Neurologic Complications of Recreational Drugs

Cocaine

Cocaine is a widely used, highly addictive stimulant that increases monoamine neurotransmitters through inhibition of reuptake. It is taken in a variety of different ways including by snorting, smoking (often as “crack” cocaine), and intravenous injection. Acute intoxication effects and risk depend on the method of ingestion and dose but, in general, as with other stimulants, a variety of neuropsychiatric effects—including psychosis and paranoia—can occur in addition to the expected euphoria and increased energy.

Adverse neurologic effects may include tremor and a number of other movement disorders including acute dystonia, tics, and dyskinesias, the latter of which can be long-lasting in some patients. As with other stimulant drugs, seizures can occur with acute intoxication and are difficult to predict by dose or route of drug administration; generalized tonic-clonic seizures are most common, but cocaine lowers the seizure threshold and can lead to focal-onset seizures in patients with an underlying brain lesion. Thus, any focality to seizures occurring in the setting of cocaine use should lead to urgent neuroimaging to exclude an underlying structural cause.

The most recognizable of the acute neurologic complications associated with cocaine are cerebrovascular in nature. Dramatic rises in blood pressure shortly after use can lead to intracerebral hemorrhage as a result of exceeding the upper limits of the cerebral autoregulatory curve. In addition, patients with intracranial aneurysms may be at risk of rupture with the hypertension that accompanies intoxication. Ischemic stroke can also occur shortly after use due to the promotion of thrombosis via platelet activation and other downstream mechanisms; this hypercoagulability was first described in myocardial infarction but applies similarly to ischemic stroke.

In contrast to the acute effects, chronic cocaine use can lead to ischemic stroke and cerebral transient ischemic attacks (TIAs) through a variety of mechanisms, many of which remain incompletely understood. Some cocaine abusers appear to develop a noninflammatory vasculopathy similar to accelerated atherosclerosis in both large and small vessels of the intracranial circulation, predisposing them to stroke at a young age. It has been suggested that part of the rise in stroke incidence in younger populations is accounted for by the increased use of recreational stimulants such as cocaine. Other purported mechanisms of cocaine-induced stroke have included vasospasm of small arteries and an increased incidence of cervical artery dissection—these appear to be less common than atherosclerotic-like changes but should be considered in cocaine-related stroke and TIAs.

In addition to direct effects on the cerebral circulation, a variety of ischemic cocaine-related complications stem from the varied effects of the drug on the heart. Cocaine-induced arrhythmias, both atrial and ventricular, can predispose to cardioembolic events with either acute or chronic use of the drug. The cardiomyopathy that accompanies cocaine-related myocarditis can also lead to cardioembolic disease when the ejection fraction is moderately-to-severely depressed. Myocardial infarction in the setting of acute use is one of the more common causes of concern when a cocaine user presents to the emergency department with chest pain. Stroke can occur when wall motion abnormalities of the heart or an apical aneurysm set the stage for stasis and intracardiac clot formation that can subsequently embolize to the cerebral circulation. Acute aortic dissection, which is well described in cocaine users due to effects on the aortic endothelium and to acute hypertension, can lead to cerebrovascular events when the dissection involves the origins of the great vessels, leading to either hypoperfusion or a proximal embolic source.

Acute and chronic white matter changes have also been described with cocaine use. Chronic changes likely reflect in part the effects of sustained hypertensive episodes and may present with cognitive decline featuring prominent executive dysfunction. A more fulminant acute leukoencephalopathy may in some cases be due to adulterants found in cocaine, including the antiparasitic medication levamisole.

Methamphetamines

The numerous methamphetamine-containing compounds that are available to recreational users all work through a common mechanism of increased norepinephrine, epinephrine, and serotonin transmission at the synapse while also activating dopamine receptors. The stimulant effects of acute intoxication are therefore similar in many respects to those occurring with cocaine, with euphoria and increased energy predominating along with the risk of occasional paradoxical reactions including agitation and paranoia. As the effects of the drug wear off, dysphoria and increased sleep commonly occur, mimicking some of the effects of sedatives.

Other neurologic effects of acute intoxication involve intracerebral hemorrhage due presumably in part to severe hypertension, even in patients without a history of chronic use; subcortical locations of hemorrhage are most common. As with other stimulants, tremor and tonic-clonic seizures can occur with acute intoxication. Any focal features of the seizure or in the postictal period should trigger a neuroimaging search for an underlying lesion.

A number of neuropsychatric complications are well described in chronic users of methamphetamines. Psychosis, attention-deficit hyperactivity disorder, and chronic memory and executive function deficits may occur, with resultant-poor psychosocial and behavioral outcomes. Individuals who chronically abuse methamphetamines typically require psychologic assistance in addition to substance abuse counseling. The chronic neurotoxicity that leads to these complications is thought to involve both dopaminergic and serotonergic fronto-striatal-thalamocortical networks. Compulsive performance of repetitive, mechanical tasks such as assembling or disassembling an object, termed “punding,” is likely the result of this dopaminergic overactivity and is well described in chronic users of methamphetamines (termed “tweaking” by some users). Although studies have been mixed, users of methamphetamines may have an increased risk of developing parkinsonism later in life due to involvement of striatal dopamine pathways; additional longitudinal investigations are addressing this possibility.

Cerebrovascular complications of chronic methamphetamine use include the development of an often dramatic cerebral vasculopathy with fusiform enlargement of the large vessels of the brain with a tendency toward aneurysm formation ( Fig. 34-1 ). These aneurysms can be large enough to contain clot, which serves as an embolic source for ischemic stroke. Other patients with vasculopathy in the setting of methamphetamine use demonstrate narrowing of some distal branches of the cerebral vessels, leading to ischemia. It is likely that this vasculopathy is a result, at least in part, of direct toxicity of the drug or adulterants rather than simply the consequence of hypertension. Some have suggested an inflammatory process (e.g., cerebral vasculitis) within the vessel wall, although studies supporting this have been mixed, and typical findings in the cerebrospinal fluid and on histologic and gross pathologic examination are noninflammatory.

In addition to an increased risk of ischemic stroke, methamphetamine abusers have an increased risk of subarachnoid hemorrhage relating to their tendency to aneurysm formation. In patients with methamphetamine-related subarachnoid hemorrhage, the complications of vasospasm and delayed cerebral ischemia are particularly common and severe, even when adjusted for severity of bleed. These effects are apparently more long-lasting than in most patients with aneurysmal subarachnoid hemorrhage and require vigilance for 3 to 4 weeks following initial bleed. As a result, subarachnoid hemorrhage has a worse prognosis when related to methamphetamine use than otherwise, when adjusted for Hunt and Hess grade. Similar to cocaine, methamphetamines can also importantly lead to a cardiomyopathy, myocardial ischemia, or aortic dissection, all of which predispose patients to stroke.

Bath Salts and Flakka

An increase of the use of so-called bath salts has been recently observed, particularly in the United States. These compounds, which contain various synthetic cathinones and have no relationship with actual substances used in bathing, are usually swallowed or snorted with effects similar to other stimulants. The mechanism of action involves interactions with plasma membrane transporters for dopamine, norepinephrine, and serotonin; the duration of action is typically 3 to 4 hours. Low doses often produce euphoria and increased alertness, but neurologic side effects include tremors and seizures as well as hallucinations, agitation, and dysphoria among some users. An agitated delirium can result that is often accompanied by tachycardia and hyperthermia; this constellation of findings should alert healthcare workers to possible ingestion of these substances, which are not detected by typical drug screens. These compounds were until recently widely available legally in over-the-counter form. A related synthetic compound, “flakka”, was previously legally available and has led to outbreaks beginning in 2014 of a striking hyperactive delirium and rhabdomyolysis; combining this so-called zombie drug with other sedatives and amphetamines is common, especially among young persons.

MDMA (Ecstasy)

The synthetic compound 3,4-methylenedioxymethamphetamine (MDMA, ecstasy, “Molly”) is a serotonergic amphetamine that became popular at dance parties (“raves”) and is often taken in combination with other psychotropic drugs. As with other stimulants, the desired effects among users are euphoria and a sense of well-being. Ecstasy is also known for leading to disinhibition and sexual arousal. In some patients, agitation and anxiety can paradoxically occur at the time of intoxication or once the acute effects of the drug have worn off.

The association between severe hyponatremia and MDMA ingestion is important to recognize and can lead to serious neurologic complications. Users of the drug develop both a primary polydipsia and a drug-induced increase in antidiuretic hormone secretion, limiting the ability of the kidneys to secrete water and leading to, at times, a precipitous decline in the serum sodium level. The polydipsia may be in part due to an attempt among users to avoid hyperthermia in crowded dance arenas. The resultant hyponatremia may lead to seizures as well as potentially fatal cerebral edema; therefore, serum sodium measurement is important in any patient presenting with altered mental status or seizures following MDMA use. Careful correction is important to avoid osmotic demyelination, as discussed in Chapter 17 , although in the setting of life-threatening neurologic complications, more rapid correction may be necessary. As is the case with most stimulants, seizures can also occur with MDMA ingestion independent of the serum sodium level.

Use of MDMA can also lead to a serotonin syndrome characterized by altered mental status, fever, and other neurologic abnormalities such as clonus, myoclonus, and tremor. There is likely a spectrum of this disorder ranging from mild confusion to life-threatening circulatory collapse when autonomic instability occurs. The risk of serotonin syndrome increases when MDMA is combined with other serotonergic drugs such as selective serotonin reuptake inhibitors. Treatment options include supportive care in a cool environment for milder cases to treatment with cyproheptadine in more severe instances.

Individuals with a history of heavy use of MDMA appear to demonstrate cognitive problems in memory and attentional domains that may be long-lasting. Some studies, however, have suggested that these cognitive deficits may relate, at least in part, to underlying comorbidities, including the behavioral and psychologic disturbances that led originally to use of recreational drugs. These chronic cognitive effects seem to be mainly observed in those with a history of heavy use rather than in those with more infrequent use of the drug.