Neurologic Complications of Recreational Drugs

Keywords

cocaine, opiates, methamphetamines, bath salts, MDMA (ecstasy), gamma hydroxybutyrate, benzodiazepines, LSD, ketamine, marijuana, intravenous drug

Recreational drug use can lead to neurologic problems stemming from both acute intoxication and chronic use, and physicians must be aware of these complications when faced with any patient having a neurologic disorder. In the past decade, the landscape of drug use has shifted from primarily illicit substances manufactured with the sole purpose of recreational drug use, to an ever-increasingly common realization that many drugs of abuse are medications prescribed for a variety of medical conditions. No longer do abusers need to obtain drugs exclusively on the street; physician offices, pharmacies, and medicine cabinets now have become common sources of these substances. Practitioners need to be aware not only of the potential for abuse by patients when prescribing these substances but also of the potential for these drugs to fall into the hands of other users, including family members and acquaintances of patients. This shift to abuse of prescription drugs has also likely changed the demographics of those at risk of drug abuse; young and old alike, spanning the full array of socioeconomic backgrounds, are at risk of abuse in the setting of relatively easy accessibility to these substances.

Standard urinary drug screens are inexpensive and utilized in most emergency departments when concern exists for acute intoxication. These screens also are employed in drug treatment programs and employee screens in order to monitor compliance with abstinence. They test for commonly used recreational drugs or their metabolites including alcohol, amphetamines, barbiturates, benzodiazepines, cannabis, and cocaine. Although this list captures many drugs of abuse, other agents discussed here are not included in typical urinary screens and either cannot be tested for easily or are only detected using serum screens that tend to be expensive and time-consuming. These serum screens remain the gold standard for testing, especially outside the emergency setting. Other options for testing are employed much less commonly and include saliva and hair analysis, the latter having the advantage of detecting drugs of abuse weeks to even months after ingestion.

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; indeed this hypercoagulability was first described in myocardial infarction but likely applies similarly to ischemic stroke.

In contrast to the acute effects, chronic cocaine use can lead to ischemic stroke and cerebral transient ischemic attacks through a variety of mechanisms, many of which remain incompletely understood. Some cocaine abusers appear to develop a non-inflammatory 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 transient ischemic attacks.

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. Finally, 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.

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; ongoing 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 non-inflammatory.

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 via the mechanisms discussed earlier.

Bath Salts

A recent increase of the use of so-called “bath salts” has been 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, leading to the moniker “fake cocaine” due in part to their addictive properties. 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 health care workers to possible ingestion of these substances, which are not detected by typical drug screens. These compounds until recently have been widely available in over-the-counter form. Although various governments have recently made these compounds illegal, new cathinones have been introduced, staying one step ahead of regulatory bodies.

MDMA (Ecstasy)

The synthetic compound 3,4 methylenedioxymethamphetamine (MDMA, ecstasy) is a serotonergic amphetamine that became popular at dance parties (“raves”) and can be 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 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 13 , Chapter 15 , 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.

Gamma Hydroxybutyrate (GHB)

Gamma hydroxybutyrate (GHB) leads to both euphoria and stimulant effects with purported sexual enhancement and disinhibition. The drug is the precursor to γ-aminobutyric acid (GABA), one of the most common inhibitory neurotransmitters in the central nervous system. Previously marketed for bodybuilding, it is now used recreationally, often simultaneously with other “club drugs” including MDMA. The drug is ingested orally, usually in liquid form. GHB has a narrow window of safety and therefore overdosing and emergency department visits are common. Interestingly, the drug has found a therapeutic purpose and is marketed in the United States and Europe for treatment of narcolepsy with cataplexy or excessive daytime sleepiness.

The most commonly cited neurologic effect of GHB intoxication is coma, which may occur rapidly after ingestion and necessitate intubation and admission to the hospital in order to protect the airway and avoid fatal ventilatory failure. Since GHB is not detected in most routine urine toxicology screens, neurologists are often consulted for an otherwise unexplained coma in a young person. An impressively sudden reversal of coma is sometimes observed, which is strongly suggestive of GHB intoxication. Other neurologic complications of acute use include ataxia and nystagmus; the effects on consciousness may preclude safe driving.

When GHB wears off, an agitated delirium with self-injurious behavior may be observed, and some patients will alternate quickly between agitated and sedated states. Patients with GHB intoxication are at risk of seizures, and myoclonus is typically seen especially when patients are in the agitated phase. Patients using GHB are usually quite amnestic to events, even when they are conscious, leading to its use in sexual assault as a “date rape” drug.

Sedative-Hypnotics

The sedative-hypnotic class of drugs is mainly used for medical purposes including induction of sleep and relief of anxiety. However, these compounds have developed into common drugs of abuse with a potential for dependence as prescription drug abuse has increased. Historically, barbiturates were replaced by the benzodiazepine class of drugs in part due to an increased safety profile in overdose; however, both classes of drug have a similar potential for abuse. The sedative and anxiolytic properties of all of these medications resemble those of alcohol since both act in part at the level of the GABA system in the brain, and alcohol withdrawal syndromes are treated with long-acting forms of these drugs.

The sedation that accompanies acute intoxication represents an important neurologic manifestation of these compounds that is typically easy to recognize. Reversal of acute intoxication with benzodiazepines by flumazenil, a benzodiazepine receptor antagonist, for purely diagnostic purposes is generally discouraged, and its use is limited to life-threatening situations, given its tendency to produce seizures and rapidly induce withdrawal.

The most important neurologic effects of sedative medications involve withdrawal, which can lead to tachycardia, agitation, tremor, and hallucinations that may develop into frank psychosis. Seizures are an important concern, and abrupt withdrawal of these medications can lead to ictal events even in those without an underlying epileptic disorder. Treatment for these seizures usually involves administration of benzodiazepines, often in intravenous form, followed by a slow taper which may need to last for days or weeks depending on the duration and dose of use prior to withdrawal. As a general rule, traditional antiepileptic medications that are not of the benzodiazepine or barbiturate class are ineffective.

Recently, a number of benzodiazepine-related substances including zolpidem, zaleplon, and eszopiclone have emerged with a safety profile that is so favorable that they are available in many countries without a prescription for use as a short-term sleeping aid. With this greater availability has emerged a potential for abuse as well as symptoms of withdrawal with prolonged exposure. Zolpidem in particular has been widely used by teenagers in the United States to produce a high rather than induction of sleep. Neurologic symptoms that have been described include depression, behavioral changes including irritability, unusual complex behaviors similar to sleepwalking, and severe amnesia for events, leading it to be used by sexual predators.

Opiates

Abuse of opiates remains an extremely important public health concern. In the last decade, the emphasis has shifted from abuse of intravenous heroin and similar substances to recreational use of opiates prescribed for pain relief. Physicians need to be particularly aware of this possibility when prescribing these medications—many of these drugs end up either for sale on the street or abused by persons other than the individual for whom the prescription was intended.

The neurologic effects of opiate intoxication are well known and include miosis and an altered mental status that can progress to coma with high doses, especially in those without previous exposure to this class of medications. Some specific opiates can lead to seizures, including fentanyl, meperidine (particularly in the setting of renal insufficiency), tramadol, and pentazocine. Individuals taking opiates reliably demonstrate diffuse myoclonus, which can be mistaken for seizures, often leading to neurologic consultation; this condition is generally self-limited and of no consequence, reversing with discontinuation of the drug. Patients in whom opiate intoxication has led to profound respiratory depression are at risk of hypoxic-ischemic injury to the brain and may present with persistent coma even after withdrawal or reversal of opiates. Changes on neuroimaging may be nonexistent or subtle in cases of hypoxic-ischemic injury, and therefore the condition is a diagnosis of exclusion.

There are a number of neuromuscular complications of which opiate abusers are at risk. Myalgias can represent direct muscle involvement from opiate intoxication; frank rhabdomyolysis remains a rare but important complication that needs to be treated aggressively in order to prevent acute kidney injury. Repeated intramuscular injections of opiates may lead to a fibrotic myopathy due to a local direct toxic effect, and therefore users who inject opiates should be asked regarding site of injection.

Beginning in the mid-1990s, an epidemic of wound botulism was described, mainly in California, in users of so-called “black tar heroin” when the drug was administered via skin popping. This important public health concern can present with “outbreaks” of multiple cases of botulism in a single community when a batch of the substance becomes contaminated with C. botulinum . Patients present with weakness and depressed muscle stretch reflexes, often along with bulbar signs that include difficulty swallowing, double vision, and slurred speech from facial weakness. The pupils may be dilated and poorly reactive to light, but this varies with the serotype of the offending organism and therefore should not be used to make or exclude the diagnosis. If botulism is recognized at an early stage, antitoxin administration is important to avoid ventilatory failure from neuromuscular weakness, which in many cases may be prolonged and necessitate tracheostomy.

Withdrawal from opiate medications reliably leads to dysphoria and akathisia. Muscle pain, nausea, vomiting, yawning, and rhinorrhea are a few of the non-neurologic symptoms of withdrawal that are well-recognized. Treatment of life-threatening acute intoxication involves administration of opiate antagonists such as naloxone; complications from withdrawal symptoms should be anticipated when these antagonists are given, especially in patients who are chronic users or in whom use involves longer-acting opiate preparations.

When an opiate, often heroin, is inhaled by the user after vaporization on a piece of aluminum foil (“chasing the dragon”), a toxic leukoencephalopathy may result and is characterized on magnetic resonance imaging (MRI) by diffuse and symmetric T2 hyperintensities in the white matter ( Fig. 34-2 ). Symptoms range from mild abulia and parkinsonism to akinetic mutism or coma. Onset of the disorder may be delayed by days to weeks following opiate exposure, and clinical and neuroimaging features may progress before reaching a plateau after a few weeks. There is no effective treatment. Postmortem examination reveals a spongiform-like degeneration in the white matter that spares the U-fibers.