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

27
28 Journal of Clinical Forensic Medicine
produces the white crystals or powder that are the
commonest presentation of the abused drug. The
powder is slightly bitter and numbs the oral mucosa.
Cocaine hydrochloride is most commonly taken by
ÔsnortingÕ it nasally, but intravenous, oral and rectal
routes may be used. A ÔlineÕ of cocaine contains
roughly 50 mg of cocaine hydrochloride. ÔFree base,Õ
the natural cocaine alkaloid, is water insoluble,
colourless, and tasteless. It vaporises above 100 °C,
but remains chemically stable and is therefore
abused by inhalation. Purer cocaine can be extracted
from cocaine hydrochloride by dissolution in an
alkaline solution, followed by the addition of a
solvent such as ether. The mixture separates into
two layers, the uppermost containing cocaine, which
can be extracted by evaporating the solvent, pro-
ducing Ôfree base.Õ To avoid the inflammability and
burns associated with ether extraction, cocaine re-
finery from cocaine hydrochloride commonly em-
ploys the method of dissolution in water made
alkaline by the addition of baking soda. The cocaine
base precipitates, and hardens after drying, pro-
ducing a Ôrock,Õ which is broken up into crystals.
When heated, the crystals make a popping sound,
and this pure form of cocaine is therefore termed
Ôcrack cocaine.Õ Crack is now the most prevalent
form of the drug abused. It is smoked, producing a
more rapid and intense high than cocaine hydro-
chloride (i.e., within one lung–brain circulation time
of 6–8 s), but the associated euphoria is short-lived
(generally less than 15 min, compared to up to
60 min for intranasally administered cocaine hydro-
chloride).3 The psychophysiological effects of smok-
ing crack are similar to those of intravenous
injection.4 It appears to be more addictive, and the
incidence of its abuse is increasing.5
After administration, cocaine is rapidly redis-
tributed from the plasma, reaching high concentra-
tion in vessel-rich body compartments (e.g., brain).
Redistribution to vessel-poor compartments (e.g.,
fat) occurs with time. 5% of cocaine is excreted
unchanged in the urine (detectable 3–6 h after use).
Eight five percent is metabolised by plasma and li-
ver esterases to produce ecgonine methyl esters and
benzoylecgonine (which also forms spontaneously3 ),
which are detectable in urine for up to 14 days after
consumption.6 Plasma pseudocholinesterase displays
genetic polymorphism,7 and a small proportion of
the population esterify cocaine slowly, which may
result in prolonged euphoria and increased inci-
dence of cocaine-related pathology.8 Likewise,
plasma cholinesterase activity is reduced in infants,
pregnancy and old age.9 Tissue cocaine concentra-
tion, when measured at post mortem, can be unre-
liable, depending on the time since ingestion, the
time to analysis, the temperature at the scene of
death and the temperature at which the corpse was
stored.10
Both the minimum toxic dose and lethal dose of
cocaine are uncertain.11 Most cocaine-related deaths
occur in those who abuse cocaine in high doses over a
long period of time. Isolated blood measurements do
not equate to toxicity, and no particular plasma
concentration of cocaine can be guaranteed to be
safe.12;13
The pharmacodynamic properties of cocaine are
complex. Local anaesthesia is achieved through
competitive inhibition of fast sodium channels in
neurones, thus ablating saltatory nerve conduction in
peripheral nerves. Both the rate and amplitude of the
sino-atrial pacemaker potential are reduced. Depo-
larisation throughout the conducting system of the
heart is interrupted. Ventricular standstill can occur
in massive overdose.14
Cocaine inhibits presynaptic norepinephrine and
dopamine reuptake, and inhibits the action of
monoamine oxidase (which catabolises epinephrine,
norepinephrine, and dopamine) at synapses. As a
consequence, intrasynaptic norepinephrine concen-
tration remains high after nerve depolarisation.
This results in prolonged activation of the sympa-
thetic nervous system, which causes vasoconstric-
tion, cardiac inochronotropism, hypertension,
cardiac dysrhythmias, hyperglycaemia, hyperther-
mia, and mydriasis. In addition, cocaine effects in-
creased release of epinephrine from the adrenal
medulla.
Cocaine abuse increases excitatory neurotrans-
mitter levels in the brain, which produces euphoria in
the short term and addiction in the long term, but
may also lead to the development of seizures. In
overdose, cocaine acts as an antimuscarinic drug,
inhibiting gastric motility and increasing the likeli-
hood of gastric ulceration and perforation.
The pathology associated with cocaine abuse can
be subdivided into four groups: pathology associated
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.
PATHOLOGY ASSOCIATED WITH A DRUG
ABUSING LIFESTYLE
Throughout the 1970s and 1980s, cocaine was an
expensive drug to abuse. Its use tended to be limited
to young urban males, earning higher than average
wages from a stressful job. The emergence of crack

cocaine in America in the late 1980s, together with
improved cocaine refinery, global marketing, excess
production and the widespread, persistent belief that
cocaine is a benign and non-addictive drug, led to
both a rapid fall in the street price and a marked rise
in consumption. In relation to earnings, the price of
cocaine fell 75% over the 15 years before 1996.15
Nevertheless, the average street price of cocaine in the
UK remains at £30 per gram ($45).16 With a purity of
between 25% and 90%,17 and an average weekly in-
take of 3 g in recreational users (5–10 g in chronic,
heavy users),16;18 cocaine abuse remains an expensive
habit. The addictive nature of cocaine means that
users must find a way of funding their habit. In
practice, this can result in criminal activity. Both
sexes may resort to violence, theft, and prostitution.
Homicide, often committed by the traffickers of
drugs, accounts for 20% of deaths in individuals
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-
lihood and virulence of HIV infection, though this
has not yet been proven in prospective clinical stud-
ies.20–23
Cocaine, in common with other stimulants, sup-
presses appetite, and users may buy drugs rather than
food. Therefore diet can often be poor, which tends
to compound the other pathology associated with
cocaine.24 Similarly, the children of drug abusers may
be undernourished and at risk of illness.25 Without a
regular income (unemployment is more common
among drug abusers26 ), a downward spiral of poverty
can ensue, resulting in imprisonment and poor per-
sonal and social welfare.
Cocaine is rarely abused in isolation. Polydrug
abuse is common, thereby exposing the user to the
pathologies associated with both cocaine and the
other drugs abused. Marijuana may be used to
ameliorate the psychophysiological effects of Ôcoming
downÕ after a dose of cocaine.27 Contemporaneous
alcohol use is widespread, because alcohol prolongs
the euphoria of cocaine. In the presence of alcohol,
hepatic transesterification of cocaine occurs, forming
cocaethylene, which is a pharmacologically active
agent28 with a half life of 150 min (compared to the
30–90 min of cocaine).29 Cigarette smoking, associ-
ated with enabling marijuana consumption, is pre-
valent and deeper inhalation of smoke may occur,
particularly amongst those who abuse cannabis or
crack cocaine by inhalation (a reinforced learning
behaviour that maximises the uptake and onset of
these drugs). Carcinogen exposure through smoking
marijuana is further increased, as the smoke is
seldom filtered and users tend to breath hold after
inhalation.30
The pathophysiology of cocaine abuse 29
PATHOLOGY OCCURRING WHILST
INTOXICATED
Cocaine is not hallucinogenic like lysergide, mesca-
line, or phencyclidine,31 but accidental death or injury
can happen during intoxication. Dysfunction of ce-
rebral serotonergic neurotransmission occurs shortly
after minimal cocaine ingestion, which can lead to
impulsive, aggressive behaviour, suicidal tendency
and acute psychosis (although psychosis is rare).32
Suicide is the cause of death in up to 10% of cocaine-
related deaths.19 The neuropsychiatric effects of co-
caine may also have an effect on co-ordination and
perception, resulting in an excess, for example, of
road traffic accidents amongst the acutely intoxi-
cated33 (although cocaine ingestion has been found to
improve alcohol-related changes in psychomotor
performance34 ).
PATHOLOGY ASSOCIATED WITH METHOD
OF ADMINISTRATION
Intranasal insufflation of cocaine remains the com-
monest method of self-administration, at least in the
UK. However, cocaine-mediated vasoconstriction
can lead to ischaemic necrosis of nasal cartilages,
with nasal septal perforation being the result of long
term usage. Oropharyngeal ulceration can occur by
the same mechanism.35 Mucosal vasoconstriction is
followed by rebound hyperaemia, which can be
worsened by chemical irritation due to adulterants.36
Symptomatically this produces a blocked nose, with
persistent rhinitis and rhinorrhea.37 Anosmia may be
experienced.
Inhalation of crack and free base cocaine also has
significant associated pathology. The anaesthetic ef-
fects of cocaine on the oropharyngeal mucosa can
result in prolonged exposure to hot cocaine vapours,
causing acute inflammation and necrosis, epiglottitis,
laryngotracheobronchitis,37 and laryngospasm. Sin-
ged eyebrows and eyelashes,38 carbonaceous sputum,
wheezing, hoarseness, and stridor may be observed
after thermal injury. Volatile ether, used in free base
extraction, can lead to severe burns of the upper
airway. Carbonaceous impurities from materials used
to vaporise cocaine may lead to pulmonary granu-
lomata or a pneumoconiosis like reaction.39 Deep,
prolonged inspiration is used to maximise cocaine
uptake into the bloodstream. This is further increased
if a Valsalva manoeuvre is employed during expira-
tion. Both manoeuvres, by their resultant effect on
transpulmonary pressure gradients, can lead to alve-
olar rupture, producing pneumothorax and pneu-
momediastinum.40
30 Journal of Clinical Forensic Medicine
Intravenous cocaine abuse is less common, as
significant morbidity and mortality are associated
with the virtually instantaneous acquisition of maxi-
mum plasma cocaine levels.41 All the injected drug is
bioavailable, as are chemicals that adulterate the in-
jectate. Seizures, cardiac arrest, hypertensive crises,
and hyperthermia have been reported, particularly
amongst chronic users.42 Intravenous drug abuse is
generally associated with vasculitis,43 myocarditis,44
infective endocarditis, pulmonary and cerebral em-
bolism and infarction, and infection (hepatitis B and
C, cytomegalovirus, syphilis and HIV). Adulterants
can produce additional morbidity.45 Intravenous in-
jection of cocaine and heroin mixtures – ÔspeedballsÕ –
combine the effects of both drugs, and may be asso-
ciated with a higher risk of psychopathology.46
Inadvertent intraarterial injection of cocaine will in-
duce spasm in smaller arteries, which could lead to
limb threatening ischaemia and gangrene.47
ÔBodypackingÕ or Ôbodystuffing,Õ though not actual
methods of cocaine administration, can have fatal
consequences, similar to those occurring during in-
travenous overdose. ÔBodypackersÕ are used to ille-
gally transport drugs across national borders.
Quantities in excess of 500 g may be smuggled by
sealing cocaine in condoms or cellophane which are
swallowed, and recovered after transit through the
bowel.48;49 ÔBodystuffersÕ conceal evidence of drug
trafficking by swallowing wraps of drugs when facing
imminent arrest. From personal experience, one of
the authors (SMW) has had to remove 17 such wraps
(each weighing about 0.5 g) from the oropharynx of a
semi-comatose patient, to prevent airway obstruction
and acute overdose of cocaine. In both packers and
stuffers, accidental leakage of cocaine into the GI
tract (through the wall of the condom, or if condom
rupture occurs) leads to a large absorption of cocaine
into the circulation, particularly if the cocaine is rel-
atively pure. Cocaine-abusing bodypackers may be
able to tolerate a high blood cocaine concentration,
but non-abusers invariably suffer from agitation,
confusion and seizures and may progress malignant
cardiac dysrhythmias, hyperthermia, excited delirium
and death.48;50;51 Autopsy reveals pulmonary and ce-
rebral oedema. There may be idiosyncratic fatal
reactions to even small doses.
PATHOLOGY RESULTING FROM
PHARMACOLOGICAL ACTION OF THE DRUG
The pathology described in this section falls into two
broad categories: expected effects, which are pre-
dictable dose-related extensions of pharmacological
actions, and idiosyncratic effects, which are uncom-
mon, unrelated to dose and occur randomly in the
cocaine-abusing population. The pathology associ-
ated with both categories may be summarised by
describing the effects of cocaine on each physiological
system.
Cardiovascular system
Cardiac complications are the commonest cause of
death amongst cocaine users,16 and can occur after
acute or chronic abuse. Chest pain, myocardial is-
chaemia and infarction, cardiac dysrhythmias and
sudden death have been reported. Myocarditis and
aortic rupture may also occur, but rarely.52
Ischaemia and infarction usually occur in chronic
abusers, but infarction can occur after initial use of
cocaine.53 Cocaine (usually) has a positive inochro-
notropic action on the heart, through peripheral and
central stimulation of the sympathetic nervous sys-
tem,54 and increased adrenal medullary epinephrine
production.55 Heart rate, blood pressure, systemic
vascular resistance, and left ventricular rate-pressure
product56 are acutely increased, and myocardial ox-
ygen demand is increased in parallel.57 However,
myocardial oxygen delivery is reduced, due to raised
left ventricular end diastolic pressure, myocardial
arteriolar vasoconstriction, reduced coronary dia-
stolic filling time during tachycardia and cocaine-in-
duced coronary artery vasospasm.58;59 Myocardial
ischaemia results from the imbalance between oxygen
supply and demand. Q or non-Q wave infarcts may
ensue. Coronary artery dissection has been re-
ported.60 Spasm may be worsened by the coadmin-
istration of cigarette smoke (which elevate
carboxyhaemoglobin levels and increase blood vis-
cosity, which further reduces myocardial oxygen
supply).61;62
Infarction is made more likely by the prothrom-
botic effects of cocaine.63 Platelet aggregation and
activation are enhanced64;65 and fibrinolysis is de-
creased (by an increase in levels of endogenous tissue
plasminogen activator inhibitor).66
Underlying heart disease is not a prerequisite for
the development of cocaine-related ischaemia and
infarction,67 but its presence significantly increases
the likelihood of infarction and worsens the prog-
nosis after infarction. Coronary atherosclerosis re-
duces the arterial endothelial release of coronary
vasodilators (nitric oxide and prostacycline), en-
hancing coronary vasospasm at the site of athero-
sclerotic plaque.68 In addition, endothelial damage
may occur after coronary vasospasm, promoting
further atherosclerotic change, and thrombosis.69
Moreover, platelet activation releases smooth muscle
growth factors, which promote vascular hyperplasia

and coronary luminal occlusion.70 Indeed, cocaine
appears to be an independent accelerant of coronary
atherosclerosis.71
Cocaine-related chest pain annually accounts for
37,000 admissions to hospital in the United States.72
The pain is commonly described as sharp, stabbing or
pleuritic,73 and may represent ischaemia secondary to
coronary vasospasm. Chest pain is invariably present
prior to cocaine-related infarction. 6% with chest
pain proceed to infarction.74 4% die after infarc-
tion,75 4–12% develop life-threatening arrhythmias,
and congestive cardiac failure occurs in 5–7%.76
Electrocardiography is only sensitive for infarction in
a third of cases of cocaine-related chest pain73
(compared to 61% of non-cocaine-related chest
pain77 ), though abnormalities are seen in two thirds.78
CK and CK-MB levels may be raised in cocaine users
who have not had an infarct (due to increased motor
activity, seizures, hyperthermia, and rhabdomyoly-
sis). Troponin I levels may be more beneficial in di-
agnosing cocaine-related myocardial infarction.79
Cocaine ingestion may result in cardiac dysrhyth-
mia. Initial ingestion may be associated with brady-
cardia,80 although tachycardia is most common
Multifocal ventricular ectopics, ventricular tachycar-
dia, ventricular fibrillation and asystole81 occur with
increasing dose. Sudden death, accounting for the
majority of cocaine-related deaths, is most likely at-
tributable to a combination of dysrhythmia and
cardiomyopathy.82 Several mechanisms contribute to
cocaine induced dysrhythmia: myocardial ischaemia,
raised plasma catecholamine concentrations, cen-
trally upregulated sympathetic nervous system out-
flow, hyperpyrexia, metabolic acidosis and cardiac
myocyte membrane stabilisation by cocaine (by in-
terference with transmembranal Naþ and Ca2þ flux).
Intracardiac nerve impulses undergo slowed, hetero-
geneous depolarisations, with prolonged repolarisa-
tions.83 More recently, cocaine and cocaethylene have
been shown to effectively block HERG-related (Hu-
man ether-a-go-go-related gene) potassium channels,
thereby suppressing the delayed-rectifier potassium
current (I(K)) resulting in prolongation of cardiac
repolarisation.84;85 Reentrant dysrhythmias occur,
and may be promoted by the formation of myocar-
dial contraction bands, which are non-contracting,
disorganised, amorphous masses of cardiac myofi-
brils that are associated with prolonged, high intake
of cocaine (amongst other causes).86 Massive doses of
cocaine can result in ventricular standstill.
Left ventricular hypertrophy occurs in 54% of
cocaine abusers and regional wall motion abnor-
malities in 21%.87 Contractile dysfunction may occur
with prolonged, high dose abuse, secondary to the
effects of catecholamines,88 progressive myocytolysis,
The pathophysiology of cocaine abuse 31
and focal fibrosis (in response to recurrent episodes of
myocardial ischaemia and infarction) and myocardial
contraction band formation. In addition, cocaine
directly causes myocyte apoptosis (particularly dur-
ing episodes of oxidative stress).89 Poor contractile
function may be reversible by reducing (and main-
taining) circulating catecholamine levels to the nor-
mal range.90
Cocaine-related myocarditis may occur in a to
toxic, dose-dependent manner, secondary to a hy-
persensitivity (dose-independent) reaction. Toxic
myocarditis was found in 20% of cocaine abusers at
autopsy,91 and is manifest by small areas of myo-
cardial necrosis and loss of cardiac myofibrils. Co-
caine-related chest pain may be a symptom of
myocarditis.
Cocaine-related episodes of hypertension, in the
presence of atherosclerotic blood vessels, can result in
potentially fatal aortic dissection or rupture.92 This
usually involves the ascending aorta. Aortic root
dissection may impinge coronary artery blood flow,
leading to further myocardial infarction.
Respiratory system
The deleterious effects of cocaine on the upper airway
have been described above. Other respiratory com-
plications associated with the smoking of crack co-
caine include pneumonitis, pulmonary haemorrhage,
vascular lesions, and pulmonary oedema.
Cocaine is a direct irritant to the airways and a
persistent cough is common. Bronchial hyperreac-
tivity and hypersecretion are increased, and may be
potentiated by thermal airway injury. Severe bron-
chospasm may result.93 Cocaine may excite an anti-
genic response. Repeated exposure can lead to an
immunoglobulin-E mediated pnemonitis, character-
ised by fever, bronchospasm, dyspnoea, and cough.
Eosinophilia is apparent and diffuse alveolar and
interstitial infiltrates may be seen on chest radio-
graphs and in biopsy samples. Bronchiolitis obliter-
ans is similar to hypersensitivity pneumonitis (except
for the occurrence of eosinophilia) and produces
chronic inflammatory alveolar and interstitial infil-
trates.94
Haemoptysis occurs in 6–26% of cocaine users,95
and may be due to a combination of toxic vasculitis,
alveolar haemorrhage, thermal injury, and bronchial
and pulmonary arterial vasoconstriction, infarction,
and ischaemia.96
Recurrent episodes of pulmonary damage, to-
gether with cocaine-related bronchial smooth muscle
hypertrophy,97 may result in right heart failure. Pul-
monary oedema may occur secondary to left ven-
tricular failure, toxic pulmonary endothelial damage
32 Journal of Clinical Forensic Medicine
(with increased membrane permeability), high nega-
tive intrathoracic pressures (that occur during the act
of inhaling, or as a consequence of upper airways
obstruction) or a neurogenic cause (secondary to
cocaine-induced up-regulation of central sympathetic
nervous discharge).98
Central nervous system
The pathological effects of cocaine on the central
nervous system can be subdivided into three groups:
cerebrovascular effects, neurological effects, and
psychological effects.
Intracranial haemorrhage and cerebral infarction
have been widely reported to occur after cocaine
abuse. The rapid rise in blood pressure that occurs
shortly after administration, together with impaired
cerebral autoregulation,99;100 may precipitate sponta-
neous haemorrhage.101 Subarachnoid haemorrhage is
more common in the presence of preexisting cerebral
pathology, such as cerebral aneurysm or arteriove-
nous malformations. In 78% of cases of subarach-
noid haemorrhage secondary to cocaine abuse
underlying vascular anomalies are found.102 Intra-
nasal cocaine hydrochloride tends to produce haem-
orrhagic, rather than embolic, stroke (80%/20%);103
both types of stroke occur with similar frequency
after smoking ÔcrackÕ cocaine. Cerebral ischaemia
after a stroke may be worsened by cerebral vaso-
spasm104 (due to cocaine or intracerebral blood),
hypercoagulability and thrombosis,105 hyperpyrexia,
hyperglycaemia and an increased cerebral metabolic
rate (consequent to the neuroexcitatory effects of
cocaine); cerebral vasculitis has also been re-
ported.106;107 Reperfusion injury, with altered calcium
flux, may extend the area of cerebral damage occur-
ring after the initial insult.
Seizures usually occur in chronic abusers, but may
occur after the first intoxication. Seizure activity is
related to the peak plasma concentration of cocaine,
and usually occurs within minutes of dosage, al-
though it can occur up to 24 h after ingestion; one
study in rats suggested that delayed seizure activity is
related to the cocaine metabolite, benzoylecgonine,108
but this is yet to be demonstrated in humans. Gen-
eralised, self-terminating tonic-clonic seizures are
usual, but multiple seizures or status epilepticus can
occur,109 which can be lethal, particularly in associ-
ation with hyperpyrexia, cardiac dysrhythmia, and
cerebral haemorrhage. Cocaine reduces the seizure
threshold by chronic subthreshold stimulation of the
limbic system – the Ôkindling effectÕ (reverse toler-
ance).110 Intrasynaptic accumulation of excitatory
neurotransmitters occurs (notably serotonin), which
is thought to precipitate epileptiform activity. In
addition, hyperthermia, metabolic acidosis, cerebral
ischaemia, cerebral haemorrhage, and co-adminis-
tration of other epileptogens may lead to fitting.111
Centrally mediated hyperthermia results from
brainstem D1 dopamine receptor downregulation.112
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
sign of progression to excited delirium. Cocaine-
mediated changes in intrasynaptic dopamine con-
centrations also provide a causative mechanism for
the occurrence of movement disorders, such as cho-
reoathetosis and akathisia.113 Chronic abuse may
lead to alpha-synuclein overexpression levels in do-
pamine neurons, which induces dopamine nerve ter-
minal degeneration; in addition, alpha-synuclein is a
major component of Lewy bodies in ParkinsonÕs
disease (PD). We report here that from chronic co-
caine abusers. Chronic abuse may therefore place
aging cocaine addicts at risk for developing the motor
abnormalities of ParkinsonÕs disease.114
Elevated dopamine levels in the mesolimbic and
mesocortical areas of the brain give rise to intense
euphoria. Simultaneously, cocaine suppresses the
activity of the pontine nucleus and locus coeruleus,
producing anxiolysis.115 However, dopamine deple-
tion, caused by repetitive cocaine use, produces tol-
erance to the euphoric effects of cocaine, as well as
physiological cocaine addiction.116
Sexual dysfunction is common amongst cocaine
users. Low doses may delay ejaculation and orgasm,
and heighten sexual excitement, but prolonged high
doses may cause sexual disinterest, impotence, anor-
gasmia, compulsive masturbation and premature
ejaculation.117
Psychiatric illness may be the presenting manifes-
tation of cocaine abuse, or merely an observed side
effect. Acute or chronic psychosis,118;119 schizophre-
nia,120 depression,121 suicidal ideation,122 and obses-
sive–compulsive disorders123 have been reported. Sleep
disorders124 and decreased appetite125 are common.
Gastrointestinal system126
There are two case reports of bowel ischaemia after
cocaine ingestion,127 although formal studies have not
been performed in humans. (However, the portal ve-
nous fraction of total hepatic blood flow was found to
be abnormal in 100% of polydrug abusers in one
study.128 ) Gastric mucosal cells and duodenal villi
rapidly become ischaemic in response to reductions in
mesenteric blood flow, leading to gastritis and ulcera-
tion;129 this may theoretically be potentiated by co-
caine-mediated gastric hypomotility and delayed
gastric emptying (which prolongs mucosal exposure to

gastric acid).130 Mesenteric vasoconstriction can result
in ischaemia and acute inflammation or infarction
along the length of the bowel.131 Gangrenous perfo-
ration may be unrecognised for a hazardous length of
time, but should be considered in the presence of acute,
persistent abdominal pain and leukocytosis.
Acute and subacute hepatocellular necrosis, acute
and chronic hepatic failure, ischaemic and viral hep-
atitis, centrilobular necrosis, and hepatic haemor-
rhage have been reported.132;133
Renal system
Cocaine may directly damage the kidneys by causing
renal infarction (secondary to renal artery spasm,
atherosclerosis, and thrombosis)134 or focal segmental
glomerulosclerosis (by increasing mesangial cell pro-
liferation).135
More commonly, however, cocaine exerts a neph-
rotoxic effect by causing rhabdomyolysis. Rhabd-
omyolysis can occur by several mechanisms:136
skeletal muscular ischaemia secondary to prolonged
arterial vasoconstriction, hyperthermia, direct muscle
cell apoptosis, tissue trauma (whilst intoxicated), and
tonic-clonic seizures. Muscular pain and hyperkala-
emia occur. Myoglobin precipitates in renal tubules,
causing obstruction and inflammation, which is ag-
gravated by ischaemic renal tubular disease. Acute
renal failure may ensue.137
Effects on the mother, fetus, and neonate138
Studies in the USA have suggested cocaine abuse
rates of between 6.4% and 24.3% amongst pregnant
women in urban prenatal clinics.139 Figures are not
available for the UK.
Cocaine abuse appears to be an aetiological factor
for spontaneous abortion. In rats, exposure to co-
caine is associated with increased frequency of reab-
sorbtion of fetuses, equivalent to spontaneous
abortion in humans.140 Cocaine abusing mothers in
one study141 had 4 (2:3) pregnancies compared with
2.6 (1:6) pregnancies in non-addicted controls, but
only 1.3 (1:4) babies compared to 0.9 (1:1), having
had 1.8 (1:6) abortions, compared with 0.6 (1:1) in
the control group. A recent prospective study of co-
caine addicted mothers, analysing their habit by hair
and urine sample toxicology, showed a 50% increase
in the rate of spontaneous abortion.142 This was ap-
parently dose independent, suggesting that any level
of cocaine exposure is associated with spontaneous
abortion, though the authors point out that even the
careful design of their study was open to methodo-
logical problems. An editorial in the same edition of
the journal, however, draws the conclusion that any
The pathophysiology of cocaine abuse 33
link between cocaine and spontaneous abortion is
weak and inconsistent.143
Cocaine is a vasoconstrictor, which provides a
physiological reason for its adverse effects on the fe-
tus. In the placenta, increased vascular tone reduces
placental blood flow, producing fetal ischaemia.144
The fetus has developed physiological methods of
protection from ischaemic episodes, but these may be
insufficient during repeated exposures to cocaine.
Fetal death may occur during prolonged ischaemia,
which can occur during cocaine-induced maternal
dysrhythmia or seizure.145
Cocaine crosses the placenta to the fetus by diffu-
sion. There are reports of possible human teratoge-
nicity, including genitourinary tract abnormalities,146
ileal atresia,147 microcephaly,148 and neural tube de-
fects.149 Growth retardation involving length, weight,
and head circumference150 is more common.151 Co-
caine abuse (and cigarette smoking) during pregnancy
impairs transplacental amino acid transport, which
may impair fetal growth.152 Third trimester cocaine
exposure is associated with a statistically significant
increased risk of placental abruption within 30 min of
maternal cocaine abuse.151;153;154
30–50% of cocaine abusing mothers deliver pre-
maturely.155 Deliberate excessive abuse may occur to
induce labour (or abortion), or to escape the pain of
labour. Premature rupture of membranes occurs in
15–32%, chorioamnionitis in 10%.141
After birth, longer term effects of cocaine exposure
are apparent. Weight gain is delayed.156 There is an
increased incidence of sleep apnoea (responsive to
theophylline therapy)157 and sudden infant death
syndrome (5.2/1000 infants exposed to intrauterine
cocaine, odds ratio 3.9158 ). Abnormal sleep, tremor,
poor feeding, hypertension and vomiting may be
apparent.155
There is an increasing body of research to support
the existence of neurobehavioural morbidity in neo-
nates exposed to cocaine in utero.159 Studies have
suggested that fetal cocaine exposure is associated
with, amongst others, impaired auditory information
processing,160 inferior performance on the Neonatal
Behavioural Assessment Score (but higher Neonatal
Stress Scale scores),161 movement and tone abnor-
malities together with sensory asymmetries,162 jitter-
iness,163 and overreaction to environmental stimuli.164
Cocaine excited delirium
ÔExcited,Õ or Ôagitated,Õ delirium describes an idio-
syncratic cocaine-associated syndrome that involves a
rapid progression (over 2–4 h) of symptoms from
hyperthermia to delirium, cardiorespiratory arrest,
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.


creased abuse of cocaine. A similar condition is seen
amongst abusers of other drugs, schizophrenics and
patients taking neuroleptic medications. Malignant
hyperpyrexia and exercise-induced hyperthermia may
be associated diseases that have a common genetic
predisposition.
Excited delirium occurs in long term, high dose
stimulant abusers,167 rather than after acute over-
dose. Death may occur at home and be unattributed
to cocaine. The progression of symptoms may be self-
terminating, though the incidence of such an occur-
rence is unknown.
Initially hyperthermia occurs, due to brainstem
D1 -dopamine receptor downregulation. Core tem-
perature rises in excess of 40 °C. The individual feels
hot, sweats profusely and attempts to cool themselves
by removing their clothes and splashing themselves
with water.
Confusion, agitation, and frank psychosis follow,
which may occur in part due to the rapid rise in core
temperature, but may also be due to upregulation of
kappa-2 receptors in the amygdala.168 Police inter-
vention often occurs at this stage, as the individual
may be causing a public disturbance by shouting or
using threatening behaviour. Restraint169 is difficult
because the patient may show unexpected strength.
Chemical incapacitating agents fail to work. Until
recently, positional restraint techniques (Ôhog-tyingÕ)
were thought to aggravate the condition, asphyxia
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-
latory requirements were increased by violent strug-
gling (i.e., relative hypoventilation). However, a
recent review of the literature has challenged the va-
lidity of positional asphyxia as a contributory cause
in cocaine-related deaths in which restraint was an
issue.173
After a period of time the individual becomes sub-
dued and their strength diminishes, the reason for
which is unclear, but may be related to progressive
metabolic acidosis, hyperkalaemia and hyperthermia,
and their effects on skeletal muscular function. Re-
spiratory arrest and cardiac arrest follow shortly, often
whilst the individual is still restrained, or during
transport.
Death is not inevitable,174 but survival requires
prompt recognition and treatment (removal of re-
straints, hospitalisation, cooling, dantrolene, fluids,
sedation, ventilation, and intensive care may all be
beneficial). Survivors of initial resuscitation are at
high risk of death from multiple organ failure.175;176
At autopsy, pulmonary oedema, and myocardial
abnormalities (ventricular hypertrophy and fibrosis)
may be seen. Blood cocaine concentrations are
The pathophysiology of cocaine abuse 35
moderate or low, but blood benzoylecgonine con-
centration may be high,175 indicating long-term co-
caine abuse. Evidence of excessive restraint and the
stigmata of drug abuse may also be manifest.
Death from excited delirium has occurred after
police intervention, giving rise to allegations of police
brutality.177 In addition, ethnic minorities are an
over-represented amongst the deceased.178 In 1998–
1999, 65 people died in custody, in the UK. 9% were
black. In the same period, there were five deaths
where restraint was an issue – 2 of the deceased were
black. Such a statistic may not represent either an
increased rate of stimulant abuse amongst the black
population or racist brutality by the police. The
possibility of genetic predisposition to the develop-
ment of excited delirium requires investigation. Death
rates in custody that recently reported have now
halved in number.
Cocaine-related death can occur after acute or
chronic abuse, though mortality after acute use is
most commonly associated with massive overdose.
Chronic use causes central and peripheral neuro-
chemical changes that result in hypertension-related
morbidity and mortality, including myocardial in-
farction and cerebrovascular accidents. The inci-
dence of cocaine-related disorders and death reflects
the availability and price of cocaine; currently, co-
caine is in plentiful supply, and is cheap to buy (see
Fig. 1).
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