Вы находитесь на странице: 1из 13

Journal of Clinical Forensic Medicine (2003) 10, 27–39

Ó 2003 Elsevier Science Ltd and APS. All rights reserved.


doi:10.1016/S1353-1131(03)00003-8

REVIEW

The pathophysiology of cocaine abuse


Stuart M. White,1 Cheryl J. T. Lambe2
1
Department of Anaesthesia, St. ThomasÕ Hospital, London, UK; 2Henfield Medical Centre, Henfield,
West Sussex, UK

SUMMARY. Cocaine is a naturally occurring alkaloid that increases dopamine concentrations in the reward
centers of the brain. There has been a marked increase in cocaine abuse over the last two decades. A neuropsy-
chological stimulant, cocaine also reduces somnolence, increases alertness and improves concentration. However,
cocaine abuse has many pathophysiological consequences. These fall broadly into four groups: pathology asso-
ciated with a drug abusing lifestyle, pathology that occurs whilst intoxicated with (but not directly due to) the drug,
pathology associated with drug administration and pathology resulting from pharmacological action of the drug.
This review provides a detailed description of the physiological, pharmacological, and pathological effects of
cocaine, and highlights the forensic and medicolegal implications of cocaine abuse.
Ó 2003 Elsevier Science Ltd and APS. All rights reserved.
Keywords: Cocaine: adverse effects; Cocaine: toxicity; Substance-related disorders: legislation and jurisprudence

Journal of Clinical Forensic Medicine (2003) 10, 27–39

Erythroxylon coca, the plant from which cocaine maximum safe dose permitted for medical use is
(benzoylmethylecgonine, C17 H21 NO4 ) is extracted, is 3 mg/kg. However, the medicinal use of cocaine has
native to the Andes and western South America, but declined markedly since its heyday (1880–1900) when
will grow almost anywhere.1 Coca has been used by the marked increase in production of refined cocaine
Andean Indians for over a thousand years, who chew led to an equally marked increase in medical reports
the leaves to release cocaine, the stimulant properties of cocaine-related toxicity and mortality. Medical
of which offset symptoms associated with living at usage was further reduced by the development of
high altitude (e.g., dizziness and nausea). Bolivian leaf other local anaesthetic agents, such as lignocaine,
contains only 0.5% cocaine, and the content falls that did not produce sympathomimetic side-effects.
rapidly after harvesting. Chewing the leaf further de- Cocaine resurfaced as a drug of abuse in the 1970s
creases the amount of cocaine that reaches the and 1980s, due to an increase in supply and decline in
bloodstream, therefore cocaine toxicity, even after production costs. As had happened 90 years previ-
years of use, is rare amongst Andean Indians.2 ously, this resulted in an increased incidence of co-
Cocaine is still used medicinally. It is a vasocon- caine-related pathology, which was exacerbated by
stricting local anaesthetic agent – properties that are the introduction of crack cocaine.
beneficial in surgery for the ear, nose, and throat. The This article aims to provide the physician with a
detailed description of the pharmacology and sys-
Received 27 September 2002 temic pathology associated with cocaine, and high-
Accepted 16 December 2002 lights specific adverse effects (including medicolegal
implications) that are of relevance to the practice of
forensic medicine.
Stuart M. White, FRCA, BSc, Lecturer in Anaesthesia,
Department of Anaesthesia, St. ThomasÕ Hospital,
Lambeth Palace Road, London SE1 7EH, UK.
Cheryl J. T. Lambe, MB.BS, Registrar in General Practice, and PHARMACOLOGY OF COCAINE
Forensic Medical Examiner (Sussex Constabulary), Henfield
Medical Centre, Deer Park, Henfield, West Sussex BN5 9EH, UK
Cocaine hydrochloride (89% cocaine by weight) is
Correspondence to: Stuart M. White, FRCA, BSc, produced by dissolving the alkaloid in hydrochloric
Tel.: +0207-928-9292; E-mail: igasbest@hotmail.com acid. The salt formed is water soluble – dehydration

27
28 Journal of Clinical Forensic Medicine

produces the white crystals or powder that are the time to analysis, the temperature at the scene of
commonest presentation of the abused drug. The death and the temperature at which the corpse was
powder is slightly bitter and numbs the oral mucosa. stored.10
Cocaine hydrochloride is most commonly taken by Both the minimum toxic dose and lethal dose of
ÔsnortingÕ it nasally, but intravenous, oral and rectal cocaine are uncertain.11 Most cocaine-related deaths
routes may be used. A ÔlineÕ of cocaine contains occur in those who abuse cocaine in high doses over a
roughly 50 mg of cocaine hydrochloride. ÔFree base,Õ long period of time. Isolated blood measurements do
the natural cocaine alkaloid, is water insoluble, not equate to toxicity, and no particular plasma
colourless, and tasteless. It vaporises above 100 °C, concentration of cocaine can be guaranteed to be
but remains chemically stable and is therefore safe.12;13
abused by inhalation. Purer cocaine can be extracted The pharmacodynamic properties of cocaine are
from cocaine hydrochloride by dissolution in an complex. Local anaesthesia is achieved through
alkaline solution, followed by the addition of a competitive inhibition of fast sodium channels in
solvent such as ether. The mixture separates into neurones, thus ablating saltatory nerve conduction in
two layers, the uppermost containing cocaine, which peripheral nerves. Both the rate and amplitude of the
can be extracted by evaporating the solvent, pro- sino-atrial pacemaker potential are reduced. Depo-
ducing Ôfree base.Õ To avoid the inflammability and larisation throughout the conducting system of the
burns associated with ether extraction, cocaine re- heart is interrupted. Ventricular standstill can occur
finery from cocaine hydrochloride commonly em- in massive overdose.14
ploys the method of dissolution in water made Cocaine inhibits presynaptic norepinephrine and
alkaline by the addition of baking soda. The cocaine dopamine reuptake, and inhibits the action of
base precipitates, and hardens after drying, pro- monoamine oxidase (which catabolises epinephrine,
ducing a Ôrock,Õ which is broken up into crystals. norepinephrine, and dopamine) at synapses. As a
When heated, the crystals make a popping sound, consequence, intrasynaptic norepinephrine concen-
and this pure form of cocaine is therefore termed tration remains high after nerve depolarisation.
Ôcrack cocaine.Õ Crack is now the most prevalent This results in prolonged activation of the sympa-
form of the drug abused. It is smoked, producing a thetic nervous system, which causes vasoconstric-
more rapid and intense high than cocaine hydro- tion, cardiac inochronotropism, hypertension,
chloride (i.e., within one lung–brain circulation time cardiac dysrhythmias, hyperglycaemia, hyperther-
of 6–8 s), but the associated euphoria is short-lived mia, and mydriasis. In addition, cocaine effects in-
(generally less than 15 min, compared to up to creased release of epinephrine from the adrenal
60 min for intranasally administered cocaine hydro- medulla.
chloride).3 The psychophysiological effects of smok- Cocaine abuse increases excitatory neurotrans-
ing crack are similar to those of intravenous mitter levels in the brain, which produces euphoria in
injection.4 It appears to be more addictive, and the the short term and addiction in the long term, but
incidence of its abuse is increasing.5 may also lead to the development of seizures. In
After administration, cocaine is rapidly redis- overdose, cocaine acts as an antimuscarinic drug,
tributed from the plasma, reaching high concentra- inhibiting gastric motility and increasing the likeli-
tion in vessel-rich body compartments (e.g., brain). hood of gastric ulceration and perforation.
Redistribution to vessel-poor compartments (e.g., The pathology associated with cocaine abuse can
fat) occurs with time. 5% of cocaine is excreted be subdivided into four groups: pathology associated
unchanged in the urine (detectable 3–6 h after use). with a drug abusing lifestyle, pathology that occurs
Eight five percent is metabolised by plasma and li- whilst intoxicated with (but not directly due to) the
ver esterases to produce ecgonine methyl esters and drug, pathology associated with drug administration
benzoylecgonine (which also forms spontaneously3 ), and pathology resulting from pharmacological action
which are detectable in urine for up to 14 days after of the drug.
consumption.6 Plasma pseudocholinesterase displays
genetic polymorphism,7 and a small proportion of
the population esterify cocaine slowly, which may PATHOLOGY ASSOCIATED WITH A DRUG
result in prolonged euphoria and increased inci- ABUSING LIFESTYLE
dence of cocaine-related pathology.8 Likewise,
plasma cholinesterase activity is reduced in infants, Throughout the 1970s and 1980s, cocaine was an
pregnancy and old age.9 Tissue cocaine concentra- expensive drug to abuse. Its use tended to be limited
tion, when measured at post mortem, can be unre- to young urban males, earning higher than average
liable, depending on the time since ingestion, the wages from a stressful job. The emergence of crack
The pathophysiology of cocaine abuse 29

cocaine in America in the late 1980s, together with PATHOLOGY OCCURRING WHILST
improved cocaine refinery, global marketing, excess INTOXICATED
production and the widespread, persistent belief that
cocaine is a benign and non-addictive drug, led to Cocaine is not hallucinogenic like lysergide, mesca-
both a rapid fall in the street price and a marked rise line, or phencyclidine,31 but accidental death or injury
in consumption. In relation to earnings, the price of can happen during intoxication. Dysfunction of ce-
cocaine fell 75% over the 15 years before 1996.15 rebral serotonergic neurotransmission occurs shortly
Nevertheless, the average street price of cocaine in the after minimal cocaine ingestion, which can lead to
UK remains at £30 per gram ($45).16 With a purity of impulsive, aggressive behaviour, suicidal tendency
between 25% and 90%,17 and an average weekly in- and acute psychosis (although psychosis is rare).32
take of 3 g in recreational users (5–10 g in chronic, Suicide is the cause of death in up to 10% of cocaine-
heavy users),16;18 cocaine abuse remains an expensive related deaths.19 The neuropsychiatric effects of co-
habit. The addictive nature of cocaine means that caine may also have an effect on co-ordination and
users must find a way of funding their habit. In perception, resulting in an excess, for example, of
practice, this can result in criminal activity. Both road traffic accidents amongst the acutely intoxi-
sexes may resort to violence, theft, and prostitution. cated33 (although cocaine ingestion has been found to
Homicide, often committed by the traffickers of improve alcohol-related changes in psychomotor
drugs, accounts for 20% of deaths in individuals performance34 ).
abusing cocaine.19 Prostitution carries the risk of
sexually transmitted disease, notably HIV and hepa-
titis B; cocaine, per se, appears to increase the like- PATHOLOGY ASSOCIATED WITH METHOD
lihood and virulence of HIV infection, though this OF ADMINISTRATION
has not yet been proven in prospective clinical stud-
ies.20–23 Intranasal insufflation of cocaine remains the com-
Cocaine, in common with other stimulants, sup- monest method of self-administration, at least in the
presses appetite, and users may buy drugs rather than UK. However, cocaine-mediated vasoconstriction
food. Therefore diet can often be poor, which tends can lead to ischaemic necrosis of nasal cartilages,
to compound the other pathology associated with with nasal septal perforation being the result of long
cocaine.24 Similarly, the children of drug abusers may term usage. Oropharyngeal ulceration can occur by
be undernourished and at risk of illness.25 Without a the same mechanism.35 Mucosal vasoconstriction is
regular income (unemployment is more common followed by rebound hyperaemia, which can be
among drug abusers26 ), a downward spiral of poverty worsened by chemical irritation due to adulterants.36
can ensue, resulting in imprisonment and poor per- Symptomatically this produces a blocked nose, with
sonal and social welfare. persistent rhinitis and rhinorrhea.37 Anosmia may be
Cocaine is rarely abused in isolation. Polydrug experienced.
abuse is common, thereby exposing the user to the Inhalation of crack and free base cocaine also has
pathologies associated with both cocaine and the significant associated pathology. The anaesthetic ef-
other drugs abused. Marijuana may be used to fects of cocaine on the oropharyngeal mucosa can
ameliorate the psychophysiological effects of Ôcoming result in prolonged exposure to hot cocaine vapours,
downÕ after a dose of cocaine.27 Contemporaneous causing acute inflammation and necrosis, epiglottitis,
alcohol use is widespread, because alcohol prolongs laryngotracheobronchitis,37 and laryngospasm. Sin-
the euphoria of cocaine. In the presence of alcohol, ged eyebrows and eyelashes,38 carbonaceous sputum,
hepatic transesterification of cocaine occurs, forming wheezing, hoarseness, and stridor may be observed
cocaethylene, which is a pharmacologically active after thermal injury. Volatile ether, used in free base
agent28 with a half life of 150 min (compared to the extraction, can lead to severe burns of the upper
30–90 min of cocaine).29 Cigarette smoking, associ- airway. Carbonaceous impurities from materials used
ated with enabling marijuana consumption, is pre- to vaporise cocaine may lead to pulmonary granu-
valent and deeper inhalation of smoke may occur, lomata or a pneumoconiosis like reaction.39 Deep,
particularly amongst those who abuse cannabis or prolonged inspiration is used to maximise cocaine
crack cocaine by inhalation (a reinforced learning uptake into the bloodstream. This is further increased
behaviour that maximises the uptake and onset of if a Valsalva manoeuvre is employed during expira-
these drugs). Carcinogen exposure through smoking tion. Both manoeuvres, by their resultant effect on
marijuana is further increased, as the smoke is transpulmonary pressure gradients, can lead to alve-
seldom filtered and users tend to breath hold after olar rupture, producing pneumothorax and pneu-
inhalation.30 momediastinum.40
30 Journal of Clinical Forensic Medicine

Intravenous cocaine abuse is less common, as mon, unrelated to dose and occur randomly in the
significant morbidity and mortality are associated cocaine-abusing population. The pathology associ-
with the virtually instantaneous acquisition of maxi- ated with both categories may be summarised by
mum plasma cocaine levels.41 All the injected drug is describing the effects of cocaine on each physiological
bioavailable, as are chemicals that adulterate the in- system.
jectate. Seizures, cardiac arrest, hypertensive crises,
and hyperthermia have been reported, particularly
Cardiovascular system
amongst chronic users.42 Intravenous drug abuse is
generally associated with vasculitis,43 myocarditis,44 Cardiac complications are the commonest cause of
infective endocarditis, pulmonary and cerebral em- death amongst cocaine users,16 and can occur after
bolism and infarction, and infection (hepatitis B and acute or chronic abuse. Chest pain, myocardial is-
C, cytomegalovirus, syphilis and HIV). Adulterants chaemia and infarction, cardiac dysrhythmias and
can produce additional morbidity.45 Intravenous in- sudden death have been reported. Myocarditis and
jection of cocaine and heroin mixtures – ÔspeedballsÕ – aortic rupture may also occur, but rarely.52
combine the effects of both drugs, and may be asso- Ischaemia and infarction usually occur in chronic
ciated with a higher risk of psychopathology.46 abusers, but infarction can occur after initial use of
Inadvertent intraarterial injection of cocaine will in- cocaine.53 Cocaine (usually) has a positive inochro-
duce spasm in smaller arteries, which could lead to notropic action on the heart, through peripheral and
limb threatening ischaemia and gangrene.47 central stimulation of the sympathetic nervous sys-
ÔBodypackingÕ or Ôbodystuffing,Õ though not actual tem,54 and increased adrenal medullary epinephrine
methods of cocaine administration, can have fatal production.55 Heart rate, blood pressure, systemic
consequences, similar to those occurring during in- vascular resistance, and left ventricular rate-pressure
travenous overdose. ÔBodypackersÕ are used to ille- product56 are acutely increased, and myocardial ox-
gally transport drugs across national borders. ygen demand is increased in parallel.57 However,
Quantities in excess of 500 g may be smuggled by myocardial oxygen delivery is reduced, due to raised
sealing cocaine in condoms or cellophane which are left ventricular end diastolic pressure, myocardial
swallowed, and recovered after transit through the arteriolar vasoconstriction, reduced coronary dia-
bowel.48;49 ÔBodystuffersÕ conceal evidence of drug stolic filling time during tachycardia and cocaine-in-
trafficking by swallowing wraps of drugs when facing duced coronary artery vasospasm.58;59 Myocardial
imminent arrest. From personal experience, one of ischaemia results from the imbalance between oxygen
the authors (SMW) has had to remove 17 such wraps supply and demand. Q or non-Q wave infarcts may
(each weighing about 0.5 g) from the oropharynx of a ensue. Coronary artery dissection has been re-
semi-comatose patient, to prevent airway obstruction ported.60 Spasm may be worsened by the coadmin-
and acute overdose of cocaine. In both packers and istration of cigarette smoke (which elevate
stuffers, accidental leakage of cocaine into the GI carboxyhaemoglobin levels and increase blood vis-
tract (through the wall of the condom, or if condom cosity, which further reduces myocardial oxygen
rupture occurs) leads to a large absorption of cocaine supply).61;62
into the circulation, particularly if the cocaine is rel- Infarction is made more likely by the prothrom-
atively pure. Cocaine-abusing bodypackers may be botic effects of cocaine.63 Platelet aggregation and
able to tolerate a high blood cocaine concentration, activation are enhanced64;65 and fibrinolysis is de-
but non-abusers invariably suffer from agitation, creased (by an increase in levels of endogenous tissue
confusion and seizures and may progress malignant plasminogen activator inhibitor).66
cardiac dysrhythmias, hyperthermia, excited delirium Underlying heart disease is not a prerequisite for
and death.48;50;51 Autopsy reveals pulmonary and ce- the development of cocaine-related ischaemia and
rebral oedema. There may be idiosyncratic fatal infarction,67 but its presence significantly increases
reactions to even small doses. the likelihood of infarction and worsens the prog-
nosis after infarction. Coronary atherosclerosis re-
duces the arterial endothelial release of coronary
PATHOLOGY RESULTING FROM vasodilators (nitric oxide and prostacycline), en-
PHARMACOLOGICAL ACTION OF THE DRUG hancing coronary vasospasm at the site of athero-
sclerotic plaque.68 In addition, endothelial damage
The pathology described in this section falls into two may occur after coronary vasospasm, promoting
broad categories: expected effects, which are pre- further atherosclerotic change, and thrombosis.69
dictable dose-related extensions of pharmacological Moreover, platelet activation releases smooth muscle
actions, and idiosyncratic effects, which are uncom- growth factors, which promote vascular hyperplasia
The pathophysiology of cocaine abuse 31

and coronary luminal occlusion.70 Indeed, cocaine and focal fibrosis (in response to recurrent episodes of
appears to be an independent accelerant of coronary myocardial ischaemia and infarction) and myocardial
atherosclerosis.71 contraction band formation. In addition, cocaine
Cocaine-related chest pain annually accounts for directly causes myocyte apoptosis (particularly dur-
37,000 admissions to hospital in the United States.72 ing episodes of oxidative stress).89 Poor contractile
The pain is commonly described as sharp, stabbing or function may be reversible by reducing (and main-
pleuritic,73 and may represent ischaemia secondary to taining) circulating catecholamine levels to the nor-
coronary vasospasm. Chest pain is invariably present mal range.90
prior to cocaine-related infarction. 6% with chest Cocaine-related myocarditis may occur in a to
pain proceed to infarction.74 4% die after infarc- toxic, dose-dependent manner, secondary to a hy-
tion,75 4–12% develop life-threatening arrhythmias, persensitivity (dose-independent) reaction. Toxic
and congestive cardiac failure occurs in 5–7%.76 myocarditis was found in 20% of cocaine abusers at
Electrocardiography is only sensitive for infarction in autopsy,91 and is manifest by small areas of myo-
a third of cases of cocaine-related chest pain73 cardial necrosis and loss of cardiac myofibrils. Co-
(compared to 61% of non-cocaine-related chest caine-related chest pain may be a symptom of
pain77 ), though abnormalities are seen in two thirds.78 myocarditis.
CK and CK-MB levels may be raised in cocaine users Cocaine-related episodes of hypertension, in the
who have not had an infarct (due to increased motor presence of atherosclerotic blood vessels, can result in
activity, seizures, hyperthermia, and rhabdomyoly- potentially fatal aortic dissection or rupture.92 This
sis). Troponin I levels may be more beneficial in di- usually involves the ascending aorta. Aortic root
agnosing cocaine-related myocardial infarction.79 dissection may impinge coronary artery blood flow,
Cocaine ingestion may result in cardiac dysrhyth- leading to further myocardial infarction.
mia. Initial ingestion may be associated with brady-
cardia,80 although tachycardia is most common
Respiratory system
Multifocal ventricular ectopics, ventricular tachycar-
dia, ventricular fibrillation and asystole81 occur with The deleterious effects of cocaine on the upper airway
increasing dose. Sudden death, accounting for the have been described above. Other respiratory com-
majority of cocaine-related deaths, is most likely at- plications associated with the smoking of crack co-
tributable to a combination of dysrhythmia and caine include pneumonitis, pulmonary haemorrhage,
cardiomyopathy.82 Several mechanisms contribute to vascular lesions, and pulmonary oedema.
cocaine induced dysrhythmia: myocardial ischaemia, Cocaine is a direct irritant to the airways and a
raised plasma catecholamine concentrations, cen- persistent cough is common. Bronchial hyperreac-
trally upregulated sympathetic nervous system out- tivity and hypersecretion are increased, and may be
flow, hyperpyrexia, metabolic acidosis and cardiac potentiated by thermal airway injury. Severe bron-
myocyte membrane stabilisation by cocaine (by in- chospasm may result.93 Cocaine may excite an anti-
terference with transmembranal Naþ and Ca2þ flux). genic response. Repeated exposure can lead to an
Intracardiac nerve impulses undergo slowed, hetero- immunoglobulin-E mediated pnemonitis, character-
geneous depolarisations, with prolonged repolarisa- ised by fever, bronchospasm, dyspnoea, and cough.
tions.83 More recently, cocaine and cocaethylene have Eosinophilia is apparent and diffuse alveolar and
been shown to effectively block HERG-related (Hu- interstitial infiltrates may be seen on chest radio-
man ether-a-go-go-related gene) potassium channels, graphs and in biopsy samples. Bronchiolitis obliter-
thereby suppressing the delayed-rectifier potassium ans is similar to hypersensitivity pneumonitis (except
current (I(K)) resulting in prolongation of cardiac for the occurrence of eosinophilia) and produces
repolarisation.84;85 Reentrant dysrhythmias occur, chronic inflammatory alveolar and interstitial infil-
and may be promoted by the formation of myocar- trates.94
dial contraction bands, which are non-contracting, Haemoptysis occurs in 6–26% of cocaine users,95
disorganised, amorphous masses of cardiac myofi- and may be due to a combination of toxic vasculitis,
brils that are associated with prolonged, high intake alveolar haemorrhage, thermal injury, and bronchial
of cocaine (amongst other causes).86 Massive doses of and pulmonary arterial vasoconstriction, infarction,
cocaine can result in ventricular standstill. and ischaemia.96
Left ventricular hypertrophy occurs in 54% of Recurrent episodes of pulmonary damage, to-
cocaine abusers and regional wall motion abnor- gether with cocaine-related bronchial smooth muscle
malities in 21%.87 Contractile dysfunction may occur hypertrophy,97 may result in right heart failure. Pul-
with prolonged, high dose abuse, secondary to the monary oedema may occur secondary to left ven-
effects of catecholamines,88 progressive myocytolysis, tricular failure, toxic pulmonary endothelial damage
32 Journal of Clinical Forensic Medicine

(with increased membrane permeability), high nega- addition, hyperthermia, metabolic acidosis, cerebral
tive intrathoracic pressures (that occur during the act ischaemia, cerebral haemorrhage, and co-adminis-
of inhaling, or as a consequence of upper airways tration of other epileptogens may lead to fitting.111
obstruction) or a neurogenic cause (secondary to Centrally mediated hyperthermia results from
cocaine-induced up-regulation of central sympathetic brainstem D1 dopamine receptor downregulation.112
nervous discharge).98 Body temperature may rise by up to 1 °C after co-
caine use. Severe hyperthermia, in excess of 40 °C, is
associated with a poor outcome and may be the first
Central nervous system
sign of progression to excited delirium. Cocaine-
The pathological effects of cocaine on the central mediated changes in intrasynaptic dopamine con-
nervous system can be subdivided into three groups: centrations also provide a causative mechanism for
cerebrovascular effects, neurological effects, and the occurrence of movement disorders, such as cho-
psychological effects. reoathetosis and akathisia.113 Chronic abuse may
Intracranial haemorrhage and cerebral infarction lead to alpha-synuclein overexpression levels in do-
have been widely reported to occur after cocaine pamine neurons, which induces dopamine nerve ter-
abuse. The rapid rise in blood pressure that occurs minal degeneration; in addition, alpha-synuclein is a
shortly after administration, together with impaired major component of Lewy bodies in ParkinsonÕs
cerebral autoregulation,99;100 may precipitate sponta- disease (PD). We report here that from chronic co-
neous haemorrhage.101 Subarachnoid haemorrhage is caine abusers. Chronic abuse may therefore place
more common in the presence of preexisting cerebral aging cocaine addicts at risk for developing the motor
pathology, such as cerebral aneurysm or arteriove- abnormalities of ParkinsonÕs disease.114
nous malformations. In 78% of cases of subarach- Elevated dopamine levels in the mesolimbic and
noid haemorrhage secondary to cocaine abuse mesocortical areas of the brain give rise to intense
underlying vascular anomalies are found.102 Intra- euphoria. Simultaneously, cocaine suppresses the
nasal cocaine hydrochloride tends to produce haem- activity of the pontine nucleus and locus coeruleus,
orrhagic, rather than embolic, stroke (80%/20%);103 producing anxiolysis.115 However, dopamine deple-
both types of stroke occur with similar frequency tion, caused by repetitive cocaine use, produces tol-
after smoking ÔcrackÕ cocaine. Cerebral ischaemia erance to the euphoric effects of cocaine, as well as
after a stroke may be worsened by cerebral vaso- physiological cocaine addiction.116
spasm104 (due to cocaine or intracerebral blood), Sexual dysfunction is common amongst cocaine
hypercoagulability and thrombosis,105 hyperpyrexia, users. Low doses may delay ejaculation and orgasm,
hyperglycaemia and an increased cerebral metabolic and heighten sexual excitement, but prolonged high
rate (consequent to the neuroexcitatory effects of doses may cause sexual disinterest, impotence, anor-
cocaine); cerebral vasculitis has also been re- gasmia, compulsive masturbation and premature
ported.106;107 Reperfusion injury, with altered calcium ejaculation.117
flux, may extend the area of cerebral damage occur- Psychiatric illness may be the presenting manifes-
ring after the initial insult. tation of cocaine abuse, or merely an observed side
Seizures usually occur in chronic abusers, but may effect. Acute or chronic psychosis,118;119 schizophre-
occur after the first intoxication. Seizure activity is nia,120 depression,121 suicidal ideation,122 and obses-
related to the peak plasma concentration of cocaine, sive–compulsive disorders123 have been reported. Sleep
and usually occurs within minutes of dosage, al- disorders124 and decreased appetite125 are common.
though it can occur up to 24 h after ingestion; one
study in rats suggested that delayed seizure activity is
Gastrointestinal system126
related to the cocaine metabolite, benzoylecgonine,108
but this is yet to be demonstrated in humans. Gen- There are two case reports of bowel ischaemia after
eralised, self-terminating tonic-clonic seizures are cocaine ingestion,127 although formal studies have not
usual, but multiple seizures or status epilepticus can been performed in humans. (However, the portal ve-
occur,109 which can be lethal, particularly in associ- nous fraction of total hepatic blood flow was found to
ation with hyperpyrexia, cardiac dysrhythmia, and be abnormal in 100% of polydrug abusers in one
cerebral haemorrhage. Cocaine reduces the seizure study.128 ) Gastric mucosal cells and duodenal villi
threshold by chronic subthreshold stimulation of the rapidly become ischaemic in response to reductions in
limbic system – the Ôkindling effectÕ (reverse toler- mesenteric blood flow, leading to gastritis and ulcera-
ance).110 Intrasynaptic accumulation of excitatory tion;129 this may theoretically be potentiated by co-
neurotransmitters occurs (notably serotonin), which caine-mediated gastric hypomotility and delayed
is thought to precipitate epileptiform activity. In gastric emptying (which prolongs mucosal exposure to
The pathophysiology of cocaine abuse 33

gastric acid).130 Mesenteric vasoconstriction can result link between cocaine and spontaneous abortion is
in ischaemia and acute inflammation or infarction weak and inconsistent.143
along the length of the bowel.131 Gangrenous perfo- Cocaine is a vasoconstrictor, which provides a
ration may be unrecognised for a hazardous length of physiological reason for its adverse effects on the fe-
time, but should be considered in the presence of acute, tus. In the placenta, increased vascular tone reduces
persistent abdominal pain and leukocytosis. placental blood flow, producing fetal ischaemia.144
Acute and subacute hepatocellular necrosis, acute The fetus has developed physiological methods of
and chronic hepatic failure, ischaemic and viral hep- protection from ischaemic episodes, but these may be
atitis, centrilobular necrosis, and hepatic haemor- insufficient during repeated exposures to cocaine.
rhage have been reported.132;133 Fetal death may occur during prolonged ischaemia,
which can occur during cocaine-induced maternal
dysrhythmia or seizure.145
Renal system
Cocaine crosses the placenta to the fetus by diffu-
Cocaine may directly damage the kidneys by causing sion. There are reports of possible human teratoge-
renal infarction (secondary to renal artery spasm, nicity, including genitourinary tract abnormalities,146
atherosclerosis, and thrombosis)134 or focal segmental ileal atresia,147 microcephaly,148 and neural tube de-
glomerulosclerosis (by increasing mesangial cell pro- fects.149 Growth retardation involving length, weight,
liferation).135 and head circumference150 is more common.151 Co-
More commonly, however, cocaine exerts a neph- caine abuse (and cigarette smoking) during pregnancy
rotoxic effect by causing rhabdomyolysis. Rhabd- impairs transplacental amino acid transport, which
omyolysis can occur by several mechanisms:136 may impair fetal growth.152 Third trimester cocaine
skeletal muscular ischaemia secondary to prolonged exposure is associated with a statistically significant
arterial vasoconstriction, hyperthermia, direct muscle increased risk of placental abruption within 30 min of
cell apoptosis, tissue trauma (whilst intoxicated), and maternal cocaine abuse.151;153;154
tonic-clonic seizures. Muscular pain and hyperkala- 30–50% of cocaine abusing mothers deliver pre-
emia occur. Myoglobin precipitates in renal tubules, maturely.155 Deliberate excessive abuse may occur to
causing obstruction and inflammation, which is ag- induce labour (or abortion), or to escape the pain of
gravated by ischaemic renal tubular disease. Acute labour. Premature rupture of membranes occurs in
renal failure may ensue.137 15–32%, chorioamnionitis in 10%.141
After birth, longer term effects of cocaine exposure
are apparent. Weight gain is delayed.156 There is an
Effects on the mother, fetus, and neonate138
increased incidence of sleep apnoea (responsive to
Studies in the USA have suggested cocaine abuse theophylline therapy)157 and sudden infant death
rates of between 6.4% and 24.3% amongst pregnant syndrome (5.2/1000 infants exposed to intrauterine
women in urban prenatal clinics.139 Figures are not cocaine, odds ratio 3.9158 ). Abnormal sleep, tremor,
available for the UK. poor feeding, hypertension and vomiting may be
Cocaine abuse appears to be an aetiological factor apparent.155
for spontaneous abortion. In rats, exposure to co- There is an increasing body of research to support
caine is associated with increased frequency of reab- the existence of neurobehavioural morbidity in neo-
sorbtion of fetuses, equivalent to spontaneous nates exposed to cocaine in utero.159 Studies have
abortion in humans.140 Cocaine abusing mothers in suggested that fetal cocaine exposure is associated
one study141 had 4 (2:3) pregnancies compared with with, amongst others, impaired auditory information
2.6 (1:6) pregnancies in non-addicted controls, but processing,160 inferior performance on the Neonatal
only 1.3 (1:4) babies compared to 0.9 (1:1), having Behavioural Assessment Score (but higher Neonatal
had 1.8 (1:6) abortions, compared with 0.6 (1:1) in Stress Scale scores),161 movement and tone abnor-
the control group. A recent prospective study of co- malities together with sensory asymmetries,162 jitter-
caine addicted mothers, analysing their habit by hair iness,163 and overreaction to environmental stimuli.164
and urine sample toxicology, showed a 50% increase
in the rate of spontaneous abortion.142 This was ap-
Cocaine excited delirium
parently dose independent, suggesting that any level
of cocaine exposure is associated with spontaneous ÔExcited,Õ or Ôagitated,Õ delirium describes an idio-
abortion, though the authors point out that even the syncratic cocaine-associated syndrome that involves a
careful design of their study was open to methodo- rapid progression (over 2–4 h) of symptoms from
logical problems. An editorial in the same edition of hyperthermia to delirium, cardiorespiratory arrest,
the journal, however, draws the conclusion that any and death. The syndrome is uncommon, but is more
34 Journal of Clinical Forensic Medicine

prevalent than cocaine associated cerebrovascular cocaine epidemic of the late 1980s in the United
accident.165 Excited delirium was first described in States. In excess of 60 cases were reported in the UK
psychiatric patients in 1849 (BellÕs mania). Cocaine- between 1988 and 1997,166 and the incidence of ex-
associated delirium became more common during the cited delirium is expected to rise in line with the in-

Fig. 1 Summary of pathophysiology associated with cocaine abuse.


The pathophysiology of cocaine abuse 35

creased abuse of cocaine. A similar condition is seen moderate or low, but blood benzoylecgonine con-
amongst abusers of other drugs, schizophrenics and centration may be high,175 indicating long-term co-
patients taking neuroleptic medications. Malignant caine abuse. Evidence of excessive restraint and the
hyperpyrexia and exercise-induced hyperthermia may stigmata of drug abuse may also be manifest.
be associated diseases that have a common genetic Death from excited delirium has occurred after
predisposition. police intervention, giving rise to allegations of police
Excited delirium occurs in long term, high dose brutality.177 In addition, ethnic minorities are an
stimulant abusers,167 rather than after acute over- over-represented amongst the deceased.178 In 1998–
dose. Death may occur at home and be unattributed 1999, 65 people died in custody, in the UK. 9% were
to cocaine. The progression of symptoms may be self- black. In the same period, there were five deaths
terminating, though the incidence of such an occur- where restraint was an issue – 2 of the deceased were
rence is unknown. black. Such a statistic may not represent either an
Initially hyperthermia occurs, due to brainstem increased rate of stimulant abuse amongst the black
D1 -dopamine receptor downregulation. Core tem- population or racist brutality by the police. The
perature rises in excess of 40 °C. The individual feels possibility of genetic predisposition to the develop-
hot, sweats profusely and attempts to cool themselves ment of excited delirium requires investigation. Death
by removing their clothes and splashing themselves rates in custody that recently reported have now
with water. halved in number.
Confusion, agitation, and frank psychosis follow, Cocaine-related death can occur after acute or
which may occur in part due to the rapid rise in core chronic abuse, though mortality after acute use is
temperature, but may also be due to upregulation of most commonly associated with massive overdose.
kappa-2 receptors in the amygdala.168 Police inter- Chronic use causes central and peripheral neuro-
vention often occurs at this stage, as the individual chemical changes that result in hypertension-related
may be causing a public disturbance by shouting or morbidity and mortality, including myocardial in-
using threatening behaviour. Restraint169 is difficult farction and cerebrovascular accidents. The inci-
because the patient may show unexpected strength. dence of cocaine-related disorders and death reflects
Chemical incapacitating agents fail to work. Until the availability and price of cocaine; currently, co-
recently, positional restraint techniques (Ôhog-tyingÕ) caine is in plentiful supply, and is cheap to buy (see
were thought to aggravate the condition, asphyxia Fig. 1).
occurring if bodyweight was used to subdue the pa-
tient or if ties were used in such a way as to restrict
ventilation,170–172 at a time when the patientÕs venti- REFERENCES
latory requirements were increased by violent strug- 1. Karch SB. Cocaine: history, use and abuse. JRSM 1999;
gling (i.e., relative hypoventilation). However, a 92: 393–397.
recent review of the literature has challenged the va- 2. Holmstedt B, Lindgren J, Rivier L, Plowman T. Cocaine in
blood of coca chewers. J Ethnopharmacol 1979; 1: 69–78.
lidity of positional asphyxia as a contributory cause 3. Warner EA. Cocaine abuse. Ann Intern Med 1993; 119:
in cocaine-related deaths in which restraint was an 226–235.
issue.173 4. Allred RJ, Ewer S. Fatal pulmonary edema following
intravenous ÔfreebaseÕ cocaine use. Ann Emerg Med 1981;
After a period of time the individual becomes sub- 10: 441–442.
dued and their strength diminishes, the reason for 5. Jekel JF et al. Epidemic free-base cocaine use: case study
which is unclear, but may be related to progressive from the Bahamas. Lancet 1986; 1: 459–462.
6. Fleming JA, Byck R, Barash PG. Pharmacology and
metabolic acidosis, hyperkalaemia and hyperthermia, therapeutic applications of cocaine. Anesthesiology 1990;
and their effects on skeletal muscular function. Re- 73: 518–531.
spiratory arrest and cardiac arrest follow shortly, often 7. Hoffman RS, Henry GC, Howland MA, Weisman RS, Weil
L, Goldfrank LR. Association between life threatening
whilst the individual is still restrained, or during cocaine toxicity and plasma cholinesterase activity. Ann
transport. Emerg Med 1992; 21: 247–253.
Death is not inevitable,174 but survival requires 8. Hoffman RS, Henry GC, Wax PM, Weisman RS, Howland
MA, Goldfrank LR. Decreased plasma cholinesterase activity
prompt recognition and treatment (removal of re- enhances cocaine toxicity in mice. J Pharm Exp Ther 1992;
straints, hospitalisation, cooling, dantrolene, fluids, 263(2): 698–702.
sedation, ventilation, and intensive care may all be 9. Ambre JJ, Ruo T-H, Smith GL, Backes D, Smith CM.
Ecgonine methyl ester, a major metabolite of cocaine.
beneficial). Survivors of initial resuscitation are at J Anal Toxicol 1982; 6: 26–29.
high risk of death from multiple organ failure.175;176 10. Hearn W, Keran E, Wei H, Hime G. Site-dependant
At autopsy, pulmonary oedema, and myocardial postmortem changes in blood cocaine concentrations.
J Forensic Sci 1991; 36: 673–684.
abnormalities (ventricular hypertrophy and fibrosis) 11. Smart R, Anglin R. Do we know the lethal dose of cocaine?
may be seen. Blood cocaine concentrations are J Forensic Sci 1986; 32: 303–312.
36 Journal of Clinical Forensic Medicine

12. Karch S, Stephens B, Ko CH. Relating cocaine blood destructive process mimicking midline reticulosis and
concentrations to toxicity – an autopsy study of 99 cases. limited WegenerÕs granulomatosis. J Rheumatol 1990; 17:
J Forensic Sci 1998; 43: 41–45. 838–840.
13. Karch SB, Stephens BS. When is cocaine the cause of death? 36. Smith JC, Kacker A, Anand VK. Midline nasal and hard
Am J Forensic Med Pathol 1991; 12: 1–2. palate destruction in cocaine abusers and cocaineÕs role in
14. Wetli CV, Mittlemann RE. The Ôbody packer syndromeÕ – rhinologic practice. ENT J 2002; 81(3): 172–177.
toxicity following ingestion of illicit drugs packaged for 37. Taylor RF, Bernard GR. Airway complications from
transportation. J Forensic Sci 1981; 26: 492–500. freebasing cocaine. Chest 1989; 95: 476–477.
15. Office of National Drug Control Policy. The National Drug 38. Tames SM, Goldenring JM. Madarosis from cocaine use.
Control Strategy. Washington DC, The White House, 1996. NEJM 1986; 314: 1324.
16. Braddock K et al. Something like a phenomenon. The Face 39. Klinger JR, Bensadoun E, Corrao WM. Pulmonary
magazine, May 2001, supplement. complications from alveolar accumulation of carbonaceous
17. Cregler LL, Mark H. Medical complications of cocaine abuse. material in a cocaine smoker. Chest 1992; 101: 1171–1173.
NEJM 1986; 315: 1495–1500. 40. Shesser R, Davis C, Edelstein S. Pneuomediastinum and
18. Siegel RK. Cocaine smoking. J Psychoactive Drugs 1982; pneumothorax after inhaling alkaloidal cocaine. Ann Emerg
14: 271–343. Med 1981; 10: 213–215.
19. Tardiff K, Gross E, Wu J, Stajic M, Millman R. Analysis 41. Warner EA. Cocaine abuse. Ann Intern Med 1993; 119:
of cocaine related fatalities. J Forensic Sci 1989; 34: 53–63. 226–235.
20. Pellegrino T, Bayer BM. In vivo effects of cocaine on immune 42. Chitwood DD. Patterns and consequences of cocaine use.
cell function. J Neuroimmunol 1998; 83(1–2): 139–147. Natl Inst Drug Abuse Res Monogr Ser 1985; 61: 111–129.
21. Roth MD, Tashkin DP, Choi R, Jamieson BD, Zack JA, 43. Fredericks RK, Lefkowitz DS, Challa VR, Troost BT.
Baldwin GC. Cocaine enhances human immunodeficiency Cerebral vasculitis associated with cocaine abuse. Stroke
virus replication in a model of severe combined 1991; 22(11): 1437–1439.
immunodeficient mice implanted with human peripheral 44. Rump AF, Theisohn M, Klaus W. The pathophysiology
blood leukocytes. J Infect Dis 2002; 185(5): 701–705. of cocaine cardiotoxicity. Forensic Sci Int 1995; 71(2):
22. Baldwin GC, Roth MD, Tashkin DP. Acute and chronic 103–115.
effects of cocaine on the immune system and the possible 45. Shannon M. Clinical toxicity of cocaine adulterants. Ann
link to AIDS. J Neuroimmunol 1998; 83(1): 133–138. Emerg Med 1988; 17: 1243–1247.
23. Goodkin K, Shapshak P, Metsch LR et al. Cocaine abuse 46. Malow RM, West JA, Corrigan SA, Pena JM, Lott WC.
and HIV-1 infection: epidemiology and neuropathogenesis. Cocaine and speedball users: differences in psychopathology.
J Neuroimmunol 1998; 83(1): 88–101. J Subst Abuse Treat 1992; 9(4): 287–291.
24. Mohs ME, Watson RR, Leonard-Green T. Nutritional 47. Raso AM, Visentin I, Zan S, Rispoli P, Conforti M, Moniaci
effects of marijuana, heroin, cocaine, and nicotine. J Am D, Ortensio M. Vascular pathology of surgical interest in drug
Dietet Assoc 1990; 90(9): 1261–1267. addicts. Min Cardioangiolog 2000; 48(10): 287–296.
25. Miller TL, Easley KA, Zhang W et al. Pediatric Pulmonary 48. Wetli CV, Mittlemann RE. The Ôbody packer syndromeÕ –
and Cardiovascular Complications of Vertically Transmitted toxicity following ingestion of illicit drugs packaged for
HIV Infection (P2C2 HIV) Study Group. National Heart, transportation. J Forensic Sci 1981; 26: 492–500.
Lung, and Blood Institute, Bethesda, MD. Maternal and 49. Wetli CV, Rao A, Rao VJ. Fatal heroin body packing. Am J
infant factors associated with failure to thrive in children Forensic Med Pathol 1997; 18: 312–318.
with vertically transmitted human immunodeficiency virus-1 50. Merigian KS, Park LJ, Leeper KV, Browning RG, Giometi R.
infection: the prospective, P2C2 human immunodeficiency Adrenergic crisis from crack cocaine ingestion: report of five
virus multicenter study. Pediatrics 2001; 108(6): 1287–1296. cases. J Emerg Med 1994; 12: 507–514.
26. Cohen S. Cocaine: acute medical and psychiatric 51. Fishbain DA, Wetli CV. Cocaine intoxication, delirium and
complications. Psychiatr Ann 1984; 14: 747–749. death in a cocaine bodypacker. Ann Emerg Med 1981; 10:
27. Abelson HI, Miller JD. A decade of trends in cocaine use 531–532.
in the household population. Natl Inst Drug Abuse Res 52. Rump AFE, Theisohn M, Klaus W. The pathophysiology
Monogr Ser 1985; 61: 35–49. of cocaine cardiotoxicity. Forensic Sci Int 1995; 71: 103–115.
28. Cami J, Farre M, Gonzalez ML, Segura J, de la Torre R. 53. Fernandez MS, Pichard AD, Marchant E, Lindsay Jr J.
Cocaine metabolism in humans after use of alcohol. Acute myocardial infarction with normal coronary arteries:
Clinical and research implications. Recent Dev Alcohol in vivo demonstration of coronary thrombosis during the
1998; 14: 437–455. acute episode. Clin Cardiol 1983; 6: 553–559.
29. Wilson LD, Henning RJ, Suttheimer C, Lavins E, Balraj E, 54. Goldfrank LR, Hoffman RS. The cardiovascular effects of
Earl S. Cocaethylene causes dose dependant reductions in cocaine. Ann Emerg Med 1991; 20: 165–175.
cardiac function in anaesthetised dogs. J Cardiovasc 55. Knuepfer MM, Branch CA. Cardiovascular responses to
Pharmacol 1995; 26: 965–973. cocaine are initially mediated by the central nervous system
30. Wu TC, Tashkin DP, Djahed B et al. Pulmonary hazards in rats. J Pharmacol Exp Ther 1992; 263: 734–741.
of smoking marijuana as compared with tobacco. NEJM 56. Fischman MW et al. Cardiovascular and subjective effects
1988; 318: 347. of intravenous cocaine administration in humans. Arch Gen
31. Jansen K. Adverse psychological effects associated with use Psychiatry 1976; 33: 983–989.
of ecstasy (MDMA) and their treatment. In: Saunders N (ed.) 57. Howard RE, Hueter DC, Davis GJ. Acute myocardial
Ecstasy reconsidered. London: Nicholas Saunders, 1997. infarction following cocaine abuse in a young woman with
32. Coccaro EF, Siever LJ, Klar HM. Serotonergic studies in normal coronary arteries. JAMA 1985; 254: 95–96.
patients with affective and personality disorders: correlates 58. Cregler LL, Mark H. Relation of acute myocardial
with suicidal and impulsive behaviour. Arch Gen Psychiatry infarction to cocaine abuse. Am J Cardiol 1985; 56: 794.
1989; 46: 587–599. 59. Lange RA et al. Cocaine induced coronary artery
33. Carmen del Rio M, Alvarez FJ. Presence of illegal drugs vasoconstriction. NEJM 1989; 321: 1557–1562.
in drivers involved in fatal road traffic accidents in Spain. 60. Jaffe BD, Broderick TM, Leier CV. Cocaine induced
Drug Alc Dep 2000; 57(3): 177–182. coronary artery dissection. NEJM 1994; 330: 510–511.
34. Farre M, de la Torre R, Llorente M, Lamas X, Ugena B, 61. Kales SN et al. Carboxyhaemoglobin levels in patients
Segura J, Cami J. Alcohol and cocaine interactions in with cocaine related chest pain. Chest 1994; 106: 147–150.
humans. J Pharmacol Exp Ther 1993; 266(3): 1364–1373. 62. Moliterno DJ et al. Coronary artery vasoconstriction
35. Dagget RB, Haghighi P, Terkeltaub RA. Nasal cocaine induced by cocaine, cigarette smoking, or both. NEJM
abuse causing an aggressive midline intranasal and pharyngeal 1994; 330: 454–459.
The pathophysiology of cocaine abuse 37

63. Kugelmass AD, Oda A, Monahan K, Cabral C, Ware AJ. after surgery and review of the literature. Eur Heart J 1985;
Activation of human platelets by cocaine. Circulation 1993; 6: 539–544.
88: 876–883. 89. Zhiang L, Xiao Y, He J. Cocaine and apoptosis in myocardial
64. Rezkalla S, Mazza JJ, Kloner RA, Tillema V, Chang SH. cells. Anat Rec 1999; 257(6): 208–216.
The effect of cocaine on human platelets. Am J Cardiol 90. Henzlova MJ, Smith SH, Prachal VM, Helmcke FR.
1993; 72: 243–246. Apparent reversibility of cocaine induced congestive
65. Rinder HM, Ault K, Jatlow PI, Kosten TR, Smith BR. cardiomyopathy. Am Heart J 1991; 122: 577–579.
Platelet alpha granule release in cocaine users. Circulation 91. Virmani R, Robinowitz M, Smialek JE, Smyth DF.
1994; 90: 1162–1167. Cardiovascular effects of cocaine: an autopsy study of40
66. Molliterno DJ et al. Influence of intranasal cocaine on plasma patients. Am Heart J 1988; 115: 1068–1076.
constituents associated with endogenous thrombosis and 92. Barth III CW, Bray M, Roberts WC. Rupture of the
thrombolysis. Am J Med 1994; 96: 492–496. ascending aorta during cocaine intoxication. Am J Cardiol
67. Isner JM et al. Acute cardiac events temporally related to 1986; 57: 496.
cocaine abuse. NEJM 1986; 315(23): 1438–1443. 93. Rubin RB, Neugarten J. Cocaine-associated asthma.
68. Flores ED, Lange RA, Cigarroa RG, Hills LD. Effect of Am J Med 1990; 88: 438–439.
cocaine on coronary artery dimensions in atherosclerotic 94. Patel RC, Dutta D, Schonfeld SA. Free-base cocaine use
coronary artery disease: enhanced vasoconstriction at sites associated with bronchiolitis obliterans organizing
of significant stenosis. J Am Coll Cardiol 1990; 16: 74–79. pneumonia. Ann Intern Med 1987; 107: 186–187.
69. Zimmerman FH, Gustafson GM, Kemp Jr HG. Recurrent 95. Godwin JE, Harley RA, Miller KS, Hefner JE. Cocaine,
myocardial infarction associated with cocaine abuse in a pulmonary haemorrhage and haemoptysis. Ann Intern Med
young man with normal coronary arteries: evidence for 1989; 110: 843–844.
coronary artery spasm culminating in thrombosis. J Am Coll 96. Baldwin GC, Choi R, Roth MD, Shay AH, Kleerup EC,
Cardiol 1987; 9: 964–968. Simmons MS, Tashkin DP. Evidence of chronic damage to
70. Simpson RW, Edwards WD. Pathogenesis of cocaine induced the pulmonary microcirculation in habitual users of alkaloidal
ischaemic heart disease: autopsy findings in a 21 year old man. (‘‘crack’’) cocaine. Chest 2002; 121: 1231–1238.
Arch Pathol Lab Med 1986; 110: 479–484. 97. Murray RJ, Smialek JE, Golle M, Albin RJ. Pulmonary artery
71. Dressler FA, Malekzadeh S, Roberts WC. Quantitative medial hypertrophy in cocaine user without foreign particle
analysis of amounts of coronary artery narrowing in cocaine microembolisation. Chest 1989; 96: 1050–1053.
addicts. Am J Cardiol 1990; 65: 303–308. 98. Kline JN, Hirasuna JD. Pulmonary edema after freebase
72. Hollander JE et al. Prospective multicenter evaluation of cocaine smoking – not due to an adulterant. Chest 1990; 97:
cocaine associated chest pain. Acad Emerg Med 1994; 1: 1009–1010.
330–339. 99. Kibayashi K, Mastri AR, Hirsch CS. Cocaine induced
73. Hollander JE. Cocaine associated myocardial infarction. intracerebral hemorrhage: analysis of predisposing factors and
JRSM 1996; 89: 443–447. mechanisms causing hemorrhagic strokes. Hum Pathol 1995;
74. Spivey WH et al. Comparison of labetalol, diazepam and 26: 659–663.
haloperidol for the treatment of cocaine toxicity in a swine 100. Herning RI, Better W, Nelson R, Gorelick D, Cadet JL. The
model. Ann Emerg Med 1990; 19: 467–468. regulation of cerebral blood flow during intravenous cocaine
75. Hollander JE et al. Cocaine associated myocardial infarction. administration in cocaine abusers. Ann NY Acad Sci 1999;
Mortality and complications. Arch Intern Med 1995; 155: 890: 489–494.
1081–1086. 101. Lichtenfeld PJ, Rubin DB, Feldman RS. Subaracnoid
76. Hollander JE. The management of cocaine associated haemorrhage precipitated by cocaine snorting. Arch Neurol
myocardial ischaemia. NEJM 1995; 333(19): 1267–1272. 1984; 41: 223–224.
77. Erhardt L, Herlitz J, Bossaert L et al. Task Force on the 102. Green RM, Kelly KM, Gabrielsen T, Levine SR, Vanderzant
management of chest pain. Eur Heart J 2002; 23: C. Multiple intracerebral haemorrhages after smoking
1153–1176. ÔcrackÕcocaine. Stroke 1990; 21: 957–962.
78. Guinn MM, Bedford JA, Wilson MC. Antagonism of 103. Levine SR et al. A comparative study of the cerebrovascular
intravenous cocaine lethality in nonhuman primates. Clin complications of cocaine: alkaloidal versus hydrochloride.
Toxicol 1980; 16: 499–508. Neurology 1991; 141: 1173–1177.
79. McLaurin MD, Henry TD, Apple FS, Sharkey SW. 104. Konzen JP, Levine SR, Gracia JH. Vasospasm and thrombus
Cardiac troponin I, T and CK-MB in patients with cocaine formation as possible mechanisms of stroke related to
related chest pain. Circulation 1994; 90: I278, abstract. alkaloidal cocaine. Stroke 1995; 26: 1114–1118.
80. Castro VJ, Nacht R. Cocaine-induced bradyarrhythmia: an 105. Petty GW, Brust JC, Tatemichi TK, Barr ML. Embolic
unsuspected cause of syncope. Chest 2000; 117: 275–277. stroke after smoking ÔcrackÕ cocaine. Stroke 1990; 21:
81. Nanji AA, Filipenko JD. Asystole and ventricular 957–962.
fibrillation associated with cocaine intoxication. Chest 1984; 106. Fredericks RK, Lefkowitz DS, Challa VR, Troost BT.
85: 132–133. Cerebral vasculitis associated with cocaine abuse.
82. Karch SB. Cardiac arrest in cocaine users. Am J Emerg Med Stroke 1991; 22: 1437–1439.
1996; 14(1): 79–81. 107. Merkel PA, Koroshetz WJ, Irizarry MC, Cudkowicz ME.
83. Przywara DA, Dambach GE. Direct action of cocaine on Cocaine associated cerebral vasculitis. Sem Arth Rheum
cardiac cellular electrical activity. Circ Res 1989; 65: 185–192. 1995; 25(3): 172–183.
84. Ferreira S, Crumb Jr WJ, Carlton CG, Clarkson CW. Effects 108. Konkol RJ, Erickson BA, Doerr JK, Hoffman RG, Madden
of cocaine and its major metabolites on the HERG-encoded JA. Seizures induced by the cocaine metabolite
potassium channel. J Pharmacol Exp Ther 2001; 299: 220–226. benzoylecgonine in rats. Epilepsia 1992; 33: 420–427.
85. OÕLeary ME. Inhibition of human ether-a-go-go potassium 109. Dhuna A, Pascual Leone A, Langendorf F, Anderson DC.
channels by cocaine. Mol Pharmacol 2001; 59: 269–277. Epileptogenic properties of cocaine in humans.
86. Tazelaar HD, Karch SB, Stephens BG, Billingham ME. Neurotoxicology 1991; 12: 621–626.
Cocaine and the heart. Hum Pathol 1987; 18: 195–199. 110. Pascual Leone A, Dhuna A, Langendorf F. Suggestion of
87. Chakko S et al. Cardiac manifestations of cocaine abuse: a kindling with habitual cocaine abuse. Epilepsia 1990; 31:
cross sectional study of asymptomatic men with a history of 662.
long term abuse of ÔcrackÕ cocaine. J Am Coll Cardiol 1992; 111. Holland RW, Marx JA, Earnest MP, Ranniger S. Grand
29: 1168–1174. mal seizures temporally related to cocaine use: clinical
88. Stenstrom G, Holmberg S. Cardiomyopathy in and diagnostic features. Ann Emerg Med 1992; 21:
phaeochromocytoma: report of a case with a 16 year follow up 772–776.
38 Journal of Clinical Forensic Medicine

112. Staley JK, Hearn WL, Ruttenber JA, Wetli CV, Mash DC. 138. White SM. The effect of controlled drugs on the unborn
High affinity cocaine recognition sites on the dopamine child and foetus. J Clin Forensic Med 2001; 8: 1–11.
transporter are elevated in fatal cocaine overdose victims. 139. Zuckerman B, Frank DA, Hingson R et al. Effects of
J Pharmacol Exp Ther 1994; 271: 1678–1685. maternal marijuana and cocaine use on foetal growth.
113. Cardoso FE, Jankovic J. Cocaine related movement disorders. NEJM 1989; 320: 762.
Mov Disord Soc 1993; 8: 175–178. 140. Church MW. Prenatal cocaine exposure in the Long Evans
114. Mash DC, Ouyang Q, Pablo J, Izenwasser S, Jo E, Basile rat. Dose dependant effects on gestation, mortality and
MJ, Druid H. Cocaine abusers have an overexpression of postnatal maturation. Neurotoxicol Teratol 1990; 12:
alpha-synuclein in dopamine neurons: neuroplasticity or 327–334.
pathway to ParkinsonÕs disease. Unreported. Abstract 141. Keith LG, MacGregor S, Fridell S et al. Substance abuse
presented to 2001 Society for Neuroscience meeting. in pregnant women: recent experience at the perinatal center
115. Prakash A, Das G. Cocaine and the nervous system. Int J Clin for chemical dependence of Northwestern Memorial Hospital.
Pharmacol Ther Toxicol 1993; 31: 575–581. Obstet Gynaecol 1989; 73: 715.
116. Lago JA, Kosten TR. Stimulant withdrawal. Addiction 142. Ness RN et al. Cocaine and tobacco use and the risk of
1994; 89: 1477–1481. spontaneous abortion. NEJM 1999; 340: 333–340.
117. Siegel RK. Cocaine and sexual dysfunction: the curse of 143. Mills JL. Cocaine, smoking and spontaneous abortion.
mama coca. J Psychoactive Drugs 1982; 14: 71–74. NEJM 1999; 340: 380–381.
118. Harris D, Batki SL. Stimulant psychosis: symptom profile and 144. Woods Jr JR, Plessinger MA, Clark KE. Effect of cocaine
acute clinical course. Am J Add 2000; 9: 28–37. use on uterine blood flow and foetal oxygenation. JAMA
119. Brady KT, Lydiard RB, Malcolm R, Ballenger JC. 1987; 257: 957–961.
Cocaine-induced psychosis. J Clin Psych 1991; 52: 509–512. 145. Slutsker R. Risks associated with cocaine use during
120. Ellison G. Stimulant-induced psychosis, the dopamine theory pregnancy. Obstet Gynaecol 1992; 79: 778–789.
of schizophrenia, and the habenula. Brain Res – Brain Res 146. Chasnoff IJ, Chisum GM, Kaplan WE. Maternal cocaine use
Rev 1994; 19: 223–239. and genitourinary malformations. Teratology 1988; 37: 201.
121. McDowell DM, Levin FR, Seracini AM. Venlafaxine 147. Hadeed AJ, Siegel SR. Maternal cocaine use during
treatment of cocaine abusers with depressive disorders. pregnancy: effect on the newborn infant. Pediatrics 1989;
Am J Drug Alcohol Abuse 2000; 26: 25–31. 84: 205.
122. Roy A. Characteristics of cocaine-dependent patients who 148. Bateman DA, Chiriboga CA. Dose–response effect of
attempt suicide. Am J Psych 2001; 158: 1215–1219. cocaine on newborn head circumference. Pediatrics 2000;
123. Compton III WM, Cottler LB, Abdallah AB, Phelps DL, 106(3): E33;
Spitznagel EL, Horton JC. Substance dependence and other Bingol M, Fuchs M, Diaz V et al. Teratogenicity of cocaine
psychiatric disorders among drug dependent subjects: race in humans. J Pediatr 1987; 110: 93.
and gender correlates. Am J Add 2000; 9: 113–125. 149. Chasnoff IJ, Griffith DR, MacGregor S et al. Temporal
124. Weddington WW, Brown BS, Haertzen CA, Cone EJ, Dax patterns of cocaine use in pregnancy. JAMA 1989; 261: 1741.
EM, Herning RI, Michaelson BS. Changes in mood, craving, 150. Weathers WT. Cocaine use in women from a defined
and sleep during short-term abstinence reported by male population: prevalence at delivery and effects on growth in
cocaine addicts. A controlled, residential study. Arch Gen infants. Pediatrics 1993; 91: 350–354.
Psych 1990; 47: 861–868. 151. LeBlanc PE, Parekh AJ, Naso B et al. Effects of intrauterine
125. Kristensen P, Judge ME, Thim L et al. Hypothalamic exposure to alkaloidal cocaine (‘‘crack’’). Am J Dis Child
CART is a new anorectic peptide regulated by leptin. 1987; 141: 937.
Nature 1998; 393: 72–76. 152. Pastrakuljic A, Derewlany LO, Koren G. Maternal
126. Van Thiel DH, Perper JA. Gastrointestinal complications cocaine use and cigarette smoking in pregnancy in relation
of cocaine abuse. Rec Dev Alcoholism 1992; 10: 331–334. to amino acid transport and fetal growth. Placenta 1999;
127. Nalbandian H, Sheth N, Dietrich R, Georgiou J. Intestinal 20(7): 499–512.
ischaemia caused by cocaine ingestion: report of two cases. 153. Lutiger B et al. Relationship between gestational cocaine
Surgery 1985; 97: 371–376. use and pregnancy outcome: a meta-analysis. Teratology
128. Sarper R, Faraj BA, Tarcan YA, Chandora DB, Lenton JD. 1991; 44: 405–414.
Assessment of splanchnic blood flow in alcohol and drug 154. Acker DB, Sachs BP, Tracey KJ et al. Abruptio placentae
abuse using radionuclide angiography. J Subst Abuse 1993; associated with cocaine use. Am J Obstet Gynaecol 1983;
5: 295–303. 146: 220.
129. Miller JS, Hendren SK, Liscum KR. Giant gastric ulcer in a 155. Ryan L, Ehrlich S, Finnegan L. Cocaine abuse in
body packer. J Traum Injury Infect Crit Care 1998; 45(3): pregnancy: effects on the fetus and newborn. Neurotioxicol
617–619. Teratol 1987; 9: 295.
130. Abramson DL, Gertler JP, Lewis T, Kral JG. Crack related 156. Oro AS, Dixon SD. Perinatal cocaine and
perforated gastropyloric ulcer. J Clin Gastroenterol 1991; 13: methamphetamine exposure: maternal and neonatal
17–19. correlates. J Pediat 1987; 111: 5471.
131. Brown DN, Rosenholtz MJ, Marshall JB. Ischaemic colitis 157. Chasnoff IJ, Hunt CE, Kletter R et al. Prenatal cocaine
related to cocaine abuse. Am J Gastroenterol 1994; 89: 1558– exposure is associated with respiratory pattern
1561. abnormalities. Am J Dis Child 1989; 143: 583.
132. Van Thiel DH, Perper JA. Hepatotoxicity associated with 158. Fares I, McCulloch KM, Raju TN. Intrauterine cocaine
cocaine abuse. Rec Dev Alcohol 1992; 10: 331–334. exposure and the risk for sudden infant death syndrome: a
133. Mallat A, Dhumeaux D. Cocaine and the liver. J Hepatol meta-analysis. J Perinatol 1997; 17: 179–182.
1991; 12(3): 275–278. 159. Chiriboga CA. Neurological correlates of fetal cocaine
134. Sharff JA. Renal infarction associated with intravenous exposure. Ann NY Acad Sci 1998; 846: 109–125.
cocaine use. Ann Emerg Med 1984; 13: 1145–1147. 160. Potter SM, Zelazo PR, Stack DM, Papageorgiou AN.
135. Mattana J, Gibbons N, Singhal PC. Cocaine interacts with Adverse effects of fetal cocaine exposure on neonatal auditory
macrophages to modulate mesangial cell proliferation. information processing. Pediatrics 2000; 105(3): E40.
J Pharmacol Exp Ther 1994; 271: 311–318. 161. Datta-Bhutada S, Johnson HL, Rosen TS. Intrauterine
136. Roth D, Alarcon FJ, Fernandez J, Preston RA, Bourgoignie cocaine and crack exposure: neonatal outcome. J Perinatol
JJ. Acute rhabdomyolysis associated with acute cocaine 1998; 18(3): 183–188.
intoxication. NEJM 1988; 319: 673–677. 162. Singer LT, Arendt R, Minnes S, Farkas K, Salvator A.
137. Pogue VA, Nurse HM. Cocaine associated acute myoglobinuric Neurobehavioral outcomes of cocaine-exposed infants.
renal failure. Am J Med 1989; 86: 183–186. Neurotoxicol Teratol 2000; 22(5): 653–666.
The pathophysiology of cocaine abuse 39

163. Andrews K, Francis DJ, Riese ML. Prenatal cocaine exposure 171. Chan TC, Vilke GM, Neuman T, Clausen JL. Restraint
and prematurity: neurodevelopmental growth. J Dev Behav position and positional asphyxia. Ann Emerg Med 1997; 30:
Pediatr 2000; 21(4): 262–270. 578–586.
164. Keller Jr RW, Snyder-Keller A. Prenatal cocaine exposure. 172. OÕHalloran RL, Lewman LV. Restraint asphyxiation in excited
Ann NY Acad Sci 2000; 909: 217–232. delirium. Am J Forensic Med Pathol 1993; 14: 289–295.
165. Wetli CV, Mash D, Karch SB. Cocaine associated agitated 173. Chan TC, Vilke GM, Neuman T. Reexamination of custody
delirium and the neuroleptic malignancy syndrome. restraint position and positional asphyxia. Am J Forensic
Am J Emerg Med 1996; 14: 425–428. Med Pathol 1998; 19: 201–205.
166. Ross DL. Factors associated with excited delirium deaths in 174. Ruttenber AJ, McAnally HB, Wetli CV. Cocaine associated
police custody. Modern Pathology 1998; 11: 1127–1137. rhabdomyolysis and excited delirium: different stages of the
167. Wetli CV, Fishbain DA. Cocaine induced psychosis and same syndrome. Am J Forensic Med Pathol 1999; 20:
sudden death in recreational cocaine users. J Forensic Sci 120–127.
1985; 30: 873–880. 175. Wetli CV, Mash D, Karch SB. Cocaine associated agitated
168. Staley JK, Rothman RB, Rice KC, Partilla J, Mash DC. delirium and the neuroleptic malignancy syndrome. Am J
Kappa2 opioid receptors in limbic areas of the human brain Emerg Med 1996; 14: 425–428.
are upregulated by cocaine in fatal overdose victims. J 176. Ruttenber AJ, Lawler-Heavner J, Yin M, Wetli CV, Hearn
Neurosci 1997; 17: 8225–8233. WL, Mash DC. Fatal excited delirium following cocaine
169. Pollanen MS, Chiasson DA, Cairns JT, Young JG. use: epidemiologic findings provide new evidence for
Unexpected death related to restraint for excited delirium: a mechanisms of cocaine toxicity. J Forensic Sci 1997; 42:
retrospective study of deaths in police custody and in the 25–31.
community. CMAJ 1998; 158: 1603–1607. 177. Davis N. Death in custody. JRSM 1999; 92: 611.
170. Reay DT. Positional asphyxia during law enforcement 178. Police Complaints Authority. Annual report. London: PCA,
transport. Am J Forensic Med Pathol 1993; 14: 170–171. 1999.