction, with subsequent increase in recidivism. This argument suggests that the
addictions might need to be classified as neurological disorders, with emphasis on an
approach that includes thorough neuropsychological and neuroimaging assessments patients
who present for treatment of these severe disorders. Additionally, more efforts are needed to
encourage postmortem evaluations of the brains of these patients. This approach has recently
been successfully applied in the cases of affective and schizophrenic disorders and has
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stimulated important potential new leads toward the elucidation of the molecular pathology
of these disorders.
Acknowledgments
This paper is supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), NIH,
and DHHS. V. Bisagno is a Fulbright Fellow, United States Department of State and is also supported by grants
PIP11420100100072 and PICT 2012-0924, Argentina.

References
Author Manuscript
1. Albertson DN, Pruetz B, Schmidt CJ et al. (2004) Gene expression profile of the nucleus accumbens
of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem 88:1211–1219
[PubMed: 15009677]
2. Andersen SN, Skullerud K (1999) Hypoxic/ischaemic brain damage, especially pallidal lesions, in
heroin addicts. Forensic Sci Int 102:51–59 [PubMed: 10423852]
3. Angoa-Pérez M, Kane MJ, Briggs DI et al. (2013) Mephedrone does not damage dopamine nerve
endings of the striatum, but enhances the neurotoxicity of methamphetamine, amphetamine, and
MDMA. J Neurochem 125:102–110 [PubMed: 23205838]
4. Angoa-Pérez M, Kane MJ, Francescutti DM et al. (2012) Mephedrone, an abused psychoactive
component of “bath salts” and methamphetamine congener, does not cause neurotoxicity to
dopamine nerve endings of the striatum. J Neurochem 120:1097–1107 [PubMed: 22191803]
5. Anthony IC, Norrby KE, Dingwall T et al. (2010) Predisposition to accelerated Alzheimer-related
changes in the brains of human immunodeficiency virus negative opiate abusers. Brain 133:3685–
3698 [PubMed: 21126996]
Author Manuscript
6. Barnea-Goraly N, Menon V, Eckert M et al. (2005) White matter development during childhood and
adolescence: a cross-sectional diffusion tensor imaging study. Cerebral cortex (New York, NY:
1991) 15:1848–1854
7. Barrós-Loscertales A, Garavan H, Bustamante JC et al. (2011) Reduced striatal volume in cocaine-
dependent patients. NeuroImage 56:1021–1026 [PubMed: 21338692]
8. Batalla A, Bhattacharyya S, Yücel M et al. (2013) Structural and functional imaging studies in
chronic cannabis users: a systematic review of adolescent and adult findings. PLoS ONE 8:e55821
[PubMed: 23390554]
9. Battaglia G, Brooks BP, Kulsakdinun C, De Souza EB (1988) Pharmacologic profile of MDMA
(3,4-methylenedioxymethamphetamine) at various brain recognition sites. Eur J Pharmacol
149:159–163 [PubMed: 2899513]
10. Baumann MH, Partilla JS, Lehner KR (2013) Psychoactive “bath salts”: not so soothing. Eur J
Pharmacol 698:1–5 [PubMed: 23178799]
11. Baumann MH, Partilla JS, Lehner KR et al. (2013) Powerful cocaine-like actions of 3,4-
Author Manuscript
methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive “bath salts”

products. Neuropsychopharmacology 38:552–562 [PubMed: 23072836]
12. Bechara A, Damasio AR, Damasio H, Anderson SW (1994) Insensitivity to future consequences
following damage to human prefrontal cortex. Cognition 50:7–15 [PubMed: 8039375]
13. Bell RP, Foxe JJ, Nierenberg J et al. (2011) Assessing white matter integrity as a function of
abstinence duration in former cocaine-dependent individuals. Drug Alcohol Depend 114:159–168
[PubMed: 21075564]
14. Berman SM, Voytek B, Mandelkern MA et al. (2008) Changes in cerebral glucose metabolism
during early abstinence from chronic methamphetamine abuse. Mol Psychiatry 13:897–908
[PubMed: 17938635]
15. Boghdadi MS, Henning RJ (1997) Cocaine: pathophysiology and clinical toxicology. Heart Lung
26:466–483 [PubMed: 9431493]
16. Bolla KI, Cadet JL, London ED (1998) The neuropsychiatry of chronic cocaine abuse. J
Neuropsychiatry Clin Neurosci 10:280–289 [PubMed: 9706535]
17. Bolla KI, Eldreth DA, Matochik JA, Cadet JL (2005) Neural substrates of faulty decision-making
Author Manuscript
in abstinent marijuana users. Neuroimage 26:480–492 [PubMed: 15907305]

18. Bora E, Yücel M, Fornito A et al. (2012) White matter micro-structure in opiate addiction. Addict
Biol 17:141–148 [PubMed: 21070508]
19. Bowyer JF, Davies DL, Schmued L et al. (1994) Further studies of the role of hyperthermia in
methamphetamine neurotoxicity. J Pharmacol Exp Ther 268:1571–1580 [PubMed: 8138969]
20. Brisman JL, Song JK, Newell DW (2006) Cerebral aneurysms. N Engl J Med 355:928–939
[PubMed: 16943405]
21. Brust JC (1997) Vasculitis owing to substance abuse. Neurol Clin 15:945–957 [PubMed: 9367974]

22. Buchert R, Obrocki J, Thomasius R et al. (2001) Long-term effects of “ecstasy” abuse on the
human brain studied by FDG PET. Nucl Med Commun 22:889–897 [PubMed: 11473208]
Author Manuscript
23. Büttner A (2011) Review: the neuropathology of drug abuse. Neuropathol Appl Neurobiol 37:118–
134 [PubMed: 20946118]
24. Büttner A, Mall G, Penning R et al. (2003) The neuropathology of cocaine abuse. Leg Med
5(Suppl 1):S240–S242
25. Büttner A, Mall G, Penning R, Weis S (2000) The neuropathology of heroin abuse. Forensic Sci Int
113:435–442 [PubMed: 10978659]
26. Büttner A, Rohrmoser K, Mall G et al. (2006) Widespread axonal damage in the brain of drug
abusers as evidenced by accumulation of beta-amyloid precursor protein (beta-APP): an
immunohistochemical investigation. Addiction 101:1339–1346 [PubMed: 16911734]
27. Cadet JL, Brannock C (1998) Free radicals and the pathobiology of brain dopamine systems.
Neurochem Int 32:117–131 [PubMed: 9542724]
28. Caldicott DGE, Holmes J, Roberts-Thomson KC, Mahar L (2005) Keep off the grass: marijuana
use and acute cardiovascular events. Eur J Emerg Med 12:236–244 [PubMed: 16175062]
29. Callaghan RC, Cunningham JK, Sykes J, Kish SJ (2012) Increased risk of Parkinson’s disease in
Author Manuscript
individuals hospitalized with conditions related to the use of methamphetamine or other

amphetamine-type drugs. Drug Alcohol Depend 120:35–40 [PubMed: 21794992]
30. Capela JP, Carmo H, Remião F et al. (2009) Molecular and cellular mechanisms of ecstasy-induced
neurotoxicity: an overview. Mol Neurobiol 39:210–271 [PubMed: 19373443]
31. Cardoso FE, Jankovic J (1993) Cocaine-related movement disorders. Mov Disord 8:175–178
[PubMed: 8474485]
32. Carvalho M, Carmo H, Costa VM et al. (2012) Toxicity of amphetamines: an update. Arch Toxicol
86:1167–1231 [PubMed: 22392347]
33. Chang L, Cloak C, Patterson K et al. (2005) Enlarged striatum in abstinent methamphetamine
abusers: a possible compensatory response. Biol Psychiatry 57:967–974 [PubMed: 15860336]
34. Commins DL, Vosmer G, Virus RM et al. (1987) Biochemical and histological evidence that
methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain. J Pharmacol
Exp Ther 241:338–345 [PubMed: 2883295]
35. Cordner S, Leahy F (2013) Ethical research on bodies in the jurisdiction of coroners or medical
Author Manuscript
examiner. Acad Forensic Pathol 3:301–313

36. Cousijn J, Wiers RW, Ridderinkhof KR et al. (2012) Grey matter alterations associated with
cannabis use: results of a VBM study in heavy cannabis users and healthy controls. NeuroImage
59:3845–3851 [PubMed: 21982932]
37. Cowan RL, Lyoo IK, Sung SM et al. (2003) Reduced cortical gray matter density in human
MDMA (Ecstasy) users: a voxel-based morphometry study. Drug Alcohol Depend 72:225–235
[PubMed: 14643939]
38. Cowan RL, Roberts DM, Joers JM (2008) Neuroimaging in human MDMA (Ecstasy) users. Ann N
Y Acad Sci 1139:291–298 [PubMed: 18991874]
39. Daglish MRC, Nutt DJ (2003) Brain imaging studies in human addicts. Eu Neuropsychopharmacol
13:453–458
40. Dalton VS, Zavitsanou K (2010) Cannabinoid effects on CB1 receptor density in the adolescent
brain: an autoradiographic study using the synthetic cannabinoid HU210. Synapse 64:845–854
[PubMed: 20842718]
Author Manuscript
41. Danos P, Kasper S, Grünwald F et al. (1998) Pathological regional cerebral blood flow in opiate-
dependent patients during withdrawal: a HMPAO-SPECT study. Neuropsychobiology 37:194–199
[PubMed: 9648127]
42. Dargan PI, Albert S, Wood DM (2010) Mephedrone use and associated adverse effects in school
and college/university students before the UK legislation change. QJM 103:875–879 [PubMed:
20675396]
43. Daumann J, Koester P, Becker B et al. (2011) Medial prefrontal gray matter volume reductions in
users of amphetamine-type stimulants revealed by combined tract-based spatial statistics and
voxel-based morphometry. Neuroimage 54:794–801 [PubMed: 20817105]

44. De Win MML, Jager G, Booij J et al. (2008) Neurotoxic effects of ecstasy on the thalamus. Br J
Psychiatry 193:289–296 [PubMed: 18827290]
Author Manuscript
45. Dean AC, Groman SM, Morales AM, London ED (2013) An evaluation of the evidence that
methamphetamine abuse causes cognitive decline in humans. Neuropsychopharmacology 38:259–
274 [PubMed: 22948978]
46. Dean B, Sundram S, Bradbury R et al. (2001) Studies on [3H] CP-55940 binding in the human
central nervous system: regional specific changes in density of cannabinoid-1 receptors associated
with schizophrenia and cannabis use. Neuroscience 103:9–15 [PubMed: 11311783]
47. Degenhardt L, Hall W (2012) Extent of illicit drug use and dependence, and their contribution to
the global burden of disease. Lancet 379:55–70 [PubMed: 22225671]
48. den Hollander B, Rozov S, Linden AM, Uusi-Oukari M, Ojanperä I, Korpi ER (2013) Long-term
cognitive and neurochemical effects of “bath salt” designer drugs methylone and mephedrone.
Pharmacol Biochem Behav 103:501–509. doi:10.1016/j.pbb.2012.10.006 [PubMed: 23099177]
49. Doorn KJ, Lucassen PJ, Boddeke HW et al. (2012) Emerging roles of microglial activation and
non-motor symptoms in Parkinson’s disease. Progress Neurobiol 98:222–238
50. Elliott JM, Beveridge TJR (2005) Psychostimulants and monoamine transporters: upsetting the
Author Manuscript
balance. Curr Opin Pharmacol 5:94–100 [PubMed: 15661632]

51. Elsohly MA, Slade D (2005) Chemical constituents of marijuana: the complex mixture of natural
cannabinoids. Life Sci 78:539–548 [PubMed: 16199061]
52. Erritzoe D, Frokjaer VG, Holst KK et al. (2011) In vivo imaging of cerebral serotonin transporter
and serotonin(2A) receptor binding in 3,4-methylenedioxymethamphetamine (MDMA or
“ecstasy”) and hallucinogen users. Arch Gen Psychiatry 68:562–576 [PubMed: 21646575]
53. Escriba PV, Sastre M, Garcia-Sevilla JA (1994) Increased density of guanine nucleotide-binding
proteins in the postmortem brains of heroin addicts. Arch Gen Psychiatry 51:494–501 [PubMed:
8192552]
54. Esse K, Fossati-Bellani M, Traylor A, Martin-Schild S (2011) Epidemic of illicit drug use,
mechanisms of action/addiction and stroke as a health hazard. Brain Behav 1:44–54 [PubMed:
22398980]
55. Fein G, Di Sclafani V, Meyerhoff DJ (2002) Prefrontal cortical volume reduction associated with
frontal cortex function deficit in 6-week abstinent crack-cocaine dependent men. Drug Alcohol
Author Manuscript
Depend 68:87–93 [PubMed: 12167554]

56. Fessler RD, Esshaki CM, Stankewitz RC et al. (1997) The neurovascular complications of cocaine.
Surg Neurol 47:339–345 [PubMed: 9122836]
57. Fitzgerald JL, Reid JJ (1994) Sympathomimetic actions of methylenedioxymethamphetamine in rat
and rabbit isolated cardiovascular tissues. J Pharm Pharmacol 46:826–832 [PubMed: 7699571]
58. Fox RJ, Cronin T, Lin J, Wang X, Sakaie K, Ontaneda D, Mahmoud SY, Lowe MJ, Phillips MD
(2011) Measuring myelin repair and axonal loss with diffusion tensor imaging. Am J Neuroradiol
32(1):85–91 [PubMed: 20947644]
59. Frost L, Mostofsky E, Rosenbloom JI et al. (2013) Marijuana use and long-term mortality among
survivors of acute myocardial infarction. Am Heart J 165:170–175 [PubMed: 23351819]
60. Gabilondo AM, Meana JJ, Barturen F et al. (1994) mu-Opioid receptor and alpha 2-adrenoceptor
agonist binding sites in the postmortem brain of heroin addicts. Psychopharmacology 115:135–140
[PubMed: 7862885]
61. Galiègue S, Mary S, Marchand J et al. (1995) Expression of central and peripheral cannabinoid
receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 232: 54–61
Author Manuscript
[PubMed: 7556170]
62. Garcéa-Sevilla JA, Ventayol P, Busquets X et al. (1997) Marked decrease of immunolabelled 68
kDa neurofilament (NF-L) proteins in brains of opiate addicts. NeuroReport 8:1561–1565
[PubMed: 9189892]
63. Gash A, Karliner JS, Janowsky D, Lake CR (1978) Effects of smoking marihuana on left
ventricular performance and plasma norepinephrine: studies in normal men. Ann Intern Med
89:448–452 [PubMed: 697222]
64. Geibprasert S, Gallucci M, Krings T (2010) Addictive illegal drugs: structural neuroimaging. Am J
Neuroradiol 31:803–808. doi:10.3174/ajnr.A1811 [PubMed: 19875473]

65. German CL, Fleckenstein AE, Hanson GR (2013) Bath salts and synthetic cathinones: an emerging
designer drug phenomenon. Life Sci. doi:10.1016/j.lfs.2013.07.023
Author Manuscript
66. Glass M, Dragunow M, Faull RL (1997) Cannabinoid receptors in the human brain: a detailed
anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain.
Neuroscience 77:299–318 [PubMed: 9472392]
67. Glauser J, Queen JR (2007) An overview of non-cardiac cocaine toxicity. J Emerg Med 32:181–
186 [PubMed: 17307630]
68. Goldstein RZ, Leskovjan AC, Hoff AL et al. (2004) Severity of neuropsychological impairment in
cocaine and alcohol addiction: association with metabolism in the prefrontal cortex.
Neuropsychologia 42:1447–1458 [PubMed: 15246283]
69. Granado N, Ares-Santos S, Moratalla R (2013) Methamphetamine and Parkinson’s disease.
Parkinson’s disease 308052
70. Green AR, Mechan AO, Elliott JM et al. (2003) The pharmacology and clinical pharmacology of
3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol Rev 55:463–508
[PubMed: 12869661]
71. Gruber SA, Silveri MM, Yurgelun-Todd DA (2007) Neuropsychological consequences of opiate
Author Manuscript
use. Neuropsychol Rev 17:299–315 [PubMed: 17690984]

72. Haden-Pinneri K, Weedn VW (2013) Organ and tissue retention. Acad Forensic Pathol 3:294–300
73. Hagan IG, Burney K (2007) Radiology of recreational drug abuse. Radiographics 27:919–940
[PubMed: 17620459]
74. Hall AP, Henry JA (2006) Acute toxic effects of “Ecstasy” (MDMA) and related compounds:
overview of pathophysiology and clinical management. Br J Anaesth 96:678–685 [PubMed:
16595612]
75. Hall W, Degenhardt L (2009) Adverse health effects of non-medical cannabis use. Lancet
374:1383–1391 [PubMed: 19837255]
76. Harrington H, Heller HA, Dawson D et al. (1983) Intracerebral hemorrhage and oral amphetamine.
Arch Neurol 40:503–507 [PubMed: 6870612]
77. Hashimoto E, Frölich L, Ozawa H et al. (1996) Alteration of glutamyltranspeptidase binding
proteins in postmortem brains of heroin addicts. Alcohol Clin Exp Res 20:301A–304A
78. Herning RI, Better WE, Tate K, Cadet JL (2005) Cerebrovascular perfusion in marijuana users
Author Manuscript
during a month of monitored abstinence. Neurology 64:488–493 [PubMed: 15699380]

79. Hillard CJ (2000) Endocannabinoids and vascular function. J Pharmacol Exp Ther 294:27–32
[PubMed: 10871291]
80. Ho EL, Josephson SA, Lee HS, Smith WS (2009) Cerebrovascular complications of
methamphetamine abuse. Neurocrit Care 10:295–305 [PubMed: 19132558]
81. Homer BD, Solomon TM, Moeller RW et al. (2008) Methamphetamine abuse and impairment of
social functioning: a review of the underlying neurophysiological causes and behavioral
implications. Psychol Bull 134:301–310 [PubMed: 18298273]
82. Hurd YL, Herkenham M (1993) Molecular alterations in the neostriatum of human cocaine addicts.
Synapse 13:357–369 [PubMed: 7683144]
83. Jayanthi S, Buie S, Moore S et al. (2010) Heavy marijuana users show increased serum
apolipoprotein C-III levels: evidence from proteomic analyses. Mol Psychiatry 15:101–112
[PubMed: 18475272]
84. Jernigan TL, Gamst AC, Archibald SL et al. (2005) Effects of methamphetamine dependence and
Author Manuscript
HIV infection on cerebral morphology. Am J Psychiatry 162:1461–1472 [PubMed: 16055767]

85. Johanson C-E, Frey KA, Lundahl LH et al. (2006) Cognitive function and nigrostriatal markers in
abstinent methamphetamine abusers. Psychopharmacology 185:327–338 [PubMed: 16518646]
86. Johnson MM, David JA, Michelhaugh SK et al. (2012) Increased heat shock protein 70 gene
expression in the brains of cocaine-related fatalities may be reflective of postdrug survival and
intervention rather than excited delirium. J Forensic Sci 57:1519–1523 [PubMed: 22803793]
87. Kalant H (2001) The pharmacology and toxicology of “ecstasy” (MDMA) and related drugs.
CMAJ 165:917–928 [PubMed: 11599334]

88. Kim Y-T, Lee S-W, Kwon D-H et al. (2009) Dose-dependent frontal hypometabolism on FDG-PET
in methamphetamine abusers. J Psychiatr Res 43:1166–1170 [PubMed: 19394959]
Author Manuscript
89. Kish SJ, Fitzmaurice PS, Chang LJ et al. (2010) Low striatal serotonin transporter protein in a
human polydrug MDMA (ecstasy) user: a case study. J Psychopharmacol 24:281–284 [PubMed:
18832433]
90. Konzen JP, Levine SR, Garcia JH (1995) Vasospasm and thrombus formation as possible
mechanisms of stroke related to alkaloidal cocaine. Stroke 26:1114–1118 [PubMed: 7762031]
91. Koob GF, Volkow ND (2010) Neurocircuitry of addiction. Neuropsychopharmacology 35:217–238
[PubMed: 19710631]
92. Kosten TR, Kleber HD (1988) Rapid death during cocaine abuse: a variant of the neuroleptic
malignant syndrome? Am J Drug Alcohol Abuse 14:335–346 [PubMed: 3055940]
93. Krasnova IN, Cadet JL (2009) Methamphetamine toxicity and messengers of death. Brain Res Rev
60:379–407 [PubMed: 19328213]
94. Krinsky CS, Reichard R (2012) Chasing the dragon: a review of toxic leukoencephalopathy. Acad
Forensic Pathol 2:67–73
95. Kristiansen LV, Bannon MJ, Meador-Woodruff JH (2009) Expression of transcripts for myelin
Author Manuscript
related genes in postmortem brain from cocaine abusers. Neurochem Res 34:46–54 [PubMed:
18357522]
96. Kumra S (2007) Schizophrenia and cannabis use. Minn Med 90:36–38
97. Kurumatani T, Kudo T, Ikura Y, Takeda M (1998) White matter changes in the gerbil brain under
chronic cerebral hypoperfusion. Stroke 29:1058–1062 [PubMed: 9596257]
98. Landfield PW, Cadwallader LB, Vinsant S (1988) Quantitative changes in hippocampal structure
following long-term exposure to delta 9-tetrahydrocannabinol: possible mediation by
glucocorticoid systems. Brain Res 443:47–62 [PubMed: 2834017]
99. Levine SR, Brust JC, Futrell N et al. (1991) A comparative study of the cerebrovascular
complications of cocaine: alkaloidal versus hydrochloride—a review. Neurology 41:1173–1177
[PubMed: 1866000]
100. Lim KO, Choi SJ, Pomara N et al. (2002) Reduced frontal white matter integrity in cocaine
dependence: a controlled diffusion tensor imaging study. Biol Psychiatry 51:890–895 [PubMed:
12022962]
Author Manuscript
101. Lim KO, Wozniak JR, Mueller BA et al. (2008) Brain macrostructural and microstructural
abnormalities in cocaine dependence. Drug Alcohol Depend 92:164–172 [PubMed: 17904770]
102. Lineberry TW, Bostwick JM (2006) Methamphetamine abuse: a perfect storm of complications.
Mayo Clin Proc 81:77–84. doi:10.4065/81.1.77 [PubMed: 16438482]
103. Little KY, Ramssen E, Welchko R et al. (2009) Decreased brain dopamine cell numbers in human
cocaine users. Psychiatry Res 168:173–180 [PubMed: 19233481]
104. London ED, Simon SL, Berman SM et al. (2004) Mood disturbances and regional cerebral
metabolic abnormalities in recently abstinent methamphetamine abusers. Arch Gen Psychiatry
61:73–84 [PubMed: 14706946]
105. Lowenstein DH, Massa SM, Rowbotham MC et al. (1987) Acute neurologic and psychiatric
complications associated with cocaine abuse. Am J Med 83:841–846 [PubMed: 3674091]
106. Lucas CE (2005) The impact of street drugs on trauma care. J Trauma 59:S57–S60 (discussion
S67-S75) [PubMed: 16355064]
107. Lyles J, Cadet JL (2003) Methylenedioxymethamphetamine (MDMA, Ecstasy) neurotoxicity:
Author Manuscript
cellular and molecular mechanisms. Brain Res Rev 42:155–168 [PubMed: 12738056]
108. Lyoo IK, Pollack MH, Silveri MM et al. (2006) Prefrontal and temporal gray matter density
decreases in opiate dependence. Psychopharmacology 184:139–144 [PubMed: 16369836]
109. Ma N, Liu Y, Li N et al. (2010) Addiction related alteration in resting-state brain connectivity.
Neuroimage 49:738–744 [PubMed: 19703568]
110. Magro CM, Dyrsen M (2008) Angiocentric lesions of the head and neck. Head Neck Pathol
2:116–130 [PubMed: 20614334]

111. Makris N, Gasic GP, Kennedy DN et al. (2008) Cortical thickness abnormalities in cocaine
addiction—a reflection of both drug use and a pre-existing disposition to drug abuse? Neuron
Author Manuscript
60:174–188 [PubMed: 18940597]

112. Maldonado R, Berrendero F, Ozaita A, Robledo P (2011) Neurochemical basis of cannabis
addiction. Neuroscience 181:1–17 [PubMed: 21334423]
113. Marusich JA, Grant KR, Blough BE, Wiley JL (2012) Effects of synthetic cathinones contained in
“bath salts” on motor behaveior and a functional observational battery in mice. Neurotoxicology
33:1305–1313 [PubMed: 22922498]
114. Mas M, Farré M, De la Torre R et al. (1999) Cardiovascular and neuroendocrine effects and
pharmacokinetics of 3, 4-methylenedioxymethamphetamine in humans. J Pharmacol Exp Ther
290:136–145 [PubMed: 10381769]
115. Mash DC, Duque L, Pablo J et al. (2009) Brain biomarkers for identifying excited delirium as a
cause of sudden death. Forensic Sci Int 190:e13–e19 [PubMed: 19541436]
116. Mash DC, Pablo J, Ouyang Q et al. (2002) Dopamine transport function is elevated in cocaine
users. J Neurochem 81:292–300 [PubMed: 12064476]
117. Mash DC, Staley JK, Izenwasser S et al. (2000) Serotonin transporters upregulate with chronic
Author Manuscript
cocaine use. J Chem Neuroanat 20:271–280 [PubMed: 11207425]

118. Matochik JA, Eldreth DA, Cadet J-L, Bolla KI (2005) Altered brain tissue composition in heavy
marijuana users. Drug Alcohol Depend 77:23–30 [PubMed: 15607838]
119. Matochik JA, London ED, Eldreth DA et al. (2003) Frontal cortical tissue composition in
abstinent cocaine abusers: a magnetic resonance imaging study. Neuroimage 19:1095–1102
[PubMed: 12880835]
120. McAllister SD, Glass M (2002) CB(1) and CB(2) receptor-mediated signalling: a focus on
endocannabinoids. Prostaglandins Leukot Essent Fatty Acids 66:161–171 [PubMed: 12052033]
121. McCann UD, Ridenour A, Shaham Y, Ricaurte GA (1994) Serotonin neurotoxicity after (±)3,4-
methylenedioxymethamphetamine (MDMA; “Ecstasy”): a controlled study in humans.
Neuropsychopharmacology 10:129–138 [PubMed: 7517677]
122. McCann UD, Szabo Z, Seckin E et al. (2005) Quantitative PET studies of the serotonin
transporter in MDMA users and controls using [11C]McN5652 and [11C]DASB.
Neuropsychopharmacology 30:1741–1750 [PubMed: 15841106]
Author Manuscript
123. McCann UD, Szabo Z, Vranesic M et al. (2008) Positron emission tomographic studies of brain
dopamine and serotonin transporters in abstinent (±)3,4-methylenedioxymethamphetamine
(“ecstasy”) users: relationship to cognitive performance. Psychopharmacology 200:439–450
[PubMed: 18661256]
124. McCann UD, Wong DF, Yokoi F et al. (1998) Reduced striatal dopamine transporter density in
abstinent methamphetamine and methcathinone users: evidence from positron emission
tomography studies with [11C]WIN-35,428. J Neurosci 18:8417–8422 [PubMed: 9763484]
125. McCarron MO, Thomas AM (1997) Cannabis and alcohol in stroke. Postgrad Med J 73:448
126. McIntosh A, Hungs M, Kostanian V, Yu W (2006) Carotid artery dissection and middle cerebral
artery stroke following methamphetamine use. Neurology 67:2259–2260 [PubMed: 17190959]
127. Meador-Woodruff JH, Little KY, Damask SP et al. (1993) Effects of cocaine on dopamine
receptor gene expression: a study in the postmortem human brain. Biol Psychiatry 34:348–355
[PubMed: 8218601]
128. Medina KL, McQueeny T, Nagel BJ et al. (2009) Prefrontal cortex morphometry in abstinent
adolescent marijuana users: subtle gender effects. Addict Biol 14:457–468 [PubMed: 19650817]
Author Manuscript
129. Milroy CM (2011) “Ecstasy” associated deaths: what is a fatal concentration? Analysis of a case
series. Forensic Sci Med Pathol 7:248–252 [PubMed: 21264549]
130. Milroy CM (2012) The “Bath Salt” Mephedrone—a new(ish) kid on the block. Acad Forensic
Pathol 250–254
131. Milroy CM, Clark JC, Forrest AR (1996) Pathology of deaths associated with “ecstasy” and “eve”
misuse. J Clin Pathol 49:149–153 [PubMed: 8655682]
132. Milroy CM, Parai JL (2011) The histopathology of drugs of abuse. Histopathology 59:579–593
[PubMed: 21261690]

133. Miotto K, Striebel J, Cho AK, Wang C (2013) Clinical and pharmacological aspects of bath salt
use: a review of the literature and case reports. Drug Alcohol Depend 132:1–12 [PubMed:
Author Manuscript
23916320]
134. Mir A, Obafemi A, Young A, Kane C (2011) Myocardial infarction associated with use of the
synthetic cannabinoid K2. Pediatrics 128:e1622–e1627. doi:10.1542/peds.2010-3823 [PubMed:
22065271]
135. Mittleman MA, Lewis RA, Maclure M et al. (2001) Triggering myocardial infarction by
marijuana. Circulation 103:2805–2809 [PubMed: 11401936]
136. Molina-Holgado F, Molina-Holgado E, Guaza C, Rothwell NJ (2002) Role of CB1 and CB2
receptors in the inhibitory effects of cannabinoids on lipopolysaccharide-induced nitric oxide
release in astrocyte cultures. J Neurosci Res 67:829–836 [PubMed: 11891798]
137. Moore THM, Zammit S, Lingford-Hughes A et al. (2007) Cannabis use and risk of psychotic or
affective mental health outcomes: a systematic review. Lancet 370:319–328 [PubMed: 17662880]
138. Moreno-López L, Catena A, Fernández-Serrano MJ et al. (2012) Trait impulsivity and prefrontal
gray matter reductions in cocaine dependent individuals. Drug Alcohol Depend 125:208–214
[PubMed: 22391134]
Author Manuscript
139. Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor
for cannabinoids. Nature 365:61–65 [PubMed: 7689702]
140. Nakama H, Chang L, Fein G et al. (2011) Methamphetamine users show greater than normal age-
related cortical gray matter loss. Addiction 106:1474–1483 [PubMed: 21438934]
141. National Institute on Drug Abuse N Costs of Substance Abuse. http://www.drugabuse.gov/related-
topics/trends-statistics#costs)
142. United Nations (2011) World drug report 2011. http://www.unodc.org/documents/data-and-
analysis/WDR2011/World_Drug_Report_2011_ebook.pdf
143. United Nations (2013) World drug report 2013. http://www.unodc.org/unodc/secured/wdr/
wdr2013/World_Drug_Report_2013.pdf
144. Neiman J, Haapaniemi HM, Hillbom M (2000) Neurological complications of drug abuse:
pathophysiological mechanisms. Eu J Neurol 7:595–606
145. Nnadi CU, Mimiko OA, McCurtis HL, Cadet JL (2005) Neuropsychiatric effects of cocaine use
disorders. J Natl Med Assoc 97:1504–1515 [PubMed: 16334497]
Author Manuscript
146. Nolte KB, Brass LM, Fletterick CF (1996) Intracranial hemorrhage associated with cocaine
abuse: a prospective autopsy study. Neurology 46:1291–1296 [PubMed: 8628469]
147. Obrocki J, Buchert R, Vaterlein O et al. (1999) Ecstasy—long-term effects on the human central
nervous system revealed by positron emission tomography. Br J Psychiatry 175:186–188
[PubMed: 10627804]
148. Oehmichen M, Meissner C, Reiter A, Birkholz M (1996) Neuropathology in non-human
immunodeficiency virus-infected drug addicts: hypoxic brain damage after chronic intravenous
drug abuse. Acta Neuropathol 91:642–646 [PubMed: 8781664]
149. Offiah C, Hall E (2008) Heroin-induced leukoencephalopathy: characterization using MRI,
diffusion-weighted imaging, and MR spectroscopy. Clin Radiol 63:146–152 [PubMed:
18194689]
150. Olsen ER (1977) Intracranial hemorrhage and amphetamine usage. Review of the effects of
amphetamines on the central nervous system. Angiology 28:464–471 [PubMed: 900566]
151. Oyesiku NM, Colohan AR, Barrow DL, Reisner A (1993) Cocaine-induced aneurysmal rupture:
an emergent negative factor in the natural history of intracranial aneurysms? Neurosurgery
Author Manuscript
32:518–525 [PubMed: 8474641]

152. Parrott AC, Sisk E, Turner JJ (2000) Psychobiological problems in heavy “ecstasy” (MDMA)
polydrug users. Drug Alcohol Depend 60:105–110 [PubMed: 10821995]
153. Parrott AC (2006) MDMA in humans: factors which affect the neuropsychobiological profiles of
recreational ecstasy users, the integrative role of bioenergetic stress. J Psychopharmacology
(Oxford, England) 20:147–63
154. Pascual-Leone A, Dhuna A, Altafullah I, Anderson DC (1990) Cocaine-induced seizures.
Neurology 40:404–407 [PubMed: 2107459]

155. Perez JA, Arsura EL, Strategos S (1999) Methamphetamine-related stroke: four cases. J Emerg
Med 17:469–471 [PubMed: 10338241]
Author Manuscript
156. Peterson PL, Roszler M, Jacobs I, Wilner HI (1991) Neurovascular complications of cocaine
abuse. J Neuropsychiatry Clin Neurosci 3:143–149 [PubMed: 1821227]
157. Pezawas LM, Fischer G, Diamant K et al. (1998) Cerebral CT findings in male opioid-dependent
patients: stereological, planimetric and linear measurements. Psychiatry Res 83:139–147
[PubMed: 9849723]
158. Raineri M, Gonzalez B, Goitia B et al. (2012) Modafinil abrogates methamphetamine-induced
neuroinflammation and apoptotic effects in the mouse striatum. PLoS ONE 7:e46599 [PubMed:
23056363]
159. Reid AG, Daglish MRC, Kempton MJ et al. (2008) Reduced thalamic grey matter volume in
opioid dependence is influenced by degree of alcohol use: a voxel-based morphometry study. J
Psychopharmacol 7–10 [PubMed: 18187528]
160. Rendell PG, Mazur M, Henry JD (2009) Prospective memory impairment in former users of
methamphetamine. Psychopharmacology 203:609–616 [PubMed: 19037633]
161. Reneman L, Endert E, De Bruin K et al. (2002) The acute and chronic effects of MDMA
Author Manuscript
(“ecstasy”) on cortical 5-HT2A receptors in rat and human brain. Neuropsychopharmacology

26:387–396 [PubMed: 11850153]
162. Richter RW, Pearson J, Bruun B et al. (1973) Neurological complications of addiction to heroin.
Bull N Y Acad Med 49:3–21 [PubMed: 4344820]
163. Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ (1987) Cocaine receptors on dopamine transporters
are related to self-administration of cocaine. Science 237:1219–1223 [PubMed: 2820058]
164. Rizzuto N, Morbin M, Ferrari S et al. (1997) Delayed spongiform leukoencephalopathy after
heroin abuse. Acta Neuropathol 94:87–90 [PubMed: 9224535]
165. Robinson TE, Kolb B (1999) Morphine alters the structure of neurons in the nucleus accumbens
and neocortex of rats. Synapse 33:160–162 [PubMed: 10400894]
166. Romero J, Garcia-Palomero E, Berrendero F et al. (1997) Atypical location of cannabinoid
receptors in white matter areas during rat brain development. Synapse 26:317–323 [PubMed:
9183820]
167. Rose JS, Branchey M, Buydens-Branchey L et al. (1996) Cerebral perfusion in early and late
Author Manuscript
opiate withdrawal: a technetium-99m-HMPAO SPECT study. Psychiatry Res 67:39–47 [PubMed:

8797241]
168. Rothrock JF, Rubenstein R, Lyden PD (1988) Ischemic stroke associated with methamphetamine
inhalation. Neurology 38:589–592 [PubMed: 3352918]
169. Ryan A, Molloy FM, Farrell MA, Hutchinson M (2005) Fatal toxic leukoencephalopathy: clinical,
radiological, and necropsy findings in two patients. J Neurol Neurosurg Psychiatry 76:1014–1016
[PubMed: 15965216]
170. Sastre M, Ventayol P, García-Sevilla JA (1996) Decreased density of I2-imidazoline receptors in
the postmortem brain of heroin addicts. NeuroReport 7:509–512 [PubMed: 8730817]
171. Schepers RJF, Oyler JM, Joseph RE et al. (2003) Methamphetamine and amphetamine
pharmacokinetics in oral fluid and plasma after controlled oral methamphetamine administration
to human volunteers. Clin Chem 49:121–132 [PubMed: 12507968]
172. Schiffer D, Brignolio F, Giordana MT et al. (1985) Spongiform encephalopathy in addicts
inhaling pre-heated heroin. Clin Neuropathol 4:174–180 [PubMed: 4053458]
173. Schuster RM, Crane NA, Mermelstein R, Gonzalez R (2012) The influence of inhibitory control
Author Manuscript
and episodic memory on the risky sexual behavior of young adult cannabis users. JINS 18:827–
833 [PubMed: 22676889]
174. Schwartz DL, Mitchell AD, Lahna DL, Luber HS, Huckans MS, Mitchell SHHW (2010) Global
and local morphometric differences in recently abstinent methamphetamine-dependent
individuals. Neuroimage 50:1392–1401 [PubMed: 20096794]
175. Scott JC, Woods SP, Matt GE et al. (2007) Neurocognitive effects of methamphetamine: a critical
review and meta-analysis. Neuropsychol Rev 17:275–297 [PubMed: 17694436]

176. Segal DM, Moraes CT, Mash DC (1997) Up-regulation of D3 dopamine receptor mRNA in the
nucleus accumbens of human cocaine fatalities. Brain Res Mol Brain Res 45:335–339 [PubMed:
Author Manuscript
9149110]
177. Sekine Y, Ouchi Y, Sugihara G et al. (2008) Methamphetamine causes microglial activation in the
brains of human abusers. J Neurosci 28:5756–5761 [PubMed: 18509037]
178. Sempere AP, Posada I, Ramo C, Cabello A (1991) Spongiform leucoencephalopathy after
inhaling heroin. Lancet 338:320
179. Sidney S (2002) Cardiovascular consequences of marijuana use. J Clin Pharmacol 42:64S–70S
[PubMed: 12412838]
180. Sim ME, Lyoo IK, Streeter CC et al. (2007) Cerebellar gray matter volume correlates with
duration of cocaine use in cocaine-dependent subjects. Neuropsychopharmacology 32: 2229–
2237 [PubMed: 17299505]
181. Singla S, Sachdeva R, Mehta JL (2012) Cannabinoids and atherosclerotic coronary heart disease.
Clin Cardiol 35:329–335 [PubMed: 22278660]
182. Solowij N, Walterfang M, Lubman DI et al. (2013) Alteration to hippocampal shape in cannabis
users with and without schizophrenia. Schizophr Res 143:179–184 [PubMed: 23201308]
Author Manuscript
183. Solowij N, Yücel M, Respondek C et al. (2011) Cerebellar white-matter changes in cannabis
users with and without schizophrenia. Psychol Med 41:2349–2359 [PubMed: 21466751]
184. Squier MV, Jalloh S, Hilton-Jones D, Series H (1995) Death after ecstasy ingestion:
neuropathological findings. J Neurol Neurosurg Psychiatry 58:756
185. Staley JK, Rothman RB, Rice KC et al. (1997) Kappa2 opioid receptors in limbic areas of the
human brain are upregulated by cocaine in fatal overdose victims. J Neurosci 17:8225–8233
[PubMed: 9334398]
186. Sulzer D, Rayport S (1990) Amphetamine and other psychostimulants reduce pH gradients in
midbrain dopaminergic neurons and chromaffin granules: a mechanism of action. Neuron 5:797–
808 [PubMed: 2268433]
187. Sulzer D, Sonders MS, Poulsen NW, Galli A (2005) Mechanisms of neurotransmitter release by
amphetamines: a review. Progr Neurobiol 75:406–433
188. Tan TP, Algra PR, Valk J, Wolters EC (1994) Toxic leukoencephalopathy after inhalation of
poisoned heroin: MR findings. AJNR 15:175–178 [PubMed: 8141052]
Author Manuscript
189. Thompson PM, Hayashi KM, Simon SL et al. (2004) Structural abnormalities in the brains of
human subjects who use methamphetamine. J Neurosci 24:6028–6036 [PubMed: 15229250]
190. Tobias MC, O’Neill J, Hudkins M et al. (2010) White-matter abnormalities in brain during early
abstinence from methamphetamine abuse. Psychopharmacology 209:13–24 [PubMed: 20101394]
191. Trescot AM, Datta S, Lee M, Hansen H (2008) Opioid pharmacology. Pain Physician 11:S133–
S153 [PubMed: 18443637]
192. Turillazzi E, Riezzo I, Neri M et al. (2010) MDMA toxicity and pathological consequences: a
review about experimental data and autopsy findings. Curr Pharm Biotechnol 11:500–509
[PubMed: 20420577]
193. Vila N, Chamorro A (1997) Ballistic movements due to ischemic infarcts after intravenous heroin
overdose: report of two cases. Clin Neurol Neurosurg 99:259–262 [PubMed: 9491301]
194. Vilke GM, DeBard ML, Chan TC et al. (2012) Excited Delirium Syndrome (ExDS): defining
based on a review of the literature. J Emerg Med 43:897–905 [PubMed: 21440403]
195. Virmani R, Robinowitz M, Smialek JE, Smyth DF (1988) Cardiovascular effects of cocaine: an
Author Manuscript
autopsy study of 40 patients. Am Heart J 115:1068–1076 [PubMed: 3364339]

196. Volkow ND, Chang L, Wang GJ et al. (2001) Association of dopamine transporter reduction with
psychomotor impairment in methamphetamine abusers. Am J Psychiatry 158:377–382 [PubMed:
11229977]
197. Volkow ND, Chang L, Wang GJ et al. (2001) Higher cortical and lower subcortical metabolism in
detoxified methamphetamine abusers. Am J Psychiatry 158:383–389 [PubMed: 11229978]
198. Volkow ND, Wang G-J, Fowler JS, Tomasi D (2012) Addiction circuitry in the human brain.
Annu Rev Pharmacol Toxicol 52:321–336 [PubMed: 21961707]
199. Warner EA (1993) Cocaine abuse. Ann Int Med 119:226–235 [PubMed: 8323092]

200. Weber W, Henkes H, Möller P et al. (1998) Toxic spongiform leucoencephalopathy after inhaling
heroin vapour. Eur Radiol 8:749–755 [PubMed: 9601960]
Author Manuscript
201. Weiss SR, Raskind R, Morganstern NL et al. (1970) Intracerebral and subarachnoid hemorrhage
following use of methamphetamine (“speed”). Int Surg 53:123–127 [PubMed: 5416024]
202. Wilson JM, Kalasinsky KS, Levey AI et al. (1996) Striatal dopamine nerve terminal markers in
human, chronic methamphetamine users. Nat Med 2:699–703 [PubMed: 8640565]
203. Wolff V, Armspach J-P, Lauer V et al. (2013) Cannabis-related Stroke: myth or reality? Stroke
44:558–563 [PubMed: 23271508]
204. Wolff V, Lauer V, Rouyer O et al. (2011) Cannabis use, ischemic stroke, and multifocal
intracranial vasoconstriction: a prospective study in 48 consecutive young patients. Stroke
42:1778–1780 [PubMed: 21512186]
205. Wolters EC, Van Wijngaarden GK, Stam FC et al. (1982) Leucoencephalopathy after inhaling
“heroin” pyrolysate. Lancet 2:1233–1237 [PubMed: 6128545]
206. Wood DM, Greene SL, Dargan PI (2011) Clinical pattern of toxicity associated with the novel
synthetic cathinone mephedrone. EMJ 28:280–282 [PubMed: 20581379]
207. Xi Z-X, Peng X-Q, Li X et al. (2011) Brain cannabinoid CB2 receptors modulate cocaine’s
Author Manuscript
actions in mice. Nat Neurosci 14:1160–1166 [PubMed: 21785434]

208. Xu J, DeVito EE, Worhunsky PD et al. (2010) White matter integrity is associated with treatment
outcome measures in cocaine dependence. Neuropsychopharmacology 35:1541–1549 [PubMed:
20393459]
209. Yen DJ, Wang SJ, Ju TH, Chen CC, Liao KK, Fuh JL, Hu HH (1994) Stroke associated with
methamphetamine inhalation. Eur Neurol 34(1):16–22 [PubMed: 8137834]
210. Yücel M, Solowij N, Respondek C et al. (2008) Regional brain abnormalities associated with
long-term heavy cannabis use. Arch Gen Psychiatry 65:694–701 [PubMed: 18519827]
211. Zachariah SB (1991) Stroke after heavy marijuana smoking. Stroke 22:406–409 [PubMed:
2003312]
212. Zalesky A, Solowij N, Yucel M et al. (2012) Effect of long-term cannabis use on axonal fibre
connectivity. Brain 135:2245–2255 [PubMed: 22669080]
Author Manuscript
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Fig. 1.
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A model of the brain reward system. The nucleus accumbens (ventral striatum) is the major
target of the mesolimbic dopaminergic system. It contains GABAergic medium spiny
neurons (MSNs) that project to the ventral pallidum (VP). Natural rewards and addictive
drugs increase the release of dopamine from the terminals of dopaminergic projections
emanating from the ventral tegmental area (VTA). Nigrostriatal dopaminergic pathways
(substantia nigra pars compacta to dorsal striatum) also participate in reward-related
processes. DA dopamine, GABA g-aminobutyric acid, glu glutamate

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Fig. 2.
Cocaine potentiates the action of dopamine on ventral and dorsal striatal neurons. Cocaine
blocks dopamine transporters (DAT) and increases DA content in the synaptic cleft. Cocaine
also disrupts calcium homeostasis and increases endoplasmic reticulum (ER) stress in
GABAergic cells within the striatum. Medium-size GABA-containing spiny neurons that
represent the main (95 %) striatal neuronal population participate in the modulation of
output signals from the basal ganglia. These neurons interact with parvalbumin-containing
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GABA-releasing interneurons, NADPH diaphorase-, and somatostatin-positive interneurons.

They also interact with large cholinergic aspiny interneurons. D1 receptors are found
predominantly in striatonigral neurons of the ‘direct pathway’, whereas D2 receptors are
mainly expressed by the striatopallidal neurons of the ‘indirect pathway’. Corticostriatal
neurons project onto GABA-releasing striatal output neurons where they exert glutamate-
mediated excitation. AC adenylyl cyclase, Ach acetylcholine, GP globus pallidus, NO nitric
oxide, PKG protein kinase G, sGC soluble guanylyl cyclase

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Fig. 3.
Schematic representation of cellular and molecular events involved in METH-induced DA
neurotoxicity within the striatum. METH enters dopaminergic neurons via DAT and passive
diffusion. Within these neurons, METH enters synaptic vesicles through VMAT-2 and
causes DA release into the cytoplasm by disturbing pH balance. In the cytoplasm, DA auto-
oxidizes to form toxic DA quinones followed by generation of superoxide radicals and
hydrogen peroxides. Subsequent formation of hydroxyl radicals through interactions of
superoxides and hydrogen peroxide with transition metals leads to oxidative stress,
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mitochondrial dysfunctions, and peroxidative damage to pre-synaptic membranes. The

involvement of endogenous DA in METH toxicity is supported by findings that the TH
inhibitor, α-methyl-p-tyrosine, which blocks DA synthesis, affords protection against
METH toxicity. Also, the role of DA is supported by observations that use of the MAO
inhibitor, clorgyline, and of the irreversible inhibitor of vesicular transport, reserpine, which
results in increases in cytoplasmic DA levels can exacerbate METH-induced toxicity. These
events are thought to be partly responsible for the loss of DA terminals. Toxic effects of
released DA appear to depend on activation of DA receptors, because DA receptor

antagonists block degeneration of DA terminals. Interactions of DA with D1 receptors on

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post-synaptic membrane cause activation of various transcription factors and subsequent up-
regulation of death cascades in post-synaptic neurons. Modified from Krasnova and Cadet
[93]
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HHS Public Access: Neuropathology of Substance Use Disorders

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Neuropathology of substance use disorders

Buenos Aires, Argentina

Christopher Mark Milroy

Marijuana use disorder

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.

symptoms are higher in regular cannabis users [137].

The pharmacological effects of cannabis occur through stimulation of cannabinoid receptors

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.

Biochemical and structural abnormalities

of exogenous cannabis exposure. Down-regulation of the endogenous cannabinoid system

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.

elucidate the long-term impact of this substance on the brain.

Cocaine use disorder

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.

malformations as causative factors for cocaine-associated intracerebral and subarachnoid

Biochemical and structural abnormalities

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.

the expression of either D1 or D2 receptor gene is affected in the nucleus accumbens,

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.

Amphetamine analog use disorders

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.

Methamphetamine use disorder

Abuse of methamphetamine has become an international public health problem [143].

methamphetamine usage with ischemic strokes, intracerebral hemorrhages, and

Biochemical and structural brain findings

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.

chronic methamphetamine users [202]. Consistent with these observations, neuroimaging

and perforant path were also reported in these patients [190].

MDMA use disorder

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.

In human studies, acute MDMA administration can cause arrhythmias, hypertension,

Biochemical and structural abnormalities

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.

organ pathology in humans has been non-specific [130].

Heroin use disorder

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.

to recurrent heroin-induced episodes of hypoxia [2, 162]. Single-photon emission computed

Biochemical and structural abnormalities

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.

A distinct entity, spongiform leukoencephalopathy, has been described after inhalation of

Approach to autopsy in drug-related deaths

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.

methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive “bath salts”

in abstinent marijuana users. Neuroimage 26:480–492 [PubMed: 15907305]

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.

individuals hospitalized with conditions related to the use of methamphetamine or other

examiner. Acad Forensic Pathol 3:301–313

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.

balance. Curr Opin Pharmacol 5:94–100 [PubMed: 15661632]

Depend 68:87–93 [PubMed: 12167554]

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.

use. Neuropsychol Rev 17:299–315 [PubMed: 17690984]

during a month of monitored abstinence. Neurology 64:488–493 [PubMed: 15699380]

HIV infection on cerebral morphology. Am J Psychiatry 162:1461–1472 [PubMed: 16055767]

Acta Neuropathol. Author manuscript; available in PMC 2020 August 28.