162 Karchs Pathology of Drug Abuse

Tashkin, D. P., Gorelick, D. et al. (1992). Respiratory efects of cocaine freebasing among habitual
cocaine users, J. Addict. Dis., 11(4), pp. 5970.
Taylor, R. F. and Bernard, G. R. (1989). Airway complications from free-basing cocaine, Chest,
95(2), pp. 4767.
Terra Filho, M., Yen, C. C. et al. (2004). Pulmonary alterations in cocaine users, Sao Paulo Med. J.,
122(1), pp. 2631.
Tomashefski, J. F., Jr. and Hirsch, C. S. (1980). Te pulmonary vascular lesions of intravenous drug
abuse, Hum. Pathol., 11(2), pp. 13345.
Tomashefski, J. F., Jr., Hirsch, C. S. et al. (1981). Microcrystalline cellulose pulmonary embolism
and granulomatosis. A complication of illicit intravenous injections of pentazocine tablets,
Arch. Pathol. Lab. Med., 105(2), pp. 8993.
Trimarchi, M., Miluzio, A. et al. (2006). Massive apoptosis erodes nasal mucosa of cocaine abusers,
Am. J. Rhinol., 20(2), pp. 1604.
Uva, J. L. (1997). Spontaneous pneumothoraces, pneumomediastinum, and pneumoperitoneum:
consequences of smoking crack cocaine, Pediatr. Emerg. Care, 13(1), pp. 246.
Viswanathan, G. and Navaneethan, S. D. (2007). An overlooked diferential diagnosis of acute chest
pain, South. Med. J., 100(8), p. 850.
Welch, G. H., Reid, D. B. et al. (1990). Infected false aneurysms in the groin of intravenous drug
abusers, Br. J. Surg., 77(3), pp. 3303.
Wolf, H., Moon, R. et al. (1990). Barotrauma and air embolism in hyperbaric oxygen therapy, Am.
J. Forensic Med. Pathol., 11(2), pp. 14953.
Yegane, R. A., Salehi, N. A. et al. (2006). Surgical approach to vascular complications of intravenous
drug abuse, Eur. J. Vasc. Endovasc. Surg., 32(4), pp. 397401.
Yellin, A. E. (1977). Ruptured mycotic aneurysm: a complication of parenteral drug abuse, Arch.
Surg., 112(8), pp. 9816.
Zolkowska, D., Rothman, R. B. et al. (2006). Amphetamine analogs increase plasma sero-
tonin: implications for cardiac and pulmonary disease, J. Pharmacol. Exp. Ter., 318(2),
pp. 60410.
1.16 Neurological Disorders, Introduction
Like all other psychostimulants, cocaine inhibits dopamine transporters (DAT) located
in the striatum; alterations in this region are deeply implicated in the process of addic-
tion. Te striatum is especially rich in dopamine transporters, and their blockade by
cocaine leads to elevated brain dopamine concentrations, transient euphoria, and addic-
tion (Kahlig and Galli, 2003). At the same time that dopamine re-uptake is blocked, so is
the re-uptake of other catecholamines, including norepinephrine, which is critical to the
function of many parts of the brain, including the prefrontal cortex, the area implicated
in attention defcit disorder. In addition to blocking 5-HT re-uptake, some of the selective
5-HT re-uptake inhibitor (SSRI) antidepressants (like paroxetine) act like cocaine and pre-
vent norepinephrine re-uptake as well. Tere is still debate about whether the prevention of
re-uptake adds to or detracts from SSRIs antidepressant efects, though it is beginning to
appear that it detracts (Nemerof and Owens, 2004). Finally, cocaine elevates the calcium
concentration within the brain (Du et al., 2006). While this efect could be the result of
raised norepinephrine concentrations, the most recent studies indicate that it is cocaine
itself, and not norepinephrine, that produces the calcium elevation. Elevated brain calcium
concentrations favor the occurrence of vasospasm and seizure, two disorders known to be
associated with cocaine abuse.
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Cocaine 163
Te results of clinical studies suggest that a high percentage of cocaine abusers exhibit
symptoms of paranoia and even hallucination (Brady et al., 1991). Heavy users ofen believe
they are being watched and/or followed. Tis complaint is not confned to cocaine users but is
also well recognized in methamphetamine abusers (Brecht et al., 2004; Urbina and Jones, 2004).
Psychosis is more likely to develop in men, and appears to be dose related (Brady et al., 1991).
Intravenous abusers are more prone to develop paranoia and hallucinations than nonintrave-
nous abusers (Kaye and Darke, 2004). Cocaine abusers with psychosis become sensitizedtheir
disease becomes more and more severe the more drug they use (Brady et al., 1991).
1.16.1 Cocaine Neurotoxicity
Within minutes of cocaine administration, there is increased expression of several difer-
ent genes; c-fos, the transcriptional regulator, is one of the frst genes to be up-regulated
(Graybiel et al., 1990), followed by an increase in production of mRNA coding for tyrosine
hydroxylase and tryptophan hydroxylase. Tese two enzymes catalyze the rate-limiting
steps in the production of both dopamine and 5-HT, the neurotransmitters most obviously
involved in the ability of cocaine to cause both euphoria and seizures.
Postmortem studies have shown that, in humans, the numbers of both D1 and D2
dopamine receptors are altered by cocaine use (Seeman and Van Tol, 1994). Te brains of
cocaine abusers contain elevated numbers of cocaine recognition sites on striatal dopamine
transporters, although no such increase is seen in victims of excited delirium. Chronic
cocaine abuse also produces striking decreases in the density of the D1 receptor subtype
throughout the striatal reward centers, probably as a result of receptor down-regulation,
which also probably explains why cocaine users quickly become tolerant to the euphoriant
efects of cocaine (Staley et al., 1994; Staley and Mash, 1996). Similar changes in D1 receptor
sensitivity and gene expression are also seen in experimental animals (Laurier et al., 1994).
Positron emission tomography (PET) scanning studies show that even low doses of
cocaine given intravenously cause cerebral hypoperfusion. Hypoperfusion is maximal at
8 minutes and is mostly dissipated by 32 minutes afer infusion. Hypoperfusion occurs
throughout the brain, but the lef hemispheric dopamine-rich sublobar region is the most
severely afected (Johnson et al., 2005). Te decrease correlates with the density of the
dopamine transporters that are blocked by cocaine, and there is strong evidence that
dopamine concentrations play an important part in the control of blood fow (Choi et al.,
2006). Magnetic resonance imaging (MRI) studies of human volunteers have also shown
that cocaine administration induces dose-related vasoconstriction, even when low doses
of cocaine are given, and even in the absence of other risk factors (Kaufman et al., 1998).
Tese changes can only make ischemic stroke more likely.
At the same time, studies with transcranial Doppler sonography, a technique that can
be used to continuously measure cerebral blood fow velocity, show a signifcant increase in
mean and systolic blood fow velocity afer intravenous cocaine injection. Tis change lasts
only for a few minutes, but it is seen even with relatively low doses of cocaine. Increases
in systolic velocity in the large vessels of the brain only occur when they are constricted,
demonstrating that cocaine, apparently in all users, induces a transient period of cerebral
vasoconstriction (Herning et al., 1999). Tese study results have been confrmed by many
others. Te only question to be answered is whether they explain the occurrence of isch-
emic stroke in cocaine users, or whether other factors such as 5-HT-depleted platelets are
involved (Heesch et al., 2000).
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164 Karchs Pathology of Drug Abuse
1.16.2 Psychiatric Syndromes
Te early workers in the feld recognized cocaine-induced paranoid psychosis. Maier,
Magnan, and Lewin (Magnan and Saury, 1889; Maier, 1926; Lewin, 1931) all wrote on
the subject and took pains to distinguish cocaine psychosis from symptoms induced by
alcohol and other drugs. More recent studies have tended to confrm the earlier observa-
tions (Siegel, 1978; Gawin and Kleber, 1986). Transient or binge paranoia is common
among heavy users; the incidence in one study was nearly 70% (Satel et al., 1990). What
distinguishes the cocaine-associated syndrome from the schizophrenic symptoms induced
by amphetamines is that the paranoia occurs only for a very brief period (Janowsky and
Risch, 1979). Te development of paranoia among cocaine abusers is unpredictable and is
not dose related. Some individuals appear to be more vulnerable than others.
When Magnan frst reported on cocaine psychosis, over 120 years ago, the three
patients he described all thought they had bugs under the skin. All three were covered
with cuts and scratch marks made in an attempt to remove the parasites. Tis particular
paranoid manifestation came to be known as Magnans syndrome, and for a time it was
thought to be diagnostic for cocaine abuse. Te syndrome is now referred to as delusional
parasitosis, and it is now obvious that these symptoms are not confned to cocaine abus-
ers. Tey may occur as a component of many diferent organic disorders (such as parkin-
sonism), or as a result of drug toxicity. It has been suggested, though not proven, that the
disorder is a result of decreased striatal dopamine transporter (DAT) functioning, leading
to elevated concentrations of dopamine in the striatum (Huber et al. 2007).
Cerebral glucose metabolism, as accessed by (
18
F)-fuorodeoxyglucose PET scanning
of cocaine abusers in early withdrawal, increases. Tis increase in glucose metabolism
involves all areas of the brain, but is particularly noticeable in the basal ganglia and orbi-
tofrontal cortex. Te increase in the latter two areas correlates with clinical measures of
cocaine craving and is consistent with the notion that the changes are due to changes in
brain dopamine activity (Volkow et al., 1990, 1991a, b).
Cocaine-induced changes in cerebral perfusion and glucose utilization appear to be
gender related. Brain scans of cocaine-dependent women failed to disclose the abnor-
malities seen in the men (Levin et al., 1994). Longer-lasting episodes of psychosis due to
chronic cocaine abuse can occur. When they do, chances are good that the victim will be
misdiagnosed as a schizophrenic. Because drug users, schizophrenic or not, ofen deny
drug use, routine drug screening of such patients is prudent (Shaner et al., 1993). Another
important diagnosis to consider in cocaine users with psychiatric symptoms is stroke.
Cocaine-induced ischemic infarcts have occasionally been mistaken for acute-onset psy-
chosis (Reeves et al., 1995).
Cocaine-related impairment is frequently an issue in court proceedings, but few satis-
factory answers are to be had. Regular cocaine users rapidly become tolerant to cocaines
stimulant efects, but whether or not this tolerance extends to performance and impair-
ment is not known, though it is beginning to appear that it does (Verdejo-Garcia et al.
2006a, b). Te majority of studies done in human volunteers suggest that, taken in small
doses, both cocaine and methamphetamine may increase energy and alertness while, at
the same time, improving mood. Both drugs can increase the ability to sustain attention
over prolonged periods of time during the performance of monotonous tasks, and both
drugs have also been shown to improve performance on auditory and visual reaction time
tests, other tests of psychomotor skills and attention, and tests of selective and divided
7880_C001.indd 164 10/25/08 2:18:50 PM
Cocaine 165
attention. Tese fndings suggest that moderate cocaine use should enhance driving per-
formance, but that supposition has never been tested directly (Higgins et al., 1990; Farre
et al., 1993; Stillman et al., 1993). Modest performance improvement on a number of cog-
nitive performance measures has also been observed afer intravenous dosing (0.325 mg or
0.650 mg/kg) (Johnson et al., 1998).
1.16.3 Ischemic Stroke
Tere was more than a 100-year hiatus between the frst reports of cocaine-associated
stroke in the 1880s and Brusts report in 1977 (Brust and Richter, 1977), but now several
new case reports appear each year, some very exotic. Tere have been reports of mesence-
phalic infarcts (Rowley et al., 1989), lateral medullary syndrome and anterior spinal syn-
drome (Mody et al., 1988), embolization from a lef atrial thrombus (Petty et al., 1990),
central retinal infarction (Devenyi et al., 1988; Zeiter et al., 1992; Libman et al., 1993;
Sleiman et al., 1994), massive cerebellar infarcts (Aggarwal and Byrne, 1991), and even one
case of apparent embolism (Petty et al., 1990). Nonetheless, the etiology of most cocaine-
associated strokes remains obscure.
During the late 1980s, cocaine-related stroke emerged as a signifcant medical prob-
lem, but its incidence seems to be decreasing. Most cases of ischemic stroke in young adults
(1545 years) are of undetermined etiology. In a recent retrospective study reviewing the
records of patients 1545 years old who were experiencing their frst-ever stroke, the etio-
logical diagnoses were: undetermined in 36%, large-artery atherosclerosis in 21%, cardio-
embolism in 17%, non-atherosclerotic vasculopathy in 17%, and other specifc etiologies in
9% (Varona et al., 2007). Tese results are in conformity with a now decade-old retrospec-
tive study from Hong Kong that failed to fnd that crack use (historical or acute) had any
signifcant association with stroke or cerebral infarction (Qureshi et al., 1997).
Whether smoking free base is more dangerous than insufation, and what type of
cerebral catastrophe is most likely to occur, is not known. Te use of free base is generally
accepted as a risk factor, especially when stroke occurs in the young, although no con-
trolled study, retrospective or prospective, clinical or autopsy, has ever demonstrated any
such relationship. In spite of the massive and ongoing cocaine pandemic, stroke remains a
disease afecting mainly the elderly. Nonetheless, data derived from MRI scanning suggest
that patients with a history of crack smoking are at risk for white matter damage medi-
ated by unknown mechanisms (Bartzokis et al., 1999a), and cerebral fow studies do show
transient hypoperfusion (Johnson et al., 2005).
More recently, MRI studies of cerebral blood vessels in human volunteers have clearly
shown that cocaine administration causes dose-related vasoconstriction, even when low
doses of cocaine are given and even in the absence of other risk factors (Kaufman et al.,
1998). An example of cocaine-induced vasoconstriction is shown in Figure 1.16.3.2. It is
not clear whether vasospasm in cocaine users is a result of some direct action exerted by
cocaine on cerebral blood vessels or is secondary to catecholamine elevation (Brust and
Richter, 1977; Levine et al., 1987; Covert et al., 1994).
Increased platelet responsiveness leading to thrombosis may be the etiology for cere-
bral infarction in some cocaine users, but the case is far from clear, and platelet responsive-
ness is only one aspect of the problem. In vitro studies have provided conficting results
(Heesch et al., 1996), with some studies suggesting increased responsiveness and others
just the opposite. Whole blood from some cocaine users has been found to contain higher
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166 Karchs Pathology of Drug Abuse
levels of activated platelets than in non-users (Rinder et al., 1994; Kosten et al., 2004) and
even higher levels of tissue plasminogen activator inhibitor (Moliterno et al., 1994). Oth-
ers have found variable changes in platelet aggregation afer administration of cocaine
to healthy volunteers (Rezkalla et al., 1990). In one of the few in vivo studies to evaluate
hematologic parameters and blood viscosity in chronic users, transient erythrocytosis was
observed, as were increases in blood viscosity and in von Willebrand factor, all changes
that could favor intravascular thrombosis (Siegel et al., 2002).
Tus, cocaine users may be subject to decreased cerebral fow, even in the face of a
normal cardiac output. Putting aside the issue of CNS atherosclerosis, there is no question
Figure 1.16.3.1 Markedly infolded, irregular internal elastic lamina in the anterior cerebral artery
of cocaine with ischemic stroke. The irregularity of the elastic lamina may be a marker for cocaine-
induced vasospasm. (From Konzen, J. P. et al., Stroke, 26, 11148, 1995. With permission.)
Figure 1.16.3.2 Cocaine-induced vasoconstriction. Axial maximum intensity projection
images at baseline (left) and 20 minutes following intravenous cocaine (0.4 mg/kg) adminis-
tration (right). Cocaine induced a signal loss at distal segments of the middle cerebral arter-
ies (upper arrowheads) and in the posterior cerebral arteries (lower arrowheads), indicative of
vasoconstriction. A indicates anterior; P, posterior; L, left; R, right. Scale bar = 1 cm. (From
Kaufman, M. J. et al., JAMA, 279(5), 379, 1998. With permission.)
7880_C001.indd 166 10/25/08 2:18:52 PM
Cocaine 167
that cocaine users are subject to accelerated atherogenesis (Dressler et al., 1990; Kolodgie
et al., 1991; Karch et al., 1995). If cardiac output is reduced, blood pressure fuctuations
could also lead to cerebral infarction, especially in the face of pre-existing CNS athero-
sclerotic lesions. Cocaine-associated cardiomyopathy (Duke, 1986; Lathers et al., 1988;
Williams, 1990) and arrhythmias are both recognized occurrences, and either of them
could result in sudden blood pressure fuctuations. A sudden drop in blood pressure com-
bined with asymptomatic stenotic lesions could lead to infarction. One report describes
a woman with cardiomyopathy (presumably, cocaine-related) who sustained a cerebral
embolism (Petty et al., 1990). Te situation is somewhat analogous to cocaine-associated
myocardial infarction. Te presence of pre-existing lesions may exacerbate transient fow
decreases which otherwise would have been asymptomatic.
Vasospasm remains another popular candidate, but vasospasm itself is a multifactorial
process. It might be the result of endothelial dysfunction, smooth muscle hypersensitivity,
oxidative stress, genetic susceptibility, or some combination thereof. Smooth muscle hyper-
sensitivity is a possible explanation, since the contraction of vascular smooth muscle depends
on the concentration of intracellular calcium (Somlyo and Somlyo, 1994), which is increased
in the presence of cocaine (Lattanzio et al., 2005). Without further studies, the mechanism
underlying stroke in this group of drug abusers remains somewhat mysterious.
1.16.4 Cerebral Vasculitis
Te frequency of cerebral vasculitis in cocaine users is very low, but episodes of biopsy-
proven vasculitis continue to be reported at the rate of one or two a year (Krendel et al.,
1990; Fredericks et al., 1991; Scully et al., 1997; Diez-Tejedor et al., 1998; Kumar and Smith,
2000; Spittell and Spittell, 2001; Gertner and Hamlar, 2002; Ruiz Martinez et al., 2004),
and authors continue to cite cocaine-induced vasculitis as a cause of stroke. Yet in virtually
all of these reports microscopic proof of causation is lacking and/or multiple drugs have
been ingested (Mockel et al., 1999). Autopsy reports of cocaine users with stroke are rare
(Klonof et al., 1989; Konzen et al., 1995; Nolte and Gelman, 1989), but in the few cases that
have been examined histologically, vasculitis has been conspicuously absent.
In the frst reported case of vasculitis, a biopsy showed that the small vessels within
an area of infarction had a transmural infltrate of acute and chronic infammatory cells.
Occasional multinucleated giant cells were also present. In the second case, there was
also lymphocytic infltration of the small vessel walls with multiple cystic, necrotic, and
gliotic areas in the cerebral white matter, especially in the frontal lobes. Multinucleated
giant cells were seen in the gliotic areas. Te process was most intense in the frontal lobes
(Figures 1.16.4.1 and 1.16.4.2) (Krendel et al., 1990). Fredericks et al. (1991) described a
second case with marked endothelial swelling and small vessel lymphocytic infltrates. In
a third report, describing a 32-year-old hypertensive man who had became hemiplegic,
surgical specimens disclosed no evidence of fbrinoid necrosis or giant cells, but there was
vasculitis involving venules and arterioles, which were infltrated with neutrophils, lym-
phocytes, and foamy macrophages. Te endothelial cells were enlarged and, in addition,
there was evidence of white matter damage.
In the fourth case report, a 21-year-old male cocaine user with encephalopathy, apraxia,
lef hemiparesis, and hemisensory loss had a cerebral angiogram that showed a lack of
vascularization in the lef precentral and central arterial groups. A corticomeningeal cere-
bral biopsy demonstrated perivascular cell collection and transmural lymphomonocytic
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168 Karchs Pathology of Drug Abuse
infltration of the small cortical vessels. Although the symptoms remitted with steroid
therapy, the patient returned again, four years later, with severe encephalopathy. A cerebral
MRI showed subcortical and periventricular lesions suggesting ischemic damage in small-
sized vessel areas as well as cortical atrophy (Martinez et al., 1996).
Even when a specifc efort has been made to detect vasculitis, it has been hard to
fnd. A study published in 1996 described selected brain samples from 14 autopsy cases
of cocaine-related cerebrovascular disease. Intracerebral or subarachnoid hemorrhage
was present in 12 cases, but in each case the intracranial arterioles were either normal or
showed only nonspecifc changes (Aggarwal et al., 1996).
Figure 1.16.4.1 Cerebral vasculitis in a cocaine user. Biopsy specimen from patient surviving
episode of vasculitis. Transmural infltration of a small cortical vessel. Both acute and chronic
infammatory cells are present. (Original magnifcation 800.) (Courtesy of Dr. David A.
Krendel, Section of Neurology, The Emory Clinic, Atlanta, GA.)
Figure 1.16.4.2 Cerebral vasculitis in a cocaine user. Autopsy specimen from another patient
with cerebral vasculitis. Illustration shows a lymphocytic infltrate around a small cerebral
vessel. (Original magnifcation 800.) (Courtesy of Dr. David A. Krendel, Section of Neurology,
The Emory Clinic, Atlanta, GA.)
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Cocaine 169
If cocaine does, in fact, cause cerebral vasculitis, it probably has nothing to do with
catecholamine toxicity. Patients with pheochromocytoma and animals treated with exog-
enous catecholamines generally do not show signs of CNS infammation. Small, perivascu-
lar hemorrhages can be induced in animals by giving massive amounts of epinephrine, but
in this model the cerebral vessel wall remains normal, with no necrosis and no infltrates
(Stief and Tokay, 1935).
Necrotizing angiitis is a form of periarteritis nodosa associated with the abuse of
amphetamine and other stimulant drugs (Citron et al., 1970; Mockel et al., 1999). It has
never been seen in cocaine users, except insofar as they used cocaine along with intravenous
amphetamines and heroin, and/or the user sufers from hepatitis B infection (Guo et al.,
2001). Necrotizing vasculitis in stimulant abusers was frst described in the early 1970s, but
its incidence seems to have steadily declined over the last 30 years. Te fact that this disorder
has essentially disappeared, while intravenous abuse of cocaine and amphetamine has not,
suggests that the originally reported cases may have been due to a contaminant introduced
into the amphetamine during the course of manufacture and/or distribution. Te current
practice of referring to cocaine pseudovasculitis (Friedman and Wolfsthal, 2005; Bhinder
and Majithia, 2007), applied whenever an ill patient has symptoms and/or laboratory fnd-
ings that mimic true vasculitis but with a negative biopsy, is particularly unhelpful.
1.16.5 Subarachnoid and Intraventricular Hemorrhage
Te relationship between cocaine and cerebral hemorrhage is much clearer than the rela-
tionship with ischemic stroke. Case reports have been appearing since the mid-1980s
(Mangiardi et al., 1988). In a retrospective review of 42 cocaine abusers with stroke (mean
age 38 8.5 years) aneurysmal bleeding was found in 15 patients, but there were mul-
tiple risk factors and confounders and many of the victims, nearly one third, were known
hypertensives (Nanda et al., 2006). Nine other cases of intracranial hemorrhages related
to cocaine usage were also described in the same paper. In the most conclusive study to
date, Nolte et al. (1996) performed a prospective autopsy study of all cases of fatal non-
traumatic intracranial hemorrhage seen over a one-year period in a large metropolitan
medical examiners ofce. Ten of 17 (59%) of all non-traumatic intracranial hemorrhages
were found to be associated with the presence of cocaine. Seven (70%) individuals had sus-
tained parenchymal hemorrhages, and the remaining three (30%) subarachnoid hemor-
rhages from ruptured berry aneurysms. No vasculitis or other vasculopathy was identifed
in any of the cases. Nolte et al. concluded that the relationship between severe cocaine-
induced hypertension and the development of subarachnoid or intracerebral hemorrhage
seems fairly clear and is apparently related to sudden transient increases of blood pressure
related to cocaine use. Nothing published in the last decade would seem to contradict this
conclusion.
Cocaine users seem to be particularly at risk for dying of subarachnoid hemorrhage.
Nearly half the strokes associated with cocaine abuse are due to either intracerebral or sub-
arachnoid hemorrhage (Nanda et al., 2006). Subarachnoid hemorrhage is more common
than intracerebral hemorrhage by a ratio of 4:3. As is the case with cocaine-related infarc-
tion, individuals are in their early thirties. Most (80%) subarachnoid hemorrhages are the
result of saccular aneurysms involving the anterior communicating artery, with the pos-
terior communicating system being the next most frequent site. Intracerebral hemorrhage
is most ofen the result of an arteriovenous malformation, although in half of the cases no
7880_C001.indd 169 10/25/08 2:18:53 PM
170 Karchs Pathology of Drug Abuse
underlying lesions are demonstrable. Bleeding into the basal ganglia and thalamus is the
most common pattern seen in cocaine users (Green et al., 1990; Nolte et al., 1996).
Saccular aneurysms involving the arteries at the base of the brain occur in 12% of the
adult population and are ofen an incidental fnding at autopsy. Usually they are located at
arterial bifurcations. Tey form as a result of multiple factors, including atheroma, degen-
erative changes, and secondary fow abnormalities (Sekhar and Heros, 1981). Te role of
hypertension in the formation and rupture of saccular aneurysms is still unclear, but the
role of hypertension in cocaine-associated subarachnoid bleeding is becoming increas-
ingly well recognized (Kibayashi et al., 1995).
Intracerebral hemorrhage is usually due to hypertension, although in some series
the number of cases due to vascular malformation roughly equals the number due to
hypertension (Gras et al., 1991). Intracerebral hemorrhages occur as a consequence of
structural changes in the small perforating vessels of the cerebral hemispheres and brain
stem (Figures 1.16.5.1 and 1.16.5.2). Tey produce deeply situated hemorrhages in the cere-
bral hemispheres (basal nuclei and thalamus) and brain stem (Kase, 1995). Much less ofen,
bleeding may occur in the subcortical white matter and cerebellum. Hemorrhage in the
white matter is usually the result of amyloid angiopathy and probably has little to do with
hypertension. Te most common site for hypertensive hemorrhage is the basal ganglia,
outnumbering the second most common site, the cerebral white matter, by a ratio of 7:1
(Adams et al., 1984).
In one study (Kibayashi et al., 1995), autopsy fndings in 26 individuals with cocaine-
induced intracerebral hemorrhage were compared with autopsy fndings in 26 cases of
cocaine-induced cerebral aneurysm rupture. Hypertensive cardiovascular disease was
much more common in the former (mean heart weights of 497 vs. 380 g), suggesting very
strongly that hypertensive cardiovascular disease, which itself can be a consequence of
cocaine use, predisposes to cocaine-induced intracerebral hemorrhage. A 1997 study
reviewed the fndings in 33 cocaine abusers with neurologic defcits who presented at a
Figure 1.16.5.1 Intracerebral hemorrhage in a young crack cocaine smoker. Stimulant
abuse is becoming an increasingly common cause of stroke in young people. Scan shows mas-
sive hemorrhage in the temporalfrontal region. (Courtesy of Dr. Kari Blaho, University of
Tennessee, Memphis.)
7880_C001.indd 170 10/25/08 2:18:54 PM
Cocaine 171
large inner-city hospital (Fessler et al., 1997). Sixteen of those patients were diagnosed
with subarachnoid hemorrhage, and 12 of them subsequently underwent four-vessel cere-
bral arteriography, which revealed 14 aneurysms. Six patients presented with intracerebral
hemorrhage and seven patients with evidence of ischemic stroke. More than half of the
patients noted onset of their symptoms while they were using cocaine, and in almost all
cases symptom onset was within six hours of use. Delayed onset of symptoms and delayed
presentation at the emergency room seem to be more characteristic for patients with isch-
emic infarction. Perhaps the most interesting fndings of that study were that, among the
patients with aneurysm, the cocaine users were much younger than a control group of
non-drug users (32.8 vs. 52.2 years) and the size of the aneurysms in the cocaine-using
group was much smaller (4.9 vs. 11.0 mm).
Long-term cocaine use may be necessary before hypertensive cardiovascular dis-
ease and intracerebral hemorrhage occur, but even occasional use can lead to transient
blood pressure elevations sufcient to cause the rupture of pre-existing malformations
or bleeding into a tumor (Yapor and Gutierrez, 1992). Experimental evidence shows that
cocaine potentiates the increases in blood pressure and cerebral blood fow produced by
the administration of norepinephrine (Muir and Ellis, 1993). Because cocaine users have
elevated circulating levels of norepinephrine, potentiation of the normal response to cat-
echolamines may account for much of the reported pathology. Hemorrhage in individuals
without underlying lesions, as in a recently reported case of spinal epidural hematoma
(Huf, 1994), remains unexplained.
1.16.6 Seizures
Grand mal seizures in cocaine users are an uncommon occurrence, and very little is
known about them (Winbery et al., 1998). Te most current animal evidence shows that
hippocampal norepinephrine transporters are up-regulated in the chronic presence of
Figure 1.16.5.2 Intracerebral hemorrhage involving the brain stem of a young crack cocaine
smoker. Brain hemorrhages in young drug abusers frequently involve pre-existing, previously
undiagnosed, AV malformations and aneurysms. (Courtesy of Dr. Kari Blaho, University of
Tennessee, Memphis.)
7880_C001.indd 171 10/25/08 2:18:54 PM
172 Karchs Pathology of Drug Abuse
cocaine. Inhibition of Na(
+
) channels by local anesthetics may also play a role in norepi-
nephrine transporter down-regulation (all local anesthetics can induce seizuresthe more
potent the local anesthetic, the worse the seizures) (Kitayama et al., 2006). Other evidence
suggests that it is the blockade of dopamine re-uptake and the resulting elevation of excit-
atory agonists that leads to cocaine-induced seizures.
Another possibility is that other neurotransmitters, especially -aminobutyric acid
(GABA), may be involved (Ye et al., 1997). When seizures do occur, they may be a conse-
quence of stroke, intracerebral hemorrhage, or even of massive overdose. Tere is also the
possibility that cocaine use may simply exacerbate a pre-existing seizure disorder. Pub-
lished case series have placed the incidence of this complication at somewhere between 2
and 10% (Lowenstein et al., 1987; Derlet and Albertson, 1989). In one series of nearly 1000
patients treated for acute medical complications of cocaine use, seizures were noted in
nearly 10%. Only four of these patients had status epilepticus, and all of them were victims
of massive overdose (Dhuna et al., 1991). Interestingly, in that same report, seizures were
three times as common in women as in men (18.4 vs. 6.2%). Tis fnding is consistent with
the results of other studies suggesting that pregnancy and other hormonal alterations can
exacerbate cocaine toxicity (Woods and Plessinger, 1990; Sharma et al., 1992).
Kindling is a term used to describe the development of generalized convulsions in
response to repeated subconvulsive brain stimuli in animals, and cocaine-induced kin-
dling can be induced in animals. Whether this process also occurs in humans as a con-
sequence of cocaine or any other kind of drug use has been debated for some time. For
example, it has been speculated, but without proof, that kindling, or some similar pro-
cess, is the mechanism responsible for seizures in chronic cocaine abusers. Te possibility
that cocaine kindling could occur in humans is suggested by the well-described case of a
37-year-old woman who experienced generalized tonic clonic seizures immediately afer
smoking crack. She then went on to develop generalized seizures even when she was not
using cocaine (Dhuna et al., 1991). Te latest data suggest that cocaine kindling is associ-
ated with increased NMDA receptor binding activity in the striatum, amygdala, and hip-
pocampus (Itzhak and Martin, 2000).
Results from animal experimentation indicate that diferent mechanisms are respon-
sible for seizures and lethality. Cocaine-induced seizures are a consequence of the efect of
cocaine on the 5-HT transporter in concert with efects on muscarinic neurons and sigma
() receptors, while interactions with the dopamine transporter determine lethality (Ritz
and George, 1993). It is also quite possible that other neurotransmitters such as GABA may
be involved in the process. Cocaine noncompetitively inhibits GABA-generated currents
in neuronal membranes, suggesting that the GABA receptor/channel complex is also a tar-
get for cocaine and may contribute to cocaine-induced seizures (Ye et al., 1997). Additional
support for GABA involvement comes from experimental animal studies showing that
drugs that enhance GABA-related neuronal inhibition, via mechanisms that are totally
distinct from the mechanisms accounting for the efectiveness of barbiturates and benzo-
diazepines, ofer the best protection against cocaine-induced seizures. Conversely, Na
+
and
Ca
2+
channel blockers ofer the least protection (Chynn, 1975).
Te limbic system plays a major role in the process. When the efects of procaine,
cocaine, and placebo were compared using single photon emission computed tomography
(SPECT) to estimate regional cerebral blood fow (rCBF), the cocaine-addicted subjects
demonstrated bilateral activation of the orbitofrontal cortex afer the procaine challenge,
whereas the comparison subjects showed activation of the anterior cingulate, bilateral
7880_C001.indd 172 10/25/08 2:18:54 PM
Cocaine 173
insula, and right amygdala regions. Afer receiving placebo, the cocaine-addicted subjects
showed markedly lower rCBF in the bilateral orbitofrontal cortex than the comparison
subjects. Te pattern of hypoperfusion in the placebo state followed by heightened activa-
tion with procaine in the cocaine-addicted subjects bears a very strong similarity to the
pattern of interictal hypoperfusion and ictal hyperperfusion that is observed in epileptics,
and may represent a type of sensitization (Adinof et al., 2001).
1.16.7 Movement Disorders
Movement disorders, including choreoathetosis, akathisia, and parkinsonism with tremor,
have all been described in cocaine users (Daras et al., 1994; Bonime, 1995; Catalano et al.,
1997; Riley et al., 2001; Supervia et al., 2006; Kamath and Bajaj, 2007). Tis phenomenon
has become so common that it has even been given the slang name of crack dancing.
Symptoms are generally self-limiting and do not bring the victims to medical attention.
However, one recent controlled study using MRI scanning demonstrated an increased
incidence of basal ganglia abnormalities that were not seen in controls (Bartzokis et al.,
1999b).
Dystonic reactions are extrapyramidal motor abnormalities that occur whenever there is
an insufcient supply of nigrostriatal dopamine. Te main symptom is spasm within isolated
muscle groups. Neuroleptic drugs are a known cause of dystonia and are the most frequently
encountered trigger, but the same symptoms can be caused by cocaine (Hegarty et al., 1991;
Cardoso and Jankovic, 1993; Fines et al., 1997; Van Harten et al., 1998). Similar reasons
may explain why cocaine users are also prone to multifocal tics, which cocaine precipitates
(Pascual-Leone and Dhuna, 1990; Pascual-Leone et al., 1990, 1991) in addition to exacerbat-
ing the clinical manifestations of Gilles de la Tourette syndrome, and why cocaine users are at
increased risk for developing neuroleptic-induced acute dystonia (Van Harten et al., 1998).
1.16.8 BloodBrain Barrier Alterations
Aquaporin-4 (AQP4) is the predominant channel by which water enters the brain; it con-
trols water movement at the bloodbrain barrier and at the braincerebrospinal fuid inter-
face. In experimental mice, deletion of the gene for AQP4 causes an increase of amino acid
and monoamine levels in some brain regions, suggesting that AQP4 may participate in
region-specifc alterations in brain amino acid and monoamine metabolism that have been
observed in experimental animals. In knockout mice unable to produce AQP4 there
is decreased locomotor activity afer acute and repeated cocaine exposure. At the same
time, there is a decrease in extracellular dopamine and glutamate levels in the nucleus
accumbens. Te nucleus accumbens is known to be critically involved in the addictive
properties of cocaine. Tus, it is speculated by some researchers that AQP4 may play a role
in regulating extracellular cocaine-induced dopamine and glutamate release in the brain
reward center. If that were the case, it would mean that AQP4 deletion attenuates cocaine
reinforcement and dependence (Li et al., 2006).
Some believe that cocaine facilitates HIV-1 invasion through brain microvascular
endothelial cells. Cocaine binds to a site on these cells that is not a transporter of bio-
genic amines, but, rather, is a binding site for estrogen. It also appears to act as a musca-
rinic receptor. Cocaine treatment of knockout mice disrupts intercellular junctions and
induces cell rufing, accounting for the observed increase in cellular permeability and
7880_C001.indd 173 10/25/08 2:18:55 PM
174 Karchs Pathology of Drug Abuse
decreased electrical resistance. Once HIV-1 enters brain microvascular cells by macropi-
nocytosis, it is transported to lysosomes and inactivated. In cocaine-treated animals, the
microvascular cells allow the virus to enter and persist in large cytoplasmic lakes. At the
same time, exposure of these microvascular cells to cocaine up-regulates transcription of
genes important in cytoskeleton organization, signal transduction, cell swelling, vesicular
trafcking, and cell adhesion. All of these actions damage the bloodbrain barrier and
may lead to increased virus neuroinvasion and some, if not all, of the observed neurovas-
cular complications of cocaine abuse (Fiala et al., 2005).
References
Adams, J., Corsellis, J. et al. (1984). Intracerebral haemorrhage. In: Greenfelds Neuropathology.
Edward Arnold, London.
Adinof, B., Devous, M. D., Sr. et al. (2001). Limbic responsiveness to procaine in cocaine-addicted
subjects, Am. J. Psychiatry, 158(3), pp. 3908.
Aggarwal, S. and Byrne, B. D. (1991). Massive ischemic cerebellar infarction due to cocaine use,
Neuroradiology, 33(5), pp. 44950.
Aggarwal, S. K., Williams, V. et al. (1996). Cocaine-associated intracranial hemorrhage: absence of
vasculitis in 14 cases, Neurology, 46(6), pp. 17413.
Bartzokis, G., Goldstein, I. B. et al. (1999a). Te incidence of T2-weighted MR imaging signal
abnormalities in the brain of cocaine-dependent patients is age-related and region-specifc,
AJNR Am. J. Neuroradiol., 20(9), pp. 162835.
Bartzokis, G., Beckson, M. et al. (1999b). Choreoathetoid movements in cocaine dependence, Biol.
Psychiatry, 45(12), pp. 16305.
Bhinder, S. K. and Majithia, V. (2007). Cocaine use and its rheumatic manifestations: a case report
and discussion, Clin. Rheumatol., 26(7), p. 1192.
Bonime, W. (1995). Te myth of masochism, J. Am. Acad. Psychoanal., 23(1), pp. 3346.
Brady, K. T., Lydiard, R. B. et al. (1991). Cocaine-induced psychosis, J. Clin. Psychiatry, 52(12),
pp. 50912.
Brecht, M. L., OBrien, A. et al. (2004). Methamphetamine use behaviors and gender diferences,
Addict. Behav., 29(1), pp. 89106.
Brust, J. C. and Richter, R. W. (1977). Stroke associated with cocaine abuse?, N. Y. State J. Med.,
77(9), pp. 14735.
Cardoso, F. E. and Jankovic, J. (1993). Cocaine-related movement disorders, Mov. Disord., 8(2),
pp. 1758.
Catalano, G., Catalano, M. C. et al. (1997). Dystonia associated with crack cocaine use, South. Med.
J., 90(10), pp. 10502.
Choi, J. K., Chen, Y. I. et al. (2006). Brain hemodynamic changes mediated by dopamine receptors:
Role of the cerebral microvasculature in dopamine-mediated neurovascular coupling, Neuro-
image, 30(3), pp. 70012.
Chynn, K. Y. (1975). Acute subarachnoid hemorrhage, JAMA, 233(1), pp. 556.
Citron, B., Halpern, M. et al. (1970). Necrotizing angiitis associated with drug abuse, N. Engl. J.
Med., 283(19), pp. 100311.
Covert, R. F., Schreiber, M. D. et al. (1994). Hemodynamic and cerebral blood fow efects of cocaine,
cocaethylene and benzoylecgonine in conscious and anesthetized fetal lambs, J. Pharmacol.
Exp. Ter., 270(1), pp. 11826.
Daras, M., Tuchman, A. J. et al. (1994). Neurovascular complications of cocaine, Acta Neurol.
Scand., 90(2), pp. 1249.
Derlet, R. W. and Albertson, T. E. (1989). Diazepam in the prevention of seizures and death in
cocaine-intoxicated rats, Ann. Emerg. Med. 18(5), pp. 5426.
7880_C001.indd 174 10/25/08 2:18:55 PM
Cocaine 175
Devenyi, P., Schneiderman, J. F. et al. (1988). Cocaine-induced central retinal artery occlusion,
CMAJ, 138(2), pp. 12930.
Dhuna, A., Pascual-Leone, A. et al. (1991). Epileptogenic properties of cocaine in humans, Neuro-
toxicology, 12(3), pp. 6216.
Diez-Tejedor, E., Frank, A. et al. (1998). Encephalopathy and biopsy-proven cerebrovascular infam-
matory changes in a cocaine abuser, Eur. J. Neurol., 5(1), pp. 1037.
Dressler, F. A., Malekzadeh, S. et al. (1990). Quantitative analysis of amounts of coronary arterial
narrowing in cocaine addicts, Am. J. Cardiol., 65(5), pp. 3038.
Du, C., Yu, M. et al. (2006). Cocaine increases the intracellular calcium concentration in brain
independently of its cerebrovascular efects, J. Neurosci., 26(45), pp. 1152231.
Duke, M. (1986). Cocaine, myocardial infarction and arrhythmiasa review, Conn. Med., 50(7),
pp. 4402.
Farre, M., de la Torre, R. et al. (1993). Alcohol and cocaine interactions in humans, J. Pharmacol.
Exp. Ter., 266(3), pp. 136473.
Fessler, R. D., Esshaki, C. M. et al. (1997). Te neurovascular complications of cocaine, Surg. Neu-
rol., 47(4), pp. 33945.
Fiala, M., Eshleman, A. J. et al. (2005). Cocaine increases human immunodefciency virus type 1
neuroinvasion through remodeling brain microvascular endothelial cells, J. Neurovirol., 11(3),
pp. 28191.
Fines, R., Brady, W. et al. (1997). Cocaine-associated dystonic reaction, Am. J. Emerg. Med., 15(5),
pp. 5135.
Fredericks, R. K., Lefowitz, D. S. et al. (1991). Cerebral vasculitis associated with cocaine abuse,
Stroke, 22(11), pp. 14379.
Friedman, D. R. and Wolfsthal, S. D. (2005). Cocaine-induced pseudovasculitis, Mayo Clin. Proc.,
80(5), pp. 6713.
Gawin, F. H. and Kleber, H. D. (1986). Abstinence symptomatology and psychiatric diagnosis in
cocaine abusers. Clinical observations, Arch. Gen. Psychiatry, 43(2), pp. 10713.
Gertner, E. and Hamlar, D. (2002). Necrotizing granulomatous vasculitis associated with cocaine
use, J. Rheumatol., 29(8), pp. 17957.
Gras, P., Arveux, P. et al. (1991). [Spontaneous intracerebral hemorrhages in young patients. Study
of 33 cases], Rev. Neurol. (Paris), 147(10), pp. 6537.
Graybiel, A. M., Moratalla, R. et al. (1990). Amphetamine and cocaine induce drug-specifc activa-
tion of the c-fos gene in striosome-matrix compartments and limbic subdivisions of the stria-
tum, Proc. Natl Acad. Sci. USA, 87(17), pp. 69126.
Green, R. M., Kelly, K. M. et al. (1990). Multiple intracerebral hemorrhages afer smoking crack
cocaine, Stroke, 21(6), pp. 95762.
Guo, X., Gopalan, R. et al. (2001.) Hepatitis B-related polyarteritis nodosa complicated by pulmo-
nary hemorrhage, Chest, 119(5), pp. 160810.
Heesch, C. M., Negus, B. H. et al. (1996). Efects of in vivo cocaine administration on human plate-
let aggregation, Am. J. Cardiol., 78(2), pp. 2379.
Heesch, C. M., Wilhelm, C. R. et al. (2000). Cocaine activates platelets and increases the formation
of circulating platelet containing microaggregates in humans, Heart, 83(6), pp. 68895.
Hegarty, A. M., Lipton, R. B. et al. (1991). Cocaine as a risk factor for acute dystonic reactions,
Neurology, 41(10), pp. 16702.
Herning, R. I., Better, W. et al. (1999). Te regulation of cerebral blood fow during intravenous
cocaine administration in cocaine abusers, Ann. N. Y. Acad. Sci., 890, pp. 48994.
Higgins, S. T., Bickel, W. K. et al. (1990). Efects of intranasal cocaine on human learning, perfor-
mance and physiology, Psychopharmacology (Berlin), 102(4), pp. 4518.
Huber, M., Kirchler, E. et al. (2007). Delusional parasitosis and the dopamine transporter. A new
insight of etiology? Med. Hypotheses, 68, pp. 13518.
Huf, J. S. (1994). Spinal epidural hematoma associated with cocaine abuse, Am. J. Emerg. Med.
12(3), pp. 3502.
7880_C001.indd 175 10/25/08 2:18:55 PM
176 Karchs Pathology of Drug Abuse
Itzhak, Y. and Martin, J. L. (2000). Scopolamine inhibits cocaine-conditioned but not uncondi-
tioned stimulant efects in mice, Psychopharmacology (Berlin), 152(2), pp. 21623.
Janowsky, D. S. and Risch, C. (1979). Amphetamine psychosis and psychotic symptoms, Psycho-
pharmacology (Berlin), 65(1), pp. 737.
Johnson, B., Overton, D. et al. (1998). Efects of acute intravenous cocaine on cardiovascular func-
tion, human learning, and performance in cocaine addicts, Psychiatry Res., 77(1), pp. 3542.
Johnson, B. A., Dawes, M. A. et al. (2005). Acute intravenous low- and high-dose cocaine reduces
quantitative global and regional cerebral blood fow in recently abstinent subjects with cocaine
use disorder, J. Cereb. Blood Flow Metab., 25(7), pp. 92836.
Kahlig, K. M. and Galli, A. (2003). Regulation of dopamine transporter function and plasma
membrane expression by dopamine, amphetamine, and cocaine, Eur. J. Pharmacol., 479(13),
pp. 1538.
Kamath, S. and Bajaj, N. (2007). Crack dancing in the United Kingdom: Apropos a video case pre-
sentation, Mov. Disord., 22(8), pp. 11901.
Karch, S. B., Green, G. S. et al. (1995). Myocardial hypertrophy and coronary artery disease in male
cocaine users, J. Forensic Sci., 40(4), pp. 5915.
Kase, C. S. (1995). Intracerebral haemorrhage, Baillieres Clin. Neurol., 4(2), pp. 24778.
Kaufman, M. J., Levin, J. M. et al. (1998). Cocaine decreases relative cerebral blood volume in
humans: a dynamic susceptibility contrast magnetic resonance imaging study, Psychopharma-
cology (Berlin), 138(1), pp. 7681.
Kaye, S. and Darke, S. (2004). Injecting and non-injecting cocaine use in Sydney, Australia: physi-
cal and psychological morbidity, Drug Alcohol Rev., 23(4), pp. 3918.
Kibayashi, K., Mastri, A. R. et al. (1995). Cocaine induced intracerebral hemorrhage: analysis of
predisposing factors and mechanisms causing hemorrhagic strokes, Hum. Pathol., 26(6), pp.
65963.
Kitayama, T., Song, L. et al. (2006). Down-regulation of norepinephrine transporter function
induced by chronic administration of desipramine linking to the alteration of sensitivity of
local-anesthetics-induced convulsions and the counteraction by co-administration with local
anesthetics, Brain Res., 1096(1), pp. 97103.
Klonof, D. C., Andrews, B. T. et al. (1989). Stroke associated with cocaine use, Arch. Neurol., 46(9),
pp. 98993.
Kolodgie, F. D., Virmani, R. et al. (1991). Increase in atherosclerosis and adventitial mast cells in
cocaine abusers: an alternative mechanism of cocaine-associated coronary vasospasm and
thrombosis, J. Am. Coll. Cardiol., 17(7), pp. 155360.
Konzen, J. P., Levine, S. R. et al. (1995). Vasospasm and thrombus formation as possible mecha-
nisms of stroke related to alkaloidal cocaine, Stroke, 26(6), pp. 11148.
Kosten, T. R., Tucker, K. et al. (2004). Platelet abnormalities associated with cerebral perfusion
defects in cocaine dependence, Biol. Psychiatry, 55(1), pp. 917.
Krendel, D. A., Ditter, S. M. et al. (1990). Biopsy-proven cerebral vasculitis associated with cocaine
abuse, Neurology, 40(7), pp. 10924.
Kumar, P. D. and Smith, H. R. (2000). Cocaine-related vasculitis causing upper-limb peripheral
vascular disease, Ann. Intern. Med., 133(11), pp. 9234.
Lathers, C. M., Tyau, L. S. et al. (1988). Cocaine-induced seizures, arrhythmias and sudden death,
J. Clin. Pharmacol., 28(7), pp. 58493.
Lattanzio, F. A., Jr., Tiangco, D. et al. (2005). Cocaine increases intracellular calcium and reactive
oxygen species, depolarizes mitochondria, and activates genes associated with heart failure
and remodeling, Cardiovasc. Toxicol., 5(4), pp. 37790.
Laurier, L. G., Corrigall, W. A. et al. (1994). Dopamine receptor density, sensitivity and mRNA levels
are altered following self-administration of cocaine in the rat, Brain Res., 634(1), pp. 3140.
Levin, J. M., Holman, B. L. et al. (1994). Gender diferences in cerebral perfusion in cocaine abuse:
technetium-99m-HMPAO SPECT study of drug-abusing women, J. Nucl. Med., 35(12), pp.
19029.
7880_C001.indd 176 10/25/08 2:18:56 PM
Cocaine 177
Levine, S. R., Washington, J. M. et al. (1987). Crack-associated stroke, Neurology, 37(6), pp.
10923.
Lewin, L. (1931). Phantastics: Narcotic and Stimulating Drugs. Teir Use and Abuse, E.P. Dutton,
New York.
Li, Z., Gao, L. et al. (2006). Aquaporin-4 knockout regulated cocaine-induced behavior and neuro-
chemical changes in mice, Neurosci. Lett., 403(3), pp. 2948.
Libman, R. B., Masters, S. R. et al. (1993). Transient monocular blindness associated with cocaine
abuse, Neurology, 43(1), pp. 2289.
Lowenstein, D. H., Massa, S. M. et al. (1987). Acute neurologic and psychiatric complications asso-
ciated with cocaine abuse, Am. J. Med., 83(5), pp. 8416.
Magnan, V. and Saury, N. (1889). Trois cas de cocainisme chronique, Compt. Rend. Soc. Biol. (Paris),
1, p. 60.
Maier, H. (1926). Der Kokanismus [O. J. Kalant, translated from German]. Addiction Research
Foundation, Toronto.
Mangiardi, J. R., Daras, M. et al. (1988). Cocaine-related intracranial hemorrhage. Report of nine
cases and review, Acta Neurol. Scand., 77(3), pp. 17780.
Martinez, N., Diez-Tejedor, E. et al. (1996). Vasospasm/thrombus in cerebral ischemia related to
cocaine abuse, Stroke, 27(1), pp. 1478.
Mockel, M., Kampf, D. et al. (1999). Severe panarteritis associated with drug abuse, Intensive Care
Med., 25(1), pp. 1137.
Mody, C., Miller, B. et al. (1988). Neurologic complications of cocaine abuse, Neurology, 38, pp.
118993.
Moliterno, D. J., Willard, J. E. et al. (1994). Coronary-artery vasoconstriction induced by cocaine,
cigarette smoking, or both, N. Engl. J. Med., 330(7), pp. 4549.
Muir, J. K. and Ellis, E. F. (1993). Cocaine potentiates the blood pressure and cerebral blood fow
response to norepinephrine in rats, Eur. J. Pharmacol., 249(3), pp. 28792.
Nanda, A., Vannemreddy, P. et al. (2006). Stroke in the young: relationship of active cocaine use
with stroke mechanism and outcome, Acta Neurochir. Suppl., 96, pp. 916.
Nemerof, C. B. and Owens, M. J. (2004). Pharmacologic diferences among the SSRIs: focus on
monoamine transporters and the HPA axis, CNS Spectr., 9(6 Suppl 4), pp. 2331.
Nolte, K. B., Brass, L. M. et al. (1996). Intracranial hemorrhage associated with cocaine abuse: a
prospective autopsy study, Neurology, 46(5), pp. 12916.
Nolte, K. B. and Gelman, B. B. (1989). Intracerebral hemorrhage associated with cocaine abuse,
Arch. Pathol. Lab. Med., 113(7), pp. 8123.
Pascual-Leone, A. and Dhuna, A. (1990). Cocaine-associated multifocal tics, Neurology, 40(6), pp.
9991000.
Pascual-Leone, A., Dhuna, A. et al. (1990). Cocaine-induced seizures, Neurology, 40(3 Pt 1), pp.
4047.
Pascual-Leone, A., Dhuna, A. et al. (1991). Longterm neurological complications of chronic, habit-
ual cocaine abuse, Neurotoxicology, 12(3), pp. 393400.
Petty, G. W., Brust, J. C. et al. (1990). Embolic stroke afer smoking crack cocaine, Stroke, 21(11),
pp. 16325.
Qureshi, A. I., Akbar, M. S. et al. (1997). Crack cocaine use and stroke in young patients, Neurology,
48(2), pp. 3415.
Reeves, R. R., McWilliams, M. E. et al. (1995). Cocaine-induced ischemic cerebral infarction mis-
taken for a psychiatric syndrome, South. Med. J., 88(3), pp. 3524.
Rezkalla, S. H., Hale, S. et al. (1990). Cocaine-induced heart diseases, Am. Heart J., 120(6 Pt 1), pp.
14038.
Riley, S. C., James, C. et al. (2001). Patterns of recreational drug use at dance events in Edinburgh,
Scotland, Addiction, 96(7), pp. 103547.
Rinder, H. M., Ault, K. A. et al. (1994). Platelet alpha-granule release in cocaine users, Circulation,
90(3), pp. 11627.
7880_C001.indd 177 10/25/08 2:18:56 PM
178 Karchs Pathology of Drug Abuse
Ritz, M. C. and George, F. R. (1993). Cocaine-induced seizures and lethality appear to be associated
with distinct central nervous system binding sites, J. Pharmacol. Exp. Ter., 264(3), pp. 133343.
Rowley, H. A., Lowenstein, D. H. et al. (1989). Talamomesencephalic strokes afer cocaine abuse,
Neurology, 39(3), pp. 42830.
Ruiz Martinez, J., Villanua, J. et al. (2004). [Vasculitis caused by toxic agents: diagnosis and follow
up by magnetic resonance angiography], Rev. Neurol., 38(5), p. 496.
Satel, S. L., Southwick, S. M. et al. (1990). Clinical features of cocaine induced paranoia, NIDA Res.
Monogr., 105, p. 371.
Scully, R. E., Mark, E. J. et al. (1997). Case records of the Massachusetts General Hospital. Weekly
clinicopathological exercises. Case 201997. A 74-year-old man with progressive cough, dys-
pnea, and pleural thickening, N. Engl. J. Med., 336(26), pp. 1895903.
Seeman, P. and Van Tol, H. H. (1994). Dopamine receptor pharmacology, Trends Pharmacol. Sci.,
15(7), pp. 26470.
Sekhar, L. N. and Heros, R. C. (1981). Origin, growth, and rupture of saccular aneurysms: a review,
Neurosurgery, 8(2), pp. 24860.
Shaner, A., Khalsa, M. E. et al. (1993). Unrecognized cocaine use among schizophrenic patients,
Am. J. Psychiatry, 150(5), pp. 75862.
Sharma, A., Plessinger, M. A. et al. (1992). Pregnancy enhances cardiotoxicity of cocaine: role of
progesterone, Toxicol. Appl. Pharmacol., 113(1), pp. 305.
Siegel, A. J., Mendelson, J. H. et al. (2002). Efect of cocaine usage on C-reactive protein, von
Willebrand factor, and fbrinogen, Am. J. Cardiol., 89(9), pp. 11335.
Siegel, R. K. (1978). Cocaine hallucinations, Am. J. Psychiatry, 135(3), pp. 30914.
Sleiman, I., Mangili, R. et al. (1994). Cocaine-associated retinal vascular occlusion: report of two
cases, Am. J. Med., 97(2), pp. 1989.
Somlyo, A. P. and Somlyo, A. V. (1994). Signal transduction and regulation in smooth muscle,
Nature, 372(6503), pp. 2316.
Spittell, J. A., Jr. and Spittell, P. C. (2001). Cocaine-related vasculitis causing upper-limb peripheral
vascular disease, Ann. Intern. Med., 135(9), p. 843.
Staley, J. K., Hearn, W. L. et al. (1994). High afnity cocaine recognition sites on the dopamine
transporter are elevated in fatal cocaine overdose victims, J. Pharmacol. Exp. Ter., 271(3), pp.
167885.
Staley, J. K. and Mash, D. C. (1996). Adaptive increase in D3 dopamine receptors in the brain
reward circuits of human cocaine fatalities, J. Neurosci., 16(19), pp. 61006.
Stief, A. and Tokay, L. (1935). Further contributions to histopathology of experimental adrenalin
intoxication, J. Nerve Ment. Disease, 81, pp. 63348.
Stillman, R., Jones, R. T. et al. (1993). Improved performance 4 hours afer cocaine, Psychopharma-
cology (Berlin), 110(4), pp. 41520.
Supervia, A., Llobera, J. et al. (2006). [Choreoathetoid movements afer crack abuse: crack danc-
ing], Med. Clin. (Barcelona), 126(14), p. 555.
Urbina, A. and Jones, K. (2004). Crystal methamphetamine, its analogues, and HIV infection:
medical and psychiatric aspects of a new epidemic, Clin. Infect. Dis., 38(6), pp. 8904.
Van Harten, P., Van Trier, J. et al. (1998). Cocaine as a risk factor for neuroleptic-induced acute
dystonia, J. Clin. Psychiatry, 59(3), pp. 12830.
Varona, J. F., Guerra, J. M. et al. (2007). Causes of ischemic stroke in young adults, and evolution of
the etiological diagnosis over the long term, Eur. Neurol., 57(4), pp. 2128.
Verdejo-Garcia, A., Bechara, A. et al. (2006a). Executive dysfunction in substance dependent indi-
viduals during drug use and abstinence: an examination of the behavioral, cognitive and emo-
tional correlates of addiction, J. Int. Neuropsychol. Soc., 12(3), pp. 40515.
Verdejo-Garcia, A. J., Perales, J. C. et al. (2006b). Cognitive impulsivity in cocaine and heroin poly-
substance abusers, Addict. Behav., 32(5), 95066.
Volkow, N. D., Fowler, J. S. et al. (1990). Metabolic studies of drugs of abuse, NIDA Res. Monogr.,
105, pp. 4753.
7880_C001.indd 178 10/25/08 2:18:56 PM
Cocaine 179
Volkow, N. D., Fowler, J. S. et al. (1991a). Use of positron emission tomography to study cocaine in
the human brain, NIDA Res. Monogr., 112, pp. 16879.
Volkow, N. D., Fowler, J. S. et al. (1991b). Changes in brain glucose metabolism in cocaine depen-
dence and withdrawal, Am. J. Psychiatry, 148(5), pp. 6216.
Williams, S. (1990). A FASEB sampler. American Societies for Experimental Biology, Science,
248(4952), p. 166.
Winbery, S., Blaho, K. et al. (1998). Multiple cocaine-induced seizures and corresponding cocaine
and metabolite concentrations, Am. J. Emerg. Med. 16(5), pp. 52933.
Woods, J. R., Jr. and Plessinger, M. A. (1990). Pregnancy increases cardiovascular toxicity to
cocaine, Am. J. Obstet. Gynecol., 162(2), pp. 52933.
Yapor, W. Y. and Gutierrez, F. A. (1992). Cocaine-induced intratumoral hemorrhage: case report
and review of the literature, Neurosurgery, 30(2), pp. 28891.
Ye, J. H., Liu, P. L. et al. (1997). Cocaine depresses GABAA current of hippocampal neurons, Brain
Res., 770(12), pp. 16975.
Zeiter, J. H., Corder, D. M. et al. (1992). Sudden retinal manifestations of intranasal cocaine and
methamphetamine abuse, Am. J. Ophthalmol., 114(6), pp. 7801.
1.17 Renal Disease
Te results of some animal studies raise the possibility that cocaine is directly nephrotoxic
(Barroso-Moguel et al., 1995) (Figure 1.17.1). Whether it is directly toxic or not, there is no
questioning that cocaine users are subject to renal disease. Te pathophysiology of cocaine-
related renal injury is multifactorial, involving renal hemodynamic changes, alterations in
glomerular matrix synthesis, oxidative stress, and perhaps even accelerated renal athero-
genesis. Renal thrombosis occurs with some frequency (Bemanian et al., 2005) and numer-
ous cases have been reported (Wohlman, 1987; Killam, 1993; Korzets et al., 1995; Webber
et al., 1999; Volcy et al., 2000; Mochizuki et al., 2003; Edmondson et al., 2004). However,
only two cases of cocaine-associated hemolytic uremic syndrome (HUS) have ever been
described, and it is not clear whether they occurred as complications of cocaine use or
whether cocaine was an incidental fnding (Tumlin et al., 1990; Ito and Komatsu, 1993).
Te most commonly reported cocaine-related renal disorder is acute tubular necro-
sis secondary to rhabdomyolysis. Rhabdomyolysis was recognized as a complication of
both narcotic abuse (Richter et al., 1971) and stimulant abuse (Kendrick et al., 1977) long
before the current wave of cocaine popularity ever began. Te frst case of rhabdomyolysis
directly related to cocaine was described in 1987 (Merigian and Roberts, 1987), and hun-
dreds of case reports have appeared since (Gitman and Singhal, 2004; Vets et al., 2006). In
a large percentage of these cases, rhabdomyolysis was not the primary disorder; it occurred
as a component of the excited delirium syndrome, where very high core temperatures and
extreme physical activity combined to cause muscle breakdown.
Except for cases of excited delirium, the underlying process by which stimulant
drugs produce rhabdomyolysis is poorly understood. In some cocaine-related cases, the
relationship to prolonged seizure activity is clear; however, seizures are rarely reported
in recreational users. In other settings, pressure-related injury seems to be the most
likely explanation (Singhal and Faulkner, 1988; Singhal et al., 1989; McCann et al., 2002;
Gitman and Singhal, 2004; Vets et al., 2006). Cocaine-induced vasospasm leading to
myocyte necrosis has also been proposed as a mechanism (Roth et al., 1988), but this mech-
anism has never been reproduced in the laboratory or even described in other case reports.
Accelerated renal artery arteriosclerosis, with histological changes reminiscent of those
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