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ScienceDirect
The neuropathology of drug abuse
Andreas Büttner
The predominantly abused illicit substances include cannabis,
opiates, cocaine, amphetamine, methamphetamine and their
derivatives. Recently, the abuse of new psychoactive
substances has become an increasing problem. In human drug
abusers a broad spectrum of changes affecting the central
nervous system are seen. The main alterations have been
assumed to result from the consequences of ischemia and
cerebrovascular diseases. However, detailed post-mortem
investigations have shown widespread morphological
alterations in the brains drug abusers. Further studies related
drug abuse with the risk of accelerated brain aging and the
development of neurodegenerative conditions.
Address
Institute of Legal Medicine, Rostock University Medical Center,
St.-Georg-Strasse 108, 18055 Rostock, Germany
Corresponding author: Büttner, Andreas
(andreas.buettner@med.uni-rostock.de)
Current Opinion in Behavioral Sciences 2017, 13:8–12
This review comes from a themed issue on Addiction
Edited by Scott Edwards and Karen D Ersche
For a complete overview see the Issue and the Editorial
Available online 19th July 2016
http://dx.doi.org/10.1016/j.cobeha.2016.07.002
2352-1546/# 2016 Elsevier Ltd. All rights reserved.
Introduction
Despite a large body of literature on animal models little is
known about the morphological consequences of drugs of
abuse on the human central nervous system. The predom-
inant drugs of abuse consumed worldwide are cannabis,
opiates, cocaine, amphetamine, methamphetamine, and
‘designer drugs’ with new psychoactive substances as a
recent alarming development [1,2]. Since the majority of
drug abusers perform polydrug abuse including alcohol and
nicotine [1–3] it is difficult to relate neuropathological
alterations to a single substance. Furthermore, many drugs
contain potentially neurotoxic adulterants and diluents
[1,2,4]. In injecting drug abusers or in drug abusers with
risky sexual behavior there is also a high incidence of HIV-
1, hepatitis B, or hepatitis C virus infection which may also
compromise the brain [1,2,5].
Neuroimaging findings
Neuroimaging studies revealed brain alterations in
several, but drug-dependent different regions [6,7–12]
Current Opinion in Behavioral Sciences 2017, 13:8–12
consisting of gray matter volume reduction, white matter
impairment, focal perfusion deficits, as well as neuro-
chemical abnormalities. Particularly involved are limbic
and reward regions [6]. The nucleus accumbens is a
crucial region of the mesocorticolimbic system and plays
an important role in mediating the rewarding effects of
drugs of abuse. A recent structural MRI study of heroin-
dependent patients showed an association between a
decreased volume of the left nucleus accumbens and
an increased depression score [13]. As the authors pointed
out their findings could constitute a clinical marker to
distinguish subgroups of patients by the volume of the
nucleus accumbens with respect to depressive symptoms.
The assumed underlying pathomechanisms of the ob-
served structural abnormalities include direct toxic drug
effects, ischemia-hypoxia, cerebrovascular conditions in-
cluding vasoconstriction, vasculitis or hypertension, in-
flammation, and abnormal brain development [6,7–9].
However, clinical correlations have rarely been provided
and the exact morphological correlates of most of these
findings are still unclear.
Cannabis
The main psychoactive component of cannabis, D9-tetra-
hydrocannabinol (THC), and other cannabinoids interact
with specific receptors. Within the brain these cannabi-
noid-receptors are distributed heterogeneously with the
highest density in regions associated with memory, per-
ception and motor control [1,2]. Their very low density
in the brain stem explains the lack of lethality of cannabis.
Despite the widespread consumption of cannabis there
are only very few reports of brain alterations. Cannabis-
related cerebrovascular events comprise ischemic stroke
and an increased likelihood of aneurysmal subarachnoid
hemorrhage [14–17]. However, these complications have
rarely been reported and due to the frequent abuse of
cannabis it is difficult and often impossible to establish
whether these observations are really associated with
cannabis, other ingested drugs, or purely coincidental.
The important question whether cannabis can cause
irreversible brain damage, or lead to an increased risk
for psychosis or schizophrenia is still a matter of debate
[18].
Opioids and derivatives
Opioids, particularly heroin, are the predominant sub-
stances that cause death in drug abusers, often in the
context of polydrug abuse [1,2]. Opioid abusers are at
high risk for fatal and non-fatal overdoses with ischemic–
hypoxic brain damage [1,2,19]. Upon autopsy rapid
opiod deaths only reveal prominent brain swelling with
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edema and vascular congestion. After a longer survival
period of some hours symmetric ischemic lesions within
the globus pallidus or hypoxic–ischemic leukoencephalo-
pathy become obvious [1,2,14,19]. In single instances
stroke, transverse myelitis/myelopathy or spongiform leu-
koencephalopathy [1,2,14,20] has been observed in
heroin abusers. The latter condition has sporadically been
described worldwide after the inhalation of pre-heated
heroin (‘chasing the dragon’, ‘Chinese blowing’). A lipo-
philic toxin related to contaminants with impairment of
oligodendrocyte mitochondria in conjunction with cere-
bral hypoxia is considered to be the cause, but a definite
toxin has not yet been identified [1].
Cocaine
Cocaine is a potent stimulant and the drug of abuse most
frequently associated with fatal and non-fatal cerebrovas-
cular complications [1,2,14,19,21]. Both hemorrhagic
and ischemic stroke may be observed [1,2,14,19,22–26]
primarily in young adults. Ischemic stroke results from
cocaine-induced vasospasm, whereas intracerebral and
subarachnoid hemorrhages result from a sudden elevation
of blood pressure and heart rate from the sympathomimetic
effects of cocaine. In cocaine-related intracerebral and
subarachnoid hemorrhage, underlying arteriovenous mal-
formations or aneurysms are often observed [26]. Cocaine
abuse has been shown to predispose aneurysm rupture at
an earlier age and in much smaller aneurysms compared to
non-drug using persons [26]. Besides cocaine-associated
seizures, movement disorders (‘crack dancing’) and excited
delirium are frequently observed in cocaine abusers [2].
Amphetamines and methamphetamine and
derivatives
Amphetamines, methamphetamine and their derivatives
are psychostimulants that predominantly act on mono-
amine transporters [1,2,19,21]. They are the second-
most-common cause (after cocaine) for fatal and non-fatal
cerebrovascular complications. Furthermore, SAH and
ICH have often been described [1,2,19]. The pathophys-
iological mechanisms are analog to cocaine with a sudden
elevation in blood pressure and vasospasm due to their
potent sympathomimetic effects. Common substances of
amphetamine and methamphetamine derivatives with
similar effects on the dopaminergic and serotonergic sys-
tem include DOM (4-methyl-2,5-dimethoxyampheta-
mine), DOB (4-bromo-2,5-dimethoxyamphetamine),
MDA (3,4-methylenedioxyamphetamine), MDE (3,4-
methylenedioxyethylamphetamine), MDMA (3,4-methy-
lenedioxymethamphetamine, ‘ecstasy’) 4-MTA (4-
methylthioamphetamine) and PMA (4-para-methoxyam-
phetamine).
The neurotoxic potential of these substances on the
dopaminergic and serotonergic system have been de-
scribed in various animal species and in humans. How-
ever, whether the animal and nonhuman primate data are
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The neuropathology of drug abuse Büttner 9
applicable to humans or if these alterations are irrevers-
ible is still discussed controversial [27–30].
New psychoactive substances (NPS)
The abuse of new (novel) psychoactive substances (NPS)
is an emerging trend over the past years. NPS constitute a
heterogeneous group of substances, which can be catego-
rized in different ways according to their pharmacological
and chemical properties or their psychoactive effects
[2,31,32,33,34–38,39,40,41]. Some of them have been
detected as adulterants in other drugs [4]. Nearly all of
these substance are legal until specifically scheduled by
legislation, therefore they are widely distributed.
Synthetic cannabinoids (‘Spice’, ‘K2’, ‘Jamaica’) are a het-
erogeneous group of compounds which share a similar
chemical structure to D9-tetrahydrocannabinol (D9-
THC), the main psychoactive component in cannabis
[2,31,32,34,35,37,38,39]. Many of them are synthetic
cannabinoid receptor agonists that were developed as
research tools or potential medicines. The substance
abbreviations typically start with the initials of the invent-
ing chemists or laboratory (e.g. JWH, AM, CP, HU)
followed by numbers. The most popular compound in
this class is named JWH-018. These substances are more
potent than D9-THC because they have greater binding
affinity for the cannabinoid CB1 receptor, as opposed to
the partial CB1/CB2 receptor agonism of D9-THC. Be-
cause of these properties they have a higher frequency
and severity of negative effects than cannabis. Although
there are several reports on acute intoxication, long-term
or residual effects on the central nervous system are
unknown. Fatal intoxications have also been reported
for several of these substances [31,34,37,39]. The pre-
dominant cause of death has been cardiac arrhythmias
[37]. Detailed neuropathological examinations are lack-
ing so far. In one voxel-based morphometry of structural
magnetic resonance imaging a gray matter density reduc-
tion in the right and left thalamus and lower gray matter
density in the left cerebellum has been observed in
synthetic cannabinoid abusers [40].
Synthetic cathinones are chemically and pharmacologically
related to cathinone, the psychoactive ingredient in the
leaves of the khat plant. They are usually sold as ‘bath
salts’ and abused for their psychostimulant and halluci-
nogenic effects [31–36,38]. The most common substances
include the b-keto-amphetamines mephedrone, methy-
lone, butylone and methylendioxypyrovalerone [31,35].
Tryptamines are a group of monoamine alkaloids, derived
from the amino acid tryptophan and similar to serotonin
(5-hydroxytryptamine, 5-HT). They act as 5HT2A re-
ceptor agonists and serotonin reuptake inhibitor inducing
visual hallucinations, alterations in sensory perception,
and depersonalization. The most common and potent
Current Opinion in Behavioral Sciences 2017, 13:8–12
10 Addiction
hallucinogenic substance of this class is lysergic acid
diethylamide (LSD) [2,31,32,34,36,38].
Phenethylamines (2Cs, 2Ds) encompass substances with a
molecular structure and effects similar to those of am-
phetamine. There action on serotonergic receptors
induces psychedelic effects [2,31,32,34,36,38].
Piperazine has initially been introduced as an anti-hel-
mintic. Piperazines and derivatives, for example ben-
zylpiperazine, trigger the release of dopamine and
norepinephrine and inhibit the uptake of dopamine,
norepinephrine and serotonin. Therefore they can be
stimulating as well as hallucinogenic [2,31,32,
34,36,38].
Arylcyclohexylamines are dissociative anesthetics that dis-
tort perceptions of sight and sound and produce feelings
of dissociation from the environment and self without
hallucinations. The most common substances include
ketamine, phencyclidine (PCP), dextromethorphan and
methoxetamine [2,34,41].
From a forensic-toxicological point of view on NPS the
large number and type of isomers and their derivatives
will not be detected reliably by routine immunoassay-
based techniques [31]. With mass spectrometry these
substances may also be missed if they are not included
in the reference libraries used in forensic laboratories.
Therefore, the analytical methods have to be continu-
ously adapted to the developments on the drug market
with an estimated number of hundreds of new substances
every year. In order to confirm the consumption of
synthetic cannabinoids, blood analysis using highly spe-
cific and sensitive analytical methods, such as liquid
chromatography–tandem mass spectrometry (LC–MS/
MS), is required.
Besides public health issues the detection of newly
introduced substances have important legal implications,
for example the investigation of road traffic offenses
unexplained deaths, or assessment of criminal responsi-
bility.
Autopsy studies
Large autopsy series and own experiences showed that
the majority of drug deaths are polysubstance abusers.
Therefore, it is difficult to relate brain alterations to a
single substance. An additional problem is to differentiate
between drug-specific and secondary effects by adulter-
ants, underlying diseases (e.g. infections, neurodevelop-
mental abnormalities) or the lifestyle of the drug abuser
[1,2].
In the past, detailed neuropathological studies of hu-
man drug abusers were scarce and predominantly fo-
cused on the consequences of hypoxia–ischemia or
Current Opinion in Behavioral Sciences 2017, 13:8–12
apparent cerebrovascular events [1,42]. Thus, the
effects of drugs of abuse on the cellular elements of
the human brain have not been studied systematically in
these cases. The observations of edema, vascular con-
gestion, ischemic nerve cell damage with subsequent
neuronal loss have been considered to be unspecific
[1,42]. However, recent systematic morphological stud-
ies revealed profound drug-induced alterations consist-
ing of neuronal loss, numerical reduction of GFAP-
positive astrocytes, axonal damage, as well as microglia
activation in the white matter and in subcortical regions
[1,42–44].
In addition, vascular alterations similar to those seen in
HIV-1 infection and in patients with hypertension could
be detected [42,45,46]. Further findings included reactive
endothelial cell proliferation, endothelial swelling and
hyperplasia, an impaired basal lamina [42] and a blood–
brain barrier breakdown [47,48]. This non-inflammatory
vasculopathy with impairment of the neurovascular unit
could represent one morphological substrate of the neu-
roimaging findings.
In the last years, several neuroimaging and postmortem
studies provided evidence that drug abusers show signs of
accelerated brain aging and may develop neurodegenera-
tion or Parkinsonism as they age [1,10–12,28,30,49–52]. In
younger opiate abusers an increase in hyperphosphory-
lated tau-positive neurofibrillary pretangles, fully formed
tangles and neuritic threads as well as ubiquitin-positive
and p62-positive neuronal inclusions have been detected
[49,51,53]. Within the substantia nigra there was a de-
crease of the numerical density of pigmented neurons
[42] and the presence of ubiquitinated cytoplasmic neu-
ronal inclusions [45]. In long-term cocaine abusers an
accumulation of a-synuclein protein was found [52],
which could not been demonstrated in heroin abusers
[51]. In abusers of amphetamines, methamphetamine
and their derivatives is evidence for dopaminergic and
serotonergic axonal damage [27–30].
Summarized, drugs of abuse initiate a cascade of inter-
acting toxic, vascular and hypoxic factors which finally
result in widespread disturbances within the complex
network of the brain cell-interactions. Furthermore, there
is strong evidence of accelerated brain aging and the
development of neurodegenerative diseases. However,
there still exist many unresolved questions in unraveling
the exact mechanisms and the extent of these alterations.
Further neuropathological studies with well-defined
cases, profound toxicological analyses (including hair
analysis), evaluation of the clinical history, and sophisti-
cated morphological techniques might reveal the serious
consequences of drugs of abuse on the human brain.
Conflict of interest statement
Nothing declared.
www.sciencedirect.com

References and recommended reading
Papers of particular interest, published within the period of review,
have been highlighted as:
 of special interest
 of outstanding interest
1. Büttner A: The neuropathology of drug abuse. Neuropathol Appl
Neurobiol 2011, 37:118-134.
2. Karch SB, Drummer O (Eds): Karch’s Pathology of Drug Abuse,
 edn 5. Boca Raton, FL: CRC Press, Taylor & Francis Group; 2016.
The reference text book of the (histo)pathology of drugs of abuse on all
human organs with a comprehensive covering of epidemiological, clinical
and toxicological data.
3. Connor JP, Gullo MJ, White A, Kelly AB: Polysubstance use:
diagnostic challenges, patterns of use and health. Curr Opin
Psychiatry 2014, 27:269-275.
4. Giné CV, Espinosa IF, Vilamala MV: New psychoactive
substances as adulterants of controlled drugs. A worrying
phenomenon? Drug Test Anal 2014, 6:819-824.
5. Passarino G, Ciccone G, Siragusa R, Tappero P, Mollo F:
Histopathological findings in 851 autopsies of drug addicts,
with toxicologic and virologic correlations. Am J Forensic Med
Pathol 2005, 26:106-116.
6. Brown GG, Jacobus J, McKenna B: Structural imaging for
 addiction medicine: from neurostructure to neuroplasticity.
Prog Brain Res 2016, 224:105-127.
The article present a review of structural brain changes associated with
the abuse of cannabis, stimulants, and opiates detected by quantitative
MRI morphometry and diffusion tensor imaging.
7. Geibprasert S, Gallucci M, Krings T: Addictive illegal drugs:
structural neuroimaging. AJNR Am J Neuroradiol 2010, 31:803-
808.
8. Kaufman MJ (Ed): Brain Imaging in Substance Abuse: Research,
Clinical, and Forensic Applications. Totowa, NJ: Humana Press;
2001.
9. Tamrazi B, Almast J: Your brain on drugs: imaging of drug-
related changes in the central nervous system. Radiographics
2012, 32:701-719.
10. Bartzokis G, Beckson M, Lu PH, Edwards N, Rapoport R,
Wiseman E, Bridge P: Age-related brain volume reductions in
amphetamine and cocaine addicts and normal controls:
implications for addiction research. Psychiatry Res 2000, 98:93-
102.
11. Cheng GLF, Zeng H, Leung MK, Zhang HJ, Lau BWM, Liu Y-P,
Liu G-X, Sham PC, Chan CCH, So K-F, Lee TMC: Heroin abuse
accelerates biological aging: a novel insight from
telomerase and brain imaging interaction. Transl Psychiatry
2013, 3:e260.
12. Ersche KD, Jones PS, Williams GB, Robbins TW, Bullmore ET:
Cocaine dependence: a fast-track for brain ageing? Mol
Psychiatry 2013, 18:134-135.
13. Seifert C, Magon S, Sprenger T, Lang U, Huber C, Denier N,
Vogel M, Schmidt A, Radue E-W, Borgwardt S, Walter M:
Reduced volume of the nucleus accumbens in heroin
addiction. Eur Arch Psychiatry Clin Neurosci 2015, 265:637-645.
14. Fonseca AC, Ferro JM: Drug abuse and stroke. Curr Neurol
Neurosci Rep 2013, 13:325.
15. Rumalla K, Reddy AY, Mittal MK: Recreational marijuana use
and acute ischemic stroke: a population-based analysis of
hospitalized patients in the United States. J Neurol Sci 2016,
364:191-196.
16. Rumalla K, Reddy AY, Mittal MK: Association of recreational
marijuana use with aneurysmal subarachnoid hemorrhage. J
Stroke Cerebrovasc Dis 2016, 25:452-460.
17. Thanvi BR, Treadwell SD: Cannabis and stroke: is there a link?
Postgrad Med J 2009, 85:80-83.
18. Ksir C, Hart CL: Cannabis and psychosis: a critical overview of
the relationship. Curr Psychiatry Rep 2016, 18:12.
www.sciencedirect.com
The neuropathology of drug abuse Büttner 11
19. Brust JCM (Ed): Neurological Aspects of Substance Abuse, edn 2.
Philadelphia, PA: Elsevier, Butterworth-Heinemann Ltd.; 2004.
20. Krinsky CS, Reichard RR: Chasing the dragon: a review of toxic
leukoencephalopathy. Acad Forensic Pathol 2012, 2:67-73.
21. Heal DJ, Smith SL, Henningfield JE: CNS stimulants.
 Neuropharmacology 2014, 87:1-222.
This special issue of Neuropharmacology on CNS stimulants covers
molecular mechanisms, animal models, medical applications and the
problems of abuse and addiction with a thorough review on their neu-
rotoxic effects.
22. Cheng Y-C, Ryan KA, Qadwai SA, Shad J, Sparks MJ,
Wozniak MA, Stern BJ, Phipps MS, Cronin CA, Magder LS,
Cole JW, Kittner SJ: Cocaine use and risk of ischemic stroke in
young adults. Stroke 2016, 47:918-922.
23. Martin-Schild S, Albright KC, Hallevi H, Barreto AD, Philip M,
Misra V, Grotta JC, Savitz SI: Intracerebral hemorrhage in
cocaine users. Stroke 2010, 41:680-684.
24. Sordo L, Indave B, Barrio G, Degenhardt L, De La Fuente L,
Bravo M: Cocaine use and risk of stroke: a systematic review.
Drug Alcohol Depend 2014, 142:1-13.
25. Treadwell SD, Robinson TG: Cocaine use and stroke. Postgrad
Med J 2007, 83:389-394.
26. Vannemreddy P, Caldito G, Willis B, Nanda A: Influence of
cocaine on ruptured intracranial aneurysms: a case control
study of poor prognostic indicators. J Neurosurg 2008,
108:470-476.
27. Curran HV: Is MDMA (‘‘ecstasy’’) neurotoxic in humans? An
overview of evidence and of methodological problems in
research. Neuropsychobiology 2000, 42:34-41.
28. Gouzoulis-Mayfrank E, Daumann J: Neurotoxicity of
methylenedioxyamphetamines (MDMA; ecstasy) in humans:
how strong is the evidence for persistent brain damage?
Addiction 2006, 101:348-361.
29. Parrott AC, Marsden CA: MDMA (3,4-
methylenedioxymethamphetamine) or ecstasy: the
contemporary human and animal research perspective.
J Psychopharmacol 2006, 20:143-146.
30. Thrash B, Thiruchelvan K, Ahuja M, Suppiramaniam V,
Dhanasekaran M: Methamphetamine-induced neurotoxicity:
the road to Parkinson’s disease. Pharmacol Rep 2009, 61:966-
977.
31. Dargan PI, Wood DM (Eds): Novel Psychoactive Substances:
Classification, Pharmacology and Toxicology. London, UK:
Academic Press, Elsevier Inc.; 2013.
32. Baumann MH, Solis EJ, Watterson LR, Marusich JA,
Fantegrossi WE, Wiley JL: Baths salts, spice, and related
designer drugs: the science behind the headlines. J Neurosci
2014, 34:15150-15158.
33. German CL, Fleckenstein AE, Hanson GR: Bath salts and
 synthetic cathinones: an emerging designer drug
phenomenon. Life Sci 2014, 97:2-8.
This article is part of a special issue of Life Sciences summarizing a
symposium organized by the National Institute on Drug Abuse (NIDA) on
emerging trends in the abuse of designer drugs and with an update on
chemistry, pharmacology, toxicology and addiction potential.
34. Krabseth HM, Tuv SS, Strand MC, Karinen RA, Wiik E,
Vevelstad MS, Westin AA, Øiestad EL, Vindenes V: Novel
psychoactive substances. Tidsskr Nor Laegeforen 2016,
136:714-717.
35. Lewin AH, Seltzman HH, Carroll FI, Mascarella SW, Reddy PA:
Emergence and properties of spice and bath salts: a medicinal
chemistry perspective. Life Sci 2014, 97:9-19.
36. Miotto K, Striebel J, Cho AK, Wang C: Clinical and
pharmacological aspects of bath salt use: a review of
the literature and case reports. Drug Alcohol Depend 2013,
132:1-12.
37. Trecki J, Gerona RR, Swartz MD: Synthetic cannabinoid-related
illnesses and deaths. N Engl J Med 2016, 373:103-107.
Current Opinion in Behavioral Sciences 2017, 13:8–12
12 Addiction
38. Zawilska JB: ‘‘Legal highs’’ — an emerging epidemic of novel
psychoactive substances. Int Rev Neurobiol 2015, 120:273-300.
39. Castaneto MS, Gorelick DA, Desrosiers NA, Hartman RL, Pirard S,
 Huestis MA: Synthetic cannabinoids: epidemiology,
pharmacodynamics, and clinical implications. Drug Alcohol
Depend 2014, 144:12-41.
This systematic literature analysis gives a comprehensive review on the
action of the epidemiology and pharmacology of synthetic cannabinoids
and their clinical implications.
40. Nurmedov S, Metin B, Ekmen S, Noyan O, Yilmaz O, Darcin A,
Dilbaz N: Thalamic and cerebellar gray matter volume
reduction in synthetic cannabinoids users. Eur Addict Res
2015, 21:315-320.
41. Morris H, Wallach J: From PCP to MXE: a comprehensive review
of the non-medical use of dissociative drugs. Drug Test Anal
2014, 6:614-632.
42. Büttner A, Weis S: Neuropathological alterations in drug
abusers — the involvement of neurons, glial and vascular
systems. Forensic Sci Med Pathol 2006, 2:115-126.
43. Anthony IC, Ramage SN, Carnie FW, Simmonds P, Bell JE: Does
drug abuse alter microglial phenotype and cell turnover in the
context of advancing HIV infection? Neuropathol Appl
Neurobiol 2005, 31:325-338.
44. Tomlinson GS, Simmonds P, Busuttil A, Chiswick A, Bell JE:
Upregulation of microglia in drug users with and without pre-
symptomatic HIV infection. Neuropathol Appl Neurobiol 1999,
25:369-379.
45. Bell JE, Arango JC, Robertson R, Brettle RP, Leen C, Simmonds P:
HIV and drug misuse in the Edinburgh cohort. J Acquir Immune
Defic Syndr 2002, 31(Suppl. 2):S35-S42.
46. Connor MD, Lammie GA, Bell JE, Warlow CP, Simmonds P,
Brettle RP: Cerebral infarction in adult AIDS patients:
observations from the Edinburgh HIV autopsy cohort. Stroke
2000, 31:2117-2126.
Current Opinion in Behavioral Sciences 2017, 13:8–12
47. Bell JE, Arango JC, Anthony IC: Neurobiology of multiple insults:
HIV-1-associated brain disorders in those who use illicit
drugs. J Neuroimmune Pharmacol 2006, 1:182-191.
48. Egleton RD, Abbruscato T: Drug abuse and the neurovascular
 unit. Adv Pharmacol 2014, 71:451-480.
This article focus on the recent insights of the impact of acute and chronic
drug abuse to the neurovascular unit (brain endothelial cell, neuron,
astrocyte, microglia, and pericyte), which has long been neglected.
49. Anthony IC, Norrby KE, Dingwall T, Carnie FW, Millar T, Arango JC,
Robertson R, Bell JE: Predisposition to accelerated Alzheimer-
related changes in the brains of human immunodeficiency
virus negative opiate abusers. Brain 2010, 133:3685-3698.
50. Callaghan RC, Cunningham JK, Sykes J, Kish SJ: Increased
risk of Parkinson’s disease in individuals hospitalized with
conditions related to the use of methamphetamine or other
amphetamine-type drugs. Drug Alcohol Depend 2012,
120:35-40.
51. Kovacs GG, Horvath MC, Majtenyi K, Lutz MI, Hurd YL, Keller E:
 Heroin abuse exaggerates age-related deposition of
hyperphosphorylated tau and p62-positive inclusions.
Neurobiol Aging 2015, 36:3100-3107.
The study investigated neurodegeneration-related proteins (amyloid-
beta, a-synuclein, tau, p62, TDP-43) in heroin fatalities aged 19–40 years.
The authors confirmed previous findings that heroin abuse is associated
with tau hyperphosphorylation. In addition, p62-positive neuronal depos-
its were present. Interestingly, amyloid-beta deposits, a-synuclein and
TDP-43 could not be detected in the examined age group.
52. Mash DC, Ouyang Q, Pablo J, Basile M, Izenwasser S,
Lieberman A, Perrin RJ: Cocaine users have an overexpression
of a-synuclein in dopamine neurons. J Neurosci 2003, 23:2564-
2572.
53. Ramage SN, Anthony IC, Carnie FW, Busuttil A, Robertson R,
Bell JE: Hyperphosphorylated tau and amyloid
precursor protein deposition is increased in the brains of
young drug abusers. Neuropathol Appl Neurobiol 2005,
31:439-448.
www.sciencedirect.com