Address correspondence to Dr John C. M. Brust, Department of Neurology, Columbia University Medical Center, Neurological Institute of New York, 710 West 168th St, New York, NY 10032, ude.aibmuloc@2bcJ.
Copyright © 2014 by the American Academy of Neurology.This review familiarizes clinicians with the symptoms of overdose and withdrawal, as well as neurologic complications, associated with particular illicit drugs.
Recent arrivals on the recreational drug scene include synthetic cathinone analogs, synthetic cannabinoid agonists, and a variety of novel hallucinogens.
Clinicians need to be aware of neurologic disorders associated with particular illicit drugs and should consider drug abuse in any patient with unexplained symptoms and signs.
In addition to tobacco and alcohol, a large number of substances, legal and illegal, are used recreationally. Broad categories include opioids, psychostimulants, marijuana and related agents, sedatives, hallucinogens, inhalants, phencyclidine and related agents, and anticholinergics. Each type of agent has its own characteristic symptoms of overdose and withdrawal, and many agents are associated with trauma, infection, seizures, stroke, cognitive impairment, and teratogenicity. Some drugs have unique neurologic complications not encountered with other agents. A history of recreational drug use should be sought in any neurologic patient regardless of age or socioeconomic status.
Drug dependence is of two types: psychic dependence and physical dependence.1 Psychic dependence leads to craving and drug-seeking behavior. Physical dependence produces somatic symptoms and signs during withdrawal. Psychic and physical dependence can occur alone or together, and they involve different neuronal circuits. The term addiction refers to psychic dependence. Tolerance is the need for increasing doses of a drug to achieve desired effects or to avoid withdrawal symptoms. Abuse refers to recreational use of a substance despite evidence of its harmfulness.
Worldwide, a large number of substances are used recreationally, either legally or illegally ( Table 8-1 ). Recreational drug use often involves more than one agent, resulting in confusing symptoms and signs. A user might be simultaneously intoxicated with one agent while withdrawing from another.
Categories of Recreational Drugs
This review addresses the major categories of recreational drug use other than alcohol and tobacco, focusing on intoxication, withdrawal, and neurologic complications.
Opioids include agonists, antagonists, and mixed agonist/antagonists ( Table 8-2 ). Heroin (diacetyl morphine) is classified by the US Food and Drug Administration (FDA) as schedule I (ie, no accepted medical use, high potential for abuse). Each of the agonists and agonist/antagonists in Table 8-2 has abuse potential, however. During the past two decades, the United States has experienced a surge in recreational use of prescription opioids, especially products containing oxycodone and hydrocodone.2 In Eastern Europe, the designer opioid desomorphine (known as crocodile) has become increasingly popular.3
Commonly Used Opioids
At desired levels of intoxication, opioid agonists produce dreamy euphoria, analgesia, cough suppression, miosis, and often nausea, vomiting, sweating, pruritus, hypothermia, postural hypotension, constipation, and decreased libido. Injected parenterally or smoked (often with other drugs, especially alkaloidal “crack” cocaine), heroin produces a “rush”—a brief ecstatic feeling followed by euphoria and either relaxed nodding or garrulous hyperactivity.
Overdose produces the triad of coma, respiratory depression, and miosis. Treatment includes respiratory support and IV naloxone. Naloxone is short acting, so management requires close observation to detect relapse.
Opioid withdrawal produces fever, myalgia, lacrimation, rhinorrhea, productive cough, sweating, piloerection, yawning, nausea and vomiting, diarrhea, abdominal cramps, and tachycardia. Although unpleasant, such symptoms in adults are rarely dangerous, and drug craving is disproportionately severe. Symptoms of heroin withdrawal peak at 24 to 72 hours and last 7 to 10 days, but full recovery can take many weeks. Prevention or treatment is with methadone. Seizures are not a feature of opioid withdrawal (except perhaps in newborns), and their occurrence in an overdosed patient mandates a search for a more likely cause (eg, cocaine toxicity or ethanol withdrawal) (Case 8-1).
In neonates, untreated opioid withdrawal can be severe, with jitteriness, hypertonia, screaming, lacrimation, sweating, fever, respiratory distress, tachycardia, vomiting, diarrhea, and probably myoclonus and seizures (which can be difficult to distinguish from jitteriness). Mortality is as high as 90% without treatment, which includes methadone or paregoric (tincture of opium). A barbiturate can be added if seizures require treatment or additional drug withdrawal (eg, ethanol) is suspected.
A 27-year-old man was brought unresponsive to the emergency department. His respirations were 5 breaths per minute and shallow. His pupils were 1 mm in diameter, and reactivity to light was difficult to determine. Movements of the limbs to noxious stimuli were limited but seemingly purposeful. The oculocephalic maneuver produced full horizontal eye movements. After the patient was given 0.8 mg of naloxone, he became alert, with normal respirations and pupils. He refused admission and departed. An hour later, he was brought back obtunded with miosis and a respiratory rate of 15 breaths per minute. After being given 2 mg naloxone, he became alert but within a few minutes developed tearing, yawning, rhinorrhea, sweating, and marked irritability. He then had a major motor seizure.
Comment. Opioid overdose causes coma, respiratory depression, and pinpoint pupils, and the drug’s effects can recur when the effects of an antagonist have worn off. The naloxone dosages in this case were inappropriate: too low initially and too high later. Recommended naloxone dosage depends on respiration. If the patient is hypoventilating, naloxone 2 mg (preferably intravenously) is given and repeated up to 20 mg. If breathing is normal, 0.4 mg to 0.8 mg is given, and if the patient does not respond, 2 mg is given and repeated as needed. Because opioid toxicity can outlast the effects of opioid antagonism, a patient should be admitted and closely observed for evidence of recurrent intoxication.
Trauma. Brain, spinal cord, or peripheral nerve injury may be a consequence of drug intoxication, but with illicit drugs such as heroin such trauma is most often related to illegal activities surrounding dealing and procurement.
Infection. Heroin is immunosuppressive, and, independent of HIV, parenteral users are at risk for a wide array of systemic and CNS infections. Hepatitis A, B, and C are common, and liver failure causes encephalopathy. Endocarditis can lead to brain infarction, brain abscess, meningitis, or septic (ie, mycotic) aneurysm. Tetanus, usually severe, especially affects drug users who inject subcutaneously. Botulism and anthrax may occur at injection sites.4
Over the three decades of the AIDS pandemic, parenteral drug users or their sexual partners have represented an increasing proportion of AIDS patients reported to the United States Centers for Disease Control and Prevention. Progressive myelopathy occurs in parenteral users infected with human T-cell lymphotrophic virus (HTLV)–I or HTLV-II.
Seizures. Opioids lower the seizure threshold, but seizures in the presence of overdose are more likely the result of concomitant intoxication (eg, cocaine) or withdrawal (eg, ethanol). An exception is meperidine, of which a toxic metabolite (ie, normeperidine) causes agitation, tremor, delirium, hallucinations, myoclonus, and seizures. A case-control study found that heroin use, both past and current, was a risk factor for new-onset seizures independent of overdose, head injury, infection, stroke, ethanol, or other illicit drugs.5
Stroke. Reports of ischemic and hemorrhagic stroke in heroin users are anecdotal, but occurrence in young patients lacking other risk factors suggests more than coincidence. Proposed mechanisms include heroin nephropathy with hypertension, liver failure with defective clotting, endocarditis, overdose with shock, particle embolism, and toxic or allergic vasculitis.6
Acute paraparesis, sensory loss, and urinary retention have followed heroin injection, often after a period of abstinence. Symptoms are sometimes present on awakening from coma, suggesting border zone infarction of the spinal cord. Other possible mechanisms include embolism of foreign material, direct toxicity, and hypersensitivity.
Neuromuscular complications. Anecdotal reports describe Guillain-Barré polyradiculoneuropathy and brachial or lumbosacral plexopathy. Acute rhabdomyolysis may be related to adulterants in street preparations. Repeated IM injection can cause fibrotic myositis with contracture.
Spongiform encephalopathy. “Chasing the dragon” refers to heating heroin on metal foil and inhaling the vapor through a straw. Drug users practicing this technique have developed rapidly progressive abulia, cerebellar ataxia, chorea, myoclonus, quadriparesis, and blindness, often ending fatally. MRI shows striking signal abnormalities in cerebral and cerebellar white matter, and biopsy or autopsy reveals spongiform leukoencephalopathy. The disorder has not been reproduced in animals, and a responsible neurotoxin has not been identified (Case 8-2).7
N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine and parkinsonism. During the 1980s, severe parkinsonism was described in users of a meperidine analog sold on the street as “synthetic heroin.” The responsible toxin is an unintended byproduct of the drug’s manufacture, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is metabolized to N-methyl-4-phenylpyridium (MPP+). Uptake of MPP+ by substantia nigra neurons results in cell death. The syndrome is irreversible, but the symptoms respond to levodopa.
Effects on cognition. As with other drugs of abuse, assessing the effects of chronic opioid use on cognition is confounded by comorbid psychiatric disease, polysubstance use, street drug adulterants, previous overdose, and lack of neurobehavioral information before drug use. Long-term mental status change has not been convincingly demonstrated in opioid users (including those receiving methadone maintenance therapy). Structural and functional imaging, however, has demonstrated reduced cerebral gray matter density and decreased white matter fractional anisotropy in heroin users,8 as well as abnormal connectivity patterns in both heroin users9 and recreational users of prescription opioids such as oxycodone and hydrocodone.10 In adult rats, chronic administration of morphine or heroin inhibits hippocampal neurogenesis.11
Evaluating children exposed to heroin in utero is similarly problematic, with reports of cognitive or behavioral abnormalities confounded by inadequate prenatal care, concomitant in utero drug exposure (especially ethanol and tobacco), variable reliability of maternal reporting, and socioeconomic considerations. Animal studies of prenatal exposure to morphine or methadone have been inconsistent.
A 40-year-old man and his 21-year-old girlfriend were hospitalized after they developed progressive gait ataxia, dysmetria, and dysarthria over a few weeks. Both patients reported abusing heroin by an inhalation technique known as “chasing the dragon.” Once hospitalized, the woman progressed to an akinetic mute state with decorticate posturing and spastic quadriparesis. The man developed a less severe spastic quadriparesis and freezing of gait. T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI revealed diffuse symmetric white matter hyperintensities in the posterior limbs of the internal capsule, the splenium of the corpus callosum, the cerebellum, and the brainstem. Biopsy of the woman’s brain revealed spongiform degeneration of the white matter.
Comment. Parenteral heroin is administered either intravenously or subcutaneously. Fear of AIDS increased the popularity of snorting or smoking heroin. Chasing the dragon consists of placing the drug on metal foil and heating it from beneath; the vapor is then inhaled through a tube or straw. Neurologic symptoms usually begin with bradyphrenia and cerebellar ataxia, followed by progressive spastic hemiparesis or quadriparesis, chorea, myoclonus, pseudobulbar palsy, blindness, and sometimes death. Autopsies or biopsies reveal spongiform white matter degeneration. A responsible toxin has never been identified.
Psychostimulants include a number of licit and illicit agents, of which cocaine, methamphetamine (ie, speed), and methylenedioxymethamphetamine (MDMA; ecstasy) are the principal drugs of abuse ( Table 8-3 ). Cocaine is an alkaloid present in the South American plant Erythroxylum coca. As an urban street drug, cocaine hydrochloride is sniffed or injected; alkaloidal crack cocaine is smoked. Methamphetamine—easily manufactured from commercial pseudoephedrine—can be injected or, as “ice,” smoked. MDMA is usually taken orally.
Commonly Used Psychostimulants
In recent years, numerous synthetic psychostimulants have become available in Europe and the United States, purchased through the Internet as “legal highs.”12 Mephedrone (methcathinone), methylone, and methylenedioxypyrovalerone are derivatives of cathinone, an amphetaminelike alkaloid present in khat, a recreationally used shrub indigenous to East Africa and Arabia. These drugs are often sold as “bath salts.”13 5,6-Ethyenedioxy-2-aminoindane is an analog of MDMA.14
The intended major effect of cocaine or methamphetamine is an ecstatic rush distinguishable from that produced by opioids. Repeated use can result in stereotypic activity and paranoia progressing to dyskinesia and psychosis. MDMA is more serotonergic and less dopaminergic than cocaine or methamphetamine, and its intended effects seem to straddle those of amphetaminelike psychostimulants and lysergic acid diethylamide (LSD)–like hallucinogens—namely, enhanced communication or empathy, euphoria or ecstasy, and perceptual alteration that at high doses can be hallucinatory.
Psychostimulant overdose causes varying combinations of delirium, psychosis, tachycardia, hypertensive crisis, malignant hyperthermia, cardiac arrhythmia, rhabdomyolysis, myoclonus, and seizures, sometimes progressing to shock, coma, and death. Treatment includes sedation with benzodiazepines, oxygen, bicarbonate for acidosis, anticonvulsants, blood pressure control (preferably with an alpha-blocker or direct vasodilator), respiratory and blood pressure support, and cardiac monitoring (Case 8-3).
Fulminant and often fatal encephalopathy was described in HIV-infected cocaine users. MRI revealed basal ganglia and thalamic hyperintensities on T2 and FLAIR images but no restriction on diffusion-weighted images. At autopsy there was overwhelming microglia activation in the basal ganglia, and the disorder was attributed to synergistic effects of the drug with HIV proteins.15
Psychostimulant withdrawal produces depression, fatigue, and increased appetite. Other than suicidal ideation, symptoms are not dangerous, but craving is intense.
Seizures. With amphetaminelike psychostimulants, seizures usually occur in the setting of obvious overdose. Cocaine-related seizures are more likely to occur without other evidence of intoxication, perhaps related to cocaine’s local anesthetic properties. Cocaine-related seizures demonstrate “kindling,” a progressively lowered seizure threshold with repeated nonescalating doses of the drug. Cocaine metabolites are pharmacologically active, and seizures can occur hours or days after use.
Stroke. Anecdotal reports describe ischemic and hemorrhagic stroke in users of dextroamphetamine and methamphetamine. Some cases occurred in the setting of a systemic vasculitis resembling polyarteritis nodosa. In some, the suggestion of brain vasculitis was based on angiographic beading, a nonspecific finding. Hemorrhagic strokes were plausibly attributed to acute surges of blood pressure during intoxication.
More than 600 cases of stroke have been reported in cocaine users, roughly half ischemic and half hemorrhagic.6 Most reports are anecdotal, but in a case-control study of incident stroke in women, cocaine was a strong risk factor (odds ratio of 13.9).16 Angiography in patients with cocaine-related intracranial hemorrhage often reveals saccular aneurysm or vascular malformation, which presumably bleed during acute hypertension.
In healthy young cocaine users, cocaine caused dose-related cerebral vasoconstriction.17 Pathologically verified cocaine-related vasculitis has rarely been described. Cocaine also causes hypercoagulation, including platelet activation. Cardiomyopathy and myocardial infarction in cocaine users can result in cardioembolic stroke.
Less frequent anecdotal reports describe ischemic and hemorrhagic stroke associated with other psychostimulants, including MDMA, phenylpropanolamine, ephedrine, herbal remedies containing ephedra, and methylphenidate.
Cognition and behavior. In animal models, chronic amphetamine administration damages brain dopaminergic nerve terminals; chronic methamphetamine damages both dopaminergic and serotonergic nerve terminals; and chronic MDMA selectively damages serotonergic nerve terminals. The mechanism of these neurotoxicities is unknown, and the damage is partially reversible, but patterns of reinnervation are abnormal, possibly contributing to reported long-term cognitive and behavioral abnormalities in heavy users of these drugs.18
As with other agents, assessing long-term cognitive effects is beset with confounders. Volunteers who had never used MDMA but were likely to do so in the future underwent psychological testing and neuroimaging studies, which were repeated after 36 months; those who had used MDMA in the interim demonstrated cognitive impairment and brain abnormalities on diffusion tensor MRI.19 Serotonin transporter binding was decreased in the cerebral cortex of MDMA users abstinent for a mean 45 days, who demonstrated subtle abnormalities on cognitive testing.20
MDMA is an independent risk factor for sleep apnea. Whether sleep apnea in turn contributes to cognitive impairment is unclear.21
Cocaine does not damage nerve terminals, yet long-term cognitive impairment is described in heavy users. Animals exposed to cocaine demonstrate pathologic changes in limbic structures, and both humans and animals demonstrate MRI diffusion tensor abnormalities.22,23,24,25
Whether psychostimulant users are at increased risk for depression is controversial. Many users are probably self-medicating preexisting depression.
Methcathinone-induced movement disorder. Methcathinone is manufactured by oxidizing ephedrine or pseudoephedrine with potassium permanganate. Users develop a movement disorder characterized by hypokinesia, dysarthria, dystonia, and postural instability. Tremor, rigidity, and shuffling gait are not features. T1-weighted MRI reveals signal hyperintensity in the globus pallidus, which contains deposited manganese. The substantia nigra compacta is not affected, and Lewy bodies are not present. Levodopa does not relieve symptoms, which persist even as MRI signals clear.26
Fetal effects. Prenatal exposure to methamphetamine is significantly associated with restricted fetal growth; depressed arousal in neonates; and later abnormalities in memory, attention, and visual-motor integration, as well as lasting metabolic and structural changes especially involving frontostriatal circuitry.27,28 Prenatal exposure to MDMA is associated with long-term behavioral disturbance.29
Neuropsychological testing in children exposed in utero to cocaine revealed impulsivity and abnormalities in executive function; MRI revealed thinning of dorsolateral prefrontal cortex, and diffusion tensor imaging showed frontal white matter abnormalities.30,31,32 As with other drugs, it is difficult to determine the degree to which these findings are the result of cocaine per se.33
A 33-year-old woman was hospitalized, delirious and hallucinating (visual and auditory) with vertical nystagmus, dilated but reactive pupils, profuse sweating, blood pressure 70/50 mm Hg, and temperature 41.5°C (106.8°F). Gradually improving with treatment that included cooling, fluids, lorazepam, and haloperidol, she reported having taken 100 mg of methylenedioxymethamphetamine (MDMA or “ecstasy”) with a friend and within 10 minutes developing formed visual hallucinations, followed by teeth chattering, sweating, and a feeling of dread. She recalled nothing of the subsequent 24 hours. She also reported taking ecstasy a month before but described feeling only euphoric and pleasantly relaxed after that dose. The patient continued to have hallucinations for several days and then was depressed and felt “unable to handle stress” for several months.
Comment. MDMA has both amphetaminelike and lysergic acid diethylamide (LSD)–like properties. Overdose causes hyperthermia, hypertensive crisis, cardiac arrhythmia, panic, paranoia, delirium, disseminated intravascular coagulation, rhabdomyolysis, seizures, coma, shock, and death. Cerebral infarction has been reported. In contrast to amphetaminelike psychostimulants, which are neurotoxic to dopaminergic synaptic endings, MDMA is neurotoxic to serotonergic synaptic endings. Cognitive impairment is convincingly described in abstinent MDMA users.
Marijuana is prepared from flowers and leaves of the hemp plant, Cannabis sativa, which contains several dozen cannabinoid compounds of which Δ-9-tetrahydrocannabinol (Δ-9-THC) is the principal psychoactive ingredient. Preparations made from the plant resin (ie, hashish) are more potent than marijuana. In the brain, Δ-9-THC acts at stereospecific receptors, which, along with endogenous ligands, comprise a widely distributed endocannabinoid system.
Increasingly popular over the past decade are herbal marijuana alternatives (eg, spice, K2), consisting of noncannabis herbs laced with synthetic cannabinoid compounds that are agonists at human cannabinoid receptors.34 Spice is now the second most used illicit drug (after marijuana) among US high school seniors.
Usually smoked but also taken orally, marijuana produces euphoria, relaxation, and often jocularity. Depersonalization, subjective time slowing, memory impairment, unsteadiness, conjunctival injection, tachycardia, systolic hypertension with postural hypotension, or increased appetite may occur. High doses cause visual and auditory illusions or hallucinations and psychotic excitement or depression. Without other signs of toxicity, marijuana can cause acute paranoia, confusion, or panic lasting hours or days. Other than suicide, fatal overdose has not been reported.
Abrupt abstinence may be asymptomatic or produce jitteriness, anorexia, insomnia, and gastrointestinal upset. Marijuana is an addictive drug, and craving is common.
Cognition and behavior. Whether the use of marijuana causes lasting cognitive or behavioral alteration has been controversial for decades. As with other drugs, confounders include failure to correct for residual acute effects or withdrawal or to determine cognitive function before drug use. Investigative strategies include neuropsychological testing,35 functional imaging during cognitive tasks,36,37 and identification of brain morphologic alteration.38,39,40 A study using diffusion-weighted MRI and connectivity mapping demonstrated microstructural alterations affecting axonal pathways in long-term marijuana users.41 Such studies provide mounting evidence that marijuana use, especially by children and adolescents, damages the brain.42 Moreover, epidemiologic studies have shown marijuana to be a significant risk factor for schizophrenia.43 In utero exposure to marijuana is associated with impaired executive function persisting into adolescence.44
Stroke. As of 2012, 59 cases of stroke had been reported in marijuana users. Fifty-eight were ischemic (including five TIAs), and one was hemorrhagic.45 Most anecdotal reports describe stroke occurring during or shortly after marijuana smoking by young people without other risk factors. A population-based study of hospitalized patients reported an adjusted odds ratio of 1.76 for marijuana exposure associated with ischemic stroke.46 Marijuana also increases the risk for myocardial infarction.47
Proposed mechanisms for stroke include cardioembolism and cerebral vasospasm. Multifocal intracranial stenosis associated with marijuana use was reported in 10 of 48 consecutive young people with acute ischemic stroke.48 The authors speculated that marijuana might cause reversible vasoconstriction syndrome and that marijuana use associated with stroke might be underreported.
Seizures. Anecdotal reports of seizures associated with marijuana use are rare. In fact, a case-control study of new-onset seizures found that marijuana was protective.5
Sedative drugs include barbiturates, benzodiazepines, and miscellaneous agents ( Table 8-4 ). Barbiturates and benzodiazepines are GABA-ergic; stereospecific receptors for γ-aminobutyric acid (GABA), barbiturates, and benzodiazepines form parts of a supramolecular GABA-A-benzodiazepine-chloride ion channel complex.
Commonly Used Sedatives and Hypnotics
Recreational use of sedatives is usually oral, and intended effects are euphoria and drowsiness. Overdose causes coma and respiratory depression. Withdrawal symptoms resemble those seen with ethanol, namely tremor, hallucinations, seizures, and potentially life-threatening delirium tremens. Symptoms of neonatal barbiturate withdrawal resemble those of neonatal opioid abstinence.
Benzodiazepines have less abuse potential than barbiturates and are less likely to cause respiratory depression. Paradoxical reactions can suggest withdrawal, with anxiety, agitation, or delirium.
Cognition and behavior. Chronic barbiturate abuse leads to psychological and social deterioration; impaired attentiveness and short-term memory are described. Long-term benzodiazepine use, with or without dependence, appears to be without permanent behavioral or cognitive consequences.
Cognitive abnormalities have been described in children and animals exposed prenatally to barbiturates.
γ-Hydroxybutyric acid (GHB) and its precursors γ-butyrolactone and 1,4-butanediol are popular euphoriants and, often taken with ethanol, are notorious as “date-rape” drugs. Overdose causes either delirium or coma with respiratory depression. Withdrawal symptoms resemble those of other sedatives or ethanol.49
Dozens of hallucinogenic plants are ritualistically or recreationally used around the world. In the United States the most popular agents are the indolealkylamines psilocybin and psilocin (in several mushroom species), the phenylalkylamine mescaline (in peyote cactus), and the synthetic ergot LSD.
Increasingly popular in the United States and Europe is Salvia divinorum, an herb native to Mexico that can be chewed or smoked. Its main active ingredient is the kappa opioid receptor agonist salvinorin A.50 Also available are numerous “designer” hallucinogens with street names such as FLY, DragonFLY, and Bromo-DragonFLY.51
Acute effects following oral ingestion of hallucinogens are somatic (eg, dizziness, tremor, paresthesia), psychological (eg, altered mood, depersonalization), and perceptual (eg, distortions or hallucinations, usually visual and elaborately formed). Some users experience paranoia or panic (ie, “bad trips”), and some experience flashbacks, a spontaneous recurrence of drug effects days to months after taking the drug. High doses of LSD cause hypertension, obtundation, and seizures, but fatalities are usually the result of accidents or suicide. Treatment of overdose consists of calm reassurance and, if necessary, a benzodiazepine. Withdrawal symptoms do not occur.
In some LSD users, flashbacks evolve into posthallucinogenic perceptual disorder, in which perceptual distortions or spontaneous imagery are continuous rather than paroxysmal and persist for years (Case 8-4).52
Like other ergot agents, LSD is vasoconstrictive, and ischemic stroke has been described in young users without other risk factors.
Anecdotal reports describe permanent paranoia, depression, or impaired memory in LSD users, but direction of causality is difficult to establish.
A wide variety of commercial products are sniffed or huffed ( Table 8-5 ), especially by adolescents.1 Volatile compounds include halogenated, aliphatic, and aromatic hydrocarbons, toluene, n-hexane, butane, trichloroethylene, nitrous oxide, and amyl or butyl nitrite. Desired effects resemble ethanol intoxication, but high doses can cause hallucinations and seizures. Death can result from cardiac arrhythmia, accidents, or aspiration of vomit. Treatment includes cardiac and respiratory monitoring, and symptoms usually clear within a few hours. Withdrawal symptoms are unlikely, but craving occurs.
Commonly Used Inhalants
Persistent encephalopathy follows toluene exposure, with cognitive impairment, cerebellar ataxia, and corticospinal signs. The neuropathology is principally a leukoencephalopathy.53
Severe sensorimotor axonal polyneuropathy affects sniffers of glue or lacquer thinners containing n-hexane.54 Weakness can progress to quadriplegia, and recovery is incomplete.
Sniffing of nitrous oxide, present in whipped cream canisters, causes a myeloneuropathy clinically indistinguishable from cobalamin (vitamin B12) deficiency and combined systems disease.55 Macrocytic anemia is usually absent, and blood vitamin B12 levels are usually normal. The cause is oxidation of cobalamin by nitrous oxide, rendering inactive the vitamin B12–dependent enzymes methionine synthetase and methylmalonyl–coenzyme A (CoA) mutase.
Trigeminal neuropathy affects sniffers of products containing trichloroethylene.
Sniffers of amyl or butyl nitrite develop methemoglobinemia that can cause stupor, seizures, cardiac arrhythmia, and circulatory failure.56
Sniffing of gasoline containing tetraethyl lead has caused lead encephalopathy.57
A fetal solvent syndrome similar to fetal alcohol syndrome—including microcephaly, craniofacial anomalies, and retarded growth—is described in children exposed in utero to inhalants. Animal studies confirm the teratogenicity of several inhalants.58
The symptoms in this case are taken from a 19th century description of mescaline effects by Havelock Ellis.
A 27-year-old female polydrug user who had been abstinent for 2 weeks was under observation by her doctor. Resting in a dimly lit room, she suddenly felt weak, dizzy, and chilly; she then noted visual distortions (a violet shadow enveloped objects in the room, and her hands appeared to her to be “heightened in color, almost monstrous.” Closing her eyes produced vivid afterimages and then kaleidoscopic hallucinations, which gradually became semiformed and distinct: “a vast field of golden jewels… ever-changing.” The air around her seemed to be “flushed with vague perfume,” and she had no discomfort except for a slight tremor of her hands. Visual hallucinations continued; she described jewels springing up into flowerlike shapes and then turning into “gorgeous butterfly forms or endless folds of glistening iridescent wings of wonderful insects… Every color and tone conceivable to me appears at one time or another.” She remained mentally clear and unable to influence the images except by enhancing them with eye closure. After several hours, during which time her visions were chiefly of human figures, she described as “fantastic and Chinese in character,” she fell asleep.
Comment. Users of lysergic acid diethylamide (LSD) or other hallucinogenic drugs can experience flashbacks, the spontaneous recurrence of drug symptoms without taking the drug. With a reported frequency of 15% to 77%, flashbacks most often affect frequent users, but they can occur after a single exposure. Usually paroxysmal, they may last only a few seconds, and they tend to diminish with time. Some LSD users, however, develop posthallucinogenic perceptual disorder, with continuous visual disturbances that can last years.
Classified as a “dissociative anesthetic,” phencyclidine (PCP; angel dust) is usually smoked. Related agents include ketamine and the antitussive dextromethorphan.59 A designer drug related to ketamine, methoxetamine, has a much longer duration of action.60
Low doses of PCP produce either euphoria or dysphoria and a feeling of numbness. Higher doses cause agitation, tachycardia, hypertension, fever, ataxia, nystagmus, paranoid or catatonic psychosis, hallucinations, myoclonus, seizures, rhabdomyolysis, coma, respiratory depression, and death. Treatment includes benzodiazepines, forced diuresis, cooling, antihypertensives, anticonvulsants, and cardiorespiratory support.61 Violent behavior may require restraints.
Withdrawal signs are mild, with tremor and nervousness, but craving occurs.
Unlike psychostimulants such as methamphetamine, PCP produces a full schizophrenic syndrome, with symptoms that are both positive (eg, paranoia, delusions, hallucinations) and negative (eg, alogia, affective flattening, avolition).62 Psychosis can last days to weeks after a single dose, and many chronic users display persistent behavioral or cognitive abnormalities. As with other drugs, direction of causality is unclear.
PCP-induced hypertension can also last days, and PCP has direct vasoconstrictive actions on cerebral arteries. Ischemic and hemorrhagic stroke, as well as hypertensive encephalopathy, have been described.63
Anecdotal reports describe abnormal behavior in infants exposed in utero to PCP. PCP’s action as an N-methyl-D-aspartate (NMDA) receptor antagonist provides teratogenic plausibility.
The plant Datura stramonium (Jimson weed) contains atropine and scopolamine, and recreational use is popular among American adolescents. Anticholinergic abuse also includes antiparkinsonian drugs, the antihistamine diphenhydramine, and the tricyclic antidepressant amitriptyline.
Desired effects are euphoria and sedation. Overdose produces decreased sweating, fever, tachycardia, dry mouth, mydriasis, and delirium with hallucinations. Severe poisoning causes myoclonus, seizures, coma, and death. Treatment includes IV physostigmine, gastric lavage, cooling, bladder catheterization, respiratory and cardiovascular monitoring, and, if necessary, anticonvulsants. Neuroleptic agents, which have anticholinergic activity, are contraindicated.
Recreational anticholinergic users are unlikely to take the drug on a daily basis; rarely, withdrawal irritability and craving are encountered.
Illicit drug use is a shifting target. The popularity of specific agents varies from country to country and, within a country, from region to region. New agents appear unpredictably. It behooves clinicians to be familiar with the effects of particular agents and to consider drug abuse in any patient with unexplained symptoms or signs.
Drug dependence can be either psychic (addiction, with drug-seeking behavior) or physical (with withdrawal symptoms and signs).
Opioid overdose causes coma, miosis, and respiratory depression. Opioid withdrawal causes disagreeable systemic symptoms and craving but not seizures or delirium. In newborns, opioid withdrawal can be fatal.Seizures in the setting of heroin overdose are more likely to be attributable to concomitant cocaine intoxication or alcohol withdrawal than to direct heroin toxicity.
Using heroin by an inhalation technique known as chasing the dragon is associated with severe leukoencephalopathy.
Psychostimulant overdose causes delirium, psychosis, cardiac arrhythmia, hypertensive crisis, malignant hyperthermia, rhabdomyolysis, seizures, shock, and death.
Psychostimulant withdrawal causes depression, hunger, and fatigue.Hemorrhagic strokes in cocaine users are often associated with intracranial aneurysm or vascular malformation.
Ischemic strokes in cocaine users are often associated with cerebral vasoconstriction.Users of cocaine or methylenedioxymethamphetamine (MDMA) are at risk for morphologic brain abnormalities and long-term cognitive impairment.
Methamphetamine and cocaine are probably teratogenic.Synthetic cannabinoid compounds are the second most abused illicit drugs (after marijuana) among US high school students.
Adolescents who are heavy marijuana users are at risk for structural brain abnormalities, cognitive impairment, and schizophrenia.
Stroke in marijuana users might be underreported; some cases might be secondary to reversible cerebral vasoconstriction syndrome.
Notorious as “date-rape” drugs, γ-hydroxybutyric acid (GHB) and its precursor compounds produce intoxication and withdrawal symptoms similar to the effects of ethanol and sedatives.
Users of lysergic acid diethylamide (LSD) can develop flashbacks and in some cases posthallucinogenic perceptual disorder.
Toluene exposure can cause leukoencephalopathy, with cognitive impairment and cerebellar ataxia. n-Hexane exposure can cause peripheral neuropathy. Nitrous oxide exposure can cause myeloneuropathy. Nitrite exposure can cause methemoglobinemia. A number of inhaled substances appear to be teratogenic.In contrast to amphetaminelike psychostimulants or cocaine, phencyclidine produces both positive and negative schizophrenic symptoms.
Ingestion of the plant Datura stramonium produces symptoms of anticholinergic poisoning.Relationship Disclosure: Dr Brust serves as an editor for Current Neurology and Neuroscience Reports and has received compensation for reviewing medical records related to a hospital malpractice suit.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Brust reports no disclosure.
1. Brust JCM. Neurological aspects of substance abuse. 2nd ed. Philadelphia: Elsevier Butterworth Heinemann, 2004. [Google Scholar]
2. Centers for Disease Control and Prevention (CDC). CDC grand rounds: prescription drug overdoses—a U.S. epidemic. MMWR Morb Mortal Wkly Rep 2012; 61 (1) : 10–13. [PubMed] [Google Scholar]
3. Skowronek R,, Celinski R,, Chowaniec C. “Crocodile”—new dangerous designer drug of abuse from the East. Clin Toxicol (Phila) 2012; 50 (4) : 269. [PubMed] [Google Scholar]
4. Hicks CW,, Sweeney DA,, Cui X, et al. An overview of anthrax infection including the recently identified form of disease in injection drug users. Intensive Care Med 2012; 38 (7) : 1092–1104. [PMC free article] [PubMed] [Google Scholar]
5. Ng SK,, Brust JC,, Hauser WA,, Susser M. Illicit drug use and the risk of new-onset seizures. Am J Epidemiol 1990; 132 (1) : 47–57. [PubMed] [Google Scholar]
6. Brust JCM. Stroke and substance abuse. In Mohr JP, Wolf PA, Grotta JC, Moskowitz MA, Mayberg MR, von Kummer R, editors. Stroke: pathophysiology, diagnosis, and management, 5th ed. Philadelphia: Elsevier Saunders, 2011: 790–813. [Google Scholar]
7. Cordova JP,, Balan S,, Romero J, et al. ‘Chasing the dragon’: new knowledge from an old practice. Am J Ther 2011. Apr 23 [Epub ahead of print]. [PubMed] [Google Scholar]
8. Wang X,, Li B,, Zhou X, et al. Changes in gray matter in abstinent heroin addicts. Drug Alcohol Depend 2012. [Epub ahead of print]. [PubMed] [Google Scholar]
9. Liu J,, Liang J,, Qin W, et al. Dysfunctional connectivity patterns in chronic heroin users: an fMRI study. Neurosci Lett 2009; 460 (1) : 72–77. [PubMed] [Google Scholar]
10. Upadhyay J,, Maleki N,, Potter J, et al. Alterations in brain structure and functional connectivity in prescription opioid-dependent patients. Brain 2010; 133 (pt 7) : 2098–2114. [PMC free article] [PubMed] [Google Scholar]
11. Eisch AJ,, Barrot M,, Schad CA, et al. Opiates inhibit neurogenesis in the adult rat hippocampus. Proc Natl Acad Sci U S A 2000; 97 (13) : 7579–7584. [PMC free article] [PubMed] [Google Scholar]
12. Gibbons S. ‘Legal highs’—novel and emerging psychoactive drugs: a chemical overview for the toxicologist. Clin Toxicol 2012; 50 (1) : 15–24. [PubMed] [Google Scholar]
13. Miotto K,, Striebel J,, Cho AK,, Wang C. Clinical and pharmacological aspects of bath salt use: a review of the literature and case reports. Drug Alcohol Dep 2013; 132 (1–2) : 1–12. [PubMed] [Google Scholar]
14. Gallagher CT,, Assi S,, Stair JL, et al. 5,6-methlenedioxy-2-aminoindane: from laboratory curiosity to ‘legal high’. Hum Psychopharmacol Clin Exp 2012; 27 (2) : 106–112. [PubMed] [Google Scholar]
15. Newsome SD,, Johnson E,, Pardo C, et al. Fulminant encephalopathy with basal ganglia hyperintensities in HIV-infected drug users. Neurology 2011; 76 (9) : 787–794. [PMC free article] [PubMed] [Google Scholar]
16. Petitti DB,, Sidney S,, Queensberry C,, Bernstein A. Stroke and cocaine or amphetamine use. Epidemiology 1998; 9 (6) : 596–600. [PubMed] [Google Scholar]
17. Kaufman MJ,, Levin JM,, Ross MH, et al. Cocaine-induced cerebral vasoconstriction detected in humans with magnetic resonance angiography. JAMA 1998; 279 (5) : 376–380. [PubMed] [Google Scholar]
18. Murphy PN,, Wareing M,, Fisk JE,, Montgomery C. Executive working memory deficits in abstinent ecstasy/MDMA users: a critical review. Neuropsychobiology 2009; 60 (3–4) : 159–175. [PubMed] [Google Scholar]
19. deWin MM,, Jager G,, Booij J, et al. Sustained effects of ecstasy on the human brain: a prospective neuroimaging study in novel users. Brain 2008; 131 (pt 11) : 2936–2945. [PubMed] [Google Scholar]
20. Kish SJ,, Lerch J,, Furukawa Y, et al. Decreased cerebral cortical serotonin transporter binding in ecstasy users: a positron emission tomography/[(11)C]DASB and structural brain imaging study. Brain 2010; 133 (pt 6) : 1779–1797. [PMC free article] [PubMed] [Google Scholar]
21. McCann UD,, Sgambati FP,, Schwartz AR,, Ricaurte GA. Sleep apnea in young abstinent recreational MDMA (“ecstasy”) consumers. Neurology 2009; 73 (23) : 2011–2017. [PMC free article] [PubMed] [Google Scholar]
22. Lucantonio F,, Stalnaker TA,, Shaham Y, et al. The impact of orbitofrontal dysfunction on cocaine addiction. Nat Neurosci 2012; 15 (3) : 358–366. [PMC free article] [PubMed] [Google Scholar]
23. Narayana PA,, Ahobila-Vajjula P,, Ramu J, et al. Diffusion tensor imaging of cocaine-treated rodents. Psychiatry Res 2009; 171 (3) : 242–251. [PMC free article] [PubMed] [Google Scholar]
24. Tau GZ,, Marsh R,, Torres-Sanchez T, et al. Neural correlates of reward-based learning in persons with cocaine dependence. Neuropsychopharmacology 2013, Aug 6 [Epub ahead of print]. [PMC free article] [PubMed] [Google Scholar]
25. Sudai E,, Croitoru O,, Shaldubina A, et al. High cocaine dosage decreases neurogenesis in the hippocampus and impairs working memory. Addict Biol 2011; 16 (2) : 251–260. [PubMed] [Google Scholar]
26. Stepens A,, Groma V,, Skuja S, et al. The outcome of the movements disorder in methcathinone abusers: clinical, MRI and manganesemia changes, and neuropathology. Eur J Neurol 2014; 21 : 199–205. [PubMed] [Google Scholar]
27. Rousette FF,, Bramen JE,, Nunez SC, et al. Abnormal brain activation during working memory in children with prenatal exposure to drugs of abuse: the effects of methamphetamine, alcohol, and polydrug exposure. Neuroimage 2011; 54 (4) : 3067–3075. [PMC free article] [PubMed] [Google Scholar]
28. Cloak CC,, Ernst T,, Fujii LL, et al. Lower diffusion in white matter of children with prenatal methamphetamine exposure. Neurology 2009; 72 (24) : 2068–2075. [PMC free article] [PubMed] [Google Scholar]
29. Thompson VB,, Heiman J,, Chambers JB, et al. Long-term behavioral consequences of prenatal MDMA exposure. Physiol Behav 2009; 96 (4–5) : 593–601. [PMC free article] [PubMed] [Google Scholar]
30. Liu J,, Lester BM,, Neyzi N, et al. Regional brain morphometry and impulsivity in adolescents following prenatal exposure to cocaine and tobacco. JAMA Pediatr 2013; 167 (4) : 348–354. [PMC free article] [PubMed] [Google Scholar]
31. Bandstra ES,, Morrow CE,, Mansoor E,, Accornero VH. Prenatal drug exposure: infant and toddler outcomes. J Addict Dis 2010; 29 (2) : 245–258. [PubMed] [Google Scholar]
32. Lane SD,, Steinberg JL,, Ma L, et al. Diffusion tensor imaging and decision making in cocaine dependence. PLoS One 2010; 5 (7) : e11591. [PMC free article] [PubMed] [Google Scholar]
33. Lambert BL,, Bauer CR. Developmental and behavioral consequences of prenatal cocaine exposure: a review. J Perinatol 2012; 32 (11) : 819–828. [PMC free article] [PubMed] [Google Scholar]
34. Seely KA,, Lapoint J,, Moran JH,, Fattore L. Spice drugs are more than harmless herbal blends: a review of the pharmacology and toxicology of synthetic cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry 2012; 39 (2) : 234–243. [PMC free article] [PubMed] [Google Scholar]
35. Bolla KI,, Eldreth DA,, Matochik JA,, Cadet JL. Neural substrates of faulty decision-making in abstinent marijuana users. Neuroimage 2005; 26 (2) : 480–492. [PubMed] [Google Scholar]
36. Jager G,, Van Hell HH,, De Win MM, et al. Effects of frequent cannabis use on hippocampal activity during an associative memory task. Eur Neuropsychopharmacol 2007; 17 (4) : 289–297. [PubMed] [Google Scholar]
37. Chang L,, Yakupov R,, Cloak C,, Ernst T. Marijuana is associated with a reorganized visual-attention network and cerebellar hypoactivation. Brain 2006; 129 (pt 5) : 1096–1112. [PubMed] [Google Scholar]
38. Lorinzetti V,, Lubman DI,, Whittle S, et al. Structural MRI findings in long-term cannabis users: what do we know? Subst Use Misuse 2010; 45 (11) : 1787–1808. [PubMed] [Google Scholar]
39. Cousijn J,, Wiers RW,, Ridderinkhof KR, et al. Grey matter alterations associated with cannabis use: results of a VBM study in heavy cannabis users and healthy controls. Neuroimage 2012; 59 (4) : 3845–3851. [PubMed] [Google Scholar]
40. Ashtari M,, Cervellione K,, Cottone J, et al. Diffusion abnormalities in adolescents and young adults with a history of heavy cannabis use. J Psychiatr Res 2009; 43 (3) : 189–204. [PMC free article] [PubMed] [Google Scholar]
41. Zalesky A,, Solowij N,, Yucel M, et al. Effect of long-term cannabis on axonal connectivity. Brain 2012; 135 (pt 7) : 2245–2255. [PubMed] [Google Scholar]
42. Brust JC. Cognition and cannabis: from anecdote to advanced technology. Brain 2012; 135 (pt 7) : 2004–2005. [PubMed] [Google Scholar]
43. Le Bec PY,, Fatseas M,, Denis C, et al. Cannabis and psychosis: search for a causal link through a critical and systematic review. Encephale 2009; 35 (4) : 377–385. [PubMed] [Google Scholar]
44. Smith AM,, Fried PA,, Hogan MJ,, Cameron I. Effects of prenatal marijuana on visuospatial working memory: an fMRI study in young adults. Neurotoxicol Teratol 2006; 28 (2) : 286–295. [PubMed] [Google Scholar]
45. Wolff V,, Armspach JP,, Lauer V, et al. Cannabis-related stroke: myth or reality? Stroke 2013; 44 (2) : 558–563. [PubMed] [Google Scholar]
46. Westover AN,, McBride S,, Haley RW. Stroke in young adults who abuse amphetamines or cocaine: a population-based study of hospitalized patients. Arch Gen Psychiatry 2007; 64 (4) : 495–502. [PubMed] [Google Scholar]
47. Mittleman MA,, Lewis RA,, Maclure M, et al. Triggering myocardial infarction by marijuana. Circulation 2001; 103 (23) : 2805–2809. [PubMed] [Google Scholar]
48. Wolff V,, Lauer V,, Rouyer O, et al. Cannabis use, ischemic stroke, and multifocal intracranial vasoconstriction: a prospective study in 48 consecutive young patients. Stroke 2011; 42 (6) : 1778–1780. [PubMed] [Google Scholar]
49. Wojtowicz JM,, Yarema MC,, Wax PM. Withdrawal from gamma-hydroxybutyrate, 1,4-butanediol, and gamma-butyrolactone: a case report and systematic review. CJEM 2008; 10 (1) : 69–74. [PubMed] [Google Scholar]
50. Ranganathan M. Schnakenberg A,, Skolsnik PD, et al. Dose-related behavioral, subjective, endocrine, and psychophysiological effects of the κ opioid agonist Salvinorin A in humans. Biol Psychiatry 2012; 72 (10) : 871–879. [PMC free article] [PubMed] [Google Scholar]
51. Hill SL,, Thomas SH. Clinical toxicology of newer recreational drugs. Clin Toxicol (Phila) 2011; 49 (8) : 705–719. [PubMed] [Google Scholar]
52. Hermle L,, Simon M,, Ruchsow M,, Geppert M. Hallucinogen-persisting perception disorder. Ther Adv Psychopharmacol 2012; 2 (5) : 199–205. [PMC free article] [PubMed] [Google Scholar]
53. Rosenberg NL,, Kleinschmidt-DeMasters BK,, Davis KA, et al. Toluene abuse causes diffuse central nervous system white matter changes. Ann Neurol 1988; 23 (6) : 611–614. [PubMed] [Google Scholar]
54. Lolin Y. Chronic neurological toxicity associated with exposure to volatile substances. Hum Toxicol 1989; 8 (4) : 293–300. [PubMed] [Google Scholar]
55. Heyer EJ,, Simpson DM,, Bodis-Wollner I, et al. Nitrous oxide: clinical and electrophysiologic investigation of neurologic complications. Neurology 1986; 36 : 1618–1622. [PubMed] [Google Scholar]
56. Hunter L,, Gordge L,, Dargan P,, Wood DM. Methaemoglobinaemia associated with the use of cocaine and volatile nitrites as recreational drugs: a review. Br J Clin Pharmacol 2011; 72 (1) : 18–26. [PMC free article] [PubMed] [Google Scholar]
57. Maruff P,, Burns CB,, Tyler P, et al. Neurological and cognitive abnormalities associated with chronic petrol sniffing. Brain 1998; 121 : 1903–1917. [PubMed] [Google Scholar]
58. Wilkins-Haug L. Teratogen update: toluene. Teratology 1997; 55 (2) : 145–151. [PubMed] [Google Scholar]
59. Majlesi N,, Lee DC,, Ali SS. Dextromethorphan abuse masquerading as a recurrent seizure disorder. Pediatr Emerg Care 2011; 27 (3) : 210–211. [PubMed] [Google Scholar]
60. Corazza O,, Schifano F,, Simonato P, et al. Phenomenon of new drugs on the Internet: the case of ketamine derivative methoxetamine. Hum Psychopharmacol 2012; 27 (2) : 145–149. [PubMed] [Google Scholar]
61. McCarron MM,, Schultze B,, Thompson GA, et al. Acute phencyclidine intoxication: clinical patterns, complications, and treatment. Ann Emerg Med 1981; 10 (6) : 290–297. [PubMed] [Google Scholar]
62. Javitt DC,, Zukin SR,, Heresco-Levy U,, Umbricht D. Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia. Schizophr Bull 2012; 38 (5) : 958–966. [PMC free article] [PubMed] [Google Scholar]
63. Bessen HA. Intracranial hemorrhage associated with phencyclidine abuse. JAMA 1982; 248 (5) : 585–586. [PubMed] [Google Scholar]
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