Neuropathology and Applied Neurobiology (2011), 37, 118–134
Review: The neuropathology of drug abuse
A. Büttner
Institute of Forensic Medicine, University of Rostock, Rostock, Germany
A. Büttner (2011) Neuropathology and Applied Neurobiology 37, 118–134
The neuropathology of drug abuse
Drug abuse represents a significant health issue. The
major substances abused include cannabis, opiates,
cocaine, amphetamine, methamphetamine and ‘ecstasy’.
Alterations of intracellular messenger pathways, tran-
scription factors and immediate early genes within the
brain reward system seem to be fundamentally important
for the development of addiction and chronic drug abuse.
Genetic risk factors and changes in gene expression asso-
ciated with drug abuse are still poorly understood. Besides
cardiovascular complications, psychiatric and neurologic
symptoms are the most common manifestations of drug
toxicity. A broad spectrum of changes affecting the central
nervous system is seen in drug abusers. The major find-
ings result from the consequences of ischaemia and cere-
brovascular diseases. Except for a few observations of
vasculitis, the aetiology of these cerebrovascular acci-
dents is not fully understood. The abuse of amphetamine,
Keywords: astrocytes, cerebral microvasculature, drug abuse, microglia, neurodegeneration
Introduction
Drug abuse represents a serious health issue worldwide.
Drugs of abuse can be grouped as stimulants, analgesics
and narcotics, hypnotics as well as antidepressants, nico-
tine and alcohol [1–3]. Besides the latter two substances,
the predominant substances abused include cannabis,
opiates, cocaine, amphetamine, methamphetamine and
designer drugs [1,2]. Although individuals with a drug
habit may favour one or other class of drug, depending in
Correspondence: Andreas Büttner, Institute of Forensic Medicine,
University of Rostock, St.-Georg-Strasse 108, 18055 Rostock,
Germany. Tel: +49 381 494 9900; Fax: +49 381 494 9902; E-mail:
andreas.buettner@med.uni-rostock.de
118
Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society
doi: 10.1111/j.1365-2990.2010.01131.
_ 118..134
methamphetamine and MDMA has been related to neuro-
toxicity in human long-term abusers and to the risk of
developing Parkinson’s disease. However, whether such
neurotoxicity occurs remain to be established. Systematic
histological, immunohistochemical and morphometric
investigations have shown profound morphological
alterations in the brains of polydrug abusers. The major
findings comprise neuronal loss, neurodegenerative
alterations, a reduction of glial fibrillary acidic protein-
immunopositive astrocytes, widespread axonal damage
with concomitant microglial activation as well as reactive
and degenerative changes of the cerebral microvascula-
ture. These observations demonstrate that drugs of abuse
initiate a cascade of interacting toxic, vascular and
hypoxic factors, which finally result in widespread distur-
bances within the complex network of central nervous
system cell-to-cell interactions.
part on what is available, most perform polysubstance
abuse [4–8].
The methodological problems in investigating the
effects of drugs of abuse on the central nervous system
(CNS) consist of distinguishing between substance-
specific effects related to the properties of the drug itself,
the influence of adulterants, and of secondary effects
related to the lifestyle of drug abusers, for example, mal-
nutrition, infections and systemic diseases. Because
polysubstance abuse is seen in the majority of cases, it is
difficult to relate the observed findings to a single sub-
stance. Therefore, in most cases the exact aetiology of the
various CNS alterations remains unclear.
Injecting drug abuse is also a risk factor for the
acquisition of HIV-1 infection and there is evidence that
© 2011 The Author

HIV-1-associated CNS disorders are accentuated in drug
abusers [9,10].
Infection of the brain with hepatitis viruses, especially
with hepatitis C virus (HCV) is another potential con-
founding factor in the neuropathological appearances of
the observed brain changes. Injection drug abusers are
the largest group of persons infected with HCV, with a
prevalence of 50–90% [11]. The transmission of HCV is
not the effect of the drug injected but of sharing con-
taminated equipment [11]. In contrast to HIV, HCV is
detectable in high concentrations in other utensils for
heroin injection, such as filters, spoons and rinsing
liquids. Besides hepatic encephalopathy, there is also
emerging evidence of neurocognitive impairment in HCV
infection independently of drug abuse or HIV-1 infection
[12–15].
Research on the neurobiology of addiction has shown
that the reinforcing properties of most drugs of abuse are
mediated by activation of the mesolimbic dopaminergic
system, the orbitofrontal cortex and the extended
amygdala [16–19]. Alterations of the intracellular mes-
senger pathways, transcription factors and immediate
early gene expression in these reward circuits are believed
to be important for the development of addiction and
chronic drug abuse [16–20].
Possible genetic risk factors for drug addiction and
changes in gene expression, associated with drug abuse,
are still poorly understood [21,22].
Although a broad spectrum of alterations affecting the
CNS has been described in drug abusers [1,2,23], there is
no specific change that is characteristic and little is known
about the fundamental neuropathological alterations of
the cellular elements of the human brain. Therefore,
despite a large body of literature on animal models, the
following review will focus on the relevant human CNS
findings. The pharmacology and CNS alterations in
alcohol and nicotine abuse are reviewed elsewhere
[3,24–27].
Neuroimaging findings
Neuroimaging studies revealed widespread alterations in
the brains of drug abusers [28]:
Computed tomography studies have shown diffuse
brain atrophy [29–31].
On magnetic resonance imaging decreased grey and
white matter volume has been demonstrated in particular
areas of the brain [32–37]. Moreover, focal demyelina-
© 2011 The Author
Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society, 37, 118–134
The neuropathology of drug abuse 119
tions and hyperintense lesions have been demonstrated
in the white matter, which were attributed to ischaemic
lesion [34,38–40].
Single photon emission computed tomography showed
focal perfusions deficits in various brain regions [41–45].
On positron emission tomography a reduction of the
global glucose metabolism has been demonstrated
[46,47].
Studies using proton magnetic resonance spectroscopy
have identified several biochemical changes in the brain
that may underlie the neuropathology that subsequently
gives rise to the cognitive and behavioural impairments
associated with drug addiction [48]. Some neurochemical
abnormalities have been attributed to alterations in non-
neuronal brain tissue [48].
Diffusion tensor imaging revealed microstructural
abnormalities in the white matter and the corpus callo-
sum, suggestive of axonal injury [49–54].
Despite these numerous neuroimaging studies, the
cause or possible morphological correlates of these alter-
ations are still not fully resolved.
CNS effects of the major drugs of abuse
Depending of the frequency and types of drugs abused,
the predominant neurologic-psychiatric complications
of drug abuse include a high prevalence of depression,
memory loss and cognitive decline, and the possible pre-
disposition to schizophrenia.
Cannabis
Cannabis is the most commonly used illicit drug world-
wide [2,55–59].
Cannabis preparations (marihuana, hashish) are
usually mixed with tobacco and smoked. Oral ingestion as
tea or addition to pastries is also widespread. Cannabis is
unsuitable for intravenous use as it is relatively water-
insoluble. The concentration of the major psychoactive
component of cannabis, D9-tetrahydrocannabinol (THC),
varies according to the preparation and the origin of the
plant from 1% to 7% in marihuana, 2% to 10% in hashish
and 10% to 60% in hash oil [55,57].
Cannabis combines many of the properties of alcohol,
tranquillizers, opiates and hallucinogens; it is anxiolytic,
sedative, analgesic and psychedelic [55]. The psychotropic
action of cannabis starts after several minutes reaches a
maximum by 20–30 min and persists for 2–4 h. However,
120 A. Büttner
the action of cannabis is of highly individual variability.
Furthermore, there is a dose-related impairment of cogni-
tive and psychomotor performance. Acute effects include
euphoria and relaxation with perceptual changes.
However, dysphoric reactions, including anxiety and
panic, depression, paranoia and psychosis can also
occur. Systemic effects include a dose-related tachycardia,
vasodilation and postural hypotension [55–59].
THC is a lipid-soluble substance that is distributed het-
erogeneously within the brain, with its highest concentra-
tions in neocortical, limbic, sensory and motor areas
[55–58]. THC and other cannabinoids exert their effects
by the interaction with specific cannabinoid receptors,
which are distributed heterogeneously within the brain
[59–64].
Two cannabinoid receptors, CB1 and CB2, have been
pharmacologically characterized and anatomically
localized. CB1 receptors are found predominantly in the
central and peripheral nervous system, where they have
been implicated in presynaptic inhibition of neurotrans-
mitter release. CB2 receptors are present on immune
cells, where they may be involved in cytokine release
[59–65].
The highest density of CB1 receptors is found in the
substantia nigra, the basal ganglia, the hippocampus and
the cerebellum [63,66,67]. Within the neocortex they are
present with the highest density in the frontal cortex, the
dentate gyrus, the mesolimbic dopaminergic system and
the temporal lobe [63,66,67]. This specific distribution of
CB1 receptors correlates well with the effects of cannab-
inoids on memory, perception and movement control. The
very low density of CB1 receptors in the brain stem and
medulla oblongata explains the low acute toxicity and
lack of lethality of cannabis [55,59,66]. Nevertheless, the
CNS toxicity of cannabis seems to have been underesti-
mated for a long time [68], as recent findings revealed
THC-induced neuronal death in cultured rat neurones
[69–71].
The discovery of specific endogenous cannabinoid
receptor ligands (endocannabinoids), and the distribution
of their receptors, strongly suggests that these lipid neu-
rotransmitter systems play an important role in higher
cortical-emotional functions, memory storage, move-
ment coordination and several pathological conditions
[59,62–65,72,73].
Despite its widespread abuse, cannabis-related cere-
brovascular events are infrequently reported. They are
believed to be due to a cannabis-induced vasospasm or a
Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society, 37, 118–134
cannabis-induced hypotension [74–78]. However, due to
the widespread use of this drug, it is difficult and often
impossible to establish whether these strokes are truly
associated with cannabis, other ingested drugs, or purely
coincidental.
The important question whether cannabis can cause
irreversible brain damage, particularly to adolescents,
or lead to increased risk for schizophrenia, persisting
beyond transient intoxication, is still a matter of debate
[79,80].
Opioids and derivatives
Opioids, especially heroin, are the leading substances that
cause death in drug abusers. Derivatives include mor-
phine, hydrocodone, oxycodone, hydromorphine, codeine
and other narcotics such as fentanyl, meperidene, metha-
done and opium [2,3]. Heroin is made from opium and
crosses the blood–brain barrier (BBB) faster than
morphine [81].
Heroin is usually administered intravenously. Intrana-
sal and subcutaneous administration is also possible.
Heroin alkaloid may be prepared for inhalation by heating
on metallic foil (‘chasing the dragon’) that results in a
higher bioavailability of heroin compared with smoking
in a cigarette [3].
Intravenous heroin induces an extreme euphoria
lasting for several minutes. Subsequently, there is a pleas-
ant dream-like state with drowsiness and analgesia [81].
However, marked tolerance develops to euphoria. Opiate
overdose produces the triad of coma, respiratory depres-
sion and miosis [81]. Between 50% and 70% of intrave-
nous heroin abusers have experienced a non-fatal
overdose at some time in their lives [4]. Medical complica-
tions of long-term heroin abuse include thrombophlebitis,
endocarditis, hepatitis, pneumonia, nephropathy and
immunodepression [2,81]. Due to the practise of needle-
sharing, there is a high risk for infections [11].
Risk factors for opioid-induced deaths include overdose,
concomitant use of other CNS depressants and loss of tol-
erance after a period of abstinence [4–8].
At necropsy, up to 90% of all cases of persons dying of
heroin overdose show brain oedema with prominent ton-
sillar herniation and uncal grooving. However, rapid
death after heroin intake will not lead to any morphologi-
cal evidence of neuronal cell injury. In cases of delayed
death after a survival period of 5 h or longer, hypoxic-
ischaemic leukoencephalopathy with loss of neurones in
© 2011 The Author

the hippocampal formation, the Purkinje cell layer and/or
the olivary nucleus, as well as vascular congestion, will
become apparent [82–86]. In the globus pallidus, neu-
ronal loss and bilateral, symmetrical ischaemic lesions/
necrosis have been described in 5–10% of cases [85,87].
All the above mentioned alterations are assumed to be
caused rather by recurrent episodes of hypoxia during the
intoxicated state than to be related to direct neurotoxic
effects of the opioid drugs [82–87].
Stroke in heroin abusers, occurring in the absence of
endocarditis or mycotic aneurysms, has rarely been
observed [84,88–93].
Within the hippocampus of heroin deaths, enhanced
expression of glial fibrillary acidic protein (GFAP) by astro-
cytes and/or a proliferation of microglia have been found
[84]. However, an increased GFAP expression could not be
confirmed by other authors [23]. An increase in polysialic
acid neural cell adhesion molecule positive hippocampal
neurones and astrocytes is assumed to reflect an attempt
to repair cell damage [94].
Perivascular pigment-laden macrophages and pigment
depositions are sometimes observed and are attributed to
repeated intravenous injections of impure heroin [95], or
to BBB breakdown [23,96].
Infections in heroin abusers result from unsterile injec-
tion techniques and from immunosuppression, caused by
chronic opiate abuse [1,2,11,85,97]. Endocarditis might
lead to septic foci in the brain or to intracranial mycotic
aneurysms [1,2,85,97].
Transverse myelitis/myelopathy is an exceptionally rare
lesion described in heroin abusers [1,2,85,98,99]. The
aetiology is still unclear and neither the clinical picture
nor the pathological changes correspond to any particular
pattern.
A distinct entity, spongiform leukoencephalopathy, has
been reported to occur almost exclusively after inhalation
of heroin pyrolysate vapours (‘chasing the dragon’)
[1,2,100–102]. The most characteristic finding is the
selective involvement of the posterior limb of the internal
capsule and sparing of subcortical U-fibres. Neuropatho-
logical examination reveals spongiform degeneration of
the deep white matter with vacuolation of the myelin
sheath, loss of oligodendrocytes, axonal reduction and
astrogliosis. The grey matter is usually unremarkable and
the brainstem, spinal cord and peripheral nerves are
spared [100–102]. A lipophilic toxin-induced process was
considered to be due to contaminants, but a definite toxin
could not yet be identified.
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Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society, 37, 118–134
The neuropathology of drug abuse 121
Alterations of neurotransmitters and receptors
Long-term heroin abuse seems not to be related with a
reduced density of CNS m- and d-opioid receptors [103–
106]. Instead, the molecular mechanisms underlying
opiate addiction seem to involve the second messenger
signalling system [16,18,19,104,107–114]. Necropsy
studies revealed that long-term heroin abuse causes an
increase in certain G proteins in different regions of the
brain [105,107,110]. Others have shown a decreased
level of Ca2+-dependent protein kinase C-a [104] and an
increased level of a membrane-associated G protein-
coupled receptor kinase [113].
Further findings include the downregulation of the
adenylyl-cyclase subtype I [109,111], a decrease in the
density of alpha 2-adrenoreceptors [103], a decrease in
the immunoreactivity of protein kinase C-ab [114], and
decreased levels of neurofilament proteins [115].
Within the dopaminergic system the levels of tyrosine
hydroxylase protein and those of the dopamine (DA)
metabolite homovanillic acid were reduced in the
nucleus accumbens [116]. Striatal levels of serotonin
(5-hydroxytryptamine or 5-HT) were either normal or
elevated, whereas the concentration of the 5-HT metabo-
lite 5-hydroxyindoleacetic acid was decreased [116].
According to the authors, chronic heroin abuse might
produce a modest reduction in dopaminergic and seroton-
ergic activity that could affect motivational state and
impulse control.
Maintenance therapy for heroin addiction includes
codeine, dihydrocodeine, methadone and buprenorphine
[117–120]. In the majority of deaths related to these sub-
stances, additional CNS depressant drugs, mainly alcohol
and benzodiazepines, can be detected. The neuropatho-
logical findings are similar to those encountered in heroin
deaths.
Cocaine
Cocaine is derived from the leaves of the coca plant.
Cocaine hydrochloride is a water-soluble white salt and
the most frequent preparation of the drug that is available
in form of cystals, granules or a white powder. It can be
administered intranasally (‘snorting’) or injected [2,3].
The free alkaloid form (‘free base’) that had been extracted
with volatile solvents is usually smoked. ‘Crack cocaine’ is
produced by first dissolving the hydrochloride salt in
water, then mixing with baking soda and heating. The
122 A. Büttner
cracking sound made by the crystals when they are heated
provides the name [2].
Cocaine initially induces profound subjective well-being
together with alertness and increased self-confidence.
Subsequently, there is a mild euphoria followed by fatigue.
Acute psychiatric disturbances include dysphoria, agita-
tion, aggressive behaviour, depression, paranoia, psy-
chosis and hallucinations. Medical complications include
vasoconstriction, tachycardia, hypertension and sudden
cardiac death [3,25,31].
Cocaine is a potent CNS stimulant. It crosses the BBB
rapidly due to its highly lipophilic properties [121,122].
Throughout the brain, cocaine and its major metabolites
are widely distributed and receptors with varying
affinities are found [123,124]. Cocaine acts by binding to
specific receptors at presynaptic sites preventing the
reuptake of neurotransmitters [2,3,122]. The major
synaptic effect of cocaine is the release of dopamine
(DA) from the synaptic vesicles and the blocking of DA
reuptake resulting in an enhanced dopaminergic neu-
rotransmission [2,3,122].
Cocaine is the most frequent drug of abuse associated
with fatal and non-fatal cerebrovascular events, with
either haemorrhagic or ischaemic strokes [89,91–
93,125–135]. In contrast to the non-drug-using popula-
tion, cocaine-related stroke occurs primarily in young
adults [1,125–128].
Cocaine-related ischaemic infarctions can occur in
every brain region [2,128,130]. The underlying cause is
attributed to cerebral vasospasm either by cocaine or its
metabolites [92,128,131,136–138]. Other mechanisms
include cocaine-induced cardiac arrhythmia with second-
ary cerebral ischaemia, or the direct effects of cocaine
on haemostasis with increased platelet aggregation
[89,128,131,135,139,140].
In cocaine-related intracerebral (ICH) and subarach-
noidal (SAH) haemorrhage, underlying arteriovenous
malformations or aneurysms are frequently observed
[93,125,127–130,132,141,142]. Cocaine abuse has
been shown to predispose to aneurysmal rupture at a sig-
nificantly earlier age, and in much smaller aneurysms,
compared with non-drug-using persons [125,143].
Cocaine-related ICH is associated more frequently with
subcortical locations, a higher risk of intraventricular
haemorrhage, and poor prognosis compared with non-
drug-abusing patients with spontaneous ICH [144].
Rupture of an arteriovenous malformation, or aneurysm,
are most likely related to the sudden elevation of blood
Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society, 37, 118–134
pressure and heart rate from the sympathomimetic effect
of the drug [92,128–130,132,141,145].
A cocaine-induced cerebral vasculitis as a cause for
cerebrovascular events could only be demonstrated in rare
cases [89,146,147].
In experimental models, cocaine enhances leucocyte
migration across the cerebral vessel wall and opens the
BBB to HIV-1 invasion by a direct effect on brain endothe-
lial cells and by the induction of pro-inflammatory
cytokines and chemokines [148,149].
Alterations of neurotransmitters and receptors
In the striatum of cocaine-related deaths, reductions in
the levels of enkephalin mRNA, m-opioid receptor binding
and DA uptake site binding, along with elevation in levels
of dynorphin mRNA and k-opioid receptor binding have
been described [150]. In chronic cocaine abusers, a
decreased level of DA was identified in the caudate nucleus
and frontal cortex, but not in the putamen, nucleus
accumbens and cerebral cortex [151–155]. This decrease
was not paralleled by an increase of DA D1 and D2 gene
expression [156]. Simultaneously, there was an increase
of cocaine binding sites on the DA transporter with a
decrease of the DA D1 receptor density in the striatum
and of DA D1 and DA D3 receptor density in the nucleus
accumbens [152–154,157–159]. A marked reduction
in immunoreactivity of the vesicular monoamine
transporter-2 [151] and of the transcription factor
NURR1 [160] in necropsy samples of human cocaine
abusers might reflect damage to the dopaminergic system.
An overexpression of a-synuclein in midbrain DA neu-
rones in chronic cocaine abusers may occur as a protec-
tive response to changes in DA turnover and increased
oxidative stress resulting from cocaine abuse [161]. This
accumulation of a-synuclein protein in long-term cocaine
abuse might increase the risk of developing Parkinsonism
[161].
Further necropsy findings include an upregulation of
k2-opioid receptors in the limbic system [162] and of
cAMP response element-binding protein in the ventral
tegmental area [163].
In the serotonergic system an increase of the 5-HT
transporter in the striatum, substantia nigra and limbic
system has been demonstrated [164]. In the putamen, a
DA-rich brain area, the activity of phospholipase A2
and phosphocholine cytidylyltransferase was selectively
decreased [165].
© 2011 The Author

Amphetamines and methamphetamine
Amphetamines and methamphetamine are widely used
psychostimulants that act on monoamine transporters
[2,3].
These substances are available as powder, capsules,
tablets or fluids. Therefore, they can be swallowed,
‘snorted’, injected intravenously or smoked. The composi-
tion, purity and dose are highly variable [2].
Their potent sympathomimetic effects include an eleva-
tion of pulse rate, blood pressure and an increased level
of alertness. Adverse effects include insomnia, excitability,
seizures, panic attacks, psychosis and aggressive behav-
iour [2,3,25]. Throughout the brain, methamphetamine
is heterogeneously distributed [166].
Amphetamines and methamphetamine are the
second most common cause (after cocaine) of strokes
occurring largely in persons younger than 45 years
[127]. Furthermore, SAH and ICH have been described
[2,3,91,92,125,126,129,167–172]. Similar to cocaine, a
sudden elevation in blood pressure [167,169,171] is pos-
tulated as a major mechanism. The vasoconstrictive effect
of both substances may also lead to the development of
ischaemic infarction [167,171]. Methamphetamine has
been shown to induce inflammatory genes in human
brain endothelial cells [173].
Alterations of neurotransmitters and receptors
The neurotoxic effects of amphetamines and metham-
phetamine on the dopaminergic system have been
described in various animal species and in humans. These
effects are characterized by desensitization of DA receptor
function, marked reduction of DA transporters and of DA
levels as well as other dopaminergic axonal markers [174–
181]. Similar alterations have been observed in the sero-
tonergic system [175]. However, the irreversibility of
these changes has not been established [175].
Although these alterations have been attributed to neu-
rodegeneration, direct evidence for the loss of nerve ter-
minals and/or their corresponding substantia nigra cell
bodies have not been provided unequivocally [175,177].
Nevertheless, based on animal studies, there is concern
that the alterations in the dopaminergic system may
predispose methamphetamine abusers to develop
Parkinsonism as they age [175,182,183]. Because
neuroimaging and necropsy studies of human metham-
phetamine abusers suggest changes in only some
© 2011 The Author
Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society, 37, 118–134
The neuropathology of drug abuse 123
dopaminergic system markers [181,184], the evidence is
inconclusive in regard to dopaminergic system degenera-
tion. To define methamphetamine abuse as a risk factor in
Parkinson disease, it would be important to know whether
these alterations represent neurodegenerative changes or
a drug-induced compensatory response to the disruption
of neurochemical homeostasis [182,183].
The mechanisms of methamphetamine-induced
neurotoxicity are thought to be mediated by multiple
mechanisms including the generation of free radicals
and nitric oxide, excitotoxicity, mitochondrial dysfunc-
tion, and the induction of immediate early genes as well
as transcription factors [175–177,182–185]. However,
whether neurotoxicity occurs in human methamphet-
amine and amphetamine abusers remains to be
established.
Amphetamine and methamphetamine
derivatives
Amphetamine and methamphetamine derivatives
(‘designer drugs’) comprise a broad spectrum of sub-
stances [2,186]. The street name ‘ecstasy’ subsumes
different hallucinogenic amphetamine derivatives with
MDMA (3,4-methylenedioxymethamphetamine) and
MDE (3,4-methylenedioxyethylamphetamine) being the
main components [187]. These drugs are taken orally in
form of tablets that are usually embossed with a logo
[2]. The effects of MDMA and MDEA last about 3–5 h
and include relaxation, euphoria, sensual enhancement,
reduction of anxiety and emotional closeness to others.
This psychological profile has been called ‘entactogenic’
and has the connotation of ‘inducing a feeling of touch
with the world within’. In addition, these substances also
have stimulant-like and hallucinogenic effects [2,188–
191]. The effects of MDMA vary according to the dose and
the frequency and duration of use [190]. Adverse effects
include headache, nausea, tooth grinding (bruxism),
tachycardia and an increase in body temperature. Fur-
thermore, hyperactivity, flight of ideas, depersonalization,
panic attacks, anxiety, depression, agitation, delirium, and
insomnia may occur [190].
MDMA interacts with various neurotransmitter circuits
but predominantly affects the dopaminergic and seroton-
ergic system [186,188–191]. In human post mortem
tissue, a distinct immunopositive reaction for MDMA and
MDA was observed in the white matter in all cortical
regions and in neurones of the basal ganglia, the hypo-
124 A. Büttner
thalamus, the hippocampus and the cerebellar vermis, but
relatively weak staining of neurones in the brainstem was
seen [192].
In reports on human fatalities following MDMA con-
sumption, detailed neuropathological examinations were
mostly not performed [193–196].
Cerebrovascular complications after ‘ecstasy’ consump-
tion have been described only occasionally [197–203]. In
the globus pallidus bilateral hyperintense lesions have
been found [204,205]. On neuropathological examina-
tion necrosis of the globus pallidus, diffuse astrogliosis
and spongiform changes of the white matter have been
described [205]. Other neuropathological findings in
deaths after ‘ecstasy’ abuse were mainly due to the com-
plications of hyperthermia with disseminated intravascu-
lar coagulopathy and consisted of cerebral oedema, focal
haemorrhages and nerve cell loss [196].
Alterations of neurotransmitters and receptors
In the brains of laboratory animals, including non-
human primates, exposure to MDMA has been associated
with dopaminergic and especially serotonergic neurotox-
icity [176,188–191,206–209]. There is strong evidence
for neurodegeneration and axonal loss, although the
exact mechanism is still unclear [189–191,206–209].
Current hypotheses include the formation of toxic MDMA
metabolites with generation of free radicals as well as oxi-
dative stress, excitotoxicity, apoptosis and mitochondrial
dysfunction [176,209–212].
Although in recent years, the question of ‘ecstasy’-
induced neurotoxicity and possible functional sequelae
has been addressed in several studies, the extent to which
these animal and non-human primate data are applicable
to humans and whether persistent neurotoxicity occurs in
humans is still controversial [42,207–209,213–219].
To date, the most consistent findings associate subtle
cognitive, particularly memory, impairments with heavy
ecstasy abuse [213,218,219].
Neuropathological studies
The consequences of drugs of abuse on the cellular ele-
ments of the human brain have not been studied system-
atically. There are only few reports on histopathological
alterations in the brains of human drug abusers describ-
ing oedema, vascular congestion, ischaemic nerve cell
damage and neuronal loss [83–85,96,220]. These alter-
Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society, 37, 118–134
ations have been attributed to drug-induced respiratory
failure and were therefore considered to be non-specific
[84,220]. However, in most of these studies, there was no
control group and systematic data on frequency or topog-
raphy of the lesions are lacking. Subsequent systematic
neuropathological studies of polydrug abusers revealed
ischaemia-independent widespread neuronal loss, a
reduction of GFAP-positive astrocytes, an axonal damage
with concomitant microglia activation as well as reactive
and degenerative vascular changes [23].
Neurones
The neuronal loss has been ascribed to be due to a direct
impairment of neurones by drugs of abuse and, indirectly,
to drug-induced damage of astrocytes, axons and the
cerebral vasculature [23]. In support of this finding is the
observation in animal models that drugs of abuse can
induce apoptotic neuronal cell death [69,175,221–225].
In human studies drug-induced alterations of neurofila-
ment proteins [115,226,227], of neuronal TUNEL posi-
tivity [96] or of transcription factors, for example, cAMP
response element-binding protein [112] and c-fos [20] is
thought to be an alternative pathway for neuronal loss.
In young opiate abusers an increase in the number and
distribution of hyperphosphorylated tau-positive neu-
rofibrillary pretangles, fully formed tangles and neuritic
threads has been reported [228]. This, together with
reports of occasional ubiquitin-positive inclusions in
neurones of drug abusers [96], indicates drug-related
neurodegeneration. Whether these changes are poten-
tially reversible is still unclear.
Within the substantia nigra there was a decrease of the
numerical density of the pigmented neurones, whereas
the density of the non-pigmented neurones was
unchanged [23]. The presence of eosinophilic ubiquiti-
nated cytoplasmic inclusions, which did not resemble
classic Lewy bodies, and which are negative for
a-synuclein, indicates abnormal cytoplasmic protein
sequestration [96]. To date it is not clear whether this
finding represents a transient neuronal abnormality
or commitment to an irreversible neurodegenerative
pathway [96].
White matter
In the white matter of polydrug abusers a widespread
axonal damage has been demonstrated by using b-APP
© 2011 The Author

Figure 1. Immunohistochemistry demonstrating
b-APP-immunopositive bundles and b-APP-immunopositive
globular deposits in the pons of polydrug abusers, counterstained
with haematoxylin, original magnification ¥100.
immunohistochemistry [23,229]. The alterations con-
sisted of b-APP-immunopositive bundles and globular
depositions (Figure 1), but they never showed the exten-
sive pattern seen in traumatic brain injury [23,229].
Furthermore, there is a concomitant activation of
microglia predominantly in the white matter and in
most subcortical regions [23,83,220,229]. This upregula-
tion of microglia has also been shown in drug abusers
with and without pre-symptomatic HIV-1 infection
[230,231]. Activated microglial cells are a source of pro-
inflammatory cytokines, which are linked to neuronal
damage and loss [10]. The axonal injury suggests a toxic-
metabolic drug effect, as there were no sufficient findings
for a secondary phenomenon in these cases, neither due to
a generalized hypoxic-ischaemic condition, nor to a brain
oedema and the concomitant activation of microglia
is indicative of a long-standing progressive process
[23,229]. These alterations might be the morphological
correlate of the observed demyelination and hyperintense
areas seen on magnetic resonance imaging.
Astrocytes
Although astrocytes play an essential role, for example, in
the maintenance of BBB, regulation of glutamatergic
neurotransmission and neurotransmitter metabolism,
little is known about alterations of these cells in human
drug abusers [232,233]. In an older study ‘widespread
fragmentation’ and a numerical depletion of astrocytes in
the white matter have been reported in the brains of drug
deaths [85]. In HIV-1-positive opiate abusers, HIV-1-
© 2011 The Author
Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society, 37, 118–134
The neuropathology of drug abuse 125
negative drug abusers and non-drug using controls there
was no statistical difference between these groups in rela-
tion to astrocytes [231,234].
In the brains of polydrug abusers the numerical density
of GFAP-positive astrocytes has been shown to be reduced
[23]. This reduction of GFAP-positive astrocytes is believed
to be due to the interference of drugs with the GFAP gene
transcription, inducing an altered GFAP phosphorylation
[235], as well as the generation of free radicals by induc-
tion of a cytochrome P450 isoform [236]. I2-imidazoline
receptors are involved in the regulation of the GFAP
expression [226]. In the frontal cortex of heroin deaths
the density of I2-imidazoline receptors and the immu-
noreactivity of the related imidazoline receptor protein
were decreased [237].
Vascular changes
In AIDS patients concentric small-vessel wall thickening,
perivascular space dilatation, pigment deposition, vessel
wall mineralization and perivascular inflammatory cell
infiltrates were seen in 50% of the former drug abusers
[238]. Similar vascular alterations can be observed in
HIV-1-negative polydrug abusers (Figure 2A) [23,96].
The presence of acute and chronic BBB breakdown in
drug abusers, suggests that the brain parenchyma is
exposed to unusual quantities of serum proteins, includ-
ing immunoglobulins, as well as other blood-borne
factors, including HIV [96]. It may further be the stimu-
lus for the occasional perivascular lymphocytic aggre-
gates that are seen in the brains of HIV-1-negative
drug abusers (Figure 2B) [10]. Furthermore, reactive
endothelial cell proliferation, degenerative hyalinotic
thickening, marked endothelial swelling and endothelial
cell hyperplasia are present in the brains of polydrug
abusers (Figure 2C,D) [23]. In addition, a decrease of the
collagen type IV content of the vascular basal lamina
[239] and a disruption of the BBB tight junctions [10]
have been observed. This non-inflammatory vasculopa-
thy has been interpreted as the morphological substrate
of a disturbed BBB and might be the morphological
substrate of the alterations seen on neuroimaging
[23,240].
In conclusion, drugs of abuse initiate a cascade of inter-
acting toxic, vascular and hypoxic factors that finally
result in widespread disturbances within the complex
network of CNS cell interactions (Figure 3). However,
much work will need to be done to clarify the yet
126 A. Büttner

A
B

C
D

Figure 2. Photomicrographs illustrating the spectrum of cerebral vascular changes in polydrug abusers. (A) Small artery in occipital white
matter showing concentric wall thickening. The surrounding perivascular space contains occasional macrophages and pigment deposition.
H&E, original magnification ¥200. (B) Small vessel in the orbital white matter with perivascular lymphocytic aggregates. H&E, original
magnification ¥200. (C) Endothelial proliferation in the dentate nucleus, H&E, original magnification ¥200. (D) Endothelial hyperplasia in
the parietal white matter, H&E, original magnification ¥200.

unresolved questions of the disastrous role of drugs of

abuse on the CNS.

Acknowledgements
The help of Claire Delbridge in correcting the manuscript
is highly appreciated. I thank Jeanne Bell, Institute of
Neuropathology, University of Edinburgh for critical dis-
cussions and Serge Weis, Laboratory of Neuropathology,
Neuropsychiatric Hospital Wagner-Jauregg, Linz, Austria
for his long-standing support and friendship.

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Received 26 July 2010
Accepted after revision 30 September 2010
Published online Article Accepted on 6 October 2010
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