Central nervous system — Cocaine euphoria is associated with transient increases in EEG activity followed by longer-lasting increases in activity. Seizures may occur in persons without a seizure history, even with first time use of cocaine. These are usually single, generalized tonic-clonic seizures occurring within 90 minutes of cocaine use.
Craving for cocaine is associated with increased activity in the so-called mesocorticolimbic reward circuit in the brain. This includes the inferior frontal-orbitofrontal gyrus, amygdala (thought to mediate stimulus-reward association), anterior cingulate (mediating anticipation of reward), and nucleus accumbens/subcalllosal gyrus (mediating incentive motivation).
Cerebral vasoconstriction, cerebrovascular disease, and hemorrhagic and ischemic stroke are increased in cocaine users, even in patients with no other risk factors. Etiologic mechanisms include tachycardia and increased blood pressure from sympathetic activation, vasoconstriction, vasospasm, and intravascular thrombosis due to increased platelet aggregation.
MRI, SPECT, and PET imaging in chronic cocaine users demonstrate structural and functional brain abnormalities: cerebral gray matter atrophy and decreased glucose metabolism in the frontal and temporal lobes, small cerebral perfusion defects, increased creatine concentration in parietal white matter (suggesting abnormal energy metabolism), and decreased D2 dopamine receptors in the striatum. Impairment of behavioral inhibition in cocaine users has been associated with reduced activity in the anterior cingulate and prefrontal cortices.
Cocaine use is associated with a variety of movement disorders, including stereotyped behaviors, acute dystonic reactions, choreoathetosis and akathisia (so-called “crack dancers”), buccolingual dyskinesias (“twisted mouth” or “boca torcida”), and exacerbation of Tourette’s syndrome and tardive dyskinesia. Cocaine users are at increased risk of acute dystonic reactions from neuroleptic (antipsychotic) medications.
Cardiovascular system — Cocaine acutely increases heart rate, blood pressure, and systemic vascular resistance by increasing adrenergic activity in the heart, and indirectly via the CNS. The increased myocardial oxygen demand, coupled with decreased coronary blood flow from vasospasm and vasoconstriction, can cause acute myocardial infarction, even in young persons without atherosclerosis. Cocaine use is a factor in about one-quarter of nonfatal heart attacks in persons younger than 45 years. Frequent cocaine users are up to seven times more likely to have a nonfatal heart attack than are nonusers. Cocaine use is not usually associated with chronic hypertension, but may be more prevalent among patients with severe hypertension than among the general population. Cocaine use appears to enhance the progression of renal disease in patients with hypertension.
Cocaine use is associated with cardiac arrhythmias (such as ventricular tachycardia or fibrillation) and sudden death. The mechanisms include blockade of myocyte sodium channels (resulting in impaired cardiac conduction and areas of localized conduction block) and increased concentration of plasma norepinephrine (which sensitizes the myocardium). Chronic cocaine users have a higher defibrillation threshold than non-users, but appear to have better neurologic recovery from cardiac arrest than do age-matched non-users.
Chronic cocaine use is associated with left ventricular hypertrophy, cardiomyopathy, myocardial fibrosis, and myocarditis. These may be due to direct toxic effects of cocaine or to high concentrations of circulating norepinephrine. The symptoms of cocaine-associated myocarditis may mimic those of acute myocardial infarction. Autopsy series of current cocaine users have found myocarditis in up to 20 percent.
Respiratory system — The effects of cocaine on the respiratory system depend on the route of administration. Intranasal cocaine use (“snorting”) may cause chronic rhinitis, perforation of the nasal septum, oropharyngeal ulcers, and osteolytic sinusitis, due to vasoconstriction and resulting ischemic necrosis. Anosmia is rare.
Smoked cocaine use produces acute respiratory symptoms in up to half of users, including productive cough, shortness of breath, wheezing, chest pain, hemoptysis, and exacerbation of asthma. Rarer complications include pulmonary edema, pulmonary hemorrhage, pneumothorax, pneumomediastinum, and thermal airway injury. These effects are probably due to direct damage to the alveolar-capillary membrane by cocaine or inhaled microparticles, damage to the pulmonary vascular bed from vasoconstriction, and/or interstitial disease. Chronic cocaine smokers generally have normal spirometry tests, but may have increased alveolar epithelial permeability and moderately decreased pulmonary diffusion capacity, even when asymptomatic.
Gastrointestinal system — Cocaine use by any route of administration reduces salivary secretions (xerostomia) and causes bruxism. Cocaine reduces gastric motility and delays gastric emptying. Cocaine-induced vasoconstriction and ischemia may result in gastrointestinal ulceration, infarction, perforation, and ischemic colitis. Cocaine-associated ulcers are distributed primarily in the greater curvature and prepyloric region of the stomach, pyloric canal, but, similar to peptic ulcers, also occur in the first portion of the duodenum.
Liver — There is no direct evidence that cocaine is hepatotoxic in humans, although it does cause liver damage in rodents. The hepatotoxic chemical norcocaine, a major metabolite of cocaine in rodents, is only a minor metabolite in humans. Liver abnormalities in cocaine users can almost always be accounted for by viral hepatitis from injection drug use, alcoholic liver disease, or other consequences of a drug-using lifestyle. Concurrent alcohol intake may sensitize hepatocytes to damage by cocaine, as well as generating the hepatotoxic metabolite cocaethylene.
Kidneys — Cocaine use can impair kidney function by a variety of mechanisms. Cocaine-induced rhabdomyolysis is a significant cause of acute renal failure. Cocaine use by hypertensive patients enhances their decline in kidney function and the progression from hypertensive nephrosclerosis to end-stage renal disease . While cocaine promotes atherosclerosis in renal vessels, cocaine-induced renal infarction is relatively rare.
Endocrine — Acute cocaine use activates the hypothalamic-pituitary-adrenal (HPA) axis, increasing levels of epinephrine, corticotropin-releasing hormone (CRH), ACTH, cortisol, and luteinizing hormone, and decreasing plasma prolactin levels. Chronic cocaine users, however, usually have normal plasma levels of prolactin, testosterone, cortisol, luteinizing hormone, and thyroid hormones.
Skin — Cocaine use is associated with a variety of pseudovasculitic lesions that may mimic rheumatologic syndromes such as Wegener’s granulomatosis, necrotizing vasculitis, and Henoch Schonlein purpura.
Topical cocaine is classified as pregnancy category C (risk cannot be ruled out because human studies are lacking) by the US Food and Drug Administration (FDA). Maternal cocaine use has been associated with vaginal bleeding, abruptio placenta, placenta previa, premature rupture of membranes, premature birth, decreased head circumference, low birth weight, and autonomic instability. However, it is unclear to what extent these adverse effects are due to prenatal (in utero) cocaine exposure, rather than to other factors in the cocaine-using lifestyle, such as concomitant drug use (including alcohol, nicotine, and opiates), poor nutrition, and lack of prenatal care. Rodent and monkey studies, in which these confounding factors are excluded, show few direct adverse effects of prenatal exposure to cocaine.
The long-term effects of prenatal exposure to cocaine are also unclear. Well-controlled, prospective studies of children born to cocaine-using mothers have not confirmed most earlier concerns regarding long-term cognitive impairment and behavioral problems.
Cocaine appears in breast milk and may cause irritability, sleep disturbance, and tremors in the nursing infant.
David A Gorelick, MD, PhD
H Nancy Sokol, MD